VOLUME 15

e e BULLETIN
SUMMARY

NUMBER 6

Prescribing antiplatelet drugs in primary care

This Bulletin considers the prescribing of antiplatelet drugs (aspirin, clopidogrel and modifiedrelease [MR] dipyridamole) for the prevention of cardiovascular (CV) events in primary care. The recommendations below are subject to any specific warnings and contraindications specified in the Summaries of Product Characteristics (www.medicines.org.uk) for individual preparations. Secondary prevention Low-dose aspirin (75mg daily) is recommended indefinitely for long-term secondary prevention following a myocardial infarction (MI), and in people with symptomatic peripheral arterial disease (PAD). MR-dipyridamole 200mg twice daily plus low-dose aspirin (50mg or 75mg daily) is recommended for secondary prevention following an ischaemic stroke or a transient ischaemic attack (TIA) for a period of two years from the most recent event. Thereafter, or if dipyridamole is not tolerated, preventative therapy should revert to long-term treatment with low-dose aspirin alone. For patients with dyspepsia on low-dose aspirin, or who are at risk from gastrointestinal (GI) bleeding, co-prescription of a proton pump inhibitor (PPI) should be considered initially. Clopidogrel 75mg daily is a suitable alternative to aspirin (or aspirin plus MR-dipyridamole post-stroke) where aspirin is contraindicated or genuinely not tolerated (i.e. proven hypersensitivity to aspirin-containing medicines or history of severe dyspepsia induced by low-dose aspirin). In patients with non-ST-segment-elevation acute coronary syndrome (ACS) who are at moderate to high risk of MI or death, clopidogrel 75mg daily should be considered in combination with low-dose aspirin (75mg daily) for up to 12 months following the most recent acute event. Thereafter, treatment should revert to low-dose aspirin alone. This is the only indication for which a combination of aspirin and clopidogrel is currently licensed in the UK. Primary prevention For primary prevention of CV events, low-dose aspirin (75mg daily) should be considered for all patients over the age of 50 at high risk of coronary heart disease (CHD) (10-year CHD risk of 15% or more) provided hypertension is controlled. Clopidogrel and MR-dipyridamole are not indicated or licensed for primary prevention of CV events.

Introduction This Bulletin reviews the use of antiplatelet drugs for the prevention of CV events in primary care. Prescribing recommendations for their use for secondary and primary prevention are provided, based on consideration of the clinical evidence (summarised in Panel 1 on page 22 and Panel 2 on page 23, respectively) and recent, relevant NICE guidance.16,17 Use of antiplatelet drugs in the treatment of atrial fibrillation, heart failure, stable angina, and acute treatment of CV events, or before and after surgical procedures, are not covered. Prescribing of antiplatelet drugs in people with diabetes was reviewed in MeReC Briefing Issue No. 26 (www.npc.co.uk).

Implementing evidence in practice As with other measures for reducing the risk of CV events (e.g. lifestyle modification, control of hypertension and hyperlipidaemia), antiplatelet drugs should be prescribed in the context of the individual patient's CV risk, the likely absolute benefits and harms of treatment, cost, and patient preference. Secondary prevention A huge body of evidence supports the use of aspirin for the secondary prevention of CV events in patients who have suffered a MI, stroke/TIA or who have symptomatic PAD. Unless contraindicated, low-dose aspirin should be used indefinitely in all these people.16

This publication was correct at the time of preparation: July 2005

This MeReC Publication is produced by the NHS for the NHS

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Prescribing antiplatelet drugs in primary care

