Evidence based treatment of chronic stable angina

International Journal of Cardiology 63 (1998) 21–25

Evidence based treatment of chronic stable angina Andrew D. Staniforth Department of Cardiovascular Medicine, D Floor South Block, Queens Medical Centre, Nottingham NG7 2 UH, UK Received 26 June 1997; accepted 2 September 1997

1. Introduction The clinical trials data on which we base the everyday management of patients with chronic stable angina is far from complete. In this editorial I have sub-divided the results of a number of important studies according to their end-points (mortality, silent ischaemia, exercise capacity, and symptoms), since this will also allow me to discuss the relevance of the study end-points themselves.

ment arm of the Swedish Angina Pectoria Aspirin Trial (SAPAT) study gives us an indication of the current mortality rate in chronic stable angina [5]. Symptom controlled subjects on b blocker monotherapy and aspirin had a mortality rate of 8% over the 6 year follow-up period, whilst asymptomatic patients randomised to symptom guided medical therapy in the Asymptomatic Cardiac Ischaemic Pilot (ACIP) study had a 2 year mortality rate of 6.6% [6].

3. Treatment options 2. The size of the problem Two million people in the United Kingdom suffer with angina pectoris [1,2], and the annual incidence is 0.83 per thousand head of population aged 31–70 years [3]. It is a common condition. Although 30% of subjects with recent onset angina undergo spontaneous remission or are rendered symptom free by medication, it remains a serious condition. Seven percent of patients experience a non-fatal myocardial infarction within the first year, and 4% die. Chronic stable angina genuinely has a better outlook than recent onset angina, but it cannot be overemphasised that this also is far from benign. In a recent US study the average patient experiences two angina attacks per week despite medical therapy [4]. Although most subjects were taking more than one anti-anginal medication, morbidity remained high; 50% of subjects described their quality of life as only ‘‘fair’’ and 12% described it as ‘‘poor.’’ The treat-

Chronic stable angina can be treated medically or by intervention. High risk subjects aside (unstable angina, main stem disease and triple vessel disease with impaired ventricular function), the accepted wisdom is that intervention should be reserved for those patients who remain symptomatic on medical therapy. Even patients who are rendered asymptomatic by medical therapy are at an increased risk compared with the general population, however, and the ACIP study has shown that early revascularisation (by surgery or angioplasty) may offer a survival advantage [6]. These results were at variance with the Ramdomised Intervention Treatment of Angina (RITA-2) study (intervention by angioplasty alone) in which it was medical therapy that produced a 3% absolute reduction in the combined end-point of death or non-fatal infarction at 2.7 years follow-up [7]. These studies differed not only according to the interventional strategy adopted, but also in the

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baseline cardiovascular risks of their subjects. The ideal management strategy for patients with stable angina remains to be determined, however it may be clarified in the near future as the significance and optimal treatment of silent ischaemia becomes more fully understood. In the absence of evidence to contrary, patients with stable angina will continue to be treated medically in the first instance. The main classes of drugs available are nitrates, b blockers, calcium channel blockers and potassium channel openers. All these agents have been shown to be effective in relieving patient symptoms. As well as reducing ischaemia and its complications, medical therapy in chronic angina should also be directed towards preventing thrombosis and bringing about regression of coronary atherosclerosis. The value of antiplatelet drugs [5] and treating hypercholesterolaemia in high risk subjects [8] has been well documented.

4. Mortality studies Death is the ultimate trial end-point since it is both readily identifiable and clinically relevant. No prospective placebo controlled mortality studies have been performed in patients with symptomatic chronic angina. The studies of acute coronary syndromes give us some information on which agents are likely to be beneficial in chronic angina. Tachycardia increases myocardial oxygen consumption and is a marker of poor prognosis in ischaemic heart disease, so we might expect any agent that reduces heart rate to be cardioprotective. Most information is available for b blockers. In the ISIS-1 study atenolol was administered acutely in patients with suspected myocardial infarction (45% definite myocardial infarction), and produced a 0.6% absolute reduction in 7 day mortality [9]. Secondary prevention studies with propranolol [10] (2.6% absolute mortality reduction at 25 months) and timolol [11] (5.9% absolute reduction in total mortality at 17 months) have also confirmed the value of b blockers following myocardial infarction. These results lend some credibility to the findings of retrospective studies in hypertensive patients suggesting a primary prevention effect [12], and a greater adverse effect on b blocker withdrawal than

