European Heart Journal (1996) 17 {Supplement F), 16-29

Treatment for acute myocardial infarction

Overview of randomized clinical trials
S. Yusuf, S. Anand, A. Avezum Jr, M. Flather and M. Coutinho
Division of Cardiology, McMaster University and Hamilton Civic Hospital Research Centre, Hamilton General Hospital, Hamilton, Ontario, Canada

This review summarizes the results of several pharmacological interventions that have been evaluated in the management of acute myocardial infarction. Of these, thrombolytic therapy, aspirin, beta-blockers and angiotensin converting enzyme inhibitors have all been proven to reduce mortality risk and the latter three classes of drugs have also been shown to reduce morbidity. Routine use of heparin or nitrates is not recommended although they may be useful in specific circumstances such as post-infarction angina or large infarcts. Drugs that have as yet not been shown to have a role in the routine management of acute

myocardial infarction include Class I antiarrhythmic agents, magnesium and calcium antagonists. Management of patients with acute myocardial infarction can now be appropriately based on the evidence generated from well conducted randomized clinical trials and appropriate therapeutic choices based on such information can be expected to reduce their morbidity and mortality risks. (Eur Heart J 1996; 17 (Suppl F): 16-29) Key Words: Acute myocardial infarction, drug treatment, randomized clinical trials.

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Introduction
Death following acute myocardial infarction (AMI) is usually due to one or more of the following causes: pumping failure, arrhythmias, cardiac rupture or reinfarction. A number of pharmacological interventions have now been shown to be beneficial in reducing the morbidity and mortality associated with AMI while others are widely used but not supported by good evidence, and may even be harmful. In the last few decades, there has been a growing acceptance of randomized controlled trials as a useful and reliable method to evaluate treatments, and it has also become apparent that most treatments in cardiovascular diseases typically have at best only moderate reductions (10%, 15% or 20%) on major outcomes such as death or myocardial infarction. To detect such differences reliably (10% mortality reduced to 9% or 8-5%) studies with a few thousand events (tens of thousands of patients) are usually required1'1. The results of these trials have dramatically altered the management of patients with AMI and current therapy is now much more 'evidence-based' than previously. In this review the results of these trials are placed in the context of clinical practice.

Thrombolytic therapy Mechanism of action

Physiological thrombolysis occurs via the action of plasmin on fibrin thrombi. Plasmin, a non-specific protease which dissolves fibrin clots and other plasma proteins, including several coagulation factors, is formed from plasminogen by cleavage of a single peptide bond. Thrombolytic agents dissolve both pathological thrombi as well as fibrin deposits at the sites of vascular injury, and streptokinase (SK), a 47 000 Dalton protein produced by streptococcus bacteria, forms a non-covalent 1:1 complex with plasminogen. This produces a conformational change which exposes the active site on plasminogen to induce the formation of plasmin, which initiates fibrinolysis. Tissue plasminogen activator (tPA) is a serine protease which contains 525 amino-acid residues and has significant plasminogen activator activity. Tissue plasminogen activator binds to fibrin via a lysine site at its amino terminal and directly activates fibrin-bound plasminogen, leading to the formation of plasmin and ultimately to clot lysis'21.

Large clinical trials

Correspondence. Salim Yusuf, Division of Cardiology, McMaster During the past decade, thrombolytic therapy such as University, McMaster Clinic, Hamilton General Hospital, 237 SK and tPA have become standard treatment for AMI. Randomized clinical trials involving tens of thousands Barton Street East, Hamilton, Ontario, Canada L8L 2X2. 0195-668X/96/0F0016+14 $25.00/0 19% The European Society of Cardiology

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Table 1 Proportional and absolute differences in mortality during days 0-35 with thrombolytic therapy
Deaths during days 0-35 Day of death Fibrinolytic (n = 29 315) 695 (2-4) 475 (1-7) 847 (3-0) 803 (2-9) 2820 (9-6) Control (n = 29 285) 554 (1-9) 549 (1-9) 1100 (3-9) 1154 (4-3) 3357 (115) Proportional reduction (%) Benefit per 1000

Day 0 Day 1 Days 2-7 Days 8-35 All, in days 0-35

- 26, SD 6 ( - 3 8 to - 13) 13, SD 6 (2 to 25) 23, SD 4 (16 to 31) 32, SD 4 (24 to 39) 18, SD 2 (13 to 23)

- 5 , SD 1** (-7to -2) 3, SD 1* (0 to 5) 9, SD 2 " * (6 to 12) 13, SD 2*** (10 to 16) 18, SD3*** (13 to 23)

*P<005, **/><0001, ***/><000001. For deaths, figures in parentheses indicate percentages; for proportional reduction and benefit, figures in parentheses indicate 95% confidence intervals. SD = standard deviation. (From131.)

of patients have demonstrated reliably and consistently that thrombolytic therapy reduces mortality following AMI. The Fibrinolytic Therapy Trialists' Collaborative Group performed a systematic overview of the effects of treatment on patient mortality and major morbidity in those trials that randomized over 1000 patients with suspected AMI to fibrinolytic therapy or control'31. This overview included nine studies (GISSI-1, ISAM, AIMS, ISIS-2, ASSET, USIM, ISIS-3 'uncertain indication' group, EMERAS and LATE) with a total of 58 600 patients. Among the patients studied in these nine trials, 22% presented between 7 and 12 h and 16% between 13 and 24 h after the onset of symptoms. Ten percent were older than 75 years. During days 0-35 there were 2820 (9-6%) deaths among 29 315 patients allocated fibrinolytic therapy, compared with 3357 (11-5%) deaths among 29 285 controls. The overall relative risk reduction in 35-day mortality with fibrinolytic treatment was 18% (/><000001) which corresponds to the avoidance of 18 deaths per 1000 patients allocated to treatment. Overall, fibrinolytic therapy was associated with an excess of deaths during days 0-1 (early hazard), but this was outweighed by a much larger benefit during days 2-35 (Table 1). The main benefit was observed among patients presenting within 12 h from symptom onset, irrespective of age, sex, blood pressure, heart rate or previous history of MI or diabetes and was greater the earlier the treatment began. Among 45 000 patients presenting with ST elevation or bundle branch block, there was a highly significant relative risk reduction in mortality of 20%, which translates into 30 lives saved per 1000 patients treated within 0-6 h. In patients treated between 7-12 h, there was a relative risk reduction of 13%, which translates into 20 lives saved per 1000 patients treated. In patients treated within 13-24 h, there was only a small and statistically uncertain relative risk reduction of 5%, which translates into 10 lives saved per 1000. In the first 6 h the relative mortality reduction was 30% between 0 and 1 h, 25% between 2 and 3 h and 18%

