Download Pharmacological treatment of ischaemic heart disease

European Heart Journal (1997) 18 (Supplement B), B27-B34
Pharmacological treatment of ischaemic heart
disease
Monotherapy vs combination therapy
P. F. Cohn
Department of Medicine, Division of Cardiology, State University of New York Health Sciences Center,
Stony Brook, New York, U.S.A.
Non-invasive treatment continues to be the mainstay of
anti-ischaemic therapy. The imbalance between myocardial
oxygen supply and demand provides the basis for myocardial ischaemia, which may present as symptomatic, asymptomatic or, in most cases, a mixture of the two. Both
symptomatic and silent ischaemia are major prognostic
indicators in patients with coronary artery disease and
treatment should therefore be directed towards both the
amelioration of symptoms and the resolution of the signs of
ischaemia. Anti-ischaemic therapy may decrease oxygen
demand, increase myocardial oxygen supply, or both. Interventional therapies, such as percutaneous transluminal coronary angioplasty and bypass grafting, improve supply but
do not alter demand. Drug therapy is associated with a
variety of effects upon both supply and demand, depending
upon the agent used. Nitrates alter both myocardial oxygen
supply and demand, while /?-blockers decrease myocardial
oxygen demand. Calcium channel blockers reduce afterload and myocardial contractility and, thus, lower oxygen
demand, while the coronary artery relaxation that occurs in
response to their use acts to increase supply. The use of
combination therapy, is considered by many to be the
most rational approach to the treatment of myocardial
ischaemia, in that it allows maximal reduction in demand
and increase in supply.
(Eur Heart J 1997; 18 (Suppl B): B27-B34)
Key Words: Ischaemic heart disease, /7-blockers, calcium
channel blockers, nitrates, combination therapy.
factor that causes an increase in myocardial oxygen
demand or a reduction in myocardial oxygen supply can
Despite the increasing popularity of interventional pro- provoke ischaemia. Myocardial oxygen requirements
cedures, non-invasive treatment continues to be the rise with increases in heart rate, contractility or left
mainstay of anti-ischaemic management. Many cardi- ventricular wall stress. Myocardial oxygen supply is
ologists regard combined administration of conven- determined by coronary blood flow and myocardial
tional anti-anginal medications (including nitrates, oxygen extraction, with the latter normally being near
^-blockers and calcium channel blockers) to be a more maximal at rest.
rational approach to the management of patients with
For some time, residual coronary flow reserve
angina than single-agent therapy. The rationale for this was thought to remain constant in the presence of a fixed
therapeutic strategy is based primarily on our knowledge atherosclerotic obstruction. However, Maseri proposed
of the pathophysiology of myocardial ischaemia and the that residual coronary flow reserve is not fixed, but
mechanism of action of the various anti-ischaemic rather is subject to variations throughout the day in
drugs.
response to dynamic changes in vasomotor tone12'.
Although residual coronary flow reserve still has an
upper limit, this value fluctuates in response to changes
Pathophysiology
in resistance at the site of flow-limiting stenoses.
Ischaemic episodes continue to occur at high levels of
The imbalance between myocardial oxygen supply and
demand (such as with physical exertion) when that
myocardial oxygen demand is viewed as the pathodemand exceeds the maximal residual coronary flow
physiological basis of myocardial ischaemia'11. Any
reserve, but ischaemia may also occur at lower levels of
energy
consumption due to a transient reduction in flow
Correspondence: Dr Peter F. Cohn, Cardiology Division, Health
Sciences Center (T-17-020), Stony Brook, New York 11794-8171, reserve. Episodes of intense vasoconstriction can impair
resting coronary flow, resulting in ischaemia at rest.
U.S.A.
Introduction
0195-668X/97/0B0027+08 $18.00/0
1997 The European Society of Cardiology
B28
P. F. Cohn
Table 1 New England Deaconess Hospital angina survey
Response
Question
1.
2.
3.
4.
5.
6.
7.
8.
9.
Yes
Do you ever nave angina when you are at rest?
Does your angina sometimes occur at varying levels of exertion?
Do you ever have angina when you are under emotional stress?
Do you ever have angina that awakens you from sleep?
Do you ever have angina with exposure to cold air in the
absence of physical activity?
Do you ever have angina with exposure to cold air at a level of
exertion that could be performed free of pain at a warmer
temperature?
Do you ever have angina immediately after a meal?
Does the time of day influence the development of angina for
any particular activity?
