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European Heart Journal (2000) 21, 11251134

doi:10.1053/euhj.1999.2206, available online at http://www.idealibrary.com on

Review Article
Management of patients with myocardial infarction and
hypertension
G. Y. H. Lip, C. Lydakis and D. G. Beevers
University Department of Medicine and Department of Cardiology, City Hospital, Birmingham, U.K.

Introduction
A patient presenting with acute myocardial infarction
and severe or uncontrolled hypertension represents an
emergency situation requiring prompt and accurate
evaluation of both conditions, and treatment should be
neither inadequate nor overzealous. The acute coronary
event may be accompanied by raised blood pressure
either due to acute stress or secondary to long-standing
but possibly undiagnosed hypertension. Very rarely,
such a presentation may be part of a true hypertensive
emergency, such as malignant phase hypertension,
hypertensive encephalopathy or dissection of the aorta.
Whilst both myocardial infarction and uncontrolled
hypertension require treatment, the question is not only
what should I use to lower the pressure but also how
much time do I have in order to obtain the potential
benefit from thrombolytic treatment; indeed immediate
and rapid normalization of blood pressure is not the
goal of initial therapy in most cases. Treating one
condition but not the other also creates potential problems. For example, giving thrombolytic therapy to a
patient with severe hypertension may increase the risk of
cerebral bleeding. By contrast, treating the hypertension
alone and ignoring the heart attack may result in
complications secondary to myocardial infarction,
including severe cardiac dysfunction, arrhythmias and
valve dysfunction. This has led to some debate and
confusion over the management of such patients, leading
to suboptimal care and dierent treatment policies in
dierent coronary care units. Some of the treatments
that are being employed have even been shown to be
dangerous.
Manuscript submitted 6 August 1999, and accepted 13 October
1999.
Correspondence: Dr G. Y. H. Lip, University Department
of Medicine and Department of Cardiology, City Hospital,
Birmingham B18 7QH, U.K.
0195-668X/00/141125+10 $35.00/0

In this review, we briefly discuss the pathophysiology


of myocardial perfusion in hypertensive patients and the
eects of blood pressure normalization. Following this,
we discuss two clinical situations, firstly, the emergency
reduction in blood pressure in patients with very severe
hypertension, and secondly, the choice of antihypertensive drugs in heart attack survivors on a longer term, less
urgent basis.

Pathophysiology
An understanding of the perfusionregulation of the
heart is necessary to appreciate the pathophysiological
basis of treating patients with myocardial infarction and
uncontrolled hypertension. The cerebral and coronary
vascular beds have the ability of autoregulation, so that
organ perfusion is kept constant within a range of
systemic blood pressures.
For example, cerebral blood flow normally remains
stable at 50 ml . min 1 . 100 g 1 of brain tissue[1]. However, cerebral blood flow in hypertensive patients is not
dierent from that found in normotensive subjects,
which reflects a shift of the autoregulation flow curve to
the right within the range of mean arterial pressure from
100 to 180 mmHg (Fig. 1(b)), whilst in normotensives
the corresponding range is 60 to 120 mmHg. This
explains why patients with long-standing uncontrolled
hypertension cannot tolerate rapid great reductions in
blood pressure even to that within normotensive levels.
In the myocardium, a similar autoregulatory mechanism is present, although several dierences exist between
the vascular trees of the brain and heart. Cerebral blood
flow is profoundly influenced by changes in arterial
carbon dioxide tension[2], and in cases of ischaemia the
brain compensates by extracting more oxygen from the
blood[3]. By contrast, myocardial blood flow depends
upon arterial oxygen saturation[4] and coronary sinus
oxygen saturation at rest is usually around 30%,
 2000 The European Society of Cardiology

1126

G. Y. H. Lip et al.

Table 1 Types of hypertensive emergencies in patients.


