Which is right for which patients? The stakes are high: myocardial infarction, intracerebral hemorrhage, ischemic stroke, peripheral arterial disease, stent thrombosis, gastrointestinal bleeding, unaffordable drug costs, non-compliance...
Since the discovery that low-dose aspirin can reduce the risk of heart attack, anti-platelet therapy agents have become an increasingly important tool for preventing cardiovascular events. While aspirin is the most widely used and best studied anti-platelet agent, the use of clopidogrel (Plavix) has increased substantially in recent years. Heavy marketing to physicians and direct-to-consumer advertising have now made it the second best-selling drug in the world after Lipitor. But how do its efficacy and safety compare to the gold standard? At four dollars per tablet ($1,460 per year of therapy), should clopidogrel (Plavix) routinely be used to replace aspirin at 2 1/2 cents per tablet?
A number of large randomized controlled trials with catchy names (CAPRIE, CURE, CHARISMA, COMMIT, CLARITY) have evaluated clopidogrel (Plavix) and aspirin, with mixed results. In several categories of patients, clopidogrel (Plavix) and aspirin were found to produce similar results. Used together, the combination can increase the risk of serious hemorrhagic events, often with little or no countervailing benefit. Yet there are certain well-defined situations in which clopidogrel (Plavix) is superior to aspirin, and others in which a clopidogrel (Plavix)-aspirin combination is the regimen of choice. The major trials are reviewed below, along with their implications for practice.
Which patients have been shown to benefit from aspirin?
Randomized controlled trials have shown that low-dose aspirin will prevent subsequent cardiovascular events in patients* with:
Patients without evident vascular disease who are at risk because of age or risk factors will also benefit from aspirin if their likelihood of a cardiovascular event is sufficiently high (e.g., >6% over the next 10 years). Several websites make it easy to calculate this likelihood for a given patient (see www.med-decisions.com). 2
When is clopidogrel (Plavix) useful? The evidence is mixed.
CONVINCING EVIDENCE FOR USE:
Coronary stent insertion: Patients undergoing coronary stenting benefit from dual therapy with clopidogrel (Plavix) and aspirin. The duration of clopidogrel (Plavix) use depends on the type of stent inserted. It has been recommended that patients who receive drug-eluting stents and are not at high risk of bleeding receive this combination for up to 12 months.3
Peripheral vascular disease (PVD): In CAPRIE, patients who had intermittent claudication or who had undergone amputation or peripheral revascularization benefited from clopidogrel (Plavix) more than aspirin.4 Dual anti-platelet therapy in patients with PVD was assessed in CHARISMA, and was not superior to aspirin alone.5 Therefore, for patients with PVD, the use of clopidogrel (Plavix) without aspirin is appropriate.
Acute myocardial infarction (MI): The combination of clopidogrel (Plavix) and aspirin was significantly better in the CURE trial than aspirin alone for patients with non-ST-segment elevation myocardial infarction ("N-STEMI") or unstable angina (UA).6 In this trial, dual therapy was started in hospital and was continued for up to a year after the event. Patients with ST-elevation MI ("STEMI") also derive significant benefit from dual therapy.7,8
The current American Heart Association-American College of Cardiology guidelines recommend clopidogrel (Plavix) for patients who cannot take aspirin because of major gastrointestinal intolerance.9 However, a recent trial of patients who developed ulcer bleeding on aspirin found that aspirin plus a proton pump inhibitor was significantly more effective than clopidogrel (Plavix) at reducing the risk of bleeding.10
LESS CONVINCING DATA FOR OTHER INDICATIONS:
Patients with cardiovascular risk factors but no documented vascular disease: No trials have evaluated clopidogrel (Plavix) alone for primary prevention. The CHARISMA trial evaluated dual anti-platelet therapy in patients with multiple vascular risk factors5 and found no additional benefit to combining clopidogrel (Plavix) and aspirin vs. aspirin alone. In addition, bleeding rates were higher in patients treated with two anti-platelet agents.
Stable angina: There is no compelling evidence of superiority for clopidogrel (Plavix) over aspirin in patients with stable angina.5
Prior MI and unstable angina: In the CAPRIE trial, clopidogrel was equivalent to aspirin for patients with a recent (but not acute) MI.4 Some subgroups of patients with cardiovascular disease in this trial seemed to benefit more from clopidogrel (Plavix) than from aspirin: those with a history of bypass surgery, a prior stroke or MI, arterial disease in two or more areas, diabetes, or high cholesterol.11 Clopidogrel (Plavix) may be a reasonable choice for these patients. Patients with a past history of MI within the prior 5 years don't seem to derive any more benefit from dual therapy.5
Stroke: In the CAPRIE trial, stroke patients given clopidogrel (Plavix) had outcomes equivalent to those of patients treated with aspirin alone.4 One exception may be high-risk patients (i.e., those with a history of bypass surgery, events involving multiple vascular beds, more than one ischemic event, diabetes, or high cholesterol), who may benefit more from clopidogrel (Plavix).
