COMMIT-CCS2 logo ClOpidogrel and Metoprolol in Myocardial Infarction Trial
FACT SHEET 1
CLOPIDOGREL: Questions and Answers about the COMMIT/CCS-2 results
Q What are the main results from COMMIT/CCS-2 for clopidogrel?
A Adding 75mg daily of oral clopidogrel to aspirin within 24 hours of the onset of a heart attack significantly reduced the relative risk of death in hospital by 7% and the risk of death, repeat heart attack or stroke by about 10%, without any significant increase in serious bleeding. These benefits were additional to standard heart attack treatments, and were seen even in older patients and those presenting many hours after the onset of symptoms (who do not typically receive “clot busting” fibrinolytic therapy).
Q What are the main implications of the clopidogrel results?
A On average, adding clopidogrel to current therapies benefits one in every 100 heart attack patients. So, for every million patients having a heart attack, giving this simple additional treatment for about two weeks would save 5,000 lives and prevent another 5,000 repeat heart attacks or strokes. As there are about 10 million heart attacks in the world every year, the findings from this study – if implemented appropriately widely – would make an important contribution to saving lives and reducing disability.
Q What has COMMIT/CCS-2 told us that we did not know before?
A The use of aspirin for the emergency treatment of heart attacks had been shown previously in ISIS-2 (Second International Study of Infarct Survival) to reduce the risk of death and repeat heart attacks by about one quarter. As a consequence of that research, which was also conducted by our team, aspirin is now used routinely during a heart attack (and is then continued long-term). Aspirin and clopidogrel are anti-platelet drugs that work through different pathways. COMMIT/CCS-2 has now shown that blocking both of these pathways with the combination of aspirin and clopidogrel is even more effective at preventing death and repeat heart attacks than using aspirin alone.
Q Both aspirin and clopidogrel are anti-platelet drugs. Is their combination safe?
A The major concern related to any anti-platelet drug is bleeding, but the study showed that adding clopidogrel to aspirin for a few weeks in hospital is remarkably safe. There was a small increase in the risk of minor bleeding and bruising. But, this large study did not find any material increase in the risks of haemorrhagic stroke or other serious bleeding (i.e. fatal or transfused bleed) with the use of clopidogrel in this setting.
Q How important do you rate the findings?
A Very important. These new findings show that clopidogrel should now be considered routinely for a wide range of patients admitted to hospital with suspected heart attacks (largely irrespective of their age, other characteristics, or the use of other treatments).
Q Are these results for clopidogrel definitive?
A The large numbers of deaths and relevant non-fatal events on which these results are based make the findings extremely reliable and definitive.
Q Were the COMMIT/CCS-2 clopidogrel results in line with what you expected?
A Adding clopidogrel to aspirin had previously been shown to reduce the risk of heart attacks in people who had unstable angina or were undergoing percutaneous coronary intervention (PCI) balloon angioplasty or stenting. So, although the use of clopidogrel as an emergency treatment for heart attacks had not previously been extensively studied, it was reasonable to hope that it might add to the benefits produced by aspirin.
Q Were there any disappointments with the clopidogrel findings?
A No – these results are good news for people who are having a heart attack.
Q Were there any differences between the findings for clopidogrel in men and women or in different age groups?
A No. The efficacy and safety findings for clopidogrel were consistent in men and women, and at different ages (including even among the large numbers of participants aged over 70 who are quite often not well represented in such studies).
Q Were there any differences between the findings for patients with heart attacks of differing severity?
A No. Again, the findings for clopidogrel were generally consistent between patients presenting at different levels of risk (including those who presented with heart failure).
Q Did the results reveal any types of patients that are definitely not suitable for clopidogrel?
A Patients who were thought to be at increased risk of bleeding because they had active bleeding or a history of a bleeding disorder were excluded from the study. Among the patients included in the study, however, no particular group could be identified who would not benefit from clopidogrel.
Q COMMIT/CCS-2 was looking at short-term treatment in hospital. Do the findings tell us anything about longer-term use of these drugs?
