Louis Kuritzky, MD

Although an estimated 1 out of 3 people in the United States has been diagnosed with hypertension, data from the 2007-2008 National Health and Nutrition Examination Survey found that just 72% are currently being treated and, of those, just half have their blood pressure (BP) controlled with lifestyle changes and/or medication.¹

The failure of so many people with hypertension to obtain BP control, despite the availability of numerous effective medications, is partially due to a lack of adherence to recommended treatments (eg, taking medication, following a diet, and executing lifestyle changes). Adherence is a significant problem in hypertension and evidence shows that just half of patients who initiate drug therapy are persistent with treatment after 1 year.²

Although few studies link nonadherence with long-term outcomes, 1 study found that patients who “forgot” to take their antihypertensive medication were nearly one-third more likely to experience a cardiovascular event or death (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.04-1.57).³ Adherence is important not only for the health of the patient, but also to provide overall cost savings from the reductions of hospitalizations for complications from an untreated disease.⁴

Barriers to adherence

A significant contributor to nonadherence is treatment complexity, which manifests in hypertension as pill burden. Up to 75% of patients will require more than 1 medication to control their BP; those with resistant hypertension will require 4 or more.^5,6 These medications must often be taken at different times of the day, with varying frequency.^6-9

Reducing the number of daily doses has been consistently found to enhance adherence, and should be considered routinely as a first-line strategy. Complex strategies (eg, group visits, designated office staff to assist hypertensive patients, pharmacist consultation and comanagement, exercise counseling, dietary counseling, multidisciplinary hypertension team care, specific interviewing techniques such as motivational interviewing) are promising, but individual clinicians may not have the resources to take advantage of such labor-intensive intervention. Further, when multimodal intervention is employed, it is often difficult to discern which component(s) of the intervention were most impactful, unless multifactorial study design is employed, which it rarely is. We await further randomized controlled trials in this regard.

A study of approximately 85,000 members of a large managed care organization found that the greater the number of antihypertensive medications prescribed, the lower the rate of patient adherence. Just 63% of those receiving 3-drug regimens and 55% of those receiving 4-drug regimens were completely adherent.¹⁰

In addition, many patients with hypertension, particularly older patients, have comorbid conditions (eg, dyslipidemia or diabetes) that also require treatment, leading to increased treatment complexity and pill burden.^11,12

One option for reducing pill burden is the use of fixed-dose therapies ( TABLE ). Since 2000, many new fixed-dose combinations, including at least 3 triple therapies, have entered the market.¹³ In addition, a so-called “poly-pill” that combines aspirin, 3 antihypertensives, and a statin is under investigation and demonstrating good results in reducing BP and cholesterol levels.¹⁴

TABLE

Currently available combination therapies

Studies have found that patients receiving fixed-dose combination pills are more likely to reach their target BP, physicians are more satisfied with their ability to manage hypertension, and adverse effects are either similar or less with the fixed-dose therapies compared with monotherapies.^15,16

Studies of adherence patterns among patients treated with fixed-dose combinations of antihypertensive agents vs separate antihypertensive agents demonstrate increased adherence among patients treated with fixed-dose combinations.^17-21 In a clinical trial involving 4146 participants who were treated with a fixed dose of amlodipine and atorvastatin or separate pills, 33% of patients in the fixed-dose cohort had ceased treatment by 12 months compared with 59% of patients who were taking the 2-pill regimen (HR, 2.17; 95% CI, 2.05–2.13; P < .0001), resulting in a 117% higher rate of nonadherence in the 2-pill regimen. The median persistence time (ie, time to discontinuation with medication) was 8 months with the 2-pill regimen, but 37 months or longer with the fixed-dose combination.²¹

A meta-analysis of 9 studies found that fixed-dose combinations reduced the risk of nonadherence by 26% compared with single-pill combination therapy.²²

One downside to fixed-dose therapy is cost. Out-of-pocket costs are a significant barrier to medication adherence and most fixed-dose options are branded drugs that generally require higher copayments or coinsurance vs generic single-pill drugs that may have copayments as low as $4.⁶

Other opportunities to improve adherence to antihypertensive medications

Other evidence-based opportunities to improve adherence to antihypertensive medications include improved relationships with, and communication from, health care providers, given that patients often do not understand their disease and recommended treatments.^23,24

Interviews with 826 patients with hypertension found that although 90% knew that lowering their BP would improve their health and 91% reported that a health care provider had told them that they had hypertension or high BP, 41% did not know their BP level. In addition, just 34% of patients with hypertension identified systolic BP (SBP) as the “top” number of their reading and only 32% identified diastolic BP (DBP) as the “bottom” number. Finally, only one-third of patients were able to identify both SBP and DBP, and one-quarter of them did not know the optimal level for either.²⁵

Other provider interventions that have resulted in improved adherence include changing medication to reduce or avoid adverse effects, simplifying dosing (as described earlier), and switching to less-expensive drugs if cost is an issue. Nurses and pharmacists are also important members of the team when it comes to improving adherence and reinforcing education.²⁴

Home blood pressure monitoring

Another reason for nonadherence is that patients may not believe they need treatment since hypertension rarely manifests with symptoms. Furthermore, patients may not perceive that the medication they take has any effect because they did not have symptoms to begin with. Home BP monitoring (HBPM), or self BP monitoring, is one tool for improving adherence, possibly by providing immediate feedback to patients on how well their BP is controlled.²⁶ Many major medical societies recommend HBPM as part of any hypertension management strategy.^27-30

Patients who use HBPM can avoid many limitations associated with office BP monitoring (OBPM), including poor measurement techniques, infrequent measurement, white coat hypertension, and masked hypertension. Patients can also avoid reverse white coat hypertension, where OBPM is normal although out-of-office BP is high.²⁸ Patients should take 3 readings at 1-minute intervals, usually in the morning and evening. The weekly average of these readings is their home BP (normotension is defined as an average BP <135/85 mm Hg).³¹ Typically, the HBPM monitoring is more accurate in identifying risk than OBPM when there are discrepancies between them.²⁸ It is good practice to instruct patients utilizing HBPM to bring their home BP device to the office for a comparison.

There is some evidence that HBPM may contribute to improved adherence. A systematic review of 11 randomized controlled trials found that in 6 trials the use of HBPM resulted in improved medication adherence, although in 5 of those studies additional interventions were used. These interventions included patient counseling about adverse effects of the medication, timepiece caps that reminded patients to take their medication, tips to enhance adherence, and reinforcement of positive behavior by nurses, pharmacists, lay health workers, or a telephonic system.³² This illustrates an important point in adherence interventions: more is better, and it usually takes a combination of approaches to improve adherence.^33,34

The only trial in the review that demonstrated that HBPM alone improved adherence randomized 628 patients to either HBPM or usual care for 6 weeks. The groups had similar compliance rates at baseline, and both demonstrated less adherence at the end of the 6-week trial. However, patients who measured their BP at home still demonstrated greater compliance than those receiving usual care (P < .05).³⁵

A more recent trial in 57 patients, 38 of whom measured their BP at home and 19 of whom received usual care, found greater medication adherence in the HBPM group than in the control group (100% vs 88%, P < .031). The HBPM group also reached their treatment goals significantly faster than the control group (P = .02).³⁶

Conclusion

Approximately 50% of individuals with hypertension who receive antihypertensive medication still do not reach their BP goal. One reason is nonadherence to medication, which is often related to treatment complexity, or pill burden. Given that most patients with hypertension will require more than 1 drug to manage their blood pressure, it is important that clinicians identify opportunities to simplify treatment. This may include fixed-dose combination therapy, which can improve adherence, as well as additional education regarding the efficacy and adverse effects of therapy.

The use of HBPM may also improve adherence by providing frequent feedback on treatment effectiveness.

It is important, however, that clinicians understand that no single approach to adherence will work for every patient. The greatest success comes with combining several approaches based on the barriers that affect each individual patient.