with diuretics [13]. In a retrospective study of patients admitted with myocardial infarction, those patients treated with b blockers prior to admission were found to have a 50% relative risk reduction in 28 day mortality [14]. In a prospective study of patients at risk of cardiovascular disease undergoing non-cardiac surgery, perioperative treatment with atenolol resulted in a 11% absolute mortality reduction at 1 year [15]. All these studies point indirectly towards an expected benefit from b blockade in chronic angina. More direct evidence of a primary prevention effect on mortality in patients with chronic angina may come from studies in patients with known coronary artery disease and asymptomatic ischaemia on Holter monitoring. The possible significance of silent ischaemia will be discussed below, but the obvious advantage of this patient sub-group from an experimental point of view is that is not currently unethical to enter them into placebo controlled studies. In the Atenolol Silent Ischaemia Study (ASIST) subjects randomised to atenolol had a 0.44 relative risk reduction in the combined end-point of event free survival at 8 months [16]. Further studies are required since the total number of deaths in ASIST was only five subjects. Little mortality data is available for the calcium channel blockers. Dihydropyridine monotherapy (specifically short acting preparations of nifedipine [17]) is probably associated with an adverse outcome in coronary artery disease owing to its tendency to increase heart rate. In the Total Ischaemic Burden European Trial (TIBET) study, treatment with atenolol, nifedipine or both was compared in patients with chronic stable angina [18]. There was no significant difference between the three treatment arms with regard to their effect on hard end-points (death, non-fatal myocardial infarction and unstable angina) after 2 years, although there was a trend towards fewer events with combination therapy. This study did not include a placebo arm and was too small (n5682) to demonstrate a difference between three effective treatments, which does not necessarily mean that they were equivalent. The rate reducing calcium channel blockers have been shown to have neutral [19] or slight beneficial [20] effects in acute coronary syndromes. The Angina Prognosis Study in Stockholm (APSIS) study failed to demonstrate a

A.D. Staniforth / International Journal of Cardiology 63 (1998) 21 – 25

difference in prognosis between patients with chronic angina treated with either metoprolol or verapamil for 3.4 years, but once again this study was not placebo controlled [21]. The safety and tolerability of nitrates in patients with angina has been confirmed by two large secondary prevention studies in patients following myocardial infarction [22,23]. No mortality benefit was observed in either of these studies, and no mortality studies have been performed in the setting of chronic angina.

5. Is silent ischaemia an important end-point? There has been much recent interest over the prognostic significance of silent ischaemia in a variety of coronary syndromes. Asymptomatic myocardial ischaemia has been identified as a marker of unfavourable outcome in patients with unstable angina [24], following myocardial infarction [25,26], and in ambulatory subjects with chronic stable angina [27,28]. There is fairly good evidence that the majority of ischaemic episodes in chronic angina are preceded by a rise in heart rate [29], and that the early morning surge in ischaemic episodes reported by some observers is related to the increase in heart rate associated with ambulatory activity [30,31]. This information may potentially be useful for tailoring therapy to an individual patient. Ischaemia related to exercise would be expected to respond best to negatively chronotropic agents, whilst ischaemia unrelated to heart rate changes (i.e. vasospastic) should improve with dihydropyridine calcium channel blockers or nitrates. Ambulatory ECG has been advocated as a tool for the risk stratification of patients with a variety of coronary syndromes. Although plausible, there is little data to support the theory that silent daily ischaemia is causally related to an increase in mortality. The results of the ASIST were highly suggestive of a causal relationship, but this study was weakened by the small number of deaths recorded [16]. It may be that silent ischaemia is just acting as a marker of the severity of the underlying coronary artery disease. Even less information is available concerning the likely mechanisms of death in these high risk patients with silent ischaemia. Although the