Is your angina predictable; in other words, do episodes of
anginal pain or discomfort occur at the same level of exertion?
No
n
%
n
%
64
75
64
31
33
58
68
58
28
30
46
35
46
79
77
42
31
42
72
69
52
47
58
52
36
23
33
21
74
87
67
78
51
46
59
Reproduced from Nesto et a/.[4) with permission.
Ischaemia induces haemodynamic changes during both
systole and diastole. These changes include an increase
in left ventricular end-diastolic pressure, a decrease in
cardiac output, an increase in diastolic stiffness and the
development of left ventricular wall motion abnormalities. The electrocardiographic effects of myocardial
ischaemia include not only the ST-segment and Twave changes typical of subendocardial or transmural
ischaemia, but also arrhythmias.
Clinical syndromes
Most ischaemic states are a mixture of symptomatic
episodes, associated with anginal pain, and asymptomatic episodes, characterized by ST-segment depression
in the absence of pain. At present, there is no clear
explanation for the occurrence of pain during some
ischaemic episodes and the absence of pain during
others'31.
Clinical data support the concept of mixed
angina (or ischaemia), as well as the traditional stable
and unstable forms of disease. For example, a survey by
Nesto et a/.'41 documented symptoms of mixed ischaemia
in a high percentage of 110 consecutive patients with a
diagnosis of stable angina pectoris (Table 1). Angina
occurred at rest in 64 (58%) of these patients and at
varying levels of exertion in 75 (68%). Thirty-one
patients (28%) reported being awakened from sleep by
anginal pain and 52 (47%) experienced angina at lesser
levels of exertion upon exposure to cold air. These
findings suggest individual variations in the degree of
vasoconstriction and the responsiveness of the fixed
lesion.
Cardiologists have focused considerable attention on the factors responsible for the conversion of a
chronic stenotic lesion to an active lesion, i.e. the
transition from stable to unstable ischaemia. This
Eur Heart J, Vol. 18, Suppl B 1997
process is most likely attributable to disruption of
the luminal surface of an atherosclerotic plaque. The
probable mechanisms of acute myocardial ischaemia
include haemorrhage and rupture of the atheromatous
plaque, subsequent formation of an intravascular
thrombus, dynamic alterations in coronary tone and
rapid progression of atherosclerotic lesions'51. These
latter alterations may range from minor vasomotor
changes to total spastic occlusion that may be caused, at
least in part, by local platelet aggregation with the
release of vasoactive substances. Disruption of normal
hormonal balance and impaired coagulation homeostasis resulting from damage to the endothelium may
lead to thrombosis, spasm or both. As the disease
progresses to acute ischaemia, these events may occur
independently or in combination.
Treatment of myocardial ischaemia
Why treat ischaemia? Besides relieving angina, is there
any benefit to relieving ischaemia per se? Studies
employing exercise testing, thallium-201 perfusion
scanning and left ventricular imaging have clearly
documented the adverse prognostic implications of
myocardial ischaemia. Results of these investigations
show that both silent and painful ischaemia are major
prognostic factors in patients with coronary artery
disease (CAD)'61. It is reasonable, therefore, that the
treatment of ischaemia should be directed towards both
the amelioration of anginal symptoms and the resolution
of signs of ischaemia, as documented by the objective
tests outlined above.
The findings of one small study suggested that
such treatment may indeed have a favourable effect on
outcome'71. In this investigation, adverse cardiac events
occurred during a 9-month follow-up period in only
one (8%) of 12 patients in whom episodes of painless
Ischaemic heart disease: mono vs combination therapy
ischaemia were controlled by anti-ischaemic medication.
In contrast, such events occurred in 10 (45%) of 22
patients in whom pharmacological treatment failed to
eliminate episodes of silent ischaemia. Larger multicentre trials are currently underway to establish the
effect of the treatment of ischaemia per se on prognosis.
One of them, the Atenolol Silent Ischemia Trial
(ASIST)t8), has been completed and has demonstrated a
beneficial effect of atenolol compared with placebo in
reducing morbidity associated with ischaemia.