Panel 1. Clinical evidence for secondary prevention of CV events

Secondary prevention: aspirin A systematic review and meta-analysis of 195 randomised controlled trials (RCTs) (n=144,051) conducted by the Antithrombotic Trialists' Collaboration provides conclusive evidence for the benefits of antiplatelet drugs, primarily aspirin, in preventing CV events in high-risk patients.1 Overall, serious CV events (non-fatal MI, non-fatal stroke or vascular death) occurred in 10.7% of patients on antiplatelet therapy compared with 13.2% of patients in the control groups (P<0.0001). Significant relative risk reductions (RRRs) were seen across all high-risk subgroups (Table 1) and for individual primary outcome events (non-fatal MI 34%; non-fatal stroke 25%; vascular death 15%; all P<0.0001). Excluding patients with acute stroke, the absolute risk reduction (ARR) was 3.1% and was similar for all antiplatelet trials (n=103,230) and for those that assessed aspirin alone (n=59,395). Offset against these benefits is the risk of serious side effects, the most frequent of which is bleeding. However, in patients at high risk of occlusive vascular events, the absolute benefits of antiplatelet therapy far outweigh the risk of any hazards unless the absolute risk of extracranial bleeding is high (Table 1).1 Aspirin is an effective antithrombotic agent at doses between 50mg and 1500mg daily.2 There is no evidence that higher doses are more effective than lower doses, although the risk of bleeding complications increases with dose. A recent meta-analysis of 31 trials (n=192,036) identified an approximate three-fold-lower rate of bleeding complications for patients taking aspirin doses of <100mg daily compared with those taking 100200mg or >200mg doses.3 Secondary prevention: MR-dipyridamole A large (n=6,602) double-blind RCT (European Stroke Prevention Study, ESPS-2) demonstrated that MR-dipyridamole (200mg twice daily) plus aspirin (25mg twice daily) was more effective than aspirin or MR-dipyridamole alone for the prevention of stroke in patients who had recently suffered an ischaemic stroke or TIA.4 The two-year occurrences of stroke were 9.5% for MR-dipyridamole plus aspirin, 12.5% for aspirin alone, 12.8% for MR-dipyridamole alone, and 15.2% for placebo. The relative risk (RR) for the combination versus aspirin alone was 0.76 (95% CI 0.63 to 0.93)16 number needed to treat (NNT) 34 over two years. However, the study found no significant benefit on mortality (one of the primary endpoints) for any of the treatments. Bleeding episodes (any site) were significantly more frequent in the MRdipyridamole plus aspirin (8.7%) and the aspirin alone (8.2%) groups compared with the MR-dipyridamole alone (4.7%) and placebo (4.2%) groups. A systematic review identified no clear benefit of standard-release dipyridamole for the prevention of serious vascular events when prescribed alone, or in combination with aspirin, to patients with vascular disease.5 Secondary prevention: clopidogrel Evidence supporting the use of clopidogrel for secondary prevention of CV events comes predominantly from the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study.6 This double-blind RCT recruited 19,185 patients who had recently suffered an ischaemic stroke (not TIA), a recent MI, or who had symptomatic PAD. It compared clopidogrel 75mg daily with aspirin 325mg daily for a mean duration of 1.9 years. The risk of suffering an ischaemic stroke, MI, or CV death (primary composite outcome) was slightly lower with clopidogrel than with aspirin (5.32%/year vs. 5.83%/year, NNT 196), with a RRR of 8.7% (95% CI 0.3 to 16.5%, P=0.043). A statistically significant benefit was found in the subgroup of patients with PAD (RR 0.78, 95% CI 0.66 to 0.92),16 but not in the subgroups of patients who had suffered a MI or stroke. However, these data should be interpreted cautiously as the study was not powered to detect differences in treatment effects between these subgroups. Aspirin and clopidogrel were equally well tolerated, even though the study used a high (325mg) dose of aspirin. The only statistically significant differences between groups for severe adverse events were for skin rash (clopidogrel 0.26%, aspirin 0.10%, number needed to harm [NNH] 625), and GI bleeding (clopidogrel 0.49%, aspirin 0.71%, NNH 455). The double-blind, placebo-controlled MATCH (Management of ATherothrombosis with Clopidogrel in High-risk patients) trial compared 18month treatment with clopidogrel and aspirin (both 75mg daily) with clopidogrel 75mg daily alone in 7,599 patients who had suffered a TIA (21%) or ischaemic stroke (79%) within the previous three months, and who had at least one additional CV risk factor within the previous three years.7 There was no significant effect of the combination treatment over clopidogrel alone with regard to the primary endpoint, a composite of ischaemic stroke, MI, vascular death and rehospitalisation for an acute ischaemic event (15.7% vs. 16.7%, RRR 6.4%, 95% CI 4.6 to 16.3). However, patients taking the combination experienced more significant life-threatening bleeds than those taking clopidogrel alone (2.6% vs. 1.3%, NNH 77, P<0.0001). The absence of an aspirin-only arm of the study meant that no direct comparison of the benefits and risks of clopidogrel and aspirin could be made. ACS: clopidogrel plus aspirin The CURE (Clopidogrel in Unstable Angina to prevent Recurrent Events) study was a double-blind RCT of 12,562 patients with symptoms (within 24 hours of treatment) suggestive of ACS with non-ST-segment elevation on ECG.8 Most patients were at high risk of cardiac ischaemia and necrosis, based on ECG changes and/or elevation of cardiac enzymes. The study compared a loading dose of clopidogrel 300mg followed by 75mg daily for three to 12 months (mean nine months) or placebo in addition to standard aspirin therapy (75 to 325mg daily, according to local practice). Clopidogrel was associated with significantly fewer primary outcome events (a composite of CV death, non-fatal MI, or stroke) (9.3% vs. 11.4%, NNT 48 over 9 months; RR 0.80, 95% CI 0.72 to 0.90, P<0.001). However, the combination was associated with a significantly greater incidence of major bleeding than aspirin alone (3.7% vs. 2.7%, NNH 100, P=0.001). Benefits of clopidogrel in CURE appeared within 30 days and were maintained up to 12 months. However, most of the benefit was apparent during the first three months. For individual time periods, statistically significant risk reductions were obtained up to one month (RRR 22%, 95% CI 8.6% to 33.4%) and from one to three months (RRR 32%, 95% CI 12.8% to 46.4%), but not during subsequent three monthly periods.9 The incidence of major bleeding increased significantly with increasing aspirin doses (<100mg, 101-199 mg, >200mg) in both the clopidogrel plus aspirin group (3.0%, 3.4%, and 4.9%, P=0.0009) and the aspirin alone group (1.9%, 2.8%, 3.7%, P=0.0001), respectively.10 The absolute increased risk of bleeding from adding clopidogrel to aspirin was similar regardless of the aspirin dose (range 1.1 to 1.2%). Evidence supports addition of clopidogrel to aspirin before and after percutaneous coronary intervention (PCI),12 although the value of continuing clopidogrel beyond a few months post-PCI is uncertain.13 In a study of patients receiving fibrinolytic therapy immediately following a STsegment-elevation MI (STEMI), adding clopidogrel to aspirin for up to eight days before angiography (median 3.5 days) significantly improved the patency of infarct-related arteries, without any increased risk of bleeding.11 However, long-term benefits of treatment were not evaluated.

