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Ethan Cumbler, MD
Erin Egan, MD
Jeannette Guerrasio, MD

In This Edition

CLINICAL SHORTS

Benzodiazepines Commonly Prescribed to Geriatric Patients

Upon hospital discharge, 3.1% of elderly patients have a new prescription for a benzodiazepine. Half will become chronic users of this risky class of medication.

Citation: Bell CM, Fischer HD, Gill SS, et al. Initiation of benzodiazepines in the elderly after hospitalization. J Gen Intern Med. 2007 Jul;22(7):1024-1029.

Intensive Statin Therapy Appears Beneficial, Safe in Older Patients

A randomized controlled trial in the elderly demonstrates 19% relative risk reduction for major cardiovascular events with high-dose statin therapy compared with low-dose statin treatment.

Citation: Wenger NK, Lewis SJ, Herrington DM, et al. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007 Jul 3;147(1):1-9.

A Third of Top MI Hospitals Fall Outside Highest Performing Quartile

The “America’s Best Hospitals” for treatment of acute myocardial infarction designation awarded by U.S. News & World Report reflects an overall decreased mortality for patients treated at highly ranked hospitals. Up to a third of the ranked hospitals fell outside the best-performing quartile for risk standardized mortality rates.

Citation: Wang O, Wang Y, Lichtman JH, et al. “America’s Best Hospitals” in the treatment of acute myocardial infarction. Arch Intern Med. 2007 Jul 9;167(13):1345-1351.

Quality of Chest Compressions Most Important Factor for Successful Resuscitation after Cardiac Arrest

In animals resuscitated five minutes after induction of a complete left anterior descending artery occlusion, the adequacy of the chest compressions was the most relevant factor in whether animals were successfully resuscitated. Adequacy of compressions was a more important factor than time to cardioversion or whether cardioversion preceded compressions.

Citation: Ristagno G, Tang W, Yun-Te C, et al. The quality of chest compressions during cardiopulmonary resuscitation overrides importance of timing of defibrillation. Chest. 2007 Jun 5;132(2);70-75.

The Next Chapter in Fluoroquinolone Resistance

In addition to resistance to sulfonamides, tetracyclines, and penicillins, a 16-year multisite sentinel surveillance now demonstrates fluoroquinolone resistant strains of Neisseria gonorrhoeae in 70% of cities.

Citation: Wang S, Harvey AB, Conner SM, et al. Antimicrobial resistance for Neisseria gonorrhoeae in the United States, 1998 to 2003: The spread of fluoroquinolone resistance. Ann Intern Med. 2007 Jul 17;147(2):81-88.

Do Beta-Blockers Slow Progression of Coronary Atherosclerosis?

Although a post-hoc, pooled analysis of individual patient data demonstrated that beta-blockers significantly decrease atheroma volume, this study was limited by significant differences between the treatment and the control groups.

Citation: Sipahi I, Tuzcu EM, Wolski KE, et al. B-blockade and progression of coronary atherosclerosis: Pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med. 2007 Jul 3;147(1):10-18.

Do Incentives to Encourage Use of Certain Medications Affect Care?

Background: Insurers are increasingly using financial mechanisms to affect pharmaceutical usage. These practices may affect medication use and health outcomes in ways that are poorly defined and difficult to detect.

Study design: Literature review

Synopsis: There are numerous structures for drug-cost sharing, and this study evaluated co-payments, tiers/co-insurance, benefit caps, formulary limitations, and reference pricing strategies for their effect on prescription drug usage and healthcare outcomes.

 

 

Included articles varied widely in study design, making generalizable results difficult to isolate, and insurers may have instituted more than one cost-sharing mechanism simultaneously. Overall, for every 10% increase in cost sharing (via copayments or co-insurance) there was an associated 2%-6% decrease in prescription drug spending. Increasing consumer costs for medications clearly decreases usage.

Some studies demonstrated that the decrease in medication utilization was more pronounced for “nonessential” medications over “essential” medications. However, in specific chronic illnesses this is clearly associated with greater usage of inpatient and emergency medical services.

Cost sharing was also more likely to have adverse health consequences in vulnerable populations, particularly the elderly and poor. One in four Medicaid patients couldn’t fill at least one prescription in the past year, as opposed to one in 10 privately insured patients who couldn’t purchase one or more medications.

Further impact on healthcare consumption and outcomes may be masked because it is difficult to determine individual disease severity, and the effect on the more severely ill would be expected to be greater. These authors attempted to sort out a complex interaction between cost, consumption, and health, and they found important trends.

The goal of cost sharing is to align consumption more clearly with appropriate and economic products, thereby using cost sharing as a public health tool. The consequence of creating the incentives for ill patients to forego necessary treatments is a counterbalancing concern that is supported in some, but not all, of the literature.

Bottom line: Cost sharing for prescription medications decreases medication spending and utilization but disproportionately affects the disadvantaged and increases consumption of more costly healthcare services in patients with some chronic illnesses.

Citation: Goldman DP, Joyce GF, Zheng Y. Prescription drug cost sharing: associations with medication and medical utilization and spending and health. JAMA. 2007;298(1):61-69.

Does Antibiotic Requirement for Suspected CAP Increase Misdiagnosis?

Background: Early administration of antibiotics in community-acquired pneumonia (CAP) improves patient outcomes. The Infectious Disease Society of America instituted guidelines that recommend initiation of antibiotics to all patients with suspected CAP within four hours of triage, and some payors are using this as a quality measure affecting reimbursement. However, this incentive may cause premature diagnosis of CAP and overuse of antibiotics.

Study design: Retrospective chart review

Setting: A large, high-volume teaching hospital with more than 500 beds and more than 112,000 annual emergency department (ED) visits

Synopsis: Charts of all patients with an admitting diagnosis of CAP were reviewed over two six-month periods. The initial review was prior to initiation of a four-hour antibiotics rule; the second was after a financial incentive to initiate antibiotics within four hours of triage was initiated.

After initiation of the four-hour rule, of the patients with an admitting diagnosis of CAP, significantly more patients received antibiotics within four hours of triage (66% versus 54%). However, the number of patients with abnormal chest X-ray findings associated with the diagnosis of CAP decreased from 28.5% to 20.6%, and the proportion of patients with a discharge diagnosis of CAP decreased from 75.9% to 58.9%.

The authors also used two diagnostic paradigms to make an independent diagnosis of CAP based on chart data. With the less rigorous independent analysis 44.7% of patients actually had CAP prior to the four-hour rule, and this fell to 36% after the four-hour rule. Using a more rigorous definition, only 32.7% of patients actually had CAP prior to initiation of the four-hour rule, and this fell to 27%.

There was no difference in length of stay or ICU transfers between the two analysis periods. The authors concluded that a four-hour rule increases premature diagnosis of CAP, presumably because providers felt compelled to initiate antibiotics before they had complete clinical data.

 

 

This tendency was associated with misuse and overuse of antibiotics, and increased laboratory testing, such as blood cultures, which had to be obtained before antibiotics were initiated. The authors emphasized the importance of reimbursement-associated quality measures creating incentives to treat the right patients for the correct diagnosis, and the potential harmful consequences of applying a quality-driven protocol to the wrong patient.

