Therapeutics Drugs used in secondary prevention after myocardial infarction: Case presentation

Part I of this case presentation focused on the emergency management of a patient with an acute anterior myocardial infarction who presented with sudden onset chest pain [1]. In part II, we will deal with the subsequent management of the case as from the early hours after admission to the Coronary Care Unit. A 57 year old man was rushed to his local hospital with a 30 min history of severe chest pain associated with dizziness and nausea [1]. On examination he was pale, sweaty and tachycardic and an electrocardiogram demonstrated changes consistent with an acute anterior myocardial infarction. He was treated immediately with aspirin, opiate analgesia, oxygen and was given early intravenous streptokinase therapy in the absence of any contraindication (the potential benefits of tissue plasminogen activator were considered). The importance of initiating treatment as early as possible, the importance of the dedicated coronary care unit setting and the potential uses of heparin, magnesium, intravenous β-adrenoceptor blockade and insulin in the acute, early setting were also discussed [1]. We now contemplate his further management and consider therapeutic measures that will reduce his morbidity and increase his chances of survival in the coming months and years ( Table 1). The benefits of aspirin therapy given daily in the first 5 weeks on early mortality after myocardial infarction are well established and have been reviewed [1]. Aspirin inhibits the enzyme cyclooxygenase I in platelets reducing aggregation and the platelet release reaction at much lower doses than those required for its anti-inflammatory actions [2]. Although aspirin is rapidly cleared by renal excretion (plasma half-life 30 min [3]) doses as low as 75 mg lead to irreversible inhibition of cyclooxygenase I and its antiplatelet effects that can persist for several days depending on platelet turnover. A variety of doses have been used in randomized trials examining the impact of regular prophylactic aspirin in secondary prevention following myocardial infarction. The ISIS 2 study demonstrated a significant 23% reduction in vascular mortality at 35 days in patients randomized to receive 162 mg enteric coated aspirin daily following a myocardial infarction or an absolute benefit of 24 vascular deaths per 1000 patients treated [4]. Ten year mortality data show persistence of the early mortality benefit [5]. It is less clear whether any additive benefit accrues from continuing aspirin beyond the first month. The Antiplatelet Trialists' Collaboration provided an overview of antiplatelet therapy that included 45 controlled trials of ‘prolonged’ (at least 1 month) aspirin therapy 75 mg to 1500 mg daily in patients at high risk of vascular disease [6]. A meta-analysis of the 11 largest antiplatelet trials in patients with prior myocardial infarction suggested that 36 (s.d. 6) vascular events were avoided for every 1000 survivors treated for a mean of 27 months. However, a smaller number of trials have included patients randomized beyond this period and the totality of the data suggest that the proportional benefit of treatment on vascular events is reduced in year 3 of treatment and beyond. All aspirin doses between 75 mg and 325 mg seem to be similarly efficacious and aspirin alone seems to be as efficacious as any other antiplatelet regimen. The commonest adverse effect of chronic aspirin therapy is gastrointestinal toxicity with an increased risk of bleeding and ulceration despite doses as low as 75 mg daily [7]. A recent review concluded that long-term aspirin prophylaxis is associated with approximately 2.5 major and 7 minor gastrointestinal bleeding episodes per 1000 patient-years [8]. Another overview of randomized trials involving over 75 000 person years of exposure to aspirin suggested that there was a dose-related increase in gastrointestinal bleeding (2.5–7.7 bleeds per 1000 person years) and peptic ulcer (0.5–3.3 per 1000 person years) but that fatal bleeds were extremely rare [9]. These risks are heavily outweighed by the above benefit in most survivors of a myocardial infarction. Although the more expensive enteric-coated aspirin preparations have been associated with less peptic ulceration both in an endoscopic study [10] and a case-control study [11], a recent review of gastrointestinal bleeding episodes failed to show a clear benefit [12]. Another option for aspirin intolerant patients is its combination with antiulcer therapy. An endoscopic study of subjects taking 300 mg aspirin daily randomized to receive placebo or omeprazole (20 mg/40 mg) treatment showed a reduction in ulceration at 14 days from 12% to 3%/2% [13]. Ranitidine (a histamine type 2 receptor antagonist) treatment reduced duodenal ulceration in the setting of long-term aspirin therapy but was not as efficacious as proton pump inhibition [14]. Other antiulcer agents such as