Medical vs surgical therapy
Anti-ischaemic medications eliminate or reduce angina
by decreasing myocardial oxygen demand, increasing
myocardial oxygen supply, or both. They do not correct
the underlying cause of ischaemia, although regression
of atherosclerosis has been reported with aggressive
lipid-lowering regimens in studies such as the Cholesterol Lowering Atherosclerosis Study (CLAS)'9-101,
the Monitored Atherosclerosis Regression Study
(MARS)1111 and the Familial Atherosclerosis Treatment
Study (FATS)[12). Mechanical approaches to the treatment of myocardial ischaemia do not alter myocardial
oxygen demand but do improve myocardial oxygen
supply by relieving or circumventing the atherosclerotic
obstruction responsible for anginal symptoms. Initially
successful coronary artery bypass grafting and percutaneous transluminal coronary angioplasty (PTCA),
however, may be followed by the recurrence of angina
due to graft occlusion, restenosis post angioplasty or the
progression of CAD.
Recommendations regarding surgical as compared with medical management of angina are based on
the results of large, comparative, multicentre trials sponsored by different sources'13"151. These trials provided no
evidence to indicate that surgical treatment is superior to
medical treatment in increasing longevity in patients
with mild anginal symptoms and those with one or two
diseased coronary arteries. For this reason such patients
are best treated medically. Surgery has been shown to be
more effective than medical therapy in increasing longevity in symptomatic and asymptomatic patients with
significant stenosis of the left main coronary artery1161.
Surgical management may also be preferable to medical
therapy in patients with triple-vessel disease, regardless
of symptoms, especially in those with continuing ischaemia and impaired left ventricular function. Surgery is
also recommended for patients with angina that fails to
respond to medical therapy. Comparison of coronary
angioplasty with bypass surgery has shown no clearcut
advantage in terms of morbidity and mortality1171.
Anti-ischaemic drugs
Three drug classes, nitrates, /?-blockers and calcium
channel blockers, are currently approved by the U.S.
Food and Drug Administration for use in the treatment
B29
of angina pectoris'181. The anti-ischaemic effectiveness of
each of these three classes in an individual patient will
vary depending on the underlying cause or causes of
ischaemia. Drugs that reduce myocardial oxygen consumption would be expected to be a particularly rational
choice for the management of ischaemic episodes caused
exclusively by an increase in myocardial oxygen
demand, such as with physical exertion. Agents that act
to reduce coronary vasomotor tone are most likely to be
beneficial in the management of ischaemia caused by a
reduction in myocardial oxygen supply. In patients with
mixed angina, anti-ischaemic medications that affect
both myocardial demand and supply may be most
appropriate. The other pharmacological properties of
anti-ischaemic drugs, as well as their associated side
effects and interactions, are also important considerations in the selection of an optimal pharmacological
approach to the treatment of angina in an individual
patient.
Nitrates
These are the oldest of the available agents. Organic
nitrates have been used for the relief of anginal symptoms for more than 100 years and remain the cornerstone of angina therapy today. In addition to their
clinical efficacy in the management of symptomatic and
asymptomatic angina, nitrates generally are well tolerated. Nitrate-induced side effects typically are seen in the
early phase of treatment and tend to resolve as therapy
continues. Nitrates are also less expensive than many
of the anti-ischaemic medications introduced in more
recent years.
The diverse pharmacological actions of nitrate
compounds result in alterations in both myocardial
oxygen supply and demand, making these drugs especially useful in the treatment of myocardial ischaemia
related to decreased supply, increased demand, or both.
When given in low doses, nitrates produce venodilation
and venous pooling with decreased venous return. As a
result, left ventricular volume (pre-load) and pressure
and diastolic wall tension are reduced and myocardial
oxygen demand is lowered'191. Larger nitrate doses cause
some degree of arterial vasodilation, thereby lowering
peripheral vascular resistance and left ventricular
systolic wall tension and further reducing myocardial
demand. In addition, nitrates dilate epicardial coronary
arteries, improve coronary collateral flow and reverse
coronary artery spasm, effects that result in an improvement in coronary blood flow. More recent data suggest
that nitrates may also have anti-platelet and antithrombotic properties1201 which, if confirmed, could have
particular relevance for the management of angina
related to an acute decrease in coronary blood
flow. Both the vasodilatory action of nitrates and the
proposed anti-platelet effect of these drugs are believed
to involve nitric oxide. Nitric oxide, which is now known
to be identical to endothelium-derived relaxing factor1211,
is formed in the vascular smooth muscle membrane
as a result of the interaction of nitrates with reduced
sulfhydryl groups.
Eur Heart J, Vol. 18, Suppl B 1997
B30 P. F. Cohn
Nitrates are available in a wide range of formulations and delivery systems. Sublingual tablets containing nitroglycerin or isosorbide dinitrate have a very rapid
onset of effect but a short duration of action that limits
their use to the arrest of acute anginal attacks or the
prevention of anticipated attacks. Transdermal patches
containing nitroglycerin and oral isosorbide dinitrate
formulations are more appropriate for the long-term
prophylactic treatment of patients with chronic angina.
