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Paper text:
the dutch branch of sanofi - synthelabo sent this wine to collaborators of the clopidogrel versus aspirin in patients at risk of ischaemic events ( caprie ) trial   to celebrate the regulation of reimbursement for clopidogrel in the netherlands on 26 july . the official indication for this novel antiplatelet drug reads : ' secondary prevention in patients with atherosclerotic disease and proven aspirin sensitivity ' .
sanofi - synthelabo appealed against the limitation to patients intolerant to aspirin , but lost the lawsuit .
what is the background of this legal quarrel ? the cornerstone is clinical evidence from the caprie trial , a ran - domised , blinded , international study .
clopidogrel ( 75 mg daily ) and aspirin ( 325 mg daily ) were compared in the prevention of the composite outcome event ' vascular death , nonfatal stroke or nonfatal myocardial infarction ' .
clopidogrel reduced the annual risk of such a vascular event from 5.83 to 5.32% in comparison with aspirin , corresponding to a relative risk reduction ( rrr ) of 8.7% .
the 95% confidence interval just kept clear of the neutral value and ranged from 0.3 to 16.5% .
the design of the study was based on the paradigm prevalent in the early 1990s : all clinical presentations of atherosclerotic disease should be regarded as different manifestations of a single disorder of the arterial vascular tree . the data of the caprie trial do not necessarily support this paradigm , because the rrr values of the three diagnostic strata ( each with over 6000 patients ) differed considerably : -3.7% for myocardial infarction , + 7.3% for ischaemic stroke , and 23.8% for peripheral arterial disease ( p = 0.042 ) . a similar difference between different categories of atherosclerotic disease had been observed by the antiplatelet trialists ' collaboration .
the rrr values achieved by aspirin ( compared with placebo ) ranged from 18% for cerebral ischaemia to 35% for unstable angina .
both thienopyridines block the activation of platelets by selective and irreversible inhibition of binding of adp to its platelet receptor . a recent review by the cochrane library reviewed the effects of this class of drugs .
four trials on the comparison of thienopyridines with aspirin , with a total of 22,656 patients , were identified .
most information came from the caprie trial ( 72% of the outcome events ) and virtually all other data originated from the ticlopidine aspirin stroke study .
this latter trial enrolled patients with a recent transient ischaemic attack ( tia ) or minor ischaemic stroke and found a 6% rrr ( 95% confidence interval , -7% to + 17% ) of vascular events , an effect quite similar to that observed in the caprie stroke stratum .
one of the reasons for developing clopidogrel was the risk of neutropenia with ticlopidine use ( neutropenia occurred in 2.3% of the ticlopidine treated patients in the ticlopidine aspirin stroke study ) necessitating monitoring of white blood cell counts .
this side effect occurred far less frequently in the caprie trial , which closely monitored for these events ; no differences in this regard were observed between clopidogrel and aspirin . with respect to other side effects , more skin rash and diarrhoea were reported with clopidogrel whereas aspirin use led to more upper gastrointestinal discomfort , gastrointestinal haemorrhage and abnormalities of the liver function .
the new england journal of medicine posted an expedited publication on its website earlier this year on 11 cases of thrombotic thrombocytopenic purpura , which was triggered by similar adverse effects from ticlopidine .
the rate of thrombocytopenic purpura associated with clopidogrel ( 3.7 per million ) appears to be similar to what might be expected in the community .
the recent publicity on this life threatening side effect is , however , likely to increase the awareness of clinicians of clopidogrel related thrombocytopenic purpura , which might lead to more such reports .
another issue is whether the primary outcome of the caprie trial should consist of the composition of several types of vascular events .
albers   recently argued that stroke trials should use stroke as an outcome , rather than all vascular events .
his main argument was of a statistical nature : because the most important effects in a stroke trial are obtained in the prevention of stroke , the inclusion of non - stroke vascular events would dilute such an effect .
a patient presenting with vascular disease , either cerebrovascular , cardiac , or peripheral , has a high risk of future vascular events anywhere in the arterial tree .
indeed , new events tend to be most frequent in the presenting organ during the first years after presentation , but the whole vascular bed is later at risk . because a patient does not want to be harmed by either a stroke or a myocardial infarction , protection against any such event should be offered .
trials should thus be designed in such a way that they can address this point of view by means of a composite vascular outcome event .
one may even argue , from the patient 's perspective , to include major bleeding complications as one of the most important side effects in the evaluation of antithrombotic treatment .
a second objection to albers ' reasoning is that sample size requirements need not necessarily be advantageous with a stricter outcome definition .
the benefit gained by a ( expected ) higher treatment effect may be offset by a smaller number of outcome events .
we thus consider the choice of the primary outcome event of the caprie trial appropriate for use in clinical practice .
restricted outcome definitions , which always come free with the use of composite events , may nevertheless be useful in unravelling pathophysiological mechanisms .
hankey and warlow calculated that it would cost approximately us$33,000 to avoid one stroke in secondary stroke prevention with clopidogrel , whereas aspirin would cost only us$1400 in the same situation .
meanwhile , sanofi - synthelabo and bristol - meyers advertise their drug and are sometimes overenthusiastic about clopidogrel .
one advertisement stated that clopidogrel reduced the number of ischaemic events by 26% compared with aspirin treatment .
this misleading number represented a relative efficacy , on comparison with an imaginary placebo group , derived from data of the antiplatelet trialists ' collaboration .
at least one new study with clopidogrel as a secondary prevention drug is about to start .
the combination of 75 mg clopidogrel and 75 mg aspirin daily will be compared with clopidogrel only in the match trial ( ie management of atherothrombosis with clopidogrel in high - risk patients with recent tia or ischaemic stroke ) .
the primary outcome of this trial will be the same composite event used in the caprie trial extended with rehospitalisation for acute ischaemic events .
the match study will also not answer the question whether it is useful to add clopidogrel to aspirin , but will answer only the reverse question .
more data are available on the efficacy of aspirin , the current standard in patients with ischaemic brain disease , than on the efficacy of clopidogrel .
in summary , clopidogrel appears to be somewhat more effective than aspirin if one is willing to accept the unitary atherosclerosis paradigm .
the gain , however , is modest : about 200 patients should use clopidogrel rather than aspirin for 1 year to prevent just one vascular event . if one is sceptical about the atherosclerosis paradigm , there is little reason to use clopidogrel after myocardial infarction and good grounds to replace aspirin by clopidogrel in peripheral arterial disease .
the data are not convincing after ischaemic stroke , and cost considerations would tip the balance in favour of aspirin .
the conservative attitude of the dutch authorities in their regulation of reimbursement of clopidogrel is understandable .
we have to await the results of studies on the combined efficacy of clopidogrel and aspirin for a reassessment of the position of clopidogrel .
the cornerstone in clinical evidence of the relative efficacy of thienopyridines ( clopidogrel , ticlopidine ) versus aspirin in the secondary prevention of vascular disease is the clopidogrel versus aspirin in patients at risk of ischaemic events trial . 
 this trial showed a modest benefit in the reduction of vascular events by clopidogrel . 
 the results differed according to qualifying disorder : myocardial infarction , -3.7% ; ischaemic stroke , + 7.3% ; and peripheral arterial disease , + 23.8% ( p = 0.042 ) . 
 similar results were found for ticlopidine after brain ischaemia . 
 the safety of clopidogrel appears to be similar to that of aspirin and better than that of ticlopidine . 
 however , the recent report of thrombotic thrombocytopenic purpura in association with clopidogrel causes concern .