(Modified from ref.[8])
Hypertensive encephalopathy
Cerebral infarction
Intracerebral haemorrhage, subarachnoid haemorrhage
Myocardial ischaemia
Left ventricular failure and acute pulmonary oedema
Aortic dissection
Acute renal insuciency
Microangiographic haemolytic anaemia

Hypertensive emergencies and


myocardial infarction

Figure 1 Autoregulation of myocardial (a) and cerebral


(b) blood flow (from ref.[8] with permission).
indicating that oxygen extraction is maximal[4]. Furthermore, the subendocardial region appears to be more
vulnerable to reduced perfusion pressure, in comparison
to the subepicardium; this is probably due to the lack of
homogeneity of the compressive pressure exerted upon
myocardial vessels during systole, which may occasionally lead to subendocardial vessel occlusion during cardiac contraction[5]. As a consequence, during a critical
fall in systemic arterial pressure leading to a reduction of
coronary blood flow, autoregulation will be exhausted
initially in the subendocardial layer, before the subepicardial layer is aected (Fig. 1(a)). Similarly, the eects
of coronary artery narrowing will be much more severe
in the subendocardium than in the epicardium[4]. Since
the extraction of oxygen is almost maximal under normal conditions, it is not surprising that the hypertrophied myocardium in hypertensives is vulnerable to
ischaemic complications when blood pressure is lowered
below a critical level[6]. Therefore rapid reduction of
diastolic pressure may potentially be more dangerous to
the heart than to the brain.
Indeed, in the hypertensive hypertrophic heart, resting myocardial blood flow is approximately the same
as that of a normotensive patient, that is about
70 ml . min 1 . 100 g 1, but the flow reserve is greatly
reduced[7]. It is often presumed that in the hypertensive
subendocardium, autoregulation is shifted towards a
higher pressure (Fig. 1(a)). Although long-term antihypertensive treatment can shift the cerebral autoregulation curve back towards normal (Fig. 1(b)), no such
readaptation of autoregulation of myocardial blood
flow has been described[8].
Eur Heart J, Vol. 21, issue 14, July 2000

The several types of hypertensive emergencies in heart


attack patients are shown in Table 1. In some patients
there may be a degree of false elevation of blood
pressure due to the stress of illness, transportation to
hospital and the intimidating environment in a high
technology coronary care unit. This diagnosis should be
suspected, particularly if the ECG or echocardiogram
shows absolutely no evidence of left ventricular hypertrophy. Repeated blood pressure measurements using
reliable automated blood pressure monitors may demonstrate a steady reduction of blood pressure if the
patient settles in 1 or 2 h.
To the admitting clinician, a patient presenting with
an acute myocardial infarction and very high blood
pressure constitutes a clinical conundrum. Should he
administer life-saving thrombolytic therapy for the heart
attack, yet ignore the risk of cerebral bleeding with the
uncontrolled hypertension, or should he withhold treatment? Alternatively, should strenuous eorts be made to
reduce blood pressure at the cost of losing valuable time
before administering thrombolysis, since greater myocardial salvage is achieved by earlier reperfusion. Furthermore, should alternative reperfusion strategies such
as primary angioplasty, if access to such an option is
available, be considered?
Immediate normalization of the blood pressure is not
the goal of initial treatment in hypertensive emergencies.
Rarely, a patient with myocardial infarction and very
high blood pressure may present as a true hypertensive
emergency caused by accelerated/malignant hypertension. This is diagnosed by the presence of severe hypertension with bilateral retinal haemorrhages and exudes,
with or without papilloedema[9]. There is no absolute
level above which malignant hypertension develops. The
histological hallmark (although not pathognomonic) of
malignant hypertension is necrotising arteriolitis and
fibrinoid necrosis, on renal biopsy[10]. As a consequence
of arteriolar damage, impairment of organ perfusion
and loss of autoregulation of blood flow occurs[11]. An
abrupt reduction of blood pressure may precipitate
a cerebrovascular event or may worsen the coronary
ischaemia for the pathophysiological reasons already
discussed. A useful therapeutic goal is to reduce mean

Review

Table 2

1127

Drugs for hypertensive emergencies with acute coronary event. (Adapted from ref.[16])

Drug

Dose

Onset and duration of action

Nitroglycerin

0580 g . kg 1 min 1
(i.v. infusion)