They suggest a six-hour rule would decrease the misdiagnosis of CAP. They also feel eliminating a mandatory time frame and requiring only that the first dose of antibiotics be administered in the ED will further ameliorate these effects.

Bottom line: Mandatory administration of antibiotics to patients with suspected CAP within four hours of triage increases the percentage of patients who receive antibiotics within four hours, but also increases the rate of misdiagnosis of CAP, inappropriate administration of antibiotics, and increased use of some laboratory services.

Citation: Kanwar M, Brar N, Khatib R, et al. Misdiagnosis of community-acquired pneumonia and inappropriate utilization of antibiotics: side effects of the 4-hour antibiotic administration rule. Chest. 2007 Jun;131(6):1865-1869.

Does prophylactic cardiac revascularization benefit patients undergoing vascular surgery?

Background: American College of Cardiology/American Heart Association Guidelines recommend referral for patients with multiple cardiac risk factors for non-invasive cardiac stress testing prior to surgery and prophylactic revascularization in high-risk patients. The authors performed a pilot analysis to determine how many patients would be needed to prospectively validate this recommendation in those with more significant ischemic cardiac disease.

Study design: Randomized controlled pilot study of 1,880 consecutive patients undergoing elective vascular surgery

Setting: Brazil, Belgium, the Netherlands, Italy, Serbia, and Montenegro

Synopsis: This was a pilot study to determine the necessary power to prove or disprove the benefit of the recommendation for cardiac revascularization in high-risk patients before major vascular surgery.

Prior research had shown that prophylactic revascularization is not of demonstrable benefit in this cohort. However, the majority of the patients in this previous trial had two-vessel disease and preserved left ventricular function. This study examined a sicker cohort of patients with more significant coronary artery disease and depressed left ventricular function.

This pilot screened all patients undergoing high-risk vascular surgery. All patients with three or more risk factors underwent non-invasive evaluation for cardiac ischemia. Patients with extensive ischemia were randomized to invasive evaluation and revascularization as appropriate or non-invasive management. Both arms received optimal medical management.

Prophylactic revascularization did not improve 30-day outcome after vascular surgery, demonstrated no difference in perioperative cardiac events, and found no difference in all-cause mortality or nonfatal myocardial infarction. Similarly, there was no evidence of long-term (at one year) difference between groups. The sample size needed to definitively establish that coronary revascularization is superior to medical therapy would be 300 patients per arm. That would require screening 9,000 patients.

Bottom line: Prophylactic revascularization has no clear benefit for high-risk patients undergoing vascular surgery, but a much larger sample size would be required to definitively prove or disprove benefit.

Citation: Poldermans D, Schouten O, Vidakovic R, et al. Clinical randomized trial to evaluate the safety of a noninvasive approach in high-risk patients undergoing major vascular surgery: the DECREASE-V pilot study. J. Am Coll Cardiol. 2007;49(17):1763-1769.

How Does Aspirin Resistance Affect Patients with Coronary Artery Disease?

Background: Although aspirin is used to decrease the risk of ischemic events, up to 45% of patients do not derive adequate anti-platelet activity. Few prospective studies have used laboratory-measured aspirin resistance to assess clinical outcomes.

Study design: Blinded cohort

Setting: Patients affiliated with Queen Mary Hospital, the University of Hong Kong.

 

 

Synopsis: Aspirin-induced platelet inhibition was measured quantitatively on 468 patients with stable coronary artery disease who take 80-325 mg of aspirin per day. The study found 128 patients were aspirin resistant. Aspirin resistance was more prevalent with increased age, female gender, renal insufficiency, anemia, and with use of low-dose aspirin. At follow up, aspirin-resistant patients were more likely to develop a primary outcome event: cardiovascular deaths, myocardial infarction, stroke, transient ischemic attack, and unstable angina. Aspirin resistance was an independent risk factor for developing the aforementioned outcomes, as are diabetes, prior myocardial infarction, and low hemoglobin.

Bottom line: Aspirin resistance, as defined by an aggregation-based assay, is associated with adverse outcomes in patients with stable coronary artery disease.

Citation: Chen W, Cheng X, Lee PY, et al. Aspirin resistance and adverse clinical events in patients with coronary artery disease. Am J Med. 2007 Jul;120(7):631-635.

Which Agents Best Prevent Venous Thromboembolism?

Background: Pulmonary emboli have been linked to 10% of in-hospital deaths. There continues to be a strong emphasis on prevention. Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and selective factor Xa inhibitors are used for prophylaxis.

Study design: A meta-analysis of randomized controlled trials

Synopsis: The meta-analysis included 36 studies of hospitalized medical patients that compared UFH with control, LMWH with control, LMWH with UFH, and a selective factor Xa inhibitor with a placebo.

When each was compared with a control, UFH and LMWH were associated with a decreased risk of deep venous thrombosis (DVT) (risk ratio=0.33; 0.56) and pulmonary embolism (PE) (risk ratio=0.64; 0.37). Compared with control, LMWH three times daily was more effective than twice-daily dosing (risk ratio=0.27, 0.52). Through direct comparison of UFH and LMWH, LMWH was shown to have decreased DVT risk (risk ratio=0.68) and fewer injection site hematomas (risk ratio=0.47).

Neither UFH nor LMWH reduced mortality. LMWH and UFH were associated with significantly more bleeding events than control, but this increased risk was significant only for minor bleeding.

Bottom line: LMWH appears to have greater efficacy than UFH as a prophylactic agent against DVT/PE. If UFH is used, three times daily dosing is preferred.

Citation: Wein L, Wein S, Haas SJ, et al. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients. Arch Intern Med. 2007;167(14):1476-1486.

What Is the Association Between Antipsychotic Drugs and Mortality?

Background: Atypical antipsychotics prescribed off-label for problematic behaviors in dementia have been associated with risks including diabetes, stroke, and increased mortality. This resulted in the FDA placing a “black box” warning on atypical antipsychotics used for dementia. Subsequent studies have suggested that conventional antipsychotics are perhaps even more problematic.

Study Design: Retrospective cohort study

Synopsis: This trial found a small but significant increase in the risk of death in patients taking an antipsychotic medication.

The adjusted hazard ratio for death with the use of atypical antipsychotics in community dwelling patients with dementia was 1.3 (confidence interval 1.02-1.70). Similar to prior research, the authors found that conventional antipsychotics carried a higher risk than atypical agents.

Patients in long-term care settings also suffered increased risk compared with community dwelling patients. Interestingly, the increased risk of death was apparent after as little as a month of treatment.

As with all retrospective observational cohort trials, there remains the risk that an unanticipated confounding factor could skew the data and create a false association. However, the findings of this research support prior concerns that antipsychotics carry risk of increased mortality. This research bolsters the argument that these agents should not be used lightly or without full discussion of risks and benefits with the patient and/or proxy.

 

 

Bottom line: Antipsychotic agents used in patients with dementia may create increased risk of death. Potential benefit needs to be carefully weighted against this serious harm.

Citation: Gill S, Bronskill SE, Normand SL, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med. 2007 June 5;146(11):775-786.