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increased mortality observed by Deedwania and Carbajal was attributable to ‘‘sudden’’ cardiac death [27], we can only speculate over the actual mechanism of death. Holter monitor guided medical therapy for silent ischaemia should not necessarily be expected to produce a reduction in mortality. Yeung et al. [28] have shown that the abolition of silent ischaemia with medical therapy does not reduce risk of these patients to that of subjects without silent ischaemia. Medical therapy in the ACIP study did not improve prognosis, and only intervention produced a significant reduction in the primary end-point [6]. This study was also limited by its small sample size, and hopefully the larger ACIP-II study will help clarify the real significance of silent ischaemia. The assessment of silent ischaemia by Holter monitoring is an attractive tool with which to compare the ‘‘effectiveness’’ of various drug treatments. There is good evidence that all the major classes of anti-anginal medications reduce the occurrence of silent ischaemia in patients with chronic angina [32]. b blockers have been shown to be the more effective than dihydropyridine calcium channel blockers, partly because most episodes of ischaemia are related to an increase in heart rate. The addition of a calcium channel antagonist to a b blocker nevertheless results in further reduction in silent ischaemia. Until silent ischaemia is conclusively shown to be causally related to the mechanism of death in this high risk group of patients, it cannot be used as a surrogate end-point with which to imply that one drug is likely to have a beneficial effect on mortality.

6. Formal exercise testing and symptom control Formal exercise testing is an invaluable tool for diagnosing and risk stratifying patients with angina. It is incorrect to regard it as an essential research tool with which to establish the efficacy of any new anti-anginal medication. Although formal testing has the advantage of being both reproducible and objective, it tells you nothing about the effect a drug is likely to have on either symptom control during everyday life or prognosis. The central problem is that few patients exercise maximally (or for that matter sub-maximally) as part of their everyday life, and so many of the interpretations that have been

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drawn from studies using formal exercise testing in isolation are questionable. With all the problems that are inherent to treadmill testing, there has been a recent movement towards the increased use of symptom diaries and self-paced corridor walk tests when assessing the benefits of new therapies in chronic angina. Nitrates improve daily symptoms [33,34] and exercise capacity [34,35] in a dose dependent fashion [36,37]. b blocker monotherapy is effective at improving exercise capacity and reducing everyday symptoms. There is some evidence that b blockers alone are superior to dihydropyridine calcium channel blockers [38,39], probably as a result of the beneficial effects of reducing heart rate. Rate reducing calcium channel blockers are probably as effective as b blockers, although most of the studies to date are extremely small [40]. In the APSIS study verapamil was superior to b blocker with respect to treadmill exercise capacity, although b blockers had the upper hand when it came to ambulatory ischaemia [41]. In the ASIS study diltiazem was as effective as b blocker in reducing daily symptoms and improving exercise capacity [42]. Some studies confirm an additional benefit on exercise capacity and symptom relief from combining a b blocker with either a rate reducing [43,44] or a dihydropyridine calcium channel blockers [38,45,46]; others do not [47]. Rate reducing calcium channel blockers are probably more effective than dihydropyridines when used as monotherapy [48,49]. Although nicorandil has been shown to be comparable to other medications as monotherapy [50], there is only limited evidence showing benefit in combination with other agents. There is no real evidence that the addition of a third agent to the combination of a b blocker and a calcium channel blocker provides additional clinical benefit.

7. Conclusions There is no hard evidence to show that any medical anti-anginal therapy is associated with improved prognosis in chronic stable angina, although circumstantial evidence would lead us intuitively to believe that b blockers may be beneficial. Useful information may come from ongoing large studies in patients with coronary artery disease and asymptomatic daily ischaemia.

Nitrates, b blockers, calcium channel antagonists and potassium channel openers are all effective at relieving the symptoms of angina. The dihydropyridines (specifically short acting preparations of nifedipine) have recently attracted adverse publicity. The long term safety of these agents may need to be re-evaluated, especially as monotherapy. There is good evidence that b blockers are the agents of first choice, and that additional symptomatic relief may be achieved with combination therapy of two agents, but probably not three. Revascularisation is an effective treatment for symptoms, but there is currently no convincing evidence that it improves prognosis in ‘‘low risk’’ patients with chronic angina.

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