The benefits of low-dose aspirin monotherapy in patients with underlying occlusive vascular disease are not in doubt—a reduction in serious vascular events, such as myocardial infarction (MI), and stroke in high-risk patients.1,2 Clopidogrel is a suitable alternative for patients who are unable to tolerate aspirin,3 but the advice for considering the use of dual antiplatelet therapy is not so straightforward. It varies depending on the vascular bed involved and differing interpretations of the evidence by various national clinical guidelines.
After an ischaemic stroke, the combination of low-dose aspirin and slow-release dipyridamole in a dose of 200 mg twice daily for a minimum of 2 years has been shown to be both clinically and cost effective in preventing further events.3 In patients who do not tolerate aspirin, clopidogrel monotherapy rather than dipyridamole therapy would be the preferred option.3 Patients with occlusive vascular disease in one or more vascular beds—the coronary arteries, and the cerebral and peripheral circulation—are at an increased risk of another event such as an episode of acute coronary syndrome (ACS) or ischaemic stroke.
Antiplatelet therapy for acute coronary syndrome
Myocardial infarction is part of the spectrum of ACS, characterised by a combination of appropriate clinical history, electrocardiogram changes, and rise in troponin enzymes. Acute coronary syndrome encompasses unstable coronary artery disease from unstable angina to ST-segment or non-ST-segment elevation MI.4
The majority of patients with ACS are currently treated with dual antiplatelet therapy (aspirin and clopidogrel) for variable lengths of time depending on the circumstances.5,6 Based on results from the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT/CCS), patients with ST elevation ACS should continue combination aspirin/clopidogrel therapy for up to 4 weeks.5 The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study demonstrated clinical benefit for the use of aspirin/clopidogrel combination for 1 year after an episode of non-ST elevation ACS.5,6 The NICE technology appraisal on clopidogrel for ACS recommends this 1-year period on cost-effectiveness grounds that assume a constant relative risk reduction across all time periods.6 This assumption may not be the case so the SIGN guideline on the management of ACS recommends treatment duration of 3 months.5
Current clinical practice will result in a large majority of patients with ACS being treated with a percutaneous coronary intervention (PCI) and the implantation of a bare metal or drug-eluting stent. In the latter case, a period of at least 6 months of dual antiplatelet therapy is likely to be necessary.5
Both NICE and the Scottish Medicines Consortium have recently issued guidance and approval for the use of a newer antiplatelet agent, prasugrel, in patients with ACS.7,8 The licence for prasugrel allows for therapy using a maintenance dose of 10 mg for up to 12 months.7 Prasugrel given orally, inhibits platelet activation and aggregation through its active metabolite, which binds irreversibly to the P2Y12 adenosine diphosphate (ADP) receptors on platelets. The NICE technology appraisal recommends the use of prasugrel in patients with ACS having a PCI only when:
- immediate primary PCI for ST-segment elevation MI is necessary or
- stent thrombosis has occurred during clopidogrel treatment or
- the patient has diabetes mellitus.
Prasugrel vs clopidogrel
In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel- Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38, a total of 13,608 patients (10,074 patients with unstable angina or non-ST elevation MI and 3534 patients with ST elevation MI) who were scheduled to receive a PCI were randomised to receive either clopidogrel or prasugrel, in addition to aspirin.9 The median treatment time was 14.5 months with the primary end point being a non-fatal MI, non-fatal stroke, or death from cardiovascular (CV) causes. The prasugrel group had better outcomes compared with the clopidogrel group in terms of rate reduction:9
- MI (7.4% vs 9.7%, p<0.001)
- Urgent target vessel revascularisation (2.5% vs 3.7%, p<0.001)
- Stent thrombosis (1.1% vs 2.4%, p<0.001).
Death rates from CV causes (2.1% vs 2.4%) and non-fatal stroke (1.0% vs 1.0%) were, however, not statistically significant with the p values being 0.31 and 0.93, respectively.9
The increased clinical benefit was, however, associated with increased rates of bleeding in the prasugrel group:9
- Life-threatening bleeding—1.4% vs 0.9% (hazard ratio [HR] 1.52; 95% confidence interval [CI] 1.08 to 2.13, p=0.01)
- Fatal bleeding—0.4% vs 0.1% (HR 4.19; 95% CI 1.58 to 11.11, p=0.002).
The NICE evidence review group did note that the bleeding risk in the UK may be less because of the increased trend to perform PCI using radial artery access.7 During consideration of both the clinical and cost effectiveness of prasugrel, the NICE appraisal committee agreed that there was a valuable advantage in using the drug for patients with ST elevation MI who need immediate PCI. They also felt it would be appropriate to consider prasugrel for patients with diabetes who are having a PCI, as they represented a group with more severe cardiovascular disease (CVD) and at greater risk of CV events during and after PCI. The NICE committee was unable to define all patients at high risk of a stent thrombosis but accepted that when this condition occurs in patients with diabetes and in those on clopidogrel, then the risk is sufficient to justify use with prasugrel.7
General practitioners are now likely, as a result of this NICE guidance, to have to continue the use of prasugrel in a limited number of patients with ACS upon discharge from hospital.