The MATCH trial found that clopidogrel (Plavix) plus aspirin following a recent stroke or transient ischemic attack (TIA) was no better than clopidogrel (Plavix) alone.12 Similarly, patients in CHARISMA with a history of stroke or transient ischemic attack did not do better on dual anti-platelet therapy compared to aspirin alone.5 As a result, combining clopidogrel (Plavix) and aspirin for most patients with a history of stroke or transient ischemic attack is not recommended.
What about the risks?
All anti-platelet agents, including aspirin, increase the risk of gastrointestinal and intracranial bleeding, even at low doses, and the risk increases with higher doses.13 The CAPRIE trial compared rates of gastrointestinal hemorrhage with clopidogrel (Plavix) vs. relatively high doses of aspirin (325 mg). The risk was higher with aspirin, but it is unknown whether clopigorel (Plavix) is safer than lower doses of aspirin, such as the 81 or 162 mg doses that are more commonly used.
Combining clopidogrel (Plavix) and aspirin increases the risk of bleeding vs. aspirin alone in patients treated for more than a brief period of time.5,6
The economics are striking
The cost of clopidogrel (Plavix) is an astonishing 160 times that of aspirin.14 Despite this, it can still be economically reasonable if it is prescribed appropriately to carefully chosen patients. For example, clopidogrel (Plavix) used alone in patients with peripheral vascular disease appears to be highly cost-effective.15 For patients with a non-ST elevation MI or unstable angina,16 clopidogrel (Plavix) plus aspirin for 12 months followed by aspirin alone is cost-effective, as is this combination in patients undergoing coronary stent insertion.17 Several other analyses have assessed the cost-effectiveness of clopidogrel (Plavix) and found that in some situations its benefit falls far short of the usual standards for reasonable economic value, such as using clopidogrel (Plavix) alone or with aspirin for prolonged periods of time for secondary prevention in unselected patients.18
Recommendations
1. Use low-dose aspirin (81-162 mg/day) in these patients:
no known vascular disease but at high risk because of age and/or risk factors stable angina MI over 1 year previously and not at high risk of vascular events (none of the following): bypass surgery, events involving multiple vascular beds, >1 ischemic event, diabetes, or high cholesterol stroke (acute or remote) but no other reason for having a high risk of vascular events
2. Use clopdiogrel (Plavix) alone (75 mg/day) in these patients:
allergic to aspirin (note: patients with a history of aspirin-induced gastrointestinal bleeding should receive aspirin plus a proton-pump inhibitor) prior MI (over 1 year previous) or stroke, and at high risk of vascular events peripheral vascular disease that is symptomatic or was surgically corrected
3. Use clopidogrel (Plavix) (75 mg/day) plus aspirin (81-162 mg/day) and re-assess after 1 year in these patients:
This overview was prepared for the Independent Drug Information Service by Niteesh Choudhry, MD, PhD, instructor in medicine at Harvard Medical School, and Jerry Avorn, MD, professor of medicine at Harvard Medical School. These are general recommendations only; specific clinical decisions should be made by the treating physician based on assessment of the individual patient.
References
1. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of anti-platelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. Jan 12 2002;324(7329):71-86. 2. Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med. Jan 15 2002;136(2):157-160. 3. Smith SC, Jr., et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). Available at: http://www.americanheart.org. Accessed Apr 12 2006. 4. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. Nov 16 1996;348(9038):1329-1339. 5. Bhatt DL, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of acute coronary syndromes without ST-segment elevation. N Engl J Med. Aug 16 2001;354(16):1706-1717. 6. Yusuf S, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. Aug 16 2001;345(7):494-502. 7. Chen ZM, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. Nov 5 2005;366(9497):1607-1621. 8. Sabatine MS, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. Mar 24 2005;352(12):1179-1189. 9. Antman EM, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). J Am Coll Cardiol. Aug 4 2004;44(3):E1-E211. 10. Chan FK, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. Jan 20 2005;352(3):238-244. 11. Hirsh J, Bhatt DL. Comparative benefits of clopidogrel and aspirin in high-risk patient populations: lessons from the CAPRIE and CURE studies. Arch Intern Med. Oct 25 2004;164(19):2106-2110. 12. Diener HC, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. Jul 24-30 2004;364(9431):331-337. 13. Peters RJ, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. Oct 7 2003;108(14):1682-1687. 14. Drugstore.com. Available at: www.drugstore.com. Accessed Apr 9 2006. 15. Schleinitz MD, et al. Clopidogrel versus aspirin for secondary prophylaxis of vascular events: a cost-effectiveness analysis. Am J Med. Jun 15 2004;116(12):797-806. 16. Schleinitz MD, Heidenreich PA. A cost-effectiveness analysis of combination anti-platelet therapy for high-risk acute coronary syndromes: clopidogrel plus aspirin versus aspirin alone. Ann Intern Med. Feb 15 2005;142(4):251-259. 17. Mahoney EM, et al. Long-term cost-effectiveness of early and sustained clopidogrel therapy for up to 1 year in patients undergoing percutaneous coronary intervention after presenting with acute coronary syndromes without ST-segement elevation. Am Heart J. Jan 2006;151(1):219-227. 18. Gaspoz JM, et al. Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary heart disease. N Engl J Med. Jun 6 2002;346(23):1800-1806. |