Does Combination Therapy Help Prevent Serious Vascular Ischemic Events?

Background: Peripheral arterial disease (PAD) manifests as claudication and limb ischemia affecting 8.5 million Americans. Atherosclerotic disease in the periphery also reflects increased risk for ischemic events in the coronary and cranial circulations. Both antiplatelet agents and anticoagulation will decrease the probability of thrombus formation, although this must be weighed against bleeding risk.

Study design: Randomized, open-label, multicenter trial

Setting: Eighty centers in Europe, Asia, Australia, and North America

Synopsis: This trial randomized more than 2,000 patients with PAD to treatment with antiplatelet therapy (aspirin, ticlopidine, or clopidogrel) with or without additional anticoagulation.

During the next 3.5 years serious vascular events occurred at approximately the same rate in both combination and monotherapy groups (15.9% versus 17.4%, p=0.37). There was no significant difference between the occurrence of the composite ischemic endpoints or any of the individual endpoints. There was, however, a significantly higher rate of both moderate and life-threatening bleeding in the combination therapy group.

The 4% risk of life-threatening hemorrhage in the combination group exceeded the 1.2% rate of the monotherapy group creating a relative risk for bleeding of 3.4.

This trial demonstrates that for patients with PAD on antiplatelet therapy, the increased rate of bleeding without significant added benefit makes addition of warfarin inadvisable.1 Evidence of utility of combination therapy from studies in other arterial systems provides mixed results.2-4 Based on the results of this study, combination therapy cannot be advocated if the primary symptoms are from PAD.

Bottom line: This study provides further evidence that more is not always better when it comes to preventing thrombosis and ischemia in the peripheral arterial system. Antiplatelet agents are preferable for PAD to combination antiplatelet plus anticoagulation.

Citations:

  1. The Warfarin Antiplatelet Vascular Evaluation Trial Investigators. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med. 2007 Jul 19;357(3):217-227.

  2. Hurlen M, Abdelnoor M, Smith P, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002 Sep 26;347(13):969-974.

  3. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001 Nov 15;345(20):1444-1451.

  4. The ESPRIT Study Group. Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): a ran­dom­ised controlled trial. Lancet Neurol. 2007 Feb;6:115-124.

Does Transient Atrial Fibrillation Increase Stroke Risk After ST-Elevation Myocardial Infarction?

Background: Prior research has demonstrated that 2.1% of patients will suffer a stroke in the year following a heart attack. Persistent and paroxysmal atrial fibrillation (AF) are well recognized as risk factors for stroke, but the significance of transient ischemia-induced AF is less clear.

Study design: Retrospective cohort study

Setting: Queen Mary Hospital, Hong Kong

Synopsis: The study involved patients admitted for acute inferior ST-segment-elevation myocardial infarction (MI) with preserved left ventricular ejection fraction.

Transient AF that had converted back to normal sinus rhythm by discharge was observed in 14% of patients after the MI. Over the next three years the transient AF patients were 15 times more likely than those who remained in sinus rhythm during the index hospitalization to have recurrent AF (34% versus 2%). Despite antiplatelet therapy in both groups, ischemic stroke developed in 22% of patients who had transient AF following their MI, compared with only 4% in patients who did not (HR 5.1, confidence interval 2.4-11.2). Cerebrovascular accidents generally occurred simultaneously with recurrence of paroxysmal AF.1-2

 

 

The finding that patients with transient-ischemia-induced AF represents a group with markedly higher risk of ischemic stroke is compelling. It suggests that these patients may be candidates for combined antiplatelet and anticoagulant therapy. Trials of combined therapy following MI demonstrate that this strategy reduces the rate of recurrent cardiac ischemia, stroke, or death but does carry significantly increased risk of bleeding.3-4

Bottom line: The presence of transient AF following MI represents a significant risk factor for the development of subsequent paroxysmal AF. These patients have a five-fold increased risk of ischemic stroke over the next three years and should be considered for combined antiplatelet and anticoagulant therapy.

Citations:

  1. Chung-Wah S, Man-Hong J, Hee-Hwa H, et al. Transient atrial fibrillation complicating acute inferior myocardial infarction: implications for future risk of ischemic stroke. Chest. 2007 Mar 30;132(1):44-49.

  2. Witt BJ, Ballman KV, Brown RD Jr., Meverden RA, Jacobsen SJ, Roger VL. The incidence of stroke after myocardial infarction: a meta-analysis. Am J. Med. 2006;119(4):354 e1-9.

  3. Van Es RF, Jonker J, Verheugt F, et al. Aspirin and Coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet. 2002 Jul 13;360(9327):109-113.

  4. Hurlen M, Abdelnoor M, Smith P, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002 Sep 26;347(13):969-974. TH

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The Hospitalist - 2007(11)
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Author(s)
Ethan Cumbler, MD
Erin Egan, MD
Jeannette Guerrasio, MD
Author(s)
Ethan Cumbler, MD
Erin Egan, MD
Jeannette Guerrasio, MD

In This Edition

CLINICAL SHORTS

Benzodiazepines Commonly Prescribed to Geriatric Patients

Upon hospital discharge, 3.1% of elderly patients have a new prescription for a benzodiazepine. Half will become chronic users of this risky class of medication.

Citation: Bell CM, Fischer HD, Gill SS, et al. Initiation of benzodiazepines in the elderly after hospitalization. J Gen Intern Med. 2007 Jul;22(7):1024-1029.

Intensive Statin Therapy Appears Beneficial, Safe in Older Patients

A randomized controlled trial in the elderly demonstrates 19% relative risk reduction for major cardiovascular events with high-dose statin therapy compared with low-dose statin treatment.

Citation: Wenger NK, Lewis SJ, Herrington DM, et al. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007 Jul 3;147(1):1-9.

A Third of Top MI Hospitals Fall Outside Highest Performing Quartile

The “America’s Best Hospitals” for treatment of acute myocardial infarction designation awarded by U.S. News & World Report reflects an overall decreased mortality for patients treated at highly ranked hospitals. Up to a third of the ranked hospitals fell outside the best-performing quartile for risk standardized mortality rates.

Citation: Wang O, Wang Y, Lichtman JH, et al. “America’s Best Hospitals” in the treatment of acute myocardial infarction. Arch Intern Med. 2007 Jul 9;167(13):1345-1351.

Quality of Chest Compressions Most Important Factor for Successful Resuscitation after Cardiac Arrest

In animals resuscitated five minutes after induction of a complete left anterior descending artery occlusion, the adequacy of the chest compressions was the most relevant factor in whether animals were successfully resuscitated. Adequacy of compressions was a more important factor than time to cardioversion or whether cardioversion preceded compressions.

Citation: Ristagno G, Tang W, Yun-Te C, et al. The quality of chest compressions during cardiopulmonary resuscitation overrides importance of timing of defibrillation. Chest. 2007 Jun 5;132(2);70-75.

The Next Chapter in Fluoroquinolone Resistance

In addition to resistance to sulfonamides, tetracyclines, and penicillins, a 16-year multisite sentinel surveillance now demonstrates fluoroquinolone resistant strains of Neisseria gonorrhoeae in 70% of cities.