Although an estimated 1 out of 3 people in the United States has been diagnosed with hypertension, data from the 2007-2008 National Health and Nutrition Examination Survey found that just 72% are currently being treated and, of those, just half have their blood pressure (BP) controlled with lifestyle changes and/or medication.¹

The failure of so many people with hypertension to obtain BP control, despite the availability of numerous effective medications, is partially due to a lack of adherence to recommended treatments (eg, taking medication, following a diet, and executing lifestyle changes). Adherence is a significant problem in hypertension and evidence shows that just half of patients who initiate drug therapy are persistent with treatment after 1 year.²

Although few studies link nonadherence with long-term outcomes, 1 study found that patients who “forgot” to take their antihypertensive medication were nearly one-third more likely to experience a cardiovascular event or death (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.04-1.57).³ Adherence is important not only for the health of the patient, but also to provide overall cost savings from the reductions of hospitalizations for complications from an untreated disease.⁴

Barriers to adherence

A significant contributor to nonadherence is treatment complexity, which manifests in hypertension as pill burden. Up to 75% of patients will require more than 1 medication to control their BP; those with resistant hypertension will require 4 or more.^5,6 These medications must often be taken at different times of the day, with varying frequency.^6-9

Reducing the number of daily doses has been consistently found to enhance adherence, and should be considered routinely as a first-line strategy. Complex strategies (eg, group visits, designated office staff to assist hypertensive patients, pharmacist consultation and comanagement, exercise counseling, dietary counseling, multidisciplinary hypertension team care, specific interviewing techniques such as motivational interviewing) are promising, but individual clinicians may not have the resources to take advantage of such labor-intensive intervention. Further, when multimodal intervention is employed, it is often difficult to discern which component(s) of the intervention were most impactful, unless multifactorial study design is employed, which it rarely is. We await further randomized controlled trials in this regard.

A study of approximately 85,000 members of a large managed care organization found that the greater the number of antihypertensive medications prescribed, the lower the rate of patient adherence. Just 63% of those receiving 3-drug regimens and 55% of those receiving 4-drug regimens were completely adherent.¹⁰

In addition, many patients with hypertension, particularly older patients, have comorbid conditions (eg, dyslipidemia or diabetes) that also require treatment, leading to increased treatment complexity and pill burden.^11,12

One option for reducing pill burden is the use of fixed-dose therapies ( TABLE ). Since 2000, many new fixed-dose combinations, including at least 3 triple therapies, have entered the market.¹³ In addition, a so-called “poly-pill” that combines aspirin, 3 antihypertensives, and a statin is under investigation and demonstrating good results in reducing BP and cholesterol levels.¹⁴

TABLE

Currently available combination therapies

Studies have found that patients receiving fixed-dose combination pills are more likely to reach their target BP, physicians are more satisfied with their ability to manage hypertension, and adverse effects are either similar or less with the fixed-dose therapies compared with monotherapies.^15,16

Studies of adherence patterns among patients treated with fixed-dose combinations of antihypertensive agents vs separate antihypertensive agents demonstrate increased adherence among patients treated with fixed-dose combinations.^17-21 In a clinical trial involving 4146 participants who were treated with a fixed dose of amlodipine and atorvastatin or separate pills, 33% of patients in the fixed-dose cohort had ceased treatment by 12 months compared with 59% of patients who were taking the 2-pill regimen (HR, 2.17; 95% CI, 2.05–2.13; P < .0001), resulting in a 117% higher rate of nonadherence in the 2-pill regimen. The median persistence time (ie, time to discontinuation with medication) was 8 months with the 2-pill regimen, but 37 months or longer with the fixed-dose combination.²¹

A meta-analysis of 9 studies found that fixed-dose combinations reduced the risk of nonadherence by 26% compared with single-pill combination therapy.²²

One downside to fixed-dose therapy is cost. Out-of-pocket costs are a significant barrier to medication adherence and most fixed-dose options are branded drugs that generally require higher copayments or coinsurance vs generic single-pill drugs that may have copayments as low as $4.⁶

Other opportunities to improve adherence to antihypertensive medications

Other evidence-based opportunities to improve adherence to antihypertensive medications include improved relationships with, and communication from, health care providers, given that patients often do not understand their disease and recommended treatments.^23,24

Interviews with 826 patients with hypertension found that although 90% knew that lowering their BP would improve their health and 91% reported that a health care provider had told them that they had hypertension or high BP, 41% did not know their BP level. In addition, just 34% of patients with hypertension identified systolic BP (SBP) as the “top” number of their reading and only 32% identified diastolic BP (DBP) as the “bottom” number. Finally, only one-third of patients were able to identify both SBP and DBP, and one-quarter of them did not know the optimal level for either.²⁵

Other provider interventions that have resulted in improved adherence include changing medication to reduce or avoid adverse effects, simplifying dosing (as described earlier), and switching to less-expensive drugs if cost is an issue. Nurses and pharmacists are also important members of the team when it comes to improving adherence and reinforcing education.²⁴

Home blood pressure monitoring

Another reason for nonadherence is that patients may not believe they need treatment since hypertension rarely manifests with symptoms. Furthermore, patients may not perceive that the medication they take has any effect because they did not have symptoms to begin with. Home BP monitoring (HBPM), or self BP monitoring, is one tool for improving adherence, possibly by providing immediate feedback to patients on how well their BP is controlled.²⁶ Many major medical societies recommend HBPM as part of any hypertension management strategy.^27-30

Patients who use HBPM can avoid many limitations associated with office BP monitoring (OBPM), including poor measurement techniques, infrequent measurement, white coat hypertension, and masked hypertension. Patients can also avoid reverse white coat hypertension, where OBPM is normal although out-of-office BP is high.²⁸ Patients should take 3 readings at 1-minute intervals, usually in the morning and evening. The weekly average of these readings is their home BP (normotension is defined as an average BP <135/85 mm Hg).³¹ Typically, the HBPM monitoring is more accurate in identifying risk than OBPM when there are discrepancies between them.²⁸ It is good practice to instruct patients utilizing HBPM to bring their home BP device to the office for a comparison.

There is some evidence that HBPM may contribute to improved adherence. A systematic review of 11 randomized controlled trials found that in 6 trials the use of HBPM resulted in improved medication adherence, although in 5 of those studies additional interventions were used. These interventions included patient counseling about adverse effects of the medication, timepiece caps that reminded patients to take their medication, tips to enhance adherence, and reinforcement of positive behavior by nurses, pharmacists, lay health workers, or a telephonic system.³² This illustrates an important point in adherence interventions: more is better, and it usually takes a combination of approaches to improve adherence.^33,34

The only trial in the review that demonstrated that HBPM alone improved adherence randomized 628 patients to either HBPM or usual care for 6 weeks. The groups had similar compliance rates at baseline, and both demonstrated less adherence at the end of the 6-week trial. However, patients who measured their BP at home still demonstrated greater compliance than those receiving usual care (P < .05).³⁵

A more recent trial in 57 patients, 38 of whom measured their BP at home and 19 of whom received usual care, found greater medication adherence in the HBPM group than in the control group (100% vs 88%, P < .031). The HBPM group also reached their treatment goals significantly faster than the control group (P = .02).³⁶

Conclusion

Approximately 50% of individuals with hypertension who receive antihypertensive medication still do not reach their BP goal. One reason is nonadherence to medication, which is often related to treatment complexity, or pill burden. Given that most patients with hypertension will require more than 1 drug to manage their blood pressure, it is important that clinicians identify opportunities to simplify treatment. This may include fixed-dose combination therapy, which can improve adherence, as well as additional education regarding the efficacy and adverse effects of therapy.

The use of HBPM may also improve adherence by providing frequent feedback on treatment effectiveness.

It is important, however, that clinicians understand that no single approach to adherence will work for every patient. The greatest success comes with combining several approaches based on the barriers that affect each individual patient.

Although an estimated 1 out of 3 people in the United States has been diagnosed with hypertension, data from the 2007-2008 National Health and Nutrition Examination Survey found that just 72% are currently being treated and, of those, just half have their blood pressure (BP) controlled with lifestyle changes and/or medication.¹

The failure of so many people with hypertension to obtain BP control, despite the availability of numerous effective medications, is partially due to a lack of adherence to recommended treatments (eg, taking medication, following a diet, and executing lifestyle changes). Adherence is a significant problem in hypertension and evidence shows that just half of patients who initiate drug therapy are persistent with treatment after 1 year.²

Although few studies link nonadherence with long-term outcomes, 1 study found that patients who “forgot” to take their antihypertensive medication were nearly one-third more likely to experience a cardiovascular event or death (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.04-1.57).³ Adherence is important not only for the health of the patient, but also to provide overall cost savings from the reductions of hospitalizations for complications from an untreated disease.⁴

Barriers to adherence

A significant contributor to nonadherence is treatment complexity, which manifests in hypertension as pill burden. Up to 75% of patients will require more than 1 medication to control their BP; those with resistant hypertension will require 4 or more.^5,6 These medications must often be taken at different times of the day, with varying frequency.^6-9

Reducing the number of daily doses has been consistently found to enhance adherence, and should be considered routinely as a first-line strategy. Complex strategies (eg, group visits, designated office staff to assist hypertensive patients, pharmacist consultation and comanagement, exercise counseling, dietary counseling, multidisciplinary hypertension team care, specific interviewing techniques such as motivational interviewing) are promising, but individual clinicians may not have the resources to take advantage of such labor-intensive intervention. Further, when multimodal intervention is employed, it is often difficult to discern which component(s) of the intervention were most impactful, unless multifactorial study design is employed, which it rarely is. We await further randomized controlled trials in this regard.

