Antiplatelet therapy:

Aggregating the latest evidence

Evaluating the choices for a preventive therapy with impressive benefits and important risks

Antiplatelet agents have a proven role in the primary and secondary prevention of cardiovascular events. However, they increase the risk of bleeding, so their use should be limited to patients whose clinical benefit is likely to outweigh that risk.^1-4

These drugs are sometimes overused.

Clopidogrel use by indication⁵:

53% Clopidogrel prescribed without an evidence-based indication
39% FDA-approved indications (e.g. acute coronary syndrome, recent stroke, peripheral artery disease)
8% Additional evidence-based indications (e.g. history of coronary artery disease or stroke)

Acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI): Use dual antiplatelet therapy in most patients.

Clopidogrel plus aspirin is the best-tested regimen in this setting and has become the standard of care.

Patients randomized to receive clopidogrel plus aspirin had a relative reduction of 20%. In the rate of cardiovascular death, nonfatal MI, or stroke compared to patients treated with aspirin alone.⁶

More intensive antiplatelet agents such as prasugrel and ticagrelor further reduce ischemic events, but cause more bleeding.

Reduction in risk of major vascular events and increased risk of major bleeding with prasugrel plus aspirin and ticagrelor plus aspirin, compared to clopidogrel plus aspirin (baseline).^3,4

How long to continue therapy?

In patients with ACS or elective PCI, there is good evidence for use of dual antiplatelet therapy for at least 1 year. Prolonged use beyone this time frame has not been adequately studied; several ongoing trails are seeking to evaluate the benefits and risks of continuing treatment beyone one year.

Stable coronary artery disease: Use aspirin alone in most patients.

The value of dual antiplatelet therapy is less well established for patients with stable coronary artery disease, including those with stable angina and a history of MI. For these patients, aspirin alone (81 mg/day) is usually the most appropriate regimen.

Adding clopidogrel to aspirin did not significantly reduce the risk of major vascular events.⁷
- 7% relative risk reduction (not statistically significant)

Incidence of myocardial infarction, stroke, or death from cardiovascular causes in the CHARISMA trial. The rate of events with combination therapy (6.8%) was quite close to that seen with aspirin alone (7.3%), p=0.22, but the combination produced significantly more moderate or severe bleeding than aspirin alone.

Stroke or TIA: Use clopidogrel alone, or dipyridamole plus aspirin.

In patients who have had a stroke or a transient ischemic attack, several trials have compared aspirin or clopidogrel alone with clopidogrel plus aspirin or dipyridamole plus aspirin.^7-11

In patients with ischemic stroke or TIA in the prior 3 months, the evidence favors clopidogrel alone or dipyridamole plus aspirin.
- In this setting, avoid combination therapy with clopidogrel and aspirin unless a patient has additional indications, such as PCI.
Use aspirin for most patients with a more remote history of stroke.

Peripheral arterial disease (PAD): Use clopidogrel alone.

The CAPRIE trial found clopidogrel alone to be more effective than aspirin alone for patients with severe PAD. In the CHARISMA trial, the combination of clopidogrel plus aspirin was no better than aspirin alone.⁷

Choosing an optimal aspirin dose: Use low-dose aspirin.

Whether used alone or in combination with another drug, low-dose aspirin (e.g. 81 mg) confers the same benefit with a lower risk of bleeding. Higher doses of aspirin (such as 325 mg per day) increase the risk of bleeding, but do not meaningfully increase benefit.^13-14

Primary prevention of cardiovascular disease: Use low-dose aspirin in selected patients.

Because of the bleeding risk caused by any antiplatelet therapy, aspriin should be prescribed for primary prevention only in patients for whom its benefits are likely to outweigh its harms. Some patients who take aspirin for primary prevention (e.g. low-risk diabetes) may derive less benefit than formerly believed.