between 4 and 6 h (Fig. 1). During the first 35 days the absolute benefits appeared to be largest among high risk patients, such as those with a systolic blood pressure less than lOOmmHg, a heart rate of 100 beats, min" 1 or more, previous MI or diabetes. Overall, fibrinolytic therapy was associated with a small but significant excess of four extra strokes per 1000 (1-2 vs 08%; /><000001) patients treated, mainly during days 0-1, and a seven per 1000 excess of major non-cerebral bleeds (11% vs 0-4%; /^OOOOOl)131. Prehospital thrombolytic therapy can augment the success of treatment by shortening the interval between symptom onset and treatment initiation and may thereby reduce mortality. The EMIP (European Myocardial Infarction Project) group has evaluated 5469 patients, comparing prehospital vs hospital thrombolysis, and has demonstrated a 30-day mortality reduction of 13% (/ > =008). Meta-analysis of five such studies of prehospital vs in-hospital thrombolysis involving a total of about 6300 patients (including EMIP) showed that prehospital thrombolysis reduced the mean delay in treatment by approximately 1 h and was associated with a relative risk reduction of 17% in mortality (/"=003) compared with in-hospital thrombolysis, even when it was administered rapidly after arrival'4'.

Comparison of different thrombolytic agents

The GISS1-2 (Gruppo Italiano per lo Studio della Soprawivenza nell'Infarcto Miocardico) trial and its international extension compared the efficacy of SK and tPA (alteplase) in 20 891 patients with AMI within 6 h from onset of symptoms. No significant differences in hospital mortality were found between SK (8-5%) and tPA (S-9%)15'61. The ISIS-3 (Third International Study of Infarct Survival) trial compared SK vs tPA (alteplase) vs anistreplase in 41 299 patients with AMI within 6h from onset of symptoms. The mortality rates were
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18 S. Yusufet al.

40 - 13000
\

14 000
1 * \

30 -

12 000 19000

i
Q
20 --

10 -

(7000 1 . . .
6

1
12

i , X. , , i
18 \ 24

Hours from symptom onset to randomization

Figure 1 Absolute reduction in 35-day mortality vs delay from symptom onset to randomization among 45 000 patients with ST elevation or BBB. Loss of benefit per hour of delay to randomization: 1-6 SD 0-6 per 1000 patients. (Reproduced from|31 with permission.) similar in days 0-35 among the three different agents (10-6% in the SK, 103% in the tPA, and 10-5% in the anistreplase groups)'71. Results from the GUSTO (Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) trial indicate that an aggressive thrombolytic strategy (accelerated tPA given with intravenous heparin) provides a significant but small further reduction in mortality compared with SKI8). The mortality rates in the four groups were: SK and subcutaneous heparin, 7-2%; SK and intravenous heparin, 7-4%; accelerated tPA and intravenous heparin, 63%, and the combination of both thrombolytic agents and intravenous heparin, 70% (14% mortality reduction, /><0-04 for accelerated tPA as compared with SK and subcutaneous heparin). There was a significant excess of haemorrhagic strokes with the use of tPA compared to streptokinase (0-72% vs 0-54%; />=003), which translates into 5-6 new haemorrhagic strokes per 1000 patients treated. The effect on the combined outcomes of death or disabling stroke showed a significant but small reduction in favour of tPA (tPA: 6-9% vs both SK arms: 7-8%; / > <0006). The confidence limits of the difference were wide so that the real benefits may well be more modest than the point estimate. As tPA is more expensive than SK, economic analyses should be conducted in each country to help further clarify which is the most cost-effective agent to use for patients presenting with AMI. It is important to recognize that the largest number of lives saved results from widespread and rapid use of any thrombolytic therapy and that any incremental benefit of tPA over SK is only modest. Recent data have indicated that utilization of a double bolus of tPA may improve coronary
Eur Heart J, Vol. 17, Suppl F 1996

patency to a greater extent than the front-loaded regimen of tPA[9]. However, a recent trial was terminated prematurely because of an increase in intracranial bleeds and no apparent difference in mortality (presented at the European Congress of Cardiology 1995; unpublished). The recombinant plasminogen activator (reteplase) with a long plasma half-life, allowing bolus administration was recently compared with standard SK therapy in a double-blinded randomized trial (n = 6010). The 35-day mortality was 902% for reteplase and 9-53% in the SK group ( 0-51% difference, 90% CI of 1-74% to 0-73%, ns). Six-month mortality rates were 1102% for reteplase and 1205% for SK (-1-03% difference, 95% CI - 2-65%, 0-59%, ns). There was no significant difference between the groups in the incidence of in-hospital strokes'101.

Antithrombotic therapy
Aspirin Mechanism of action. Aspirin irreversibly inactivates platelet cyclooxygenase by acetylating this enzyme at the active site. As a result of cyclooxygenase inhibition, platelets from patients taking aspirin fail to synthesize thromboxane A2, and thus show reduced platelet aggregation in response to many stimuli. However, inhibition of cyclooxygenase does not fully account for aspirin's antithrombotic activity1""131. Large clinical trials. The ISIS-2 (Second International Study of Infarct Survival) trial randomly assessed