A study of approximately 85,000 members of a large managed care organization found that the greater the number of antihypertensive medications prescribed, the lower the rate of patient adherence. Just 63% of those receiving 3-drug regimens and 55% of those receiving 4-drug regimens were completely adherent.¹⁰

In addition, many patients with hypertension, particularly older patients, have comorbid conditions (eg, dyslipidemia or diabetes) that also require treatment, leading to increased treatment complexity and pill burden.^11,12

One option for reducing pill burden is the use of fixed-dose therapies ( TABLE ). Since 2000, many new fixed-dose combinations, including at least 3 triple therapies, have entered the market.¹³ In addition, a so-called “poly-pill” that combines aspirin, 3 antihypertensives, and a statin is under investigation and demonstrating good results in reducing BP and cholesterol levels.¹⁴

TABLE

Currently available combination therapies

Studies have found that patients receiving fixed-dose combination pills are more likely to reach their target BP, physicians are more satisfied with their ability to manage hypertension, and adverse effects are either similar or less with the fixed-dose therapies compared with monotherapies.^15,16

Studies of adherence patterns among patients treated with fixed-dose combinations of antihypertensive agents vs separate antihypertensive agents demonstrate increased adherence among patients treated with fixed-dose combinations.^17-21 In a clinical trial involving 4146 participants who were treated with a fixed dose of amlodipine and atorvastatin or separate pills, 33% of patients in the fixed-dose cohort had ceased treatment by 12 months compared with 59% of patients who were taking the 2-pill regimen (HR, 2.17; 95% CI, 2.05–2.13; P < .0001), resulting in a 117% higher rate of nonadherence in the 2-pill regimen. The median persistence time (ie, time to discontinuation with medication) was 8 months with the 2-pill regimen, but 37 months or longer with the fixed-dose combination.²¹

A meta-analysis of 9 studies found that fixed-dose combinations reduced the risk of nonadherence by 26% compared with single-pill combination therapy.²²

One downside to fixed-dose therapy is cost. Out-of-pocket costs are a significant barrier to medication adherence and most fixed-dose options are branded drugs that generally require higher copayments or coinsurance vs generic single-pill drugs that may have copayments as low as $4.⁶

Other opportunities to improve adherence to antihypertensive medications

Other evidence-based opportunities to improve adherence to antihypertensive medications include improved relationships with, and communication from, health care providers, given that patients often do not understand their disease and recommended treatments.^23,24

Interviews with 826 patients with hypertension found that although 90% knew that lowering their BP would improve their health and 91% reported that a health care provider had told them that they had hypertension or high BP, 41% did not know their BP level. In addition, just 34% of patients with hypertension identified systolic BP (SBP) as the “top” number of their reading and only 32% identified diastolic BP (DBP) as the “bottom” number. Finally, only one-third of patients were able to identify both SBP and DBP, and one-quarter of them did not know the optimal level for either.²⁵

Other provider interventions that have resulted in improved adherence include changing medication to reduce or avoid adverse effects, simplifying dosing (as described earlier), and switching to less-expensive drugs if cost is an issue. Nurses and pharmacists are also important members of the team when it comes to improving adherence and reinforcing education.²⁴

Home blood pressure monitoring

Another reason for nonadherence is that patients may not believe they need treatment since hypertension rarely manifests with symptoms. Furthermore, patients may not perceive that the medication they take has any effect because they did not have symptoms to begin with. Home BP monitoring (HBPM), or self BP monitoring, is one tool for improving adherence, possibly by providing immediate feedback to patients on how well their BP is controlled.²⁶ Many major medical societies recommend HBPM as part of any hypertension management strategy.^27-30

Patients who use HBPM can avoid many limitations associated with office BP monitoring (OBPM), including poor measurement techniques, infrequent measurement, white coat hypertension, and masked hypertension. Patients can also avoid reverse white coat hypertension, where OBPM is normal although out-of-office BP is high.²⁸ Patients should take 3 readings at 1-minute intervals, usually in the morning and evening. The weekly average of these readings is their home BP (normotension is defined as an average BP <135/85 mm Hg).³¹ Typically, the HBPM monitoring is more accurate in identifying risk than OBPM when there are discrepancies between them.²⁸ It is good practice to instruct patients utilizing HBPM to bring their home BP device to the office for a comparison.

There is some evidence that HBPM may contribute to improved adherence. A systematic review of 11 randomized controlled trials found that in 6 trials the use of HBPM resulted in improved medication adherence, although in 5 of those studies additional interventions were used. These interventions included patient counseling about adverse effects of the medication, timepiece caps that reminded patients to take their medication, tips to enhance adherence, and reinforcement of positive behavior by nurses, pharmacists, lay health workers, or a telephonic system.³² This illustrates an important point in adherence interventions: more is better, and it usually takes a combination of approaches to improve adherence.^33,34

The only trial in the review that demonstrated that HBPM alone improved adherence randomized 628 patients to either HBPM or usual care for 6 weeks. The groups had similar compliance rates at baseline, and both demonstrated less adherence at the end of the 6-week trial. However, patients who measured their BP at home still demonstrated greater compliance than those receiving usual care (P < .05).³⁵

A more recent trial in 57 patients, 38 of whom measured their BP at home and 19 of whom received usual care, found greater medication adherence in the HBPM group than in the control group (100% vs 88%, P < .031). The HBPM group also reached their treatment goals significantly faster than the control group (P = .02).³⁶

Conclusion

Approximately 50% of individuals with hypertension who receive antihypertensive medication still do not reach their BP goal. One reason is nonadherence to medication, which is often related to treatment complexity, or pill burden. Given that most patients with hypertension will require more than 1 drug to manage their blood pressure, it is important that clinicians identify opportunities to simplify treatment. This may include fixed-dose combination therapy, which can improve adherence, as well as additional education regarding the efficacy and adverse effects of therapy.

The use of HBPM may also improve adherence by providing frequent feedback on treatment effectiveness.

It is important, however, that clinicians understand that no single approach to adherence will work for every patient. The greatest success comes with combining several approaches based on the barriers that affect each individual patient.

Introduction

The importance of acute coronary syndrome (ACS) (ie, patients with ST-segment elevation myocardial infarction [MI] [STEMI], non-ST segment elevation MI [NSTEMI], or unstable angina) in primary care is highlighted by its prevalence. Acute coronary syndrome was the primary or secondary discharge diagnosis in 1.19 million hospitalizations in the United States in 2009, a slight majority of which were in men.¹ Platelet activation plays a central role in the pathophysiology of ACS. Despite well established benefits of antiplatelet therapy in both primary and secondary prevention of ACS, adverse events—particularly bleeding—require ongoing vigilance.² Among the several classes of antiplatelet agents currently available, the thromboxane A₂ inhibitor (ie, aspirin) and P2Y₁₂ inhibitors (ie, clopidogrel, prasugrel, and ticagrelor) are those most commonly used; ticlopidine is not commonly used due to nausea/vomiting and bone marrow toxicity.³

Antiplatelet Agents

It is well established that hemostasis is protected by multilayered, overlapping, and sometimes redundant pathways. Even though currently available antiplatelet agents are highly efficacious in inhibiting 1 or more phases of platelet activity pertinent to coagulation (eg, activation, adhesion, and aggregation), because of the multiple backup pathways involved, no single antiplatelet agent is anticipated to totally eliminate platelet activity. In addition, every combination of antiplatelet agents—though potentially more efficacious because of multipathway activity—is also laden with greater bleeding risk. The 3 primary pathways of platelet activation for which pharmacologic antagonists have been developed are the thromboxane, adenosine diphosphonate (ADP)-P2Y₁₂, and ADP-A₂ pathways. While dual antiplatelet therapy with aspirin and clopidogrel may be the current standard of care, the focus of this review is on the ADP-P2Y₁₂ inhibitors as the two newest agents, prasugrel and ticagrelor, are less familiar to family physicians. The second section addresses questions often encountered by family physicians when caring for patients who have recently experienced ACS.

P2Y₁₂ Inhibitors

Two groups of agents exert their antiplatelet effects by inhibiting the platelet P2Y₁₂ receptor: (1) thienopyridines (ie, ticlopidine, clopidogrel, and prasugrel) and (2) the cyclopentyltriazolopyrimidines (ie, ticagrelor). Both groups inhibit ADP-dependent platelet function but at different sites on the platelet P2Y₁₂ receptor. Thienopyridine activity is mediated via short-lived active metabolites formed in the liver. Platelet exposure to the active metabolite of prasugrel is about 10-fold higher than to the active metabolite of clopidogrel, resulting in a higher level and less individual variation of platelet inhibition with prasugrel. Hepatic metabolism of clopidogrel makes it subject to genetic, as well as drug-induced, variation in activity; prasugrel is not affected by these same limitations. Recovery of platelet function following withdrawal of thienopyridine therapy occurs over 7 to 8 days as a function of platelet turnover.^2,3 This slow recovery of platelet function has important implications when any surgical intervention is needed.

