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European Heart Journal 17 {Supplement F), 30-36
Secondary preventive potential of nitrates in
ischaemic heart disease
U. Thadani
Division of Cardiology, Department of Medicine, University of Oklahoma, Health Sciences Center, Oklahoma City,
Oklahoma, U.S.A.
due to the smaller doses of nitrates used and the diluting
effect of the widespread use of open-label nitrates in the
placebo group. In patients with congestive heart failure,
including those of ischaemic aetiology, nitrates together
with hydralazine have clearly demonstrated a significant,
reduction in the medium term mortality risk.
Introduction
This review will concentrate on their therapeutic attributes in the treatment of ischaemic heart disease,
critically examine the results of clinical trials with regard
to the secondary preventative potential of these drugs
and offer recommendation regarding the use of nitrates
in the various myocardial ischaemic syndromes.
Nitrates are widely recognised as clinically efficacious
for the treatment of acute and chronic myocardial
ischaemic syndromes'1^1. Their potent dilatation of the
systemic resistance vessels and venous capacitance system reduces dilatation of the ischaemic ventricle and
enhances blood flow to ischaemic sub-endocardial
regions'5"81. Nitrates also directly dilate epicardial coronary arteries and particularly those with eccentric
stenoses. However, it is still controversial whether these
drugs reduce the morbidity and mortality risks of patients with stable or unstable angina pectoris or of
survivors of acute myocardial infarction'4'9"151. Nitrates
are, however, amongst the safest of drugs currently used
in the treatment of ischaemic myocardial syndromes.
Nitrates have the undoubted ability, probably greater than
any other single anti-anginal drug, to rapidly and often
completely relieve the pain and breathlessness associated
with myocardial ischaemia. They are haemodynamically
efficacious in reducing dilatation of the ischaemic left
ventricle and enhancing coronary blood flow to ischaemic
areas. Although their preventative impact in survivors of
acute myocardial infarction awaits clarification, they have
been shown in combination with hydralazine to extend
survival in patients with congestive heart failure, including
those of ischaemic origin.
(Eur Heart J 1996; 17 (Suppl F): 30-36)
Key Words: Ischaemic heart disease, angina, myocardial
infarction, heart failure, nitrates.
Rationale of nitrate therapy for
secondary prevention
(a) Mechanism of anti-ischaemic effects of
nitrates
Nitrates reduce myocardial oxygen demand by their
systemic vasodilator activity*5'16'17' (Table 1). At the
same time, they increase coronary blood flow preferCorrespondence: Professor Udho Thadani, Cardiology Section,
6 7 18 2 1
University of Oklahoma, HSC, 920 Stanton Young Blvd 5SP-300, entially to ischaemic subendocardial regions' ' ' " '
(Table 2). Due to their unique ability to increase
Oklahoma City, OK 73104, U.S.A.
0195-668X/96/0F0O36+O7 $25.00/0
© 1996 The European Society of Cardiology
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Nitrates exert their anti-anginal activity by a number of
mechanisms. By reducing venous return and left ventricular
end-diastolic pressure they lower myocardial oxygen demand and at the same time enhance blood flow to the
sub-endocardium. They also directly increase myocardial
oxygen supply by dilating the coronary artery stenoses and
increasing collateral blood flow. These pharmacodynamic
attributes are clinically efficacious in all the ischaemic
myocardial syndromes. In stable angina pectoris, nitrates
reduce myocardial ischaemia and ischaemic pain and increase exercise tolerance. In unstable angina, nitrates similarly reduce electrocardiographic evidence of myocardial
ischaemia and relieve anginal pain. Following acute myocardial infarction, nitrates reduce ventricular dilatation and
by so doing reduce pulmonary congestion and mitral regurgitation. The weak anti-aggregatory effect of nitrates on
platelets may also play an adjuvant role in their antiischaemic activity. Early small-scale studies with both intravenous and oral nitrates demonstrated a trend to
reduced mortality and reinfarction in survivors of acute
myocardial infarction. However, the later and larger ISIS-4
and GISSI-3 trials have not confirmed this trend possibly
Preventative potential of nitrates in IHD
Table 1 Effects of nitrates on haemodynamics
MVO2 reduction
jPreload
JVenous return
|LV and RV size
|LV and RV pressure
JWall stress
lAfterload
iSystolic pressure
tAortic compliance and conductance
ISystolic wall stress
Table 2 Effects of nitrates on coronary blood flow
Increased flow to ischaemic areas
Dilation of epicardial vessels
Dilation of atherosclerotic eccentric stenoses
Vasodilation despite endothelial dysfunction
Decrease LV end-diastolic pressure
Collateral flow increase
Prevention of coronary artery spasm
Anti-aggregatory
Anti-adhesion
Decreased thrombus formation
Decreased platelet thrombus induced vasoconstriction
collateral blood flow117-18'2'1, dilate coronary eccentric
stenoses'61, and reduce left ventricular end-diastolic
pressure at rest and during exercise1'91, these agents
preferentially increase blood flow to the vulnerable
subendocardial regions.
