Beta-Blocking Drugs and Coronary Heart Disease - Springer Link

Cardiovascular Drugs and Therapy 1997;11:219–225 © Kluwer Academic Publishers. Boston. Printed in U.S.A.

Beta-Blocking Drugs and Coronary Heart Disease

Beta-Blocking Drugs and CHD

Goldstein

Sidney Goldstein Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, Michigan; Case Western Reserve University, Cleveland, Ohio, USA

Summary. Since the development of beta-adrenergic blocking agents over 30 years ago, they have been established as an important therapeutic modality in the treatment of coronary heart disease. This article reviews the role of betablockers in the treatment of hypertension, angina, acute myocardial infarction, and heart failure. A number of multicenter studies indicate that beta-blockers have an important effect in decreasing morbidity and mortality in patients with hypertension and appear to have a relatively increased importance in elderly patients with hypertension. Although their long-term effects on the mortality of angina pectoris have not been fully investigated, investigations indicate that, compared with other drugs, beta-adrenergic blocking agents signi~cantly decrease the frequency and duration of angina pectoris. The largest use of these drugs has been examined in the treatment of acute myocardial infarction. Two major trials, the Norwegian Timolol Trial and the Beta Blocker Heart Attack Trial, con~rm the long-term bene~t in patients following acute myocardial infarction. Their use in heart failure is under close investigation following a series of preliminary studies suggesting they may decrease mortality risk. Although the tolerability of these drugs has been questioned, careful examination of clinical trials indicate that they are relatively well tolerated. These observations emphasize the importance of beta-adrenergic blocking agents in hypertension, angina, and acute myocardial infarction and speak to a wider clinical use of these drugs. Cardiovasc Drugs Ther 1997;11:219–225 Key Words. beta blockers, acute myocardial infarction, angina pectoris, hypertension

Beta-adrenergic receptor blockers were introduced initially for the treatment of arrhythmias and angina almost 30 years ago. In 1948 Ahlquist [1] classi~ed adrenergic action in various organs by studying the pattern of activity of six catecholamines. He observed two distinct orders of potency of the six catecholamines, which were termed alpha and beta, which he postulated were mediated by two types of adrenergic receptors. Most alpha actions were excitatory, while the beta actions were inhibiting, with the notable exception that cardiac stimulation was mediated by beta receptors. Sir James Black [2] was the ~rst to appreciate the possible clinical bene~t of sympathetic inhibition of the heart and developed beta-receptor blockers for the treatment of ischemic heart disease and arrhythmias. As beta-blockers gained wider use in car-

diovascular diseases, it became evident that they had a role in the treatment of hypertension and, subsequently, in acute and recurrent myocardial infarction and many other conditions. Beta-blockers have gained increased interest in the last few years as an important mode of therapy for ischemic and hypertensive cardiovascular disease. This review provides a brief summary of the current state of our knowledge about betablockers in the treatment of hypertension, acute myocardial infarction, and heart failure.

Hypertension It has been long known that patients with hypertension, even those with mildly elevated blood pressure, are at increased risk for cardiovascular disease expressed as either stroke or acute myocardial infarction. A recent meta-analysis of major intervention studies in middle-aged patients with hypertension demonstrated that sustained blood pressure reduction resulted in a 42% decrease in nonfatal stroke and a 14% decrease in acute myocardial infarction [3]. As a class, all beta-blockers have a bene~cial effect on hypertension, although in the major trials propranolol, metoprolol, and atenolol have been the drugs most extensively investigated. The comparison between beta-blockers and other drugs has been examined in a number of clinical trials. Most recently, the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure [4] listed six groups of drugs as acceptable and effective for ~rstline therapy, including thiazides, beta-blockers, calcium antagonists, ACE inhibitors, and combination of alpha/beta-blockers. Preference was given to thiazides and beta-blocking agents based on the results of major studies that have demonstrated signi~cant bene~t on morbidity and mortality endpoints. A number of studies have examined the comparison of the bene~ts between beta-blockers and diuretics. In Europe the Medical Research Council Trial, the Heart Attack Primary Prevention in Hypertension (HAPPHY) study [5], and the International Prospective Pri-

