Current Drug Therapy

Dabigatran etexilate (Pradaxa) is a new oral anticoagulant that has distinct advantages over warfarin (Coumadin) in terms of its ease of administration, efficacy, and safety.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial),¹ in patients with nonvalvular atrial fibrillation, dabigatran 110 mg twice a day was found to be as good as warfarin in preventing systemic embolization and stroke (the primary outcome of the study), and at 150 mg twice a day it was superior.¹ It has also shown efficacy in treating acute deep vein thrombosis and pulmonary embolism and in preventing these complications in orthopedic surgical patients.^2–4

Dabigatran has been approved in 75 countries. It carries the trade name Pradaxa in Europe and the United States and Pradax in Canada. In October 2010, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee endorsed two twice-daily doses (75 mg and 150 mg) of dabigatran for the prevention of systemic embolization and stroke in patients with nonvalvular atrial fibrillation.

However, dabigatran is relatively expensive, and its current high cost might be a barrier to its wider use.

MANY PATIENTS NEED ANTICOAGULATION

Anticoagulation plays a vital role in the primary and secondary prevention of stroke in patients with atrial fibrillation and of pulmonary embolism in patients with venous thromboembolism. It is also used during cardiothoracic and vascular surgery, endovascular procedures, and dialysis and in patients with mechanical heart valves and hypercoagulable conditions.

Atrial fibrillation affects 3.03 million people in the United States (2005 figures), and this number is predicted to be as high as 7.56 million by 2050.⁵ More than 10% of people over the age of 80 years have it, and the lifetime risk of developing it is approximately 25%.^6,7 Its most serious complication is ischemic stroke (the risk of which increases with age) and systemic embolization.^5,8

Until the recent introduction of dabigatran, the only oral anticoagulant available in the United States for treating patients with atrial fibrillation was warfarin. Although warfarin has a number of disadvantages (see below), it is actually very effective for preventing ischemic stroke, reducing the incidence by as much as 65%.^9,10

Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.¹¹ Although its exact incidence is unknown, nearly 1 million cases of it (incident or recurrent, fatal and nonfatal events) occur in the United States each year.¹² Many patients with venous thromboembolism need oral anticoagulation long-term, and currently warfarin remains the only option for them as well.

NEEDED: A BETTER ANTICOAGULANT

Warfarin has been the most commonly prescribed oral anticoagulant in the United States for more than 60 years. As of 2004, more than 30 million outpatient prescriptions for it were filled annually in this country alone.¹³ However, warfarin has several important limitations.

Warfarin has a narrow therapeutic index. Patients taking it require monitoring of their international normalized ratio (INR) and frequent dose adjustments, and this is time-consuming and inconvenient. The target INR for patients with venous thromboembolism and atrial fibrillation is 2.0 to 3.0, whereas patients with a mechanical heart valve need a higher INR (2.5 to 3.5). If the INR is below these ranges, warfarin is less effective, with a risk of new thrombosis. On the other hand, if the INR is too high, there is a risk of bleeding.¹⁴ In fact, the most important side effect of warfarin is the risk of major and minor bleeding.¹³ However, even in well-designed clinical trials in which patients are closely managed, only 55% to 60% of patients regularly achieve their therapeutic target INR.^1,2,14,15

Warfarin also interacts with many drugs and with some foods. Compliance is difficult. It has a slow onset of action. Genetic variations require dose adjustments. When switching from a parenteral anticoagulant, overlapping is required. Skin necrosis is a possible side effect. And warfarin is teratogenic.

Despite these limitations, the American College of Chest Physicians endorses warfarin to prevent or treat venous thromboembolism, and to prevent stroke in patients with atrial fibrillation.¹⁶

Recently, a number of new oral and parenteral anticoagulants have been developed (Table 1) with the aim of overcoming some of the drawbacks of warfarin and the other currently available agents, and to improve the prevention and treatment of thromboembolic disorders.

DABIGATRAN, A THROMBIN INHIBITOR

Dabigatran, developed by Boehringer Ingelheim, is a potent, competitive, and reversible inhibitor of both free and clot-bound thrombin, inhibiting both thrombin activity and generation (Table 2).^17,18

A prodrug, dabigatran is rapidly absorbed and converted to its active form. Its plasma concentration reaches a peak 1.5 to 3 hours after an oral dose, and it has an elimination half-life of 12 to 14 hours. About 80% of its excretion is by the kidneys and the remaining 20% is through bile.

Dabigatran is not metabolized by cytochrome P450 isoenzymes, and therefore it has few major interactions with other drugs. An exception is rifampin, a P-glycoprotein inducer that blocks dabigatran’s absorption in the gut, so this combination should be avoided. Another is quinidine, a strong P-glycoprotein inhibitor that is contraindicated for use with dabigatran. Also, amiodarone (Cordarone), another P-glycoprotein inhibitor, increases blood levels of dabigatran, and therefore a lower dose of dabigatran is recommended if these drugs are given together.^18–20

 

DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED?

Dabigatran has a predictable pharmacodynamic effect, and current data indicate it does not need regular monitoring.^18–20 However, one may need to be able to measure the drug’s activity in certain situations, such as suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children.²⁰

Dabigatran has little effect on the prothrombin time or the INR, even at therapeutic concentrations.¹⁹ Further, its effect on the activated partial thromboplastin time (aPTT) is neither linear nor dose-dependent, and the aPTT reaches a plateau and becomes less sensitive at very high concentrations. Therefore, the aPTT does not appear to be an appropriate test to monitor dabigatran’s therapeutic anticoagulant effect, although it does provide a qualitative indication of anticoagulant activity.^18,19

The thrombin time is a very sensitive method for determining if dabigatran is present, but the test lacks standardization; the ecarin clotting time provides better evidence of the dose but is not readily available at most institutions.^18,19,21

EVALUATED IN CLINICAL TRIALS

Dabigatran has been evaluated in a number of trials for its ability to prevent ischemic stroke and systemic embolization in patients with atrial fibrillation and to prevent and treat venous thromboembolism in surgical orthopedic patients, and in patients with acute coronary syndrome (Table 3).^{1–4,22–25}

DABIGATRAN IS EXPENSIVE BUT MAY BE COST-EFFECTIVE

The estimated price of dabigatran 150 mg twice a day in the United States is about $6.75 to $8.00 per day.^26,27

Warfarin, in contrast, costs as little as $50 per year.²⁸ However, this low price does not include the cost of monitoring the INR (office visits and laboratory testing), and these combined expenses are much higher than the price of the warfarin itself.²⁹ In addition, warfarin requires time-consuming management when bridging to a parenteral anticoagulant (for reversal of its anticoagulant action) before routine health maintenance procedures such as dental work and colonoscopy and interventional procedures and surgery. Any bleeding complication will also add to its cost and will be associated with a decrease in the patient’s perceived health and quality of life, but this is true for both drugs.³⁰

In today’s health care environment, controlling costs is a universal priority, but it may be unfair to compare the cost of dabigatran with that of warfarin alone. The expense and morbidity associated with stroke and intracranial bleeding are high, and if patients on dabigatran have fewer strokes (as seen in the RE-LY trial with dabigatran 150 mg twice a day) and no added expense of monitoring, then dabigatran may be cost-effective.

Freeman et al³¹ analyzed the cost-effectiveness of dabigatran, using an estimated cost of $13.70 per day and data from the RE-LY trial. They concluded that dabigatran may be a cost-effective alternative to warfarin in preventing ischemic stroke in patients considered at higher risk for ischemic stroke or intracranial hemorrhage, ie, those with a CHADS₂ score of 1 or higher or equivalent. (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack.)

As more new-generation oral anticoagulants become available (see below), the price of dabigatran will undoubtedly decrease. Until then, warfarin will remain a cost-effective and cost-saving drug that cannot yet be considered obsolete.

WHO SHOULD RECEIVE DABIGATRAN?

The ideal patient for dabigatran treatment is not yet defined. The decision to convert a patient’s treatment from warfarin to dabigatran will likely depend on several factors, including the patient’s response to warfarin and the physician’s comfort with this new drug.

Many patients do extremely well with warfarin, requiring infrequent monitoring to maintain a therapeutic INR and having no bleeding complications. For them, it would be more practical to continue warfarin. Another reason for staying with warfarin would be if twice-a-day dosing would pose a problem.

Dabigatran would be a reasonable choice for a patient whose INR is erratic, who requires more frequent monitoring, for whom cost is not an issue, and for whom there is concern about dietary or drug interactions.

Another consideration is whether the patient has access to a health care facility for warfarin monitoring: this is difficult for those who cannot drive, who depend on others for transportation, and who live in rural areas.

Additionally, dabigatran may be a cost-effective alternative to warfarin for a patient with a high CHADS₂ score who is considered at a higher risk for stroke.³¹

In all cases, the option should be considered only after an open discussion with the patient about the risks and benefits of this new drug.

WHO SHOULD NOT RECEIVE IT?

Dabigatran is a twice-daily drug with a short half-life. No patient with a history of poor compliance will be a good candidate for dabigatran. Since there are no practical laboratory tests for monitoring compliance, one will have to reinforce at every visit the importance of taking this medication according to instructions.

Patients with underlying kidney disease will need close monitoring of their creatinine clearance, with dose adjustment if renal function deteriorates.

Additionally, one should use caution when prescribing dabigatran to obese patients, pregnant women, or children until more is known about its use in these populations.

ADVANTAGES AND DISADVANTAGES OF DABIGATRAN

In addition to its pharmacologic advantages, dabigatran demonstrated two other major advantages over warfarin in the RE-LY trial in patients with atrial fibrillation (Table 4). First, the rate of intracranial bleeding, a major devastating complication of warfarin, was 60% lower with dabigatran 150 mg twice a day than with warfarin—and lower still with dabigatran 110 mg twice a day.¹ Second, the rate of stroke or systemic embolism was 34% lower in the group that got dabigatran 150 mg twice a day than in the group that got warfarin.

A reason may be that patients with atrial fibrillation and poor INR control have higher rates of death, stroke, myocardial infarction, and major bleeding.¹⁴ In most clinical trials, only 55% to 60% of patients achieve a therapeutic INR on warfarin, leaving them at risk of thrombosis or, conversely, bleeding.^1,2,15,32 Dabigatran has predictable pharmacokinetics, and its twice-daily dosing allows for less variability in its anticoagulant effect, making it more consistently therapeutic with less potential for bleeding or thrombosis.¹

The Canadian Cardiovascular Society included dabigatran in its 2010 guidelines on atrial fibrillation, recommending it or warfarin.³³ The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society now give dabigatran a class I B recommendation (benefit greater than risk, but limited populations studied) in secondary stroke prevention.³⁴

On the other hand, major concerns are the lack of an antidote for dabigatran and a lack of experience in treating bleeding complications. Since dabigatran is not monitored, physicians may be uncertain if we are overdosing or undertreating. As we gain experience, we will learn how to treat bleeding complications. Until then, it will be important to anticipate this problem and to develop an algorithm based on the best available evidence in managing this complication.

Although the overall rates of bleeding in the RE-LY trial were lower with dabigatran than with warfarin, there were more gastrointestinal bleeding events with the 150-mg dose of dabigatran, which was not readily explained.

Further, the rate of dyspepsia was almost twice as high with dabigatran than with warfarin, regardless of the dose of dabigatran. There were also more dropouts in the 2nd year of follow-up in the dabigatran groups, with gastrointestinal intolerance being one of the major reasons. Therefore, dyspepsia may cause intolerance and noncompliance.¹

Dabigatran must be taken twice a day and has a relatively short half-life. For a noncompliant patient, missing one or two doses will cause a reversal of its anticoagulation effect, leaving the patient susceptible to thrombosis. In comparison, warfarin has a longer half-life and is taken once a day, so missing a dose is less likely to result in a similar reversal of its anticoagulant effect.

 

SPECIAL CONDITIONS

Switching from other anticoagulants to dabigatran

When making the transition from a subcutaneously administered anticoagulant, ie, a low-molecular-weight heparin or the anti-Xa inhibitor fondaparinux (Arixtra), dabigatran should be started 0 to 2 hours before the next subcutaneous dose of the parenteral anticoagulant was to be given.^21,35

When switching from unfractionated heparin given by continuous intravenous infusion, the first dose of dabigatran should be given at the time the infusion is stopped.

When switching from warfarin, dabigatran should be started once the patient’s INR is less than 2.0.

Switching from dabigatran to a parenteral anticoagulant

When switching from dabigatran back to a parenteral anticoagulant, allow 12 to 24 hours after the last dabigatran dose before starting the parenteral agent.^21,35

Elective surgery or invasive procedures

The manufacturer recommends stopping dabigatran 1 to 2 days before elective surgery for patients who have normal renal function and a low risk of bleeding, or 3 to 5 days before surgery for patients who have a creatinine clearance of 50 mL/min or less. Before major surgery or placement of a spinal or epidural catheter, the manufacturer recommends that dabigatran be held even longer.³⁵

If emergency surgery is needed

If emergency surgery is needed, the clinician must use his or her judgment as to the risks of bleeding vs those of postponing the surgery.^21,35

Overdose or bleeding

No antidote for dabigatran is currently available. It has a short half-life (12–14 hours), and the treatment for overdose or bleeding is to discontinue it immediately, maintain adequate diuresis, and transfuse fresh-frozen plasma or red blood cells as indicated.

The role of activated charcoal given orally to reduce absorption is under evaluation, but the charcoal must be given within 1 to 2 hours after the overdose is taken.²¹

Dabigatran does not bind very much to plasma proteins and hence is dialyzable—an approach that may be necessary in cases of persistent or life-threatening bleeding.

Recombinant activated factor VII or prothrombin complex concentrates may be additional options in cases of severe bleeding.^18,21

TOPICS OF FUTURE RESEARCH

A limitation of the dabigatran trials was that they did not enroll patients who had renal or liver impairment, cancer, or other comorbidities; pregnant women; or children. Other topics of future research include its use in patients weighing less than 48 kg or more than 110 kg, its efficacy in patients with thrombophilia, in patients with mechanical heart valves, and in long-term follow-up and the use of thrombolytics in patients with acute stroke who are on dabigatran.

WILL DABIGATRAN CHANGE CLINICAL PRACTICE?

Despite some of the challenges listed above, we believe that dabigatran is likely to change medical practice in patients requiring anticoagulation.

Dabigatran’s biggest use will most likely be in patients with atrial fibrillation, mainly because this is the largest group of people receiving anticoagulation. In addition, the incidence of atrial fibrillation rises with age, the US population is living longer, and patients generally require life-long anticoagulation once this condition develops.

Dabigatran may be approved for additional indications in the near future. It has already shown efficacy in primary and secondary prevention of venous thromboembolism. Other important areas to be studied include its use in patients with mechanical heart valves and thrombophilia.

Whether dabigatran will be a worthy substitute for the parenteral anticoagulants (heparin, low-molecular-weight heparins, or factor Xa inhibitors) is not yet known, but it will have an enormous impact on anticoagulation management if proved efficacious.

If dabigatran becomes a major substitute for warfarin, it will affect the anticoagulation clinics, with their well-trained staff, that are currently monitoring millions of patients in the United States. These clinics would no longer be needed, and laboratory and technical costs could be saved. A downside is that patients on dabigatran will not be as closely supervised and reminded to take their medication as patients on warfarin are now at these clinics. Instead, they will likely be supervised by their own physician (or assistants), who will need to become familiar with this anticoagulant. This may affect compliance with dabigatran.

OTHER NEW ORAL ANTICOAGULANTS ARE ON THE WAY

Other oral anticoagulants, including rivaroxaban (Xarelto) and apixaban (Eliquis), have been under study and show promise in preventing both thrombotic stroke and venous thromboembolism. They will likely compete with dabigatran once they are approved.

Rivaroxaban, an oral direct factor Xa inhibitor, is being investigated for stroke prevention in patients with atrial fibrillation. It has also been shown to be not inferior to (and to be less expensive than) enoxaparin in treating and preventing venous thromboembolism in patients undergoing hip or knee arthroplasty.^32,36,37 Rivaroxaban has recently been approved by the FDA for this indication.

Apixaban, another direct factor Xa inhibitor, is also being studied for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. To date, there are no head-to-head trials comparing dabigatran with either of these new oral anticoagulants.

Dabigatran etexilate (Pradaxa) is a new oral anticoagulant that has distinct advantages over warfarin (Coumadin) in terms of its ease of administration, efficacy, and safety.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial),¹ in patients with nonvalvular atrial fibrillation, dabigatran 110 mg twice a day was found to be as good as warfarin in preventing systemic embolization and stroke (the primary outcome of the study), and at 150 mg twice a day it was superior.¹ It has also shown efficacy in treating acute deep vein thrombosis and pulmonary embolism and in preventing these complications in orthopedic surgical patients.^2–4

Dabigatran has been approved in 75 countries. It carries the trade name Pradaxa in Europe and the United States and Pradax in Canada. In October 2010, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee endorsed two twice-daily doses (75 mg and 150 mg) of dabigatran for the prevention of systemic embolization and stroke in patients with nonvalvular atrial fibrillation.

However, dabigatran is relatively expensive, and its current high cost might be a barrier to its wider use.

MANY PATIENTS NEED ANTICOAGULATION

Anticoagulation plays a vital role in the primary and secondary prevention of stroke in patients with atrial fibrillation and of pulmonary embolism in patients with venous thromboembolism. It is also used during cardiothoracic and vascular surgery, endovascular procedures, and dialysis and in patients with mechanical heart valves and hypercoagulable conditions.

Atrial fibrillation affects 3.03 million people in the United States (2005 figures), and this number is predicted to be as high as 7.56 million by 2050.⁵ More than 10% of people over the age of 80 years have it, and the lifetime risk of developing it is approximately 25%.^6,7 Its most serious complication is ischemic stroke (the risk of which increases with age) and systemic embolization.^5,8

Until the recent introduction of dabigatran, the only oral anticoagulant available in the United States for treating patients with atrial fibrillation was warfarin. Although warfarin has a number of disadvantages (see below), it is actually very effective for preventing ischemic stroke, reducing the incidence by as much as 65%.^9,10

Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.¹¹ Although its exact incidence is unknown, nearly 1 million cases of it (incident or recurrent, fatal and nonfatal events) occur in the United States each year.¹² Many patients with venous thromboembolism need oral anticoagulation long-term, and currently warfarin remains the only option for them as well.

NEEDED: A BETTER ANTICOAGULANT

Warfarin has been the most commonly prescribed oral anticoagulant in the United States for more than 60 years. As of 2004, more than 30 million outpatient prescriptions for it were filled annually in this country alone.¹³ However, warfarin has several important limitations.

Warfarin has a narrow therapeutic index. Patients taking it require monitoring of their international normalized ratio (INR) and frequent dose adjustments, and this is time-consuming and inconvenient. The target INR for patients with venous thromboembolism and atrial fibrillation is 2.0 to 3.0, whereas patients with a mechanical heart valve need a higher INR (2.5 to 3.5). If the INR is below these ranges, warfarin is less effective, with a risk of new thrombosis. On the other hand, if the INR is too high, there is a risk of bleeding.¹⁴ In fact, the most important side effect of warfarin is the risk of major and minor bleeding.¹³ However, even in well-designed clinical trials in which patients are closely managed, only 55% to 60% of patients regularly achieve their therapeutic target INR.^1,2,14,15

Warfarin also interacts with many drugs and with some foods. Compliance is difficult. It has a slow onset of action. Genetic variations require dose adjustments. When switching from a parenteral anticoagulant, overlapping is required. Skin necrosis is a possible side effect. And warfarin is teratogenic.

Despite these limitations, the American College of Chest Physicians endorses warfarin to prevent or treat venous thromboembolism, and to prevent stroke in patients with atrial fibrillation.¹⁶

Recently, a number of new oral and parenteral anticoagulants have been developed (Table 1) with the aim of overcoming some of the drawbacks of warfarin and the other currently available agents, and to improve the prevention and treatment of thromboembolic disorders.

DABIGATRAN, A THROMBIN INHIBITOR

Dabigatran, developed by Boehringer Ingelheim, is a potent, competitive, and reversible inhibitor of both free and clot-bound thrombin, inhibiting both thrombin activity and generation (Table 2).^17,18

A prodrug, dabigatran is rapidly absorbed and converted to its active form. Its plasma concentration reaches a peak 1.5 to 3 hours after an oral dose, and it has an elimination half-life of 12 to 14 hours. About 80% of its excretion is by the kidneys and the remaining 20% is through bile.

Dabigatran is not metabolized by cytochrome P450 isoenzymes, and therefore it has few major interactions with other drugs. An exception is rifampin, a P-glycoprotein inducer that blocks dabigatran’s absorption in the gut, so this combination should be avoided. Another is quinidine, a strong P-glycoprotein inhibitor that is contraindicated for use with dabigatran. Also, amiodarone (Cordarone), another P-glycoprotein inhibitor, increases blood levels of dabigatran, and therefore a lower dose of dabigatran is recommended if these drugs are given together.^18–20

 

DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED?

Dabigatran has a predictable pharmacodynamic effect, and current data indicate it does not need regular monitoring.^18–20 However, one may need to be able to measure the drug’s activity in certain situations, such as suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children.²⁰

Dabigatran has little effect on the prothrombin time or the INR, even at therapeutic concentrations.¹⁹ Further, its effect on the activated partial thromboplastin time (aPTT) is neither linear nor dose-dependent, and the aPTT reaches a plateau and becomes less sensitive at very high concentrations. Therefore, the aPTT does not appear to be an appropriate test to monitor dabigatran’s therapeutic anticoagulant effect, although it does provide a qualitative indication of anticoagulant activity.^18,19

The thrombin time is a very sensitive method for determining if dabigatran is present, but the test lacks standardization; the ecarin clotting time provides better evidence of the dose but is not readily available at most institutions.^18,19,21

EVALUATED IN CLINICAL TRIALS

Dabigatran has been evaluated in a number of trials for its ability to prevent ischemic stroke and systemic embolization in patients with atrial fibrillation and to prevent and treat venous thromboembolism in surgical orthopedic patients, and in patients with acute coronary syndrome (Table 3).^{1–4,22–25}

DABIGATRAN IS EXPENSIVE BUT MAY BE COST-EFFECTIVE

The estimated price of dabigatran 150 mg twice a day in the United States is about $6.75 to $8.00 per day.^26,27

Warfarin, in contrast, costs as little as $50 per year.²⁸ However, this low price does not include the cost of monitoring the INR (office visits and laboratory testing), and these combined expenses are much higher than the price of the warfarin itself.²⁹ In addition, warfarin requires time-consuming management when bridging to a parenteral anticoagulant (for reversal of its anticoagulant action) before routine health maintenance procedures such as dental work and colonoscopy and interventional procedures and surgery. Any bleeding complication will also add to its cost and will be associated with a decrease in the patient’s perceived health and quality of life, but this is true for both drugs.³⁰

In today’s health care environment, controlling costs is a universal priority, but it may be unfair to compare the cost of dabigatran with that of warfarin alone. The expense and morbidity associated with stroke and intracranial bleeding are high, and if patients on dabigatran have fewer strokes (as seen in the RE-LY trial with dabigatran 150 mg twice a day) and no added expense of monitoring, then dabigatran may be cost-effective.

Freeman et al³¹ analyzed the cost-effectiveness of dabigatran, using an estimated cost of $13.70 per day and data from the RE-LY trial. They concluded that dabigatran may be a cost-effective alternative to warfarin in preventing ischemic stroke in patients considered at higher risk for ischemic stroke or intracranial hemorrhage, ie, those with a CHADS₂ score of 1 or higher or equivalent. (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack.)

As more new-generation oral anticoagulants become available (see below), the price of dabigatran will undoubtedly decrease. Until then, warfarin will remain a cost-effective and cost-saving drug that cannot yet be considered obsolete.

WHO SHOULD RECEIVE DABIGATRAN?

The ideal patient for dabigatran treatment is not yet defined. The decision to convert a patient’s treatment from warfarin to dabigatran will likely depend on several factors, including the patient’s response to warfarin and the physician’s comfort with this new drug.

Many patients do extremely well with warfarin, requiring infrequent monitoring to maintain a therapeutic INR and having no bleeding complications. For them, it would be more practical to continue warfarin. Another reason for staying with warfarin would be if twice-a-day dosing would pose a problem.

Dabigatran would be a reasonable choice for a patient whose INR is erratic, who requires more frequent monitoring, for whom cost is not an issue, and for whom there is concern about dietary or drug interactions.

Another consideration is whether the patient has access to a health care facility for warfarin monitoring: this is difficult for those who cannot drive, who depend on others for transportation, and who live in rural areas.

Additionally, dabigatran may be a cost-effective alternative to warfarin for a patient with a high CHADS₂ score who is considered at a higher risk for stroke.³¹

In all cases, the option should be considered only after an open discussion with the patient about the risks and benefits of this new drug.

WHO SHOULD NOT RECEIVE IT?

Dabigatran is a twice-daily drug with a short half-life. No patient with a history of poor compliance will be a good candidate for dabigatran. Since there are no practical laboratory tests for monitoring compliance, one will have to reinforce at every visit the importance of taking this medication according to instructions.