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aspirin compared to placebo and the separate and combined effects of intravenous SK and of oral aspirin in 17 187 patients with suspected AMI'141. There was a reduction in the odds of death by 23% (95% CI, 15% to 30%; 7><000001) in the aspirin group, by 25% (95% CI, 18% to 32%; /><0-00001) in the SK group, and by 42% (95% CI, 34% to 50%; /><000001) with the combination of SK and aspirin, compared with the control group. Aspirin added to the benefit of SK in all subgroups examined, including the elderly. The 4-year mortality follow-up of ISIS-2 has shown the persistence of significant benefit among those allocated to aspirin'151. In addition to reducing mortality, aspirin also reduces strokes and myocardial infarction. The exact mechanisms of the benefit of aspirin is not known. Recent data suggest that facilitation of coronary recanalization occurs with aspirin use after successful thrombolysis[16]. The Antiplatelet Trialists' Collaboration performed an overview of randomized trials of antiplatelet therapy to assess the effects of prolonged aspirin use in the post-MI setting to determine the incidence of vascular death, non-fatal MI or non-fatal stroke1'71. Among about 20 000 patients with a past history of MI, there was significant relative risk reduction of 31% in nonfatal reinfarction (18 reinfarctions prevented per 1000 patients; P<000001), relative risk reduction of 15% in vascular deaths (13 deaths per 1000 patients treated; /><0005), and relative risk reduction of 39% in nonfatal strokes (six strokes prevented per 1000 patients treated; />=00005). Total mortality was also reduced. These data indicate that aspirin should be used in AMI in all suitable patients, starting as soon as possible, and that therapy should probably be continued long-term. Given that aspirin can be used widely and is also very inexpensive, it is probably the most effective intervention in AMI. Unfractionated heparin Mechanism of action. The antihaemostatic effect of heparin includes: (a) binding to antithrombin III to form a heparin-antithrombin III complex which then inactivates factors Ha (thrombin), Xa, IXa, XIa, and XII; (b) binding to heparin cofactor II and inactivation of factor Ila (this anticoagulant effect requires a very high concentrations of heparin); and (c) binding to platelets which inhibits platelet function and may contribute to the haemorrhagic effects of heparin1181. Preliminary clinical trials. An overview of 20 trials (involving 5700 patients) comparing subcutaneous or intravenous heparin to control therapy before thrombolytic therapy and aspirin were widely used, has shown a mortality reduction of 17% (/><0005), reduction in incidence of deep vein thrombosis of 66% (/><0001), reduction in pulmonary embolism of 54% (/3<0001), reduction in reinfarction of 22% (P<005), and a reduction in stroke of 50%(/ > <0005) in the patients allocated heparin compared to those allocated control'191. The SCATI (Studio Sulla Calciparina Nell'Angina E Nella Trombosi Ventricolare NelFInfarto) trial provided

information on mortality with the addition of heparin to thrombolysis in the absence of aspirin'201. Heparin was given intravenously, followed 9h later by 12 500 units subcutaneously twice daily. Subgroup analysis from 433 patients in the SCATI trial that were given streptokinase showed a significant mortality reduction in the heparin treated patients (4-6% vs 88%; />=005). Large clinical trials. The data for combined treatment with aspirin and heparin as adjunctive therapy are also available from large randomized trials: GISSI-2, ISIS-3 and GUSTO. The GISSI-2 trial and its international extension compared the efficacy of streptokinase and tPA and tested the effects of delayed subcutaneous heparin (12 500 units twice daily) initiated 12 h after thrombolytic therapy in 20 891 patients. All patients received aspirin. The addition of subcutaneous heparin to aspirin and thrombolysis had no significant effect on in-hospital mortality (8-5% heparin group vs 8-9% no heparin group; P=0-29) or total mortality at 35 days (9-3% vs 9-4%; P=0S2). Subcutaneous heparin was associated with an excess of major bleeds (1% vs 0-5%), but did not affect the incidence of stroke or reinfarction'5'61. ISIS-3 compared aspirin plus subcutaneous heparin vs aspirin alone following the use of one of the three thrombolytic agents among 41 299 patients with suspected AMI. Subcutaneous heparin was given in a dose of 12 500 units twice daily, starting about 4 h after randomization for 7 days or prior discharge. The addition of heparin to aspirin was associated with an increased need for transfusion (1% vs 08%; P<00\) and of definite or probable cerebral haemorrhage (0-56% vs 0-4%; P<005), with no significant difference in total strokes (1-28% vs 118%). Reinfarctions were slightly less common among those allocated aspirin plus heparin (316%) vs aspirin alone (3-47%; P=009). There was no significant difference in the pre-specified endpoint of 35-day mortality (10-3% in the aspirin plus heparin group vs 10-6% in the aspirin alone group). There were fewer deaths between day 0 and 7 (scheduled heparin treatment period) in the heparin plus aspirin group (7-4% vs 7-9%; P=006) [7] . When ISIS-3 and GISSI-2 results were combined, there was a significant but small mortality reduction during the scheduled treatment period in the heparin plus aspirin group (6-8% vs 7-3%; P<00\) with little difference at 35 days'71. The GUSTO trial randomized 41 021 patients to four different thrombolytic strategies: streptokinase plus subcutaneous heparin, streptokinase plus intravenous heparin, accelerated tPA plus intravenous heparin and a combination of streptokinase and tPA plus intravenous heparin'81. Within the GUSTO trial there was a randomized comparison of subcutaneous heparin (12 500 units beginning 4 h after SK) vs intravenous heparin (1000 units per hour following a 5000 unit bolus dose) in conjunction with streptokinase. The 30-day mortality rates were 7-2% in the streptokinase plus subcutaneous heparin group and 7-4% in the streptokinase plus intravenous heparin group (P=ns), and severe or life-threatening bleeding was 0-3% and 0-5%, and
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moderate bleeding 5-6% and 5-8%, respectively. These data suggest that adding heparin intravenously to streptokinase does not confer any added benefit over giving it subcutaneously, which in turn has not been found to be beneficial compared to no heparin. Conclusions. The question of whether to use intravenous heparin with tPA and aspirin has not been adequately assessed in randomized controlled trials. However, it is generally recommended (but not proven) that i.v. heparin be used in addition to tPA. However, adding heparin to streptokinase increases the risk of bleeding with no clear evidence of benefit, but in the absence of thrombolytic therapy and aspirin, there is a clearer benefit with heparin from old studies. At the present time it seems reasonable to discourage the use of heparin in AMI and reserve it for certain high risk patients (i.e. on-going angina or large anterior infarcts), especially if they are not treated with thrombolytic therapy. Low molecular weight heparin Low molecular weight heparin (LMWH) given by subcutaneous injection has superior bioavailability and longer duration in the circulation than subcutaneous unfractionated heparin'2l>22]. Several studies suggest that LMWH is an efficient and safe alternative to unfractionated heparin'23'241. A dose-finding study with LMWH in 72 patients with AMI has shown that LMWH appears to be safe'251, although minor haemorrhage may occur in patients receiving aspirin concomitantly. This study also suggested that LMWH may help left ventricular thrombi, but there are currently only limited data regarding the efficacy and safety of LMWH when used in conjunction with thrombolytic therapy or aspirin. The recent FRISC trial indicated that LMWH reduced myocardial infarction in patients with unstable angina compared to placebo. However, LMWH was not superior to unfractionated heparin in a subsequent trial (FRIC). At present there is no reason to prefer LMWH to unfractionated heparin (presented at European Congress on Cardiology, 1995; unpublished). 65% in the hirudin group and 57% in the heparin group {P=ns), but at 18 to 36 h it was 98% and 89%, respectively CP=0-01). Reocclusion at 18 to 36 h was 1-6% in the hirudin group and 6-7% in the heparin group (/>=0-07); death or reinfarction during the hospital period was 6-8% and 16-7% (/*=001) and major spontaneous haemorrhage was 1-2% and 4-7% (P=009), respectively. The TIMI 6 trial was a pilot study designed to evaluate the safety and tolerability of hirudin vs heparin when given with streptokinase and aspirin to AMI patients'291. There was no added risk of major haemorrhage between heparin (6%) and any of the hirudin doses (5%, 6%, 6%). Early studies of hirudin which were relatively small have been promising, but larger studies (GUSTO Ha and TIMI 9A) have had to be modified because of increased bleeding including intracranial bleeds. The risks of bleeding were particularly pronounced in patients receiving concomitant thrombolytic therapy. The TIMI 9A trial compared the efficacy and safety of intravenous hirudin (0-6 mg . kg~' bolus and 0-2 mg . kg" ' per hour infusion) with heparin as adjunctive therapy to thrombolysis and aspirin in patients with AMI'301. This trial was modified after 757 patients had been included because rates of haemorrhage in both treatment arms were higher than expected. Major spontaneous bleeding at a non-intracranial site occurred more frequently with hirudin (7% vs 3%, P=002), while intracranial bleeding was 1-7% in the hirudin group and 1-9% in the heparin group (P=ns). It appears that the doses of both heparin and hirudin were too high in TIMI 9A. Therefore the study was redesigned and used a lower hirudin bolus and infusion (0-20 and 010 mg . kg" ' respectively) and lower heparin infusion (TIMI 9B). The GUSTO-IIa study evaluated hirudin (same regimen as TIMI 9A) vs heparin in patients within 12 h from the onset of ischaemic chest discomfort with an abnormal ECG'3'1. This trial was also modified early because of an excess of intracerebral haemorrhagic events after 2564 patients were enrolled. The incidence of haemorrhagic stroke was 1-3% (17/1273) in the hirudin group and 0-7% (9/1291) in the heparin group (/ > =011). Hirudin caused more haemorrhagic strokes than heparin, both in those receiving and those not receiving thrombolytic therapy (no thrombolytic therapy: 0-5% vs 0, and with thrombolytic therapy: 2-2% vs 1-5%, respectively). This study has also been modified (GUSTO I IB) to use lower doses (0-2mg.kg~' bolus and infusion of OlOmg.kg-'.h-'). Hirulog is a synthetic peptide that is a highly specific direct inhibitor of free and clot-bound thrombin. A comparison between hirulog and heparin as adjunctive therapy to streptokinase in AMI in a small study has shown that clot lysis occurred more rapidly with no apparent increase in bleeding complications in the hirulog group1321. The ASIS (American Study of Infarct Survival) trial is currently evaluating the use of hirudin in patients with AMI who are not eligible for thrombolytic therapy, and is in the pilot phase. The OASIS (Organization to Assess Strategies for Ischemic