Citation: Wang S, Harvey AB, Conner SM, et al. Antimicrobial resistance for Neisseria gonorrhoeae in the United States, 1998 to 2003: The spread of fluoroquinolone resistance. Ann Intern Med. 2007 Jul 17;147(2):81-88.

Do Beta-Blockers Slow Progression of Coronary Atherosclerosis?

Although a post-hoc, pooled analysis of individual patient data demonstrated that beta-blockers significantly decrease atheroma volume, this study was limited by significant differences between the treatment and the control groups.

Citation: Sipahi I, Tuzcu EM, Wolski KE, et al. B-blockade and progression of coronary atherosclerosis: Pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med. 2007 Jul 3;147(1):10-18.

Do Incentives to Encourage Use of Certain Medications Affect Care?

Background: Insurers are increasingly using financial mechanisms to affect pharmaceutical usage. These practices may affect medication use and health outcomes in ways that are poorly defined and difficult to detect.

Study design: Literature review

Synopsis: There are numerous structures for drug-cost sharing, and this study evaluated co-payments, tiers/co-insurance, benefit caps, formulary limitations, and reference pricing strategies for their effect on prescription drug usage and healthcare outcomes.

 

 

Included articles varied widely in study design, making generalizable results difficult to isolate, and insurers may have instituted more than one cost-sharing mechanism simultaneously. Overall, for every 10% increase in cost sharing (via copayments or co-insurance) there was an associated 2%-6% decrease in prescription drug spending. Increasing consumer costs for medications clearly decreases usage.

Some studies demonstrated that the decrease in medication utilization was more pronounced for “nonessential” medications over “essential” medications. However, in specific chronic illnesses this is clearly associated with greater usage of inpatient and emergency medical services.

Cost sharing was also more likely to have adverse health consequences in vulnerable populations, particularly the elderly and poor. One in four Medicaid patients couldn’t fill at least one prescription in the past year, as opposed to one in 10 privately insured patients who couldn’t purchase one or more medications.

Further impact on healthcare consumption and outcomes may be masked because it is difficult to determine individual disease severity, and the effect on the more severely ill would be expected to be greater. These authors attempted to sort out a complex interaction between cost, consumption, and health, and they found important trends.

The goal of cost sharing is to align consumption more clearly with appropriate and economic products, thereby using cost sharing as a public health tool. The consequence of creating the incentives for ill patients to forego necessary treatments is a counterbalancing concern that is supported in some, but not all, of the literature.

Bottom line: Cost sharing for prescription medications decreases medication spending and utilization but disproportionately affects the disadvantaged and increases consumption of more costly healthcare services in patients with some chronic illnesses.

Citation: Goldman DP, Joyce GF, Zheng Y. Prescription drug cost sharing: associations with medication and medical utilization and spending and health. JAMA. 2007;298(1):61-69.

Does Antibiotic Requirement for Suspected CAP Increase Misdiagnosis?

Background: Early administration of antibiotics in community-acquired pneumonia (CAP) improves patient outcomes. The Infectious Disease Society of America instituted guidelines that recommend initiation of antibiotics to all patients with suspected CAP within four hours of triage, and some payors are using this as a quality measure affecting reimbursement. However, this incentive may cause premature diagnosis of CAP and overuse of antibiotics.

Study design: Retrospective chart review

Setting: A large, high-volume teaching hospital with more than 500 beds and more than 112,000 annual emergency department (ED) visits

Synopsis: Charts of all patients with an admitting diagnosis of CAP were reviewed over two six-month periods. The initial review was prior to initiation of a four-hour antibiotics rule; the second was after a financial incentive to initiate antibiotics within four hours of triage was initiated.

After initiation of the four-hour rule, of the patients with an admitting diagnosis of CAP, significantly more patients received antibiotics within four hours of triage (66% versus 54%). However, the number of patients with abnormal chest X-ray findings associated with the diagnosis of CAP decreased from 28.5% to 20.6%, and the proportion of patients with a discharge diagnosis of CAP decreased from 75.9% to 58.9%.

The authors also used two diagnostic paradigms to make an independent diagnosis of CAP based on chart data. With the less rigorous independent analysis 44.7% of patients actually had CAP prior to the four-hour rule, and this fell to 36% after the four-hour rule. Using a more rigorous definition, only 32.7% of patients actually had CAP prior to initiation of the four-hour rule, and this fell to 27%.

There was no difference in length of stay or ICU transfers between the two analysis periods. The authors concluded that a four-hour rule increases premature diagnosis of CAP, presumably because providers felt compelled to initiate antibiotics before they had complete clinical data.

 

 

This tendency was associated with misuse and overuse of antibiotics, and increased laboratory testing, such as blood cultures, which had to be obtained before antibiotics were initiated. The authors emphasized the importance of reimbursement-associated quality measures creating incentives to treat the right patients for the correct diagnosis, and the potential harmful consequences of applying a quality-driven protocol to the wrong patient.

They suggest a six-hour rule would decrease the misdiagnosis of CAP. They also feel eliminating a mandatory time frame and requiring only that the first dose of antibiotics be administered in the ED will further ameliorate these effects.

Bottom line: Mandatory administration of antibiotics to patients with suspected CAP within four hours of triage increases the percentage of patients who receive antibiotics within four hours, but also increases the rate of misdiagnosis of CAP, inappropriate administration of antibiotics, and increased use of some laboratory services.

Citation: Kanwar M, Brar N, Khatib R, et al. Misdiagnosis of community-acquired pneumonia and inappropriate utilization of antibiotics: side effects of the 4-hour antibiotic administration rule. Chest. 2007 Jun;131(6):1865-1869.

Does prophylactic cardiac revascularization benefit patients undergoing vascular surgery?

Background: American College of Cardiology/American Heart Association Guidelines recommend referral for patients with multiple cardiac risk factors for non-invasive cardiac stress testing prior to surgery and prophylactic revascularization in high-risk patients. The authors performed a pilot analysis to determine how many patients would be needed to prospectively validate this recommendation in those with more significant ischemic cardiac disease.

Study design: Randomized controlled pilot study of 1,880 consecutive patients undergoing elective vascular surgery

Setting: Brazil, Belgium, the Netherlands, Italy, Serbia, and Montenegro

Synopsis: This was a pilot study to determine the necessary power to prove or disprove the benefit of the recommendation for cardiac revascularization in high-risk patients before major vascular surgery.

Prior research had shown that prophylactic revascularization is not of demonstrable benefit in this cohort. However, the majority of the patients in this previous trial had two-vessel disease and preserved left ventricular function. This study examined a sicker cohort of patients with more significant coronary artery disease and depressed left ventricular function.

This pilot screened all patients undergoing high-risk vascular surgery. All patients with three or more risk factors underwent non-invasive evaluation for cardiac ischemia. Patients with extensive ischemia were randomized to invasive evaluation and revascularization as appropriate or non-invasive management. Both arms received optimal medical management.