Isosorbide-5-mononitrate, an active metabolite of isosorbide dinitrate, is a newer oral nitrate preparation also
indicated for the long-term management of angina. In
contrast to isosorbide dinitrate, which is extensively
metabolized in the liver, isosorbide-5-mononitrate is not
subject to first-pass hepatic extraction. As a result, the
bioavailability of isosorbide-5-mononitrate approaches
100% compared with 19-26% for oral isosorbide dinitrate1221. The lack of hepatic metabolism of isosorbide5-mononitrate reduces the marked inter-individual variations in peak plasma nitrate concentrations reported
with isosorbide dinitrate.
Nitrate tolerance, manifested by diminution of
the haemodynamic or anti-anginal effects of therapy, is a
major problem. Tolerance may occur as early as 24 h
after initiation of treatment with continuous transdermal1231 or i.v.[24) administration and has been reported
within 1-4 weeks of the initiation of treatment with a
three- or four times daily oral nitrate regimen1251. Nitrate
tolerance can be prevented by the use of intermittent
dosing schedules that allow for a prolonged nitrate-free
interval. In the case of transdermal formulations, the
optimal regimen appears to be a 12-14-h period of patch
application, followed by an 'off' period of 10-12-h,
usually during the night. Eccentric, as opposed to concentric, dosing schedules appear to be most effective in
preventing tolerance to oral nitrate formulations.
$-adrenergic blockers
/?-adrenergic blockers are effective in reducing both
symptomatic and silent myocardial ischaemia'26"281.
Competitive inhibition of /?-adrenergic receptors in
cardiac tissue represents the principal mechanism
responsible for the anti-ischaemic effect of this class of
drugs. The resulting reductions in heart rate, blood
pressure and cardiac contractility decrease myocardial
oxygen demand129'. While the negative chronotropic and
negative inotropic effects are integral to the therapeutic
activity of ^-blockers, these properties do contraindicate the use of these agents in patients with advanced
heart block, symptomatic bradycardia, low cardiac output and severe left ventricular impairment. Among the
less desirable consequences of /^-blockade is an increase
in left ventricular dilation. The resulting increase in
myocardial oxygen demand may counteract the beneficial effect of the other haemodynamic changes
induced by these drugs1'91.
In general, however, these drugs have little effect
on increasing myocardial oxygen supply. In fact, unopposed a-adrenergic stimulation as a result of fiblockade can precipitate coronary spasm, thereby
Eur Heart J, Vol. 18, Suppl B 1997
decreasing coronary blood flow and worsening anginal
symptoms. For this reason, a nitrate or a calcium
channel blocker is preferred over a y?-blocker for the
treatment of patients in whom coronary artery spasm is
believed to be an important component of the ischaemic
syndrome.
A large number of /^-blocking drugs have been
developed since the introduction of propranolol in the
1960s. These various agents appear to be equivalent in
terms of their anti-anginal efficacy but vary in such
properties as relative ftx selectivity, intrinsic sympathomimetic activity and lipophilicity. These differences can
be important in selecting a specific ^-blocker for use in
an individual patient. For example, /?-blockers with a
high level of f}2 blockade can produce bronchoconstriction and vasoconstriction and are, therefore, inappropriate for the management of patients with either
obstructive airways diseases or peripheral vascular
disease, respectively. Antagonism of /?2 receptors also
complicates the use of non-cardio-selective ^-blockers
in patients with diabetes mellitus. Lipophilic ^-blockers
are more likely to cross the blood brain barrier than
hydrophilic compounds and, therefore, have a greater
potential for central nervous system side effects.
Calcium channel blockers
The calcium channel blockers are a chemically diverse
group of compounds that can be categorized into three
separate classes: the phenylalkylamines (verapamil), the
benzothiazepines (diltiazem) and the dihydropyridines
(nifedipine, nicardipine, amlodipine, felodipine). These
agents have a common mechanism of action, namely the
inhibition of the influx of calcium ions into myocardial
and vascular smooth muscle tissue. The vasorelaxation
induced by calcium channel blockade lowers peripheral
vascular resistance (afterload), thereby reducing myocardial oxygen demand'191 which may be further decreased
by a reduction in myocardial contractility by some calcium channel blockers. The coronary artery relaxation
that occurs in response to calcium channel blocker
therapy improves coronary blood flow, thus increasing
myocardial oxygen supply. The anti-ischaemic effects of
these drugs are often impressive, especially the newer
agents such as amlodipine (Fig. l) [30) .