The choice of antiplatelet drugs for ACS is likely to increase further with the launch in the next year of ticagrelor, a direct inhibitor of the same platelet receptor as prasugrel. Results from A Study of Platelet Inhibition and Patient Outcomes (PLATO) showed that ticagrelor when compared with clopidogrel significantly reduced the rate of death from vascular causes, MI, or stroke (HR 0.84; 95% CI 0.77 to 0.92, p<0.001) without an increase in the rate of overall bleeding, but with an increase in the rate of non-procedure related bleeding.10 A technology appraisal from NICE on the use of ticagrelor for ACS is not expected until July 2011 at the earliest.11
The current approach to the use of low-dose aspirin in patients without vascular disease also needs to be considered. The traditional view has been that if the 10-year of CVD risk exceeds 20% and blood pressure is controlled, then the benefit of aspirin in preventing events outweighs the level of harm from bleeding events.12 A recent meta-analysis could not identify a clear benefit of aspirin for the primary prevention of major CV events or mortality in people with diabetes.13 A Cochrane review published in 2004 concluded that for patients with elevated blood pressure, the magnitude of benefit bestowed by antiplatelet therapy, seen as a reduction in MI for primary prevention, is negated by a harm of similar magnitude with an increase in major haemorrhage.14
Faced with the current uncertainty, GPs should maximise use of approaches known to reduce CV risk in those at high risk of an event but without established CVD.15,16 This includes stopping smoking, good glucose control, or the use of statins before considering adding aspirin.12,16 For individuals without vascular disease who are already on aspirin, it would be sensible to discuss, on an individual basis, the patient’s global risk, taking into account all risk factors and the risk of bleeding, and then making an informed decision on whether to continue with this therapy or not.
The use of antiplatelet therapy can be confusing for healthcare professionals working in both primary and secondary care. The agents and the combinations that should be used, as well as the length of treatment varies between different clinical situations. The use of aspirin in primary prevention is even more confusing, and currently controversial. As newer agents are developed, guideline developers have a major role in ensuring consistent, clear, and up-to-date guidance is available for clinicians to use.
- Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373 (9678): 1849–1860.
- 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 2002; 324 (7329): 71–86.
- National Institute for Health and Care Excellence. Clopidogrel and dipyridamole for the prevention of atherosclerotic events. Technology Appraisal 90. London: NICE, 2004. Available at: www.nice.org.uk/guidance/TA90
- Sivers F, Begg A, Milne D. Follow your heart; optimal care after a heart attack. Br J Cardio 2009; 6 (4): 187–191.
- Scottish Intercollegiate Guidelines Network. Acute coronary syndromes. SIGN 93. Edinburgh: SIGN, 2007. Available at: www.sign.ac.uk/guidelines/fulltext/93-97/index.html
- National Institute for Health and Care Excellence. Clopidogrel in the treatment of non-ST-segment-elevation acute coronary syndrome. Technology Appraisal 80. London: NICE, 2004. Available at: www.nice.org.uk/guidance/TA80
- National Institute for Health and Care Excellence. Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention. Technology Appraisal 182. London: NICE, 2009. Available at: www.nice.org.uk/guidance/TA182
- Scottish Medicines Consortium. Prasugrel 5 and 10 mg tablets. SMC, 2009. Available at: www.scottishmedicines.org.uk/files/prasugrel%205%20and%2010%20mg%20tablets%20(Efient)
- Wiviott S, Braunwald E, McCabe C et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357 (20): 2001–2015.
- Wallentin L, Becker R, Budaj A et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11): 1045–1057.
- National Institute for Health and Care Excellence website. Acute coronary syndromes—ticagrelor. www.nice.org.uk/guidance/TA/Wave20/70
- British Cardiac Society, British Hypertension Society, Diabetes UK et al. JBS 2: Joint British societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91 (Supplement V): 1–52.
- De Berardis G, Sacco M, Strippoli G et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ 2009; 339: b4531.
- Lip G, Felmeden D. Antiplatelet agents and anticoagulants for hypertension. Cochrane Database Syst Rev 2004; (3): CD003186.
- Haynes R, Bowman L, Armitage J. Aspirin for primary prevention of vascular disease in people with diabetes. BMJ 2009; 339: b4596.
- Begg A. Risk assessment can help in the primary prevention of CVD. Guidelines in Practice 2009; 12 (10): 45–51. G