Recent studies suggest that nitrates may possess
further preventative qualities (Table 3). Both in vitro
and in vivo they have been shown to reduce platelet
aggregation, deposition, and adhesion to injured endothelium and thus have the potential to decrease
thrombus formation'22"26'. However, it is unknown if
these anti-platelet effects of nitrates summate with those
of aspirin, another potent platelet anti-aggregating agent
frequently used in ischaemic syndromes. In theory at
least, the potential of added beneficial effects of nitrates
in patients receiving aspirin remains a distinct possibility as nitrates exert their effects on platelets via the
production of nitric oxide1271 while aspirin inhibits
cyclooxygenase128'.
(b) Effects of nitrates on remodelling and
left ventricular dilation following an acute
myocardial infarction
Left ventricular hypertrophy and chamber dilation commonly follow acute myocardial infarction and adversely
affect prognosis'29"34'. Similar to angjotensin converting
enzyme inhibitors'35'361 nitrates may prevent or retard
remodelling of the dilated infarcted ventricle137"421. In
animal studies early post-infarct treatment with intravenous nitrates has been shown to reduce infarct size
and maintain left ventricular geometry and function
by preventing remodelling1411. In patients with anterior
myocardial infarction, intravenous nitroglycerin has
also been shown to improve haemodynamics, prevent left ventricular dilation and reduce ventricular
arrhythmias140'421.
Nitrates in angina pectoris
(a) In stable angina
Nitrates improve exercise performance and reduce
exercise-induced myocardial ischaemia143'441. Despite
reports of the diminished efficacy of nitrates due to the
development of tolerance145"471, when used appropriately
nitrate tolerance can be minimized or avoided'48"5'1. In
this regard, mononitrate has an advantage over other
agents as it has a rapid onset of action and intermittent
twice-a-day treatment is not associated with a rebound
increase in nocturnal or early morning angina'49'501 a
phenomenon reported with intermittent patch treatment'481. However, it is unknown if long-term use of
nitrates reduces morbidity and mortality risk in patients
with stable angina pectoris.
(b) In unstable angina
Intravenous nitroglycerin relieves myocardial ischaemia
and chest pain in many patients with unstable
angina'52*531. During this acute phase of ischaemic heart
disease, nitrates have a high safety record but it is
unknown whether they reduce subsequent morbidity or
mortality risk'531. Tolerance to intravenous nitroglycerin
frequently develops but can be overcome by dose
escalation and clinical benefit maintained for at least
48-72 h'53"551.
Nitrates in acute myocardial infarction
Nitrates are efficacious in relieving acute pulmonary
congestion and pulmonary oedema following acute
myocardial infarction'5*1. Both in animals and in
patients, intravenous nitroglycerin has been shown
to reduce infarct size and ischaemic mitral regurgitation'38"41' 57"59]. This has been attributed to the prevention of ventricular remodelling129'301. Nitrates rapidly
relieve anginal pain in the post-infarct period and
reduce electrocardiographic evidence of myocardial
ischaemia'601. It remains to be determined whether
nitrates prevent reinfarction, reduce the risk of development of congestive heart failure and lower increased
mortality risk following myocardial infarction'9"16'6'1.