Prophylactic revascularization did not improve 30-day outcome after vascular surgery, demonstrated no difference in perioperative cardiac events, and found no difference in all-cause mortality or nonfatal myocardial infarction. Similarly, there was no evidence of long-term (at one year) difference between groups. The sample size needed to definitively establish that coronary revascularization is superior to medical therapy would be 300 patients per arm. That would require screening 9,000 patients.

Bottom line: Prophylactic revascularization has no clear benefit for high-risk patients undergoing vascular surgery, but a much larger sample size would be required to definitively prove or disprove benefit.

Citation: Poldermans D, Schouten O, Vidakovic R, et al. Clinical randomized trial to evaluate the safety of a noninvasive approach in high-risk patients undergoing major vascular surgery: the DECREASE-V pilot study. J. Am Coll Cardiol. 2007;49(17):1763-1769.

How Does Aspirin Resistance Affect Patients with Coronary Artery Disease?

Background: Although aspirin is used to decrease the risk of ischemic events, up to 45% of patients do not derive adequate anti-platelet activity. Few prospective studies have used laboratory-measured aspirin resistance to assess clinical outcomes.

Study design: Blinded cohort

Setting: Patients affiliated with Queen Mary Hospital, the University of Hong Kong.

 

 

Synopsis: Aspirin-induced platelet inhibition was measured quantitatively on 468 patients with stable coronary artery disease who take 80-325 mg of aspirin per day. The study found 128 patients were aspirin resistant. Aspirin resistance was more prevalent with increased age, female gender, renal insufficiency, anemia, and with use of low-dose aspirin. At follow up, aspirin-resistant patients were more likely to develop a primary outcome event: cardiovascular deaths, myocardial infarction, stroke, transient ischemic attack, and unstable angina. Aspirin resistance was an independent risk factor for developing the aforementioned outcomes, as are diabetes, prior myocardial infarction, and low hemoglobin.

Bottom line: Aspirin resistance, as defined by an aggregation-based assay, is associated with adverse outcomes in patients with stable coronary artery disease.

Citation: Chen W, Cheng X, Lee PY, et al. Aspirin resistance and adverse clinical events in patients with coronary artery disease. Am J Med. 2007 Jul;120(7):631-635.

Which Agents Best Prevent Venous Thromboembolism?

Background: Pulmonary emboli have been linked to 10% of in-hospital deaths. There continues to be a strong emphasis on prevention. Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and selective factor Xa inhibitors are used for prophylaxis.

Study design: A meta-analysis of randomized controlled trials

Synopsis: The meta-analysis included 36 studies of hospitalized medical patients that compared UFH with control, LMWH with control, LMWH with UFH, and a selective factor Xa inhibitor with a placebo.

When each was compared with a control, UFH and LMWH were associated with a decreased risk of deep venous thrombosis (DVT) (risk ratio=0.33; 0.56) and pulmonary embolism (PE) (risk ratio=0.64; 0.37). Compared with control, LMWH three times daily was more effective than twice-daily dosing (risk ratio=0.27, 0.52). Through direct comparison of UFH and LMWH, LMWH was shown to have decreased DVT risk (risk ratio=0.68) and fewer injection site hematomas (risk ratio=0.47).

Neither UFH nor LMWH reduced mortality. LMWH and UFH were associated with significantly more bleeding events than control, but this increased risk was significant only for minor bleeding.

Bottom line: LMWH appears to have greater efficacy than UFH as a prophylactic agent against DVT/PE. If UFH is used, three times daily dosing is preferred.

Citation: Wein L, Wein S, Haas SJ, et al. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients. Arch Intern Med. 2007;167(14):1476-1486.

What Is the Association Between Antipsychotic Drugs and Mortality?

Background: Atypical antipsychotics prescribed off-label for problematic behaviors in dementia have been associated with risks including diabetes, stroke, and increased mortality. This resulted in the FDA placing a “black box” warning on atypical antipsychotics used for dementia. Subsequent studies have suggested that conventional antipsychotics are perhaps even more problematic.

Study Design: Retrospective cohort study

Synopsis: This trial found a small but significant increase in the risk of death in patients taking an antipsychotic medication.

The adjusted hazard ratio for death with the use of atypical antipsychotics in community dwelling patients with dementia was 1.3 (confidence interval 1.02-1.70). Similar to prior research, the authors found that conventional antipsychotics carried a higher risk than atypical agents.

Patients in long-term care settings also suffered increased risk compared with community dwelling patients. Interestingly, the increased risk of death was apparent after as little as a month of treatment.

As with all retrospective observational cohort trials, there remains the risk that an unanticipated confounding factor could skew the data and create a false association. However, the findings of this research support prior concerns that antipsychotics carry risk of increased mortality. This research bolsters the argument that these agents should not be used lightly or without full discussion of risks and benefits with the patient and/or proxy.

 

 

Bottom line: Antipsychotic agents used in patients with dementia may create increased risk of death. Potential benefit needs to be carefully weighted against this serious harm.

Citation: Gill S, Bronskill SE, Normand SL, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med. 2007 June 5;146(11):775-786.

Does Combination Therapy Help Prevent Serious Vascular Ischemic Events?

Background: Peripheral arterial disease (PAD) manifests as claudication and limb ischemia affecting 8.5 million Americans. Atherosclerotic disease in the periphery also reflects increased risk for ischemic events in the coronary and cranial circulations. Both antiplatelet agents and anticoagulation will decrease the probability of thrombus formation, although this must be weighed against bleeding risk.

Study design: Randomized, open-label, multicenter trial

Setting: Eighty centers in Europe, Asia, Australia, and North America

Synopsis: This trial randomized more than 2,000 patients with PAD to treatment with antiplatelet therapy (aspirin, ticlopidine, or clopidogrel) with or without additional anticoagulation.

During the next 3.5 years serious vascular events occurred at approximately the same rate in both combination and monotherapy groups (15.9% versus 17.4%, p=0.37). There was no significant difference between the occurrence of the composite ischemic endpoints or any of the individual endpoints. There was, however, a significantly higher rate of both moderate and life-threatening bleeding in the combination therapy group.

The 4% risk of life-threatening hemorrhage in the combination group exceeded the 1.2% rate of the monotherapy group creating a relative risk for bleeding of 3.4.

This trial demonstrates that for patients with PAD on antiplatelet therapy, the increased rate of bleeding without significant added benefit makes addition of warfarin inadvisable.1 Evidence of utility of combination therapy from studies in other arterial systems provides mixed results.2-4 Based on the results of this study, combination therapy cannot be advocated if the primary symptoms are from PAD.

Bottom line: This study provides further evidence that more is not always better when it comes to preventing thrombosis and ischemia in the peripheral arterial system. Antiplatelet agents are preferable for PAD to combination antiplatelet plus anticoagulation.

Citations:

  1. The Warfarin Antiplatelet Vascular Evaluation Trial Investigators. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med. 2007 Jul 19;357(3):217-227.

  2. Hurlen M, Abdelnoor M, Smith P, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002 Sep 26;347(13):969-974.

  3. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001 Nov 15;345(20):1444-1451.

  4. The ESPRIT Study Group. Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): a ran­dom­ised controlled trial. Lancet Neurol. 2007 Feb;6:115-124.