Direct thrombin inhibitors

Hirudin and hirulog Hirudin derived originally from the medicinal leech, is currently the most potent and specific thrombin inhibitor known, and is now produced in sufficient quantities for clinical research by recombinant DNA technology1261. Hirudin selectively binds to thrombin in a 1:1 stoichiometric manner at two sites, and inhibits all the major actions of thrombin1271. The advantages of hirudin and hirulog, a synthetic analog of hirudin, are direct thrombin inhibition, a more predictable anticoagulent response, and action on fibrin bound thrombin. The TIMI 5 (Thrombolysis in Myocardial Infarction) trial has assessed hirudin vs heparin as adjunctive therapy to thrombolysis (tPA) in 246 AMI patients'281. At 90 min TIMI grade 3 coronary flow was
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Table 2 Early intervention: total mortality in days 0-7 from all available randomized trials of early beta-blockade (starting with an intravenous dose) in acute myocardial infarction
Death/no. of patients Early intervention trials Beta-blocker Control Calculations (treated group only) Approximate percent change in odds of death - 9 13 - 15 14 -129 15 7 - 146 P

26 small trials MIAMI trial Subtotal: All intervention trials other than ISIS-1 ISIS-1 trial Total mortality available (From [351.)

117/2901 79/2877 196/5778 317/8037 513/13 815 (3-7%)

126/2830 93/2901 219/5731 367/7990 586/13 721 (4-3%)

ns ns ns <005 <0-02

Syndromes) pilot study, evaluated the role of two doses of hirudin ( O 4 m g . k g ~ ' bolus+ 0-15 mg. kg" 1 . h ~ ' for 72 h and 0-2mg.kg~' bolus+OlOmg.kg" 1 . h ~ ' for 72 h) vs intravenous heparin in patients with unstable angina or myocardial infarction without ST elevation. The initial results of this trial suggest that hirudin (especially the higher dose) is superior to heparin in reducing cardiovascular death, myocardial infarction and the need for urgent revascularization procedures. There was no excess in major bleeds with hirudin. These superior clinical effects were paralleled with greater suppression of markers of coagulation reflecting thrombin activity ([33], unpublished data). A study of 10 000 patients evaluating the medium dose of hirudin is underway (OASIS-2). These promising results require confirmation in larger and more definitive trials. Beta-blockers Mechanism of action. Beta-blockers reduce myocardial (OASIS-2) oxygen consumption, by lowering heart rate, blood pressure and myocardial contractility, block the adverse effects of catecholamines which have arrhythmogenic and direct toxic effects on myocardial metabolism, increase the threshold for ventricular fibrillation and favourably influence the distribution of myocardial blood flow. These effects result in a reduction in infarct size, decreased myocardial wall stress, prevention of cardiac rupture, and a lower risk of recurrent ischaemia. The protective effects of beta-blockers probably extend beyond their antiarrhythmic activity and ability to reduce myocardial oxygen demand. Beta-blockers have direct but weak antiplatelet effect and perhaps have indirect antithrombotic properties. These may also reduce the risk of coronary artery plaque rupture by exerting less shear forces on the plaque and subsequent thrombosis1'-34^71. Clinical trials. Reliable information about the effects on mortality of early intravenous beta-blockade followed

