Lunch menu

VOLUME 10
NATIONAL PRESCRIBING CENTRE
NUMBER 2, 1999
Contents: Secondary prevention of myocardial infarction
Secondary prevention of myocardial infarction
Survivors of a myocardial
infarction (MI) are at greatly
increased risk of reinfarction
or death.1 Evidence of the
effectiveness of strategies to
prevent such events (secondary
prevention) is convincing.
Despite this, many patients
may not be receiving optimal
preventative treatment.2
The National Service Framework
for coronary heart disease (CHD),
emphasises the need to ensure
that effective interventions are
used post-MI.3 This bulletin
outlines the main interventions
used for secondary prevention
of MI and advises on their use
in general practice.
Risk factors for coronary heart
disease
The risk of dying from CHD is
much greater when several risk
factors are present (see table 1).
Secondary prevention aims to
manage these risks, where
possible, to prevent a further MI.
Which interventions should be
considered in all patients?
Lifestyle measures
All patients with CHD should
be advised to stop smoking
as it is a strong risk factor for
a first MI and for fatal and
non-fatal recurrences. Smoking
cessation reduces the risk of
death by around 50% over a
15 year period.4
Dietary modification can also
be beneficial post-MI. In 2,033
male survivors of an MI, eating
two portions of oily fish a week
SUMMARY
* Many patients do not receive optimal secondary
prevention after myocardial infarction (MI), despite
good evidence that certain interventions
reduce mortality.
* After an MI, patients should be advised to stop
smoking and, provided there are no contraindications, take aspirin and a beta-blocker. ACE
inhibitors are likely to benefit patients with signs of
heart failure or evidence of left ventricular dysfunction.
* The use of statins post-MI, along with dietary advice,
should be considered when total cholesterol is
≥ 5mmol/l and/or LDL-cholesterol is ≥ 3mmol/l.
Before prescribing statins, GPs should ensure that
all suitable patients are receiving aspirin and a
beta-blocker as a first priority.
* Lifestyle measures, such as eating a Mediterranean
diet and oily fish, may also reduce mortality post-MI
as can cardiac rehabilitation programmes. Maintaining
blood pressure below 140/85mm Hg reduces the risk
of further cardiovascular events.
* Anticoagulants are usually reserved for those postMI patients with, for example, a large anterior
infarction or atrial fibrillation, as they are no more
beneficial than aspirin alone.
* Calcium-channel blockers should not be used
routinely post-MI. However, diltiazem or verapamil
may benefit patients without heart failure who have
continuing angina, if beta-blockers are inappropriate.
* Amiodarone may be of benefit to patients with severe,
symptomatic arrythmias post-MI. However, class I
antiarrythmics, such as flecainide, should be avoided
as they increase mortality post-MI.
The MeReC Bulletin is produced
by the NHS for the NHS
MeReC Bulletin Volume 10, Number 2, 1999
5
•
•
•
•
•
•
•
Modifiable risk factors
Smoking
Hyperlipidaemia
Hypertension
Diabetes mellitus
Obesity
Excessive alcohol consumption
Lack of exercise
•
•
•
•
Non-modifiable risk factors
Family history of coronary heart disease
Increasing age
Male sex
Ethnic origin, e.g. Asians
Table 1. Risk factors for coronary heart disease.
reduced the absolute risk of
mortality by 3.5% over two
years.5 A Mediterranean diet,
replacing red meat with poultry
and increasing intake of fish,
vegetables, fruit and olive oil, also
reduces mortality post-MI compared with a low fat diet alone.6
Cardiac rehabilitation may
help patients achieve physical
and psychological recovery
after an MI and can also
reduce mortality.7 The most
effective form of rehabilitation
involves a combination of
exercise, education and
psychological interventions.7
Control of blood pressure
As raised blood pressure is a risk
factor for further cardiovascular
events post-MI, blood pressure
should be maintained below
140/85mm Hg where practical.8
Beta-blockers are the preferred
antihypertensive post-MI as they
have been shown to reduce
mortality in these patients.
Alternatives include thiazide
diuretics or angiotensin-converting enzyme (ACE) inhibitors, if
beta-blockers cannot be tolerated
or are contra-indicated.