Onset within minutes, duration


23 min after infusion stopped

Labetalol

2 mg . min 1 to total of
2 mg . kg 1 (i.v. infusion)
0380 g . kg 1 min 1
(i.v. infusion)
515 mg . h 1 (i.v. infusion)

Onset 510 min, duration 18 h


after infusion stopped
Onset instantaneous, duration
23 min after infusion stopped
Onset 515 min, duration 30
40 min after infusion stopped

Nitroprusside
Nicardipine

arterial pressure by about 1525% within the first 24


48 h or to a range of 100110 mmHg diastolic and
160170 mmHg systolic[12].
Individualization of treatment should be considered.
For example, younger patients with recent onset hypertension secondary to acute glomerulonephritis can tolerate more rapid blood pressure reduction even to
normotensive levels, whereas elderly people may
experience complications when the diastolic pressure is
reduced to 100 mmHg. This level of blood pressure
appears to be the lower limit of the autoregulatory
range in patients with long-standing uncontrolled
hypertension (Fig. 1).
In patients with acute myocardial infarction, the
initial goal is to lower blood pressure in a controlled
manner without compromising coronary blood flow.
Nitroglycerin infusion has the safest profile in this
respect and is recommended as first line treatment
(Table 2). Nitroglycerin causes venous dilatation at low
doses (5 g . min 1) and as the infusion rate is increased
usually by titrating the dose every 35 min, arteriolar
dilatation also occurs[11]. Coronary vasodilation also
occurs at the ischaemic area, thus avoiding a coronary
steal eect. Hypotension with moderate tachycardia[13]
or more rarely, bradycardia[14,15] can also occur.
As an alternative, labetalol, which has combined
alpha and beta blocker activity (ratio 1:7) by infusion or
minibolus injection, at an initial dose of 2 mg . min 1,
reduces blood pressure without compromising myocardial oxygenation[15] and without any reflex tachycardia[16]. The beta-blocking eects of this drug make it
unsuitable for patients with cardiac failure, severe airways disease and second- or third-degree atrioventricular block. Sodium nitroprusside, which is a dilator of
veins and arteries, results in a reduction of both pre- and
afterload, at a dose of 038 g . kg 1[16]. This agent is
best reserved for patients with gross pulmonary oedema
due to left heart failure, and also for patients with
suspected or proven aortic dissection, and very high
blood pressure. Sodium nitroprusside has a linear dosedependent eect on the blood pressure, thus needing
careful monitoring, and the peripheral vasodilation
causes secondary sympathetic stimulation with an increase of heart rate. The latter is undesirable in patients
with coronary insuciency and therefore sodium nitroprusside should be considered as second line treatment.

Comments
Administer by syringe pump (drug
is absorbed by soft plastic containers)
Avoid in cardiac failure, asthma,
second or third degree block
Requires careful monitoring
New agent, still under evaluation,
may cause tachycardia

Finally, intravenous nicardipine, a newly instituted drug


in the treatment of hypertensive emergencies, seems to
have a safe profile by producing a steady progressive fall
in blood pressure with little change in heart rate[17]. It
should be noted that other vasodilator agents, such as
hydralazine and diazoxide, should be avoided in the
presence of coronary insuciency, since reflex
tachycardia may worsen ischaemia.
Patients with very high blood pressures at the time of
myocardial infarction alone but with no signs of heart
failure can safely be treated with oral beta-blockers, for
example, atenolol or metoprolol, initially in low dosage.
Atenolol can reduce very high pressures over 2 to 3 h.
This treatment may be particularly helpful in patients
suspected of having stress-induced false elevations in
pressure.