Does Transient Atrial Fibrillation Increase Stroke Risk After ST-Elevation Myocardial Infarction?

Background: Prior research has demonstrated that 2.1% of patients will suffer a stroke in the year following a heart attack. Persistent and paroxysmal atrial fibrillation (AF) are well recognized as risk factors for stroke, but the significance of transient ischemia-induced AF is less clear.

Study design: Retrospective cohort study

Setting: Queen Mary Hospital, Hong Kong

Synopsis: The study involved patients admitted for acute inferior ST-segment-elevation myocardial infarction (MI) with preserved left ventricular ejection fraction.

Transient AF that had converted back to normal sinus rhythm by discharge was observed in 14% of patients after the MI. Over the next three years the transient AF patients were 15 times more likely than those who remained in sinus rhythm during the index hospitalization to have recurrent AF (34% versus 2%). Despite antiplatelet therapy in both groups, ischemic stroke developed in 22% of patients who had transient AF following their MI, compared with only 4% in patients who did not (HR 5.1, confidence interval 2.4-11.2). Cerebrovascular accidents generally occurred simultaneously with recurrence of paroxysmal AF.1-2

 

 

The finding that patients with transient-ischemia-induced AF represents a group with markedly higher risk of ischemic stroke is compelling. It suggests that these patients may be candidates for combined antiplatelet and anticoagulant therapy. Trials of combined therapy following MI demonstrate that this strategy reduces the rate of recurrent cardiac ischemia, stroke, or death but does carry significantly increased risk of bleeding.3-4

Bottom line: The presence of transient AF following MI represents a significant risk factor for the development of subsequent paroxysmal AF. These patients have a five-fold increased risk of ischemic stroke over the next three years and should be considered for combined antiplatelet and anticoagulant therapy.

Citations:

  1. Chung-Wah S, Man-Hong J, Hee-Hwa H, et al. Transient atrial fibrillation complicating acute inferior myocardial infarction: implications for future risk of ischemic stroke. Chest. 2007 Mar 30;132(1):44-49.

  2. Witt BJ, Ballman KV, Brown RD Jr., Meverden RA, Jacobsen SJ, Roger VL. The incidence of stroke after myocardial infarction: a meta-analysis. Am J. Med. 2006;119(4):354 e1-9.

  3. Van Es RF, Jonker J, Verheugt F, et al. Aspirin and Coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet. 2002 Jul 13;360(9327):109-113.

  4. Hurlen M, Abdelnoor M, Smith P, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002 Sep 26;347(13):969-974. TH

In This Edition

CLINICAL SHORTS

Benzodiazepines Commonly Prescribed to Geriatric Patients

Upon hospital discharge, 3.1% of elderly patients have a new prescription for a benzodiazepine. Half will become chronic users of this risky class of medication.

Citation: Bell CM, Fischer HD, Gill SS, et al. Initiation of benzodiazepines in the elderly after hospitalization. J Gen Intern Med. 2007 Jul;22(7):1024-1029.

Intensive Statin Therapy Appears Beneficial, Safe in Older Patients

A randomized controlled trial in the elderly demonstrates 19% relative risk reduction for major cardiovascular events with high-dose statin therapy compared with low-dose statin treatment.

Citation: Wenger NK, Lewis SJ, Herrington DM, et al. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007 Jul 3;147(1):1-9.

A Third of Top MI Hospitals Fall Outside Highest Performing Quartile

The “America’s Best Hospitals” for treatment of acute myocardial infarction designation awarded by U.S. News & World Report reflects an overall decreased mortality for patients treated at highly ranked hospitals. Up to a third of the ranked hospitals fell outside the best-performing quartile for risk standardized mortality rates.

Citation: Wang O, Wang Y, Lichtman JH, et al. “America’s Best Hospitals” in the treatment of acute myocardial infarction. Arch Intern Med. 2007 Jul 9;167(13):1345-1351.

Quality of Chest Compressions Most Important Factor for Successful Resuscitation after Cardiac Arrest

In animals resuscitated five minutes after induction of a complete left anterior descending artery occlusion, the adequacy of the chest compressions was the most relevant factor in whether animals were successfully resuscitated. Adequacy of compressions was a more important factor than time to cardioversion or whether cardioversion preceded compressions.

Citation: Ristagno G, Tang W, Yun-Te C, et al. The quality of chest compressions during cardiopulmonary resuscitation overrides importance of timing of defibrillation. Chest. 2007 Jun 5;132(2);70-75.

The Next Chapter in Fluoroquinolone Resistance

In addition to resistance to sulfonamides, tetracyclines, and penicillins, a 16-year multisite sentinel surveillance now demonstrates fluoroquinolone resistant strains of Neisseria gonorrhoeae in 70% of cities.

Citation: Wang S, Harvey AB, Conner SM, et al. Antimicrobial resistance for Neisseria gonorrhoeae in the United States, 1998 to 2003: The spread of fluoroquinolone resistance. Ann Intern Med. 2007 Jul 17;147(2):81-88.

Do Beta-Blockers Slow Progression of Coronary Atherosclerosis?

Although a post-hoc, pooled analysis of individual patient data demonstrated that beta-blockers significantly decrease atheroma volume, this study was limited by significant differences between the treatment and the control groups.

Citation: Sipahi I, Tuzcu EM, Wolski KE, et al. B-blockade and progression of coronary atherosclerosis: Pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med. 2007 Jul 3;147(1):10-18.

Do Incentives to Encourage Use of Certain Medications Affect Care?

Background: Insurers are increasingly using financial mechanisms to affect pharmaceutical usage. These practices may affect medication use and health outcomes in ways that are poorly defined and difficult to detect.

Study design: Literature review

Synopsis: There are numerous structures for drug-cost sharing, and this study evaluated co-payments, tiers/co-insurance, benefit caps, formulary limitations, and reference pricing strategies for their effect on prescription drug usage and healthcare outcomes.

 

 

Included articles varied widely in study design, making generalizable results difficult to isolate, and insurers may have instituted more than one cost-sharing mechanism simultaneously. Overall, for every 10% increase in cost sharing (via copayments or co-insurance) there was an associated 2%-6% decrease in prescription drug spending. Increasing consumer costs for medications clearly decreases usage.

Some studies demonstrated that the decrease in medication utilization was more pronounced for “nonessential” medications over “essential” medications. However, in specific chronic illnesses this is clearly associated with greater usage of inpatient and emergency medical services.

Cost sharing was also more likely to have adverse health consequences in vulnerable populations, particularly the elderly and poor. One in four Medicaid patients couldn’t fill at least one prescription in the past year, as opposed to one in 10 privately insured patients who couldn’t purchase one or more medications.

Further impact on healthcare consumption and outcomes may be masked because it is difficult to determine individual disease severity, and the effect on the more severely ill would be expected to be greater. These authors attempted to sort out a complex interaction between cost, consumption, and health, and they found important trends.

The goal of cost sharing is to align consumption more clearly with appropriate and economic products, thereby using cost sharing as a public health tool. The consequence of creating the incentives for ill patients to forego necessary treatments is a counterbalancing concern that is supported in some, but not all, of the literature.