Patients with underlying kidney disease will need close monitoring of their creatinine clearance, with dose adjustment if renal function deteriorates.

Additionally, one should use caution when prescribing dabigatran to obese patients, pregnant women, or children until more is known about its use in these populations.

ADVANTAGES AND DISADVANTAGES OF DABIGATRAN

In addition to its pharmacologic advantages, dabigatran demonstrated two other major advantages over warfarin in the RE-LY trial in patients with atrial fibrillation (Table 4). First, the rate of intracranial bleeding, a major devastating complication of warfarin, was 60% lower with dabigatran 150 mg twice a day than with warfarin—and lower still with dabigatran 110 mg twice a day.¹ Second, the rate of stroke or systemic embolism was 34% lower in the group that got dabigatran 150 mg twice a day than in the group that got warfarin.

A reason may be that patients with atrial fibrillation and poor INR control have higher rates of death, stroke, myocardial infarction, and major bleeding.¹⁴ In most clinical trials, only 55% to 60% of patients achieve a therapeutic INR on warfarin, leaving them at risk of thrombosis or, conversely, bleeding.^1,2,15,32 Dabigatran has predictable pharmacokinetics, and its twice-daily dosing allows for less variability in its anticoagulant effect, making it more consistently therapeutic with less potential for bleeding or thrombosis.¹

The Canadian Cardiovascular Society included dabigatran in its 2010 guidelines on atrial fibrillation, recommending it or warfarin.³³ The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society now give dabigatran a class I B recommendation (benefit greater than risk, but limited populations studied) in secondary stroke prevention.³⁴

On the other hand, major concerns are the lack of an antidote for dabigatran and a lack of experience in treating bleeding complications. Since dabigatran is not monitored, physicians may be uncertain if we are overdosing or undertreating. As we gain experience, we will learn how to treat bleeding complications. Until then, it will be important to anticipate this problem and to develop an algorithm based on the best available evidence in managing this complication.

Although the overall rates of bleeding in the RE-LY trial were lower with dabigatran than with warfarin, there were more gastrointestinal bleeding events with the 150-mg dose of dabigatran, which was not readily explained.

Further, the rate of dyspepsia was almost twice as high with dabigatran than with warfarin, regardless of the dose of dabigatran. There were also more dropouts in the 2nd year of follow-up in the dabigatran groups, with gastrointestinal intolerance being one of the major reasons. Therefore, dyspepsia may cause intolerance and noncompliance.¹

Dabigatran must be taken twice a day and has a relatively short half-life. For a noncompliant patient, missing one or two doses will cause a reversal of its anticoagulation effect, leaving the patient susceptible to thrombosis. In comparison, warfarin has a longer half-life and is taken once a day, so missing a dose is less likely to result in a similar reversal of its anticoagulant effect.

 

SPECIAL CONDITIONS

Switching from other anticoagulants to dabigatran

When making the transition from a subcutaneously administered anticoagulant, ie, a low-molecular-weight heparin or the anti-Xa inhibitor fondaparinux (Arixtra), dabigatran should be started 0 to 2 hours before the next subcutaneous dose of the parenteral anticoagulant was to be given.^21,35

When switching from unfractionated heparin given by continuous intravenous infusion, the first dose of dabigatran should be given at the time the infusion is stopped.

When switching from warfarin, dabigatran should be started once the patient’s INR is less than 2.0.

Switching from dabigatran to a parenteral anticoagulant

When switching from dabigatran back to a parenteral anticoagulant, allow 12 to 24 hours after the last dabigatran dose before starting the parenteral agent.^21,35

Elective surgery or invasive procedures

The manufacturer recommends stopping dabigatran 1 to 2 days before elective surgery for patients who have normal renal function and a low risk of bleeding, or 3 to 5 days before surgery for patients who have a creatinine clearance of 50 mL/min or less. Before major surgery or placement of a spinal or epidural catheter, the manufacturer recommends that dabigatran be held even longer.³⁵

If emergency surgery is needed

If emergency surgery is needed, the clinician must use his or her judgment as to the risks of bleeding vs those of postponing the surgery.^21,35

Overdose or bleeding

No antidote for dabigatran is currently available. It has a short half-life (12–14 hours), and the treatment for overdose or bleeding is to discontinue it immediately, maintain adequate diuresis, and transfuse fresh-frozen plasma or red blood cells as indicated.

The role of activated charcoal given orally to reduce absorption is under evaluation, but the charcoal must be given within 1 to 2 hours after the overdose is taken.²¹

Dabigatran does not bind very much to plasma proteins and hence is dialyzable—an approach that may be necessary in cases of persistent or life-threatening bleeding.

Recombinant activated factor VII or prothrombin complex concentrates may be additional options in cases of severe bleeding.^18,21

TOPICS OF FUTURE RESEARCH

A limitation of the dabigatran trials was that they did not enroll patients who had renal or liver impairment, cancer, or other comorbidities; pregnant women; or children. Other topics of future research include its use in patients weighing less than 48 kg or more than 110 kg, its efficacy in patients with thrombophilia, in patients with mechanical heart valves, and in long-term follow-up and the use of thrombolytics in patients with acute stroke who are on dabigatran.

WILL DABIGATRAN CHANGE CLINICAL PRACTICE?

Despite some of the challenges listed above, we believe that dabigatran is likely to change medical practice in patients requiring anticoagulation.

Dabigatran’s biggest use will most likely be in patients with atrial fibrillation, mainly because this is the largest group of people receiving anticoagulation. In addition, the incidence of atrial fibrillation rises with age, the US population is living longer, and patients generally require life-long anticoagulation once this condition develops.

Dabigatran may be approved for additional indications in the near future. It has already shown efficacy in primary and secondary prevention of venous thromboembolism. Other important areas to be studied include its use in patients with mechanical heart valves and thrombophilia.

Whether dabigatran will be a worthy substitute for the parenteral anticoagulants (heparin, low-molecular-weight heparins, or factor Xa inhibitors) is not yet known, but it will have an enormous impact on anticoagulation management if proved efficacious.

If dabigatran becomes a major substitute for warfarin, it will affect the anticoagulation clinics, with their well-trained staff, that are currently monitoring millions of patients in the United States. These clinics would no longer be needed, and laboratory and technical costs could be saved. A downside is that patients on dabigatran will not be as closely supervised and reminded to take their medication as patients on warfarin are now at these clinics. Instead, they will likely be supervised by their own physician (or assistants), who will need to become familiar with this anticoagulant. This may affect compliance with dabigatran.

OTHER NEW ORAL ANTICOAGULANTS ARE ON THE WAY

Other oral anticoagulants, including rivaroxaban (Xarelto) and apixaban (Eliquis), have been under study and show promise in preventing both thrombotic stroke and venous thromboembolism. They will likely compete with dabigatran once they are approved.

Rivaroxaban, an oral direct factor Xa inhibitor, is being investigated for stroke prevention in patients with atrial fibrillation. It has also been shown to be not inferior to (and to be less expensive than) enoxaparin in treating and preventing venous thromboembolism in patients undergoing hip or knee arthroplasty.^32,36,37 Rivaroxaban has recently been approved by the FDA for this indication.

Apixaban, another direct factor Xa inhibitor, is also being studied for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. To date, there are no head-to-head trials comparing dabigatran with either of these new oral anticoagulants.

Dabigatran etexilate (Pradaxa) is a new oral anticoagulant that has distinct advantages over warfarin (Coumadin) in terms of its ease of administration, efficacy, and safety.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial),¹ in patients with nonvalvular atrial fibrillation, dabigatran 110 mg twice a day was found to be as good as warfarin in preventing systemic embolization and stroke (the primary outcome of the study), and at 150 mg twice a day it was superior.¹ It has also shown efficacy in treating acute deep vein thrombosis and pulmonary embolism and in preventing these complications in orthopedic surgical patients.^2–4

Dabigatran has been approved in 75 countries. It carries the trade name Pradaxa in Europe and the United States and Pradax in Canada. In October 2010, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee endorsed two twice-daily doses (75 mg and 150 mg) of dabigatran for the prevention of systemic embolization and stroke in patients with nonvalvular atrial fibrillation.

However, dabigatran is relatively expensive, and its current high cost might be a barrier to its wider use.

MANY PATIENTS NEED ANTICOAGULATION

Anticoagulation plays a vital role in the primary and secondary prevention of stroke in patients with atrial fibrillation and of pulmonary embolism in patients with venous thromboembolism. It is also used during cardiothoracic and vascular surgery, endovascular procedures, and dialysis and in patients with mechanical heart valves and hypercoagulable conditions.

Atrial fibrillation affects 3.03 million people in the United States (2005 figures), and this number is predicted to be as high as 7.56 million by 2050.⁵ More than 10% of people over the age of 80 years have it, and the lifetime risk of developing it is approximately 25%.^6,7 Its most serious complication is ischemic stroke (the risk of which increases with age) and systemic embolization.^5,8

Until the recent introduction of dabigatran, the only oral anticoagulant available in the United States for treating patients with atrial fibrillation was warfarin. Although warfarin has a number of disadvantages (see below), it is actually very effective for preventing ischemic stroke, reducing the incidence by as much as 65%.^9,10

Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.¹¹ Although its exact incidence is unknown, nearly 1 million cases of it (incident or recurrent, fatal and nonfatal events) occur in the United States each year.¹² Many patients with venous thromboembolism need oral anticoagulation long-term, and currently warfarin remains the only option for them as well.

NEEDED: A BETTER ANTICOAGULANT

Warfarin has been the most commonly prescribed oral anticoagulant in the United States for more than 60 years. As of 2004, more than 30 million outpatient prescriptions for it were filled annually in this country alone.¹³ However, warfarin has several important limitations.

Warfarin has a narrow therapeutic index. Patients taking it require monitoring of their international normalized ratio (INR) and frequent dose adjustments, and this is time-consuming and inconvenient. The target INR for patients with venous thromboembolism and atrial fibrillation is 2.0 to 3.0, whereas patients with a mechanical heart valve need a higher INR (2.5 to 3.5). If the INR is below these ranges, warfarin is less effective, with a risk of new thrombosis. On the other hand, if the INR is too high, there is a risk of bleeding.¹⁴ In fact, the most important side effect of warfarin is the risk of major and minor bleeding.¹³ However, even in well-designed clinical trials in which patients are closely managed, only 55% to 60% of patients regularly achieve their therapeutic target INR.^1,2,14,15

Warfarin also interacts with many drugs and with some foods. Compliance is difficult. It has a slow onset of action. Genetic variations require dose adjustments. When switching from a parenteral anticoagulant, overlapping is required. Skin necrosis is a possible side effect. And warfarin is teratogenic.

Despite these limitations, the American College of Chest Physicians endorses warfarin to prevent or treat venous thromboembolism, and to prevent stroke in patients with atrial fibrillation.¹⁶

Recently, a number of new oral and parenteral anticoagulants have been developed (Table 1) with the aim of overcoming some of the drawbacks of warfarin and the other currently available agents, and to improve the prevention and treatment of thromboembolic disorders.

DABIGATRAN, A THROMBIN INHIBITOR

Dabigatran, developed by Boehringer Ingelheim, is a potent, competitive, and reversible inhibitor of both free and clot-bound thrombin, inhibiting both thrombin activity and generation (Table 2).^17,18

A prodrug, dabigatran is rapidly absorbed and converted to its active form. Its plasma concentration reaches a peak 1.5 to 3 hours after an oral dose, and it has an elimination half-life of 12 to 14 hours. About 80% of its excretion is by the kidneys and the remaining 20% is through bile.

Dabigatran is not metabolized by cytochrome P450 isoenzymes, and therefore it has few major interactions with other drugs. An exception is rifampin, a P-glycoprotein inducer that blocks dabigatran’s absorption in the gut, so this combination should be avoided. Another is quinidine, a strong P-glycoprotein inhibitor that is contraindicated for use with dabigatran. Also, amiodarone (Cordarone), another P-glycoprotein inhibitor, increases blood levels of dabigatran, and therefore a lower dose of dabigatran is recommended if these drugs are given together.^18–20

 

DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED?

Dabigatran has a predictable pharmacodynamic effect, and current data indicate it does not need regular monitoring.^18–20 However, one may need to be able to measure the drug’s activity in certain situations, such as suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children.²⁰

Dabigatran has little effect on the prothrombin time or the INR, even at therapeutic concentrations.¹⁹ Further, its effect on the activated partial thromboplastin time (aPTT) is neither linear nor dose-dependent, and the aPTT reaches a plateau and becomes less sensitive at very high concentrations. Therefore, the aPTT does not appear to be an appropriate test to monitor dabigatran’s therapeutic anticoagulant effect, although it does provide a qualitative indication of anticoagulant activity.^18,19

The thrombin time is a very sensitive method for determining if dabigatran is present, but the test lacks standardization; the ecarin clotting time provides better evidence of the dose but is not readily available at most institutions.^18,19,21

EVALUATED IN CLINICAL TRIALS

Dabigatran has been evaluated in a number of trials for its ability to prevent ischemic stroke and systemic embolization in patients with atrial fibrillation and to prevent and treat venous thromboembolism in surgical orthopedic patients, and in patients with acute coronary syndrome (Table 3).^{1–4,22–25}

DABIGATRAN IS EXPENSIVE BUT MAY BE COST-EFFECTIVE

The estimated price of dabigatran 150 mg twice a day in the United States is about $6.75 to $8.00 per day.^26,27

Warfarin, in contrast, costs as little as $50 per year.²⁸ However, this low price does not include the cost of monitoring the INR (office visits and laboratory testing), and these combined expenses are much higher than the price of the warfarin itself.²⁹ In addition, warfarin requires time-consuming management when bridging to a parenteral anticoagulant (for reversal of its anticoagulant action) before routine health maintenance procedures such as dental work and colonoscopy and interventional procedures and surgery. Any bleeding complication will also add to its cost and will be associated with a decrease in the patient’s perceived health and quality of life, but this is true for both drugs.³⁰

In today’s health care environment, controlling costs is a universal priority, but it may be unfair to compare the cost of dabigatran with that of warfarin alone. The expense and morbidity associated with stroke and intracranial bleeding are high, and if patients on dabigatran have fewer strokes (as seen in the RE-LY trial with dabigatran 150 mg twice a day) and no added expense of monitoring, then dabigatran may be cost-effective.

Freeman et al³¹ analyzed the cost-effectiveness of dabigatran, using an estimated cost of $13.70 per day and data from the RE-LY trial. They concluded that dabigatran may be a cost-effective alternative to warfarin in preventing ischemic stroke in patients considered at higher risk for ischemic stroke or intracranial hemorrhage, ie, those with a CHADS₂ score of 1 or higher or equivalent. (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack.)

As more new-generation oral anticoagulants become available (see below), the price of dabigatran will undoubtedly decrease. Until then, warfarin will remain a cost-effective and cost-saving drug that cannot yet be considered obsolete.

WHO SHOULD RECEIVE DABIGATRAN?

The ideal patient for dabigatran treatment is not yet defined. The decision to convert a patient’s treatment from warfarin to dabigatran will likely depend on several factors, including the patient’s response to warfarin and the physician’s comfort with this new drug.

Many patients do extremely well with warfarin, requiring infrequent monitoring to maintain a therapeutic INR and having no bleeding complications. For them, it would be more practical to continue warfarin. Another reason for staying with warfarin would be if twice-a-day dosing would pose a problem.

Dabigatran would be a reasonable choice for a patient whose INR is erratic, who requires more frequent monitoring, for whom cost is not an issue, and for whom there is concern about dietary or drug interactions.

Another consideration is whether the patient has access to a health care facility for warfarin monitoring: this is difficult for those who cannot drive, who depend on others for transportation, and who live in rural areas.

Additionally, dabigatran may be a cost-effective alternative to warfarin for a patient with a high CHADS₂ score who is considered at a higher risk for stroke.³¹

In all cases, the option should be considered only after an open discussion with the patient about the risks and benefits of this new drug.

WHO SHOULD NOT RECEIVE IT?

Dabigatran is a twice-daily drug with a short half-life. No patient with a history of poor compliance will be a good candidate for dabigatran. Since there are no practical laboratory tests for monitoring compliance, one will have to reinforce at every visit the importance of taking this medication according to instructions.

Patients with underlying kidney disease will need close monitoring of their creatinine clearance, with dose adjustment if renal function deteriorates.

Additionally, one should use caution when prescribing dabigatran to obese patients, pregnant women, or children until more is known about its use in these populations.

ADVANTAGES AND DISADVANTAGES OF DABIGATRAN

In addition to its pharmacologic advantages, dabigatran demonstrated two other major advantages over warfarin in the RE-LY trial in patients with atrial fibrillation (Table 4). First, the rate of intracranial bleeding, a major devastating complication of warfarin, was 60% lower with dabigatran 150 mg twice a day than with warfarin—and lower still with dabigatran 110 mg twice a day.¹ Second, the rate of stroke or systemic embolism was 34% lower in the group that got dabigatran 150 mg twice a day than in the group that got warfarin.

A reason may be that patients with atrial fibrillation and poor INR control have higher rates of death, stroke, myocardial infarction, and major bleeding.¹⁴ In most clinical trials, only 55% to 60% of patients achieve a therapeutic INR on warfarin, leaving them at risk of thrombosis or, conversely, bleeding.^1,2,15,32 Dabigatran has predictable pharmacokinetics, and its twice-daily dosing allows for less variability in its anticoagulant effect, making it more consistently therapeutic with less potential for bleeding or thrombosis.¹

The Canadian Cardiovascular Society included dabigatran in its 2010 guidelines on atrial fibrillation, recommending it or warfarin.³³ The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society now give dabigatran a class I B recommendation (benefit greater than risk, but limited populations studied) in secondary stroke prevention.³⁴

On the other hand, major concerns are the lack of an antidote for dabigatran and a lack of experience in treating bleeding complications. Since dabigatran is not monitored, physicians may be uncertain if we are overdosing or undertreating. As we gain experience, we will learn how to treat bleeding complications. Until then, it will be important to anticipate this problem and to develop an algorithm based on the best available evidence in managing this complication.

Although the overall rates of bleeding in the RE-LY trial were lower with dabigatran than with warfarin, there were more gastrointestinal bleeding events with the 150-mg dose of dabigatran, which was not readily explained.

Further, the rate of dyspepsia was almost twice as high with dabigatran than with warfarin, regardless of the dose of dabigatran. There were also more dropouts in the 2nd year of follow-up in the dabigatran groups, with gastrointestinal intolerance being one of the major reasons. Therefore, dyspepsia may cause intolerance and noncompliance.¹

Dabigatran must be taken twice a day and has a relatively short half-life. For a noncompliant patient, missing one or two doses will cause a reversal of its anticoagulation effect, leaving the patient susceptible to thrombosis. In comparison, warfarin has a longer half-life and is taken once a day, so missing a dose is less likely to result in a similar reversal of its anticoagulant effect.

 

SPECIAL CONDITIONS

Switching from other anticoagulants to dabigatran

When making the transition from a subcutaneously administered anticoagulant, ie, a low-molecular-weight heparin or the anti-Xa inhibitor fondaparinux (Arixtra), dabigatran should be started 0 to 2 hours before the next subcutaneous dose of the parenteral anticoagulant was to be given.^21,35

When switching from unfractionated heparin given by continuous intravenous infusion, the first dose of dabigatran should be given at the time the infusion is stopped.

When switching from warfarin, dabigatran should be started once the patient’s INR is less than 2.0.

Switching from dabigatran to a parenteral anticoagulant

When switching from dabigatran back to a parenteral anticoagulant, allow 12 to 24 hours after the last dabigatran dose before starting the parenteral agent.^21,35

Elective surgery or invasive procedures

The manufacturer recommends stopping dabigatran 1 to 2 days before elective surgery for patients who have normal renal function and a low risk of bleeding, or 3 to 5 days before surgery for patients who have a creatinine clearance of 50 mL/min or less. Before major surgery or placement of a spinal or epidural catheter, the manufacturer recommends that dabigatran be held even longer.³⁵

If emergency surgery is needed

If emergency surgery is needed, the clinician must use his or her judgment as to the risks of bleeding vs those of postponing the surgery.^21,35

Overdose or bleeding

No antidote for dabigatran is currently available. It has a short half-life (12–14 hours), and the treatment for overdose or bleeding is to discontinue it immediately, maintain adequate diuresis, and transfuse fresh-frozen plasma or red blood cells as indicated.

The role of activated charcoal given orally to reduce absorption is under evaluation, but the charcoal must be given within 1 to 2 hours after the overdose is taken.²¹

Dabigatran does not bind very much to plasma proteins and hence is dialyzable—an approach that may be necessary in cases of persistent or life-threatening bleeding.

Recombinant activated factor VII or prothrombin complex concentrates may be additional options in cases of severe bleeding.^18,21

TOPICS OF FUTURE RESEARCH

A limitation of the dabigatran trials was that they did not enroll patients who had renal or liver impairment, cancer, or other comorbidities; pregnant women; or children. Other topics of future research include its use in patients weighing less than 48 kg or more than 110 kg, its efficacy in patients with thrombophilia, in patients with mechanical heart valves, and in long-term follow-up and the use of thrombolytics in patients with acute stroke who are on dabigatran.

WILL DABIGATRAN CHANGE CLINICAL PRACTICE?

Despite some of the challenges listed above, we believe that dabigatran is likely to change medical practice in patients requiring anticoagulation.

Dabigatran’s biggest use will most likely be in patients with atrial fibrillation, mainly because this is the largest group of people receiving anticoagulation. In addition, the incidence of atrial fibrillation rises with age, the US population is living longer, and patients generally require life-long anticoagulation once this condition develops.

Dabigatran may be approved for additional indications in the near future. It has already shown efficacy in primary and secondary prevention of venous thromboembolism. Other important areas to be studied include its use in patients with mechanical heart valves and thrombophilia.

Whether dabigatran will be a worthy substitute for the parenteral anticoagulants (heparin, low-molecular-weight heparins, or factor Xa inhibitors) is not yet known, but it will have an enormous impact on anticoagulation management if proved efficacious.

If dabigatran becomes a major substitute for warfarin, it will affect the anticoagulation clinics, with their well-trained staff, that are currently monitoring millions of patients in the United States. These clinics would no longer be needed, and laboratory and technical costs could be saved. A downside is that patients on dabigatran will not be as closely supervised and reminded to take their medication as patients on warfarin are now at these clinics. Instead, they will likely be supervised by their own physician (or assistants), who will need to become familiar with this anticoagulant. This may affect compliance with dabigatran.

OTHER NEW ORAL ANTICOAGULANTS ARE ON THE WAY

Other oral anticoagulants, including rivaroxaban (Xarelto) and apixaban (Eliquis), have been under study and show promise in preventing both thrombotic stroke and venous thromboembolism. They will likely compete with dabigatran once they are approved.

Rivaroxaban, an oral direct factor Xa inhibitor, is being investigated for stroke prevention in patients with atrial fibrillation. It has also been shown to be not inferior to (and to be less expensive than) enoxaparin in treating and preventing venous thromboembolism in patients undergoing hip or knee arthroplasty.^32,36,37 Rivaroxaban has recently been approved by the FDA for this indication.

Apixaban, another direct factor Xa inhibitor, is also being studied for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. To date, there are no head-to-head trials comparing dabigatran with either of these new oral anticoagulants.

Almost all the data about the safety and efficacy of bisphosphonate drugs for treating osteoporosis are from patients who took them for less than 5 years.

Reports of adverse effects with prolonged use have caused concern about the long-term safety of this class of drugs. This is particularly important because these drugs are retained in the skeleton longer than 10 years, because there are physiologic reasons why excessive bisphosphonate-induced inhibition of bone turnover could be damaging, and because many healthy postmenopausal women have been prescribed bisphosphonates in the hope of preventing fractures that are not expected to occur for 20 to 30 years.

Because information from trials is scant, opinions differ over whether bisphosphonates should be continued indefinitely. In this article, I summarize the physiologic mechanisms of these drugs, review the scant existing data about their effects beyond 5 years, and describe my approach to bisphosphonate therapy (while waiting for better evidence).

MORE THAN 4 MILLION WOMEN TAKE BISPHOSPHONATES

The first medical use of a bisphosphonate was in 1967, when a girl with myositis ossificans was given etidronate (Didronel) because it inhibited mineralization. Two years later, it was given to patients with Paget disease of bone because it was found to inhibit bone resorption.¹ Etidronate could not be given for longer than 6 months, however, because patients developed osteomalacia.

Adding a nitrogen to the molecule dramatically increased its potency and led to the second generation of bisphosphonates. Alendronate (Fosamax), the first amino-bisphosphonate, became available in 1995, It was followed by risedronate (Actonel), ibandronate (Boniva), and zoledronic acid (Reclast). These drugs are potent inhibitors of bone resorption; however, in clinical doses they do not inhibit mineralization and therefore do not cause osteomalacia.

Randomized clinical trials involving more than 30,000 patients have provided grade A evidence that these drugs reduce the incidence of fragility fractures in patients with osteoporosis.² Furthermore, observational studies have confirmed that they prevent fractures and have a good safety profile in clinical practice.