Nifedipine
Nifedipine, a calcium channel antagonist of the 1,4
dihydropyridine class, has frequently been used in cases
where an immediate reduction of blood pressure seemed
desirable. The onset of action of nifedipine has been
reported to be within 5 to 30 min, with the peak eect
within 30 min to 1 h[12]. The ease of administration
(orally), its eectiveness with a rapid onset of action and
the lack of side eects (in early reports) resulted in its
recommendation as the first line drug for hypertensive
emergencies[1820]. The use of sublingual nifedipine
should nevertheless be discouraged, as it is not absorbed
by the oral or oesophageal mucosa, and the liquid
released from the crushed nifedipine capsule is erratically absorbed later, resulting in fluctuating eects,
including a sudden and rapid fall in blood pressures.
The initial studies in favour of nifedipine in the
treatment of hypertensive emergencies were small (2030
patients each) and all showed an eective reduction of
blood pressure without severe adverse eects, especially
since no dangerous hypotension was reported[2124].For
example, Komsuoglu et al.[24] studied 22 patients with
hypertensive encephalopathy who were administered
20 mg liquid nifedipine orally (equivalent to biting a
capsule), where the mean blood pressure fell from 236/
121 mmHg to 172/96 mmHg after 30 min with no significant side eects. In a further study of 25 patients with
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G. Y. H. Lip et al.

hypertensive emergencies, blood pressure decreased


from 220/126 mmHg to 152/89 mmHg within 30 min
after oral ingestion of 10 or 20 mg of nifedipine[21]. The
absolute decrease in blood pressure following treatment
of malignant hypertension with nifedipine was more
prominent than that observed in mild to moderate
hypertension[21,25]. In view of the cerebral autoregulation data discussed earlier, the sudden, large reductions in blood pressure with sublingual nifedipine are
excessive and can be potentially dangerous.
Several cases of nifedipine-induced myocardial ischaemia or infarction in patients with or without ischaemic
heart disease have been published. For example,
Jariwalla and Anderson[26] reported that 10 mg of nifedipine given in three patients with ischaemic heart disease
induced severe angina attacks. OMailia et al.[27] described three patients with essential hypertension with
high blood pressure (systolic blood pressure 180
230 mmHg, diastolic blood pressure 110130 mmHg)
without acute hypertensive complications who were
given 10 mg of nifedipine sublingually, and within minutes a significant fall in the systolic blood pressure
(down to 8085 mmHg) was noted; two of their patients
developed a myocardial infarction, whilst the third
patient had electrocardiographic evidence of cardiac
ischaemia[27]. In the report by Wachter (1987) two
patients with symptomless severe hypertension (blood
pressure 230/160 mmHg and 220/140 mmHg) developed
severe symptomatic hypotension (systolic blood pressure
80110 mmHg, diastolic 55 mmHg) with electrocardiographic findings of cardiac ischaemia, after having
been given repeated doses of 10 mg sublingual nifedipine[28]. In the same report, a third patient presenting
with malignant phase hypertension (230/170 mmHg)
also developed severe hypotension (10070 mmHg) and
electrocardiographic ischaemic changes after the administration of nitroglycerin and sublingual nifedipine
20 mg.
In addition to coronary complications, acute cerebrovascular events with nifedipine have been described in
several reports. Sublingual, oral or slow-release preparations of nifedipine have been implicated as causing
cerebral ischaemia[29], bilateral visual loss[30], left hemiparesis[31] and cortical blindness[32]. The acute hypotensive eect of nifedipine (especially when given
sublingually) is unpredictable and in some cases was
hazardous. In a study of an heterogenous group of
patients with severe hypertension, the magnitude of the
hypotensive response was found to correlate with the
pre-treatment blood pressure level[18]. In patients with
cardiac ischaemia or myocardial infarction, a precipitous fall in blood pressure accompanied by reflex acceleration of the heart rate and an increase in myocardial
oxygen demand is highly undesirable[33]. In addition, the
nifedipine-induced preferential vasodilation in nonischaemic myocardium at lower pressures may cause
diversion of blood flow away from ischaemic areas,
commonly referred to as a coronary steal phenomenon[34]. This adverse haemodynamic profile renders
nifedipine an inappropriate choice for hypertensive
Eur Heart J, Vol. 21, issue 14, July 2000