Address for correspondence: Sidney Goldstein, M.D., Henry Ford Heart & Vascular Institute 2799 West Grand Boulevard Detroit, MI 48202-2689, USA. 219

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mary Prevention Study in Hypertension (IPPPSH) [6] study all showed similar effects of both drug groups. The Metoprolol Atherosclerosis Prevention Study in Hypertension (MAPHY) [7] observed a greater decrease in death due to coronary heart disease and stroke in patients treated with metoprolol than in those treated with thiazide diuretics, despite equivalent blood pressure control. All of these studies demonstrated a signi~cant bene~t of beta-blockers in terms of overall mortality. Studies in elderly patients treated with adrenergicblocking agents, diuretics, or both in combination have achieved similar bene~ts in the treatment of stroke and coronary heart disease. One exception is the Medical Research Council trial in hypertensive patients between the ages of 65 and 74. In this study diuretics demonstrated a decrease in mortality and beta-blockers had no effect [8], but the study had relatively poor compliance. The Swedish Trial of Older Patients with Hypertension [9] examined the use of beta-blockers or diuretics, and observed a 47% decrease in mortality during a 2-year follow-up when compared with placebo. The greatest absolute bene~t in terms of reducing mortality in hypertension can be achieved in elderly patients, who are at a higher risk and, therefore, experience a greater absolute mortality. Although controversy remains as to the best drug for the treatment of hypertension, the use of some short-acting calcium entry blockers has recently been challenged based on a lack of bene~t and perhaps an increased mortality associated with their use [10,11]. The mechanism by which beta-blockers express their bene~t is not clear. The argument for blood pressure lowering itself, as a surrogate for bene~t, has been challenged in light of the Cardiac Arrhythmia Suppression Trial [12] and the reliance of other surrogates for mortality decrease, such as suppression of ventricular ectopy. It is quite possible that beta-blockers express their effect on that group of patients with hypertension who also have coronary artery disease. In subsequent sections, possible mechanisms are discussed. Recent studies in animals suggest a role of beta-blockers in the prevention of atherosclerosis. [13] This potential effect in a high-risk population with hypertension could be an additional bene~t. Optimal therapy requires a consistent blood pressure reduction over a 24-hour period and, therefore, drugs that have controlled release, such as long-acting propranolol or controlled-release metoprolol, may be the drugs of choice.

Angina Pectoris Improvement in symptoms of angina pectoris was perceived as an initial therapuetic bene~t of beta-blocking drugs. Beta-blockers, along with a veriety of other drugs, including nitroglycerin preparations and calcium blockers, all have been shown to improve exercise tolerance and to relieve symptomatic angina. Beta-

blockers modify the ST-segment depression response to exercise, angina frequency, and duration of angina by modifying the blood pressure and pulse rate response to exercise. Unfortunately, there are no large, long-term studies assessing the effect of these drugs on mortality in patients with angina pectoris. Recent studies of the Asymptomatic Cardiac Ischemia Pilot Study [14] compared beta-blockers with calcium blocking agents and demonstrated that beta-blockers achieved a greater bene~t in terms of reduction of duration of angina and number of morbid cardiac events. Both medical therapies were less effective than coronary bypass surgery or angioplasty for the relief of ischemia. Ambulatory electrocardiographic monitoring has demonstrated that asymptomatic ischemic episodes occur almost four times as frequently as symptomatic episodes. Angina, symptomatic or asymptomatic, occurs more frequently in the early morning hours and persists during the waking hours. Studies comparing calcium blocking agents with beta-blockers for the control of ischemic episodes over a 24-hour period showed that a greater bene~t was achieved with beta-blocker therapy [15]. The suppression of ischemic events was closely related to the ability to modify the early morning increase in blood pressure and pulse rate. Concomitant use of beta-blockers and nitrate therapy is common in patients with angina pectoris in addition to combination with calcium channel blockers, particularly dihydropyridines such as nifedipine. There is little evidence to suggest that one beta- blocker is better than another in the treatment of angina. There are also little comparative data examining the differential bene~t of beta-blockers with or without intrinsic sympathomimetic activity or cardioselectivity in regard to angina treatment. It does appear that, as in hypertension control, the long-acting preparations have a greater bene~t, particularly in suppressing early morning ischemic events.