Therefore, the use of these drugs has become common. In 2008, an estimated 4 million women in the United States were taking them.³

BISPHOSPHONATES STRENGTHEN BONE BY INHIBITING RESORPTION

On a molecular level, bisphosphonates inhibit farnesyl pyrophosphate synthase, an enzyme necessary for formation of the cytoskeleton in osteoclasts. Thus, they strongly inhibit bone resorption. They do not appear to directly inhibit osteoblasts, the cells that form new bone, but they substantially decrease bone formation indirectly.⁴

To understand how inhibition of bone resorption affects bone physiology, it is necessary to appreciate the nature of bone remodeling. Bone is not like the skin, which is continually forming a new layer and sloughing off the old. Instead, bone is renewed in small units. It takes about 5 years to remodel cancellous bone and 13 years to remodel cortical bone⁵; at any one time, about 8% of the surface is being remodeled.

The first step occurs at a spot on the surface, where the osteoclasts resorb some bone to form a pit that looks like a pothole. Then a team of osteoblasts is formed and fills the pit with new bone over the next 3 to 6 months. When first formed, the new bone is mainly collagen and, like the tip of the nose, is not very stiff, but with mineral deposition the bone becomes stronger, like the bridge of the nose. The new bone gradually accumulates mineral and becomes harder and denser over the next 3 years.

When a bisphosphonate is given, the osteoclasts abruptly stop resorbing the bone, but osteoblasts continue to fill the pits that were there when the bisphosphonate was started. For the next several months, while the previous pits are being filled, the bone volume increases slightly. Thereafter, rates of both bone resorption and bone formation are very low.

A misconception: Bisphosphonates build bone

While semantically it is true that the bone formation rate in patients taking bisphosphonates is within the normal premenopausal range, this often-repeated statement is essentially misleading.

Copyright Susan Ott, used with permission

The most direct measurement of bone formation is the percentage of bone surface that takes a tetracycline label, termed the mineralizing surface. Figure 1 shows data on the mineralizing surface in normal persons,⁶ women with osteoporosis, and women taking various other medications for osteoporosis. Bisphosphonate therapy reduces bone formation to values that are lower than in the great majority of normal young women.⁷ A study of 50 women treated with bisphosphonates for 6.5 years found that 33% had a mineralizing surface of zero.⁸ This means that patients taking bisphosphonates are forming very little new bone, and one-third of them are not forming any new bone.

With continued bisphosphonate use, the bone gradually becomes more dense. There is no further new bone, but the existing bone matrix is packed more tightly with mineral crystals.⁹ The old bone is not resorbed. The bone density, measured radiographically, increases most rapidly during the first 6 months (while resorption pits are filling in) and more gradually over the next 3 years (while bone is becoming more mineralized).

Another common misunderstanding is that the bone density increases because the drugs are “building bone.” After 3 years, the bone density in the femur reaches a plateau.¹⁰ I have seen patients who were very worried because their bone density was no longer increasing, and their physicians did not realize that this is the expected pattern. The spinal bone density continues to increase modestly, but some of this may be from disk space narrowing, harder bone edges, and soft-tissue calcifications. Spinal bone density frequently increases even in those on placebo.

 

 

Bisphosphonates suppress markers of bone turnover

These changes in bone remodeling with bisphosphonates are reflected by changes in markers of bone formation and resorption. The levels of markers of bone resorption—N-telopeptide cross-linked type I collagen (NTx) and C-telopeptide cross-linked type I collagen (CTx)—decrease rapidly and remain low. The markers of bone formation—propeptide of type I collagen, bone alkaline phosphatase, and osteocalcin—decrease gradually over 3 to 6 months and then remain low. As measured directly at the bone, bone formation appears to be more suppressed than as measured by biochemical markers in the serum.

In a risedronate trial,¹¹ the fracture rate decreased as the biochemical markers of bone turnover decreased, except when the markers were very low, in which case the fracture rate increased.

Without remodeling, cracks can accumulate

The bisphosphonates do not significantly increase bone volume, but they prevent microscopic architectural deterioration of the bone, as shown on microscopic computed tomographic imaging.¹² This prevents fractures for at least 5 years.

But bisphosphonates may have long-term negative effects. One purpose of bone remodeling is to refresh the bone and to repair the microscopic damage that accumulates within any structure. Without remodeling, cracks can accumulate. Because the development and repair of microcracks is complex, it is difficult to predict what will happen with long-term bisphosphonate use. Studies of biopsies from women taking bisphosphonates long-term are inconsistent: one study found accumulation of microcracks,¹³ but another did not.⁸

STUDIES OF LONG-TERM USE: FOCUS ON FRACTURES

For this review, I consider long-term bisphosphonate use to be greater than 5 years, and I will focus on fractures. Bone density is only a surrogate end point. Unfortunately, this fact is often not emphasized in the training of young physicians.

The best illustration of this point was in a randomized clinical trial of fluoride,¹⁴ in which the bone density of the treated group increased by 8% per year for 4 years, for a total increase of 32%. This is more than we ever see with current therapies. But the patients had more fractures with fluoride than with placebo. This is because the quality of bone produced after fluoride treatment is poor, and although the bone is denser, it is weaker.

Observational studies of fracture incidence in patients who continued taking bisphosphonates compared with those who stopped provide some weak evidence about long-term effectiveness.

Curtis et al¹⁵ found, in 9,063 women who were prescribed bisphosphonates, that those who stopped taking them during the first 2 years had higher rates of hip fracture than compliant patients. Those who took bisphosphonates for 3 years and then stopped had a rate of hip fracture during the next year similar to that of those who continued taking the drugs.

Meijer et al¹⁶ used a database in the Netherlands to examine the fracture rates in 14,750 women who started taking a bisphosphonate for osteoporosis between 1996 and 2004. More than half of the women stopped taking the drug during the first year, and they served as the control group. Those who took bisphosphonates for 3 to 4 years had significantly fewer fractures than those who stopped during the first year (odds ratio 0.54). However, those who took them for 5 to 6 years had slightly more fractures than those who took them for less than a year.

Mellström et al¹⁷ performed a 2-year uncontrolled extension of a 5-year trial of risedronate that had blinded controls.¹⁸ Initially, 407 women were in the risedronate group; 68 completed 7 years.

The vertebral fracture rate in the placebo group was 7.6% per year during years 0 through 3. In the risedronate group, the rate was 4.7% per year during years 0 through 3 and 3.8% per year during years 6 and 7. Nonvertebral fractures occurred in 10.9% of risedronate-treated patients during the first 3 years and in 6% during the last 2 years. Markers of bone turnover remained reduced throughout the 7 years. Bone mineral density of the spine and hip did not change from years 5 to 7. The study did not include those who took risedronate for 5 years and then discontinued it.

Bone et al¹⁹ performed a similar, 10-year uncontrolled extension of a 3-year controlled trial of alendronate.²⁰ There were 398 patients randomly assigned to alendronate, and 164 remained in the study for 8 to 10 years.

During years 8 through 10, bone mineral density of the spine increased by about 2%; no change was seen in the hip or total body. The nonvertebral fracture rate was similar in years 0 through 3 and years 6 through 10. Vertebral fractures occurred in approximately 3% of women in the first 3 years and in 9% in the last 5 years.

The FLEX trial: Continuing alendronate vs stopping

Only one study compared continuing a bisphosphonate vs stopping it. The Fracture Intervention Trial Long-Term Extension (FLEX)¹⁰ was an extension of the Fracture Intervention Trial (FIT)^21,22 of alendronate. I am reviewing this study in detail because it is the only one that randomized patients and was double-blinded.

In the original trial,^21,22 3,236 women were in the alendronate group. After a mean of 5 years on alendronate, 1,099 of them were randomized into the alendronate or placebo group.¹⁰ Those with T scores lower than −3.5 or who had lost bone density during the first 5 years were excluded.

The bone mineral density of the hip in the placebo group decreased by 3.4%, whereas in the alendronate group it decreased by 1.0%. At the spine, the placebo group gained less than the alendronate group.

Despite these differences in bone density, no significant difference was noted in the rates of all clinical fractures, nonvertebral fractures, vertebral fractures as measured on radiographs taken for the study (“morphometric” fractures, 11.3% vs 9.8%), or in the number of severe vertebral fractures (those with more than a two-grade change on radiography) between those who took alendronate for 10 years and those who took it for 5 years followed by placebo for 5 years.

However, fewer “clinical spine fractures” were observed in the group continuing alendronate (2.4% vs 5.3%). A clinical spine fracture was one diagnosed by the patient’s personal physician.

In FIT, these clinical fractures were painful in 90% of patients, and although the community radiographs were reviewed by a central radiologist, only 73% of the fractures were confirmed by subsequent measurements on the per protocol radiographs done at the study centers. About one-fourth of the morphometric fractures were also clinical fractures.²³ Therefore, I think morphometric fractures provide the best evidence about the effects of treatment—ie, that treatment beyond 5 years is not beneficial. Other physicians, however, disagree, emphasizing the 55% reduction in clinical fractures.²⁴

Markers of bone turnover gradually increased after discontinuation but remained lower than baseline even after 5 years without alendronate.¹⁰ There were no significant differences in fracture rates between the placebo and alendronate groups in those with baseline bone mineral density T scores less than −2.5.¹⁰ Also, after age adjustment, the fracture incidence was similar in the FIT and the FLEX studies.

Several years later, the authors published a post hoc subgroup analysis of these data.²⁵ The patients were divided into six subgroups based on bone density and the presence of vertebral fractures at baseline. This is weak evidence, but I include it because reviews in the literature have emphasized only the positive findings, or have misquoted the data: Schwartz et al stated that in those with T scores of −2.5 or below, the risk of nonvertebral fracture was reduced by 50%²⁵; and Shane²⁶ concluded in an editorial that the use of alendronate for 10 years, rather than for 5 years, was associated with significantly fewer new vertebral fractures and nonvertebral fractures in patients with a bone mineral density T score of −2.5 or below.²⁶

Data from Schwartz AV, et al; FLEX Research Group. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX Trial. J Bone Miner Res 2010; 25:976–982.

What was actually seen in the FLEX study was no difference between alendronate and placebo in morphometric vertebral fractures in any subgroup. In one of the six subgroups (N = 184), women with osteoporosis without vertebral fractures had fewer nonvertebral fractures with alendronate. There was no benefit with alendronate in the other five subgroups (Figure 2), not even in those with the greatest risk—women with osteoporosis who had a vertebral compression fracture, shown in the first three columns of Figure 2.²⁵ Nevertheless, several recent papers about this topic have recommended that bisphosphonates should be used continuously for 10 years in those with the highest fracture risk.^24,27–29

 

ATYPICAL FEMUR FRACTURES

Bush LA, Chew FS. Subtrochanteric femoral insufficiency fracture in woman on bisphosphonate therapy for glucocorticoid-induced osteoporosis. Radiology Case Reports (online) 2009; 4:261.

Recent reports, initially met with skepticism, have described atypical fractures of the femur in patients who have been taking bisphosphonates long-term (Figure 3).^28–30

By March 2011, there were 55 papers describing a total of 283 cases, and about 85 individual cases (listed online in Ott SM. Osteoporosis and Bone Physiology. http://courses.washington.edu/bonephys/opsubtroch.html. Accessed 7/30/2011).

The mean age of the patients was 65, bisphosphonate use was longer than 5 years in 77% of cases, and bilateral fractures were seen in 48%.

The fractures occur with minor trauma, such as tripping, stepping off an elevator, or being jolted by a subway stop, and a disproportionate number of cases involve no trauma. They are often preceded by leg pain, typically in the mid-thigh.

These fractures are characterized by radiographic findings of a transverse fracture, with thickened cortices near the site of the fracture. Often, there is a peak on the cortex that may precede the fracture. These fractures initiate on the lateral side, and it is striking that they occur in the same horizontal plane on the contralateral side.

Radiographs and bone scans show stress fractures on the lateral side of the femur that resemble Looser zones (ie, dark lines seen radiographically). These radiographic features are not typical in osteoporosis but are reminiscent of the stress fractures seen with hypophosphatasia, an inherited disease characterized by severely decreased bone formation.³¹

Bone biopsy specimens show very low bone formation rates, but this is not a necessary feature. At the fracture site itself there is bone activity. For example, pathologists from St. Louis reviewed all iliac crest bone biopsies from patients seen between 2004 and 2007 who had an unusual cortical fracture while taking a bisphosphonate. An absence of double tetracycline labels was seen in 11 of the 16 patients.³²

The first reports were anecdotal cases, then some centers reported systematic surveys of their patients. In a key report, Neviaser et al³³ reviewed all low-trauma subtrochanteric fractures in their large hospital and found 20 cases with the atypical radiographic appearance; 19 of the patients in these cases had been taking a bisphosphonate. A similar survey in Australia found 41 cases with atypical radiographic features (out of 79 subtrochanteric low-trauma fractures), and all of the patients had been taking a bisphosphonate.³⁴

By now, more than 230 cases have been reported. The estimated incidence is 1 in 1,000, based on a review of operative cases and radiographs.³⁵

However, just because the drugs are associated with the fractures does not mean they caused the fractures, because the patients who took bisphosphonates were more likely to get a fracture in the first place. This confounding by indication makes it difficult to prove beyond a doubt that bisphosphonates cause atypical fractures.

Further, some studies have found no association between bisphosphonates and subtrochanteric fractures.^36,37 These database analyses have relied on the coding of the International Classification of Diseases, Ninth Revision (ICD-9), and not on the examination of radiographs. We reviewed the ability of ICD-9 codes to identify subtrochanteric fractures and found that the predictive ability was only 36%.³⁸ Even for fractures in the correct location, the codes cannot tell which cases have the typical spiral or comminuted fractures seen in osteoporosis and which have the unusual features of the bisphosphonate-associated fractures. Subtrochanteric and shaft fractures are about 10 times less common than hip fractures, and the atypical ones are about 10 times less common than typical ones, so studies based on ICD-9 codes cannot exonerate bisphosphonates.

A report of nearly 15,000 patients from randomized clinical trials did not find a significant incidence of subtrochanteric fractures, but the radiographs were not examined and only 500 of the patients had taken the medication for longer than 5 years.³⁹

A population-based, nested case-control study using a database from Ontario, Canada, found an increased risk of diaphyseal femoral fractures in patients who had taken bisphosphonates longer than 5 years. The study included only women who had started bisphosphonates when they were older than 68, so many of the atypical fractures would have been missed. The investigators did not review the radiographs, so they combined both osteoporotic and atypical diaphyseal fractures in their analysis.⁴⁰

At the 2010 meeting of the American Society for Bone and Mineral Research, preliminary data were presented from a systematic review of radiographs of patients with fractures of the femur from a health care plan with data about the use of medications. The incidence of atypical fractures increased progressively with the duration of bisphosphonate use, and was significantly higher after 5 years compared with less than 3 years.²⁸

OTHER POSSIBLE ADVERSE EFFECTS

There have been conflicting reports about esophageal cancer with bisphosphonate use.^41,42

Another possible adverse effect, osteonecrosis of the jaw, may have occurred in 1.4% of patients with cancer who were treated for 3 years with high intravenous doses of bisphosphonates (about 10 to 12 times the doses recommended for osteoporosis).⁴³ This adverse effect is rare in patients with osteoporosis, occurring in less than 1 in 10,000 exposed patients.⁴⁴

 

BISPHOSPHONATES SHOULD BE USED WHEN THEY ARE INDICATED

The focus of this paper is on the duration of use, but concern about long-term use should not discourage physicians or patients from using these drugs when there is a high risk of an osteoporotic fracture within the next 10 years, particularly in elderly patients who have experienced a vertebral compression fracture or a hip fracture. Patients with a vertebral fracture have a one-in-five chance of fracturing another vertebra, which is a far higher risk than any of the known long-term side effects from treatment, and bisphosphonates are effective at reducing the risk.

Low bone density alone can be used as an indication for bisphosphonates if the hip T score is lower than −2.5. A cost-effectiveness study concluded that alendronate was beneficial in these cases.⁴⁵ In the FIT patients without a vertebral fracture at baseline, the overall fracture rate was significantly decreased by 36% with alendronate in those with a hip T score lower than −2.5, but there was no difference between placebo and alendronate in those with T scores between −2 and −2.5, and a 14% (nonsignificant) higher fracture rate when the T score was better than −2.0.²²

A new method of calculating the risk of an osteoporotic fracture is the FRAX prediction tool (http://www.shef.ac.uk/FRAX), and one group has suggested that treatment is indicated when the 10-year risk of a hip fracture is greater than 3%.⁴⁶ Another group, from the United Kingdom, suggests using a sliding scale depending on the fracture risk and the age.⁴⁷

It is not always clear what to do when the hip fracture risk is greater than 3% for the next decade but the T score is better than −2.5. These patients have other factors that contribute to fracture risk. Their therapy must be individualized, and if they are at risk of fracture because of low weight, smoking, or alcohol use, it makes more sense to focus the approach on those treatable factors.

Women who have osteopenia and have not had a fragility fracture are often treated with bisphosphonates with the intent of preventing osteoporosis in the distant future. This approach is based on hope, not evidence, and several editorial reviews have concluded that these women do not need drug therapy.^48–50

MY RECOMMENDATION: STOP AFTER 5 YEARS

Bisphosphonates reduce the incidence of devastating osteoporotic fractures in patients with osteoporosis, but that does not mean they should be used indefinitely.

After 5 years, the overall fracture risk is the same in patients who keep taking bisphosphonates as in patients who discontinue them. Therefore, I think these drugs are no longer necessary after 5 years. The post hoc subgroup analysis that showed benefit in only one of six groups of the FLEX study does not provide compelling evidence to continue taking bisphosphonates.

In addition, there is a physiologic concern about long-term suppression of bone formation. Ideally, we would treat all high-risk patients with drugs that stop bone resorption and also improve bone formation, but such drugs belong to the future. Currently, there is some emerging evidence of harm after 5 years of bisphosphonate treatment; to date the incidence of serious side effects is less than 1 in 1,000, but the risks beyond 10 years are unknown. If we are uncertain about long-term safety, we should follow the principle of primum non nocere. Only further investigations will settle the debate about prolonged use.

While awaiting better studies, we use the approach shown in the algorithm in Figure 4.

Follow the patient with bone resorption markers

In patients who have shown some improvement in bone density during 5 years of bisphosphonate treatment and who have not had any fractures, I measure a marker of bone resorption at the end of 5 years.

The use of a biochemical marker to assess patients treated with anti-turnover drugs has not been studied in a formal trial, so we have no grade A evidence for recommending it. However, there have been many papers describing the effects of bisphosphonates on these markers, and it makes physiologic sense to use them in situations where decisions must be made when there is not enough evidence.

In FIT (a trial of alendronate), we reported that the change in bone turnover markers was significantly related to the reduction in fracture risk, and the effect was at least as strong as that observed with a 1-year change in bone density. Those with a 30% decrease in bone alkaline phosphatase had a significant reduction in fracture risk.⁵¹

Furthermore, in those patients who were compliant with bisphosphonate treatment, the reduction in fractures with alendronate treatment was significantly better in those who initially had a high bone turnover.⁵²

Similarly, with risedronate, the change in NTx accounted for half of the effect on fracture reduction during the clinical trial, and there was little further improvement in fracture benefit below a decrease of 35% to 40%.¹⁰

The baseline NTx level in these clinical trials was about 70 nmol bone collagen equivalents per millimole of creatinine (nmol BCE/mmol Cr) in the risedronate study and 60 in the alendronate study, and in both the fracture reduction was seen at a level of about 40. The FLEX study measured NTx after 5 years, and the average was 19 nmol BCE/mmol Cr. This increased to 22 after 3 years without alendronate.⁵³ At 5 years, the turnover markers had gradually increased but were still 7% to 24% lower than baseline.¹⁰

These markers have a diurnal rhythm and daily variation, but despite these limitations they do help identify low bone resorption.

In our hospital, NTx is the most economical marker, and my patients prefer a urine sample to a blood test. Therefore, we measure the NTx and consider values lower than 40 nmol BCE/mmol Cr to be satisfactory.

If the NTx is as low as expected, I discontinue the bisphosphonate. The patient remains on 1,200 mg/day of calcium and 1,000 U/day vitamin D supplementation and is encouraged to exercise.

Bone density tends to be stable for 1 or 2 years after stopping a bisphosphonate, and the biochemical markers of bone resorption remain reduced for several years. We remeasure the urine NTx level annually, and if it increases to more than 40 nmol BCE/mmol Cr an antiresorptive medication is given: either the bisphosphonate is restarted or raloxifene (Evista), calcitonin (Miacalcin), or denosumab (Prolia) is used.

 

 

Bone density is less helpful, but reassuring

Bone density is less helpful because it decreases even though the markers of bone resorption remain low. Although one could argue that bone density is not helpful in monitoring patients on therapy, I think it is reassuring to know the patient is not excessively losing bone.

Checking at 2-year intervals is reasonable. If the bone density shows a consistent decrease greater than 6% (which is greater than the difference we can see from patients walking around the room), then we would re-evaluate the patient and consider adding another medication.

If the bone density decreases but the biomarkers are low, then clinical judgment must be used. The bone density result may be erroneous due to different positioning or different regions of interest.

If turnover markers are not reduced

If a patient has been prescribed a bisphosphonate for 5 years but the NTx level is not reduced, I reevaluate the patient. Some are not taking the medication or are not taking it properly. The absorption of oral bisphosphonates is quite low in terms of bioavailability, and this decreases to nearly zero if the medication is taken with food. Some patients may have another disease, such as hyperparathyroidism, malignancy, hyperthyroidism, weight loss, malabsorption, celiac sprue, or vitamin D deficiency.

If repeated biochemical tests show high bone resorption and if the bone density response is suboptimal without a secondary cause, I often switch to an intravenous form of bisphosphonate because some patients do not seem to absorb the oral doses.

If a patient has had a fracture

If a patient has had a fracture despite several years of bisphosphonate therapy, I first check for any other medical problems. The bone markers are, unfortunately, not very helpful because they increase after a fracture and stay elevated for at least 4 months.⁵⁴ If there are no contraindications, treatment with teriparatide (Forteo) is a reasonable choice. There is evidence from human biopsy studies that teriparatide can reduce the number of microcracks that were related to bisphosphonate treatment,¹³ and can increase the bone formation rate even when there has been prior bisphosphonate treatment.^55–57 Although the anabolic response is blunted, it is still there.⁵⁸

If the patient remains at high risk

A frail patient with a high risk of fracture presents a challenge, especially one who needs treatment with glucocorticoids or who still has a hip T score below −3. Many physicians are uneasy about discontinuing all osteoporosis-specific drugs, even after 5 years of successful bisphosphonate treatment. In these patients anabolic medications make the most sense. Currently, teriparatide is the only one available, but others are being developed. Bone becomes resistant to the anabolic effects of teriparatide after about 18 months, so this drug cannot be used indefinitely. What we really need are longer-lasting anabolic medicines!

If the patient has thigh pain

Finally, in patients with thigh pain, radiography of the femur should be done to check for a stress fracture. Magnetic resonance imaging or computed tomography may be needed to diagnose a hairline fracture.

If there are already radiographic changes that precede the atypical fractures, then bisphosphonates should be discontinued. In a follow-up observational study of 16 patients who already had one fracture, all four whose contralateral side showed a fracture line (the “dreaded black line”) eventually completed the fracture.⁵⁹

Another study found that five of six incomplete fractures went on to a complete fracture if not surgically stabilized with rods.⁶⁰ This is an indication for prophylactic rodding of the femur.

Teriparatide use and rodding of a femur with thickening but not a fracture line must be decided on an individual basis and should be considered more strongly in those with pain in the thigh.

Almost all the data about the safety and efficacy of bisphosphonate drugs for treating osteoporosis are from patients who took them for less than 5 years.

Reports of adverse effects with prolonged use have caused concern about the long-term safety of this class of drugs. This is particularly important because these drugs are retained in the skeleton longer than 10 years, because there are physiologic reasons why excessive bisphosphonate-induced inhibition of bone turnover could be damaging, and because many healthy postmenopausal women have been prescribed bisphosphonates in the hope of preventing fractures that are not expected to occur for 20 to 30 years.

Because information from trials is scant, opinions differ over whether bisphosphonates should be continued indefinitely. In this article, I summarize the physiologic mechanisms of these drugs, review the scant existing data about their effects beyond 5 years, and describe my approach to bisphosphonate therapy (while waiting for better evidence).

MORE THAN 4 MILLION WOMEN TAKE BISPHOSPHONATES

The first medical use of a bisphosphonate was in 1967, when a girl with myositis ossificans was given etidronate (Didronel) because it inhibited mineralization. Two years later, it was given to patients with Paget disease of bone because it was found to inhibit bone resorption.¹ Etidronate could not be given for longer than 6 months, however, because patients developed osteomalacia.

Adding a nitrogen to the molecule dramatically increased its potency and led to the second generation of bisphosphonates. Alendronate (Fosamax), the first amino-bisphosphonate, became available in 1995, It was followed by risedronate (Actonel), ibandronate (Boniva), and zoledronic acid (Reclast). These drugs are potent inhibitors of bone resorption; however, in clinical doses they do not inhibit mineralization and therefore do not cause osteomalacia.

