Drugs 18: 130-136 (1979) 0012-6667/79/0800-0130/$01.75/0 © ADIS Press Australasia Pty Ltd. All rights reserved.

Angina Pectoris: Current Approach to Treatment Hamidlkram Department of Cardiology. Princess Margaret Hospital. Christchurch

Angina pectoris is a pain syndrome due to a variety of pathological processes, all of which have in common the induction of an adverse oxygen supply / demand situation in a portion of the myocardium (fig. I). In this article, angina which is secondary to several well known causes such as severe anaemia, thyrotoxicosis, tachycardias and obstruction of the left ventricular outflow will not be considered. Rather, the article will deal with angina due to coronary arterial narrowing. In angina pectoris the therapeutic objectives are threefold: I. The symptomatic relief of anginal pain 2. The prevention of attacks 3. Control of risk factors.

1. Symptomatic Relielof A nginal Pain (Glyceryl Trinitrate) The cornerstone of treatment of the acute episode is glyceryl trinitrate (nitroglycerin). Amyl nitrate, the first compound to be used successfully for this purpose is no longer generally used.

1.1 Mode of Action Glyceryl trinitrate dilates healthy coronary vessels in animals as well as the healthy segments of human hearts with coronary disease. Initially it was thought that the drug relieved angina by virtue of its coronary vasodilator action. However. Mason et al. (1973) showed that the pronounced venodilator action of the drug which resulted in reduced venous return and a slight fall in arterial blood pressure both led to reduced myocardial oxygen demand and hence relief of angina.

1.2 Clinical Use Glyceryl trinitrate usually relieves the pain of angina within 3 minutes in 75 % of patients, and within 4 to 15 minutes in a further I 5 %; if pain is not relieved the diagnosis should be reviewed. The drug is administered sublingually since it is well absorbed from the buccal mucosa. It is inactivated by the gastric juice and hence patients must be instructed not to swallow the tablets. The conventional prepara-

131

Angina Pectoris: Current Approach to Treatment

restriction or tolerance and efficacy does not diminish with concomitant therapy with other compounds.

tion is unstable because of a tendency to volatilise. Packing materials such as cotton wool readily absorb varying amounts of the drug. The tablets should therefore be kept in a dark bottle devoid of packing materials. Fresh supplies should be obtained rather than large stocks kept. Glyceryl trinitrate can be used both for treatment of the acute attack and prophylactically to prevent pain recurring (see section 2.1.1). The action of the drug lasts for up to 45 minutes. There is no dose

1.3 Side Effects Although the pain is relieved, flushing and headaches which are regular accompaniments may be troublesome in up to 30 % of patients. Patients may find that the side effects are worse than the angina.

Oxygen supply

Oxygen demand

(coronary blood flow)

(heart rate, contractility, myocardial wall tension)

r-------,

r--------, : I

Coronary blood flow

I

I

Potential Increase

reserve

I

with exerCise, stress, etc.

15x normal!

r--------r

,Increased

, I OXygen ' I I I conSUmption ,

f--------,

: I

Diminished coronary

:

blOod flow

,reserve I I

I

I'

I

I

I I I

I

,I

: J

,

I

I

I

~

I

Angina pectoris

I

I

With exerCise. I stress. etc. ,

I

,

, I

I

Fig. 1. Angina occurs when oxygen demand outstrips oxygen supply. ThIS figure indicates that coronary blood flow can normally increase five times above control to cope with increased demands due to exercise, stress, etc. Coronary atherosclerosis, the usual cause of angina pectoris, reduces the coronary blood flow reserve and angina can be precipitated by events which increase the 3 major determinants of myocardial oxygen demand, i.e. heart rate, contractility and wall tension (~Ieft ventricular volume x left ventricular filling pressure). Drugs used in the treatment of angina pectoris either improve myocardial oxygen supply (e.g. glyceryl trinitrate) or decrease myocardial oxygen demand (e.g. ~-adrenoceptor blockers, glyceryl trinitrate).

Angina Pectoris: Current Approach to Treatment

However, they can be reassured that side effects tend to decrease in severity with continued use while the therapeutic action is maintained.