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In most circumstances a dose of 75mg daily is appropriate.3,18,19 Clopidogrel 75mg daily can be considered as an alternative to aspirin if contraindicated or not tolerated (e.g. severe aspirin-induced dyspepsia). Although clopidogrel appeared slightly more effective than aspirin in the CAPRIE study,6 the small absolute increase in efficacy (NNT 196) does not justify its use ahead of aspirin in view of its higher cost (28-day treatment: clopidogrel 35.31; generic low-dose aspirin 0.18).19 Recent NICE guidance recommends that MRdipyridamole 200mg twice daily should be considered in addition to low-dose aspirin for a period of two years for secondary prevention of ischaemic stroke or TIA. Thereafter, or if dipyridamole is not tolerated, treatment should revert to the use of low-dose aspirin alone.16 Again, clopidogrel is an alternative for people who are intolerant to aspirin. Current evidence does not support the use of MR-dipyridamole alone, standard-release dipyridamole alone or in combination with aspirin, or a combination of aspirin and clopidogrel, for secondary prevention of stroke or TIA. It should be remembered that although antiplatelets reduce the risk of CV events they do not abolish it. For those patients who suffer a CV event while on aspirin (or clopidogrel), it should not be assumed that this is because of resistance to the drugs antiplatelet effect, or that a switch to another agent offers any greater protection. Although true resistance to the antiplatelet effects of aspirin and clopidogrel may occur in a small proportion of patients, there are currently no reliable tests to confirm this in clinical practice. Without such a test it is not possible to predict if a switch to an alternative agent would be beneficial or detrimental. Clopidogrel plus aspirin following ACS Currently, the only licensed use of a combination of clopidogrel and aspirin is in non-ST-segment-elevation ACS.9 When considering addition of clopidogrel to aspirin, the increased benefit obtained by reducing the risk of CV events must be balanced against the

Table 1. Benefits and harms of antiplatelet treatment in patients at high risk of a CV event (MI, stroke or vascular death)1
Trial category Previous MI Acute MI Previous stroke or TIA Acute stroke Other high-risk patients* All trials Treatment duration (months) 27 1 29 0.7 22 Benefit RRR 21% 27% 17% 10% 22% 19% ARR 3.5% 3.8% 3.6% 0.9% 2.2% 2.5% NNT 29 26 28 111 45 40 P-value <0.0001 <0.0001 <0.0001 0.0009 <0.0001 <0.0001 Harm ARI 0.00% 0.05% 0.50% 0.39% 0.87% 0.42% NNH 1832 202 256 115 238

