1. health and fitness
2. therapy

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
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)
Introduction
Thrombolytic therapy
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.
Mechanism of action
Key Words: Acute myocardial infarction, drug treatment,
randomized clinical trials.
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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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
Clinical trials of treatment for AMI
17
Table 1 Proportional and absolute differences in mortality during days 0-35 with
thrombolytic therapy
Deaths during days 0-35
Day of
death
Day 0
Day 1
Days 2-7
Days 8-35
All, in days 0-35
Proportional
reduction (%)
Benefit per
1000
554
(1-9)
549
(1-9)
1100
(3-9)
1154
(4-3)
- 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)
- 5 , SD 1**
(-7to -2)
3, SD 1*
(0 to 5)
9, SD 2 " *
(6 to 12)
13, SD 2***
(10 to 16)
3357
(115)
18, SD 2
(13 to 23)
18, SD3***
(13 to 23)
Fibrinolytic
(n = 29 315)
Control
(n = 29 285)
695
(2-4)
475
(1-7)
847
(3-0)
803
(2-9)
2820
(9-6)
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
Eur Heart J, Vol. 17, Suppl F 1996
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*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.)
18 S. Yusufet al.
40 - 13000
\
30 -
14 000
1
* \
i
12 000
Q
19000
20 --
10 -
(7000
1 . . .
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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6
Clinical trials of treatment for 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
Eur Heart J, Vol. 17, Suppl F 1996
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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.
19
20 S. Yusuf etal.
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.
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).
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
Eur Heart J, Vol. 17, Suppl F 1996
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
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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.
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-').
Clinical trials of treatment for AMI
21
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
P
26 small trials
MIAMI trial
Subtotal: All intervention trials
other than ISIS-1
ISIS-1 trial
117/2901
79/2877
196/5778
126/2830
93/2901
219/5731
- 9 ±13
- 15± 14
-12±9
ns
ns
ns
317/8037
367/7990
— 15 ± 7
<005
Total mortality
available
513/13 815
(3-7%)
586/13 721
(4-3%)
- 14±6
<0-02
(From [351.)
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.
Eur Heart J, Vol. 17, Suppl F 1996
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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.
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.
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
Eur Heart J, Vol. 17, Suppl F 1996
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).
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on September 9, 2014
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.
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.
Clinical trials of treatment for AMI
Randomized
comparison
Deaths/patients (% dead)
CEI
Control
11 small trials
23
Odds ratio and CI
CEI
Control
better better
L
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
Table 3 Results of long-term randomly allocated trials of ACE inhibitors on mortality in AMI
Year
reported
Patient
eligibility
Treatment
comparison
SAVE1511
1992
AMI (3-16 days)
EF^40%
AIREl 52 '
1993
TRACE 1 *"
1995
AMI (3-10 days)
Evidence of
heart failure
AMI (2-7 days)
LVD
C H F (23%)
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)
Trial
Treatment
Total
No. of Deaths/no, of
patients
patients
Control
Deaths/no, of
patients
RRR%
95%
CI of RR
P
2231
228/1115
(20%)
275/1116
(25%)
19
0-71 to 0-97 0019
1986
170/1004
(17%)
222/982
(23%)
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.
Eur Heart J, Vol. 17, Suppl F 1996
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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.)
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.
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
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
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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.
been variable with most studies indicating a lack of
benefit"'56-571.
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
(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.
(From
Control
Odds ratio
95% Confidence
interval
365/4731
330/4733
113
0-97-1-32
2/192
12/214
12/477
3/191
2/211
7/462
0-66
4-4
1-78
0-06-1-90
1-50-12-6
0-71^-49
391/5614
342/5597
(01)
1-01-1-36
124/3646
111/3680
114
0-68-1-92
14/192
8/214
8/191
7/211
1-77
113
0-75-4-18
0-40-3-17
146/4052
126/4082
119
0-93-1-52
[651
.)
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
Eur Heart J, Vol. 17, Suppl F 1996
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Total
Active
26
S. Yusufet al.
Table 5 Dosage of drugs used in trials where mortality or morbidity were reduced
Drug
Starting dose
Maintenance
Aspirin
Metoprolol
Atenolol
Propranolol
Enalapril
Captopril
Ramipril
Trandolapril
Lisinopril
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
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
Group
Antiplatelet agents
Beta-blockers
ACE inhibitors
ACE = angiotensin
i.v. = intravenous.
converting
enzyme;
b.i.d. = twice
daily;
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
times
daily;
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
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on September 9, 2014
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'.
t.i.d. = three
Clinical trials of treatment for AMI
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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