Although all calcium channel blockers share a
common mechanism of action, there are important
pharmacological distinctions among the different classes
of compounds. The dihydropyridines differ considerably
in terms of the speed of their onset and offset of action
and their duration of action. Those with a more rapid
onset of action, in terms of vasodilation, e.g. nifedipine,
are associated with a higher incidence of side effects
related to acute peripheral vasodilation, such as flushing,
hypotension, orthostatic dizziness, postural syncope
and headaches'311. Reflex sympathetic stimulation in
response to rapid vasodilation may also cause a increase
in heart rate1321.
In contrast, amlodipine is a once-daily dihydropyridine with pharmacokinetic properties that confer a
gradual onset and offset of action and a long duration
Ischaemic heart disease: mono vs combination therapy
of action (plasma elimination half-life 35-50 h). A
summary of the results from 1775 amlodipine-treated
patients and 1213 placebo-treated patients in doubleblind trials has indicated that apart from oedema (9-8%
and 2-3% of patients, respectively) and flushing (2-4%
00
B31
and 0-5%, respectively) the vasodilator effects profile of
amlodipine was not significantly different from that
of placebo1311.
Verapamil has the most pronounced negative
inotropic effect, which complicates its use in patients
with reduced cardiac output but makes it particularly
appropriate for the management of angina in patients
with obstructive cardiomyopathy. Verapamil also has
the most potent depressant effect on the sinoatrial and
atrioventricular nodes, which accounts for its clinical
utility in the treatment of supraventricular tachycardia.
Diltiazem has a more moderate effect on cardiac conduction and the dihydropyridines have no effect. The
particularly marked inhibitory effect of verapamil on
smooth muscle contraction is responsible for the higher
incidence of constipation in patients treated with
this calcium channel blocker. The above mentioned
properties of verapamil and diltiazem can create
problems in patients with ventricular dysfunction,
heart block, etc.
Anti-ischaemic drugs in combination
Amlodipine
Placebo
The complementary mechanisms of action of the various
classes of anti-ischaemic medications suggest that their
use in combination may result in a greater reduction
in myocardial oxygen demand and increase in oxygen
supply than that achieved with any one of these agents.
In addition, the pharmacological actions of some drugs
may serve to offset the undesirable side effects associated
with others.
Nitrates plus fi-blockers
The nitrates, which act primarily by causing peripheral
vasodilation, and the /?-blockers, which act principally
by reducing heart rate and myocardial contractility,
are a logical choice for combined administration. The
enhanced anti-anginal efficacy of a nitrate//?-blocker
combination was first demonstrated nearly 30 years ago
in a double-blind, crossover study in which patients with
severe angina pectoris were treated with 40-80 mg of
oral propranolol four times daily, 5 mg of sublingual
isosorbide dinitrate four times daily or the two drugs in
combination'331. Isosorbide dinitrate alone and propranolol alone each completely prevented anginal pain
during exercise testing in eight (29%) of the 28 patients
studied. With combination therapy, however, none
200
Amlodipine
Placebo
Figure 1 Comparison of frequency of transient myocardial ischaemia during initial and final monitoring. Dark
hatched areas • denote initial frequency and light hatched
areas • the frequency at week 9, #
•& show the
median, A
A the 75th percentile and O
O the 25th
percenrile. Amlodipine produced a significantly greater
reduction than placebo in (a) ischaemic events (IE)
(P=0-025) and (b) ischaemic area/ST-segment integral
(P=0-042). (Reproduced from Deanfield et aLl30] with
permission.)
Eur Heart J, Vol. 18, Suppl B 1997
B32
P. F. Cohn
AECG
(Median episode
ETT
frequency)
60
(Time to ischaemia onset)
50
Amlodipine
2
| 40
s>
Atenolol
30
20
10
Combination
Angina-guided Ischaemia-guided Revascularization
strategy
strategy
strategy
Figure 3 Percentage of patients ischaemia free on week
100 80 60 40 20 0 10 20 30 40 50 12 visit ambulatory electrocardiogram for each treatment
strategy. (Reproduced from Knatterud et al.mi with
Percentage change from placebo
permission.)
