Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.


Iscover (Bristol-Myers Squibb)
Plavix (Sanofi Winthrop)
75 mg tablets
Approved indication: vascular ischaemia
Australian Medicines Handbook Section 7.2

The aggregation of platelets in patients with vascular disease can cause ischaemic events such as myocardial infarction and stroke. Therefore, antiplatelet drugs have an important role in preventing these events.1 Clopidogrel is a new antiplatelet drug similar to ticlopidine. The platelet's glycoprotein receptor for fibrinogen is affected because clopidogrel blocks the activation of platelets by adenosine diphosphate.

Clopidogrel has been compared with aspirin in a study of more than 19 000 patients. The patients had a history of peripheral vascular disease, myocardial infarction or ischaemic stroke. They took either 325 mg aspirin and a placebo, or 75 mg clopidogrel and a placebo. The patients were followed up for approximately two years. The annual risk of death from vascular causes was 5.83% in the patients taking aspirin and 5.32% in the patients taking clopidogrel(1021 vs. 939 events). The 8.7% reduction in relative risk was statistically significant.2 There was no difference in all cause mortality between the two treatments.

The once daily dose is quickly absorbed, but very little clopidogrel can be detected in the plasma. This is because of extensive liver metabolism. As the main metabolite is inactive, it is thought that another unidentified metabolite is responsible for inhibiting platelet activation. Half of each dose is excreted in the urine, but a reduced dose is not required in the elderly or in those with reduced renal function. Although half the dose is excreted in the faeces, there is no advice on the effects of hepatic insufficiency.

In the clinical trial of clopidogrel2,21% of the patients dropped out, usually due to adverse events. When compared with aspirin, there was a similar frequency of adverse reactions. More patients taking clopidogrel complained of a rash or diarrhoea, but patients taking aspirin were more likely to have gastrointestinal discomfort or bleeding. Four patients taking clopidogrel have developed severe neutropenia. Compared with similar studies of ticlopidine, clopidogrel appears to cause less neutropenia. The overall incidence of thrombocytopenia is similar for clopidogrel and aspirin.

Clopidogrel can inhibit the activity of cytochrome P450 2C9.This creates the potential for interactions with other drugs metabolised by this system, such as tolbutamide and phenytoin. Caution is needed when prescribing clopidogrel with other drugs which increase the risk of bleeding e.g. heparin, warfarin and non-steroidal anti-inflammatory drugs including aspirin.

Although clopidogrel reduces the relative risk of death more than aspirin, the reduction is not the same in all patients. People with peripheral vascular disease had a big reduction in risk, while there was no reduction for patients who had had a myocardial infarction.

If 1000 patients are treated for a year, aspirin will prevent19 major clinical events and clopidogrel will prevent 24. Given the low price of aspirin, it will be interesting to see what the cost of purchasing the apparent additional benefit of clopidogrel will be.

References

  1. Lefkovits J. Recent advances in antiplatelet therapy. Aust Prescr1996;19:98-101.
  2. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39.