2. Prevelltioll of A /lacks 2.1 'Long Acting' Nitrates These were the earliest agents used for angina prophylaxis. For several decades there has been considerable controversy as to whether they do in fact have prolonged therapeutic activity. The reasons for this are varied. Much of the older work in this field consisted of poorly designed investigations. However, during recent years there has been a resurgence of interest in these compounds. Ironically, the new work has been stimulated by the possible use of the nitrates for impedance reduction in cardiac failure rather than as antianginal drugs. 2.1.1 Clinical Use Many workers have clearly shown haemodynamic effects sustained for 3 to 6 hours. Furthermore, several well designed studies in anginal patients have demonstrated increased exercise performance for at least 3 hours. There seems little doubt therefore that the long acting nitrates do have a useful role in the prevention of anginal attacks. Of the many long acting nitrate formulations available, three have shown undoubted effectiveness in recent clinical studies. These are: I. Sorbide nitrate (;sosorbide dinitrate): Several recent studies with this agent have shown increased effort tolerance, improvement in ischaemic ST segment depression, and changes in heart rate and blood pressure for 2 to 5 hours. The doses used in these studies were 10 to 30mg. Sublingual sorbide nitrate (5mg) has also been shown to increase exercise capacity for up to I hour after administration. However, high dose (10 to 30mg) oral sorbide nitrate appears to be the most effective formulation. 2. Oral sustained action glyceryltrinitrate: Two recent studies have documented the sustained efficacy

132

of this preparation in angina (Davidov and Mroczek, 1977; Winsor and Berger, 1975). The action lasts for at least 4 hours after an oral dose. 3. Glycer),1 trinitrate ointment: Glyceryl trinitrate as a 2 % paste has been available for over 20 years. Well designed exercise studies have confirmed its prolonged antianginal and haemodynamic action. The drug has been demonstrated to work for 3 to 6 hours after application. 2.1.2 The Need to Individualise Dosages It is now inescapable that the long acting nitrates do have a prolonged antianginal action. However, these drugs have a wide and poorly understood dose response spectrum. Hence it is imperative to tailor therapy to the individual patient. Furthermore their effects can be additive to those of the ~-blocking drugs, permitting smaller doses or a greater antianginal action to be achieved.

2.2 ~-Adrenoceptor Blocking Drugs (~-Blockers)

These drugs improve angina by diminishing the oxygen requirements of the heart, particularly during exercise. Specifically, they reduce the heart rate, blood pressure rise and the velocity of contraction. 2.2.1 Clinical Use Many double-blind studies have established the effectiveness of the ~-blockers in the treatment of angina. However, it is often difficult to assess the merits of individual compounds. Several comparative studies have indicated that most of the drugs have similar clinical effects, suggesting that ancillary properties such as membrane stabilising action and intrinsic sympathomimetic activity are clinically unimportant. Whether the more recently introduced cardioselective ~-blockers represent a significant advance in safety and effectiveness cannot be judged as yet. Clinical experience suggests that ~-blockade will benefit at least 70 % of patients with angina pectoris due to coronary disease. Propranolol continues to be the most widely used agent. Due to its relatively short

133

Angina Pectoris: Current Approach to Treatment

half-life of 3 to 6 hours it is usually prescribed on a 3 or 4 times daily basis. This frequency is inconvenient and may lead to a lack of patient compliance. However, propranolol (as with other ~-blockers) has a dose response effect such that the larger the dose, the longer the response. This effect has permitted a twice daily regimen for hypertension and this may be adequate for most anginal patients as well. The sustained release formulations of alprenolol, oxprenolol and metoprolol are sufficiently long acting for once daily or twice daily administration for angina. Dosage regimens: It is recommended that the starting dose of ~-blockers be low and that this be built up at weekly intervals. This avoids the precipitation of cardiac failure or conduction problems in susceptible

individuals and also identifies the few people who are ~-blocked even by these small doses. The optimum dosage varies for individual patients. Ideally, the correct dose is that which blocks exercise tachycardia, but in a busy clinic this may not always be possible to assess. The resting pulse rate should be around 50 to 60 per minute for adequate ~­ blockade. Treatment failures: The apparent failure of treatment requires assessment with measurement of peak exercise heart rate. The dose should be increased until the peak rate is less than 100 per minute or does not decrease further with increasing dosage. In one study this produced a satisfactory response in 15 out of 21 therapeutic 'failures' (Jackson et aI., 1975).