Antiplatelet drugs
All post-MI patients should
receive aspirin indefinitely,
provided there are no contraindications. Aspirin reduces the
absolute risk of vascular events
by 3.6%, and also decreases
non-fatal MIs, non-fatal strokes,
vascular death and all-cause
mortality.9 Doses of 75-150mg
daily are effective post-MI.
A recent study compared aspirin
325mg daily with clopidogrel
75mg daily in 19,185 patients
with atherosclerotic vascular
disease.10 Clopidogrel reduced
the absolute annual risk of
6
ischaemic stroke, MI or vascular
death by 0.5% compared with
aspirin. However, no significant
benefit of clopidogrel over
aspirin was seen in 6,302
post-MI patients. In view of its
cost and marginal additional
benefit, clopidogrel should be
reserved for the small number
of patients in whom aspirin
is contra-indicated.
Beta-blockers
All post-MI patients should
be prescribed a beta-blocker
before discharge from
hospital, provided there
are no contra-indications.
Long-term treatment with a
beta-blocker reduces the absolute
risk of mortality after an
MI by 2%, mainly by reducing
sudden deaths.11 Beta-blockers
also decrease the risk of
non-fatal reinfarction.11
What are the benefits of lowering
cholesterol levels?
There is good evidence that
patients with established CHD
benefit from a reduction in their
cholesterol levels. All patients
with hyperlipidaemia should
receive dietary advice.8
However, the extent of cholesterol
reduction is likely to be small
(1-5%) in patients who are
given dietary advice.13
If drug treatment is required to
reduce cholesterol, the best
evidence is for the use of statins
at the doses specified in the
trials. A meta-analysis of 13
secondary prevention trials14
(including 4S15 and CARE16) in
21,022 patients, found absolute
risk reductions of 3% in all-cause
mortality, and 2.3% in cardiovascular deaths in patients taking
statins compared with controls.
The LIPID trial, published after
this meta-analysis,14 included
9,014 patients with a history of
MI who had a total cholesterol
between 4-7mmol/l.17 Over six
years, patients taking pravastatin
40mg daily had an absolute risk
reduction of 2% in death from
CHD and 3% in overall mortality.
Who should receive statins?
There is little information
on the risks and benefits of
beta-blockers in patients with
relative contra-indications to
treatment, such as diabetes.
Decisions should be made on
an individual basis in these
patients, but beta-blockers may
not always need to be withheld.
The benefits of beta-blockers
are greatest in the first year
post-MI.11 It is not known
whether their protective effect
continues after 2-3 years,
although one study involving
timolol has shown continued
benefit for up to six years.12
Despite the lack of data on
duration of therapy, it seems
reasonable to continue betablockers for at least 2-3 years,
or indefinitely in patients with
angina or hypertension.
While atenolol is most commonly
prescribed post-MI, timolol
metoprolol, acebutolol and
propranolol may also be used.
From this evidence, a statin
should be considered in post-MI
patients whose total cholesterol
remains ≥ 5mmol/l and/or
LDL-cholesterol ≥ 3mmol/l
even after following dietary advice
for at least six weeks.8 However,
for those post-MI patients with
a random total cholesterol
> 6mmol/l, a statin should be
started immediately, in addition
to dietary advice.8 Simvastatin
and pravastatin have been
shown to reduce mortality
in clinical trials.15,17
Treatment targets for patients
with established coronary heart
disease are to reduce total
cholesterol to < 5mmol/l and
LDL-cholesterol to < 3mmol/l.8
Alternatively, reducing
LDL-cholesterol by more than a
third is another evidence-based
approach to treatment.8
As a rough guide to relative
treatment effects, numbers
MeReC Bulletin Volume 10, Number 2, 1999
needed to treat (NNTs) for some
secondary prevention measures
are shown in table 2. Although
statins have a relatively low NNT,
they may be less cost-effective
than other drugs or lifestyle
changes.13 Decisions around
whether to treat patients with
a statin should be considered
in the context of these other
interventions, i.e. it is essential
that all suitable patients
receive aspirin and a betablocker as a first priority.
Interventions for secondary
prevention of MI
Mediterranean diet
Eating oily fish
Stopping smoking†
Statins
Beta-blockers
Aspirin
Number needed to treat (NNT)
for five years*
9
19
21
26
30
37
This table is based on patients who have a baseline CHD risk of 3%.