by oral short-term treatment came from the ISIS-1 (First International Study of Infarct Survival) trial, which included 16 027 patients, and evaluated the effects of intravenous atenolol started within 12 h of the onset of chest pain, compared to standard therapy for the treatment of AMI'381. There was a moderate reduction in vascular mortality (3-9% vs 4-6%) and also a reduction in non-fatal cardiac arrests and reinfarctions, providing significant evidence of a beneficial effect on the combined end-points of death, cardiac arrest, and reinfarction (P<00002). The reduction in mortality was most marked during the first 2 days after the initiation of therapy (25%, f><0003), and was most likely due to a reduction in cardiac rupture and ventricular fibrillation. Similar mortality results were obtained in another trial involving 5778 patients, the MIAMI (Metoprolol In Acute Myocardial Infarction) trial, although the overall results were not statistically significant, perhaps due to its smaller size1391. Pooling the results of all 27 available randomized trials indicates that such treatment reduces mortality by about 13% (/><0-02; 95% CI, - 2 % to -25%), non-fatal reinfarction by 19% (/><001; 95% CI, - 5% to - 33%) and non-fatal cardiac arrest by 19% (f<002; 95% CI, - 2 % to -30%) in the first week. These data suggest a 16% reduction in the cumulative risk of suffering from any one of these major events CP<00001)[35] (Table 2). Information about combined beta-blocker and thrombolytic therapy and aspirin is limited. The TIMI (Thrombolysis In Myocardial Infarction) Il-B study has compared the effect of immediate intravenous vs delayed oral beta blocker therapy in 1434 patients undergoing thrombolytic therapy141. There was a lower incidence of reinfarction (27% vs 51%, P=002), recurrent chest pain (18-8% vs 241%, /><002) and intracranial haemorrhage (0% vs 0-8%, />=003) for those treated with 100 mg tPA (which was 88% of the total sample) at 6 days in the immediate intravenous group compared to the delayed oral beta-blocker group. This trial was too small to reliably detect any differences in mortality.
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22 S. Yusufct al.
Further systematic studies of beta-blocker therapy given with thrombolysis and aspirin early in AMI are desirable. In addition to short-term benefits of betablockers, several independent trials have clearly demonstrated that long-term therapy with beta-blockers for a year or two reduces mortality and reinfarction by about one quarter1341. Conclusions. Intravenous beta-blocker therapy should be started soon after the onset of AMI, continued orally over the long term, and should be considered in all patients who have no clear contraindications. Although initiating therapy in high risk patients requires greater care, these patients stand to benefit substantially. However, many of these studies were conducted at a time when patients were not routinely treated with thrombolytic therapy and aspirin, and surveys suggest that only a minority of patients who could receive such treatment are currently treated with early intravenous betablockers. Therefore, further evidence may be important to clarify the role of this potentially important therapy against a background of current practice. Angiotensin-converting enzyme inhibitors Mechanism of action. These agents act by inhibiting the conversion of inactive angiotensin I to active angiotensin II. Reduced plasma levels of angiotensin II leads to decreased tension within the wall of the left ventricle by reducing both afterload and preload, with reduction of myocardial tension and oxygen consumption. The extent of left ventricular dysfunction after AMI is one of the most important risk factors for subsequent fatal and non-fatal events. Progressive left ventricular dilatation occurs in about 30% of patients after AMI (remodelling process). The renin-angiotensin system may be activated during the course of AMI and is believed to be instrumental in the remodelling process. In a rat model of AMI, progressive left ventricular dilatation has been shown to occur as a function of the size and age of the infarct, and the long-term administration of the ACE inhibitor captopril attenuates this gradual left ventricular enlargement and prolongs survival after infarction'41^61. Clinical trials Unselected patients on day one. Many trials have evaluated the effects of early administration of ACE inhibitors within the first 24 h after the onset of AMI. Of these, four trials were large (CONSENSUS II, GISSI-3, ISIS-4, and the CCS-1). The CONSENSUS II study (Cooperative New Scandinavian Enalapril Survival Study), enrolled 6090 patients of which 3044 were assigned to intravenous enalaprilat, followed by administration of oral enalapril and 3046 to placebo'471. Survival during the 180 days after AMI was not improved in the enalapril group, while early hypotension occurred in 12% of the enalapril group and 3% in the placebo group (/ > <0001). The GISSI-3 (Gruppo Italiano per lo Studio della Soprawivenza NelPInfarto
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Miocardico) study, randomized 19 394 patients in a factorial design to oral lisinopril vs placebo and transdermal nitrate followed by oral treatment versus placebo, during the subsequent 6 weeks'481. There was a significant 12% reduction in 6-week mortality with lisinopril (6-3% in the lisinopril group vs 7-1% placebo; />=003). The CCS-1 (first Chinese Cardiac Study) randomized 12 634 patients with suspected AMI to oral captopril (6814 patients) or placebo (6820 patients)'491. Captopril was associated with a non-significant reduction in 4-week mortality (905% in the captopril group vs 9-59% in the placebo group; / > =003). The ISIS-4 (the Fourth International Study of Infarct Survival) study randomized 58 050 patients in a factorial design to oral captopril vs placebo for 28 days, oral mononitrate vs placebo for 28 days and intravenous magnesium vs open control over 24 h'501. There was a significant 7% proportional reduction in 5-week mortality with captopril (719% captopril vs 7-69% placebo; P<002). When the data from ISIS-4, GISSI-3, CCS-I, CONSENSUS II and 11 smaller trials were combined, there was a significant mortality reduction of 6-5% (P=0-006), which means 4-6 fewer deaths per 1000 patients treated (Fig. 2). However, this modest absolute benefit may be more marked in certain high risk subgroups and requires exploration in a prospective meta-analysis. High risk patients after day one. The administration of ACE inhibitors in the setting of AMI 24 h or more after onset of symptoms was evaluated in three trials. The SAVE (Survival And Ventricular Enlargement) study, included 2231 patients within 3 to 16 days (mean of 11 days) after MI, with ejection fraction of 40% or less, but without overt heart failure, to receive either captopril or placebo'511. Patients were followed for an average of 42 months (range 24 to 60 months). There was a reduction in risk of death from all causes of 19% (228/1115 vs 275/1116; />=0019), from cardiovascular causes of 21% (P=0-14), reduction in the development of severe heart failure of 37% CP<0001), reduction in congestive heart failure requiring hospitalization of 22% and a 25% reduction in recurrent MI (/>=0015). The AIRE (Acute Infarction Ramipril Efficacy) study randomized 1986 patients who had shown clinical evidence of heart failure at any time after an AMI to either ramipril or placebo, between day 3 to day 10 after the episode (mean of 5 days)1521. This trial showed a 27% reduction in mortality at a mean of 15 months followup. The TRACE (Trandolapril Cardiac Evaluation) trial assessed the efficacy of trandolapril 3-7 days after MI in 1749 patients with reduced left ventricular function demonstrated by echocardiography (wall motion index <l-2 which approximates a left ventricular ejection fraction <35%), for a minimum of 24 months'531. Twenty-three percent of patients presented with congestive heart failure. There was a 22% mortality reduction in the trandolapril-treated group compared to the placebo group (P<00007) with a mean follow-up of 2 years'54'(Table 3).