Randomized clinical trials involving more than 30,000 patients have provided grade A evidence that these drugs reduce the incidence of fragility fractures in patients with osteoporosis.² Furthermore, observational studies have confirmed that they prevent fractures and have a good safety profile in clinical practice.

Therefore, the use of these drugs has become common. In 2008, an estimated 4 million women in the United States were taking them.³

BISPHOSPHONATES STRENGTHEN BONE BY INHIBITING RESORPTION

On a molecular level, bisphosphonates inhibit farnesyl pyrophosphate synthase, an enzyme necessary for formation of the cytoskeleton in osteoclasts. Thus, they strongly inhibit bone resorption. They do not appear to directly inhibit osteoblasts, the cells that form new bone, but they substantially decrease bone formation indirectly.⁴

To understand how inhibition of bone resorption affects bone physiology, it is necessary to appreciate the nature of bone remodeling. Bone is not like the skin, which is continually forming a new layer and sloughing off the old. Instead, bone is renewed in small units. It takes about 5 years to remodel cancellous bone and 13 years to remodel cortical bone⁵; at any one time, about 8% of the surface is being remodeled.

The first step occurs at a spot on the surface, where the osteoclasts resorb some bone to form a pit that looks like a pothole. Then a team of osteoblasts is formed and fills the pit with new bone over the next 3 to 6 months. When first formed, the new bone is mainly collagen and, like the tip of the nose, is not very stiff, but with mineral deposition the bone becomes stronger, like the bridge of the nose. The new bone gradually accumulates mineral and becomes harder and denser over the next 3 years.

When a bisphosphonate is given, the osteoclasts abruptly stop resorbing the bone, but osteoblasts continue to fill the pits that were there when the bisphosphonate was started. For the next several months, while the previous pits are being filled, the bone volume increases slightly. Thereafter, rates of both bone resorption and bone formation are very low.

A misconception: Bisphosphonates build bone

While semantically it is true that the bone formation rate in patients taking bisphosphonates is within the normal premenopausal range, this often-repeated statement is essentially misleading.

Copyright Susan Ott, used with permission

The most direct measurement of bone formation is the percentage of bone surface that takes a tetracycline label, termed the mineralizing surface. Figure 1 shows data on the mineralizing surface in normal persons,⁶ women with osteoporosis, and women taking various other medications for osteoporosis. Bisphosphonate therapy reduces bone formation to values that are lower than in the great majority of normal young women.⁷ A study of 50 women treated with bisphosphonates for 6.5 years found that 33% had a mineralizing surface of zero.⁸ This means that patients taking bisphosphonates are forming very little new bone, and one-third of them are not forming any new bone.

With continued bisphosphonate use, the bone gradually becomes more dense. There is no further new bone, but the existing bone matrix is packed more tightly with mineral crystals.⁹ The old bone is not resorbed. The bone density, measured radiographically, increases most rapidly during the first 6 months (while resorption pits are filling in) and more gradually over the next 3 years (while bone is becoming more mineralized).

Another common misunderstanding is that the bone density increases because the drugs are “building bone.” After 3 years, the bone density in the femur reaches a plateau.¹⁰ I have seen patients who were very worried because their bone density was no longer increasing, and their physicians did not realize that this is the expected pattern. The spinal bone density continues to increase modestly, but some of this may be from disk space narrowing, harder bone edges, and soft-tissue calcifications. Spinal bone density frequently increases even in those on placebo.

 

 

Bisphosphonates suppress markers of bone turnover

These changes in bone remodeling with bisphosphonates are reflected by changes in markers of bone formation and resorption. The levels of markers of bone resorption—N-telopeptide cross-linked type I collagen (NTx) and C-telopeptide cross-linked type I collagen (CTx)—decrease rapidly and remain low. The markers of bone formation—propeptide of type I collagen, bone alkaline phosphatase, and osteocalcin—decrease gradually over 3 to 6 months and then remain low. As measured directly at the bone, bone formation appears to be more suppressed than as measured by biochemical markers in the serum.

In a risedronate trial,¹¹ the fracture rate decreased as the biochemical markers of bone turnover decreased, except when the markers were very low, in which case the fracture rate increased.

Without remodeling, cracks can accumulate

The bisphosphonates do not significantly increase bone volume, but they prevent microscopic architectural deterioration of the bone, as shown on microscopic computed tomographic imaging.¹² This prevents fractures for at least 5 years.

But bisphosphonates may have long-term negative effects. One purpose of bone remodeling is to refresh the bone and to repair the microscopic damage that accumulates within any structure. Without remodeling, cracks can accumulate. Because the development and repair of microcracks is complex, it is difficult to predict what will happen with long-term bisphosphonate use. Studies of biopsies from women taking bisphosphonates long-term are inconsistent: one study found accumulation of microcracks,¹³ but another did not.⁸

STUDIES OF LONG-TERM USE: FOCUS ON FRACTURES

For this review, I consider long-term bisphosphonate use to be greater than 5 years, and I will focus on fractures. Bone density is only a surrogate end point. Unfortunately, this fact is often not emphasized in the training of young physicians.

The best illustration of this point was in a randomized clinical trial of fluoride,¹⁴ in which the bone density of the treated group increased by 8% per year for 4 years, for a total increase of 32%. This is more than we ever see with current therapies. But the patients had more fractures with fluoride than with placebo. This is because the quality of bone produced after fluoride treatment is poor, and although the bone is denser, it is weaker.

Observational studies of fracture incidence in patients who continued taking bisphosphonates compared with those who stopped provide some weak evidence about long-term effectiveness.

Curtis et al¹⁵ found, in 9,063 women who were prescribed bisphosphonates, that those who stopped taking them during the first 2 years had higher rates of hip fracture than compliant patients. Those who took bisphosphonates for 3 years and then stopped had a rate of hip fracture during the next year similar to that of those who continued taking the drugs.

Meijer et al¹⁶ used a database in the Netherlands to examine the fracture rates in 14,750 women who started taking a bisphosphonate for osteoporosis between 1996 and 2004. More than half of the women stopped taking the drug during the first year, and they served as the control group. Those who took bisphosphonates for 3 to 4 years had significantly fewer fractures than those who stopped during the first year (odds ratio 0.54). However, those who took them for 5 to 6 years had slightly more fractures than those who took them for less than a year.

Mellström et al¹⁷ performed a 2-year uncontrolled extension of a 5-year trial of risedronate that had blinded controls.¹⁸ Initially, 407 women were in the risedronate group; 68 completed 7 years.

The vertebral fracture rate in the placebo group was 7.6% per year during years 0 through 3. In the risedronate group, the rate was 4.7% per year during years 0 through 3 and 3.8% per year during years 6 and 7. Nonvertebral fractures occurred in 10.9% of risedronate-treated patients during the first 3 years and in 6% during the last 2 years. Markers of bone turnover remained reduced throughout the 7 years. Bone mineral density of the spine and hip did not change from years 5 to 7. The study did not include those who took risedronate for 5 years and then discontinued it.

Bone et al¹⁹ performed a similar, 10-year uncontrolled extension of a 3-year controlled trial of alendronate.²⁰ There were 398 patients randomly assigned to alendronate, and 164 remained in the study for 8 to 10 years.

During years 8 through 10, bone mineral density of the spine increased by about 2%; no change was seen in the hip or total body. The nonvertebral fracture rate was similar in years 0 through 3 and years 6 through 10. Vertebral fractures occurred in approximately 3% of women in the first 3 years and in 9% in the last 5 years.

The FLEX trial: Continuing alendronate vs stopping

Only one study compared continuing a bisphosphonate vs stopping it. The Fracture Intervention Trial Long-Term Extension (FLEX)¹⁰ was an extension of the Fracture Intervention Trial (FIT)^21,22 of alendronate. I am reviewing this study in detail because it is the only one that randomized patients and was double-blinded.

In the original trial,^21,22 3,236 women were in the alendronate group. After a mean of 5 years on alendronate, 1,099 of them were randomized into the alendronate or placebo group.¹⁰ Those with T scores lower than −3.5 or who had lost bone density during the first 5 years were excluded.

The bone mineral density of the hip in the placebo group decreased by 3.4%, whereas in the alendronate group it decreased by 1.0%. At the spine, the placebo group gained less than the alendronate group.

Despite these differences in bone density, no significant difference was noted in the rates of all clinical fractures, nonvertebral fractures, vertebral fractures as measured on radiographs taken for the study (“morphometric” fractures, 11.3% vs 9.8%), or in the number of severe vertebral fractures (those with more than a two-grade change on radiography) between those who took alendronate for 10 years and those who took it for 5 years followed by placebo for 5 years.

However, fewer “clinical spine fractures” were observed in the group continuing alendronate (2.4% vs 5.3%). A clinical spine fracture was one diagnosed by the patient’s personal physician.

In FIT, these clinical fractures were painful in 90% of patients, and although the community radiographs were reviewed by a central radiologist, only 73% of the fractures were confirmed by subsequent measurements on the per protocol radiographs done at the study centers. About one-fourth of the morphometric fractures were also clinical fractures.²³ Therefore, I think morphometric fractures provide the best evidence about the effects of treatment—ie, that treatment beyond 5 years is not beneficial. Other physicians, however, disagree, emphasizing the 55% reduction in clinical fractures.²⁴

Markers of bone turnover gradually increased after discontinuation but remained lower than baseline even after 5 years without alendronate.¹⁰ There were no significant differences in fracture rates between the placebo and alendronate groups in those with baseline bone mineral density T scores less than −2.5.¹⁰ Also, after age adjustment, the fracture incidence was similar in the FIT and the FLEX studies.

Several years later, the authors published a post hoc subgroup analysis of these data.²⁵ The patients were divided into six subgroups based on bone density and the presence of vertebral fractures at baseline. This is weak evidence, but I include it because reviews in the literature have emphasized only the positive findings, or have misquoted the data: Schwartz et al stated that in those with T scores of −2.5 or below, the risk of nonvertebral fracture was reduced by 50%²⁵; and Shane²⁶ concluded in an editorial that the use of alendronate for 10 years, rather than for 5 years, was associated with significantly fewer new vertebral fractures and nonvertebral fractures in patients with a bone mineral density T score of −2.5 or below.²⁶

Data from Schwartz AV, et al; FLEX Research Group. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX Trial. J Bone Miner Res 2010; 25:976–982.

What was actually seen in the FLEX study was no difference between alendronate and placebo in morphometric vertebral fractures in any subgroup. In one of the six subgroups (N = 184), women with osteoporosis without vertebral fractures had fewer nonvertebral fractures with alendronate. There was no benefit with alendronate in the other five subgroups (Figure 2), not even in those with the greatest risk—women with osteoporosis who had a vertebral compression fracture, shown in the first three columns of Figure 2.²⁵ Nevertheless, several recent papers about this topic have recommended that bisphosphonates should be used continuously for 10 years in those with the highest fracture risk.^24,27–29

 

ATYPICAL FEMUR FRACTURES

Bush LA, Chew FS. Subtrochanteric femoral insufficiency fracture in woman on bisphosphonate therapy for glucocorticoid-induced osteoporosis. Radiology Case Reports (online) 2009; 4:261.

Recent reports, initially met with skepticism, have described atypical fractures of the femur in patients who have been taking bisphosphonates long-term (Figure 3).^28–30

By March 2011, there were 55 papers describing a total of 283 cases, and about 85 individual cases (listed online in Ott SM. Osteoporosis and Bone Physiology. http://courses.washington.edu/bonephys/opsubtroch.html. Accessed 7/30/2011).

The mean age of the patients was 65, bisphosphonate use was longer than 5 years in 77% of cases, and bilateral fractures were seen in 48%.

The fractures occur with minor trauma, such as tripping, stepping off an elevator, or being jolted by a subway stop, and a disproportionate number of cases involve no trauma. They are often preceded by leg pain, typically in the mid-thigh.

These fractures are characterized by radiographic findings of a transverse fracture, with thickened cortices near the site of the fracture. Often, there is a peak on the cortex that may precede the fracture. These fractures initiate on the lateral side, and it is striking that they occur in the same horizontal plane on the contralateral side.

Radiographs and bone scans show stress fractures on the lateral side of the femur that resemble Looser zones (ie, dark lines seen radiographically). These radiographic features are not typical in osteoporosis but are reminiscent of the stress fractures seen with hypophosphatasia, an inherited disease characterized by severely decreased bone formation.³¹

Bone biopsy specimens show very low bone formation rates, but this is not a necessary feature. At the fracture site itself there is bone activity. For example, pathologists from St. Louis reviewed all iliac crest bone biopsies from patients seen between 2004 and 2007 who had an unusual cortical fracture while taking a bisphosphonate. An absence of double tetracycline labels was seen in 11 of the 16 patients.³²

The first reports were anecdotal cases, then some centers reported systematic surveys of their patients. In a key report, Neviaser et al³³ reviewed all low-trauma subtrochanteric fractures in their large hospital and found 20 cases with the atypical radiographic appearance; 19 of the patients in these cases had been taking a bisphosphonate. A similar survey in Australia found 41 cases with atypical radiographic features (out of 79 subtrochanteric low-trauma fractures), and all of the patients had been taking a bisphosphonate.³⁴

By now, more than 230 cases have been reported. The estimated incidence is 1 in 1,000, based on a review of operative cases and radiographs.³⁵

However, just because the drugs are associated with the fractures does not mean they caused the fractures, because the patients who took bisphosphonates were more likely to get a fracture in the first place. This confounding by indication makes it difficult to prove beyond a doubt that bisphosphonates cause atypical fractures.

Further, some studies have found no association between bisphosphonates and subtrochanteric fractures.^36,37 These database analyses have relied on the coding of the International Classification of Diseases, Ninth Revision (ICD-9), and not on the examination of radiographs. We reviewed the ability of ICD-9 codes to identify subtrochanteric fractures and found that the predictive ability was only 36%.³⁸ Even for fractures in the correct location, the codes cannot tell which cases have the typical spiral or comminuted fractures seen in osteoporosis and which have the unusual features of the bisphosphonate-associated fractures. Subtrochanteric and shaft fractures are about 10 times less common than hip fractures, and the atypical ones are about 10 times less common than typical ones, so studies based on ICD-9 codes cannot exonerate bisphosphonates.

A report of nearly 15,000 patients from randomized clinical trials did not find a significant incidence of subtrochanteric fractures, but the radiographs were not examined and only 500 of the patients had taken the medication for longer than 5 years.³⁹

A population-based, nested case-control study using a database from Ontario, Canada, found an increased risk of diaphyseal femoral fractures in patients who had taken bisphosphonates longer than 5 years. The study included only women who had started bisphosphonates when they were older than 68, so many of the atypical fractures would have been missed. The investigators did not review the radiographs, so they combined both osteoporotic and atypical diaphyseal fractures in their analysis.⁴⁰

At the 2010 meeting of the American Society for Bone and Mineral Research, preliminary data were presented from a systematic review of radiographs of patients with fractures of the femur from a health care plan with data about the use of medications. The incidence of atypical fractures increased progressively with the duration of bisphosphonate use, and was significantly higher after 5 years compared with less than 3 years.²⁸

OTHER POSSIBLE ADVERSE EFFECTS

There have been conflicting reports about esophageal cancer with bisphosphonate use.^41,42

Another possible adverse effect, osteonecrosis of the jaw, may have occurred in 1.4% of patients with cancer who were treated for 3 years with high intravenous doses of bisphosphonates (about 10 to 12 times the doses recommended for osteoporosis).⁴³ This adverse effect is rare in patients with osteoporosis, occurring in less than 1 in 10,000 exposed patients.⁴⁴

 

BISPHOSPHONATES SHOULD BE USED WHEN THEY ARE INDICATED

The focus of this paper is on the duration of use, but concern about long-term use should not discourage physicians or patients from using these drugs when there is a high risk of an osteoporotic fracture within the next 10 years, particularly in elderly patients who have experienced a vertebral compression fracture or a hip fracture. Patients with a vertebral fracture have a one-in-five chance of fracturing another vertebra, which is a far higher risk than any of the known long-term side effects from treatment, and bisphosphonates are effective at reducing the risk.

Low bone density alone can be used as an indication for bisphosphonates if the hip T score is lower than −2.5. A cost-effectiveness study concluded that alendronate was beneficial in these cases.⁴⁵ In the FIT patients without a vertebral fracture at baseline, the overall fracture rate was significantly decreased by 36% with alendronate in those with a hip T score lower than −2.5, but there was no difference between placebo and alendronate in those with T scores between −2 and −2.5, and a 14% (nonsignificant) higher fracture rate when the T score was better than −2.0.²²

A new method of calculating the risk of an osteoporotic fracture is the FRAX prediction tool (http://www.shef.ac.uk/FRAX), and one group has suggested that treatment is indicated when the 10-year risk of a hip fracture is greater than 3%.⁴⁶ Another group, from the United Kingdom, suggests using a sliding scale depending on the fracture risk and the age.⁴⁷

It is not always clear what to do when the hip fracture risk is greater than 3% for the next decade but the T score is better than −2.5. These patients have other factors that contribute to fracture risk. Their therapy must be individualized, and if they are at risk of fracture because of low weight, smoking, or alcohol use, it makes more sense to focus the approach on those treatable factors.

Women who have osteopenia and have not had a fragility fracture are often treated with bisphosphonates with the intent of preventing osteoporosis in the distant future. This approach is based on hope, not evidence, and several editorial reviews have concluded that these women do not need drug therapy.^48–50

MY RECOMMENDATION: STOP AFTER 5 YEARS

Bisphosphonates reduce the incidence of devastating osteoporotic fractures in patients with osteoporosis, but that does not mean they should be used indefinitely.

After 5 years, the overall fracture risk is the same in patients who keep taking bisphosphonates as in patients who discontinue them. Therefore, I think these drugs are no longer necessary after 5 years. The post hoc subgroup analysis that showed benefit in only one of six groups of the FLEX study does not provide compelling evidence to continue taking bisphosphonates.

In addition, there is a physiologic concern about long-term suppression of bone formation. Ideally, we would treat all high-risk patients with drugs that stop bone resorption and also improve bone formation, but such drugs belong to the future. Currently, there is some emerging evidence of harm after 5 years of bisphosphonate treatment; to date the incidence of serious side effects is less than 1 in 1,000, but the risks beyond 10 years are unknown. If we are uncertain about long-term safety, we should follow the principle of primum non nocere. Only further investigations will settle the debate about prolonged use.

While awaiting better studies, we use the approach shown in the algorithm in Figure 4.

Follow the patient with bone resorption markers

In patients who have shown some improvement in bone density during 5 years of bisphosphonate treatment and who have not had any fractures, I measure a marker of bone resorption at the end of 5 years.

The use of a biochemical marker to assess patients treated with anti-turnover drugs has not been studied in a formal trial, so we have no grade A evidence for recommending it. However, there have been many papers describing the effects of bisphosphonates on these markers, and it makes physiologic sense to use them in situations where decisions must be made when there is not enough evidence.

In FIT (a trial of alendronate), we reported that the change in bone turnover markers was significantly related to the reduction in fracture risk, and the effect was at least as strong as that observed with a 1-year change in bone density. Those with a 30% decrease in bone alkaline phosphatase had a significant reduction in fracture risk.⁵¹

Furthermore, in those patients who were compliant with bisphosphonate treatment, the reduction in fractures with alendronate treatment was significantly better in those who initially had a high bone turnover.⁵²

Similarly, with risedronate, the change in NTx accounted for half of the effect on fracture reduction during the clinical trial, and there was little further improvement in fracture benefit below a decrease of 35% to 40%.¹⁰

The baseline NTx level in these clinical trials was about 70 nmol bone collagen equivalents per millimole of creatinine (nmol BCE/mmol Cr) in the risedronate study and 60 in the alendronate study, and in both the fracture reduction was seen at a level of about 40. The FLEX study measured NTx after 5 years, and the average was 19 nmol BCE/mmol Cr. This increased to 22 after 3 years without alendronate.⁵³ At 5 years, the turnover markers had gradually increased but were still 7% to 24% lower than baseline.¹⁰

These markers have a diurnal rhythm and daily variation, but despite these limitations they do help identify low bone resorption.

In our hospital, NTx is the most economical marker, and my patients prefer a urine sample to a blood test. Therefore, we measure the NTx and consider values lower than 40 nmol BCE/mmol Cr to be satisfactory.

If the NTx is as low as expected, I discontinue the bisphosphonate. The patient remains on 1,200 mg/day of calcium and 1,000 U/day vitamin D supplementation and is encouraged to exercise.

Bone density tends to be stable for 1 or 2 years after stopping a bisphosphonate, and the biochemical markers of bone resorption remain reduced for several years. We remeasure the urine NTx level annually, and if it increases to more than 40 nmol BCE/mmol Cr an antiresorptive medication is given: either the bisphosphonate is restarted or raloxifene (Evista), calcitonin (Miacalcin), or denosumab (Prolia) is used.

 

 

Bone density is less helpful, but reassuring

Bone density is less helpful because it decreases even though the markers of bone resorption remain low. Although one could argue that bone density is not helpful in monitoring patients on therapy, I think it is reassuring to know the patient is not excessively losing bone.

Checking at 2-year intervals is reasonable. If the bone density shows a consistent decrease greater than 6% (which is greater than the difference we can see from patients walking around the room), then we would re-evaluate the patient and consider adding another medication.

If the bone density decreases but the biomarkers are low, then clinical judgment must be used. The bone density result may be erroneous due to different positioning or different regions of interest.

If turnover markers are not reduced

If a patient has been prescribed a bisphosphonate for 5 years but the NTx level is not reduced, I reevaluate the patient. Some are not taking the medication or are not taking it properly. The absorption of oral bisphosphonates is quite low in terms of bioavailability, and this decreases to nearly zero if the medication is taken with food. Some patients may have another disease, such as hyperparathyroidism, malignancy, hyperthyroidism, weight loss, malabsorption, celiac sprue, or vitamin D deficiency.

If repeated biochemical tests show high bone resorption and if the bone density response is suboptimal without a secondary cause, I often switch to an intravenous form of bisphosphonate because some patients do not seem to absorb the oral doses.

If a patient has had a fracture

If a patient has had a fracture despite several years of bisphosphonate therapy, I first check for any other medical problems. The bone markers are, unfortunately, not very helpful because they increase after a fracture and stay elevated for at least 4 months.⁵⁴ If there are no contraindications, treatment with teriparatide (Forteo) is a reasonable choice. There is evidence from human biopsy studies that teriparatide can reduce the number of microcracks that were related to bisphosphonate treatment,¹³ and can increase the bone formation rate even when there has been prior bisphosphonate treatment.^55–57 Although the anabolic response is blunted, it is still there.⁵⁸

If the patient remains at high risk

A frail patient with a high risk of fracture presents a challenge, especially one who needs treatment with glucocorticoids or who still has a hip T score below −3. Many physicians are uneasy about discontinuing all osteoporosis-specific drugs, even after 5 years of successful bisphosphonate treatment. In these patients anabolic medications make the most sense. Currently, teriparatide is the only one available, but others are being developed. Bone becomes resistant to the anabolic effects of teriparatide after about 18 months, so this drug cannot be used indefinitely. What we really need are longer-lasting anabolic medicines!

If the patient has thigh pain

Finally, in patients with thigh pain, radiography of the femur should be done to check for a stress fracture. Magnetic resonance imaging or computed tomography may be needed to diagnose a hairline fracture.

If there are already radiographic changes that precede the atypical fractures, then bisphosphonates should be discontinued. In a follow-up observational study of 16 patients who already had one fracture, all four whose contralateral side showed a fracture line (the “dreaded black line”) eventually completed the fracture.⁵⁹

Another study found that five of six incomplete fractures went on to a complete fracture if not surgically stabilized with rods.⁶⁰ This is an indication for prophylactic rodding of the femur.

Teriparatide use and rodding of a femur with thickening but not a fracture line must be decided on an individual basis and should be considered more strongly in those with pain in the thigh.

Almost all the data about the safety and efficacy of bisphosphonate drugs for treating osteoporosis are from patients who took them for less than 5 years.

Reports of adverse effects with prolonged use have caused concern about the long-term safety of this class of drugs. This is particularly important because these drugs are retained in the skeleton longer than 10 years, because there are physiologic reasons why excessive bisphosphonate-induced inhibition of bone turnover could be damaging, and because many healthy postmenopausal women have been prescribed bisphosphonates in the hope of preventing fractures that are not expected to occur for 20 to 30 years.

Because information from trials is scant, opinions differ over whether bisphosphonates should be continued indefinitely. In this article, I summarize the physiologic mechanisms of these drugs, review the scant existing data about their effects beyond 5 years, and describe my approach to bisphosphonate therapy (while waiting for better evidence).

MORE THAN 4 MILLION WOMEN TAKE BISPHOSPHONATES

The first medical use of a bisphosphonate was in 1967, when a girl with myositis ossificans was given etidronate (Didronel) because it inhibited mineralization. Two years later, it was given to patients with Paget disease of bone because it was found to inhibit bone resorption.¹ Etidronate could not be given for longer than 6 months, however, because patients developed osteomalacia.