Figure 2 Relative efficacies of amlodipine, atenolol and
their combination on time to ischaemia during treadmill
exercise time vs episode frequency during ambulatory
Nitrates plus calcium channel blockers
monitoring. Atenolol caused a greater reduction in
Vasodilation
is largely responsible for the anti-ischaemic
ischaemia during ambulatory monitoring, whereas
amlodipine caused a greater delay in onset of ischaemia effects of both nitrates and calcium channel blockers.
during treadmill exercise (* denotes P<0-001). The The nitrates, however, act principally on the venous
combination was more effective than either single drug circulation, whereas the calcium channel blockers are
in both settings. AECG=ambulatory electrocardiogram; primarily arterial vasodilators. Drugs belonging to these
ETT=exercise treadmill test. (Reproduced from Davies two classes are, therefore, a rational choice for use in
et a£ |371 with permission.)
combination regimens.
of these patients experienced any discomfort during
exercise. The average increase in exercise tolerance with
propanolol and isosorbide dinitrate alone was 22 and
25%, respectively. Combination therapy resulted in a
statistically significant increase in exercise tolerance by,
on average, more than 83%. The combination regimen
also resulted in significantly less exercise-induced
ST-segment depression than either drug alone. Similar
results have also been reported with the combination of
isosorbide mononitrates and /?-blockers[34J.
In addition to the additive theraputic action of
nitrates and /?-blockers when used in combination, the
chronotropic effect of /?-blockers may blunt any reflex
increase in heart rate related to nitrate-induced vasodilation. In turn, the vasodilation produced by nitrates
may counteract the increase in peripheral vascular resistance caused by ^-blockade. Nitrates may also prevent
left ventricular dilation associated with ^-blocker
therapy.
Because nitrates must be administered intermittently to prevent the development of tolerance,
patients may have no anti-anginal protection in the
early morning hours when the risk of ischaemia, myocardial infarction and sudden cardiac death is greatest.
Concomitant administration with a long-acting fiblocker in patients receiving intermittent nitrate therapy
may provide protection during this nitrate-free interval.
Eur Heart J, Vol. 18, Suppl B 1997
Both nitrates and short-acting dihydropyridine
calcium channel blockers can produce reflex tachycardia. For this reason, diltiazem or verapamil are a more
appropriate choice than nifedipine or nicardipine for use
in combination with nitrate compounds.
^-blockers plus calcium channel blockers
A /?-blocker plus a calcium channel blocker represents a
third combination regimen for the treatment of patients
with angina unresponsive to monotherapy. The heart
rate lowering effect of yS-blockade can ameliorate the
reflex tachycardia induced by short-acting dihydropyridine calcium channel blockers. The arterial vasodilation
produced by calcium channel blockers prevents the
increase in systemic vascular resistance that may occur
with ^-blocker therapy.
Both ^-blockers and certain calcium channel
blockers have a depressant effect on myocardial contractility, making this combination an inappropriate choice
for patients with severe left ventricular dysfunction or
overt congestive heart failure. Because of the effect of
diltiazem, and particularly verapamil, on cardiac conduction, patients receiving these drugs in combination
with a )S-blocker should be closely monitored for the
development of atrioventricular block and sinus bradycardia. By contrast, the Nifedipine-Total Ischaemia
Awareness Program demonstrated the effectiveness of
various ^-blockers combined with nifedipine1351. This has
also been demonstrated with atenolol and nifedipine[36J
and atenolol and amlodipine (Fig. 2)t37).
Ischaemic heart disease: mono vs combination therapy
B33
[16] Taylor HA, Deumite NJ, Chairman BR, Davis KB, Killip T,
Rogers WJ. Asymptomatic left main coronary artery disease
in the Coronary Artery Surgery Study (CASS) Registry.
Circulation 1989; 79: 1171-9.
[17] RITA Trial Participants. Coronary angioplasty versus coronary artery bypass surgery: the Randomised Intervention
Treatment of Angina (RITA) trial. Lancet 1993; 341: 573-80.
[18] Chan P, Heo J, Garibian G, Askenase A, Segal BC,
Iskandrian AS. The role of nitrates, beta blockers, and
Ancillary measures
calcium antagonists in stable angina pectoris. Am Heart J
The effectiveness of aspirin has been confirmed in a
1988; 116:838-48.
variety of studies in various coronary syndromes139'401. [19] Thadani U. Medical therapy of stable angina pectoris. Cardiol
Similarly, lipid-lowering regimens are effective as both
Clin 1991; 9: 73-87.
primary and secondary preventive measures'41'421. Use [20] Loscalzo J. Antiplatelet and antithrombotic effects of organic
nitrates. Am J Cardiol 1992; 70: 18B-22B.
of anti-oxidants is still controversial but early results of
[21] Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chandhuri G.
vitamin E trials, for example, are encouraging1431.