emergencies, especially when treating patients with


myocardial infarction or coronary ischaemia.
It follows that the widespread use of sublingual nifedipine in non-hypertensive emergencies, for example, in
patients presenting with high blood pressure without
any evidence of acute target organ damage, as a means
of rapid blood pressure reduction, is also equally unjustified[35]. In such cases the rapid, acute intervention is
not necessary since no vital organ threat exists[33]. Secondly, the potential harm from a precipitous fall in
blood pressure (however rare) cannot be overlooked.
Thirdly, the sublingual absorption of nifedipine is negligible[35] and in fact, most of the drug gets into circulation
only after gastric absorption. Therefore, nifedipine,
especially when administered sublingually, is not an
appropriate choice for hypertensive emergencies in heart
attack patients, and may even be dangerous[16,35].

The non-emergency control of high


blood pressure in patients following
myocardial infarction
An excessively high blood pressure (>200/120 mmHg) is
a definite contra-indication to thrombolytic therapy[36].
Blood pressure should be reduced to <160/110 mmHg
(which was the cut-o in many trials of thrombolytic
therapy) before administration of thrombolysis. If available, primary angioplasty is an option for reperfusion
in patients with high blood pressure and/or a perceived
risk of stroke were thrombolysis to be given. After the
exclusion of true hypertensive emergencies by examination of the patient, the therapeutic strategy should be
focused on protecting the ischaemic myocardium. Many
classes of drugs which also have antihypertensive properties have been evaluated in the treatment of acute
myocardial infarction, including the beta-blockers,
angiotensin converting enzyme (ACE) inhibitors, nitrates and calcium antagonists. However, many of the
trials examining these agents in patients with acute
myocardial infarction were conducted before the emergence of thrombolytic therapy as a serious treatment
option, or were investigating other properties rather
than their antihypertensive eects.

Beta-blockers
Oral or intravenous treatment with beta-adrenoceptor
blockers lowers the blood pressure within hours[37]. They
also have important antiischaemic eects, so that they
should be considered as first line therapy in patients with
myocardial infarction, in the absence of contraindications. These drugs protect the jeopardized ischaemic
myocardial tissue by reducing oxygen demand (by
1530%) due to their eects in lowering heart rate,
blood pressure[38] and cardiac output[39]. Furthermore,
the beta-blockers have antiarrhythmic properties and
can cause favourable shunting of blood away from

Review

Table 3

1129

Reduction in mortality in intervention trials with beta-blockers in acute myocardial infarction

Study
Early (immediate initiation)
Goteborg Metoprolol Trial[45]
MIAMI trial[46]
ISIS-1[47]
Late (initiation 528 days later)
Norwegian Multicentre Study[48]
BHAT[49]

Year

1981
1985
1986

1395
5778
16 027

1981
1982

1884
3837

Treatment period

Reduction in mortality
Age (years), (5)

Metoprolol
Metoprolol
Atenolol

90 days
15 days
7 days

<64 (21%) 6474 (45%)


<60 (5%) 6074 (18%)
<65 (4%) <65 (23%)

Timolol
Propanolol

17 months (mean)
25 months (average)

Beta-blocker

non-ischaemic to ischaemic regions[40]. In the presence


of chronic ischaemia, beta-blockers can also increase the
ejection fraction[41], particularly during exercise[42] and
improve left ventricular function[43].
The beneficial eect of intravenous beta-blocker
therapy initiated with 24 h of an acute myocardial
infarction was shown in a meta-analysis of 32 randomized trials including nearly 29 000 patients, where a 13%
relative reduction in overall mortality (P<003) was
found[44]. The main studies of treatment with betablockers either in early (immediate) (Goteborgs Metoprolol trial[45], MIAMI[46], ISIS-1[47]) or late (several
days later) (Norwegian Multicenter study[46], BHAT[49])
intervention in patients with myocardial infarction are
shown in Table 3, although many were conducted in the
pre-thrombolysis era. In ISIS-1[47] some of the benefit
was from the reduction of cardiac rupture. Thus,
the beta-blockers have been well-studied in the myocardial infarction setting, and can initially be given
intravenously and continued orally afterwards.