Adding a nitrogen to the molecule dramatically increased its potency and led to the second generation of bisphosphonates. Alendronate (Fosamax), the first amino-bisphosphonate, became available in 1995, It was followed by risedronate (Actonel), ibandronate (Boniva), and zoledronic acid (Reclast). These drugs are potent inhibitors of bone resorption; however, in clinical doses they do not inhibit mineralization and therefore do not cause osteomalacia.

Randomized clinical trials involving more than 30,000 patients have provided grade A evidence that these drugs reduce the incidence of fragility fractures in patients with osteoporosis.² Furthermore, observational studies have confirmed that they prevent fractures and have a good safety profile in clinical practice.

Therefore, the use of these drugs has become common. In 2008, an estimated 4 million women in the United States were taking them.³

BISPHOSPHONATES STRENGTHEN BONE BY INHIBITING RESORPTION

On a molecular level, bisphosphonates inhibit farnesyl pyrophosphate synthase, an enzyme necessary for formation of the cytoskeleton in osteoclasts. Thus, they strongly inhibit bone resorption. They do not appear to directly inhibit osteoblasts, the cells that form new bone, but they substantially decrease bone formation indirectly.⁴

To understand how inhibition of bone resorption affects bone physiology, it is necessary to appreciate the nature of bone remodeling. Bone is not like the skin, which is continually forming a new layer and sloughing off the old. Instead, bone is renewed in small units. It takes about 5 years to remodel cancellous bone and 13 years to remodel cortical bone⁵; at any one time, about 8% of the surface is being remodeled.

The first step occurs at a spot on the surface, where the osteoclasts resorb some bone to form a pit that looks like a pothole. Then a team of osteoblasts is formed and fills the pit with new bone over the next 3 to 6 months. When first formed, the new bone is mainly collagen and, like the tip of the nose, is not very stiff, but with mineral deposition the bone becomes stronger, like the bridge of the nose. The new bone gradually accumulates mineral and becomes harder and denser over the next 3 years.

When a bisphosphonate is given, the osteoclasts abruptly stop resorbing the bone, but osteoblasts continue to fill the pits that were there when the bisphosphonate was started. For the next several months, while the previous pits are being filled, the bone volume increases slightly. Thereafter, rates of both bone resorption and bone formation are very low.

A misconception: Bisphosphonates build bone

While semantically it is true that the bone formation rate in patients taking bisphosphonates is within the normal premenopausal range, this often-repeated statement is essentially misleading.

Copyright Susan Ott, used with permission

The most direct measurement of bone formation is the percentage of bone surface that takes a tetracycline label, termed the mineralizing surface. Figure 1 shows data on the mineralizing surface in normal persons,⁶ women with osteoporosis, and women taking various other medications for osteoporosis. Bisphosphonate therapy reduces bone formation to values that are lower than in the great majority of normal young women.⁷ A study of 50 women treated with bisphosphonates for 6.5 years found that 33% had a mineralizing surface of zero.⁸ This means that patients taking bisphosphonates are forming very little new bone, and one-third of them are not forming any new bone.

With continued bisphosphonate use, the bone gradually becomes more dense. There is no further new bone, but the existing bone matrix is packed more tightly with mineral crystals.⁹ The old bone is not resorbed. The bone density, measured radiographically, increases most rapidly during the first 6 months (while resorption pits are filling in) and more gradually over the next 3 years (while bone is becoming more mineralized).

Another common misunderstanding is that the bone density increases because the drugs are “building bone.” After 3 years, the bone density in the femur reaches a plateau.¹⁰ I have seen patients who were very worried because their bone density was no longer increasing, and their physicians did not realize that this is the expected pattern. The spinal bone density continues to increase modestly, but some of this may be from disk space narrowing, harder bone edges, and soft-tissue calcifications. Spinal bone density frequently increases even in those on placebo.

 

 

Bisphosphonates suppress markers of bone turnover

These changes in bone remodeling with bisphosphonates are reflected by changes in markers of bone formation and resorption. The levels of markers of bone resorption—N-telopeptide cross-linked type I collagen (NTx) and C-telopeptide cross-linked type I collagen (CTx)—decrease rapidly and remain low. The markers of bone formation—propeptide of type I collagen, bone alkaline phosphatase, and osteocalcin—decrease gradually over 3 to 6 months and then remain low. As measured directly at the bone, bone formation appears to be more suppressed than as measured by biochemical markers in the serum.

In a risedronate trial,¹¹ the fracture rate decreased as the biochemical markers of bone turnover decreased, except when the markers were very low, in which case the fracture rate increased.

Without remodeling, cracks can accumulate

The bisphosphonates do not significantly increase bone volume, but they prevent microscopic architectural deterioration of the bone, as shown on microscopic computed tomographic imaging.¹² This prevents fractures for at least 5 years.

But bisphosphonates may have long-term negative effects. One purpose of bone remodeling is to refresh the bone and to repair the microscopic damage that accumulates within any structure. Without remodeling, cracks can accumulate. Because the development and repair of microcracks is complex, it is difficult to predict what will happen with long-term bisphosphonate use. Studies of biopsies from women taking bisphosphonates long-term are inconsistent: one study found accumulation of microcracks,¹³ but another did not.⁸

STUDIES OF LONG-TERM USE: FOCUS ON FRACTURES

For this review, I consider long-term bisphosphonate use to be greater than 5 years, and I will focus on fractures. Bone density is only a surrogate end point. Unfortunately, this fact is often not emphasized in the training of young physicians.

The best illustration of this point was in a randomized clinical trial of fluoride,¹⁴ in which the bone density of the treated group increased by 8% per year for 4 years, for a total increase of 32%. This is more than we ever see with current therapies. But the patients had more fractures with fluoride than with placebo. This is because the quality of bone produced after fluoride treatment is poor, and although the bone is denser, it is weaker.

Observational studies of fracture incidence in patients who continued taking bisphosphonates compared with those who stopped provide some weak evidence about long-term effectiveness.

Curtis et al¹⁵ found, in 9,063 women who were prescribed bisphosphonates, that those who stopped taking them during the first 2 years had higher rates of hip fracture than compliant patients. Those who took bisphosphonates for 3 years and then stopped had a rate of hip fracture during the next year similar to that of those who continued taking the drugs.

Meijer et al¹⁶ used a database in the Netherlands to examine the fracture rates in 14,750 women who started taking a bisphosphonate for osteoporosis between 1996 and 2004. More than half of the women stopped taking the drug during the first year, and they served as the control group. Those who took bisphosphonates for 3 to 4 years had significantly fewer fractures than those who stopped during the first year (odds ratio 0.54). However, those who took them for 5 to 6 years had slightly more fractures than those who took them for less than a year.

Mellström et al¹⁷ performed a 2-year uncontrolled extension of a 5-year trial of risedronate that had blinded controls.¹⁸ Initially, 407 women were in the risedronate group; 68 completed 7 years.

The vertebral fracture rate in the placebo group was 7.6% per year during years 0 through 3. In the risedronate group, the rate was 4.7% per year during years 0 through 3 and 3.8% per year during years 6 and 7. Nonvertebral fractures occurred in 10.9% of risedronate-treated patients during the first 3 years and in 6% during the last 2 years. Markers of bone turnover remained reduced throughout the 7 years. Bone mineral density of the spine and hip did not change from years 5 to 7. The study did not include those who took risedronate for 5 years and then discontinued it.

Bone et al¹⁹ performed a similar, 10-year uncontrolled extension of a 3-year controlled trial of alendronate.²⁰ There were 398 patients randomly assigned to alendronate, and 164 remained in the study for 8 to 10 years.

During years 8 through 10, bone mineral density of the spine increased by about 2%; no change was seen in the hip or total body. The nonvertebral fracture rate was similar in years 0 through 3 and years 6 through 10. Vertebral fractures occurred in approximately 3% of women in the first 3 years and in 9% in the last 5 years.

The FLEX trial: Continuing alendronate vs stopping

Only one study compared continuing a bisphosphonate vs stopping it. The Fracture Intervention Trial Long-Term Extension (FLEX)¹⁰ was an extension of the Fracture Intervention Trial (FIT)^21,22 of alendronate. I am reviewing this study in detail because it is the only one that randomized patients and was double-blinded.

In the original trial,^21,22 3,236 women were in the alendronate group. After a mean of 5 years on alendronate, 1,099 of them were randomized into the alendronate or placebo group.¹⁰ Those with T scores lower than −3.5 or who had lost bone density during the first 5 years were excluded.

The bone mineral density of the hip in the placebo group decreased by 3.4%, whereas in the alendronate group it decreased by 1.0%. At the spine, the placebo group gained less than the alendronate group.

Despite these differences in bone density, no significant difference was noted in the rates of all clinical fractures, nonvertebral fractures, vertebral fractures as measured on radiographs taken for the study (“morphometric” fractures, 11.3% vs 9.8%), or in the number of severe vertebral fractures (those with more than a two-grade change on radiography) between those who took alendronate for 10 years and those who took it for 5 years followed by placebo for 5 years.

However, fewer “clinical spine fractures” were observed in the group continuing alendronate (2.4% vs 5.3%). A clinical spine fracture was one diagnosed by the patient’s personal physician.

In FIT, these clinical fractures were painful in 90% of patients, and although the community radiographs were reviewed by a central radiologist, only 73% of the fractures were confirmed by subsequent measurements on the per protocol radiographs done at the study centers. About one-fourth of the morphometric fractures were also clinical fractures.²³ Therefore, I think morphometric fractures provide the best evidence about the effects of treatment—ie, that treatment beyond 5 years is not beneficial. Other physicians, however, disagree, emphasizing the 55% reduction in clinical fractures.²⁴

Markers of bone turnover gradually increased after discontinuation but remained lower than baseline even after 5 years without alendronate.¹⁰ There were no significant differences in fracture rates between the placebo and alendronate groups in those with baseline bone mineral density T scores less than −2.5.¹⁰ Also, after age adjustment, the fracture incidence was similar in the FIT and the FLEX studies.

Several years later, the authors published a post hoc subgroup analysis of these data.²⁵ The patients were divided into six subgroups based on bone density and the presence of vertebral fractures at baseline. This is weak evidence, but I include it because reviews in the literature have emphasized only the positive findings, or have misquoted the data: Schwartz et al stated that in those with T scores of −2.5 or below, the risk of nonvertebral fracture was reduced by 50%²⁵; and Shane²⁶ concluded in an editorial that the use of alendronate for 10 years, rather than for 5 years, was associated with significantly fewer new vertebral fractures and nonvertebral fractures in patients with a bone mineral density T score of −2.5 or below.²⁶

Data from Schwartz AV, et al; FLEX Research Group. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX Trial. J Bone Miner Res 2010; 25:976–982.

What was actually seen in the FLEX study was no difference between alendronate and placebo in morphometric vertebral fractures in any subgroup. In one of the six subgroups (N = 184), women with osteoporosis without vertebral fractures had fewer nonvertebral fractures with alendronate. There was no benefit with alendronate in the other five subgroups (Figure 2), not even in those with the greatest risk—women with osteoporosis who had a vertebral compression fracture, shown in the first three columns of Figure 2.²⁵ Nevertheless, several recent papers about this topic have recommended that bisphosphonates should be used continuously for 10 years in those with the highest fracture risk.^24,27–29

 

ATYPICAL FEMUR FRACTURES

Bush LA, Chew FS. Subtrochanteric femoral insufficiency fracture in woman on bisphosphonate therapy for glucocorticoid-induced osteoporosis. Radiology Case Reports (online) 2009; 4:261.

Recent reports, initially met with skepticism, have described atypical fractures of the femur in patients who have been taking bisphosphonates long-term (Figure 3).^28–30

By March 2011, there were 55 papers describing a total of 283 cases, and about 85 individual cases (listed online in Ott SM. Osteoporosis and Bone Physiology. http://courses.washington.edu/bonephys/opsubtroch.html. Accessed 7/30/2011).

The mean age of the patients was 65, bisphosphonate use was longer than 5 years in 77% of cases, and bilateral fractures were seen in 48%.

The fractures occur with minor trauma, such as tripping, stepping off an elevator, or being jolted by a subway stop, and a disproportionate number of cases involve no trauma. They are often preceded by leg pain, typically in the mid-thigh.

These fractures are characterized by radiographic findings of a transverse fracture, with thickened cortices near the site of the fracture. Often, there is a peak on the cortex that may precede the fracture. These fractures initiate on the lateral side, and it is striking that they occur in the same horizontal plane on the contralateral side.

Radiographs and bone scans show stress fractures on the lateral side of the femur that resemble Looser zones (ie, dark lines seen radiographically). These radiographic features are not typical in osteoporosis but are reminiscent of the stress fractures seen with hypophosphatasia, an inherited disease characterized by severely decreased bone formation.³¹

Bone biopsy specimens show very low bone formation rates, but this is not a necessary feature. At the fracture site itself there is bone activity. For example, pathologists from St. Louis reviewed all iliac crest bone biopsies from patients seen between 2004 and 2007 who had an unusual cortical fracture while taking a bisphosphonate. An absence of double tetracycline labels was seen in 11 of the 16 patients.³²

The first reports were anecdotal cases, then some centers reported systematic surveys of their patients. In a key report, Neviaser et al³³ reviewed all low-trauma subtrochanteric fractures in their large hospital and found 20 cases with the atypical radiographic appearance; 19 of the patients in these cases had been taking a bisphosphonate. A similar survey in Australia found 41 cases with atypical radiographic features (out of 79 subtrochanteric low-trauma fractures), and all of the patients had been taking a bisphosphonate.³⁴

By now, more than 230 cases have been reported. The estimated incidence is 1 in 1,000, based on a review of operative cases and radiographs.³⁵

However, just because the drugs are associated with the fractures does not mean they caused the fractures, because the patients who took bisphosphonates were more likely to get a fracture in the first place. This confounding by indication makes it difficult to prove beyond a doubt that bisphosphonates cause atypical fractures.

Further, some studies have found no association between bisphosphonates and subtrochanteric fractures.^36,37 These database analyses have relied on the coding of the International Classification of Diseases, Ninth Revision (ICD-9), and not on the examination of radiographs. We reviewed the ability of ICD-9 codes to identify subtrochanteric fractures and found that the predictive ability was only 36%.³⁸ Even for fractures in the correct location, the codes cannot tell which cases have the typical spiral or comminuted fractures seen in osteoporosis and which have the unusual features of the bisphosphonate-associated fractures. Subtrochanteric and shaft fractures are about 10 times less common than hip fractures, and the atypical ones are about 10 times less common than typical ones, so studies based on ICD-9 codes cannot exonerate bisphosphonates.

A report of nearly 15,000 patients from randomized clinical trials did not find a significant incidence of subtrochanteric fractures, but the radiographs were not examined and only 500 of the patients had taken the medication for longer than 5 years.³⁹

A population-based, nested case-control study using a database from Ontario, Canada, found an increased risk of diaphyseal femoral fractures in patients who had taken bisphosphonates longer than 5 years. The study included only women who had started bisphosphonates when they were older than 68, so many of the atypical fractures would have been missed. The investigators did not review the radiographs, so they combined both osteoporotic and atypical diaphyseal fractures in their analysis.⁴⁰

At the 2010 meeting of the American Society for Bone and Mineral Research, preliminary data were presented from a systematic review of radiographs of patients with fractures of the femur from a health care plan with data about the use of medications. The incidence of atypical fractures increased progressively with the duration of bisphosphonate use, and was significantly higher after 5 years compared with less than 3 years.²⁸

OTHER POSSIBLE ADVERSE EFFECTS

There have been conflicting reports about esophageal cancer with bisphosphonate use.^41,42

Another possible adverse effect, osteonecrosis of the jaw, may have occurred in 1.4% of patients with cancer who were treated for 3 years with high intravenous doses of bisphosphonates (about 10 to 12 times the doses recommended for osteoporosis).⁴³ This adverse effect is rare in patients with osteoporosis, occurring in less than 1 in 10,000 exposed patients.⁴⁴

 

BISPHOSPHONATES SHOULD BE USED WHEN THEY ARE INDICATED

The focus of this paper is on the duration of use, but concern about long-term use should not discourage physicians or patients from using these drugs when there is a high risk of an osteoporotic fracture within the next 10 years, particularly in elderly patients who have experienced a vertebral compression fracture or a hip fracture. Patients with a vertebral fracture have a one-in-five chance of fracturing another vertebra, which is a far higher risk than any of the known long-term side effects from treatment, and bisphosphonates are effective at reducing the risk.

Low bone density alone can be used as an indication for bisphosphonates if the hip T score is lower than −2.5. A cost-effectiveness study concluded that alendronate was beneficial in these cases.⁴⁵ In the FIT patients without a vertebral fracture at baseline, the overall fracture rate was significantly decreased by 36% with alendronate in those with a hip T score lower than −2.5, but there was no difference between placebo and alendronate in those with T scores between −2 and −2.5, and a 14% (nonsignificant) higher fracture rate when the T score was better than −2.0.²²

A new method of calculating the risk of an osteoporotic fracture is the FRAX prediction tool (http://www.shef.ac.uk/FRAX), and one group has suggested that treatment is indicated when the 10-year risk of a hip fracture is greater than 3%.⁴⁶ Another group, from the United Kingdom, suggests using a sliding scale depending on the fracture risk and the age.⁴⁷

It is not always clear what to do when the hip fracture risk is greater than 3% for the next decade but the T score is better than −2.5. These patients have other factors that contribute to fracture risk. Their therapy must be individualized, and if they are at risk of fracture because of low weight, smoking, or alcohol use, it makes more sense to focus the approach on those treatable factors.

Women who have osteopenia and have not had a fragility fracture are often treated with bisphosphonates with the intent of preventing osteoporosis in the distant future. This approach is based on hope, not evidence, and several editorial reviews have concluded that these women do not need drug therapy.^48–50

MY RECOMMENDATION: STOP AFTER 5 YEARS

Bisphosphonates reduce the incidence of devastating osteoporotic fractures in patients with osteoporosis, but that does not mean they should be used indefinitely.

After 5 years, the overall fracture risk is the same in patients who keep taking bisphosphonates as in patients who discontinue them. Therefore, I think these drugs are no longer necessary after 5 years. The post hoc subgroup analysis that showed benefit in only one of six groups of the FLEX study does not provide compelling evidence to continue taking bisphosphonates.

In addition, there is a physiologic concern about long-term suppression of bone formation. Ideally, we would treat all high-risk patients with drugs that stop bone resorption and also improve bone formation, but such drugs belong to the future. Currently, there is some emerging evidence of harm after 5 years of bisphosphonate treatment; to date the incidence of serious side effects is less than 1 in 1,000, but the risks beyond 10 years are unknown. If we are uncertain about long-term safety, we should follow the principle of primum non nocere. Only further investigations will settle the debate about prolonged use.

While awaiting better studies, we use the approach shown in the algorithm in Figure 4.

Follow the patient with bone resorption markers

In patients who have shown some improvement in bone density during 5 years of bisphosphonate treatment and who have not had any fractures, I measure a marker of bone resorption at the end of 5 years.

The use of a biochemical marker to assess patients treated with anti-turnover drugs has not been studied in a formal trial, so we have no grade A evidence for recommending it. However, there have been many papers describing the effects of bisphosphonates on these markers, and it makes physiologic sense to use them in situations where decisions must be made when there is not enough evidence.

In FIT (a trial of alendronate), we reported that the change in bone turnover markers was significantly related to the reduction in fracture risk, and the effect was at least as strong as that observed with a 1-year change in bone density. Those with a 30% decrease in bone alkaline phosphatase had a significant reduction in fracture risk.⁵¹

Furthermore, in those patients who were compliant with bisphosphonate treatment, the reduction in fractures with alendronate treatment was significantly better in those who initially had a high bone turnover.⁵²

Similarly, with risedronate, the change in NTx accounted for half of the effect on fracture reduction during the clinical trial, and there was little further improvement in fracture benefit below a decrease of 35% to 40%.¹⁰

The baseline NTx level in these clinical trials was about 70 nmol bone collagen equivalents per millimole of creatinine (nmol BCE/mmol Cr) in the risedronate study and 60 in the alendronate study, and in both the fracture reduction was seen at a level of about 40. The FLEX study measured NTx after 5 years, and the average was 19 nmol BCE/mmol Cr. This increased to 22 after 3 years without alendronate.⁵³ At 5 years, the turnover markers had gradually increased but were still 7% to 24% lower than baseline.¹⁰

These markers have a diurnal rhythm and daily variation, but despite these limitations they do help identify low bone resorption.

In our hospital, NTx is the most economical marker, and my patients prefer a urine sample to a blood test. Therefore, we measure the NTx and consider values lower than 40 nmol BCE/mmol Cr to be satisfactory.

If the NTx is as low as expected, I discontinue the bisphosphonate. The patient remains on 1,200 mg/day of calcium and 1,000 U/day vitamin D supplementation and is encouraged to exercise.

Bone density tends to be stable for 1 or 2 years after stopping a bisphosphonate, and the biochemical markers of bone resorption remain reduced for several years. We remeasure the urine NTx level annually, and if it increases to more than 40 nmol BCE/mmol Cr an antiresorptive medication is given: either the bisphosphonate is restarted or raloxifene (Evista), calcitonin (Miacalcin), or denosumab (Prolia) is used.

 

 

Bone density is less helpful, but reassuring

Bone density is less helpful because it decreases even though the markers of bone resorption remain low. Although one could argue that bone density is not helpful in monitoring patients on therapy, I think it is reassuring to know the patient is not excessively losing bone.

Checking at 2-year intervals is reasonable. If the bone density shows a consistent decrease greater than 6% (which is greater than the difference we can see from patients walking around the room), then we would re-evaluate the patient and consider adding another medication.

If the bone density decreases but the biomarkers are low, then clinical judgment must be used. The bone density result may be erroneous due to different positioning or different regions of interest.

If turnover markers are not reduced

If a patient has been prescribed a bisphosphonate for 5 years but the NTx level is not reduced, I reevaluate the patient. Some are not taking the medication or are not taking it properly. The absorption of oral bisphosphonates is quite low in terms of bioavailability, and this decreases to nearly zero if the medication is taken with food. Some patients may have another disease, such as hyperparathyroidism, malignancy, hyperthyroidism, weight loss, malabsorption, celiac sprue, or vitamin D deficiency.

If repeated biochemical tests show high bone resorption and if the bone density response is suboptimal without a secondary cause, I often switch to an intravenous form of bisphosphonate because some patients do not seem to absorb the oral doses.

If a patient has had a fracture

If a patient has had a fracture despite several years of bisphosphonate therapy, I first check for any other medical problems. The bone markers are, unfortunately, not very helpful because they increase after a fracture and stay elevated for at least 4 months.⁵⁴ If there are no contraindications, treatment with teriparatide (Forteo) is a reasonable choice. There is evidence from human biopsy studies that teriparatide can reduce the number of microcracks that were related to bisphosphonate treatment,¹³ and can increase the bone formation rate even when there has been prior bisphosphonate treatment.^55–57 Although the anabolic response is blunted, it is still there.⁵⁸

If the patient remains at high risk

A frail patient with a high risk of fracture presents a challenge, especially one who needs treatment with glucocorticoids or who still has a hip T score below −3. Many physicians are uneasy about discontinuing all osteoporosis-specific drugs, even after 5 years of successful bisphosphonate treatment. In these patients anabolic medications make the most sense. Currently, teriparatide is the only one available, but others are being developed. Bone becomes resistant to the anabolic effects of teriparatide after about 18 months, so this drug cannot be used indefinitely. What we really need are longer-lasting anabolic medicines!

If the patient has thigh pain

Finally, in patients with thigh pain, radiography of the femur should be done to check for a stress fracture. Magnetic resonance imaging or computed tomography may be needed to diagnose a hairline fracture.

If there are already radiographic changes that precede the atypical fractures, then bisphosphonates should be discontinued. In a follow-up observational study of 16 patients who already had one fracture, all four whose contralateral side showed a fracture line (the “dreaded black line”) eventually completed the fracture.⁵⁹

Another study found that five of six incomplete fractures went on to a complete fracture if not surgically stabilized with rods.⁶⁰ This is an indication for prophylactic rodding of the femur.

Teriparatide use and rodding of a femur with thickening but not a fracture line must be decided on an individual basis and should be considered more strongly in those with pain in the thigh.

In the past half-century, vancomycin has gone from near-orphan status to being one of the most often used antibiotics in our formulary. The driving force for its use is clear: the evolution of Staphylococcus aureus. At first, vancomycin was used to treat infections caused by penicillin-resistant strains. However, the discovery of methicillin curbed its use for more than 2 decades.¹

Then, as methicillin-resistant S aureus (MRSA) began to spread in the 1980s, the use of vancomycin began to increase, and with the rise in community-associated MRSA infections in the 1990s, it became even more widely prescribed. The recent Infectious Diseases Society of America (IDSA) guidelines for treatment of infections due to MRSA are replete with references to the use of vancomycin.²

Another factor driving the use of vancomycin is the increased prevalence of device-associated infections, many of which are caused by coagulase-negative staphylococci and other organisms that colonize the skin.³ Many of these bacteria are susceptible only to vancomycin; they may be associated with infections of vascular catheters, cardiac valves, pacemakers, implantable cardioverter-defibrillators, orthopedic implants, neurosurgical devices, and other devices.

