Angina and left ventricular dysfunction

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1 European Heart Journal (1996) 17 {Supplement G), 2-7 Angina and left ventricular dysfunction H. J. Dargie From the CRI in Heart Failure, University of Glasgow, Glasgow, U. K. Angina with left ventricular dysfunction exhibits a wide range of different presentations. Approximately 45% of patients referred for coronary artery bypass surgery have some degree of left ventricular dysfunction and, given that at least a third of those suffering from angina have a history of myocardial infarction, the prevalence of left ventricular dysfunction in such patients is likely to be substantial. The major prognostic factor in patients with coronary artery disease is the degree of left ventricular function and it is important to identify those with poor or reduced left ventricular function. High-risk patients, defined by exercise testing and echocardiography, should be considered for revascularization. For the majority of patients management should be medical, consisting of nitrates plus a /?-blocker or calcium antagonist. In severe ischaemia, the combination of these agents has been shown to provide additional efficacy. In patients with heart failure the newer calcium antagonist amlodipine has been shown to have a neutral effect upon survival, indicating that it may be used safely in patients with angina and left ventricular dysfunction. Progression of left ventricular dysfunction may be slowed through the use of angiotensin converting enzyme (ACE) inhibitors, which have also been shown to improve survival, although they should be used with caution, since there is evidence that ACE inhibitors may worsen angina in some patients. (Eur Heart J 1996; 17 (Suppl G): 2-7) Key Words; Angina, left ventricular dysfunction, /?-blocker, calcium channel blocker, ACE inhibitor. Introduction The many facets of angina and left ventricular dysfunction are illustrated in Fig. 1. In patients with coronary heart disease (CHD), left ventricular dysfunction may either be fixed, due to previous myocardial infarction (MI), or reversible, due to different manifestations of ischaemia. The type of dysfunction is likely to be systolic in patients with previous MI while ischaemia, at least initially, may give rise to diastolic dysfunction or a mixed picture. Although the symptoms with which this syndrome can present may indeed be classical chest pain, associated with exertion and relieved by rest, in most patients there will also be a component of dyspnoea. In patients with fixed left ventricular dysfunction due to previous MI, the dominant symptom may be dyspnoea but with superimposed angina, due either to reversible ischaemia in that area of the ventricle or from myocardium supplied by a different artery. However, even in patients with truly reversible left ventricular dysfunction, due to ischaemia, the principal symptom may also be dyspnoea and the patient may actually be misdiagnosed as having heart failure. Therefore, the overall situation encompassed in this simple title is complex. Correspondence: Professor Henry J. Dargie, CRI in Heart Failure, West Medical Building, University of Glasgow. Glasgow G12 8QQ, U.K X/96/0G S25.00/0 The size of the problem Given the various facets of this syndrome, it is unsurprising that the epidemiology has not yet been accurately described. Firstly, most studies have been carried out in hospital-based patients and no true community study of the prevalence of left ventricular dysfunction in a population of patients with angina due to ischaemic heart disease, in which left ventricular dysfunction has been objectively assessed, has ever been published. Data in patients identified in the community, however, do point to a high prevalence of previous MI, especially if the whole community, including the elderly in whom the disease is much more common, is assessed 1 ' 1. If one considers that between one-quarter and one-third of all Mis are 'silent' and that in many previous clinical studies at least one-third of patients with angina have a history of previous MI, then the prevalence of left ventricular dysfunction in patients with angina is likely to be substantial' 2 '. Quite clearly there is a need for a true community survey of left ventricular dysfunction in patients presenting with angina to their primary care physician for the first time, as well as in those already known to have angina. Approximately 45% of patients being referred for coronary artery bypass surgery will have some degree of left ventricular dysfunction and, although in the majority this will be mild, one large study described about 17% of patients as having left ventricular dysfunction that was moderate or severe 13 ' (Table 1). Lastly,.Q 1996 The European Society of Cardiology