Clinical trials of treatment for AMI

23

Randomized comparison 11 small trials

Deaths/patients (% dead) CEI Control

150/2175 153/2119 (6.9%) (7.2%) CONSENSUS-n 219/3044 192/3046 (7.2%) (6.3%) GISSI-3 597/9435 673/9460 - (6.3%) (7.1%) 617/6814 CCS-1 654/6820 1 (9.1%) (9.6%) ISIS-4 2088/29028 2231/29022 Hi (7.2%) (7.7%) 6.5% (SD 2.3) odds All trials 3671/50496 3903/50467 < reduction; 2P = 0.006 (7.27%) (7.73%) 4.6 (SD 1.7) fewer deaths per 1000 treated 1 1 1.0 0.5 0.75 1.25

Odds ratio and CI CEI Control better better L

Figure 2 Systematic overview of effects on short-term mortality of starting converting enzyme inhibitors (CEI) early in acute myocardial infarction. Test for heterogeneity: between 11 small trials and four larger trials jff=O-O; ns; between CONSENSUS-II, GISSI-3, CCS-1 and ISIS4 ^=5-2; ns. (Reproduced from |501 with permission.)

Table 3 Results of long-term randomly allocated trials of ACE inhibitors on mortality in AMI
Trial
Year reported Patient eligibility Treatment comparison Total Treatment No. of Deaths/no, of patients patients 2231 228/1115 (20%) 170/1004 (17%) * Control Deaths/no, of patients 275/1116 (25%) 222/982 (23%) * RRR% 95% CI of RR P

SAVE1511 AIREl 52 ' TRACE 1 *"

1992

AMI (3-16 days) EF^40% AMI (3-10 days) Evidence of heart failure AMI (2-7 days) LVD C H F (23%)

1993

1995

Captopril 150mg. d a y " ' oral (42 months) Ramipril 10 mg . d a y " ' oral (15 months) Trandolapril 2 mg . d a y " 1 oral (24 months)

19

0-71 to 0-97 0019

1986

27

0-63 to 0-90 0002

1749

22

0-67 to 0-91

0-007

RR = relative risk; RRR = relative risk reduction; Cl=confidence interval; EF=ejection fraction; LVD = left ventricular dysfunction; CHF=congestive heart failure; *=data to follow.

Conclusions. The use of ACE inhibitors in the acute phase of MI is safe and overall provides a small but significant reduction in mortality. Subgroup analyses of GISSI-3 and ISIS-4 indicate greater absolute benefit in high risk patients. Long-term therapy with ACE inhibitors started several days after the onset of AMI, in patients with left ventricular dysfunction and/or heart failure, provides greater mortality reduction. Targeting ACE-I therapy to higher risk patients may be a useful strategy in AMI. A review of the combined data from these trials in a meta-analysis of individual patient data is underway and should provide important new insights into the effects of these agents when started in the acute phase of MI. At present, it may be prudent to start ACE inhibitors on the first day in most clinically stable patients, especially those with large infarcts, CHF or

left ventricular dysfunction. After a few weeks, ACE inhibitor treatment should be reviewed and continued long-term in those patients with left ventricular dysfunction or CHF. Nitrates Mechanism of action. The mechanisms of possible beneficial effects of nitrates in AMI include dilatation of venous capacitance vessels, arterial resistance vessels, and coronary arteries, and by redistribution of blood flow to areas of myocardial ischaemia. By reducing both afterload and preload, nitrates reduce myocardial wall stress and oxygen demands. Nitroglycerin might additionally increase myocardial blood supply by relieving coronary spasm. Nitroglycerin also inhibits platelet aggregation.
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24

S. Yusufet al.

Preliminary clinical trials. A meta-analysis evaluating the effects of intravenous nitrates (nitroglycerin and nitroprusside) on mortality in AMI, showed a 35% mortality reduction (95% CI, - 1 8 % to - 4 9 % ; /><0001) compared with placebo in 2041 patients, and a non-significant 21% mortality reduction (95% CI, 16% to - 4 6 % ; F=ns) with oral nitrates compared with placebo in 1081 patients1551. Overall (oral and intravenous nitrates) there was a 31% mortality reduction (95% CI, 16% to 44%, P<0 001) in the nitrate group compared with placebo in 3122 patients. Large clinical trials. The effects of nitrates in the setting of AMI has been evaluated in two recent large randomized clinical trials involving more than 70 000 patients. The ISIS-4 trial compared 4-weeks of oral isosorbide-5-mononitrate vs placebo in 58 050 patients'501. The 35-day mortality was not significantly different in the nitrate group (7-34%) compared with the control group (7-54%). The GISSI-3 trial compared early intravenous nitroglycerin followed by topical (patch) nitroglycerin for 6-weeks vs control and included 19 394 patients'481. The 42-day mortality was also not significantly different in the nitrate group (6-5%) compared with the control group (6-9%). Overall, the combined data from ISIS^t, GISSI-3 and 20 small trials showed a 5-5% mortality reduction with nitrate use (/ > =003), which means 3-8 fewer deaths per 1000 patients treated. In both ISIS-4 and GISSI-3 studies, the power to detect any real beneficial effects with routine nitrate therapy was reduced by extensive early use (>50%) of non-trial nitrates during the first day or so in the control group (so called 'contamination'). The apparent discrepancy of the more recent trial results compared with the meta-analysis may be due to the high use of non-trial nitrates, use of other drugs such as ACE-inhibitors, and the use of drugs which may have other overlapping mechanisms of benefit such as antiplatelet agents. Conclusions. There is no clear evidence to support the routine use of nitrates in the setting of AMI. It may still be appropriate to consider using intravenous nitrates in certain high risk groups (e.g. those with heart failure, large anterior MI, multiple MI, or those with postinfarction angina). However, there is no justification from large randomized controlled trials to recommend continued long term, routine use of oral or transdermal nitrates. Calcium channel blockers Mechanism of action. Experimental studies have shown that calcium channel blockers reduce myocardial oxygen demands by lowering blood pressure and myocardial contractility, dilating coronary arteries and preventing calcium overload of ischaemic cells. However, some short-acting calcium channel blockers may also aggravate myocardial ischaemia by causing coronary steal and reflex tachycardia. The effects of calcium channel blockers on infarct size and arrhythmias have
Eur Heart J, Vol. 17, Suppl F 1996