Endothelium-derived relaxing factor produced and released
from artery and vein is nitric oxide. Proc Natl Acad Sci USA
1987; 84: 9265-9.
References
[22] Abshagen U, Betzien G, Endele R, Kaufmann B, Neugebauer
G. Pharmacokinetics and metabolism of isosorbide-dinitrate
[1] Selwyn AP, Yeung AC, Ryan TJ, Raby K.E, Barry J, Ganz P.
after intravenous and oral administration. Eur J Clin
Pathopbysiology of ischaemia in patients with coronary artery
Pharmacol 1985; 27: 637-44.
disease. Prog Cardiovasc Dis 1992; 35: 27-39.
[23] Parker JP, Fung HL. Transdermal nitroglycerin in angina
[2] Maseri A. Role of coronary artery spasm in symptomatic and
pectoris. Am J Cardiol 1984; 54: 471-6.
silent myocardial ischaemia. J Am Coll Cardiol 1987; 9: [24] Zimrin D, Beichek N, Bogin DT et al. Antianginal effects of
249-62.
intravenous nitroglycerin over 24 hours. Circulation 1988; 77:
[3] Cohn PF. Silent myocardial ischaemia. Ann Intern Med 1988;
1376-84.
109: 312-7.
[25] Thadani U, Fung HL, Darke AC, Parker JO. Oral isosorbide
[4] Nesto RW, Zarich SW, Kowalchuk GJ, Kenigsberg AE,
dinitrate in angina pectoris during acute and sustained
Shurmur SW, McAuliflfe LS. Frequency of symptoms suggestherapy. Am J Cardiol 1982; 49: 411-9.
tive of dynamic coronary artery disease in patients referred for
[26] Deedwania PC, Carbajal EV, Nelson JR, Hait H. Anticoronary angiography. Am J Cardiol 1989; 64: 1374-6.
ischemic effects of atenolol versus nifedipine in patients with
[5] Muller JE, Abela GS, Nesto RW, Tofler GH. Triggers, acute
coronary artery disease and ambulatory silent ischaemia.
risk factors and vulnerable plaques: the lexicon of a new
J Am Coll Cardiol 1991; 17: 963-9.
frontier. J Am Coll Cardiol 1994; 23: 809-13.
[6] Cohn PF. Prognosis in exercise-induced silent myocardial [27] Portegies MCM, Sijbring P, Gobel EJAM, Viersma JW,
Lie KI. Efficacy of metoprolol and diltiazem in treating silent
ischaemia and implications for screening asymptomatic
myocardial ischaemia. Am J Cardiol 1994; 74: 1095-8.
populations. Prog Cardiovasc Dis 1992; 34: 399-412.
[7] Lim R, Dyke L, Dymond DS. Effect on prognosis of abolition [28] von Arnim T and the TIBBS Investigators. Medical treatment
to reduce total ischemic burden: Total Ischemic Burden
of exercise-induced painless myocardial ischaemia by medical
Bisoprolol Study (TIBBS), a multicenter trial comparing
therapy. Am J Cardiol 1992; 69: 733-5.
bisoprolol and nifedipine. J Am Coll Cardiol 1995; 25: 231-8.
[8] Pepine CJ, Cohn PF, Deedwania PC et al. for the ASIST Study
Group: Effects of treatment on outcome in mildly symptomatic [29] Hoekenga D, Abrams J. Rational medical therapy for stable
angina pectoris. Am J Med 1984; 76: 309-14.
patients with ischaemia during daily life: the Atenolol Silent
[30] Deanfield JE, Detry J-MRG, Lichtlen PR, Magnani B, Sellier
Ischemia Study (ASIST). Circulation 1994; 90: 762-8.
P, Thaulow E for the CAPE Study Group. Amlodipine
[9] Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME,
reduces transient myocardial ischaemia in patients with corAzen SP, Cashin-Hemphill L. Beneficial effects of combined
onary artery disease:, double-blind Orcadian Anti-ischemia
colestipol-niacin therapy on coronary atherosclerosis and
Program in Europe (CAPE Trial). J Am Coll Cardiol 1994;
coronary venous bypass grafts. J Am Med Assoc 1987; 257:
24: 1460-7.