* These NNTs represent the number of people who need to be treated with an intervention
for five years to avoid one vascular death. When calculating NNTs, extrapolations may
have to be made from trials which last for less than five years. This may be important if the
event rate is not constant over time, as is the case after an MI.
† NNTs for smoking cessation are not strictly comparable with drug NNTs as the treatment
is only given once and the events prevented are counted over a lifetime.
Which interventions should only
be considered in certain patients? Table 2. Numbers needed to treat for different secondary prevention interventions.13
Angiotensin converting enzyme
(ACE) inhibitors
Trials of ACE inhibitors started
early post-MI have been combined in a systematic review
involving 98,496 patients.18
ACE inhibitors, started 0-36
hours post-MI and continued
for 4-6 weeks, significantly
reduced the absolute risk of
30-day mortality by 0.5%. Most
benefit was seen in the first week
post-MI and in high risk patients.
Significant reductions in
all-cause mortality were seen
in three trials involving patients
with left ventricular dysfunction,19,20 or clinical evidence of
heart failure.21 ACE inhibitors
were started 3-16 days post-MI
and continued for between 15
and 50 months. The absolute
risk reduction in mortality
seen with ACE inhibitors
ranged from around 4-8%.
Patients with left ventricular
dysfunction or clinical
evidence of heart failure are
most likely to benefit from
an ACE inhibitor. It is not clear
whether ACE inhibitors have a
class effect post-MI. If possible,
the drug chosen should be
titrated up to the doses used in
the trials, as listed in the BNF.
Anticoagulants
One trial showed that
anticoagulants reduce mortality
post-MI,22 whereas another found
no significant difference compared with placebo.23 The risks
of reinfarction and stroke were
also reduced, but there was an
increased risk of major bleeding
in the anticoagulant group
compared with placebo.
A combination of fixed low-dose
warfarin and aspirin showed no
significant advantage over aspirin
alone in a trial of 8,803 post-MI
patients.24 After 14 months,
no significant differences in
non-fatal MI, non-fatal ischaemic
stroke or cardiovascular death
were seen between those taking
the combination (1mg or 3mg
warfarin and 80mg aspirin daily)
and those taking aspirin alone
(160mg daily).
Although anticoagulants may be
beneficial post-MI, aspirin is first
choice in most patients because
of its lack of monitoring requirements, lower risk of side-effects
and low cost. Anticoagulants
should usually be reserved
for patients with a large anterior
infarction, left ventricular
aneurysm, chronic heart failure,
atrial fibrillation or systemic
embolic disease.8
Diltiazem and verapamil
Calcium-channel blockers
should not be used routinely
after myocardial infarction.
Although diltiazem and verapamil
have been investigated post-MI,
evidence of benefit is relatively
weak. They may be suitable
for patients without heart failure
who have continuing angina,
where beta-blockers are poorly
tolerated or contra-indicated.
Diltiazem has been shown to
reduce reinfarction in patients
with non-Q-wave MI over 14
MeReC Bulletin Volume 10, Number 2, 1999
days.25 However, no difference
in total mortality was seen
when diltiazem was compared
with placebo in a two year trial
involving 2,466 patients.26
Two double-blind, randomised
trials have investigated the use
of verapamil post-MI.27,28 The
first study compared verapamil
120mg three times daily with
placebo for 18 months in
1,775 patients.27 No significant
difference in total mortality was
seen between the two groups.
However, in the verapamil group
there was a statistically significant absolute risk reduction of
3.4% in the first major event
(death or reinfarction). A subgroup analysis of patients
without heart failure found a
significant reduction in death
and first major event in the
verapamil group.
The second study compared
modified-release verapamil
120mg three times daily with
placebo in 1,073 patients.28 There
was no significant difference in
total mortality between the
groups after three years.28 It
is important to note that both of
these studies were not powered to
detect a difference in mortality.
Amiodarone
The rationale for using
antiarrythmic drugs after MI
is that a large proportion of
late deaths are sudden and are
caused by ventricular fibrillation.
In a meta-analysis of 6,553
patients, 89% of whom had
a previous MI, amiodarone
reduced the absolute annual risk
7
of mortality by 1.4% compared
with placebo or no antiarrythmic
treatment.29 However, when this
result was adjusted for heterogeneity, the reduction in mortality
became non-significant.
In view of the above evidence,
use of amiodarone post-MI should
be reserved for suppression of
severe, symptomatic arrythmias
in selected patients.
