Myocardial Infarction
Optimising Drug Therapy

• Check List for Drug Therapy

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• Clopidogrel
• Clopidogrel alone only slightly better than aspirin alone
• Clopidogrel with aspirin better than aspirin alone after an acute coronary event
• Clopidogel with aspirin probably is better than aspirin alone in stable coronary disease

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• Warfarin
• Warfarin- instead of (or as well as) aspirin for secondary prevention

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• Beta-blockers
• After MI
• After large MI
• In heart failure

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• ACE-inhibitors
• After MI
• After large MI
• Use maximal dosages in heart failure
• For most patients after MI

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• Aldosterone antagonists
• Spirinolactone in heart failure

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• Lipid modifying therapy after MI

Clopidogrel with aspirin

Evidence for benefit after acute coronary syndromes

Findings of the CURE trial

The CURE trial was a large randomised trial that enrolled over 12,000 patients with acute coronary syndromes- the patients were randomised to treatment with aspirin alone or to aspirin plus clopidogrel. Treatment was started in hospital and continued after discharge. Average follow-up was 9 months (range 3 to 12 months).

Treatment benefits appeared early- many now use clopidogrel routinely when treating patients in hospital with acute coronary syndromes. After percutaneous intervention with bare metal stents, clopidogrel is usually continued for three weeks.

However, clopidogrel treatment is not funded by Pharmac and the question is whether we should be encouraging patients to buy clopidogrel at considerable cost to enable continued therapy for about nine months.

In the CURE trial (after an average follow-up of nine months) the primary endpoint of the composite of cardiovascular death, stroke and myocardial infarction was significantly reduced (11.47% vs 9.28%, risk ratio 0.80, P= 0.00005). When analysed individually, myocardial infarction rates were significantly less with the combined use of clopidogrel and aspirin. Stroke and death were not significantly reduced. However, it is important to always be careful with sub-group analysis- this trial was not designed to determine the impact on death alone.

There was an absolute 1% increased risk of serious bleeding and 7% increased risk of minor bleeding with the use of clopidogrel.

It is important to emphasise that the majority of the benefit from treatment with clopidogrel was obtained in the first few weeks. Hence, if one sees a patient three months after the acute event, one can not expect that starting clopidogrel treatment at three months will provide the same absolute benefits as documented by the CURE trial.

Subgroup analysis of the CURE trial results shows that high risk patients seem to obtain greater absolute benefits.

A separate analysis of patients in the CURE trial that underwent percutaneous intervention also showed benefits from prolonged treatment with clopidogrel and aspirin.

Conclusions:

• There is no confirmatory evidence from other large randomised trial comparing this combination of drugs in patients with acute coronary syndromes.
• If patients wish to take clopidogrel, then the greatest benefits are obtained if they commence treatment in hospital and continue the drug at discharge. The ideal duration of combination therapy of aspirin and clopidogrel is not known- the mean follow-up (and duration of treatment) in the CURE trial was nine months. The hypothesis generating subgroup analysis of the CHARISMA trial results could be taken to indicate that treatment beyond nine months does provide additional benefit.
• One might argue that the most cost-effective strategy is if treatment is started in hospital and then continued for only four or eight weeks when the largest benefits are obtained. However, this shorter treatment strategy has not been formally tested in clinical trials and one can not exclude the possibility of a rebound increase in events if patients only receive treatment for a short period. Such a rebound increase in events was seen when low dose fragmin was given for a few weeks in one of the low-molecular weight heparin trials.
• There is debate about the cost-effectiveness of long-term therapy with clopidogrel particularly since overall mortality was not reduced with prolonged therapy with clopidogrel. The situation is not dissimiliar to therapy for dyslipidaemia when statin costs were quite a lot higher and not funded by Pharmac.
• Analysis of the CURE trial data did show that patients in different risk groups (based on the TIMI risk calculator) obtained the same relative risk reduction. As expected this translates into greater absolute benefits for the highest risk group.
• The highest risk patients obtain greater benefits from treatment. This might include patients who, after an acute coronary syndrome, are found to have severe multi-vessel coronary disease and who are awaiting outpatient coronary bypass surgery- it is important to stop clopidogrel treatment some time before bypass surgery to reduce the risk of serious bleeding.
• Many patient with health insurance that provides partial cover for percutaneous intervention will have to make up the difference between their insurance cover and the actual cost of the procedure. For high risk patients, the benefits of paying to use clopidogrel may well be similar or greater than the benefits obtained by “low-risk” patients undergoing percutaneous coronary intervention.

References:

• Effects of clopidogrel in addition to aspirin patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494–502.
• Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 527-533