3233-40.
[10] Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, [31] Osterloh I. The safety of amlodipine. Am Heart J 1989; 118:
1114-20.
Azen SP, Blankenhorn DH. Beneficial effects of colestipolniacin on coronary atherosclerosis. A 4-year follow-up. J Am [32] Purcell H, Waller DG, Fox K. Calcium antagonists in
cardiovascular disease. Br J Clin Pract 1989; 43: 369-79.
Med Assoc 1990; 264: 3013-7.
[11] Blankenhorn DH, Azen SP, Kramsch DM et al. Coronary [33] Russek HI. Propranolol and isosorbide dinitrate. Synergism
in angina pectoris. Am J Cardiol 1968; 121: 44-54.
angiographic changes with lovastatin therapy. Results of the
Monitored Atheroscelrosis Regression Study (MARS). Ann [34] Akhras F, Jackson G. Efficacy of nifedipine and isosorbide
mononitrate in combination with atenolol in stable angina.
Intern Med 1993; 119: 969-76.
Lancet 1991; 338: 1036-9.
[12] Brown G, Albers JJ, Fisher LD et al. Regression of coronary
artery disease as a result of intensive lipid-lowering therapy in [35] Cohn PF, Vetrovec GW, Nesto R et al. The Nifedipine-Total
Ischaemia Awareness Program: a national survey of painful
men with high levels of apolipoprotein B. N Engl J Med 1990;
and painless myocardial ischaemia including results of
323: 1289-98.
antiischemic therapy. Am J Cardiol 1989; 63: 534-9.
[13] Hammermeister KE, DeRouen TA, Dodge HT. Effect of coronary surgery on survival in asymptomatic and minimally [36] El-Tamimi H, Davies GJ. Optimal control of myocardial
symptomatic patients. Circulation 1980; 62 (Suppl I): 1-98-102.
ischaemia: the benefit of afixedcombination of atenolol and
[14] CASS Principal Investigators and their Associates. Coronary
nifedipine in patients with chronic stable angina. Br Heart J
Artery Surgery Study (CASS): a randomized trial of coronary
1992; 68: 291-5.
artey bypass surgery survival data. Circulation 1983; 68: [37] Davies RF, Habibi H, Klinke WT et al for the Canadian
939-50.
Amlodipine/Atenolol in Silent Ischemia Study (CASIS) Investigators. Effect of amlodipine, atenolol and their combination
[15] Passamani E, David KB, Gillespie MJ et al. A randomized
on myocardial ischemia during treadmill exercise and ambutrial of coronary artery bypass surgery: survival of patients
with a low ejection fraction. N Engl J Med 1985; 312:1665-71.
latory monitoring. J Am Coll Cardiol 1995; 25: 619-25.
The Asymptomatic Cardiac Ischaemia Pilot
(ACIP) study1381 compared the effects of various ischaemic treatment regimens on outcome. Those that
relied on medications, whether symptom-guided or
guided by ischaemia on Holter monitoring, were not as
effective as revascularization procedures (Fig. 3).
Eur Heart J, Vol. 18, Suppl B 1997
B34
P. F. Cohn
[38] Knatterud GL, Bourassa MG, Pepine CJ et al. for the ACIP
Investigators. Effects of treatment strategies to suppress ischaemia in patients with coronary artery disease: 12-week
results of the Asymptomatic Cardiac Ischaemia Pilot (ACIP)
Study. J Am Coll Cardiol 1994; 24: 11-20.
[39] Mahony C. Effect of aspirin on myocardal ischaemia. Am J
Cardiol 1989; 64: 387-9.
[40] Nyman I, Larsson H, Wallentin IL. Prevention of serious
cardiac events by low-dose aspirin in patients with silent
myocardial ischaemia. Lancet 1992; 340: 497-501.
Eur Heart J, Vol. 18, Suppl B 1997
[41] Superko RJH, Krauss RM. Coronary artery disease regression:
convincing evidence for the benefit of aggressive lipoprotein
management. Circulation 1994; 90: 1056-69.
[42] Davey Smith G, Song F, Sheldon TA. Cholesterol lowering
and mortality: the importance of considering initial level of
risk.
Br Med J 1993; 306: 1367-73.
[43] Street DA, Comstock GW, Salkeld RM, Schiiep W, Klag MJ.
Serum antioxidants and myocardial infarction: are low
levels of carotenoids and alpha tocopherol risk factors for
myocardial infarction? Circulation 1994; 90: 1154-61.