Insulin
Diabetics are more likely to die
after an MI than non-diabetics.
In a trial involving 620 diabetics,
patients on an intensive regimen
of an insulin infusion followed
by subcutaneous injections,
showed an absolute risk
reduction in mortality of 11%
compared with the control
group.30 This effect continued for
three and a half years. However,
it was impossible to determine
whether the reduced mortality
was due to the initial infusion
or to the subsequent injections.
Local policies may need to
address follow-up care for
diabetic patients if they
are newly discharged from
hospital on insulin after an MI.
Which interventions should not be
used?
Dihydropyridine calcium-channel
blockers
There is no evidence that
dihydropyridine calcium-channel
blockers reduce mortality
or reinfarction post-MI. As
discussed in a previous MeReC
Bulletin (Vol. 9 No. 4), there are
some concerns that short-acting
dihydropyridines, such as
nifedipine, may actually increase
the risk of cardiovascular events.
There is no clear evidence that
this is the case with longer-acting
dihydropyridines. However, they
should be avoided in the initial
period post-MI if required for
patients with continuing angina.
Class I anti-arrythmic agents
following MI as they have been
associated with a significant
increase in mortality.31 Patients
who have frequent arrythmias
after an MI should be considered
for specialist investigation.
Conclusion
Effective, evidence-based
drug and lifestyle interventions
are available to prevent the
progression of coronary heart
disease after an MI. Lifestyle
measures such as stopping
smoking, adopting a healthier
diet, taking exercise and
use of cardiac rehabilitation
programmes should always
be considered alongside
drug treatment. Blood pressure
control is also beneficial post-MI.
All patients should take aspirin
and a beta-blocker after an MI
provided there are no contraindications. If there is evidence
of left ventricular dysfunction
or signs of heart failure then
ACE inhibitors are likely to
be beneficial. Lipid-lowering
therapy with statins, along with
dietary advice, should also be
considered in patients with raised
cholesterol levels.
References
1 Moher M. Evidence of effectiveness of
interventions for secondary prevention and
treatment of coronary heart disease in primary
care. NHS Executive Anglia and Oxford, 1995
2 Campbell NC, Thain J, et al. Secondary
prevention in coronary heart disease: baseline
survey of provision in general practice. BMJ
1998; 316: 1430-1434
3 Department of Health. National Service
Framework: coronary heart disease. Emerging
findings. DoH: London, November 1998
4 Daly LE, Mulcahy R, et al. Long term effect on
mortality of stopping smoking after unstable
angina and myocardial infarction. BMJ 1983;
287: 324-326
5 Burr ML, Fehily AM, et al. Effects of changes in
fat, fish and fibre intakes on death and
myocardial reinfarction: Diet and Reinfarction
Trial (DART). Lancet 1989; ii: 757-761
6 De Lorgeril M, Renaud S, et al. Mediterranean
alpha-linolenic acid-rich diet in secondary
prevention of coronary heart disease. Lancet
1994; 343: 1454-1459
7 NHS Centre for Reviews and Dissemination.
Cardiac rehabilitation. Effective Health Care
Bulletin 1998; 4(4): 1-12
8 British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society,
endorsed by the British Diabetic Association.
Joint British recommendations on prevention
of coronary heart disease in clinical practice.
Heart 1998; 80 (suppl 2): S1-S29
9 Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of
antiplatelet therapy-I: prevention of death,
myocardial infarction, and stroke by prolonged
antiplatelet therapy in various categories of
patients. BMJ 1994; 308: 81-106
10 CAPRIE Steering Committee. A randomised,
blinded, trial of clopidogrel versus aspirin in
patients at risk of ischaemic events (CAPRIE).