In contrast to the thienopyridines, ticagrelor does not require metabolic activation by the liver. Ticagrelor and its active metabolite display approximately equipotent antiplatelet activity and are direct P2Y₁₂ inhibitors. Ticargrelor non-competitively antagonizes ADP-induced receptor activation. Ticagrelor is rapidly absorbed reaching its peak plasma concentration in 1.5 to 3 hours, thereby providing a rapid antiplatelet effect. Twice-daily administration is required because of its rapid offset of platelet inhibition.^2,4,5

Prasugrel

Prasugrel is indicated by the US Food and Drug Administration (FDA) for reduction of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with ACS who are to be managed with percutaneous coronary intervention (PCI) as follows: (1) unstable angina or NSTEMI or (2) STEMI when managed with primary or delayed PCI.⁶

The efficacy and safety of prasugrel have been investigated in several clinical trials. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 is the largest and has many planned sub-analyses ( TABLE 1 ).^7-9 TRITON TIMI 38 involved patients with moderate- to high-risk ACS scheduled for PCI
(N = 13,608).⁷ Patients were randomized to prasugrel 60 mg as a loading dose followed by 10 mg daily or clopidogrel 300 mg as a loading dose followed by 75 mg daily for 6 to 15 months. Aspirin 75 to 162 mg once daily was recommended, but was left up to the physician. The primary efficacy end point was a composite of CV death, nonfatal MI, or nonfatal stroke.

Findings from TRITON TIMI 38 show that, compared with clopidogrel, prasugrel was associated with significantly reduced rates of ischemic events, including nonfatal MI and stent thrombosis. The benefit with prasugrel was primarily due to a significant reduction in the rate of MI compared with clopidogrel. However, patients treated with prasugrel experienced a higher rate of major bleeding, including fatal and life-threatening bleeding. Prasugrel was found to be more effective than clopidogrel in preventing ischemic events without excess bleeding in patients with STEMI undergoing secondary PCI (treated between 12 hours and 14 days after symptom onset). In patients with ACS undergoing PCI without stent implantation, ischemic events occurred at similar rates in patients treated with prasugrel or clopidogrel; however, bleeding was more common with prasugrel.

Not all patients benefited from prasugrel therapy. Compared with clopidogrel, patients with previous stroke/transient ischemic attack (TIA) had net harm from prasugrel. In addition, no net benefit from prasugrel compared with clopidogrel was observed in patients age ≥75 years or body weight <60 kg. The results of TRITON TIMI 38 contributed to the boxed warnings regarding bleeding risk recommending that prasugrel not be used in patients age ≥75 years, in patients with active pathological bleeding or a history of TIA or stroke, or patients likely to undergo coronary artery bypass graft (CABG) surgery. In addition, patients with body weight < 60 kg are also at increased risk for bleeding.⁶

TABLE 1

Prasugrel: TRITON-TIMI 38 and subanalyses

Ticagrelor

Ticagrelor is the most recent antiplatelet agent to be approved by the US FDA. Ticagrelor is indicated to reduce the rate of thrombotic CV events in patients with ACS (eg, unstable angina, NSTEMI, or STEMI).¹⁰

The efficacy and safety of ticagrelor has been assessed in the Study of Platelet Inhibition and Patient Outcomes (PLATO) and several planned sub-analyses ( TABLE 2 ).^11-16 PLATO was a 12-month, multicenter, double-blind, randomized trial that involved patients with ACS with or without ST-segment elevation (N = 18,624).¹¹ Patients were randomized to ticagrelor 180 mg loading dose then 90 mg twice daily or clopidogrel 300 to 600 mg loading dose then 75 mg once daily for 12 months. The primary efficacy end point was a composite of death from vascular causes, MI, or stroke.

The results of PLATO and sub-analyses show that in patients with ACS and compared with clopidogrel, ticagrelor significantly reduced the primary efficacy end point with a similar rate of major bleeding
( TABLE 1 ). These safety results contributed to the boxed warnings regarding bleeding risk that ticagrelor not be used in patients with active pathological bleeding or a history of intracranial hemorrhage, or in patients planned to undergo urgent CABG surgery. In addition, maintenance aspirin therapy at a dose above 100 mg reduces the effectiveness of ticagrelor and should be avoided.¹⁰

Consistent with the general PLATO population, in patients intended for non-invasive management, ticagrelor significantly reduced the rate of death from vascular causes, MI, or stroke compared with clopidogrel with a similar rate of major bleeding. In patients with ACS and ST elevation or left bundle branch block planned for PCI, ticagrelor reduced CV and all-cause death, MI, stent thrombosis, and improved survival compared with clopidogrel, with a similar rate of major bleeding. Ticagrelor, compared with clopidogrel, reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor. Finally, in ACS with chronic kidney disease (estimated creatinine clearance < 60 mL/minute), ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non–CABG-related bleeding.

TABLE 2

Ticagrelor: PLATO and subanalyses

Common Questions Regarding Antiplatelet Therapy in Primary Care

The preceding discussion confirms that many patients with ACS benefit from antiplatelet therapy. However, the use of antiplatelet agents in primary care can be challenging. The following are some of the evolving issues and questions regarding antiplatelet therapy faced by family physicians.

If a patient has experienced gastrointestinal bleeding while taking low-dose aspirin in the past and has an acute coronary syndrome, what course of action should be taken?

Dual antiplatelet therapy is still recommended in this setting, but therapy with a proton pump inhibitor (PPI) for gastrointestinal (GI) protection is recommended.^2,3,17 For patients at low risk of upper GI bleeding, routine PPI prophylaxis is not recommended. Currently available data do not demonstrate the prophylactic superiority of one PPI over another, but do show that PPI therapy is more effective in decreasing GI bleeding associated with aspirin and is, therefore, preferred over a histamine H₂ receptor antagonist.¹⁷ For instance, high-dose famotidine has been shown to be less effective than pantoprazole in patients with aspirin-related peptic ulcers/erosions.¹⁸

Can a proton pump inhibitor be used for gastrointestinal protection in conjunction with clopidogrel?

Yes, although the evidence is conflicting about whether specific PPIs should be avoided because of reduced clinical efficacy of clopidogrel. The results of a meta-analysis of 23 studies demonstrated a clinically significant interaction that reduces the antiplatelet effectiveness of clopidogrel when combined with some PPIs.¹⁹ The results of 4 prospective, crossover pharmacokinetic studies in healthy subjects (N = 282) also suggest an interaction between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.²⁰ A subanalysis of PLATO showed that the use of a PPI was independently associated with a higher rate of CV events in patients with ACS treated with clopidogrel or ticagrelor.²¹ The observed effect with both agents, as well as a higher rate of major bleeding among PPI vs non-PPI users suggests that PPI use may be more of a marker for rather than a cause of higher rates of CV events. In fact, data from the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) found that in patients treated with clopidogrel and aspirin, the addition of omeprazole reduced the rate of a GI event, compared with placebo at 180 days (1.1% vs. 2.9%, respectively;
P < .001).²² Overt upper GI bleeding occurred less frequently in the omeprazole group (hazard ratio, 0.13; 95% confidence interval, 0.03 to 0.56; P = .001). A CV event was observed in 4.9% of patients treated with omeprazole and 5.7% of placebo patients (P = .96). While limited, these prospective data do not suggest a detriment to clopidogrel efficacy when used in combination with a PPI. The dose of PPI to use for GI protection is not well-established; the following drugs and doses have been used: omeprazole 20 to 40 mg once daily; esomeprazole 20 mg once or twice daily; pantoprazole 20 mg once daily; or lansoprazole 30 mg once daily.^18,23-28

Should I avoid starting clopidogrel in patients with acute coronary syndrome because of concerns about “poor metabolizers”?

Clopidogrel is a prodrug, requiring CYP450 metabolism to its active metabolite. Because of genetic CYP450 variations, as many as one-third of patients lack fully active CYP450 pathways, resulting in reduced (or even absent) conversion from the parent drug to the active metabolite, with a corresponding diminution of antiplatelet effects.^3,29 Recent recommendations about dealing with these genetic polymorphisms include direct measurement of CYP450 pathway status and selection of alternative pharmacologic agents which are not dependent upon similar CYP pathway activation. There are, unfortunately, no prospective clinical trials based upon CYP2C19 genotyping confirming that patient selection based upon genotyping is associated with improved outcomes.