2 Angina and left ventricular dysfunction 3 Systolic Angina Fixed t t Diastolic Left ventricular dysfunction i Dyspnoea J Reversible Figure 1 The spectrum of presentations of angina and left ventricular dysfunction. Table 1 Prevalence of angina and left ventricular dysfunction. (Reproduced with permission from Daly et a\. /3/ ) Prevalence (n = 2510) % Normal left ventricular function Mild reduction Moderate reduction Severe reduction Previous myocardial infarction amongst patients with heart failure and asymptomatic left ventricular dysfunction in the Studies of Left Ventricular Dysfunction (SOLVD), chest pain was a common complaint, occurring in both the Treatment and Prevention trials' 451. Prognosis Once again, most studies have been carried out amongst hospital-based patients. Perhaps the largest is the Coronary Artery Surgery Study (CASS) registry of patients in whom it was clearly demonstrated that the most important prognostic factor was left ventricular function. Thus, in patients with triplevessel disease and good left ventricular function, the 4-year survival was 79%, while in patients with singlevessel disease and poor left ventricular function the 4-year survival was 67%, falling to 42% in those with triple-vessel disease 161 (Table 2). In the more recent Total Ischaemic Burden in Europe (TIBET) study, 682 patients with chronic stable angina were followed for 2 years. The most important prognostic variable was left ventricular function, as measured by echocardiography, this variable being clearly superior to any of the exercise variables or the presence of silent ischaemia on ambulatory monitoring' 71. Implications Since left ventricular dysfunction is the most important prognostic marker in patients with CHD and it is in this group of patients that the survival benefits of coronary artery bypass surgery are greatest, it would seem very Table 2 Risk stratification by coronary anatomy and left ventricular function. CASS registry ( patients). (Reproduced with permission from Mock et al.' /6J ' Vessels affected Good LVF Poor LVF Percent 4-year survival of medically-treated patients. LVF = left ventricular function important to actively identify such patients by objective techniques, since the presence of left ventricular dysfunction may not be obvious clinically. Diagnosis There is considerable debate on the best method for identifying left ventricular dysfunction in patients with CHD. From a pragmatic clinical point of view, the ECG is very important. A normal ECG obviously does not rule out the presence of CHD, but it does make the presence of significant fixed left ventricular dysfunction due to previous MI much less likely. Conversely, the presence of Q-waves, left bundle branch block, poor R-wave progression and left ventricular hypertrophy are all indicators of underlying left ventricular systolic or perhaps diastolic dysfunction. In patients with an abnormal ECG, it might be possible in the future to identify left ventricular dysfunction by the presence of an elevated level of atrial natriuretic peptide, but this is still an experimental approach and currently the simplest method would be by echocardiography using the Simpson's Rule ejection fraction 181. An immediate difficulty here is that patients who benefit from surgery have had their left ventricular function assessed by contrast angiography at the time of coronary angiography. Although this correlates well with first-pass radionuclide ventriculography, the correlation between the latter and a nuclear scan will vary amongst institutions. Moreover, the correlation between nuclear scanning and echocardiography may not always be close because of the different methods of analysis of radionuclide scans and echocardiograms' 9 ' 10 '. There is certainly a need for standardization in the assessment of left ventricular function but, from a pragmatic clinical point of view at the present time, it might be sensible to accept that significant left ventricular dysfunction exists when the patient's left ventricular function corresponds to that used as a selection criteria for the large clinical trials such as SOLVD. This was a left ventricular ejection fraction of 35% in the presence of a normal lower limit of 50%. Thus, significant left ventricular dysfunction could be defined as being present when left ventricular ejection fraction is 30% below the lower limit of normal within the range used, which is dependent upon the technique that has been employed.