ACE inhibitors
ACE inhibitors lower the blood pressure by decreasing
elevated systemic vascular resistance without inducing
reflex sympathetic activation[50]. They also exert antiischaemic eects by the reduction of myocardial oxygen
demand, reduction of ventricular wall tension and improvement of coronary blood flow[50]. The vasodilator
and neurohormonal (through inhibition of the reninangiotensin axis) eects of ACE inhibitors and their
eect on long term-remodelling may account for their
favourable properties in patients suering from acute
myocardial infarction[51,52].
The beneficial eects of the ACE inhibitors on mortality reduction were shown in randomized trials with
both late (after days) (SAVE[53], AIRE[54], TRACE[55])
and early (within hours) (SMILE[56], CONSENSUS-II[57],
GISSI-3[58], ISIS-4[59], CCS-1[60]) administration. Overall, these trials indicate a definite benefit of saving about
five lives for every 1000 patients treated[61].
The administration of ACE inhibitors in patients
presenting with acute myocardial infarction and hypertension has both a good early safety profile, especially
since dangerous hypotension was not a significant

<65 (48%) 6575 (48%)


<60 (19%) 6069 (34%)

problem in the large trials, with a favourable long-term


eect on survival. Although not encountered in randomized trials, ACE inhibitors would be expected to cause
over-rapid falls in blood pressure in patients with intravascular volume depletion secondary to large doses of
frusemide. Furthermore, rapid falls in pressure may be
encountered in patients with known or underdiagnosed
renal artery stenosis secondary to generalized atheromatous disease. This diagnosis should therefore be considered in elderly smokers with evidence of peripheral
vascular disease or vascular bruits. In such patients,
careful monitoring of blood pressure following the institution of low doses of the short acting ACE inhibitor,
captopril, is recommended together with regular checks
of renal function.

Nitrates
The antihypertensive and antiischaemic eects of
nitrates make them suitable candidate drugs for treating
patients with acute myocardial infarction (with or without raised blood pressure). Since their antianginal eect
is well documented, the research interest has been
focused in recent years in hard-end points like infarct
size, remodelling and mortality.
In a meta-analysis of Yusuf et al.[62] of ten trials of
intravenous nitroglycerin and nitroprusside that included over 2000 randomized patients, a significant
reduction of 35% in mortality (albeit with wide confidence limits) in the first week was shown, with the
benefit lasting up to several months. This beneficial
eect of nitrates shown in the pre-thrombolysis era,
however, appeared to be absent in recent large trials in
patients receiving conventional thrombolytic treatment[58,59] (Table 4). Nevertheless, in the acute phase of
myocardial infarction, whether or not accompanied by
raised blood pressure, nitrates are a safe treatment
option, and may be particularly useful if heart failure is
present.

Calcium antagonists
The antiischaemic and antihypertensive actions of the
calcium antagonists are mainly due to arteriolar
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G. Y. H. Lip et al.

Table 4 Recent trials of nitrates in acute myocardial infarction. (ISMN: isosorbide mononitrate, ISDN: isosorbide
dinitrate)
Year of
publication

n
(randomized)

GISSI-3[58]

1994

ISIS-4[59]

Morris et al.[82]

Nitrate

Duration

End-points

19 394

lisinopril 510 mg1


vs GTN i.v. initially
and transdermal 10 mg
afterwards vs combined
treatment vs plabeco

6 weeks

1995

58 050

1 month

1995

301

captopril up to
50 mg2 vs placebo.
ISMN up to 60 mg1
vs placebo. Magnesium
sulphate i.v. vs placebo
ISDN i.v. vs placebo
for the first three days

Mortality: Reduction 11% in lisinopril group


(P=003). No significant reduction in nitrate
group. Combined treatment: slight additive
eect.
Combined mortality and ventricular
dysfunction: Statistical reduction by 10% in
lisinopril group. No significant reduction in
nitrate group.
5 week mortality: Reduction 7% in captopril
group, (P=002). No significant reduction in
nitrate and magnesium group. The benefit from
captopril persisted in 1 year follow up.