*e.g. stable angina, heart failure, PAD, atrial fibrillation, diabetes RRR/ARR = relative/absolute risk reduction for having a vascular event (MI, stroke or vascular death) vs. control; ARI = absolute excess risk increase for having a fatal or non-fatal major extracranial bleed vs. control; NNT = number needed to treat; NNH = number needed to harm

increased risk of harm resulting from major side effects, notably bleeding. In absolute terms, the CURE study8 demonstrated that for every 100 patients treated for nine months, two additional patients were saved from having a major CV event by adding clopidogrel to aspirin. However, this was at the expense of one further patient suffering a major bleed. NICE considered this benefit to harm ratio sufficient to recommend the use of the combination in moderate to high-risk patients with non-ST-segment-elevation ACS for up to 12 months following the most recent acute event.17 Thereafter, treatment should revert to the use of low-dose aspirin alone (standard care). Although most of the benefit is apparent during the first three months of treatment,9 the optimal duration of treatment has not been established in clinical trials, and no specific recommendations are made. Any changes to this will be posted on the NICE website (www.nice.org.uk). American guidelines for the management of patients with STEMI recommend that patients who have undergone diagnostic cardiac catheterisation and for whom a PCI is planned,

The slight absolute benefit for clopidogrel shown in CAPRIE is insufficient to justify its use ahead of aspirin in view of its higher cost

Panel 2. Clinical evidence for primary prevention of CV events

A meta-analysis of five major trials (durations 47 years) of patients (n=53,035) without previous CV disease found that aspirin significantly reduced the risk for the combined endpoint of non-fatal MI and fatal CHD (odds ratio [OR] 0.72, 95% CI 0.60 to 0.87), but significantly increased the risk of major GI bleeds (OR 1.7, 95% CI 1.4 to 2.1).14 No significant effects in preventing stroke or all-cause mortality were identified. People at higher risk of CHD gained most benefit from the use of aspirin. The numbers of major CHD events avoided per 1,000 people treated over 5 years for aspirin therapy were estimated as 3, 8 and 14 for people at 1%, 3% and 5% 5-year CHD risk (equivalent to approximately 3%, 8% and 13% 10-year CV risk), whereas the numbers of major bleeding events caused over 5 years (haemorrhagic strokes 1, major GI bleeds 3) were independent of baseline risk. More recently, data from the Women's Health Study (WHS), which included 39,876 healthy women aged 45 years or older, found no significant reduction in major CV events (stroke, MI or CV death) with aspirin (100mg alternate days) compared with placebo (2.4% vs. 2.6%, respectively) over 10 years.15 However, a significant reduction in CV events was seen in women aged >65 years. Unlike previous primary prevention studies, the WHS did not identify a significant reduction in the risk of MI, but did find a significant reduction in the risk of stroke. These results may reflect the fact that, at any particular level of CV risk, the RR of stroke is higher (and the RR of MI lower) in women than in men. There is no clinical evidence to support the use of antiplatelet drugs other than aspirin for the primary prevention of CV events.

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Prescribing antiplatelet drugs in primary care

There is no evidence that clopidogrel or MR-dipyridamole are more effective or safer alternatives to aspirin for primary prevention of CV events

should be started and continued on clopidogrel for at least one month after stent implantation, and for up to 12 months in patients who are not at high risk of bleeding.20 Note that clopidogrel is not currently licensed for this use in the UK. Primary prevention For primary prevention, use of aspirin and other antiplatelet drugs needs to be placed in the context of other less harmful and potentially more effective primary prevention measures (e.g. lifestyle changes, treatment of hyperlipidaemia and hypertension).21 Establishing the threshold risk level for using aspirin to prevent CHD in people without existing CV disease is difficult, and for people at low risk of an event, risks of adverse events may outweigh benefits. Currently, use of low-dose aspirin is recommended for primary prevention in people aged 50 years and over with a 10-year CHD risk >15% (CVD risk >20%) provided hypertension is controlled.18 This recommendation is appropriate regardless of gender. There is no evidence that clopidogrel or MRdipyridamole are more effective and/or safer than aspirin for primary prevention of CV events, and they are not licensed for this indication. What about GI side-effects? There is no robust evidence to support the view that clopidogrel is a safer alternative to low-dose aspirin and that its use is associated with a lower risk of GI side effects. Although, in CAPRIE,6 clopidogrel was associated with an approximate
References 1 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;324:7186. 2 Patrono C, Coller B, Fitzgerald GA, et al. Platelet-active drugs: the relationships among dose, effectiveness and side effects. Chest 2004;126:234S64S. 3 Serebruany VL, Steinbuhl SR, Berger PB, et al. Analysis of risk of bleeding complications after different doses of asprin in 192,036 patients enrolled in 31 randomised controlled trials. Am J Cardiol 2005;95:121822. 4 Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;142:113. 5 Schryver ELLM, Algra A, van Gijn J. Dipyridamole for preventing stroke and other vascular events in patients with vascular disease. The Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: CD001820. DOI: 10.1002/14651858.CD001820. 6 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:132939. 7 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 2004;364:3317. 8 The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494502. 9 Summary of Product Characteristics. Plavix. Available at: www. medicines.org.uk. Accessed 23/06/2005. 10 Peters RJG, Mehta SR, Fox KAA, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes. Circulation 2003;108:16827. 11 Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:117989. 12 Mehta SM, Yusuf S, Peters RJG, et al. Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the