To use vancomycin appropriately, we need to recognize the changing minimum inhibitory concentrations (MICs), to select proper doses and dosing intervals, and to know how to monitor its use. Despite more than 50 years of experience with vancomycin, we sometimes find ourselves with more questions than answers about its optimal use.

WHAT IS VANCOMYCIN?

Vancomycin is a glycopeptide antibiotic isolated from a strain of Streptomyces orientalis discovered in a soil sample from Borneo in the mid-1950s.¹ It exerts its action by binding to a d-alanyl-d-alanine cell wall precursor necessary for peptidoglycan cross-linking and, therefore, for inhibiting bacterial cell wall synthesis.

Vancomycin is bactericidal against most gram-positive species, including streptococci and staphylococci, with the exception of Enterococcus species, for which it is bacteriostatic. Though it is bactericidal, it appears to kill bacteria more slowly than beta-lactam antibiotics, and therefore it may take longer to clear bacteremia.⁴

WHAT IS THE BEST WAY TO DOSE VANCOMYCIN?

Vancomycin is widely distributed to most tissues, with an approximate volume of distribution of 0.4 to 1 L/kg; 50% to 55% is protein-bound. Because of this large volume of distribution, vancomycin’s dosing is based on actual body weight.

Vancomycin is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. It therefore requires dosage adjustments for renal insufficiency.

Vancomycin’s molecular weight is 1,485.73 Da, making it less susceptible to removal by dialysis than smaller molecules. Dosing of vancomycin in patients on hemodialysis depends on many factors specific to the dialysis center, including but not limited to the type of filter used, the duration of filtration, and whether high-flux filtration is used.

Is continuous intravenous infusion better than standard dosing?

Giving vancomycin by continuous infusion has been suggested as a way to optimize its serum concentration and improve its clinical effectiveness.

Wysocki et al⁵ conducted a multicenter, prospective, randomized study comparing continuous and intermittent intravenous infusions of vancomycin (the latter every 12 hours) to treat severe hospital-acquired MRSA infections, including bloodstream infections and pneumonia. Although blood concentrations above 10 μg/mL were reached more than 30 hours faster with continuous infusions than with intermittent ones, the microbiologic and clinical outcomes were similar with either method.

James et al⁶ compared the pharmacodynamics of conventional dosing of vancomycin (ie, 1 g every 12 hours) and continuous infusion in 10 patients with suspected or documented gram-positive infections in a prospective, randomized, crossover study. While no adverse effects were observed, the authors also found no statistically significant difference between the treatment groups in the pharmacodynamic variables investigated, including the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio).

In view of the currently available data, the guidelines for monitoring vancomycin therapy note that there does not appear to be any difference in patient outcomes with continuous infusion vs intermittent dosing.⁷

Should a loading dose be given?

Another proposed strategy for optimizing vancomycin’s effectiveness is to give a higher initial dose, ie, a loading dose.

Wang et al⁸ performed a single-center study in 28 patients who received a 25 mg/kg loading dose at a rate of 500 mg/hour. This loading dose was safe, but the authors did not evaluate its efficacy.

Mohammedi et al⁹ compared loading doses of 500 mg and 15 mg/kg in critically ill patients receiving vancomycin by continuous infusion. The weight-based loading dose produced higher post-dose levels and a significantly higher rate of clinical cure, but there was no significant difference in the rate of survival to discharge from the intensive care unit.

While the use of a loading dose appears to be safe and likely leads to more rapid attainment of therapeutic blood levels, we lack data on whether it improves clinical outcomes, and further study is needed to determine its role.

 

WHAT IS THE BEST WAY TO MONITOR VANCOMYCIN THERAPY?

Whether and how to use the serum vancomycin concentration to adjust the dosing has been a matter of debate for many years. Convincing evidence that vancomycin levels predict clinical outcomes or that measuring them prevents toxicity is lacking.⁷

A consensus statement from the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists⁷ contains recommendations for monitoring vancomycin therapy, based on a critical evaluation of the available scientific evidence. Their recommendations:

• Vancomycin serum concentrations should be checked to optimize therapy and used as a surrogate marker of effectiveness.
• Trough, rather than peak, levels should be monitored.
• Trough levels should be checked just before the fourth dose, when steady-state levels are likely to have been achieved. More frequent monitoring may be considered in patients with fluctuating renal function.
• Trough levels should be higher than 10 mg/L to prevent the development of resistance.
• To improve antibiotic penetration and optimize the likelihood of achieving pharmacokinetic and pharmacodynamic targets, trough levels of 15 to 20 mg/L are recommended for pathogens with a vancomycin MIC of 1 mg/L or higher and for complicated infections such as endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia.
• For prolonged courses, it is appropriate to check vancomycin levels weekly in hemodynamically stable patients and more often in those who are not hemodynamically stable.

IS VANCOMYCIN NEPHROTOXIC?

In the 1950s, vancomycin formulations were sometimes called “Mississippi mud” because of the many impurities they contained.¹ These impurities were associated with significant nephrotoxicity. Better purification methods used in the manufacture of current formulations mitigate this problem, resulting in a lower incidence of nephrotoxicity.

Over the last several years, organizations such as the American Thoracic Society and the IDSA have recommended targeting higher vancomycin trough concentrations.¹⁰ The consequent widespread use of higher doses has renewed interest in vancomycin’s potential nephrotoxicity.

Lodise et al,¹¹ in a cohort study, examined the incidence of nephrotoxicity with higher daily doses of vancomycin (≥ 4 g/day), lower daily doses (< 4 g/day), and linezolid (Zyvox). They defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/dL or a decrease in calculated creatinine clearance of 50% from baseline on 2 consecutive days.

The incidence of nephrotoxicity was significantly higher in the high-dose vancomycin group (34.6%) than in the low-dose vancomycin group (10.9%) and in the linezolid group (6.7%) (P = .001). Additional factors associated with nephrotoxicity in this study included baseline creatinine clearance less than 86.6 mL/minute, weight greater than 101.4 kg (223.5 lb), and being in an intensive care unit.

Hidayat et al¹² investigated outcomes in patients with high vs low vancomycin trough levels (≥ 15 mg/L vs < 15 mg/L) in a prospective cohort study. Sixty-three patients achieved an average vancomycin trough of 15 to 20 mg/L, and of these, 11 developed nephrotoxicity, compared with no patients in the low-trough group (P = .01). Of the 11 who developed nephrotoxicity, 10 were concomitantly taking other potentially nephrotoxic agents.

Comment. The data on vancomycin and nephrotoxicity are mostly from studies that had limitations such as small numbers of patients, retrospective design, and variable definitions of nephrotoxicity. Many of the patients in these studies had additional factors contributing to nephrotoxicity, including hemodynamic instability and concomitant exposure to other nephrotoxins. Additionally, the sequence of events (nephrotoxicity leading to elevated vancomycin levels vs elevated vancomycin levels causing nephrotoxicity) is still debatable.

The incidence of nephrotoxicity associated with vancomycin therapy is difficult to determine. However, based on current information, the incidence of nephrotoxicity appears to be low when vancomycin is used as monotherapy.

IS S AUREUS BECOMING RESISTANT TO VANCOMYCIN?

An issue of increasing importance in health care settings is the emergence of vancomycin-intermediate S aureus (VISA) and vancomycin-resistant S aureus (VRSA). Eleven cases of VRSA were identified in the United States from 2002 to 2005.¹³ All cases of VRSA in the United States have involved the incorporation of enterococcal vanA cassette into the S aureus genome.¹⁴ While true VRSA isolates remain rare, VISA isolates are becoming more common.

Heteroresistant VISA: An emerging subpopulation of MRSA

Another population of S aureus that has emerged is heteroresistant vancomycin-intermediate S aureus (hVISA). It is defined as the presence of subpopulations of VISA within a population of MRSA at a rate of one organism per 10⁵ to 10⁶ organisms. With traditional testing methods, the vancomycin MIC for the entire population of the strain is within the susceptible range.¹⁵ These hVISA populations are thought to be precursors to the development of VISA.¹⁶

The resistance to vancomycin in hVISA and VISA populations is due to increased cell wall thickness, altered penicillin-binding protein profiles, and decreased cell wall autolysis.

While the true prevalence of hVISA is difficult to predict because of challenges in microbiological detection and probably varies between geographic regions and individual institutions, different studies have reported hVISA rates between 2% and 13% of all MRSA isolates.^15–17

Reduced vancomycin susceptibility can develop regardless of methicillin susceptibility.¹⁸

While hVISA is not common, its presence is thought to be a predictor of failing vancomycin therapy.¹⁵

Factors associated with hVISA bacteremia include high-bacterial-load infections, treatment failure (including persistent bacteremia for more than 7 days), and initially low serum vancomycin levels.¹⁵

 

 

‘MIC creep’: Is it real?

Also worrisome, the average vancomycin MIC for S aureus has been shifting upward, based on reports from several institutions, although it is still within the susceptible range.^19,20 However, this “MIC creep” likely reflects, at least in part, differences in MIC testing and varying methods used to analyze the data.^19,20

Holmes and Jorgensen,²¹ in a single-institution study of MRSA isolates recovered from bacteremic patients from 1999 to 2006, determined that no MIC creep existed when they tested vancomycin MICs using the broth microdilution method. The authors found the MIC₉₀ (ie, the MIC in at least 90% of the isolates) remained less than 1 mg/L during each year of the study.

Sader et al,²² in a multicenter study, evaluated 1,800 MRSA bloodstream isolates from nine hospitals across the United States from 2002 to 2006. Vancomycin MICs were again measured by broth microdilution methods. The mode MIC remained stable at 0.625 mg/L during the study period, and the authors did not detect a trend of rising MICs.

The inconsistency between reports of MIC creep at single institutions and the absence of this phenomenon in large, multicenter studies seems to imply that vancomycin MIC creep is not occurring on a grand scale.

Vancomycin tolerance

Another troubling matter with S aureus and vancomycin is the issue of tolerance. Vancomycin tolerance, defined in terms of increased minimum bactericidal concentration, represents a loss of bactericidal activity. Tolerance to vancomycin can occur even if the MIC remains in the susceptible range.²³

Safdar and Rolston,²⁴ in an observational study from a cancer center, reported that of eight cases of bacteremia that was resistant to vancomycin therapy, three were caused by S aureus.

Sakoulas et al²⁵ found that higher levels of vancomycin bactericidal activity were associated with higher rates of clinical success; however, they found no effect on the mortality rate.

The issue of vancomycin tolerance remains controversial, and because testing for it is impractical in clinical microbiology laboratories, its implications outside the research arena are difficult to ascertain at present.

IS VANCOMYCIN STILL THE BEST DRUG FOR S AUREUS?

MIC break points have been lowered

In 2006, the Clinical Laboratories and Standards Institute lowered its break points for vancomycin MIC categories for S aureus:

• Susceptible: ≤ 2 mg/L (formerly ≤ 4 mg/L)
• Intermediate: 4–8 mg/L (formerly 8–16 mg/L)
• Resistant: ≥ 16 mg/L (formerly ≥ 32 mg/L).

The rationales for these changes were that the lower break points would better detect hVISA, and that cases have been reported of clinical treatment failure of S aureus infections in which the MICs for vancomycin were 4 mg/L.²⁶

Since 2006, the question has been raised whether to lower the break points even further. A reason for this proposal comes from an enhanced understanding of the pharmacokinetics and pharmacodynamics of vancomycin.

The variable most closely associated with clinical response to vancomycin is the AUC-MIC ratio. An AUC-MIC ratio of 400 or higher may be associated with better outcomes in patients with serious S aureus infection. A study of 108 patients with S aureus infection of the lower respiratory tract indicated that organism eradication was more likely if the AUC-MIC ratio was 400 or greater compared with values less than 400, and this was statistically significant.²⁷ However, in cases of S aureus infection with a vancomycin MIC of 2 mg/L or higher, this ratio may not be achievable.

A prospective study of 414 MRSA bacteremia episodes found a vancomycin MIC of 2 mg/L to be a predictor of death.²⁸ The authors concluded that vancomycin may not be the optimal treatment for MRSA with a vancomycin MIC of 2 mg/L.²⁸ Additional studies have also suggested a possible decrease in response to vancomycin in MRSA isolates with elevated MICs within the susceptible range.^25,29

Recent guidelines from the IDSA recommend using the clinical response, regardless of the MIC, to guide antimicrobial selection for isolates with MICs in the susceptible range.²

Combination therapy with vancomycin

As vancomycin use has increased, therapeutic failures with vancomycin have become apparent. Combination therapy has been suggested as an option to increase the efficacy of vancomycin when treating complicated infections.

Rifampin plus vancomycin is controversial.³⁰ The combination is theoretically beneficial, especially in infections associated with prosthetic devices. However, clinical studies have failed to convincingly support its use, and some have suggested that it might prolong bacteremia. In addition, it has numerous drug interactions to consider and adverse effects.³¹

Gentamicin plus vancomycin. The evidence supporting the use of this combination is weak at best. It appears that clinicians may have extrapolated from the success reported by Korzeniowski and Sande,³² who found that methicillin-susceptible S aureus bacteremia was cleared faster if gentamicin was added to nafcillin. A more recent study³³ that compared daptomycin (Cubicin) monotherapy with combined vancomycin and gentamicin to treat MRSA bacteremia and endocarditis showed a better overall success rate with daptomycin (44% vs 32.6%), but the difference was not statistically significant.

Gentamicin has some toxicity. Even short-term use (for the first 4 days of therapy) at low doses for bacteremia and endocarditis due to staphylococci has been associated with a higher rate of renal adverse events, including a significant decrease in creatinine clearance.³⁴

Clindamycin or linezolid plus vancomycin is used to decrease toxin production by S aureus.³⁰

While combination therapy with vancomycin is recommended in specific clinical situations, and the combinations are synergistic in vitro, information is lacking about clinical outcomes to support their use.

 

 

Don’t use vancomycin when another drug would be better

Vancomycin continues to be the drug of choice in many circumstances, but in some instances its role is under scrutiny and another drug might be better.

Beta-lactams. In patients with infection due to methicillin-susceptible S aureus, failure rates are higher with vancomycin than with beta-lactam therapy, specifically nafcillin.^35–37 Beta-lactam antibiotics are thus the drugs of choice for treating infection with beta-lactam-susceptible strains of S aureus.

Linezolid. In theory, linezolid’s ability to decrease production of the S aureus Panton-Valentine leukocidin (PVL) toxin may be an advantage over vancomycin for treating necrotizing pneumonias. For the treatment of MRSA pneumonia, however, controversy exists as to whether linezolid is superior to vancomycin. An analysis of two prospective, randomized, double-blind studies of patients with MRSA pneumonia suggested that initial therapy with linezolid was associated with better survival and clinical cure rates,³⁸ but a subsequent meta-analysis did not substantiate this finding.³⁹ An additional comparative study has been completed, and analysis of the results is in progress.

Daptomycin, approved for skin and soft-tissue infections and bacteremias, including those with right-sided endocarditis, is a lipopeptide antibiotic with a spectrum of action similar to that of vancomycin.⁴⁰ Daptomycin is also active against many strains of vancomycin-resistant enterococci. As noted above, in the MRSA subgroup of the pivotal comparative study of treatment for S aureus bacteremia and endocarditis, the success rate for daptomycin-treated patients (44.4%) was better than that for patients treated with vancomycin plus gentamicin (32.6%), but the difference was not statistically significant.^33,41

The creatine phosphokinase concentration should be monitored weekly in patients on daptomycin.⁴² Daptomycin is inactivated by lung surfactant and should not be used to treat pneumonia.

Other treatment options approved by the US Food and Drug Administration (FDA) for MRSA infections include tigecycline (Tygacil), quinupristin-dalfopristin (Synercid), telavancin (Vibativ), and ceftaroline (Teflaro).

Tigecycline is a glycylcycline with bacteriostatic activity against S aureus and wide distribution to the tissues.⁴³

Quinupristin-dalfopristin, a streptogramin antibiotic, has activity against S aureus. Its use may be associated with severe myalgias, sometimes leading patients to stop taking it.

Telavancin, recently approved by the FDA, is a lipoglycopeptide antibiotic.⁴⁴ It is currently approved to treat complicated skin and skin structure infections and was found to be not inferior to vancomycin. An important side effect of this agent is nephrotoxicity. A negative pregnancy test is required before using this agent in women of childbearing potential.

Ceftaroline, a fifth-generation cephalosporin active against MRSA, has been approved by the FDA for the treatment of skin and skin structure infections and community-acquired pneumonia.⁴⁵

In the past half-century, vancomycin has gone from near-orphan status to being one of the most often used antibiotics in our formulary. The driving force for its use is clear: the evolution of Staphylococcus aureus. At first, vancomycin was used to treat infections caused by penicillin-resistant strains. However, the discovery of methicillin curbed its use for more than 2 decades.¹

Then, as methicillin-resistant S aureus (MRSA) began to spread in the 1980s, the use of vancomycin began to increase, and with the rise in community-associated MRSA infections in the 1990s, it became even more widely prescribed. The recent Infectious Diseases Society of America (IDSA) guidelines for treatment of infections due to MRSA are replete with references to the use of vancomycin.²

Another factor driving the use of vancomycin is the increased prevalence of device-associated infections, many of which are caused by coagulase-negative staphylococci and other organisms that colonize the skin.³ Many of these bacteria are susceptible only to vancomycin; they may be associated with infections of vascular catheters, cardiac valves, pacemakers, implantable cardioverter-defibrillators, orthopedic implants, neurosurgical devices, and other devices.

To use vancomycin appropriately, we need to recognize the changing minimum inhibitory concentrations (MICs), to select proper doses and dosing intervals, and to know how to monitor its use. Despite more than 50 years of experience with vancomycin, we sometimes find ourselves with more questions than answers about its optimal use.

WHAT IS VANCOMYCIN?

Vancomycin is a glycopeptide antibiotic isolated from a strain of Streptomyces orientalis discovered in a soil sample from Borneo in the mid-1950s.¹ It exerts its action by binding to a d-alanyl-d-alanine cell wall precursor necessary for peptidoglycan cross-linking and, therefore, for inhibiting bacterial cell wall synthesis.

Vancomycin is bactericidal against most gram-positive species, including streptococci and staphylococci, with the exception of Enterococcus species, for which it is bacteriostatic. Though it is bactericidal, it appears to kill bacteria more slowly than beta-lactam antibiotics, and therefore it may take longer to clear bacteremia.⁴

WHAT IS THE BEST WAY TO DOSE VANCOMYCIN?

Vancomycin is widely distributed to most tissues, with an approximate volume of distribution of 0.4 to 1 L/kg; 50% to 55% is protein-bound. Because of this large volume of distribution, vancomycin’s dosing is based on actual body weight.

Vancomycin is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. It therefore requires dosage adjustments for renal insufficiency.

Vancomycin’s molecular weight is 1,485.73 Da, making it less susceptible to removal by dialysis than smaller molecules. Dosing of vancomycin in patients on hemodialysis depends on many factors specific to the dialysis center, including but not limited to the type of filter used, the duration of filtration, and whether high-flux filtration is used.

Is continuous intravenous infusion better than standard dosing?

Giving vancomycin by continuous infusion has been suggested as a way to optimize its serum concentration and improve its clinical effectiveness.

Wysocki et al⁵ conducted a multicenter, prospective, randomized study comparing continuous and intermittent intravenous infusions of vancomycin (the latter every 12 hours) to treat severe hospital-acquired MRSA infections, including bloodstream infections and pneumonia. Although blood concentrations above 10 μg/mL were reached more than 30 hours faster with continuous infusions than with intermittent ones, the microbiologic and clinical outcomes were similar with either method.

James et al⁶ compared the pharmacodynamics of conventional dosing of vancomycin (ie, 1 g every 12 hours) and continuous infusion in 10 patients with suspected or documented gram-positive infections in a prospective, randomized, crossover study. While no adverse effects were observed, the authors also found no statistically significant difference between the treatment groups in the pharmacodynamic variables investigated, including the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio).

In view of the currently available data, the guidelines for monitoring vancomycin therapy note that there does not appear to be any difference in patient outcomes with continuous infusion vs intermittent dosing.⁷

Should a loading dose be given?

Another proposed strategy for optimizing vancomycin’s effectiveness is to give a higher initial dose, ie, a loading dose.

Wang et al⁸ performed a single-center study in 28 patients who received a 25 mg/kg loading dose at a rate of 500 mg/hour. This loading dose was safe, but the authors did not evaluate its efficacy.

Mohammedi et al⁹ compared loading doses of 500 mg and 15 mg/kg in critically ill patients receiving vancomycin by continuous infusion. The weight-based loading dose produced higher post-dose levels and a significantly higher rate of clinical cure, but there was no significant difference in the rate of survival to discharge from the intensive care unit.

While the use of a loading dose appears to be safe and likely leads to more rapid attainment of therapeutic blood levels, we lack data on whether it improves clinical outcomes, and further study is needed to determine its role.

 

WHAT IS THE BEST WAY TO MONITOR VANCOMYCIN THERAPY?

Whether and how to use the serum vancomycin concentration to adjust the dosing has been a matter of debate for many years. Convincing evidence that vancomycin levels predict clinical outcomes or that measuring them prevents toxicity is lacking.⁷

A consensus statement from the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists⁷ contains recommendations for monitoring vancomycin therapy, based on a critical evaluation of the available scientific evidence. Their recommendations:

• Vancomycin serum concentrations should be checked to optimize therapy and used as a surrogate marker of effectiveness.
• Trough, rather than peak, levels should be monitored.
• Trough levels should be checked just before the fourth dose, when steady-state levels are likely to have been achieved. More frequent monitoring may be considered in patients with fluctuating renal function.
• Trough levels should be higher than 10 mg/L to prevent the development of resistance.
• To improve antibiotic penetration and optimize the likelihood of achieving pharmacokinetic and pharmacodynamic targets, trough levels of 15 to 20 mg/L are recommended for pathogens with a vancomycin MIC of 1 mg/L or higher and for complicated infections such as endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia.
• For prolonged courses, it is appropriate to check vancomycin levels weekly in hemodynamically stable patients and more often in those who are not hemodynamically stable.

IS VANCOMYCIN NEPHROTOXIC?

In the 1950s, vancomycin formulations were sometimes called “Mississippi mud” because of the many impurities they contained.¹ These impurities were associated with significant nephrotoxicity. Better purification methods used in the manufacture of current formulations mitigate this problem, resulting in a lower incidence of nephrotoxicity.

Over the last several years, organizations such as the American Thoracic Society and the IDSA have recommended targeting higher vancomycin trough concentrations.¹⁰ The consequent widespread use of higher doses has renewed interest in vancomycin’s potential nephrotoxicity.

Lodise et al,¹¹ in a cohort study, examined the incidence of nephrotoxicity with higher daily doses of vancomycin (≥ 4 g/day), lower daily doses (< 4 g/day), and linezolid (Zyvox). They defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/dL or a decrease in calculated creatinine clearance of 50% from baseline on 2 consecutive days.

The incidence of nephrotoxicity was significantly higher in the high-dose vancomycin group (34.6%) than in the low-dose vancomycin group (10.9%) and in the linezolid group (6.7%) (P = .001). Additional factors associated with nephrotoxicity in this study included baseline creatinine clearance less than 86.6 mL/minute, weight greater than 101.4 kg (223.5 lb), and being in an intensive care unit.

Hidayat et al¹² investigated outcomes in patients with high vs low vancomycin trough levels (≥ 15 mg/L vs < 15 mg/L) in a prospective cohort study. Sixty-three patients achieved an average vancomycin trough of 15 to 20 mg/L, and of these, 11 developed nephrotoxicity, compared with no patients in the low-trough group (P = .01). Of the 11 who developed nephrotoxicity, 10 were concomitantly taking other potentially nephrotoxic agents.

Comment. The data on vancomycin and nephrotoxicity are mostly from studies that had limitations such as small numbers of patients, retrospective design, and variable definitions of nephrotoxicity. Many of the patients in these studies had additional factors contributing to nephrotoxicity, including hemodynamic instability and concomitant exposure to other nephrotoxins. Additionally, the sequence of events (nephrotoxicity leading to elevated vancomycin levels vs elevated vancomycin levels causing nephrotoxicity) is still debatable.

The incidence of nephrotoxicity associated with vancomycin therapy is difficult to determine. However, based on current information, the incidence of nephrotoxicity appears to be low when vancomycin is used as monotherapy.

IS S AUREUS BECOMING RESISTANT TO VANCOMYCIN?

An issue of increasing importance in health care settings is the emergence of vancomycin-intermediate S aureus (VISA) and vancomycin-resistant S aureus (VRSA). Eleven cases of VRSA were identified in the United States from 2002 to 2005.¹³ All cases of VRSA in the United States have involved the incorporation of enterococcal vanA cassette into the S aureus genome.¹⁴ While true VRSA isolates remain rare, VISA isolates are becoming more common.