vasodilation. A decrease in coronary and peripheral


resistance leads to an increase of oxygen supply to the
heart and a decrease in afterload[63]. In cases of patients
with angina, the preferential vasodilation of the coronary tree in non-ischaemic myocardium may cause
diversion of blood flow away from the ischaemic region
(coronary steal phenomenon)[34] and aggravate the
ischaemic event.
The short- and long-term eects of calcium antagonists in patients presenting with acute myocardial infarction and with (or without) raised blood pressure have
been explored in may trials. Table 5 shows the largest
trials of nifedipine (TRENT[64], HINT[65], SPRINT-I[66],
SPRINT-II[67], diltiazem (Gibson et al.[68], MDPIT[69])
and verapamil (DAVIT-I[70], DAVIT-II[71], CRIS[72] in
the acute or subacute phase of myocardial infarction or
unstable angina. The results of nifedipine trials showed
no beneficial eect on mortality, and in fact a nonsignificant increase of mortality compared to the placebo
groups has been noted in some trials (TRENT,
SPRINT-I, SPRINT-II). The HINT study was terminated prematurely because of an increase in infarction
rate in the nifedipine group compared to the metoprolol
group. Overall, from the results of the accumulated
trials, nifedipine is contraindicated in patients with acute
myocardial infarction; whereas verapamil and possibly
diltiazem may be used as an alternative to beta-blockers,
especially in patients with good left ventricular function.
The eects of verapamil reported in DAVITT-II were
also examined in the hypertensive patients in a subgroup
analysis; the benefits continued to be seen, although it is
uncertain whether the eects were due to specific properties of verapamil on the heart or were simply related to
the benefits of long-term control of blood pressure.
Eur Heart J, Vol. 21, issue 14, July 2000

6 weeks

Three days evaluation: Significant reduction of


infarct size in nitrate group only in patients
with moderate ST elevation. Non significant
trend towards increase of infarct size in nitrate
group in patients with marked ST segment
elevation.
6 weeks evaluation: No dierence in
echographic volumes between groups.

The adverse eects of calcium antagonists (mainly


nifedipine) in patients with myocardial infarction and
unstable angina were reported in a metaanalysis by Held
et al.[73] in 1989, which was followed by a second update
in 1991 that included the results of DAVIT-II and two
other smaller trials[74]. Furberg et al. recently reported
a dose-related increase in mortality in patients with
coronary disease treated with nifedipine[75], but this
dose-event correlation has been severely criticized[76].
The adverse aects of nifedipine in patients with myocardial ischaemia can be attributed, to a great extent, to
its pharmacokinetic properties. Major fluctuations of
blood pressure due to its rapid onset and oset of
antihypertensive eect during the dosing interval may
result in drugs and formulations that are short acting[77]
or some slow release nifedipine preparations[78,79]. The
intermittent increases in sympathetic activity shown with
short acting formulations may promote cardiac arrhythmias and myocardial ischaemia by increasing cardiac
work, possibly contributing to an increased mortality in
coronary patients. However, the newer (second generation) and more vascular selective dihydropyridines,
such as felodipine and amlodipine, do not appear to
share the adverse eects of nifedipine[80].
The calcium antagonists cannot therefore be considered as a uniform group of drugs. A major distinction
is between vasoselective dihydropyridines and cardioselective benzothiazepines (diltiazem) and phenylkylamines (verapamil). Within the dihydropyridine group
the newer compounds (like amlodipine) seem to have
a more favourable pharmacokinetic and pharmacodynamic profile than the older short acting compounds
(nifedipine). From the trials available in patients
presenting with acute myocardial infarction, with or

Verapamil

Diltiazem

Nifedipine

Table 5

1988

1993

1986

1988

1984

1990

SPRINT-I[66]

SPRINT-II[67]

Gibson et al.[68]

MDPIT[69]

DAVIT-I[70]

DAVIT-II[71]

1996

1986

HINT[65]

CRIS[72]

1985

Year of
publication

TRENT[64]