been variable with most studies indicating a lack of benefit"'56-571. Evidence from clinical trials. Data on mortality are available from 23 randomized trials in a total of 19 600 patients. Seven studies included more than 1000 patients each, whereas most evaluated fewer than 200 patients. This means that most trials were individually too small to reliably detect important differences in mortality and major morbidity. Although six different agents have been tested, most data come from trials of nifedipine, diltiazem and verapamil. The TRENT (Trial of Nifedipine in Acute Myocardial Infarction) study compared the effect on mortality of nifedipine for one month vs placebo in 4491 patients with suspected AMI'581. The overall one month fatality rates were 6-3% in the placebo-treated group and 6-7% in the nifedipinetreated group CP=ns). The SPRINT (Secondary Prevention Reinfarction Israeli Nifedipine Trial) study assessed the efficacy of nifedipine in 2276 patients between 7 and 21 days after AMI'591. Mortality during an average 10-month follow-up period was 5-7% in the placebo group and 5-8% among those receiving nifedipine (P=ns). Higher risk patients were recruited in the SPRINT-II trial, which was stopped when 1358 patients were randomized because of a trend towards increased early mortality in the nifedipine-treated group (15-8% vs 13-3%)[6O!. Only three small trials of early administration of diltiazem are available, evaluating the effects of treatment on infarct size. Two of these reported non-significantly lower enzyme levels in the diltiazem group and one found a significant increase in infarct size in the diltiazem group*571. The MDPIT (Multicenter Diltiazem Postinfarction Trial) trial was the only large trial studying the effects of diltiazem on mortality and reinfarction' '. A total of 2466 patients were included and the total mortality rates were nearly identical among the two treatment groups (13-5% in each) and the reinfarction rate was 8% in the diltiazem group vs 9-4% in the placebo group (/>=ns). The DAVIT I (Danish Verapamil Infarction Trial I) included 1436 patients and after 6 months the mortality rate was not statistically significantly different between verapamil and placebo (12-8% vs 13-9% respectively)'621. The DAVIT II trial included 1775 patients and the mortality and reinfarction rates again were not statistically significant different between verapamil and placebo groups (10-8% and 9-6% vs 13-3% and 11-9%, respectively)'631 (Table 4). However, there was an excess of adverse effects such as sinoatrial arrest, atrioventricular block and congestive heart failure associated with both diltiazem and verapamil'641. None of 23 individual randomized controlled trials were able to detect statistically significant differences in mortality or reinfarction with calcium channel blockers. The overall pooled data showed no indication of benefit with respect to mortality with any single drug. If the diltiazem and verapamil data are combined there is a 5% reduction in the odds of death (95% CI, - 18% to +9%; P=ns) while reinfarction rates are reduced by

Clinical trials of treatment for AMI

25

Table 4 Adverse impact of dihydropyrine calcium antagonists on mortality and reinfarction in trials of ischaemic heart disease
Active Control Odds ratio 95% Confidence interval

(A) Mortality (i) Myocardial infarction (ii) Angiographic trials: Waters el al. Lichtlen et al. (iii) Unstable angina Total (B) Reinfarction (1) Myocardial infarction (n) Angiographic trials: Waters et al. Lichtlen et al. Total (From
[651

365/4731 2/192 12/214 12/477 391/5614

330/4733 3/191 2/211 7/462 342/5597

113 0-66 4-4 1-78 (01)

0-97-1-32 0-06-1-90 1-50-12-6 0-71^-49 1-01-1-36

124/3646 14/192 8/214 146/4052

111/3680 8/191 7/211 126/4082

114 1-77 113 119

0-68-1-92 0-75-4-18 0-40-3-17 0-93-1-52

.)

21% (95% CI, - 3 3 % to - 6 % ; P<00])[ss]. In contrast, the trials with nifedipine and other short acting dihydropyridines indicate an increase in mortality and reinfarction rates'65-661. Conclusions. It appears that both diltiazem and verapamil reduce the risk of reinfarction, but there is no clear indication of benefit with respect to mortality with any single drug when started early or late after AMI. Moreover, excess mortality and increased morbidity were reported in patients treated with short-acting dihydropyridines compared to placebo-treated patients. These data indicate that prophylactic use of calcium channel blockers during the early phase of MI is not likely to be beneficial and may even be potentially harmful in some patients. Prophylactic antiarrhythmic drug therapy The presence of potentially malignant ventricular arrhythmias is known to be a cause of increased mortality after AMI independent of reduced ventricular function and silent or manifest myocardial ischaemia. The increased risk of developing potentially fatal ventricular fibrillation during the early acute stage and the risk of arrhythmia-related sudden death in those survivors who have ventricular arrhythmia offers a hypothetical basis for prophylactic treatment. Class IB. A meta-analysis in 14 randomized trials with a total of 9155 patients have studied lidocaine1671. Nine trials evaluated intravenous lidocaine (2194 patients), whereas five trials evaluated intramuscular lidocaine (6961 patients). The data from all trials indicated a 35% reduction in the odds of developing ventricular fibrillation (OR = 0-65; 95% CI, - 0 0 3 to -0-56; P<004), but a trend to early mortality. Early mortality was 38% greater among lidocaine-treated patients (OR =1-38; 95% CI, - 0 0 2 to 0-95; P<010). A more recent