Myocardial Infarction The knowledge that beta-blocking agents were effective for the treatment of myocardial infarction emerged in the 1970s after a series of small studies indicated that a bene~cial effect could be achieved with these drugs. The most persuasive data resulted from the Norwegian Timolol Trial [16] and the Beta Blocker Heart Attack Trial (BHAT) [17], both of which demonstrated a signi~cant reduction in cardiovascular morbidity and mortality. In addition, their ability to decrease ventricular ectopy associated with acute myocardial infarction, coupled with the observed decrease in mortality and sudden death, suggested that they might have a role as an antiarrhythmic agent. The success of these studies led to the investigation of their use in the acute phase of myocardial infarction.


Acute phase of myocardial infarction A meta-analysis of the use of beta-blockers for the acute phase of myocardial infarctions was carried out in 28 randomized trials in over 11,000 patients [18]. The International Study of Infarct Survival-I (ISIS-I) studied the effect of intravenous atenolol and observed a reduction in mortality of 15% when used within the ~rst 12 hours of myocardial infarction [19]. A similar bene~t was observed in the Metoprolol in Acute Myocardial Infarction (MIAMI) Study [20], using intravenous metoprolol followed by oral metoprolol. That study observed a 13% decrease in overall mortality over a 15-day period. The dose of atenolol and metoprolol used in these studies was 15 mg in three divided doses five minutes apart followed by oral therapy. The use of beta-blockers in the acute phase also demonstrated its effect on ischemic chest pain and serious ventricular arrhythmias. In the TIMI II trial [21], the effect of intravenous metoprolol was investigated when used in addition to thrombolytic therapy. A signi~cant reduction in the occurrence of reinfarction and recurrent ischemic events was achieved. Since beta-blockers express their effect in the ~rst 24 hours of therapy and thrombolytic therapy expresses its effect 2 days after intravenous injection, there is reason to presume a synergistic effect on mortality when the two drug therapies are used together. Late phase of myocardial infarction In the timolol [16] and propranolol [17] studies, drugs were administered to patients within the ~rst 1–2 weeks following acute myocardial infarction. Both studies demonstrated a reduction in the mortality rate. Timolol 20 mg daily resulted in a reduction of overall mortality of 36%, and propranolol 180–240 mg daily resulted in a 26% decrease in mortality (Fig. 1). Both studies demonstrated a signi~cant effect on sudden and nonsudden death. Meta-analysis of 16 long-term studies of beta-blockers observed a 20% relative reduction in overall mortality, with a 27% reduction in reinfarction [18]. Although the initial studies suggested that beta-blockers with intrinsic sympathomimetic activity were less effective [22], recent studies, using acebutolol in high-risk patients, demonstrated an overall mortality reduction similar to that reported is the previous studies [23]. The duration of bene~t appears to persist through the longest follow-up, 6 years in the Norwegian Timolol Trial [24]. Studies of withdrawal of beta-blockers in the years following myocardial infarction suggest that discontinuation of therapy may precipitate recurrent events [25]. In elderly patients [26] and patients with diabetes (27–29) similar bene~cial effects have been observed. Analysis of early and late intervention trials in acute myocardial infarction have demonstrated that the greatest absolute bene~t of beta-blockers is achieved in older patients [26]. Risk-strati~cation analysis demonstrated that, regardless of subset evalu-

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Fig. 1. Cumulative mortality observed in the Beta Blocker Heart Attack Trial. (From Beta-Blocker Heart Attack Trial Research Group [17], with permission.)