3 4 H. J. Dargie Table 3 Therapeutic options in the management of angina and left ventricular dysfunction Medical Interventional Lifestyle Anti-anginal drugs Aspirin/anti-coagulants ACE inhibitors Anti-arrhythmics Lipid-lowering (diet/drugs) Bypass surgery Angioplasty Transplantation Pacing/AICD Weight reduction Exercise Smoking cessation Stress management ACE = angiotensin converting enzyme; AICD=automatic implanted cardiac deflbrillator. proportion with greater degrees of left ventricular dysfunction, anti-coagulation with warfarin should also be considered. Lifestyle changes cannot be overemphasized. The patient should be encouraged to achieve a body weight of approximately ± 10% of their ideal and to undertake as active a lifestyle as possible, within the limits of their angina, since it has been shown that exercise training can have a very positive effect on symptoms and effort capacity 1 " 1. Smoking cessation is absolutely mandatory and the recent Scandinavian Simvastatin Survival Study (4S) has emphasized the importance of lipid lowering in secondary prevention 1 ' 2 '. Management strategies The management of angina and left ventricular dysfunction is potentially complex, as can be seen in Table 3. Firstly, there is the question of investigation and Fig. 2 describes a suggested approach, based on exercise testing and echocardiography, from which it can be seen that high- or medium-risk patients should be considered for coronary arteriography. This is based on the demonstration of marked reversible ischaemia at a low workload or the demonstration of impaired left ventricular function. High-risk patients should be considered for revascularization, while for a small proportion of patients with specific problems, such as very severe left ventricular dysfunction or recurrent ventricular tachyarrhythmias, the option of transplantation and the insertion of an automatic internal cardiac defibrillator or indeed physiological pacing might be indicated. For the. majority of patients, management is likely to be medical, involving more than just relief of symptoms by anti-anginal medication, although, of course, this is clearly a major aim. For secondary prevention, all patients ought to receive aspirin and, in Anti-anginal medication The approach to the patient with angina and left ventricular dysfunction is, in many cases, similar to that of other patients with angina. If there has been no evidence of cardiac failure and the principal symptom is angina, then many patients will be safely treated with either /?-blockers or calcium channel blockers. In terms of efficacy, the very large TIBET study, in which patients with mild or moderate angina were randomly allocated to atenolol, nifedipine or the combination, conclusively showed that the effects on symptoms and exercise variables were very similar in all three groups' 131. Therefore, the patient is as likely to respond to a /?-blocker as a calcium channel blocker when given as first-line therapy. In patients with more severe ischaemia, the combination of these two agents has previously been shown to be more beneficial than either drug alone 1 ' 41, but this could pose problems in patients with significant left ventricular dysfunction 1 ' 51. Caution should always be advised. However, it is clear that, in the past, many patients with significant left ventricular dysfunction, in whom the dominant symptom was angina, will have been treated successfully and safely with this approach. Prognosis I LV function Reversible ischaemia Echo/nuclear Normal Abnormal Coronary angiograro High risk Low risk Left main 3VD 2VD 1VD Medical therapy wcabg Figure 2 Proposed management plan for angina based on exercise testing and echocardiography. 3VD, 2VD and lvd=3-vessel disease, etc; CABG=coronary artery bypass grafting; LV=left ventricular; PTC A = percutaneous transluminal coronary angioplasty.

4 Angina and left ventricular dysfunction n Visual analogue score Breathlessness -, Angina Tiredness j NS j NS TP< GTN consumption Figure 3 Exacerbation of angina associated with angiotensin converting enzyme inhibitor therapy. =baseline; =captopril; M = placebo. GTN=glyceryl trinitrate. (Reproduced with permission from Cleland et al) 2l].) In those patients in whom dyspnoea is also a significant factor, it could be argued that /?