Treatment Symptomatic Relief •

Causative Factors: • • • • •

Coronary atheroscleroSIS Severe anaemia Thyrotoxicosis Tachycardias Left ventricular outflow obstruction

Glyceryl trinitrate Isublinguallyl

Prophylaxis •

\--+--+1 • • •

•

Long acting nitrates le.g. sorbide nitratel

~-Blockers Perhexiline maleate Other drugs le.g. dipyridamole, verapamil, prenylaminel Coronary surgery

Control of Risk Factors • • •

Fig. 2. Causative factors and treatment of angina pectoris (summarised).

Hypertension Cigarette smoking Hyperlipldaemia

134

Angina Pectoris: Current Approach to Treatment

Another possible reason for failure to respond is misdiagnosis. Amsterdam et al. (1969) reported that 77 % of failures of propranolol therapy occurred in anginal patients with normal coronary arteries while there was a 14 % failure rate in cases with angiographically evident atheroma. 2.2.2 Side Effects

Complications with ~-blocker therapy occur in about 5 % of patients provided those with obstructive coronary disease, untreated cardiac failure, conduction defects and major peripheral vascular disease are excluded. Patient acceptance is excellent. Side effects include vivid dreams (some compounds), gastrointestinal disturbances and lethargy. Raynaud's phenomenon and intermittent claudication may be accentuated because of a reduction in blood flow. The development of cardiac failure as a result of ~­ blocker therapy has probably been over-emphasised. Patients with cardiomegaly, gallop rhythm or a history of cardiac failure should be treated with digitalis and/ or diuretics prior to ~-blockade. If this is done, failure rarely develops after initiation of ~-blocker therapy. In theory ~-blockers with intrinsic sympathomimetic activity should be less likely to produce cardiac failure, but this is not obvious in practice. Withdrawal qf therapy: It is important to remember that abrupt withdrawal of ~-blocker therapy may be accompanied by a rebound phenomenon, i.e. worsening angina or myocardial infarction. Hence therapy should be tailed off gradually over a few days. 2.2.3 Selection

(}f~-Blocker

Although propranolol is the ~-blocking compound most commonly used, others may be indicated in certain situations. In diabetic patients it may be better to use a cardioselective drug (e.g. metoproloJ) since these do not interfere with the catecholamine mediated response of the pancreas to hypoglycaemia. Patients with Raynaud's phenomenon are also less affected by cardioselective drugs. The incidence of side effects varies from person to person and the

major benefit of the plethora of these drugs is that therapy can be adjusted to individual needs. If there is a genuine failure to respond to the first choice ~-blocker then it is probably worth trying another compound, although the chances of success are not very high. 2.3 Perhexiline Maleate This drug has been shown to be effective in a number of trials. Perhexiline often works when ~-blockers have failed. In early studies, there was a high incidence of toxic effects but with smaller doses these are very much less common. A starting dose of 50mg increasing by 50mg amounts to a maximum of 300mg daily is suggested. The mechanism of action of perhexiIine is not known with certainty but reduction in heart rate and favourable redistribution of coronary blood flow have been suggested. 2.4 Miscellaneous Drugs A number of other drugs have been marketed as having antianginal properties. These include dipyridamole, verapamil and prenylamine. Although useful in occasional patients, they have not found widespread acceptance. 2.5 Coronary Artery Bypass Graft Surgery As has been implied in previous sections, the majority of patients with angina pectoris can be adequately managed with drug therapy. However, there are a proportion ( I 0 to 30 % ) who do not respond to drug therapy, are intolerant of it, or find the restrictions imposed by drug therapy and limited exercise capacity on their life style to be unacceptable. The angina in a very high proportion of these patients can be completely or substantially improved by coronary surgery. This is an established fact of coronary artery surgery in contrast to the question of longevity,

135

Angina Pectoris: Current Approach to Treatment

Table I. Summary of the treatment of angina pectoris 1. Seek and correct aggravating factors _. anaemia, arrhythmia, thyroid dysfunction, aortic valve disease, obesity 2.