ation, patients at highest risk achieve the greatest absolute bene~t with the use of beta-blockers. This is true in terms of location of acute myocardial infarction, comparing anterior with posterior infarction in those with heart failure and the elderly. Patients of particular interest have been those individuals with left ventricular dysfunction. Retrospective analysis of the BHAT [30] demonstrated that in patients with compensated congestive heart failure, propranolol therapy resulted in a 27% decrease in mortality compared with placebo. Of particular signi~cance is a 47% decrease in sudden death in the patients with congestive heart failure treated with propranolol. The presence of congestive heart failure in the postinfarction population has contributed partially to the underutilization of beta-blockers based on the presumption that these agents may accelerate heart failure. In fact, in studies in which heart failure complicates acute myocardial infarction, there is no signi~cant long-term increase in the incidence of recurrent heart failure, although transitory increases in heart failure can occur with early administration of the drugs. As noted earlier, their bene~cial effects were most profound in heart failure patients. Similarly, the use of beta-blockers has been presumed to be contraindicated in diabetic patients. Investigation of this issue has reported the opposite conclusion with diabetic postinfarct patients, and particularly in those with heart failure receiving the greatest bene~t in terms of mortality (Fig. 2) [29]. The greatest relative reduction in mortality with beta-blockers was achieved in diabetic patients compared with nondiabetics, with an observed

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Fig. 2. The effect on survival of beta-blocker therapy compared with placebo in patients with diabetes and heart failure. (From Kjekshus et al. [29], with permission.)

decrease of 48% in diabetic patients compared with 29% in nondiabetic patients.

Chronic Congestive Heart Failure The latest area of interest is the use of beta-blockers in the treatment of congestive heart failure. Initial studies by Waagstein et al. [31], in which favorable effects, of long-term beta-blockers were observed in patients with severe idiopathic dilated cardiomyopathy, were greeted with skepticism. Subsequent reports in the BHAT [30] tended to support their potential bene~t. These reports were followed by a series of studies carried out to examine a variety of beta-blockers drugs, including metoprolol [32] and the newer drugs bucindolol [33] and carvedilol [34], in patients with heart failure. The Metoprolol Dilated Cardiomyopathy Trial [32], in which metoprolol was administered to patients with idiopathic dilated cardiomyopathy, demonstrated a signi~cant decrease in mortality and the need for cardiac transplantation. The Cardiac Insuf~ciency Bisoprolol Study [33] failed to demonstrate an overall bene~t of bisoprolol in the treatment of patients with heart failure. However, when patients were separated between those with ischemic and nonischemic heart failure, those with nonischemic heart failure appeared to achieve a decrease in mortality rate without any bene~t observed in the ischemic patients. The recent results of the use of carvedilol [34], a beta-blocker with antioxidant effects, indicates that it too has a physi-

ologic bene~t in patients with heart failure secondary to coronary artery disease. A careful examination of the effects of beta-blockers in patients with heart failure has revealed that a transitory decrease in left ventricular dysfunction may occur with the initial administration of drug. Following this initial decrease, ejection fraction and left ventricular function improved signi~cantly [35]. The mechanism by which beta-blockers express their effect in heart failure is still not fully appreciated, but it is though to be related to the modi~cation of beta-receptor sensitivity to circulating catecholomines [36]. With the administration of beta-blockers there appears to be increased sensitivity or “upregulation” of beta-receptors, making the cardiomyocytes more responsive to circulating catecholomines. Although variation in beta-receptor sensitivity has been observed with clinical and hemodynamic improvement with some beta-blockers, this observation has not been consistent. Recent studies with carvedilol, which exhibits a profound physiological bene~t, failed to demonstrate any evidence of “upregulation” [37]. It is possible that the improvement in heart failure is due to more ef~cient utilization of energy resulting from a decrease a heart rate [38].