Heteroresistant VISA: An emerging subpopulation of MRSA

Another population of S aureus that has emerged is heteroresistant vancomycin-intermediate S aureus (hVISA). It is defined as the presence of subpopulations of VISA within a population of MRSA at a rate of one organism per 10⁵ to 10⁶ organisms. With traditional testing methods, the vancomycin MIC for the entire population of the strain is within the susceptible range.¹⁵ These hVISA populations are thought to be precursors to the development of VISA.¹⁶

The resistance to vancomycin in hVISA and VISA populations is due to increased cell wall thickness, altered penicillin-binding protein profiles, and decreased cell wall autolysis.

While the true prevalence of hVISA is difficult to predict because of challenges in microbiological detection and probably varies between geographic regions and individual institutions, different studies have reported hVISA rates between 2% and 13% of all MRSA isolates.^15–17

Reduced vancomycin susceptibility can develop regardless of methicillin susceptibility.¹⁸

While hVISA is not common, its presence is thought to be a predictor of failing vancomycin therapy.¹⁵

Factors associated with hVISA bacteremia include high-bacterial-load infections, treatment failure (including persistent bacteremia for more than 7 days), and initially low serum vancomycin levels.¹⁵

 

 

‘MIC creep’: Is it real?

Also worrisome, the average vancomycin MIC for S aureus has been shifting upward, based on reports from several institutions, although it is still within the susceptible range.^19,20 However, this “MIC creep” likely reflects, at least in part, differences in MIC testing and varying methods used to analyze the data.^19,20

Holmes and Jorgensen,²¹ in a single-institution study of MRSA isolates recovered from bacteremic patients from 1999 to 2006, determined that no MIC creep existed when they tested vancomycin MICs using the broth microdilution method. The authors found the MIC₉₀ (ie, the MIC in at least 90% of the isolates) remained less than 1 mg/L during each year of the study.

Sader et al,²² in a multicenter study, evaluated 1,800 MRSA bloodstream isolates from nine hospitals across the United States from 2002 to 2006. Vancomycin MICs were again measured by broth microdilution methods. The mode MIC remained stable at 0.625 mg/L during the study period, and the authors did not detect a trend of rising MICs.

The inconsistency between reports of MIC creep at single institutions and the absence of this phenomenon in large, multicenter studies seems to imply that vancomycin MIC creep is not occurring on a grand scale.

Vancomycin tolerance

Another troubling matter with S aureus and vancomycin is the issue of tolerance. Vancomycin tolerance, defined in terms of increased minimum bactericidal concentration, represents a loss of bactericidal activity. Tolerance to vancomycin can occur even if the MIC remains in the susceptible range.²³

Safdar and Rolston,²⁴ in an observational study from a cancer center, reported that of eight cases of bacteremia that was resistant to vancomycin therapy, three were caused by S aureus.

Sakoulas et al²⁵ found that higher levels of vancomycin bactericidal activity were associated with higher rates of clinical success; however, they found no effect on the mortality rate.

The issue of vancomycin tolerance remains controversial, and because testing for it is impractical in clinical microbiology laboratories, its implications outside the research arena are difficult to ascertain at present.

IS VANCOMYCIN STILL THE BEST DRUG FOR S AUREUS?

MIC break points have been lowered

In 2006, the Clinical Laboratories and Standards Institute lowered its break points for vancomycin MIC categories for S aureus:

• Susceptible: ≤ 2 mg/L (formerly ≤ 4 mg/L)
• Intermediate: 4–8 mg/L (formerly 8–16 mg/L)
• Resistant: ≥ 16 mg/L (formerly ≥ 32 mg/L).

The rationales for these changes were that the lower break points would better detect hVISA, and that cases have been reported of clinical treatment failure of S aureus infections in which the MICs for vancomycin were 4 mg/L.²⁶

Since 2006, the question has been raised whether to lower the break points even further. A reason for this proposal comes from an enhanced understanding of the pharmacokinetics and pharmacodynamics of vancomycin.

The variable most closely associated with clinical response to vancomycin is the AUC-MIC ratio. An AUC-MIC ratio of 400 or higher may be associated with better outcomes in patients with serious S aureus infection. A study of 108 patients with S aureus infection of the lower respiratory tract indicated that organism eradication was more likely if the AUC-MIC ratio was 400 or greater compared with values less than 400, and this was statistically significant.²⁷ However, in cases of S aureus infection with a vancomycin MIC of 2 mg/L or higher, this ratio may not be achievable.

A prospective study of 414 MRSA bacteremia episodes found a vancomycin MIC of 2 mg/L to be a predictor of death.²⁸ The authors concluded that vancomycin may not be the optimal treatment for MRSA with a vancomycin MIC of 2 mg/L.²⁸ Additional studies have also suggested a possible decrease in response to vancomycin in MRSA isolates with elevated MICs within the susceptible range.^25,29

Recent guidelines from the IDSA recommend using the clinical response, regardless of the MIC, to guide antimicrobial selection for isolates with MICs in the susceptible range.²

Combination therapy with vancomycin

As vancomycin use has increased, therapeutic failures with vancomycin have become apparent. Combination therapy has been suggested as an option to increase the efficacy of vancomycin when treating complicated infections.

Rifampin plus vancomycin is controversial.³⁰ The combination is theoretically beneficial, especially in infections associated with prosthetic devices. However, clinical studies have failed to convincingly support its use, and some have suggested that it might prolong bacteremia. In addition, it has numerous drug interactions to consider and adverse effects.³¹

Gentamicin plus vancomycin. The evidence supporting the use of this combination is weak at best. It appears that clinicians may have extrapolated from the success reported by Korzeniowski and Sande,³² who found that methicillin-susceptible S aureus bacteremia was cleared faster if gentamicin was added to nafcillin. A more recent study³³ that compared daptomycin (Cubicin) monotherapy with combined vancomycin and gentamicin to treat MRSA bacteremia and endocarditis showed a better overall success rate with daptomycin (44% vs 32.6%), but the difference was not statistically significant.

Gentamicin has some toxicity. Even short-term use (for the first 4 days of therapy) at low doses for bacteremia and endocarditis due to staphylococci has been associated with a higher rate of renal adverse events, including a significant decrease in creatinine clearance.³⁴

Clindamycin or linezolid plus vancomycin is used to decrease toxin production by S aureus.³⁰

While combination therapy with vancomycin is recommended in specific clinical situations, and the combinations are synergistic in vitro, information is lacking about clinical outcomes to support their use.

 

 

Don’t use vancomycin when another drug would be better

Vancomycin continues to be the drug of choice in many circumstances, but in some instances its role is under scrutiny and another drug might be better.

Beta-lactams. In patients with infection due to methicillin-susceptible S aureus, failure rates are higher with vancomycin than with beta-lactam therapy, specifically nafcillin.^35–37 Beta-lactam antibiotics are thus the drugs of choice for treating infection with beta-lactam-susceptible strains of S aureus.

Linezolid. In theory, linezolid’s ability to decrease production of the S aureus Panton-Valentine leukocidin (PVL) toxin may be an advantage over vancomycin for treating necrotizing pneumonias. For the treatment of MRSA pneumonia, however, controversy exists as to whether linezolid is superior to vancomycin. An analysis of two prospective, randomized, double-blind studies of patients with MRSA pneumonia suggested that initial therapy with linezolid was associated with better survival and clinical cure rates,³⁸ but a subsequent meta-analysis did not substantiate this finding.³⁹ An additional comparative study has been completed, and analysis of the results is in progress.

Daptomycin, approved for skin and soft-tissue infections and bacteremias, including those with right-sided endocarditis, is a lipopeptide antibiotic with a spectrum of action similar to that of vancomycin.⁴⁰ Daptomycin is also active against many strains of vancomycin-resistant enterococci. As noted above, in the MRSA subgroup of the pivotal comparative study of treatment for S aureus bacteremia and endocarditis, the success rate for daptomycin-treated patients (44.4%) was better than that for patients treated with vancomycin plus gentamicin (32.6%), but the difference was not statistically significant.^33,41

The creatine phosphokinase concentration should be monitored weekly in patients on daptomycin.⁴² Daptomycin is inactivated by lung surfactant and should not be used to treat pneumonia.

Other treatment options approved by the US Food and Drug Administration (FDA) for MRSA infections include tigecycline (Tygacil), quinupristin-dalfopristin (Synercid), telavancin (Vibativ), and ceftaroline (Teflaro).

Tigecycline is a glycylcycline with bacteriostatic activity against S aureus and wide distribution to the tissues.⁴³

Quinupristin-dalfopristin, a streptogramin antibiotic, has activity against S aureus. Its use may be associated with severe myalgias, sometimes leading patients to stop taking it.

Telavancin, recently approved by the FDA, is a lipoglycopeptide antibiotic.⁴⁴ It is currently approved to treat complicated skin and skin structure infections and was found to be not inferior to vancomycin. An important side effect of this agent is nephrotoxicity. A negative pregnancy test is required before using this agent in women of childbearing potential.

Ceftaroline, a fifth-generation cephalosporin active against MRSA, has been approved by the FDA for the treatment of skin and skin structure infections and community-acquired pneumonia.⁴⁵

In the past half-century, vancomycin has gone from near-orphan status to being one of the most often used antibiotics in our formulary. The driving force for its use is clear: the evolution of Staphylococcus aureus. At first, vancomycin was used to treat infections caused by penicillin-resistant strains. However, the discovery of methicillin curbed its use for more than 2 decades.¹

Then, as methicillin-resistant S aureus (MRSA) began to spread in the 1980s, the use of vancomycin began to increase, and with the rise in community-associated MRSA infections in the 1990s, it became even more widely prescribed. The recent Infectious Diseases Society of America (IDSA) guidelines for treatment of infections due to MRSA are replete with references to the use of vancomycin.²

Another factor driving the use of vancomycin is the increased prevalence of device-associated infections, many of which are caused by coagulase-negative staphylococci and other organisms that colonize the skin.³ Many of these bacteria are susceptible only to vancomycin; they may be associated with infections of vascular catheters, cardiac valves, pacemakers, implantable cardioverter-defibrillators, orthopedic implants, neurosurgical devices, and other devices.

To use vancomycin appropriately, we need to recognize the changing minimum inhibitory concentrations (MICs), to select proper doses and dosing intervals, and to know how to monitor its use. Despite more than 50 years of experience with vancomycin, we sometimes find ourselves with more questions than answers about its optimal use.

WHAT IS VANCOMYCIN?

Vancomycin is a glycopeptide antibiotic isolated from a strain of Streptomyces orientalis discovered in a soil sample from Borneo in the mid-1950s.¹ It exerts its action by binding to a d-alanyl-d-alanine cell wall precursor necessary for peptidoglycan cross-linking and, therefore, for inhibiting bacterial cell wall synthesis.

Vancomycin is bactericidal against most gram-positive species, including streptococci and staphylococci, with the exception of Enterococcus species, for which it is bacteriostatic. Though it is bactericidal, it appears to kill bacteria more slowly than beta-lactam antibiotics, and therefore it may take longer to clear bacteremia.⁴

WHAT IS THE BEST WAY TO DOSE VANCOMYCIN?

Vancomycin is widely distributed to most tissues, with an approximate volume of distribution of 0.4 to 1 L/kg; 50% to 55% is protein-bound. Because of this large volume of distribution, vancomycin’s dosing is based on actual body weight.

Vancomycin is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. It therefore requires dosage adjustments for renal insufficiency.

Vancomycin’s molecular weight is 1,485.73 Da, making it less susceptible to removal by dialysis than smaller molecules. Dosing of vancomycin in patients on hemodialysis depends on many factors specific to the dialysis center, including but not limited to the type of filter used, the duration of filtration, and whether high-flux filtration is used.

Is continuous intravenous infusion better than standard dosing?

Giving vancomycin by continuous infusion has been suggested as a way to optimize its serum concentration and improve its clinical effectiveness.

Wysocki et al⁵ conducted a multicenter, prospective, randomized study comparing continuous and intermittent intravenous infusions of vancomycin (the latter every 12 hours) to treat severe hospital-acquired MRSA infections, including bloodstream infections and pneumonia. Although blood concentrations above 10 μg/mL were reached more than 30 hours faster with continuous infusions than with intermittent ones, the microbiologic and clinical outcomes were similar with either method.

James et al⁶ compared the pharmacodynamics of conventional dosing of vancomycin (ie, 1 g every 12 hours) and continuous infusion in 10 patients with suspected or documented gram-positive infections in a prospective, randomized, crossover study. While no adverse effects were observed, the authors also found no statistically significant difference between the treatment groups in the pharmacodynamic variables investigated, including the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio).

In view of the currently available data, the guidelines for monitoring vancomycin therapy note that there does not appear to be any difference in patient outcomes with continuous infusion vs intermittent dosing.⁷

Should a loading dose be given?

Another proposed strategy for optimizing vancomycin’s effectiveness is to give a higher initial dose, ie, a loading dose.

Wang et al⁸ performed a single-center study in 28 patients who received a 25 mg/kg loading dose at a rate of 500 mg/hour. This loading dose was safe, but the authors did not evaluate its efficacy.

Mohammedi et al⁹ compared loading doses of 500 mg and 15 mg/kg in critically ill patients receiving vancomycin by continuous infusion. The weight-based loading dose produced higher post-dose levels and a significantly higher rate of clinical cure, but there was no significant difference in the rate of survival to discharge from the intensive care unit.

While the use of a loading dose appears to be safe and likely leads to more rapid attainment of therapeutic blood levels, we lack data on whether it improves clinical outcomes, and further study is needed to determine its role.

 

WHAT IS THE BEST WAY TO MONITOR VANCOMYCIN THERAPY?

Whether and how to use the serum vancomycin concentration to adjust the dosing has been a matter of debate for many years. Convincing evidence that vancomycin levels predict clinical outcomes or that measuring them prevents toxicity is lacking.⁷

A consensus statement from the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists⁷ contains recommendations for monitoring vancomycin therapy, based on a critical evaluation of the available scientific evidence. Their recommendations:

• Vancomycin serum concentrations should be checked to optimize therapy and used as a surrogate marker of effectiveness.
• Trough, rather than peak, levels should be monitored.
• Trough levels should be checked just before the fourth dose, when steady-state levels are likely to have been achieved. More frequent monitoring may be considered in patients with fluctuating renal function.
• Trough levels should be higher than 10 mg/L to prevent the development of resistance.
• To improve antibiotic penetration and optimize the likelihood of achieving pharmacokinetic and pharmacodynamic targets, trough levels of 15 to 20 mg/L are recommended for pathogens with a vancomycin MIC of 1 mg/L or higher and for complicated infections such as endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia.
• For prolonged courses, it is appropriate to check vancomycin levels weekly in hemodynamically stable patients and more often in those who are not hemodynamically stable.

IS VANCOMYCIN NEPHROTOXIC?

In the 1950s, vancomycin formulations were sometimes called “Mississippi mud” because of the many impurities they contained.¹ These impurities were associated with significant nephrotoxicity. Better purification methods used in the manufacture of current formulations mitigate this problem, resulting in a lower incidence of nephrotoxicity.

Over the last several years, organizations such as the American Thoracic Society and the IDSA have recommended targeting higher vancomycin trough concentrations.¹⁰ The consequent widespread use of higher doses has renewed interest in vancomycin’s potential nephrotoxicity.

Lodise et al,¹¹ in a cohort study, examined the incidence of nephrotoxicity with higher daily doses of vancomycin (≥ 4 g/day), lower daily doses (< 4 g/day), and linezolid (Zyvox). They defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/dL or a decrease in calculated creatinine clearance of 50% from baseline on 2 consecutive days.

The incidence of nephrotoxicity was significantly higher in the high-dose vancomycin group (34.6%) than in the low-dose vancomycin group (10.9%) and in the linezolid group (6.7%) (P = .001). Additional factors associated with nephrotoxicity in this study included baseline creatinine clearance less than 86.6 mL/minute, weight greater than 101.4 kg (223.5 lb), and being in an intensive care unit.

Hidayat et al¹² investigated outcomes in patients with high vs low vancomycin trough levels (≥ 15 mg/L vs < 15 mg/L) in a prospective cohort study. Sixty-three patients achieved an average vancomycin trough of 15 to 20 mg/L, and of these, 11 developed nephrotoxicity, compared with no patients in the low-trough group (P = .01). Of the 11 who developed nephrotoxicity, 10 were concomitantly taking other potentially nephrotoxic agents.

Comment. The data on vancomycin and nephrotoxicity are mostly from studies that had limitations such as small numbers of patients, retrospective design, and variable definitions of nephrotoxicity. Many of the patients in these studies had additional factors contributing to nephrotoxicity, including hemodynamic instability and concomitant exposure to other nephrotoxins. Additionally, the sequence of events (nephrotoxicity leading to elevated vancomycin levels vs elevated vancomycin levels causing nephrotoxicity) is still debatable.

The incidence of nephrotoxicity associated with vancomycin therapy is difficult to determine. However, based on current information, the incidence of nephrotoxicity appears to be low when vancomycin is used as monotherapy.

IS S AUREUS BECOMING RESISTANT TO VANCOMYCIN?

An issue of increasing importance in health care settings is the emergence of vancomycin-intermediate S aureus (VISA) and vancomycin-resistant S aureus (VRSA). Eleven cases of VRSA were identified in the United States from 2002 to 2005.¹³ All cases of VRSA in the United States have involved the incorporation of enterococcal vanA cassette into the S aureus genome.¹⁴ While true VRSA isolates remain rare, VISA isolates are becoming more common.

Heteroresistant VISA: An emerging subpopulation of MRSA

Another population of S aureus that has emerged is heteroresistant vancomycin-intermediate S aureus (hVISA). It is defined as the presence of subpopulations of VISA within a population of MRSA at a rate of one organism per 10⁵ to 10⁶ organisms. With traditional testing methods, the vancomycin MIC for the entire population of the strain is within the susceptible range.¹⁵ These hVISA populations are thought to be precursors to the development of VISA.¹⁶

The resistance to vancomycin in hVISA and VISA populations is due to increased cell wall thickness, altered penicillin-binding protein profiles, and decreased cell wall autolysis.

While the true prevalence of hVISA is difficult to predict because of challenges in microbiological detection and probably varies between geographic regions and individual institutions, different studies have reported hVISA rates between 2% and 13% of all MRSA isolates.^15–17

Reduced vancomycin susceptibility can develop regardless of methicillin susceptibility.¹⁸

While hVISA is not common, its presence is thought to be a predictor of failing vancomycin therapy.¹⁵

Factors associated with hVISA bacteremia include high-bacterial-load infections, treatment failure (including persistent bacteremia for more than 7 days), and initially low serum vancomycin levels.¹⁵

 

 

‘MIC creep’: Is it real?

Also worrisome, the average vancomycin MIC for S aureus has been shifting upward, based on reports from several institutions, although it is still within the susceptible range.^19,20 However, this “MIC creep” likely reflects, at least in part, differences in MIC testing and varying methods used to analyze the data.^19,20

Holmes and Jorgensen,²¹ in a single-institution study of MRSA isolates recovered from bacteremic patients from 1999 to 2006, determined that no MIC creep existed when they tested vancomycin MICs using the broth microdilution method. The authors found the MIC₉₀ (ie, the MIC in at least 90% of the isolates) remained less than 1 mg/L during each year of the study.

Sader et al,²² in a multicenter study, evaluated 1,800 MRSA bloodstream isolates from nine hospitals across the United States from 2002 to 2006. Vancomycin MICs were again measured by broth microdilution methods. The mode MIC remained stable at 0.625 mg/L during the study period, and the authors did not detect a trend of rising MICs.

The inconsistency between reports of MIC creep at single institutions and the absence of this phenomenon in large, multicenter studies seems to imply that vancomycin MIC creep is not occurring on a grand scale.

Vancomycin tolerance

Another troubling matter with S aureus and vancomycin is the issue of tolerance. Vancomycin tolerance, defined in terms of increased minimum bactericidal concentration, represents a loss of bactericidal activity. Tolerance to vancomycin can occur even if the MIC remains in the susceptible range.²³

Safdar and Rolston,²⁴ in an observational study from a cancer center, reported that of eight cases of bacteremia that was resistant to vancomycin therapy, three were caused by S aureus.

Sakoulas et al²⁵ found that higher levels of vancomycin bactericidal activity were associated with higher rates of clinical success; however, they found no effect on the mortality rate.

The issue of vancomycin tolerance remains controversial, and because testing for it is impractical in clinical microbiology laboratories, its implications outside the research arena are difficult to ascertain at present.

IS VANCOMYCIN STILL THE BEST DRUG FOR S AUREUS?

MIC break points have been lowered

In 2006, the Clinical Laboratories and Standards Institute lowered its break points for vancomycin MIC categories for S aureus:

• Susceptible: ≤ 2 mg/L (formerly ≤ 4 mg/L)
• Intermediate: 4–8 mg/L (formerly 8–16 mg/L)
• Resistant: ≥ 16 mg/L (formerly ≥ 32 mg/L).

The rationales for these changes were that the lower break points would better detect hVISA, and that cases have been reported of clinical treatment failure of S aureus infections in which the MICs for vancomycin were 4 mg/L.²⁶

Since 2006, the question has been raised whether to lower the break points even further. A reason for this proposal comes from an enhanced understanding of the pharmacokinetics and pharmacodynamics of vancomycin.

The variable most closely associated with clinical response to vancomycin is the AUC-MIC ratio. An AUC-MIC ratio of 400 or higher may be associated with better outcomes in patients with serious S aureus infection. A study of 108 patients with S aureus infection of the lower respiratory tract indicated that organism eradication was more likely if the AUC-MIC ratio was 400 or greater compared with values less than 400, and this was statistically significant.²⁷ However, in cases of S aureus infection with a vancomycin MIC of 2 mg/L or higher, this ratio may not be achievable.

A prospective study of 414 MRSA bacteremia episodes found a vancomycin MIC of 2 mg/L to be a predictor of death.²⁸ The authors concluded that vancomycin may not be the optimal treatment for MRSA with a vancomycin MIC of 2 mg/L.²⁸ Additional studies have also suggested a possible decrease in response to vancomycin in MRSA isolates with elevated MICs within the susceptible range.^25,29

Recent guidelines from the IDSA recommend using the clinical response, regardless of the MIC, to guide antimicrobial selection for isolates with MICs in the susceptible range.²

Combination therapy with vancomycin

As vancomycin use has increased, therapeutic failures with vancomycin have become apparent. Combination therapy has been suggested as an option to increase the efficacy of vancomycin when treating complicated infections.

Rifampin plus vancomycin is controversial.³⁰ The combination is theoretically beneficial, especially in infections associated with prosthetic devices. However, clinical studies have failed to convincingly support its use, and some have suggested that it might prolong bacteremia. In addition, it has numerous drug interactions to consider and adverse effects.³¹

Gentamicin plus vancomycin. The evidence supporting the use of this combination is weak at best. It appears that clinicians may have extrapolated from the success reported by Korzeniowski and Sande,³² who found that methicillin-susceptible S aureus bacteremia was cleared faster if gentamicin was added to nafcillin. A more recent study³³ that compared daptomycin (Cubicin) monotherapy with combined vancomycin and gentamicin to treat MRSA bacteremia and endocarditis showed a better overall success rate with daptomycin (44% vs 32.6%), but the difference was not statistically significant.

Gentamicin has some toxicity. Even short-term use (for the first 4 days of therapy) at low doses for bacteremia and endocarditis due to staphylococci has been associated with a higher rate of renal adverse events, including a significant decrease in creatinine clearance.³⁴

Clindamycin or linezolid plus vancomycin is used to decrease toxin production by S aureus.³⁰

While combination therapy with vancomycin is recommended in specific clinical situations, and the combinations are synergistic in vitro, information is lacking about clinical outcomes to support their use.

 

 

Don’t use vancomycin when another drug would be better

Vancomycin continues to be the drug of choice in many circumstances, but in some instances its role is under scrutiny and another drug might be better.

Beta-lactams. In patients with infection due to methicillin-susceptible S aureus, failure rates are higher with vancomycin than with beta-lactam therapy, specifically nafcillin.^35–37 Beta-lactam antibiotics are thus the drugs of choice for treating infection with beta-lactam-susceptible strains of S aureus.

Linezolid. In theory, linezolid’s ability to decrease production of the S aureus Panton-Valentine leukocidin (PVL) toxin may be an advantage over vancomycin for treating necrotizing pneumonias. For the treatment of MRSA pneumonia, however, controversy exists as to whether linezolid is superior to vancomycin. An analysis of two prospective, randomized, double-blind studies of patients with MRSA pneumonia suggested that initial therapy with linezolid was associated with better survival and clinical cure rates,³⁸ but a subsequent meta-analysis did not substantiate this finding.³⁹ An additional comparative study has been completed, and analysis of the results is in progress.