Control of risk factors -

cigarette smoking, hypertension,

hyperlipidaemia 3.

Rehabilitation _. relief of anxiety, adjustment of life style and exercise

4.

patient must be strongly urged to abstain from smoking. There are further rewards in that the increased coronary mortality associated with smoking declines to that of the normal population within two years of cessation of smoking (Gordon et a\., 1974; Wilhelmsson et a\., 1975).

Therapy a) Nitrates i) Glyceryl trinitrate (treatment of acute episodes) ii) Long acting nitrates (prevention of attacks) b) IS-Blocking drugs (prevention of attacks) c)

Coronary artery bypass graft surgery

which is still the subject of clinical trial and vociferous debate.

3. Control of Risk Factors Only the three major risk factors (hypertension, smoking and hyperlipidaemia) will be considered since evidence concerning the role of other factors and the results of their alteration on the natural history of angina pectoris is decidedly ·soft'.

3.1 Hypertension This disorder directly increases myocardial work and hence exacerbates angina. Control of hypertension in an anginal patient is therefore mandatory. There may be long term benefits in the reduction of coronary events but so far there is little evidence to support this hope,

3.2 Smoking Cigarette smoking is accompanied by tachycardia and a rise in blood pressure, both factors producing increased cardiac work and hence angina. The anginal

3.3 Hyperlipidaemia Of the three major risk factors, this is the one least directly involved in angina. Indeed, once ischaemic heart disease is clinically manifest, there is no good evidence that reduction in plasma lipids makes any significant difference. However, if the lipids are grossly elevated then it is probably worth reducing them to more normal levels.

4. General Measures In addition to the above specific measures, there are several general measures which are important: I. Firstly, discussion and explanation of the symptom in detail. In particular, it is essential to allay anxiety regarding the prognosis, since angina is generally regarded as ominous by the laity. If there is a frank anxiety state present then tranquillising drugs should be prescribed. 2. The patient's daily schedule should be renewed and activities likely to produce angina attacks (e.g, heavy meals followed by exertion) eliminated or curtailed. 3. Employment advice. Patients are often concerned about their jobs; this should be fully examined on an individual basis since a change in occupation mayor may not be needed, 4. Advice on the advisability and amount of exercise is frequently asked for an" should always be offered, even if it is not specifically requested, The same applies to advice on sexual matters. 5. Aggravating factors such as obesity, anaemia, thyrotoxicosis and cardiac arrhythmias should be corrected,

Angina Pectoris: Current Approach to Treatment

References Amsterdam, E.A.; Gortin, R. and Wolfson, W.: Evaluation of long term use of propranolol in angina pectoris. Journal of the American Medical Association 210: 103 (t 969). Davidov. M.E. and Mroczek, W.J.: The effect of sustained release nitroglycerine capsules on angina frequency and exercise capacity: A double-blind evaluation. Angiology 28: 181 (t 977)

Gordon, T.; Kannel. W.B. and McGee, D.: Death and coronary attacks in men after giv ing up cigarette smoking. Lancet 2: 1345 (j 974). Jackson, G.; Atkinson, L. and Oram, S.: Reassessment of failed beta-blocker treatment in angina pectoris by peak exercise heart rate measurements. British Medical Journal 3: 616 (1975).

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Mason, D.T.; Zellis, R. and Amsterdam, E.A.: Role of the peripheral circulation in the antianginal action of nitroglycerine; in Kaltenbach et al. (Eds) 2nd International Symposium in Coronary Artery Disease, p.25 (Georg Thieme, Stuttgart 1973). Wilhelmsson, c.; Vedin, J.A.; Elonfeldt. D.; Tibblin. G. and Wilhelmsen, L: Smoking and myocardial infarction. Lancet I: 415 (1975). Winsor. T. and Berger. H.: Oral nitroglycerine as a prophylactic drug. Clinical physiologic and statistical evidence of efficacy based on a three phase experimental design. American Heart Journal 90: 611 (t 975).

Author's address: Dr Hamid Ikram, Department of Cardiology. The Princess Margaret Hospital. Cashmere Road, Christchurch. 2 (New Zealand).