meta-analysis evaluating Class IB agents showed a mortality excess of 15% with lidocaine (17 trials; OR 1-15, 95% CI, 0-9 to 1-47; P=0-27) and a mortality increase of 2% with tocainide, phenytoin and mexiletine (15 trials; OR 102, 95% CI, 0-77 to 1-25; />=0-88)[68]. There was a trend for overall increased mortality in 6% in 32 trials of Class IB agents involving 214 013 patients (OR 106, 95% CI, 0-89 to 1-26; P=0-50). Magnesium Mechanism of action. Magnesium has been described as a physiological calcium antagonist and there are several plausible mechanisms for a possible beneficial effect in AMI[69). These potentially beneficial properties include coronary and systemic vasodilatation, platelet inhibition, and antiarrhythmic effects. Preliminary clinical trials. A meta-analysis of seven small trials using intravenous magnesium in AMI, totalling 1289 patients, but only 78 deaths, suggested a 55% mortality reduction with magnesium (95% CI, 33% to 66%; /><0001)[70]. This meta-analysis stimulated further large scale trials to confirm or refute these findings. Large clinical trials. The LIMIT-2 (Second Leicester Intervention in Myocardial Infarction Trial) included 2316 patients to evaluate intravenous magnesium in the treatment of AMI[7I). In the magnesium group, there was a 24% mortality reduction (90/1159 vs 118/1157; 95% CI, 1% to 43%; />=004) and a 25% reduction in left ventricular failure (95% CI, 7% to 39%; />=0-009). However, the ISIS-4 study included 58 050 patients and showed a 35-day mortality of 7-6% in the magnesium group and 7-2% in the control group (P=ns)l50\ When the data from ISIS-4, LIMIT-2, and nine small trials were combined, there was still a non-significant mortality excess of about 20% (1-4 extra deaths per 1000 patients treated with magnesium)'501. There has been
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S. Yusufet al.

Table 5 Dosage of drugs used in trials where mortality or morbidity were reduced
Group Antiplatelet agents Beta-blockers Drug Aspirin Metoprolol Atenolol Propranolol Enalapril Captopril Ramipril Trandolapril Lisinopril converting enzyme; Starting dose Maintenance 75 to 325 mg daily 100 to 200 mg daily 100 mg daily 120 to 240 mg daily 10 mg b.i.d. 12-5 to 50 mg t.i.d. 5 mg b.i.d. 1 to 2 mg b.i.d. 10 mg daily t.i.d. = three times daily;

ACE inhibitors

5 to 15 mg i.v. 5 to 10 mg i.v. 5 to 10 mg i.v. 2-5 mg 6-25 mg 2-5 mg 1 mg 5 mg b.i.d. = twice daily;

ACE = angiotensin i.v. = intravenous.

much debate on these discrepant results of the efficacy of magnesium in AMI. There is little argument that ISIS-4 provides the most extensive data about the effects of magnesium in AMI on a background of current therapy (i.e. in ISIS-4 thrombolytic therapy was used in 70% of patients and aspirin in more than 90%) and these results should therefore guide current clinical practice. The small size of the meta-analysis with strong possibilities of publication and other biases, and the marginal statistical significance of the result of LIMIT-2 are probably sufficient to accept that the earlier data regarding magnesium in AMI were not robust enough and needed to be confirmed by the more recent, larger ISIS-4 study172'. Conclusions. Based on the large randomized clinical trials, there is no evidence of benefit of the use of intravenous magnesium in the treatment of AMI. Glucose-insulin-potassium (GIK) According to experimental studies GIK solution could restore cellular function during AMI by preventing early metabolic myocardial deterioration through an improved supply of metabolic substrates such as glycogen, creatine-phosphate and ATP, and by reduction of inorganic phosphates and free fatty acids173"751. These effects improve ventricular performance and decrease the frequency of ventricular arrhythmias. They could be useful in patients with AMI, but the effects of this therapy on mortality during AMI are not fully known. In total, seven clinical trials with GIK in AMI are available, but the results are not strictly comparable due to the use of different regimens of GIK and different follow-up periods. Also, most of the studies are quite old, and none have been conducted in the era of widespread use of thrombolytic therapy, aspirin or betablocker therapy. A simple pooling of the results from seven studies of GIK in AMI has shown a reduction in mortality rates of 14% (95% Cl 0-71-1 05, P=0\3). Pilot studies evaluating this therapy in the setting of AMI are under way including studies in Poland (personal communication: L. Ceremuzynski) and South America (personal communication: R. Diaz). GIK will need to be investigated in a large clinical trial of some
Eur Heart J, Vol. 17, Suppl F 1996

tens of thousands of patients in order to provide reliable information regarding efficacy in clinical events and mortality. In a recent study 600 patients with AMI complicated by diabetes or elevated glucose were randomized to receive i.v. glucose and insulin for 24 h followed by insulin for 1 year and compared to a group receiving standard therapy1761. At the end of one year, there was a significant 30% reduction in mortality. This emphasizes the need to evaluate the role of intensive insulin treatment in AMI patients with elevated blood glucose concentrations. Need for future studies In spite of the availability of useful therapies, mortality from AMI still remains high, and the in-hospital casefatality rate for all patients is probably more than 15%[77l It is, therefore, important to evaluate new and promising therapies, and re-evaluate existing ones in properly conducted randomized controlled trials in order to demonstrate or exclude clinically worthwhile and practical patient benefits.

Conclusions
The management of patients with AMI should be based on relevant and reliable evidence from large randomized controlled trials. In the acute phase, thrombolysis therapy is supported by such a level of evidence. In the longer term, the efficacy of aspirin, beta-blockers and ACE-inhibitors is similarly supported and they should be adopted for widespread prescription as simple effective and affordable drugs. Their dosages should be tailored to the individual but should pertain as closely as possible to those which were used in the relevant positive clinical trials (Table 5). Clinical attention and resource allocation should be directed towards therapies of established benefit and away from such unproven drugs as magnesium and the calcium channel blockers. The role of heparin and nitrates for the treatment of AMI in the acute phase remains unclear, although both may be clinically useful in specific subsets of patients. The long-term use of oral nitrates in the preventative

Clinical trials of treatment for AMI

27

role following AMI cannot be justified from the results of the large randomized controlled trials currently available. Oral anticoagulants, clot-specific thrombin inhibitors, amiodarone and other drugs are currently being evaluated but their role in the immediate and longer-term treatment of patients with AMI must await the results of their testing in large randomized controlled trials.

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