Shared decision making with the patient can help determine the best strategy. Taking 10 year cardiovascular risk into account can help clarify the decision (see www.cardiacriskcalculator.org). Concurrent NSAID use and history of ulcers raise the risk of serious gastrointestinal bleeding.¹⁶

Matching the patient with the best regimen

Condition	Recommended Treatment	Evidence
Primary prevention	aspirin alone for patients in whom benefits outweigh risks	POPADAD, JPAD, USPSTF
Acute coronary syndromes [unstable angina, non- ST-segment elevation MI (NSTEMI), and ST-segment elevation MI (STEMI)]	Undergoing PCI: clopidogrel + aspirin for ≥1 year	CURE, COMMIT, CLARITY
	For some patients, prasugrel + aspirin or ticagrelor + aspirin may be a superior choice	TRITON, PLATO
	Not undergoing PCI: clopidogrel + aspirin for some patients for ≥1 year	CURE, COMMIT, CLARITY
	For some patients, ticagrelor + aspirin may be a superior choice	PLATO
Stable angina or past MI	aspirin	Antiplatelet Trialists’ Collaboration, CHARISMA, CAPRIE
Elective PCI	clopidogrel + aspirin for ≥1 year	CREDO
Recent stroke	clopidogrel or aspirin + dipyridamole	MATCH, CHARISMA, ESPS2, ESPRIT, PRoFESS, SPS3
Past stroke	aspirin alone	CHARISMA, ATT
Peripheral artery disease	clopidogrel	CHARISMA, CAPRIE

Costs vary widely for different regimens

This is particularly important for drugs that have very similar risk-benefit profiles.

Average monthly price for commonly used antiplatelet agents*:

ticagrelor (Brillinta) 90mg twice daily: $253.00
prasugrel (Effient) 5mg-10mg daily: $215.00
aspirin-extended release dipyridamole (Aggrenox) 25mg-200mg twice daily: $180.00
clopidogrel (Plavix and/or generics) 75mg daily: $12.00
aspirin 81 mg daily: $1.30

*Prices from goodrx.com and epocrates.com, October 2012.

This material was produced by Niteesh K. Choudhry, M.D., Ph.D., Associate Professor of Medicine, Harvard Medical School; Nihar R. Desai, M.D., M.P.H., Clinical Fellow in the Division of Cardiovascular Medicine, Brigham and Women’s Hospital; Michael A. Fischer, M.D., M.S., Associate Professor of Medicine, Harvard Medical School; Jerry Avorn, M.D., Professor of Medicine, Harvard Medical School. Drs. Avorn, Choudhry, Desai, and Fischer are all physicians at the Brigham and Women’s Hospital in Boston. None of the authors accepts any personal compensation from any drug company. 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’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. The Lancet. May 30 2009; 373:1849-60. (2) The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial Investigators. 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. (3) Wiviott SD, Braunwald E, McCabe CH, Montalescot G, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. Nov 15 2007; 357(20): 2001-15. (4) Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. Sep 2010; 361(11):1045-57. (5) Choudhry NK, Levin R, Avorn J. The economic consequences of non-evidence-based clopidogrel use. Am Heart J. May 2008; 155(5):904-9. (6) Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. 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) Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. Apr 20 2006; 354(16):1706-1717. (8) Diener HC, Bogousslavsky J, Brass LM, 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. (9) Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. Nov 1996;143(1-2):1-13. (10) Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. May 20 2006; 367(9523):1665-1673. (11) Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. Sep 18 2008;359(12):1238-1251. (12) 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. (13) Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. January 12, 2002 2002;324(7329):71-86. (14) Peters RJ, Mehta SR, Fox KA, 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. (15) Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Erqou S, Sattar N, Ray KK. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med. Feb 13 2012. 172(3):209-216. (16) Aspirin for the Prevention of Cardiovascular Disease, Topic Page. December 2009. U.S. Preventive Services Task Force. www.uspreventiveservicestaskforce.org/uspstf09/aspirincvd/aspcvdsum.htm

Additional references documenting these recommendations are provided in the evidence document accompanying this material, also available at www.RxFacts.org.