In terms of alternative antiplatelet therapy in clopidogrel nonresponders, the Response to Ticagrelor in Clopidogrel Nonresponders and Responders (RESPOND) study shows ticagrelor to be beneficial, at least as measured in vitro.³⁰ Following laboratory assessment of patients’ responsiveness to clopidogrel, both responders and nonresponders were randomized to clopidogrel or ticagrelor. After 14 days, all clopidogrel nonresponders and half of the responders switched treatment. The antiplatelet effects of ticagrelor were similar whether the patient was a clopidogrel responder or not. The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) showed higher inhibition of platelet aggregation (IPA) with prasugrel 60 mg compared with clopidogrel 600 mg 6 hours after initiation.³¹ Following crossover, IPA was higher in subjects receiving prasugrel 10 mg/d compared with clopidogrel 150 mg/d (61% vs 46%, respectively; P < .0001). While not measuring clopidogrel responsiveness, this suggests that prasugrel might be effective in clopidogrel nonresponders. Not all patients treated with prasugrel achieve optimal inhibition of platelet reactivity. In patients who underwent successful PCI for ACS (N = 301) 25.2% were observed to have high on-treatment platelet reactivity following a 60 mg loading dose of prasugrel.³² Such patients had a significantly higher risk for a major adverse cardiovascular event after PCI. The clinical trials which demonstrate improved clinical outcomes when clopidogrel is compared with other antiplatelet agents suggest that the above-mentioned in vitro metrics are clinically relevant.

I’ve heard a lot about testing platelet aggregability. Should I be considering that for my patients?

Not at the present time. One prospective study evaluated the capability of platelet function tests to predict clinical outcome in patients taking clopidogrel undergoing elective stent implantation.³³ On-treatment platelet reactivity was measured using: light transmittance aggregometry, VerifyNow P2Y12, Plateletworks, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/ADP cartridge and Innovance PFA P2Y). After 1 year of follow-up, only the light transmittance aggregometry, VerifyNow, Plateletworks, and Innovance PFA P2Y tests were significantly associated with patient outcome, but had only modest predictive accuracy. Also, none of the tests studied provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation.

How concerning are the findings on ticagrelor and dyspnea?

The occurrence of dyspnea associated with ticagrelor was observed during its clinical development. While the mechanism is not known, dyspnea is a transient phenomenon, and there is no suggestion that ticagrelor is associated with an increased incidence of heart failure.

The incidence and characterization of dyspnea has been investigated in subanalyses of 2 large clinical trials of ticagrelor. Prospective analysis of the ONSET/OFFSET study (N = 123) showed that dyspnea was experienced by more patients treated with ticagrelor than clopidogrel or placebo over 6 weeks (38.6% vs 9.3% vs 8.3%, respectively; P < .001).³⁴ Episodes of dyspnea were generally mild, lasted <24 hours, and easily tolerated. Moderate dyspnea that led to study discontinuation occurred in 3 patients (5.3%) treated with ticagrelor. Dyspnea occurred within the first 24 hours in 8 of 22 patients (36.4%) and within the first week in 17 of 22 patients (77.3%) of the ticagrelor-treated patients who experienced dyspnea. Dyspnea persisted through the study follow-up (10 days after the 6 week study) in 3 of 22 patients (13.6%) treated with ticagrelor. Dyspnea was not associated with any significant adverse change in cardiac or pulmonary function tests.³⁴

In a subanalysis of the PLATO study to investigate the occurrence of dyspnea (N = 18,421), dyspnea occurred in 14.5% of patients treated with ticagrelor and 8.7% of patients treated with clopidogrel.³⁵ Severe dyspnea occurred in 0.4% and 0.3% of patients, respectively. Dyspnea had no impact on the composite end point after excluding dyspnea that occurred after the secondary end point of MI. The mechanism whereby ticagrelor induces dyspnea is not certain, but may be mediated via an adenosine-related mechanism.³⁶

Conclusion

Aspirin and clopidogrel have been the predominant antiplatelet agents used in the management of patients with ACS, yet their use can be challenging. Differences in the clinical pharmacology of prasugrel and ticagrelor provide the opportunity to address some of these challenges and better enable antiplatelet therapy to be individualized.

Introduction

The importance of acute coronary syndrome (ACS) (ie, patients with ST-segment elevation myocardial infarction [MI] [STEMI], non-ST segment elevation MI [NSTEMI], or unstable angina) in primary care is highlighted by its prevalence. Acute coronary syndrome was the primary or secondary discharge diagnosis in 1.19 million hospitalizations in the United States in 2009, a slight majority of which were in men.¹ Platelet activation plays a central role in the pathophysiology of ACS. Despite well established benefits of antiplatelet therapy in both primary and secondary prevention of ACS, adverse events—particularly bleeding—require ongoing vigilance.² Among the several classes of antiplatelet agents currently available, the thromboxane A₂ inhibitor (ie, aspirin) and P2Y₁₂ inhibitors (ie, clopidogrel, prasugrel, and ticagrelor) are those most commonly used; ticlopidine is not commonly used due to nausea/vomiting and bone marrow toxicity.³

Antiplatelet Agents

It is well established that hemostasis is protected by multilayered, overlapping, and sometimes redundant pathways. Even though currently available antiplatelet agents are highly efficacious in inhibiting 1 or more phases of platelet activity pertinent to coagulation (eg, activation, adhesion, and aggregation), because of the multiple backup pathways involved, no single antiplatelet agent is anticipated to totally eliminate platelet activity. In addition, every combination of antiplatelet agents—though potentially more efficacious because of multipathway activity—is also laden with greater bleeding risk. The 3 primary pathways of platelet activation for which pharmacologic antagonists have been developed are the thromboxane, adenosine diphosphonate (ADP)-P2Y₁₂, and ADP-A₂ pathways. While dual antiplatelet therapy with aspirin and clopidogrel may be the current standard of care, the focus of this review is on the ADP-P2Y₁₂ inhibitors as the two newest agents, prasugrel and ticagrelor, are less familiar to family physicians. The second section addresses questions often encountered by family physicians when caring for patients who have recently experienced ACS.

P2Y₁₂ Inhibitors

Two groups of agents exert their antiplatelet effects by inhibiting the platelet P2Y₁₂ receptor: (1) thienopyridines (ie, ticlopidine, clopidogrel, and prasugrel) and (2) the cyclopentyltriazolopyrimidines (ie, ticagrelor). Both groups inhibit ADP-dependent platelet function but at different sites on the platelet P2Y₁₂ receptor. Thienopyridine activity is mediated via short-lived active metabolites formed in the liver. Platelet exposure to the active metabolite of prasugrel is about 10-fold higher than to the active metabolite of clopidogrel, resulting in a higher level and less individual variation of platelet inhibition with prasugrel. Hepatic metabolism of clopidogrel makes it subject to genetic, as well as drug-induced, variation in activity; prasugrel is not affected by these same limitations. Recovery of platelet function following withdrawal of thienopyridine therapy occurs over 7 to 8 days as a function of platelet turnover.^2,3 This slow recovery of platelet function has important implications when any surgical intervention is needed.

In contrast to the thienopyridines, ticagrelor does not require metabolic activation by the liver. Ticagrelor and its active metabolite display approximately equipotent antiplatelet activity and are direct P2Y₁₂ inhibitors. Ticargrelor non-competitively antagonizes ADP-induced receptor activation. Ticagrelor is rapidly absorbed reaching its peak plasma concentration in 1.5 to 3 hours, thereby providing a rapid antiplatelet effect. Twice-daily administration is required because of its rapid offset of platelet inhibition.^2,4,5

Prasugrel

Prasugrel is indicated by the US Food and Drug Administration (FDA) for reduction of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with ACS who are to be managed with percutaneous coronary intervention (PCI) as follows: (1) unstable angina or NSTEMI or (2) STEMI when managed with primary or delayed PCI.⁶

The efficacy and safety of prasugrel have been investigated in several clinical trials. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 is the largest and has many planned sub-analyses ( TABLE 1 ).^7-9 TRITON TIMI 38 involved patients with moderate- to high-risk ACS scheduled for PCI
(N = 13,608).⁷ Patients were randomized to prasugrel 60 mg as a loading dose followed by 10 mg daily or clopidogrel 300 mg as a loading dose followed by 75 mg daily for 6 to 15 months. Aspirin 75 to 162 mg once daily was recommended, but was left up to the physician. The primary efficacy end point was a composite of CV death, nonfatal MI, or nonfatal stroke.