-blockers and first-generation calcium channel blockers would not be the drugs of first choice. Other agents that might be considered are the new calcium channel blockers which exhibit high vascular selectivity. Amlodipine [16] has recently been shown to have a neutral effect on survival in patients with heart failure. This indicates that it could at least be used safely in patients with angina and left ventricular dysfunction. However, information on its anti-anginal efficacy in this specific situation is, as yet, lacking. In all such patients prophylactic nitrates remain an important part of the treatment. In patients with left ventricular dysfunction, this may, perhaps, be even more important. Long-acting nitrates are often prescribed for patients with angina and these should obviously be tried. Retarding progression of left ventricular dysfunction In the SOLVD study, it was clearly shown that enalapril could retard the progression from asymptomatic left ventricular dysfunction to heart failure. However, in terms of survival, it is uncertain whether it is better to prescribe an angiotensin converting enzyme (ACE) inhibitor in the asymptomatic phase or wait until the development of symptoms. Furthermore, ACE inhibitors also have a beneficial effect on the remodelling process that occurs in many patients following acute Ml' 171 and improve survival to a clinically significant degree in patients with left ventricular dysfunction 1 ' 8 ' 191. The SOLVD study also provided some evidence that ACE inhibitors had a beneficial effect on a number of ischaemic endpoints, including the development of unstable angina and recurrent Ml' 201. However, this has not been a consistent finding in all of the ACE inhibitor studies 1 ' 91 and, therefore, the potential for retardation of the progression of left ventricular dysfunction following acute MI as a result of this mechanism requires clarification. Nevertheless, both in the SOLVD Prevention study and in the post-mi studies, progression to heart failure has certainly been reduced in patients with at least moderate left ventricular dysfunction. It would, therefore, seem logical to consider ACE inhibitor therapy in patients with left ventricular dysfunction, even though their dominant symptom might well be angina. In this situation, however, caution should still be used, since there is evidence that, in some patients at least, institution of ACE inhibitor therapy can lead to an exacerbation of angina. This is of particular concern if treatment is associated with a significant fall in blood pressure, as can be the case in patients with severe left ventricular dysfunction, especially when treated with high doses of diuretics' 21 ' (Fig. 3). Survival ACE inhibitors have quite clearly been shown to improve survival in patients with left ventricular dysfunction and symptoms of heart failure. However, although this has not been specifically demonstrated for patients in whom the dominant symptom is angina, many physicians would, at this time, also prescribe an ACE inhibitor in patients in whom the left ventricular ejection fraction is >35%. However, as pointed out earlier, careful monitoring should be carried out to ensure that this does not cause a deterioration in the control of angina symptoms. Against the background of ACE inhibitors and improvement of mortality in patients with left ventricular dysfunction, it must not be forgotten that there is also a very definite place for revascularization, since the greatest survival benefit associated with coronary artery bypass surgery has been demonstrated in patients with left ventricular dysfunction 121. However, since patients with severe left ventricular dysfunction have been largely excluded from randomized trials, such as in the CASS study where left ventricular ejection fraction was at least 35% l22), the evidence, such as it is, comes largely from the Duke Registry data, in which cohorts of patients treated surgically have been compared

5 6 H. J. Dargie -5" 0.8 Survival probabilities by treatment group Modest LVD I, Surgical ' 1 Medical co J5> LVEF= Years of follow-up Survival probabilities by treatment group Moderately severe LVD Surgical Medical co 0.2 i? 0.8 If 0.6 fa 03 LVEF=32 _L _L _L Years of follow-up Survival probabilities by treatment group Severe LVD Surgical Medical 0.2 LVEF=24 _L _L _L Years of follow-up Figure 4 Survival probabilities for patients with left ventricular ejection fraction (LVEF) <40%, treated using coronary artery bypass grafting or medical therapy. LVD = left ventricular dysfunction. (Reproduced with permission from Whalen et a/.' 23 '.) with control cohorts, constructed from patients with similar demography' 231 (Fig. 4). In such patients, there would appear to be a clear survival advantage associated with surgery, but obviously with an increased early mortality rate at the time of coronary artery bypass grafting. This topic has received increasing attention due to the appreciation that, amongst patients with left ventricular dysfunction, a significant proportion may be reversible, due to the presence of 'hibernating' myocardium' 241. This term describes a myocardium which is poorly contractile due to hypoperfusion and there is now increasing evidence that revascularization of such myocardium leads to recovery of contractile function. Identification of viable myocardium can be achieved in a number of ways, not only by very sophisticated metabolic assessment, using positron emission tomography, but also by simple thallium studies and stress echocardiography' 251. The recognition of this phenomenon has greatly increased interest in the