misoprostol and sucralfate also reduce aspirin-induced toxicity [15, 16]. In each case the cost associated with dual prescribing is a significant drawback. Ticlopidine is an alternative antiplatelet drug which inhibits ADP-induced platelet aggregation and shows similar efficacy and adverse event rates to aspirin therapy [17], but has the potential to cause blood disorders in a small number of patients. Clopidogrel has a similar action and has been shown to be at least equivalent to aspirin in secondary prevention following a variety of primary events [18]. On the basis of the available information we recommend that aspirin should be continued indefinitely after a myocardial infarction in doses of between 75 mg and 150 mg. Patients who cannot tolerate aspirin should be prescribed an alternative antiplatelet agent. β-adrenoceptor antagonists effectively reduce resting and exercise-induced heart rate, blood pressure, myocardial contractility and hence myocardial oxygen demand. In addition, they possess antiarrhythmic activity by antagonizing sympathetic outflow to the heart and increase the threshold for ventricular fibrillation in animal models [19]. When used in the setting of acute myocardial infarction they are associated with reduced mortality, fewer dysrhythmias, limitation of infarct size and lower incidence of ventricular septal rupture [1]. Beneficial pharmacological actions of this group are matched by well-established reductions of mortality in secondary coronary prevention ( Table 2). Three large prospective randomized trials have shown long-term mortality benefits from β-adrenoceptor blockade with timolol [20], propranolol [21], and atenolol [22] in patients who have sustained a myocardial infarction. In the Norwegian Multicentre Study Group trial timolol 10 mg twice daily was shown to significantly reduce total mortality in postinfarction patients (10.3% vs 16.2% P = 0.0003) over a mean 17 month follow-up, and at 6 years this benefit was maintained (26.4% vs 32.3% P = 0.0028) [20]. The Beta-Blocker Heart Attack Trial (BHAT) randomized 3837 postinfarction patients to receive placebo or propranolol 60–80 mg three times daily (administered according to plasma drug level) and demonstrated a significant mortality reduction at 25 months (7.2% vs 9.8%, P < 0.005) in the treated group [21]. Both studies demonstrated significant reductions in sudden cardiac death. The ISIS 1 study demonstrated a significant reduction in mortality due to early intervention with 5–10 mg intravenous atenolol followed by 100 mg oral atenolol daily for 7 days. Oral atenolol was continued in 35% of treated patients and 25% of controls at discharge, and after 1 year reduction of vascular mortality was maintained in the original treatment group (10.7% vs 12.0%, P < 0.005) [22]. Several studies of metoprolol in postinfarct patients have shown nonsignificant reductions in overall mortality in patients followed for up to 3 years [23, 27–29]. A meta-analysis of the metoprolol studies suggested a significantly reduced overall mortality [30]. No evidence is available from randomized controlled trials regarding the benefits of initiation of β-adrenoceptor blockade more than 1 year postinfarct. The duration of benefit from β-adrenoceptor blockade is uncertain but it seems prudent to continue treatment indefinitely since discontinuation after 3 years treatment is associated with an excess of angina symptoms, a nonsignificant increase in total mortality and the need to recommence β-adrenoceptor blockade in at least one third of patients [31]. Follow-up of patients randomized in the Norwegian multicentre trial has shown parallel survival curves suggesting continued benefit for at least 6 years postinfarction [20]. Some have questioned whether the benefit of β-adrenoceptor blockade in postinfarct patients is a ‘class effect’ and suggest that ancillary properties of individual drugs may be important. Pindolol and oxprenolol possess significant intrinsic sympathomimetic activity (partial agonist activity) and failed to demonstrate significant mortality reduction when used for secondary coronary prophylaxis [24, 25]. However, acebutolol possesses similar activity and 200 mg administered twice daily after myocardial infarction led to a significant reduction in total mortality at 1 year postinfarct (5.8% vs 12.0%, P < 0.01), but no significant effect was observed at 6 years postinfarction [26, 32]. Animal models have suggested that those β-adrenoceptor blockers which have greater lipid solubility such as metoprolol or propranolol may have an important central action on vagal tone and heart rate variability which could have a significant impact on postinfarct dysrhythmia and mortality [33]. Clinical studies comparing treatment with atenolol (hydrophilic) or metoprolol (lipophilic) found no significant difference in heart rate variability and failed to support the findings from the animal models [34]. 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