Findings from TRITON TIMI 38 show that, compared with clopidogrel, prasugrel was associated with significantly reduced rates of ischemic events, including nonfatal MI and stent thrombosis. The benefit with prasugrel was primarily due to a significant reduction in the rate of MI compared with clopidogrel. However, patients treated with prasugrel experienced a higher rate of major bleeding, including fatal and life-threatening bleeding. Prasugrel was found to be more effective than clopidogrel in preventing ischemic events without excess bleeding in patients with STEMI undergoing secondary PCI (treated between 12 hours and 14 days after symptom onset). In patients with ACS undergoing PCI without stent implantation, ischemic events occurred at similar rates in patients treated with prasugrel or clopidogrel; however, bleeding was more common with prasugrel.

Not all patients benefited from prasugrel therapy. Compared with clopidogrel, patients with previous stroke/transient ischemic attack (TIA) had net harm from prasugrel. In addition, no net benefit from prasugrel compared with clopidogrel was observed in patients age ≥75 years or body weight <60 kg. The results of TRITON TIMI 38 contributed to the boxed warnings regarding bleeding risk recommending that prasugrel not be used in patients age ≥75 years, in patients with active pathological bleeding or a history of TIA or stroke, or patients likely to undergo coronary artery bypass graft (CABG) surgery. In addition, patients with body weight < 60 kg are also at increased risk for bleeding.⁶

TABLE 1

Prasugrel: TRITON-TIMI 38 and subanalyses

Ticagrelor

Ticagrelor is the most recent antiplatelet agent to be approved by the US FDA. Ticagrelor is indicated to reduce the rate of thrombotic CV events in patients with ACS (eg, unstable angina, NSTEMI, or STEMI).¹⁰

The efficacy and safety of ticagrelor has been assessed in the Study of Platelet Inhibition and Patient Outcomes (PLATO) and several planned sub-analyses ( TABLE 2 ).^11-16 PLATO was a 12-month, multicenter, double-blind, randomized trial that involved patients with ACS with or without ST-segment elevation (N = 18,624).¹¹ Patients were randomized to ticagrelor 180 mg loading dose then 90 mg twice daily or clopidogrel 300 to 600 mg loading dose then 75 mg once daily for 12 months. The primary efficacy end point was a composite of death from vascular causes, MI, or stroke.

The results of PLATO and sub-analyses show that in patients with ACS and compared with clopidogrel, ticagrelor significantly reduced the primary efficacy end point with a similar rate of major bleeding
( TABLE 1 ). These safety results contributed to the boxed warnings regarding bleeding risk that ticagrelor not be used in patients with active pathological bleeding or a history of intracranial hemorrhage, or in patients planned to undergo urgent CABG surgery. In addition, maintenance aspirin therapy at a dose above 100 mg reduces the effectiveness of ticagrelor and should be avoided.¹⁰

Consistent with the general PLATO population, in patients intended for non-invasive management, ticagrelor significantly reduced the rate of death from vascular causes, MI, or stroke compared with clopidogrel with a similar rate of major bleeding. In patients with ACS and ST elevation or left bundle branch block planned for PCI, ticagrelor reduced CV and all-cause death, MI, stent thrombosis, and improved survival compared with clopidogrel, with a similar rate of major bleeding. Ticagrelor, compared with clopidogrel, reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor. Finally, in ACS with chronic kidney disease (estimated creatinine clearance < 60 mL/minute), ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non–CABG-related bleeding.

TABLE 2

Ticagrelor: PLATO and subanalyses

Common Questions Regarding Antiplatelet Therapy in Primary Care

The preceding discussion confirms that many patients with ACS benefit from antiplatelet therapy. However, the use of antiplatelet agents in primary care can be challenging. The following are some of the evolving issues and questions regarding antiplatelet therapy faced by family physicians.

If a patient has experienced gastrointestinal bleeding while taking low-dose aspirin in the past and has an acute coronary syndrome, what course of action should be taken?

Dual antiplatelet therapy is still recommended in this setting, but therapy with a proton pump inhibitor (PPI) for gastrointestinal (GI) protection is recommended.^2,3,17 For patients at low risk of upper GI bleeding, routine PPI prophylaxis is not recommended. Currently available data do not demonstrate the prophylactic superiority of one PPI over another, but do show that PPI therapy is more effective in decreasing GI bleeding associated with aspirin and is, therefore, preferred over a histamine H₂ receptor antagonist.¹⁷ For instance, high-dose famotidine has been shown to be less effective than pantoprazole in patients with aspirin-related peptic ulcers/erosions.¹⁸

Can a proton pump inhibitor be used for gastrointestinal protection in conjunction with clopidogrel?

Yes, although the evidence is conflicting about whether specific PPIs should be avoided because of reduced clinical efficacy of clopidogrel. The results of a meta-analysis of 23 studies demonstrated a clinically significant interaction that reduces the antiplatelet effectiveness of clopidogrel when combined with some PPIs.¹⁹ The results of 4 prospective, crossover pharmacokinetic studies in healthy subjects (N = 282) also suggest an interaction between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.²⁰ A subanalysis of PLATO showed that the use of a PPI was independently associated with a higher rate of CV events in patients with ACS treated with clopidogrel or ticagrelor.²¹ The observed effect with both agents, as well as a higher rate of major bleeding among PPI vs non-PPI users suggests that PPI use may be more of a marker for rather than a cause of higher rates of CV events. In fact, data from the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) found that in patients treated with clopidogrel and aspirin, the addition of omeprazole reduced the rate of a GI event, compared with placebo at 180 days (1.1% vs. 2.9%, respectively;
P < .001).²² Overt upper GI bleeding occurred less frequently in the omeprazole group (hazard ratio, 0.13; 95% confidence interval, 0.03 to 0.56; P = .001). A CV event was observed in 4.9% of patients treated with omeprazole and 5.7% of placebo patients (P = .96). While limited, these prospective data do not suggest a detriment to clopidogrel efficacy when used in combination with a PPI. The dose of PPI to use for GI protection is not well-established; the following drugs and doses have been used: omeprazole 20 to 40 mg once daily; esomeprazole 20 mg once or twice daily; pantoprazole 20 mg once daily; or lansoprazole 30 mg once daily.^18,23-28

Should I avoid starting clopidogrel in patients with acute coronary syndrome because of concerns about “poor metabolizers”?

Clopidogrel is a prodrug, requiring CYP450 metabolism to its active metabolite. Because of genetic CYP450 variations, as many as one-third of patients lack fully active CYP450 pathways, resulting in reduced (or even absent) conversion from the parent drug to the active metabolite, with a corresponding diminution of antiplatelet effects.^3,29 Recent recommendations about dealing with these genetic polymorphisms include direct measurement of CYP450 pathway status and selection of alternative pharmacologic agents which are not dependent upon similar CYP pathway activation. There are, unfortunately, no prospective clinical trials based upon CYP2C19 genotyping confirming that patient selection based upon genotyping is associated with improved outcomes.

In terms of alternative antiplatelet therapy in clopidogrel nonresponders, the Response to Ticagrelor in Clopidogrel Nonresponders and Responders (RESPOND) study shows ticagrelor to be beneficial, at least as measured in vitro.³⁰ Following laboratory assessment of patients’ responsiveness to clopidogrel, both responders and nonresponders were randomized to clopidogrel or ticagrelor. After 14 days, all clopidogrel nonresponders and half of the responders switched treatment. The antiplatelet effects of ticagrelor were similar whether the patient was a clopidogrel responder or not. The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) showed higher inhibition of platelet aggregation (IPA) with prasugrel 60 mg compared with clopidogrel 600 mg 6 hours after initiation.³¹ Following crossover, IPA was higher in subjects receiving prasugrel 10 mg/d compared with clopidogrel 150 mg/d (61% vs 46%, respectively; P < .0001). While not measuring clopidogrel responsiveness, this suggests that prasugrel might be effective in clopidogrel nonresponders. Not all patients treated with prasugrel achieve optimal inhibition of platelet reactivity. In patients who underwent successful PCI for ACS (N = 301) 25.2% were observed to have high on-treatment platelet reactivity following a 60 mg loading dose of prasugrel.³² Such patients had a significantly higher risk for a major adverse cardiovascular event after PCI. The clinical trials which demonstrate improved clinical outcomes when clopidogrel is compared with other antiplatelet agents suggest that the above-mentioned in vitro metrics are clinically relevant.

I’ve heard a lot about testing platelet aggregability. Should I be considering that for my patients?

Not at the present time. One prospective study evaluated the capability of platelet function tests to predict clinical outcome in patients taking clopidogrel undergoing elective stent implantation.³³ On-treatment platelet reactivity was measured using: light transmittance aggregometry, VerifyNow P2Y12, Plateletworks, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/ADP cartridge and Innovance PFA P2Y). After 1 year of follow-up, only the light transmittance aggregometry, VerifyNow, Plateletworks, and Innovance PFA P2Y tests were significantly associated with patient outcome, but had only modest predictive accuracy. Also, none of the tests studied provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation.