Eur Heart J, Vol. 17, Suppl F 1996
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Table 3 Effects of nitrates on platelet function
31
32
U. Thadani
(a) CAPTOPRIL comparison
Placebo:
2231/29022 (7.69%)
Captopril:
2088/29028(7.19%)
BENEFIT per 1000:4.9 (SD 2.2)
2500 -
(b) MONONITRATE comparison
Placebo:
2190/29023 (7.54%)
Mononitrate: 2129/29018 (7.34%)
BENEFIT per 1000: 2.1 (SD 2.2)
2500
Placebo
Placebo
_—-••'-
2000
2000
rTjj-" Mononitrate
1500
1500
J
Q
1000
1000
X
500
f
n
1
V
better
500
1
1
1
14
21
better
f
1
1
n
0
28
35
Days from randomization
1
1
1
14
21
28
35
Early studies in a small number of patients
showed that intravenous nitroglycerin reduced infarct
size and infarct-related complications, particularly when
administered within 10 h of onset of chest pain'56'58'62'631.
In one study there was a marked reduction in infarctrelated complications in patients treated with intravenous nitroglycerin compared to placebo141 an improvement that was greatest in those with large anterior
infarctions'401. In contrast, another study failed to show
any significant influence of nitrates on infarct size,
reperfusion and ventricular remodelling1661.
An overview of early randomized trials showed a
24% reduction in morbidity and mortality but this
has not been confirmed by later trials'9'. In the ISIS-4
study, the 35 day mortality in 29 032 patients who
received placebo was 7-45% compared to 7-34% in the
29 018 patients who received once daily 60 mg of oral
long-acting mononitrate'151. This difference was not
statistically significant (Fig. 1). Long-term follow-up of
patients treated with mononitrate demonstrated a saving
of life at 6 months of 2-9/1000 patients treated and at 12
months a saving of 1-8/1000 patients treated, but significantly less than the saving of 4-9/1000 patients treated
with captopril (Fig. 2). The small effect seen in the
patients receiving slow release mononitrate may have
been the result of the dose and the formulation of the
medication used. In the ISIS Study, a 60 mg daily dose
of slow release mononitrate was used'151, but in a recent
study in patients with stable angina pectoris this dose
was no different from placebo'5'1.
Eur Heart J, Vol. 17, Suppl F 1996
In the GISSI-3 trial, patients were treated with
either a nitrate preparation (nitroglycerin patch or
mononitrate), placebo, lisinopril, or a combination of
lisinopril plus nitrates'141. Patients received intravenous
nitroglycerin during the first 24 h followed by treatment
with long-acting nitrates. There was a small but statistically non-significant reduction in mortality in the nitrate
group compared to the placebo group (Fig. 3). In the
patients given nitrates in addition to lisinopril, there was
a significant reduction in mortality which was greater
than that observed in the lisinopril or nitrate groups
alone.
In both the ISIS and G1SSI trials, more than
50% of patients in the placebo group received open-label
nitrates which may have diluted the beneficial effect of
nitrates in both studies. Molsidomine, a nitric oxide
donor has also been shown to have no beneficial effects
in this situation'671.
Clinical efficacy of nitrates in
congestive heart failure
Isosorbide dinitrate often improves symptoms particularly breathlessness in patients with congestive heart
failure1681. In combination with hydralazine, it has been
shown to improve the central haemodynamics and significantly reduce the mortality risk in patients with mild
to moderately severe heart failure'69701. These benefits
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Figure 1 Cumulative mortality reported in days 0-35 in the ISIS-4 trial, (a) All
patients allocated one month of oral captopril (thicker line) vs all allocated matching
placebo; (b) all patients allocated one month of oral controlled-release mononitrate
(thicker line) vs all allocated matching placebo (Reproduced with permission'151.)