Daptomycin, approved for skin and soft-tissue infections and bacteremias, including those with right-sided endocarditis, is a lipopeptide antibiotic with a spectrum of action similar to that of vancomycin.⁴⁰ Daptomycin is also active against many strains of vancomycin-resistant enterococci. As noted above, in the MRSA subgroup of the pivotal comparative study of treatment for S aureus bacteremia and endocarditis, the success rate for daptomycin-treated patients (44.4%) was better than that for patients treated with vancomycin plus gentamicin (32.6%), but the difference was not statistically significant.^33,41

The creatine phosphokinase concentration should be monitored weekly in patients on daptomycin.⁴² Daptomycin is inactivated by lung surfactant and should not be used to treat pneumonia.

Other treatment options approved by the US Food and Drug Administration (FDA) for MRSA infections include tigecycline (Tygacil), quinupristin-dalfopristin (Synercid), telavancin (Vibativ), and ceftaroline (Teflaro).

Tigecycline is a glycylcycline with bacteriostatic activity against S aureus and wide distribution to the tissues.⁴³

Quinupristin-dalfopristin, a streptogramin antibiotic, has activity against S aureus. Its use may be associated with severe myalgias, sometimes leading patients to stop taking it.

Telavancin, recently approved by the FDA, is a lipoglycopeptide antibiotic.⁴⁴ It is currently approved to treat complicated skin and skin structure infections and was found to be not inferior to vancomycin. An important side effect of this agent is nephrotoxicity. A negative pregnancy test is required before using this agent in women of childbearing potential.

Ceftaroline, a fifth-generation cephalosporin active against MRSA, has been approved by the FDA for the treatment of skin and skin structure infections and community-acquired pneumonia.⁴⁵

Many patients with type 2 diabetes eventually need insulin, as their ability to produce their own insulin from pancreatic beta cells declines progressively.¹ The questions remain as to when insulin therapy should be started, and which regimen is the most appropriate.

Guidelines from professional societies differ on these points,^2,3 as do individual clinicians. Moreover, antidiabetic treatment is an evolving topic. Many new drugs—oral agents as well as injectable analogues of glucagon-like peptide-1 (GLP1) and insulin formulations—have become available in the last 15 years.

In this paper, I advocate an individualized approach and review the indications for insulin treatment, the available preparations, the pros and cons of each regimen, and how the properties of each type of insulin influence attempts to intensify the regimen.

Coexisting physiologic and medical conditions such as pregnancy and chronic renal failure and drugs such as glucocorticoids may alter insulin requirements. I will not cover these special situations, as they deserve separate, detailed discussions.

WHEN SHOULD INSULIN BE STARTED? TWO VIEWS

Early on, patients can be adequately managed with lifestyle modifications and oral hypoglycemic agents or injections of a GLP1 analogue, either alone or in combination with oral medication. Later, some patients reach a point at which insulin therapy becomes the main treatment, similar to patients with type 1 diabetes.

The American Diabetes Association (ADA), in a consensus statement,² has called for using insulin early in the disease if lifestyle management and monotherapy with metformin (Glucophage) fail to control glucose or if lifestyle management is not adequate and metformin is contraindicated. The ADA’s goal hemoglobin A_1c level is less than 7% for most patients.

The American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE), in another consensus statement, use an algorithm stratified by hemoglobin A_1c level, in which insulin is mostly reserved for when combination therapy fails.³ Their goal hemoglobin A_1c level is 6.5% or less for most patients.

Comment. Both consensus statements make exceptions for patients presenting with very high blood glucose and hemoglobin A_1c levels and those who have contraindications to drugs other than insulin. These patients should start insulin immediately, along with lifestyle management.^2,3

Both consensus statements give priority to safety. The AACE/ACE statement gives more weight to the risk of hypoglycemia with insulin treatment, whereas the ADA gives more weight to the risk of edema and congestive heart failure with thiazolidinedione drugs (although both insulin and thiazolidinediones cause weight gain) and to adequate validation of treatments in clinical trials.

Ongoing clinical trials may add insight to this issue. For example, the Outcome Reduction With Initial Glargine Intervention (ORIGIN) study is investigating the effects of the long-acting insulin glargine (Lantus) in early diabetes with regard to glycemic control, safety, and cardiovascular outcomes.⁴ This study is expected to end this year (2011). The safety of alternative treatment options is also under investigation and scrutiny. In the interim, individualized treatment should be considered, as we will see below.

MY VIEW: AN INDIVIDUALIZED APPROACH

The decision to start insulin therapy should be made individually, based on several factors:

• Whether the patient is willing to try it
• The degree of hyperglycemia
• How relevant the potential side effects of insulin are to the patient compared with those of other hypoglycemic agents
• Whether oral hypoglycemic agents with or without GLP1 analogues are expected to provide the desired benefit
• The patient’s work schedule and lifestyle factors
• Cost
• The availability of nurses, diabetes educators, and others to implement and follow the insulin treatment.

Will patients accept insulin?

Factors that affect whether patients comply with a treatment include the number of pills or injections they must take per day, how often they must check their blood glucose, adverse effects, lifestyle limitations caused by the treatment (especially insulin), and cost. Most patients feel better when their glucose levels are under good control, which is a major motivation for initiating and adhering to insulin. The anticipated reduction of diabetic complications further enhances compliance.

Education promotes compliance. Patients need to know that type 2 diabetes tends to progress and that in time their treatment will have to be intensified, with higher doses of their current drugs and new drugs added or substituted, possibly including insulin. This information is best given early, ie, when the diagnosis is made, even if hyperglycemia is mild at that time.

With newer insulin preparations and delivery devices available, more patients are finding insulin treatment acceptable.

 

 

The glycemic goal should be individualized

The key issue is glycemic control. If glycemic control is worsening or if the hemoglobin A_1c level remains above the goal, then the treatment strategy should be readdressed.

In general, one should try to achieve the best possible glycemic control with the few est adverse effects. Adequate dietary management with a regular meal schedule and predictable carbohydrate intake for each meal helps to avoid or at least minimize the two most important adverse effects of insulin, ie, weight gain and hypoglycemia.

For most patients, I believe a goal hemoglobin A_1c level of less than 7% is reasonable.² For others, a less stringent goal might be more appropriate, such as 7.5%. Several factors affect this decision, including whether the patient is willing to follow a complex insulin regimen (such as a basal-bolus regimen), his or her work schedule, other lifestyle factors, the duration of diabetes, the type or types of insulin used, coexisting medical conditions, the frequency of hypoglycemia, unawareness of hypoglycemia, age, prognosis, life expectancy, and cost.⁵

If hyperglycemia is severe (Table 1),² the goal might not be clear when insulin therapy is started. It should become obvious with ongoing follow-up.

Previously untreated patients presenting with severe hyperglycemia are a heterogeneous group. Many of them have had diabetes for a relatively short time and were recently diagnosed. These patients are likely to safely achieve near-normal glycemic control. Some of them might be adequately treated with oral hypoglycemic agents; if insulin is used, transitioning from insulin to oral hypoglycemic agents may be feasible.²

Some untreated patients may have had diabetes for several years and have advanced disease and therefore might be more difficult to treat. Only 21 (57%) of 37 previously untreated patients intensively treated with insulin reached the goal fasting glucose level of less than 126 mg/dL in one study.⁶ The only way to evaluate the feasibility of achieving near-normal glycemia safely is by following the patient’s progress over time.

The patient’s glycemic goal should be reevaluated periodically and may need to be adjusted over time, based on changes in any of the factors discussed above.

Risk of hypoglycemia

The goal should be looser in difficult-to-treat patients, ie, those with frequent hypoglycemia and decreased awareness of hypoglycemia.

Patients with advanced diabetes whose glucose levels continue to fluctuate widely after lifestyle management and the insulin regimen have been addressed should also have a looser goal. These fluctuations of glucose levels are surrogate markers for the degree of insulin deficiency. Attempting to achieve near-normal glycemic levels in this situation would be associated with a higher risk of hypoglycemia.

A higher risk of hypoglycemia and its complications (eg, falling and accidents, especially among operators of heavy machinery, construction workers, and drivers) is another reason for adopting a relaxed goal of glycemic control.

Table 2 summarizes risk factors for hypoglycemia.^5,7–9 Relationships between insulin dosage, hemoglobin A_1c level, and the risk of hypoglycemia have not been consistent among studies.⁸ Several important risk factors for hypoglycemia are not reported in prospective clinical studies because of exclusion criteria in those studies.

ADDING BASAL INSULIN TO ORAL HYPOGLYCEMIC THERAPY

When glycemic control worsens or is not adequate despite the use of oral hypoglycemic agents, often the next step is to add basal insulin therapy, ie, once-daily doses of a long-acting insulin.

NPH, detemir, or glargine?

Most often, glargine or detemir (Levemir) insulin is used. Detemir can also be given twice daily if needed. If cost is a concern, neutral protamine Hagedorn (NPH, Humulin N, Novolin N) insulin once daily at bedtime or twice daily is a reasonable alternative.

Costs of basal insulins are $22 to $50 per 1,000-unit vial for NPH, $70 to $90 per 1,000-unit vial for detemir and glargine, and $170 to $200 for a box of five detemir or glargine pens (containing 1,500 units total). Complicating this issue, vials should not be used for more than 1 month, and thus, the cost of vials vs pens depends on dosage.

Detemir vs NPH. In a trial in patients with inadequately controlled type 2 diabetes who had never taken insulin before and who were taking one or more oral hypoglycemic drugs, the addition of detemir insulin once daily or NPH at bedtime resulted in similar improvements in hemoglobin A_1c (a decrease of about 1.5%).¹⁰

Detemir had several advantages over NPH. First, the incidence of nocturnal hypoglycemia was 50% lower with detemir at bedtime than with NPH at bedtime, and 87% lower with detemir in the morning than with bedtime NPH.¹⁰ In another trial,¹¹ the risk of hypoglycemia at any time of day was 47% lower with insulin detemir than with NPH, and the risk of nocturnal hypoglycemia was 55% lower.

The risk of nocturnal hypoglycemia is lower if detemir is taken in the morning than at bedtime, although the total frequency of hypoglycemic episodes is the same.¹⁰ Therefore, another decision after starting basal insulin, based on the patient’s glucose trends and frequency of hypoglycemic events, would be whether insulin should be taken in the morning or at bedtime.

The second advantage of detemir is that it causes less weight gain: 0.7 kg at 20 weeks with detemir at bedtime vs 1.6 kg with NPH at bedtime.¹⁰

Further, detemir insulin was associated with less within-subject variability in the fasting glucose level than with NPH when these insulins were used in a basal-bolus regimen.¹²

Hermansen et al¹¹ found that if the dosage of basal insulin was aggressively increased, 70% of patients achieved a hemoglobin A_1c target of less than 7% with either NPH or detemir insulin, with fewer hypoglycemic episodes in patients treated with detemir.

Therefore, adding basal insulin to oral therapy is adequate for many patients who are new to insulin. Many patients would need more, such as the addition of insulin before meals.

Glargine vs NPH. Compared with adding NPH, adding glargine to a regimen of oral hypoglycemic agents controls blood glucose levels better and with less fluctuation in glucose levels, a lower risk of hypoglycemia, and less weight gain.^13–15 These results were the same when using glargine with either metformin¹³ or glimeperide (Amaryl).¹⁴

Glargine is usually given once daily at bedtime. One study suggested that giving it in the morning is more effective.¹⁴

Detemir vs glargine. Studies that compared detemir and glargine revealed more similarities than differences in their clinical benefits.^16,17 Both preparations effectively lower glucose levels and improve quality of life.¹⁸

Titrating the insulin regimen is a key in achieving adequate glycemic control. This includes teaching patients how to adjust their insulin, for example by increasing the dosage of glargine or detemir by 2 units every 4 to 7 days until adequate glycemic control is achieved, unless hypoglycemia becomes a barrier.

 

BASAL VS PRANDIAL INSULIN

Once-daily insulin injection is relatively convenient, but it comes with a limitation: it does not adequately control postprandial hyperglycemia. A solution is insulin before meals, ie, prandial insulin.

Kazda et al¹⁹ compared three regimens in patients not taking oral hypoglycemic agents: rapid-acting insulin lispro (Humalog) before each meal, a mix of 50% lispro and 50% protamine lispro (Humalog Mix 50/50) (the protamine delays its release) before each meal, and glargine at bedtime. The absolute change in hemoglobin A_1c was −0.3% in the glargine group, −1.1% in the lispro group, and −1.2% in the lispro mix group. The glargine group had better control of fasting glucose.

Similar advantages of better glycemic control and fewer nocturnal hypoglycemic episodes were seen in trials of a mixture of 25% lispro and 75% protamine lispro before meals compared with glargine insulin in patients on simultaneous treatment with oral hypoglycemic agents.^20,21 Buse et al²¹ reported that more patients achieved a hemoglobin A_1c level below 7% with this lispro mix (47%) than with glargine (40%). The absolute difference in mean hemoglobin A_1c between the two groups was minimal, although it reached statistical significance. As expected, weight gain was less in the glargine group.²¹

Kann et al²² reported that glycemic control was also better with a mixture of 30% aspart and 70% protamine aspart (NovoLog Mix 70/30) twice a day along with metformin than with glargine insulin once a day along with oral glimepiride, a sulfonylurea. Further, in this study, weight gain was noted in the glargine-glimepiride group only.²² Therefore, the advantage of less weight gain has not been always reproducible in glargine studies.

Comment. These studies point to the contribution of postprandial glucose to hemoglobin A_1c.^23–25 In patients with satisfactory glycemic control, the postprandial glucose level seems to be the major contributor to hemoglobin A_1c. When glycemic control worsens, the contribution of fasting glucose to hemoglobin A_1c increases.²³

Premixed insulins (lispro mix and aspart mix) provide basal coverage and control postprandial hyperglycemia. Therefore, prandial premixed insulin therapy is expected to be superior to basal insulin therapy. Premixed insulin could be considered as a simplified basal-bolus regimen (see below).

The superiority of prandial (rapid-acting) insulin alone over basal insulin therapy, as seen in the study by Kazda et al,¹⁹ has not been reproducible in other studies. For example, in one study, once-daily glargine resulted in a similar improvement in hemoglobin A_1c, a lower rate of hypoglycemic episodes, and greater patient satisfaction with treatment compared with lispro insulin before meals.²⁶ This issue remains debatable because all the trials have been open-label and thus are subject to limitations.

The main lesson is that either glargine or lispro monotherapy is a reasonable option and results in better glycemic control in patients for whom two oral hypoglycemic agents have failed. Further, both fasting and postprandial hyperglycemia are important to address. In patients with severe hyperglycemia, a combination of prandial and basal insulin may be indicated. One would expect neither basal nor prandial (bolus) insulin to be adequate in this situation.

In conclusion, adding basal insulin to oral hypoglycemic agents is a reasonable option in the advancement of diabetes therapy and has become a common way to introduce insulin. It is simple and less labor-intensive for patients and medical groups than a basal-bolus regimen. Patients usually find it acceptable. The future availability of an easy-to-deliver, safe, and effective prandial insulin may change the current treatment paradigm; several newer prandial insulins are under investigation.

In advanced diabetes, both prandial and fasting glucose levels are crucial to address. Some patients may need to be started on both basal and prandial insulin simultaneously, depending on their degree of hyperglycemia, the duration of diabetes, coexisting medical conditions, and the goal of glycemic control.

BASAL-BOLUS INSULIN REGIMENS

In the advanced stages of type 2 diabetes, as insulin deficiency worsens, patients need to start giving themselves injections of a rapid-acting insulin—regular, lispro, aspart, or glulisine (Apidra) before meals, in addition to once- or twice-daily basal insulin injections. Such a “basal-bolus” regimen could also be used for newly diagnosed patients presenting with severe hyperglycemia. In addition, some patients on basal insulin plus oral hypoglycemic drugs may develop contraindications to their oral drugs. Adding bolus insulin becomes the main option for these patients too.

For others, a basal-bolus regimen might be chosen purely because of cost. For example, a regimen of NPH and regular insulin (multiple daily injections or premixed) would be significantly less expensive than multiple oral hypoglycemic agents.

Currently, only a few classes of oral hypoglycemic drugs are available in generic formulations. For example, generic glimeperide and metformin cost as little as $4 to $12 per month, while the costs of brand-name oral hypoglycemic agents are in the range of $170 to $200 per month. In contrast, premixed NPH plus regular insulin such as Novolin 70/30 and Humulin 70/30 cost between $22 and $70 per vial.

A basal-bolus regimen should provide 50% of the total daily insulin in the form of basal insulin. A regimen of 50% basal and 50% bolus seemed to provide better glycemic control than a regimen of 35% basal and 65% bolus in several studies.^27,28

In patients already taking a single daily dose of basal insulin along with oral hypoglycemic agents, the dosage of basal insulin is usually raised gradually until adequate glycemic control is achieved. A main question is when to add prandial insulin. There is no clear cutoff for a basal insulin dosage at which prandial insulin should be added.

In the Treat-to-Target Trial,²⁹ almost 60% of patients achieved a hemoglobin A_1c level of 7% or less with the addition of either glargine or NPH insulin (basal insulin only) to oral hypoglycemic agents during 24 weeks of follow-up. As expected, glargine caused less nocturnal hypoglycemia. Fewer than half the patients who achieved a hemoglobin A_1c level less than 7% had no documented nocturnal hypoglycemia (33% of glargine-treated patients and 27% of NPH-treated patients).

Type 2 diabetes is progressive¹; over time, patients treated with once-daily basal insulin often require multiple daily injections.

Adding prandial to basal insulin clearly results in better glycemic control and less glucose variability.^{19,20,22,30–33} Two major factors in deciding to start prandial insulin are the degree of hyperglycemia and the patient’s acceptance of multiple daily injections. The higher the blood glucose levels, the sooner prandial insulin should be added, especially if hyperglycemia is influencing the prognosis of a coexisting condition or a diabetic complication (eg, an infected foot ulcer).

Adding prandial insulin should be also considered if the dosage of basal insulin has progressively been increased and the hemoglobin A_1c level is not improving, especially if a patient has both inadequate glycemic control and frequent hypoglycemia, or if the morning glucose level is within the desired range (indicating there is no room for a further increase in the basal insulin dose) in association with inadequate control of hemoglobin A_1c.

 

 

What is the best basal insulin for a basal-bolus regimen?

Glargine and detemir were shown to be equally effective as the basal component of a basal-bolus regimen.^34,35 Findings were similar to those of studies comparing NPH, detemir, and glargine added, by themselves, to oral hypoglycemic agents. When possible, either glargine or detemir is favored because of less hypoglycemia and less weight gain than with NPH. Weight gain is the least with detemir.

Adding prandial insulin to a basal regimen

In general, whether to add prandial insulin can be decided on the basis of the patient’s record of blood glucose monitoring. Insulin could be added before breakfast if the pre-lunch glucose level is elevated, or before lunch if the dinnertime blood glucose level is elevated, or before dinner if the bedtime blood glucose level is elevated—or a combination of these. Prandial insulin can be started at a low dose (4–6 units) and increased gradually.

For patients taking NPH at bedtime, adding another dose of NPH in the morning is a reasonable option for managing pre-dinner hyperglycemia (Figure 1).²

In the case of poor glycemic control on a high dosage of basal insulin, a reasonable first step would be to change the regimen to a basal-bolus regimen (about 50% basal and 50% bolus) with no change or a small decrease in the total daily dosage of insulin to avoid hypoglycemia. For example, in a patient on 80 units of glargine or detemir insulin who has inadequate control, the regimen could be changed to 35 units of either glargine or detemir and 10 to 12 units of lispro, aspart, or glulisine before each meal as the bolus component.

Further adjustments of the insulin dosage can be made according to the results of glucose monitoring before each meal and at bedtime. In all case scenarios, the insulin regimen should be re-evaluated routinely during the advancement of therapy from single daily injection of basal insulin to multiple daily injections. Redistribution of total insulin dosage to 50% basal and 50% bolus (divided into three doses before meals) should be considered for patients who continue to have fluctuations of glucose levels, inadequate control, or frequent hypoglycemia. This ratio seems to provide better control for most patients.^27,28

Starting with a basal-bolus regimen

For patients new to insulin who are starting a basal-bolus regimen, a dosage based on total body weight could be considered. The requirements vary significantly based on dietary management, level of physical activity, stress (especially illnesses), use of oral hypoglycemic agents, and degree of hyperglycemia.

A lower dosage of insulin (0.2 units per kg) should be considered for people with mild stress, with milder hyperglycemia, or on treatment with oral hypoglycemic agents. Elderly patients and patients with renal or liver failure are at higher risk of hypoglycemia and should also receive a lower dosage of insulin, at least to start with.

Others could be started on a dosage of 0.3 to 0.5 units/kg. Fifty percent of the calculated dosage could be given as basal insulin and 50% given as bolus (divided into three doses, before meals). Subsequently, the dosage would need to be titrated on the basis of the record of glucose monitoring.

Choosing a prandial insulin

Rapid-acting insulin analogues (lispro, aspart, and glulisine) control postprandial glucose levels better than regular insulin and cause less hypoglycemia. Their pharmacokinetics enable them to be taken within a few minutes of the start of a meal, or even after the meal if the patient forgets to take an injection before the meal.

For example, in one study,³⁶ taking aspart immediately before the meal provided better glycemic control than taking regular insulin 30 minutes before meals. In a basal-bolus regimen, the use of aspart along with detemir resulted in glycemic control similar to that provided by twice-daily NPH and regular insulin, with less hypoglycemia.³⁷

The dosage of prandial insulin can be adjusted according to the amount of carbohydrates in each meal (the insulin-to-carbohydrate ratio), as in patients with type 1 diabetes. This approach was associated with less weight gain.³⁸

IS THERE STILL A ROLE FOR PREMIXED INSULIN PREPARATIONS?

Basal-bolus insulin regimens have gained popularity because the prandial doses can easily be adjusted according to carbohydrate intake, glucose level (on a sliding scale), variations in meal time, missed meals (eg, when having a procedure), and exercise. For example, the dose of prandial insulin can be reduced if the patient expects to exercise within 2 or 3 hours after the meal.

Some patients may not accept giving themselves four or five injections per day with a basal-bolus regimen. They may accept a simpler regimen, ie, giving themselves three injections of a premixed insulin per day, one before each meal.

Compared with a basal-bolus regimen, the possibility of achieving adequate glycemic control using lispro mix (50% lispro, 50% lispro protamine suspension) before meals seemed to depend on the goal of glycemic control. Its use in one study showed similar ability to achieve hemoglobin A_1c less than 7.5% compared with a basal-bolus regimen of glargine and lispro. For a goal hemoglobin A_1c level of less than 7%, the use of glargine and lispro was superior. The rate of hypoglycemia was similar with both strategies.³⁹ These findings imply that the goal hemoglobin A_1c should be more relaxed (< 7.5%) when using lispro mix (50% lispro) three times daily before meals.

Biphasic insulin aspart (a mix of aspart and protamine aspart) given three times daily provided similar improvement in glycemic control with no difference in the frequency of hypoglycemia compared with a basal-bolus regimen of NPH and aspart.⁴⁰ Further, the use of biphasic insulin aspart seemed to provide better glycemic control with less weight gain compared with premixed human insulin (70% NPH, 30% regular insulin).⁴¹

Therefore, simpler premixed insulin regimens remain reasonable options for selected patients who do not accept a more complex insulin regimen (basal-bolus) or cannot adhere to it for any reason, especially if premixed insulin is given before meals three times daily. In fact, recent studies have focused on comparing premixed insulin three times daily with basal-bolus regimens (detemir or glargine as basal insulin along with pre-meal insulin analogue).

Glycemic control is harder to achieve with premixed insulin twice daily, mainly because of a higher frequency of hypoglycemia.⁴² In Europe, the use of premixed insulin three times daily is a popular option, whereas in the United States, a twice-daily schedule has been more common.

 

COST VS CONTROL

Newer insulin analogues make insulin treatment safer and more accepted by patients. The availability of several options for insulin regimens allows individualization of the treatment according to the patient’s acceptance, the safety profile, and the cost.

Patient selection and insulin titration are key issues in ensuring the achievement of adequate control with the fewest side effects. Lifestyle management (diet and physical activity) enhances the efficacy of insulin therapy and reduces the chances of side effects, namely fluctuation of glucose levels, hypoglycemic episodes, and weight gain.

Human insulins (NPH and regular) remain the least expensive, especially when using premixed NPH-regular insulin 70/30. Their use should be considered when the cost of medication is a major concern for the patient. A more relaxed goal of glycemic control may be considered in order to avoid hypoglycemia when using those insulin preparations, such as a hemoglobin A_1c level less than 7.5% or even in the range of 7.5% to 8.5%, depending on the expected seasonal variation of hemoglobin A_1c (which is higher in winter⁴³), individual factors, and whether the premixed insulin is used twice or three times daily.

RE-EVALUATE THE REGIMEN ROUTINELY

The insulin regimen should be re-evaluated routinely. It might need to be changed in response to the dynamic multifactorial process of progression of diabetes, change in stress level, presence or resolution of intercurrent illnesses, risk of hypoglycemia, concerns about weight gain, and cost.

Finally, adjustment of the regimen should be considered in response to improvement of glycemic control related to improvement of dietary management, exercising, weight loss, and medical therapies.