How concerning are the findings on ticagrelor and dyspnea?

The occurrence of dyspnea associated with ticagrelor was observed during its clinical development. While the mechanism is not known, dyspnea is a transient phenomenon, and there is no suggestion that ticagrelor is associated with an increased incidence of heart failure.

The incidence and characterization of dyspnea has been investigated in subanalyses of 2 large clinical trials of ticagrelor. Prospective analysis of the ONSET/OFFSET study (N = 123) showed that dyspnea was experienced by more patients treated with ticagrelor than clopidogrel or placebo over 6 weeks (38.6% vs 9.3% vs 8.3%, respectively; P < .001).³⁴ Episodes of dyspnea were generally mild, lasted <24 hours, and easily tolerated. Moderate dyspnea that led to study discontinuation occurred in 3 patients (5.3%) treated with ticagrelor. Dyspnea occurred within the first 24 hours in 8 of 22 patients (36.4%) and within the first week in 17 of 22 patients (77.3%) of the ticagrelor-treated patients who experienced dyspnea. Dyspnea persisted through the study follow-up (10 days after the 6 week study) in 3 of 22 patients (13.6%) treated with ticagrelor. Dyspnea was not associated with any significant adverse change in cardiac or pulmonary function tests.³⁴

In a subanalysis of the PLATO study to investigate the occurrence of dyspnea (N = 18,421), dyspnea occurred in 14.5% of patients treated with ticagrelor and 8.7% of patients treated with clopidogrel.³⁵ Severe dyspnea occurred in 0.4% and 0.3% of patients, respectively. Dyspnea had no impact on the composite end point after excluding dyspnea that occurred after the secondary end point of MI. The mechanism whereby ticagrelor induces dyspnea is not certain, but may be mediated via an adenosine-related mechanism.³⁶

Conclusion

Aspirin and clopidogrel have been the predominant antiplatelet agents used in the management of patients with ACS, yet their use can be challenging. Differences in the clinical pharmacology of prasugrel and ticagrelor provide the opportunity to address some of these challenges and better enable antiplatelet therapy to be individualized.

Introduction

The importance of acute coronary syndrome (ACS) (ie, patients with ST-segment elevation myocardial infarction [MI] [STEMI], non-ST segment elevation MI [NSTEMI], or unstable angina) in primary care is highlighted by its prevalence. Acute coronary syndrome was the primary or secondary discharge diagnosis in 1.19 million hospitalizations in the United States in 2009, a slight majority of which were in men.¹ Platelet activation plays a central role in the pathophysiology of ACS. Despite well established benefits of antiplatelet therapy in both primary and secondary prevention of ACS, adverse events—particularly bleeding—require ongoing vigilance.² Among the several classes of antiplatelet agents currently available, the thromboxane A₂ inhibitor (ie, aspirin) and P2Y₁₂ inhibitors (ie, clopidogrel, prasugrel, and ticagrelor) are those most commonly used; ticlopidine is not commonly used due to nausea/vomiting and bone marrow toxicity.³

Antiplatelet Agents

It is well established that hemostasis is protected by multilayered, overlapping, and sometimes redundant pathways. Even though currently available antiplatelet agents are highly efficacious in inhibiting 1 or more phases of platelet activity pertinent to coagulation (eg, activation, adhesion, and aggregation), because of the multiple backup pathways involved, no single antiplatelet agent is anticipated to totally eliminate platelet activity. In addition, every combination of antiplatelet agents—though potentially more efficacious because of multipathway activity—is also laden with greater bleeding risk. The 3 primary pathways of platelet activation for which pharmacologic antagonists have been developed are the thromboxane, adenosine diphosphonate (ADP)-P2Y₁₂, and ADP-A₂ pathways. While dual antiplatelet therapy with aspirin and clopidogrel may be the current standard of care, the focus of this review is on the ADP-P2Y₁₂ inhibitors as the two newest agents, prasugrel and ticagrelor, are less familiar to family physicians. The second section addresses questions often encountered by family physicians when caring for patients who have recently experienced ACS.

P2Y₁₂ Inhibitors

Two groups of agents exert their antiplatelet effects by inhibiting the platelet P2Y₁₂ receptor: (1) thienopyridines (ie, ticlopidine, clopidogrel, and prasugrel) and (2) the cyclopentyltriazolopyrimidines (ie, ticagrelor). Both groups inhibit ADP-dependent platelet function but at different sites on the platelet P2Y₁₂ receptor. Thienopyridine activity is mediated via short-lived active metabolites formed in the liver. Platelet exposure to the active metabolite of prasugrel is about 10-fold higher than to the active metabolite of clopidogrel, resulting in a higher level and less individual variation of platelet inhibition with prasugrel. Hepatic metabolism of clopidogrel makes it subject to genetic, as well as drug-induced, variation in activity; prasugrel is not affected by these same limitations. Recovery of platelet function following withdrawal of thienopyridine therapy occurs over 7 to 8 days as a function of platelet turnover.^2,3 This slow recovery of platelet function has important implications when any surgical intervention is needed.

In contrast to the thienopyridines, ticagrelor does not require metabolic activation by the liver. Ticagrelor and its active metabolite display approximately equipotent antiplatelet activity and are direct P2Y₁₂ inhibitors. Ticargrelor non-competitively antagonizes ADP-induced receptor activation. Ticagrelor is rapidly absorbed reaching its peak plasma concentration in 1.5 to 3 hours, thereby providing a rapid antiplatelet effect. Twice-daily administration is required because of its rapid offset of platelet inhibition.^2,4,5

Prasugrel

Prasugrel is indicated by the US Food and Drug Administration (FDA) for reduction of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with ACS who are to be managed with percutaneous coronary intervention (PCI) as follows: (1) unstable angina or NSTEMI or (2) STEMI when managed with primary or delayed PCI.⁶

The efficacy and safety of prasugrel have been investigated in several clinical trials. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 is the largest and has many planned sub-analyses ( TABLE 1 ).^7-9 TRITON TIMI 38 involved patients with moderate- to high-risk ACS scheduled for PCI
(N = 13,608).⁷ Patients were randomized to prasugrel 60 mg as a loading dose followed by 10 mg daily or clopidogrel 300 mg as a loading dose followed by 75 mg daily for 6 to 15 months. Aspirin 75 to 162 mg once daily was recommended, but was left up to the physician. The primary efficacy end point was a composite of CV death, nonfatal MI, or nonfatal stroke.

Findings from TRITON TIMI 38 show that, compared with clopidogrel, prasugrel was associated with significantly reduced rates of ischemic events, including nonfatal MI and stent thrombosis. The benefit with prasugrel was primarily due to a significant reduction in the rate of MI compared with clopidogrel. However, patients treated with prasugrel experienced a higher rate of major bleeding, including fatal and life-threatening bleeding. Prasugrel was found to be more effective than clopidogrel in preventing ischemic events without excess bleeding in patients with STEMI undergoing secondary PCI (treated between 12 hours and 14 days after symptom onset). In patients with ACS undergoing PCI without stent implantation, ischemic events occurred at similar rates in patients treated with prasugrel or clopidogrel; however, bleeding was more common with prasugrel.

Not all patients benefited from prasugrel therapy. Compared with clopidogrel, patients with previous stroke/transient ischemic attack (TIA) had net harm from prasugrel. In addition, no net benefit from prasugrel compared with clopidogrel was observed in patients age ≥75 years or body weight <60 kg. The results of TRITON TIMI 38 contributed to the boxed warnings regarding bleeding risk recommending that prasugrel not be used in patients age ≥75 years, in patients with active pathological bleeding or a history of TIA or stroke, or patients likely to undergo coronary artery bypass graft (CABG) surgery. In addition, patients with body weight < 60 kg are also at increased risk for bleeding.⁶

TABLE 1

Prasugrel: TRITON-TIMI 38 and subanalyses

Ticagrelor

Ticagrelor is the most recent antiplatelet agent to be approved by the US FDA. Ticagrelor is indicated to reduce the rate of thrombotic CV events in patients with ACS (eg, unstable angina, NSTEMI, or STEMI).¹⁰

The efficacy and safety of ticagrelor has been assessed in the Study of Platelet Inhibition and Patient Outcomes (PLATO) and several planned sub-analyses ( TABLE 2 ).^11-16 PLATO was a 12-month, multicenter, double-blind, randomized trial that involved patients with ACS with or without ST-segment elevation (N = 18,624).¹¹ Patients were randomized to ticagrelor 180 mg loading dose then 90 mg twice daily or clopidogrel 300 to 600 mg loading dose then 75 mg once daily for 12 months. The primary efficacy end point was a composite of death from vascular causes, MI, or stroke.