Bottom line: Cost sharing for prescription medications decreases medication spending and utilization but disproportionately affects the disadvantaged and increases consumption of more costly healthcare services in patients with some chronic illnesses.

Citation: Goldman DP, Joyce GF, Zheng Y. Prescription drug cost sharing: associations with medication and medical utilization and spending and health. JAMA. 2007;298(1):61-69.

Does Antibiotic Requirement for Suspected CAP Increase Misdiagnosis?

Background: Early administration of antibiotics in community-acquired pneumonia (CAP) improves patient outcomes. The Infectious Disease Society of America instituted guidelines that recommend initiation of antibiotics to all patients with suspected CAP within four hours of triage, and some payors are using this as a quality measure affecting reimbursement. However, this incentive may cause premature diagnosis of CAP and overuse of antibiotics.

Study design: Retrospective chart review

Setting: A large, high-volume teaching hospital with more than 500 beds and more than 112,000 annual emergency department (ED) visits

Synopsis: Charts of all patients with an admitting diagnosis of CAP were reviewed over two six-month periods. The initial review was prior to initiation of a four-hour antibiotics rule; the second was after a financial incentive to initiate antibiotics within four hours of triage was initiated.

After initiation of the four-hour rule, of the patients with an admitting diagnosis of CAP, significantly more patients received antibiotics within four hours of triage (66% versus 54%). However, the number of patients with abnormal chest X-ray findings associated with the diagnosis of CAP decreased from 28.5% to 20.6%, and the proportion of patients with a discharge diagnosis of CAP decreased from 75.9% to 58.9%.

The authors also used two diagnostic paradigms to make an independent diagnosis of CAP based on chart data. With the less rigorous independent analysis 44.7% of patients actually had CAP prior to the four-hour rule, and this fell to 36% after the four-hour rule. Using a more rigorous definition, only 32.7% of patients actually had CAP prior to initiation of the four-hour rule, and this fell to 27%.

There was no difference in length of stay or ICU transfers between the two analysis periods. The authors concluded that a four-hour rule increases premature diagnosis of CAP, presumably because providers felt compelled to initiate antibiotics before they had complete clinical data.

 

 

This tendency was associated with misuse and overuse of antibiotics, and increased laboratory testing, such as blood cultures, which had to be obtained before antibiotics were initiated. The authors emphasized the importance of reimbursement-associated quality measures creating incentives to treat the right patients for the correct diagnosis, and the potential harmful consequences of applying a quality-driven protocol to the wrong patient.

They suggest a six-hour rule would decrease the misdiagnosis of CAP. They also feel eliminating a mandatory time frame and requiring only that the first dose of antibiotics be administered in the ED will further ameliorate these effects.

Bottom line: Mandatory administration of antibiotics to patients with suspected CAP within four hours of triage increases the percentage of patients who receive antibiotics within four hours, but also increases the rate of misdiagnosis of CAP, inappropriate administration of antibiotics, and increased use of some laboratory services.

Citation: Kanwar M, Brar N, Khatib R, et al. Misdiagnosis of community-acquired pneumonia and inappropriate utilization of antibiotics: side effects of the 4-hour antibiotic administration rule. Chest. 2007 Jun;131(6):1865-1869.

Does prophylactic cardiac revascularization benefit patients undergoing vascular surgery?

Background: American College of Cardiology/American Heart Association Guidelines recommend referral for patients with multiple cardiac risk factors for non-invasive cardiac stress testing prior to surgery and prophylactic revascularization in high-risk patients. The authors performed a pilot analysis to determine how many patients would be needed to prospectively validate this recommendation in those with more significant ischemic cardiac disease.

Study design: Randomized controlled pilot study of 1,880 consecutive patients undergoing elective vascular surgery

Setting: Brazil, Belgium, the Netherlands, Italy, Serbia, and Montenegro

Synopsis: This was a pilot study to determine the necessary power to prove or disprove the benefit of the recommendation for cardiac revascularization in high-risk patients before major vascular surgery.

Prior research had shown that prophylactic revascularization is not of demonstrable benefit in this cohort. However, the majority of the patients in this previous trial had two-vessel disease and preserved left ventricular function. This study examined a sicker cohort of patients with more significant coronary artery disease and depressed left ventricular function.

This pilot screened all patients undergoing high-risk vascular surgery. All patients with three or more risk factors underwent non-invasive evaluation for cardiac ischemia. Patients with extensive ischemia were randomized to invasive evaluation and revascularization as appropriate or non-invasive management. Both arms received optimal medical management.

Prophylactic revascularization did not improve 30-day outcome after vascular surgery, demonstrated no difference in perioperative cardiac events, and found no difference in all-cause mortality or nonfatal myocardial infarction. Similarly, there was no evidence of long-term (at one year) difference between groups. The sample size needed to definitively establish that coronary revascularization is superior to medical therapy would be 300 patients per arm. That would require screening 9,000 patients.

Bottom line: Prophylactic revascularization has no clear benefit for high-risk patients undergoing vascular surgery, but a much larger sample size would be required to definitively prove or disprove benefit.

Citation: Poldermans D, Schouten O, Vidakovic R, et al. Clinical randomized trial to evaluate the safety of a noninvasive approach in high-risk patients undergoing major vascular surgery: the DECREASE-V pilot study. J. Am Coll Cardiol. 2007;49(17):1763-1769.

How Does Aspirin Resistance Affect Patients with Coronary Artery Disease?

Background: Although aspirin is used to decrease the risk of ischemic events, up to 45% of patients do not derive adequate anti-platelet activity. Few prospective studies have used laboratory-measured aspirin resistance to assess clinical outcomes.

Study design: Blinded cohort

Setting: Patients affiliated with Queen Mary Hospital, the University of Hong Kong.

 

 

Synopsis: Aspirin-induced platelet inhibition was measured quantitatively on 468 patients with stable coronary artery disease who take 80-325 mg of aspirin per day. The study found 128 patients were aspirin resistant. Aspirin resistance was more prevalent with increased age, female gender, renal insufficiency, anemia, and with use of low-dose aspirin. At follow up, aspirin-resistant patients were more likely to develop a primary outcome event: cardiovascular deaths, myocardial infarction, stroke, transient ischemic attack, and unstable angina. Aspirin resistance was an independent risk factor for developing the aforementioned outcomes, as are diabetes, prior myocardial infarction, and low hemoglobin.

Bottom line: Aspirin resistance, as defined by an aggregation-based assay, is associated with adverse outcomes in patients with stable coronary artery disease.

Citation: Chen W, Cheng X, Lee PY, et al. Aspirin resistance and adverse clinical events in patients with coronary artery disease. Am J Med. 2007 Jul;120(7):631-635.

Which Agents Best Prevent Venous Thromboembolism?

Background: Pulmonary emboli have been linked to 10% of in-hospital deaths. There continues to be a strong emphasis on prevention. Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and selective factor Xa inhibitors are used for prophylaxis.

Study design: A meta-analysis of randomized controlled trials

Synopsis: The meta-analysis included 36 studies of hospitalized medical patients that compared UFH with control, LMWH with control, LMWH with UFH, and a selective factor Xa inhibitor with a placebo.