Preventative potential of nitrates in IHD
33
(a) CAPTOPRIL comparison
(b) MONON1TRATE comparison
Month 6 Month 12
Month 6 Month 12
Placebo:
90.13%
88.01%
Mononitrate:
89.95%
87.83%
Captopril:
89.47%
87.47%
Captopril:
89.65%
87.65%
BENEFIT per 1000: 6.6 (SD 2.6) 5.4 (SD 2.8) BENEFIT per 1000: 2.9 (SD 2.6) 1.8 (SD 2.8)
1001
1
100 i
12
0
Months from randomization
22190
22019
Captopril:
Placebo:
Mononitrate: 22131
Placebo:
22078
16623
16543
Cumulative late mortality in ISIS-4 trial. (Reproduced with permission1151.)
100
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Figure 2
16563
16503
100
p (log-rank) = 0.03
p (log-rank) = 0.27
94
92
I
0
14
21
28
Control
_|
35
42
Control
92
J_
0
_L
_L
14
21
_L
28
35
42
Time after AMI (days)
Lisinopril
Nitrates
9435 9088 8948 8838 8759 8596 7625
9453 9088 8959 8839 8758 8599 7600
Control
9460 9048 8897 8783 8707 8537 7553
Control
9442 9048 8886 8782 8708 8534 7578
Figure 3 Early (6 week) survival in the GISSI-3 trial for the nitrate and ACE inhibitor groups
(Reproduced with permission1'41.)
Eur Heart J, Vol. 17, Suppl F 1996
34
U. Thadani
Randomized
comparison
Deaths/patients (% dead)
Nitrates
Control
11 small iv trials
190/1505
(12.6%)
76/998
(7.6%)
232/1500
(15.5%)
91/960
(9.5%) "
332/4731
(7.0%)
285/4722
(6.0%)
34 ly'4729
(7.2%)
312/4713
(6.6%)
1085/14519
(7.2%)
1044/14499
(7.2%)
1146/14503
(7.9%)
1044/14529
(7.2%)
3012/40974
(7.35%)
3166/40934
(7.73%)
9 small oral trials
GISSI-3
- N us nil
- N + CEI vs CEI
Odds ratio and CI
Nitrates i Control
better
better
ISIS-4
— N VS nil
- N + CEI vs CEI
ALL TRIALS
5.5% (SD 2.6) odds
reduction; 2P = 0.03
3.8 (SD 1.8) fewer deaths per 1000 treated
_L
0.5
0.75
1.0
1.25
Test for heterogeneity:
-between 20 small trials and 2 larger trials: x\ = 5-2; P = 0.02
-between GISSI-3 and ISIS-4: %\ = °- 2 ; as
were seen in both ischaemic and non-ischaemic heart
failure.
Recommendations for the use of
nitrates in the syndromes of ischaemic
heart disease
Nitrates play an important role in the management of
patients with acute and chronic ischaemic syndromes.
They are effective in relieving anginal pain and electrocardiographic evidence of myocardial ischaemia both in
patients with unstable angina and those with chronic
stable angina. In post-infarction survivors, nitrates are
associated with a small reduction in mortality risk (Fig.
4). Thus, it is prudent to use nitrates selectively in
patients with acute myocardial infarction who are at
maximum risk, i.e. those with large anterior infarction,
those with acute pulmonary oedema or signs of pulmonary congestion, those with elevated blood pressure and
those with post-infarct angina. Nitrates should not be
used in patients with right ventricular infarction'7'1 or
those who are volume depleted or hypotensive, in whom
their deleterious effects potentially outweigh their
benefits1721.
Eur Heart J, Vol. 17, Suppl F 1996
The question remains — do nitrates have a role
in secondary prevention? Their unique mechanisms of
pharmacodynamic activity, their ability to reduce
remodelling of the ischaemic left ventricle and perhaps
even their antiplatelet activity, suggest a role for their
potential in this respect. Whether further trials will be
mounted to address this important issue is problematic.
Fortunately, from the clinical standpoint, the nitrates as
a group are symptomatically efficacious and above all
safe when used to treat patients with ischaemic heart
disease from angina through myocardial infarction to
heart failure.
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Preventative potential of nitrates in IHD
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Eur Heart J, Vol. 17, Suppl F 1996
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