The results of PLATO and sub-analyses show that in patients with ACS and compared with clopidogrel, ticagrelor significantly reduced the primary efficacy end point with a similar rate of major bleeding
( TABLE 1 ). These safety results contributed to the boxed warnings regarding bleeding risk that ticagrelor not be used in patients with active pathological bleeding or a history of intracranial hemorrhage, or in patients planned to undergo urgent CABG surgery. In addition, maintenance aspirin therapy at a dose above 100 mg reduces the effectiveness of ticagrelor and should be avoided.¹⁰

Consistent with the general PLATO population, in patients intended for non-invasive management, ticagrelor significantly reduced the rate of death from vascular causes, MI, or stroke compared with clopidogrel with a similar rate of major bleeding. In patients with ACS and ST elevation or left bundle branch block planned for PCI, ticagrelor reduced CV and all-cause death, MI, stent thrombosis, and improved survival compared with clopidogrel, with a similar rate of major bleeding. Ticagrelor, compared with clopidogrel, reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor. Finally, in ACS with chronic kidney disease (estimated creatinine clearance < 60 mL/minute), ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non–CABG-related bleeding.

TABLE 2

Ticagrelor: PLATO and subanalyses

Common Questions Regarding Antiplatelet Therapy in Primary Care

The preceding discussion confirms that many patients with ACS benefit from antiplatelet therapy. However, the use of antiplatelet agents in primary care can be challenging. The following are some of the evolving issues and questions regarding antiplatelet therapy faced by family physicians.

If a patient has experienced gastrointestinal bleeding while taking low-dose aspirin in the past and has an acute coronary syndrome, what course of action should be taken?

Dual antiplatelet therapy is still recommended in this setting, but therapy with a proton pump inhibitor (PPI) for gastrointestinal (GI) protection is recommended.^2,3,17 For patients at low risk of upper GI bleeding, routine PPI prophylaxis is not recommended. Currently available data do not demonstrate the prophylactic superiority of one PPI over another, but do show that PPI therapy is more effective in decreasing GI bleeding associated with aspirin and is, therefore, preferred over a histamine H₂ receptor antagonist.¹⁷ For instance, high-dose famotidine has been shown to be less effective than pantoprazole in patients with aspirin-related peptic ulcers/erosions.¹⁸

Can a proton pump inhibitor be used for gastrointestinal protection in conjunction with clopidogrel?

Yes, although the evidence is conflicting about whether specific PPIs should be avoided because of reduced clinical efficacy of clopidogrel. The results of a meta-analysis of 23 studies demonstrated a clinically significant interaction that reduces the antiplatelet effectiveness of clopidogrel when combined with some PPIs.¹⁹ The results of 4 prospective, crossover pharmacokinetic studies in healthy subjects (N = 282) also suggest an interaction between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.²⁰ A subanalysis of PLATO showed that the use of a PPI was independently associated with a higher rate of CV events in patients with ACS treated with clopidogrel or ticagrelor.²¹ The observed effect with both agents, as well as a higher rate of major bleeding among PPI vs non-PPI users suggests that PPI use may be more of a marker for rather than a cause of higher rates of CV events. In fact, data from the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) found that in patients treated with clopidogrel and aspirin, the addition of omeprazole reduced the rate of a GI event, compared with placebo at 180 days (1.1% vs. 2.9%, respectively;
P < .001).²² Overt upper GI bleeding occurred less frequently in the omeprazole group (hazard ratio, 0.13; 95% confidence interval, 0.03 to 0.56; P = .001). A CV event was observed in 4.9% of patients treated with omeprazole and 5.7% of placebo patients (P = .96). While limited, these prospective data do not suggest a detriment to clopidogrel efficacy when used in combination with a PPI. The dose of PPI to use for GI protection is not well-established; the following drugs and doses have been used: omeprazole 20 to 40 mg once daily; esomeprazole 20 mg once or twice daily; pantoprazole 20 mg once daily; or lansoprazole 30 mg once daily.^18,23-28

Should I avoid starting clopidogrel in patients with acute coronary syndrome because of concerns about “poor metabolizers”?

Clopidogrel is a prodrug, requiring CYP450 metabolism to its active metabolite. Because of genetic CYP450 variations, as many as one-third of patients lack fully active CYP450 pathways, resulting in reduced (or even absent) conversion from the parent drug to the active metabolite, with a corresponding diminution of antiplatelet effects.^3,29 Recent recommendations about dealing with these genetic polymorphisms include direct measurement of CYP450 pathway status and selection of alternative pharmacologic agents which are not dependent upon similar CYP pathway activation. There are, unfortunately, no prospective clinical trials based upon CYP2C19 genotyping confirming that patient selection based upon genotyping is associated with improved outcomes.

In terms of alternative antiplatelet therapy in clopidogrel nonresponders, the Response to Ticagrelor in Clopidogrel Nonresponders and Responders (RESPOND) study shows ticagrelor to be beneficial, at least as measured in vitro.³⁰ Following laboratory assessment of patients’ responsiveness to clopidogrel, both responders and nonresponders were randomized to clopidogrel or ticagrelor. After 14 days, all clopidogrel nonresponders and half of the responders switched treatment. The antiplatelet effects of ticagrelor were similar whether the patient was a clopidogrel responder or not. The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) showed higher inhibition of platelet aggregation (IPA) with prasugrel 60 mg compared with clopidogrel 600 mg 6 hours after initiation.³¹ Following crossover, IPA was higher in subjects receiving prasugrel 10 mg/d compared with clopidogrel 150 mg/d (61% vs 46%, respectively; P < .0001). While not measuring clopidogrel responsiveness, this suggests that prasugrel might be effective in clopidogrel nonresponders. Not all patients treated with prasugrel achieve optimal inhibition of platelet reactivity. In patients who underwent successful PCI for ACS (N = 301) 25.2% were observed to have high on-treatment platelet reactivity following a 60 mg loading dose of prasugrel.³² Such patients had a significantly higher risk for a major adverse cardiovascular event after PCI. The clinical trials which demonstrate improved clinical outcomes when clopidogrel is compared with other antiplatelet agents suggest that the above-mentioned in vitro metrics are clinically relevant.

I’ve heard a lot about testing platelet aggregability. Should I be considering that for my patients?

Not at the present time. One prospective study evaluated the capability of platelet function tests to predict clinical outcome in patients taking clopidogrel undergoing elective stent implantation.³³ On-treatment platelet reactivity was measured using: light transmittance aggregometry, VerifyNow P2Y12, Plateletworks, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/ADP cartridge and Innovance PFA P2Y). After 1 year of follow-up, only the light transmittance aggregometry, VerifyNow, Plateletworks, and Innovance PFA P2Y tests were significantly associated with patient outcome, but had only modest predictive accuracy. Also, none of the tests studied provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation.

How concerning are the findings on ticagrelor and dyspnea?

The occurrence of dyspnea associated with ticagrelor was observed during its clinical development. While the mechanism is not known, dyspnea is a transient phenomenon, and there is no suggestion that ticagrelor is associated with an increased incidence of heart failure.

The incidence and characterization of dyspnea has been investigated in subanalyses of 2 large clinical trials of ticagrelor. Prospective analysis of the ONSET/OFFSET study (N = 123) showed that dyspnea was experienced by more patients treated with ticagrelor than clopidogrel or placebo over 6 weeks (38.6% vs 9.3% vs 8.3%, respectively; P < .001).³⁴ Episodes of dyspnea were generally mild, lasted <24 hours, and easily tolerated. Moderate dyspnea that led to study discontinuation occurred in 3 patients (5.3%) treated with ticagrelor. Dyspnea occurred within the first 24 hours in 8 of 22 patients (36.4%) and within the first week in 17 of 22 patients (77.3%) of the ticagrelor-treated patients who experienced dyspnea. Dyspnea persisted through the study follow-up (10 days after the 6 week study) in 3 of 22 patients (13.6%) treated with ticagrelor. Dyspnea was not associated with any significant adverse change in cardiac or pulmonary function tests.³⁴

In a subanalysis of the PLATO study to investigate the occurrence of dyspnea (N = 18,421), dyspnea occurred in 14.5% of patients treated with ticagrelor and 8.7% of patients treated with clopidogrel.³⁵ Severe dyspnea occurred in 0.4% and 0.3% of patients, respectively. Dyspnea had no impact on the composite end point after excluding dyspnea that occurred after the secondary end point of MI. The mechanism whereby ticagrelor induces dyspnea is not certain, but may be mediated via an adenosine-related mechanism.³⁶

Conclusion

Aspirin and clopidogrel have been the predominant antiplatelet agents used in the management of patients with ACS, yet their use can be challenging. Differences in the clinical pharmacology of prasugrel and ticagrelor provide the opportunity to address some of these challenges and better enable antiplatelet therapy to be individualized.