Lancet 1996; 348: 1329-1339
11 Yusuf S, Peto R, et al. Beta blockade during
and after myocardial infarction: an overview of
the randomized trials. Prog Cardiovasc Dis
1985; 27: 335-371
12 Pedersen TR for the Norwegian multicenter
study group. Six year follow-up of the
Norwegian multicenter study on timolol after
acute myocardial infarction. N Engl J Med
1985; 313: 1055-1058
13 NHS Centre for Reviews and Dissemination.
Cholesterol and coronary heart disease:
screening and treatment. Effective Heath Care
Bulletin 1998; 4(1): 1-16
14 Hebert PR, Gaziano JM, et al. Cholesterol
lowering with statin drugs, risk of stroke and
total mortality. JAMA 1997; 278: 313-321
15 Scandinavian Simvastatin Survival Study
Group. Randomised trial of cholesterol lowering
in 4444 patients with coronary heart disease:
the Scandanavian Simvastatin Survival Study
(4S). Lancet 1994; 344: 1383-1389
16 Sacks FM, Pfeffer MA, et al for the Cholesterol
and Recurrent Events Trial Investigators. The
effect of pravastatin on coronary events after
myocardial infarction in patients with average
cholesterol levels. N Engl J Med 1996; 335:
1001-1009
17 The Long-Term Intervention with Pravastatin in
Ischaemic Disease (LIPID) study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart
disease and a broad range of initial cholesterol
levels. N Engl J Med 1998; 339: 1349-1357
18 ACE inhibitor myocardial infarction collaborative group. Indications for ACE inhibitors in the
early treatment of acute myocardial infarction.
Circulation 1998; 97: 2202-2212
19 Pfeffer MA, Braunwald E, et al. Effect of captopril on morbidity and mortality in patients with
left ventricular dysfunction after myocardial
infarction. N Engl J Med 1992; 327: 669-677
20 Kober L, Torp-Pedersen C, et al. A clinical trial
of the angiotensin-converting-enzyme inhibitor
trandolapril in patients with left ventricular
dysfunction after myocardial infarction. N Engl
J Med 1995; 333: 1670-1676
21 The Acute Infarction Ramipril Efficacy (AIRE)
Study Investigators. Effect of ramipril on
mortality and morbidity of survivors of acute
myocardial infarction with clinical evidence of
heart failure. Lancet 1993; 342: 821-828
22 Smith P, Arnesen H, Holme I. The effect of
warfarin on mortality and reinfarction after
myocardial infarction. N Engl J Med 1990; 323:
147-152
23 Anticoagulants in the Secondary Prevention of
Events in Coronary Thrombosis (ASPECT)
Research Group. Effect of long-term oral
anticoagulant treatment on mortality and
cardiovascular morbidity after myocardial
infarction. Lancet 1994; 343: 499-503
24 Coumadin Aspirin Reinfarction Study (CARS)
Investigators. Randomised double-blind trial of
fixed low-dose warfarin with aspirin after myocardial infarction. Lancet 1997; 350: 389-396
25 Gibson RS, Boden WE, et al. Diltiazem and
reinfarction in patients with non-Q-wave
myocardial infarction. N Engl J Med 1986; 315:
423-429
26 The Multicenter Diltiazem Postinfarction Trial
Research Group. The effect of diltiazem on
mortality and reinfarction after myocardial
infarction. N Engl J Med 1988; 319: 385-392
27 The Danish Study Group on Verapamil in
Myocardial Infarction. Effect of verapamil on
mortality and major events after acute myocardial infarction (The Danish Verapamil Infarction Trial II-DAVIT II). Am J Cardiol 1990; 66:
779-785
28 Rengo F, Carbonin P, et al. A controlled trial of
verapamil in patients after acute myocardial
infarction: results of the Calcium Antagonist
Reinfarction Italian Study (CRIS). Am J Cardiol
1996; 77: 365-369
29 Amiodarone Trials Meta-Analysis Investigators.
Effect of prophylactic amiodarone on mortality
after acute myocardial infarction and in congestive heart failure: meta-analysis of individual
data from 6500 patients in randomised trials.
Lancet 1997; 350: 1417-1424
30 Malmberg K for the DIGAMI (Diabetes Mellitus,
Insulin Glucose Infusion in Acute Myocardial
Infarction) study group. Prospective randomised study of intensive insulin treatment on
long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ
1997; 314: 1512-1515
31 Teo KK, Yusuf S, Furberg CD. Effects of
prophylactic antiarrythmic drug therapy in
acute myocardial infarction. JAMA 1993; 270;
1589-1595
Class I antiarrythmics such as
Date of preparation: February 1999
flecainide should be avoided
 The National Prescribing Centre, The Infirmary, 70 Pembroke Place, Liverpool, L69 3GF.
Telephone: 0151-794 8146/8140/8143/8145 Fax: 0151-794-8139/44
8
MeReC Bulletin Volume 10, Number 2, 1999
`