6 Angina and left ventricular dysfunction identification of viable myocardium and this remains a major issue for the future. Conclusion The presence of left ventricular dysfunction is the single most important prognostic factor in patients with CHD. It would, therefore, seem prudent to advise routine assessment of left ventricular function in patients with angina who present with an abnormal ECG. Exactly how this should be done is not clear at the present time, although by far the simplest technique will be to employ echocardiography. Identification of viable myocardium by echo or nuclear techniques should also be high on the agenda in these patients. Also of considerable interest is the question of the best form of pharmacological therapy, in addition to nitrates, for patients with angina and impaired left ventricular function. Given that /?-blockers are now under discussion and trial in patients with the most severe forms of heart failure, the presence of left ventricular dysfunction need not necessarily be a contraindication to the use of /^-blockade. It would, however, only be sensible to proceed with caution when these drugs are used in this situation. There is also increasing interest in the new generation of vasoselective calcium channel blockers such as amlodipine and objective evidence of their benefit in the symptomatic treatment of patients with angina and left ventricular dysfunction is now required. References [1] Pepine CJ, Abrams J, Marks RG, Morris JJ, Scheidt SS, Handberg E for the TIDES investigators. Characteristics of a contemporary population with angina pectoris. Am J Cardiol 1994; 74: [2] Kannel WB, Sorlie P, McNamara PM. Prognosis after initial myocardial infarction: the Framingham study. Am J Cardiol 1979; 44: [3] Daly LE, Lonergan M, Graham I. Predicting operative mortality after coronary artery bypass surgery in males. Q J Med 1993; 68: [4] The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: [5] The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327: [6] Mock MB, Ringqvist I, Fisher LD et al. Survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation 1982; 66: [7] Murdoch DL, Norrie JD, Findlay IN, Ford I, Fox KM, Dargie HJ. Clinical and echocardiographic variables predicting prognosis in chronic stable angina pectoris in the TIBET study (Abstr). Eur Heart J 1994; 15 (Abstr Suppl): 546. [8] Schiller-Nelson B, Aquatella H, Ports TA et al. Left ventricular volume from paired biplane two dimensional echocardiography. Circulation 1979; 60: [9] Nusynowitz ML. Benedetto AR, Walsh RA, Starling MR. First-pass anger camera radiocardiography: biventricular ejection fraction, flow, and volume measurements. J Nucl Med 1987; 28: [10] Senior R, Sridhara BS, Basu S et al Comparison of radionuclide ventriculography and 2D echocardiography for the measurement of left ventricular ejection fraction following acute myocardial infarction. Eur Heart J 1994; 15: [11] Todd IC, Ballantyne D. Antianginal efficacy of exercise training: a comparison with ^-blockade. Br Heart J 1990; 64: [12] Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: [13] Dargie HJ for the TIBET study group. Medical treatment of angina can favourably affect outcome (Abstr). Eur Heart J 1993; 14 (Abstr Suppl): 304. [14] Dargie HJ, Lynch PG, Krikler DM el al. Nifedipine and propranolol: a beneficial drug interaction. Am J Med 1981; 71: [15] Moss JA, Oakes D, Benhorin J, Carleen E and the Multicenter Diltiazem Post-Infarction Research Group. The interaction between diltiazem and left ventricular function after myocardial infarction. Circulation 1989; 80 (Suppl IV): IV [16] Packer M, Nicod P, Khandheria BR et al. Randomized, multicenter, double-blind, placebo-controlled evaluation of amlodipine in patients with mild-to-moderate heart failure. J Am Coll Cardiol 1991; 17 (Abstr Suppl): 274A. [17] Ray SG, Pye M, Oldroyd KG et al. Early treatment with captopril after acute myocardial infarction. Br Heart J 1993; 69: [18] Pfeffer MA, Braunwald F, Moye LA et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1992; 327: [19] 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: [20] Yusuf S, Pepine CJ, Garces C et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fraction. Lancet 1992; 340: [21] Cleland JG, Henderson E, McLenachan J, Findlay IN, Dargie HJ. Effect of captopril, an angiotensin-converting enzyme inhibitor, in patients with angina pectoris and heart failure. J Am Coll Cardiol 1991; 17: [22] CASS Principal Investigators and their Associates. Coronary Artery Surgery Study (CASS): a randomized trial of coronary artery bypass surgery. Survival data. Circulation 1983; 68: [23] Whalen RE, Harrell FE, Lee KL, Rosati RA. Survival of coronary artery disease patients with stable pain and normal left ventricular function treated medically or surgically at Duke University. Circulation 1982; 65 (Suppl II): [24] Rahimtoola SH The hibernating myocardium. Am Heart J 1989; 117: [25] Dilsizian V, Bonow RO. Current diagnostic techniques of assessing myocardial viability in patients with hibernating and stunned myocardium. Circulation 1993; 87: 1-20.

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