Trial

531

1775

1436

2466

576

1006

2276

338

4491

n
(treated)

721 days after MI

7 days after MI

Immediately after MI

315 days after MI

2472 h after MI

048 h after MI

721 days after MI

Unstable angina

024 h after MI

Clinical setting

Trials of calcium antagonists in acute myocardial infarction

Verapamil 360 mg1 vs


placebo

Verapamil i.v. 01 mg/kg


followed by 120 mg3 vs
placebo
Verapamil 360 mg1 vs
placebo

Diltiazem 3090mg1 vs
placebo
Diltiazem 240 mg1 vs
placebo

Nifedipine 60 mg1 vs
placebo

Nifedipine 30mg1 vs
placebo

Nifedipine 10 mg3 vs
placebo
Nifedipine 10 mg6 vs
metoprolol 100 mg2 vs
combination vs placebo

Calcium antagonist

Mean 235 months

Mean 16 months

12 months

Mean 15 months

14 days

6 months

1 year

48 h

28 days

Duration

Mortality: verapamil: 111%, placebo: 138%. No


significant dierence. Mortality and reinfarction:
verapamil: 18%, placebo: 216%. Significant
dierence. The dierence was concentrated in the
group without heart failure
Total and cardiac mortality: no dierence.
Significant lower rate of developing angina
(RR=08) in the verapamil group. Non significant
lower reinfarctions in the verapamil group

Mortality: nifedipine: 67%, placebo: 63%. No


significant dierence
Odds ratio for developing complete MI: nifedipine:
115, metoprolol: 076, combination: 080, placebo:
1. Significant benefit of metoprolol and of
combination
Mortality: nifedipine: 58%, placebo: 57$. No
significant dierence. Reinfarction: nifedipine:
48%, placebo: 44%. No significant dierence
Mortality: nifedipine: 187%, placebo: 156%. No
significant dierence. Most of the dierence was
concentrated within the first 6 days
Reinfarction: diltiazem: 63%, placebo: 129%.
1-tailed P=0029 2-tailed P=non significant
Combined death and reinfarction: 11% less in
diltiazem group (not significant). 20% of patients
with pulmonary congestion showed hazard with
diltiazem
Mortality: verapamil: 152%, placebo: 164%. No
significant dierence

End-points Results

Review
1131

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1132

G. Y. H. Lip et al.

without hypertension, verapamil and probably diltiazem


seem to have a neutral (safe) profile and can perhaps
be used as third line drugs, after beta-blockers, ACEI
and nitrates, for treating hypertension during an acute
myocardial infarction, if left ventricular function is
preserved.

Recommendations
In a patient presenting with acute myocardial infarction
and severe hypertension, the appropriate treatment
should include the initiation of intravenous nitrates,
with intravenous labetalol, sodium nitroprusside and/or
nicardipine as alternatives, especially in very severe
hypertension or hypertensive emergencies. The reduction of blood pressure should not be abrupt, and a
gradual reduction over a period of 2448 h is recommended, so that further myocardial or brain ischaemia is
avoided. Sublingual nifedipine, which has usually been
considered as a first line drug, should be avoided, in view
of the negligible oral absorption and unpredictable
hypotensive eects.
In the majority of patients presenting as an emergency
with acute myocardial infarction and in hypertension
without signs of other acute target organ damage,
hypertension does not necessarily represent an acute
major threat. Treatment should be aimed at relieving
symptoms, protecting the ischaemic but potentially
viable myocardial tissue and reducing mortality. Blood
pressure should be reduced to <160/110 mmHg before
administration of thrombolysis, although if available,
primary angioplasty is an option for reperfusion in
patients with high blood pressure and/or the perceived
risk of stroke if thrombolysis is unacceptable. In our
evidence-based medicine era, available data from large
trials show that only beta-blockers and ACE inhibitors,
amongst the several antihypertensive drug classes, convincingly save lives in long-term post-myocardial infarction. Amongst the calcium antagonists, only verapamil
and perhaps diltiazem may be used as an alternative if
no significant left ventricular dysfunction is present.

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