When each was compared with a control, UFH and LMWH were associated with a decreased risk of deep venous thrombosis (DVT) (risk ratio=0.33; 0.56) and pulmonary embolism (PE) (risk ratio=0.64; 0.37). Compared with control, LMWH three times daily was more effective than twice-daily dosing (risk ratio=0.27, 0.52). Through direct comparison of UFH and LMWH, LMWH was shown to have decreased DVT risk (risk ratio=0.68) and fewer injection site hematomas (risk ratio=0.47).

Neither UFH nor LMWH reduced mortality. LMWH and UFH were associated with significantly more bleeding events than control, but this increased risk was significant only for minor bleeding.

Bottom line: LMWH appears to have greater efficacy than UFH as a prophylactic agent against DVT/PE. If UFH is used, three times daily dosing is preferred.

Citation: Wein L, Wein S, Haas SJ, et al. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients. Arch Intern Med. 2007;167(14):1476-1486.

What Is the Association Between Antipsychotic Drugs and Mortality?

Background: Atypical antipsychotics prescribed off-label for problematic behaviors in dementia have been associated with risks including diabetes, stroke, and increased mortality. This resulted in the FDA placing a “black box” warning on atypical antipsychotics used for dementia. Subsequent studies have suggested that conventional antipsychotics are perhaps even more problematic.

Study Design: Retrospective cohort study

Synopsis: This trial found a small but significant increase in the risk of death in patients taking an antipsychotic medication.

The adjusted hazard ratio for death with the use of atypical antipsychotics in community dwelling patients with dementia was 1.3 (confidence interval 1.02-1.70). Similar to prior research, the authors found that conventional antipsychotics carried a higher risk than atypical agents.

Patients in long-term care settings also suffered increased risk compared with community dwelling patients. Interestingly, the increased risk of death was apparent after as little as a month of treatment.

As with all retrospective observational cohort trials, there remains the risk that an unanticipated confounding factor could skew the data and create a false association. However, the findings of this research support prior concerns that antipsychotics carry risk of increased mortality. This research bolsters the argument that these agents should not be used lightly or without full discussion of risks and benefits with the patient and/or proxy.

 

 

Bottom line: Antipsychotic agents used in patients with dementia may create increased risk of death. Potential benefit needs to be carefully weighted against this serious harm.

Citation: Gill S, Bronskill SE, Normand SL, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med. 2007 June 5;146(11):775-786.

Does Combination Therapy Help Prevent Serious Vascular Ischemic Events?

Background: Peripheral arterial disease (PAD) manifests as claudication and limb ischemia affecting 8.5 million Americans. Atherosclerotic disease in the periphery also reflects increased risk for ischemic events in the coronary and cranial circulations. Both antiplatelet agents and anticoagulation will decrease the probability of thrombus formation, although this must be weighed against bleeding risk.

Study design: Randomized, open-label, multicenter trial

Setting: Eighty centers in Europe, Asia, Australia, and North America

Synopsis: This trial randomized more than 2,000 patients with PAD to treatment with antiplatelet therapy (aspirin, ticlopidine, or clopidogrel) with or without additional anticoagulation.

During the next 3.5 years serious vascular events occurred at approximately the same rate in both combination and monotherapy groups (15.9% versus 17.4%, p=0.37). There was no significant difference between the occurrence of the composite ischemic endpoints or any of the individual endpoints. There was, however, a significantly higher rate of both moderate and life-threatening bleeding in the combination therapy group.

The 4% risk of life-threatening hemorrhage in the combination group exceeded the 1.2% rate of the monotherapy group creating a relative risk for bleeding of 3.4.

This trial demonstrates that for patients with PAD on antiplatelet therapy, the increased rate of bleeding without significant added benefit makes addition of warfarin inadvisable.1 Evidence of utility of combination therapy from studies in other arterial systems provides mixed results.2-4 Based on the results of this study, combination therapy cannot be advocated if the primary symptoms are from PAD.

Bottom line: This study provides further evidence that more is not always better when it comes to preventing thrombosis and ischemia in the peripheral arterial system. Antiplatelet agents are preferable for PAD to combination antiplatelet plus anticoagulation.

Citations:

  1. The Warfarin Antiplatelet Vascular Evaluation Trial Investigators. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med. 2007 Jul 19;357(3):217-227.

  2. Hurlen M, Abdelnoor M, Smith P, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002 Sep 26;347(13):969-974.

  3. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001 Nov 15;345(20):1444-1451.

  4. The ESPRIT Study Group. Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): a ran­dom­ised controlled trial. Lancet Neurol. 2007 Feb;6:115-124.

Does Transient Atrial Fibrillation Increase Stroke Risk After ST-Elevation Myocardial Infarction?

Background: Prior research has demonstrated that 2.1% of patients will suffer a stroke in the year following a heart attack. Persistent and paroxysmal atrial fibrillation (AF) are well recognized as risk factors for stroke, but the significance of transient ischemia-induced AF is less clear.

Study design: Retrospective cohort study

Setting: Queen Mary Hospital, Hong Kong

Synopsis: The study involved patients admitted for acute inferior ST-segment-elevation myocardial infarction (MI) with preserved left ventricular ejection fraction.

Transient AF that had converted back to normal sinus rhythm by discharge was observed in 14% of patients after the MI. Over the next three years the transient AF patients were 15 times more likely than those who remained in sinus rhythm during the index hospitalization to have recurrent AF (34% versus 2%). Despite antiplatelet therapy in both groups, ischemic stroke developed in 22% of patients who had transient AF following their MI, compared with only 4% in patients who did not (HR 5.1, confidence interval 2.4-11.2). Cerebrovascular accidents generally occurred simultaneously with recurrence of paroxysmal AF.1-2

 

 

The finding that patients with transient-ischemia-induced AF represents a group with markedly higher risk of ischemic stroke is compelling. It suggests that these patients may be candidates for combined antiplatelet and anticoagulant therapy. Trials of combined therapy following MI demonstrate that this strategy reduces the rate of recurrent cardiac ischemia, stroke, or death but does carry significantly increased risk of bleeding.3-4

Bottom line: The presence of transient AF following MI represents a significant risk factor for the development of subsequent paroxysmal AF. These patients have a five-fold increased risk of ischemic stroke over the next three years and should be considered for combined antiplatelet and anticoagulant therapy.

Citations:

  1. Chung-Wah S, Man-Hong J, Hee-Hwa H, et al. Transient atrial fibrillation complicating acute inferior myocardial infarction: implications for future risk of ischemic stroke. Chest. 2007 Mar 30;132(1):44-49.

  2. Witt BJ, Ballman KV, Brown RD Jr., Meverden RA, Jacobsen SJ, Roger VL. The incidence of stroke after myocardial infarction: a meta-analysis. Am J. Med. 2006;119(4):354 e1-9.

  3. Van Es RF, Jonker J, Verheugt F, et al. Aspirin and Coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet. 2002 Jul 13;360(9327):109-113.

  4. Hurlen M, Abdelnoor M, Smith P, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002 Sep 26;347(13):969-974. TH

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