A The addition of clopidogrel to aspirin for the long-term treatment of unstable angina has previously been shown to prevent heart attacks in that setting, and the present COMMIT/CCS-2 results reinforce this evidence. Aspirin is currently used long-term after heart attacks and ischaemic strokes, and studies are ongoing to determine whether the addition of clopidogrel would safely produce greater reductions in the risks of further heart attacks and strokes.
Q Given the size of this study, are any further studies of clopidogrel necessary?
A COMMIT/CCS-2 provides clear evidence about the benefits and safety of adding clopidogrel to aspirin during and just after a heart attack, which complements the available evidence about the long-term use of this combination in unstable angina and during coronary artery procedures. Further studies about the long-term use of adding clopidogrel to aspirin after heart attacks and strokes, as well as in other situations associated with high risks of occlusive vascular events, are still needed.
Q Were you concerned about possible interactions between clopidogrel and other drugs used by patients having heart attacks?
A The doctors of patients in the study were free to use any other treatments in hospital that they considered necessary. In particular, all of the patients were given daily aspirin, about two-thirds received anticoagulants (typically heparin) and about half received fibrinolytic drugs. There was no evidence that the risks of serious bleeding with clopidogrel were materially increased in the presence of these other treatments that affect blood clotting. Nor was there any evidence that the reductions in the risks of repeat heart attacks or death with clopidogrel were materially influenced by the use of these or any other treatments (including the other study drug, metoprolol). That is, the benefits of clopidogrel appeared to be additional to those of all of the other current standard treatments used during a heart attack, without any particular safety concerns.
Q Do you think the dosage of clopidogrel used in COMMIT/CCS-2 was optimal?
A The daily dose of 75 mg clopidogrel studied has been shown to produce anti-platelet effects within a few hours and to achieve maximal anti-platelet effects within a few days. Significant benefits emerged with this clopidogrel regimen during days 0-1 (i.e. an average of 36 hours) of treatment in COMMIT/CCS-2, which indicates that it was effective early after initiation. A loading dose of 300mg clopidogrel could be used to produce maximal anti-platelet effects more rapidly, but may cause more bleeding.
Q Are the findings from this study in China applicable to other populations?
A Yes. There is no evidence that the nature of heart attacks is materially different in China than elsewhere, or that Chinese patients react differently to clopidogrel than do other populations. Furthermore, the concomitant therapies used in hospital in the study were very similar to those typically used in other countries.
Q Previous studies have already shown that clopidogrel is effective in treating heart disease. How could you justify using placebo?
A Adding clopidogrel to aspirin had previously been shown to be beneficial for people who had unstable angina or were undergoing angioplasty or stenting. Before the results of COMMIT/CCS-2 became available, however, there was no good evidence for the use of clopidogrel during a heart attack. Moreover, entry to the study was guided by the “uncertainty principle”: that is, each patient was eligible for inclusion in the study only when their responsible doctors were substantially uncertain as to whether clopidogrel was clearly indicated or clearly contraindicated.
Q Are these results for clopidogrel likely to be applicable to any other type of anti-platelet drug?
A COMMIT/CCS-2 shows that blocking platelet function in more than one way can safely produce greater reductions in serious vascular events. But, these efficacy and safety results for this particular combination of clopidogrel and aspirin cannot necessarily be extrapolated to other anti-platelet drug combinations.
Q Is clopidogrel expensive? Will this treatment be affordable in less developed countries as well as in more developed countries?
A Clopidogrel currently costs about US$2-4 per 75 mg daily dose. But, since the regimen studied in COMMIT/CCS-2 lasted an average of only about 2 weeks, it is likely to be affordable for most patients – even in less well developed countries.
Q Are you going to follow the patients long-term to assess outcomes, or is day of discharge from hospital the final outcome?
A The study aimed to assess outcome during the scheduled treatment period of 4 weeks or prior hospital discharge, and there is currently no plan to follow patients longer-term.
Q The findings on clopidogrel seem clear – that is, that it saves lives and prevents repeat heart attacks. What is the most important 'take home' message for doctors?
A Immediate use of 75 mg daily clopidogrel in addition to aspirin should be considered routinely for all patients presenting with a suspected heart attack regardless of their sex, age and the use of other standard treatments (including fibrinolytic therapy or anticoagulants), unless there is some clear contraindication (such as a particularly high risk of bleeding).