Tolerability of Beta-Blockers The observation that these drugs have adverse effects has been demonstrated in a number of clinical trials. For a number of reasons, these adverse effects have been exaggerated in regard to beta-blockers. The BHAT [17] patients, who were randomized to placebo


Table 2. Treatment group differences in mean values of lipid values over time

Table 1. Percent of patients with complaints at any time during BHAT Complaint Cardiopulmonary Shortness of breath Bronchospasm Rapid heart-beat Cold hands, feet Neuropsychiatric Tiredness Reduced sexual activity Depression Nightmares Faintness Insomnia Blacking out Hallucinations Other Diarrhea

Propranolol

Placebo

223

p

67.0 31.0 11.0 10.0

66.0 27.0 15.0 8.0

NS ,.005 ,.001 ,.025

67.0

62.0

,.005

43.0 41.0 40.0 29.0 21.0 9.0 6.0

42.0 40.0 37.0 27.0 19.0 10.0 5.0

NS NS NS NS NS NS NS

6.0

4.0

Serum lipids (mg/dl) Total cholesterol Triglycerides

HDL

Estimated LDL

Clinic visit Baseline 6 months 12 months Baseline 6 months 12 months Baseline 6 months 12 months Baseline 6 months 12 months

Propranolol (mean) 222.2 260.0 260.4 186.5 240.4 238.7 35.5 41.8 42.2 148.5 173.1 174.5

Placebo Z of (mean) difference 222.5 258.6 260.2 186.1 204.2 204.5 35.4 44.4 45.2 148.6 75.0 175.8

0.15 20.74 20.09 20.12 27.06 26.46 20.38 6.47 7.24 0.05 1.08 0.72

Adapted from Byington et al. [43], with permission.

,.01

Adapted from Beta-Blocker Heart Attack Trial Research Group [17], with permission.

and beta-blockers, were asked serially throughout the study to evaluate the occurrence of side effects (Table 1). Statistically signi~cant occurrence of tiredness, bronchospasms, diarrhea, and cold extremities were observed in the propranolol-treated patients when compared with the placebo population, although these events frequently occurred in both groups. Patients who have experienced an acute myocardial infarction face signi~cant psychological stress. Depression and a variety of psychological responses to their disease was common in both the treatment and placebo patients. It is therefore important that careful evaluation of patients with regard to their psychological response to the drug be considered in a blinded fashion and compared with placebo. It is possible that cardioselective blockers or those that are not lipophilic may have less central nervous system effects, but comparisons in this regard have been inconsistent [39]. The effect of different beta-blockers on mentation has also been evaluated and failed to demonstrate any signi~cant adverse effect [40]. Although cold extremities were reported in the BHAT, the effect of these agents on claudication is also uncertain. Analyses of a number of clinical trials indicate, in fact, that betablockers have no adverse effect on claudication [41,42]. Additional concern has been expressed with regard to their potential effect on lipid metabolism. Total cholesterol and low-density lipoproteins are not affected by beta-blockers [43]. Nonselective agents, such as propranolol, tend to decrease high-density lipoprotein by about 10% and to increase triglycerides (Table 2). Selective beta-blockers and those with intrinsic sympathomimetic activity have little or no effect on lipids

[44]. In spite of these effects, an analysis of the effect of propranolol in patients with increased plasma cholesterol and triglyceride concentrations reported an overall reduction in mortality and morbidity of propranolol on the order of 20% [43]. This review has focused on the use of beta-blockers in hypertension, coronary heart disease, and heart failure. It is clear that beta-blockers have been underutilized in the treatment of heart disease and hypertension. Current estimates indicate that less than one third of patients experiencing an acute myocardial infarction in the United States receive beta-blocker therapy. Yet, compared with currently available drugs, they clearly have been shown to achieve the greatest long-term bene~t in these patients. Whether or not newer beta-blockers with different characteristics will be more effective, such as preparations using long-acting drugs or drugs with antioxidant or vasodilator characteristics such as carvedilol and bisoprolol, remains to be determined. Nevertheless, the modi~cation of the sympathetic and cardiovascular nervous system by currently available beta-blockers results in a signi~cant decrease in morbidity and mortality, resulting in a signi~cant bene~t to the patient with hypertension, ischemic heart disease, and heart failure.

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