Aldo P Maggioni
ANMCO Research Center
Acute myocardial infarction (AMI) is the leading cause of death in the industrialised world, and although acute-phase treatments are highly efficacious, an appropriate secondary
prevention approach is arguably the most important insurance for the patient’s long-term survival. Individuals who survive an AMI have up to a ninefold greater risk of cardiovascular morbidity and mortality compared with the general population. Several large trials have revealed the potential benefit of secondary prevention that includes lifestyle modification (diet, exercise, smoking cessation) and medications. In recent years, evidence has accumulated for the clinical effectiveness of several classes of drugs, including aspirin, β-blockers, angiotensinconverting enzyme (ACE) inhibitors and statins.
Aspirin inhibits prostaglandin synthesis, decreasing platelet aggregation.(1) Its beneficial role has been proven in the secondary prevention of MI, unstable angina, all-cause and cardiovascular-associated mortality.(2–5) The benefit of prolonged antiplatelet treatment after MI has been shown by the Antiplatelet Trialists’ Collaboration overview of 145 randomised trials involving more than 100,000 patients with different degrees of risk of occlusive vascular disease.(5) Among 20,000 patients with acute MI, the rate of serious
vascular events at one month was 10% in the antiplatelet group vs 14% in the control group (40 vascular events avoided per 1,000 patients treated), and in 20,000 patients with a past history of MI treated for a mean period of 27 months the rate of total events was 13% vs 17% (2p<0.00001), the rate of vascular deaths was 8.1% vs 9.4% (2p<0.005), and that of reAMI was 4.7% vs 6.5% (2p<0.00001) in treated vs control patients respectively (see Figure 1). Unless specific contraindications exist, the use of aspirin is recommended in all patients with a previous AMI.(5) A more recent meta-analysis by the Antiplatelet Trialists’ Collaboration, which includes studies available to September 1997, confirms these results and shows that daily aspirin doses of 75–150mg seem to be as effective as higher doses for long-term treatment.(6)
Angiotensin-converting enzyme inhibitors
The use of ACE inhibitors following AMI has been investigated in trials involving more than 100,000 patients (see Table 1).(7) These drugs were initially found to benefit patients with prior MI and left ventricular dysfunction or heart failure.(8–10) An overview of these trials has found that treatment with an ACE inhibitor initiated soon after MI reduced the mortality rate from 26.5% to 22.1% (p<0.00001) and the risk of reinfarction from 12.2% to 10.2% (p<0.0004).(11) In other randomised studies, treatment was initiated early (within 24–36 hours of the onset of symptoms) in all patients with AMI irrespective of the presence of left ventricular dysfunction.(12–15) After 30 days there was a significant reduction in mortality (7.6% vs 7.1%, p=0.004) and a lower rate of nonfatal congestive heart failure episodes in the treatment arm (15.6% vs 14.6%, p<0.01).(16) More than 80% of the benefit in patients allocated to ACE inhibitors was achieved in the first week after AMI.(17) Further information on the beneficial effects of long-term treatment with ACE inhibitors in patients at high risk of cardiovascular events was derived from the HOPE study.(18) In this study, patients with heart failure were excluded. There was a significant reduction in the composite endpoint of MI, cardiovascular death and stroke from 17.5% in patients allocated to placebo to 13.9% among patients allocated to an ACE inhibitor.
There are also two ongoing trials testing the hypothesis of treating coronary patients without left ventricular dysfunction: PEACE and EUROPA.(19–21) The results will be available in 2003/2004 and will give a definitive answer with respect to the use of ACEinhibitors in patients with coronary disease.
A series of randomised trials reported in the 1980s showed that long-term administration of β-blockers improves survival after MI.(22) A meta-analysis of β-blockers in long-term secondary prevention involving 31 randomised trials and 25,000 patients showed a 23% reduction in the odds of death (95% CI 15–31). The number-needed-to-treat for two years to avoid a death is 42, which compares favourably with other treatments for patients with previous MI.(23) In the Cooperative Cardiovascular Project more than 200,000 patients with diagnosis of MI were enrolled, providing the opportunity to evaluate the relationship between treatment and outcome in a nonselected population of patients, most of whom were over 65 years of age.(24) Patients who received β-blockers had a 40% lower mortality rate than those who did not have β-blockers prescribed at discharge. This survival advantage was consistent in allsubgroups examined and also in patients with traditional contraindications, such as heart failure, pulmonary disease, older age and diabetes.
There is a widespread agreement that patients with pre-existing coronary disease should be offered ipidlowering treatment.(25–27) The Scandinavian Simvastatin Survival Study enrolled patients with elevated cholesterol levels and coronary disease (20% stable angina). The CARE and LIPID studies enrolled patients with previous MI. Similar benefits were reported in these trials, in which the incidence of recurrent MI was decreased by approximately 30% and the risk for coronary death decreased by 20–42% (see Table 2).
The recently completed Heart Protection Study (HPS) has confirmed the results of the previous trials and supports the use of statins in secondary prevention. This large trial included 20,536 patients with coronary disease or high risk of cardiovascular events, total cholesterol levels >135mg/dl, treated for at least five years. There was a 25% lower mortality in the treatment arm, and the benefit was seen in all subgroups (females, patients with diabetes, older) and in patients with LDL cholesterol <100mg/dl. The trial also confirmed the long-term safety of the statins without excessive risk of adverse effects.(28)
n-3 polyunsaturated fatty acids (n-3 PUFAs)
A large-scale clinical trial of patients surviving recent MI, the GISSI Prevenzione,(29) has provided evidence for n-3 PUFAs in reducing mortality: 11,323 patients were randomised to n-3 PUFAs or no treatment, in addition to receiving optimal pharmacological treatment and lifestyle advice. At 42 months the reduction in mortality was 21% for the n-3 group
(p<0.01). Interestingly, an ad-hoc analysis of the time course of the benefit showed an early and highly significant reduction of sudden cardiac death supporting the hypothesis of an antiarrhythmic effect of this supplementation.(30)
There are several lines of research testing new therapeutic approaches in patients who survived a coronary event.
Patients with post-MI LV dysfunction/failure
Two hypothesis are under evaluation:
- The evaluation of the efficacy of the new aldosterone receptor blocker eplerenone. The trial, called EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study), is testing the benefit/risk profile of this drug in more than 6,000 patients with post-MI LV dysfunction or failure. The results will be available in the next few weeks.
- The VALIANT (VALsartan In Acute myocardial iNfarcTion) trial is comparing valsartan vs captopril (considered the anchor treatment in patients with post-MI LV dysfunction/failure) vs the combination of valsartan plus captopril. The trial included 14,703 patients, and the results will be available by the end of 2003.
Patients at high risk of cardiovascular events
The HOPE (Heart Outcomes Prevention Evaluation) trial clearly demonstrated the efficacy of ramipril in the reduction of the rates of cardiovascular deaths, MI and stroke. The ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint) trial is comparing ramipril vs telmisartan vs the combination of the two. The hypothesis is that a more complete and specific block of the RAAS system can further improve the outcome of the patients at high risk for cardiovascular events. The results will be available within four years.
In the past two decades, advances in pharmacological and mechanical reperfusion therapy have improved the survival of patients with AMI. Despite these advances, patients recovering from MI are still at increased risk for reinfarction, heart failure and sudden death. Lifestyle modification and pharmacological interventions remain the key component of secondary prevention.
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- The Long Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. N Engl J Med 1998;339(19):1349-57.
- MRC/BHF Heart Protection Study investigators. Lancet 2002;360(9326):7-22.
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