one-third reduction in the incidence of GI bleeding compared with aspirin, this study used a 'high' 325mg dose of aspirin, known to significantly increase the risk of bleeding (possibly three-fold) relative to standard low-dose aspirin (i.e. 75mg).3 Where aspirin is contraindicated, or there is genuine aspirin intolerance, clopidogrel can be considered as an alternative for secondary prevention of CV events. However, the number of people who are genuinely intolerant of aspirin is believed to be small.16 People who experience dyspepsia while taking aspirin should have the dose reduced to 75mg daily (if on a higher dose) and co-prescription of a PPI should be considered before switching to clopidogrel. In a recent RCT of 320 patients with a history of aspirin-induced ulcer bleeding, the combination of aspirin (80mg daily) and a PPI (esomeprazole 20mg twice daily) was superior to clopidogrel (75mg daily) in preventing recurrent ulcer bleeding. The 12-month incidence of recurrent bleeding was 8.6% with clopidogrel and 0.7% with aspirin plus PPI (NNH 13 over 12 months, P=0.001).22 Although esomeprazole was used in this study, generic omeprazole in a dosage of 20mg twice daily provides nearly the same degree of acid suppression at a much lower cost.23 There is no evidence that using enteric coated or buffered formulations of aspirin provide less of a risk than the use of dispersible aspirin 75mg, which is an appropriate dosage form.24

Consider prescribing a PPI for patients with dyspepsia while on aspirin, before switching to clopidogrel

PCI-CURE study. Lancet 2001;358:52733. 13 Eriksson P. Long-term clopidogrel therapy after percutaneous coronary intervention in PCI-CURE and CREDO: the Emperors New Clothes revisited. Eur Heart J 2004;25:7202. 14 Hayden M, Pignone M, Phillips C, et al. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence. Ann Intern Med 2002;136:16172. 15 Ridker PM, Cook NR, Lee I-M, et al. A randomised trial of lowdose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293304. 16 National Institute for Health and Clinical Excellence. Clopidogrel and modified-release dipyridamole in the prevention of occlusive vascular events. Technology Appraisal 90. May 2005. Available at: www.nice.org.uk. Accessed 25/06/05. 17 National Institute for Clinical Excellence. Clopidogrel in the treatment of non-ST segment-elevation acute coronary syndrome. Technology Appraisal 80. July 2004. Available at: www.nice.org.uk. Accessed 25/06/05. 18 PRODIGY Guidance: Coronary heart disease risk identification and management. September 2004. Available at: www.prodigy.nhs.uk. Accessed 25/06/05. 19 British National Formulary No. 49. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2005. 20 Antman EM, Anbe DT, Armstrong PW, 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) 2004. Available at www.acc.org/clinical/guidelines/stemi/index.pdf. Accessed 21/06/05. 21 Jain M, Rosenberg M. Review: aspirin reduces CAD events in people with no history of cardiovascular disease, but it increases gastrointestinal bleeding. EBM 2002;7:111. 22 Chan FK, Ching JYL, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med 2005;352:23844. 23 Anon. Aspirin + PPI safer than clopidogrel if history of GI bleed. InfoPOEM Inc 2004. Available at: www.infopoems.com/infopoems/showPOEM.cfm?ID=70303. Accessed 23/06/05 24 Anon. Which prophylactic aspirin? DTB 1997;35:78.

The National Institute for Health and Clinical Excellence (NICE) is associated with MeReC Publications published by the NPC through a funding contract. This arrangement provides NICE with the ability to secure value for money in the use of NHS funds invested in its work and enables it to influence topic selection, methodology and dissemination practice. NICE considers the work of this organisation to be of value to the NHS in England and Wales and recommends that it be used to inform decisions on service organisation and delivery. This publication represents the views of the authors and not necessarily those of the Institute. The National Prescribing Centre, The Infirmary, 70 Pembroke Place, Liverpool, L69 3GF Telephone: 0151 794 8146 Fax: 0151 794 8139 www.npc.co.uk www.npc.nhs.uk

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