The results of recent large-scale, randomised, placebo-controlled trials of hydroxymethyl glutamyl coenzyme A (HMG CoA) reductase inhibitors should change our prescribing for patients following myocardial infarction.
Epidemiological data have shown a continuous, positive relationship between the incidence of coronary heart disease (CHD) and cholesterol concentrations. The relationship is curvilinear, such that the impact of increased cholesterol is greater at high concentrations. However, the role of cholesterol-lowering therapy has been questioned because of concern about its cost-effectiveness and also a possible increase in non-cardiovascular deaths. For patients at low absolute risk of CHD, e.g. in primary prevention, published evidence suggested that an increase in non-cardiovascular deaths (cancer and violent deaths) might negate the reduction in CHD events, resulting in no clear effect on total mortality.1 These trials were probably under-powered to show benefit. This was because the interventions they tested lowered cholesterol by an average of only 10%. The studies had also generally included relatively small numbers of patients followed for short periods of time.
Recent clinical trials
The recent large trials using HMG CoA reductase inhibitors after a myocardial infarction are summarised in Table 1. The trials, 4S2, CARE3 and LIPID4, conclusively established the benefits of treatment, whether or not the cholesterol level was elevated2, average or low3,4 at baseline. Not only were CHD events prevented, but strokes were also reduced. These benefits were achieved without any increase in non-cardiovascular deaths and, overall, the drugs were very well tolerated.
The LIPID study
This was a local study involving 9014 men and women, aged 31-75 years, recruited from 87 centres in Australia and New Zealand between 1990 and 1992. Follow-up continued until September 1997. The patients were taking other treatments which would be regarded as representing accepted management. Pravastatin and placebo were then compared on a background of standard dietary advice. Baseline cholesterol concentrations were very representative of patients presenting with CHD, and the study included over 3500 patients with total cholesterol <5.5 mmol/L. All the study's prespecified cardiovascular endpoints were significantly reduced by pravastatin. These included CHD events, cardiovascular and total mortality, myocardial infarction, stroke, revascularisation by bypass surgery or angioplasty, or occurrence of unstable angina. In absolute terms, treatment of only 20 patients for 6 years in the LIPID study prevented one patient dying or suffering a non-fatal myocardial
infarction or non-fatal stroke. Preliminary analyses suggest that treatment was cost-effective.
The CARE study group3 has suggested that there may be no benefit with treatment of patients who have baseline LDL cholesterol <3.2 mmol/L. In LIPID, no such `threshold' was found with analysis of total and LDL cholesterol as continuous variables.
Clinical implications and remaining questions
Patients were recruited to 4S, CARE and LIPID more than 3 months after their qualifying acute event, usually myocardial infarction. After this time, the prognosis of such patients is very similar to that of patients with stable angina. In LIPID, there were no differences in outcomes whether or not patients had suffered myocardial infarction or unstable angina. It seems reasonable to extrapolate the results to all patients diagnosed with CHD. There is no information on the value of HMG CoA reductase inhibitors in the first 3 months following myocardial infarction. Ongoing trials are addressing this area. However, it is practical to assess patients in hospital using fasting blood samples obtained in the first 24 hours. Not only may compliance be enhanced by an early explanation and initiation of treatment, but patients are less likely to be lost to follow-up. Although there is no pressure to start treatment early, if it is commenced, it should be considered to be life-long, unless there are significant adverse effects.
Recent major placebo-controlled secondary prevention trials
|Drug (dose)||simvastatin |
|Cohort||80% MI; 20% AP||Post MI||64% MI; 36% UAP|
|Baseline cholesterol||5.5-8.0 mmol/L||<6.2 mmol/L||4.0-7.0 mmol/L|
|Trial duration||5.4 years||5.0 years||6.1 years|
|Primary endpoint||Total mortality||Coronary events||CHD mortality|
|30% (0.0003)||24% (0.003)||24% (0.004)|
MI - myocardial infarction
(U)AP - (unstable) angina pectoris
CHD - coronary heart disease
The current Pharmaceutical Benefits Scheme guidelines suggest that patients with CHD could qualify for treatment with a HMG CoA reductase inhibitor if their cholesterol is >5.5 mmol/L. However, the trials, particularly LIPID, showed a significant reduction in CHD events in patients with lower cholesterol concentrations. This emphasises the need for reassessment of the current guidelines. This should take into consideration further economic analyses and methods to assess 'global' CHD risk in individual patients.
The degree to which cholesterol should be reduced and the possible target of treatment require future study. Further analyses of the large LIPID database will include these important issues.
Undoubtedly, HMG CoA reductase inhibitors are under-utilised in patients following myocardial infarction. The positive results of 4S, CARE and LIPID suggest that all these patients should now be considered for therapy, in addition to dietary advice, attention to other cardiovascular risk factors and, as appropriate, other secondary prevention treatments such as aspirin, beta blockers and ACE inhibitors.
- Keech A. Does cholesterol lowering reduce total mortality? Postgrad Med J 1992;68:870-1.
- Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.
- Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. for the Cholesterol and Recurrent Events Trial investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-9.
- The LIPID (Long-term Intervention with Pravastatin in Ischaemic Disease) Study Group. Prevention of death and cardiovascular events with pravastatin in 9014 patients with coronary heart disease and a broad range of cholesterol levels. N Engl J Med. In press.