An Approach to Cardioprotection

To reduce the incidence of sudden cardiac death, it is desirable to identify those at increased risk for this event and give them effective prophylactic treatment. The most easily identified patients at risk are those with documented coronary heart disease. However, many more persons have latent heart disease, including the 50% of patients with myocardial infarction in whom the infarction is silent [6]. A relatively small proportion of those with undeclared disease can be identified, either through known risk factors for coronary heart disease or as a result of electrocardiography or electrocardiographic stress testing. Coronary angiography yields the most information in predicting risk, but this technique is not practical for investigating large numbers of patients.

Some risk factors for coronary artery disease, such as hypertension, hyperlipidemia, and cigarette smoking, are both identifiable and treatable. Although reduction of blood pressure seems to be effective in preventing death from cerebrovascular accident, its effect on coronary mortality rates is less clear [7]. Experimental results in feline left ventricular hypertrophy [8] suggest that myocardial hypertrophy contributes to the adverse electrophysiologic consequences of ischemia and reperfusion. Effective long-term treatment of hypertension may thus have an indirect beneficial effect on the ventricular arrhythmias associated with coronary artery disease.

Although simvastatin was recently shown to reduce mortality in patients with established coronary artery disease [9], the use of lipid-lowering drugs does not have proven efficacy in primary prevention. As a result, the commitment of individual physicians to the treatment of hyperlipidemia varies markedly. The most effective preventive measure is cessation of cigarette smoking, which significantly reduces the likelihood of coronary death [10], but the success of programs to help persons stop smoking is frequently disappointing. Other lifestyle changes, such as weight reduction and the introduction of regular physical exercise, may also help but are equally hard to achieve in practice.

After high-risk persons have been identified and their risk factors modified, subsequent aims include the treatment of myocardial ischemia, if present, and the suppression of ventricular tachyarrhythmias. The cardioprotective drug chosen should ideally achieve both of these goals, and it should have been shown in clinical trials to reduce the risk for sudden cardiac death. The agents that have most successfully met these ideal criteria are the ß-blockers, and they have been shown to be consistently effective in large, long-term prevention trials [11].

ß-Blockers and Prevention of Ventricular Fibrillation: Evidence

During 30 years of surveillance, the Framingham Study investigators [12] found that the overall incidence of sudden cardiac death during each 2-year period was 6.3 cases per 1000 men and 2.0 cases per 1000 women. In persons who had no previous coronary heart disease but had definite hypertension, the risk for sudden death was more than double that in persons with normal blood pressure. Incidence rates in persons with previous coronary heart disease (31.6 cases per 1000 men and 10.0 cases per 1000 women) were six to eight times greater than those of persons without coronary heart disease (4.0 cases per 1000 men and 1.6 cases per 1000 for women). Clearly, attempts to significantly reduce overall cardiovascular mortality must address in particular the hypertensive patient and the patient with established coronary heart disease.

Primary Prevention of Coronary Disease

Risk stratification of patients in the Framingham Heart Study [13] indicates that hypertension is a highly significant risk factor for the development of coronary disease and for sudden cardiac death. The effect of treating hypertension has been assessed in several prospective clinical trials [14]. Although diuretics appear to reduce coronary events in the elderly [15, 16], angiotensin-converting enzyme inhibitors, calcium-channel blockers, and -blockers have not been shown to reduce the frequency of myocardial infarction, nor do they reduce the risk for sudden death.

In contrast, evidence shows that ß-blockers have a primary preventive role in men with hypertension. In the MAPHY (Metoprolol Atherosclerosis Prevention in Hypertensives) study [17], a mean 5-year follow-up of patients treated with metoprolol or thiazide diuretics confirmed that total mortality was significantly lower in the patients treated with metoprolol. The reduction was explained primarily by the 30% reduction in the number of sudden cardiac deaths; these deaths represented 78% of total cardiovascular mortality (Figure 1). This trial has been criticized [18, 19], but the criticisms have been answered [20]. Furthermore, data from other studies [21-23] have also shown trends favoring the use of ß-blockers in primary prevention.

View larger version (15K): [in this window] [in a new window]   Figure 1. Sudden cardiovascular deaths in hypertensive patients. Reproduced with permission from American Journal of Hypertension [17].

Secondary Prevention

After myocardial infarction, the next most frequent cause of sudden death is arrhythmia, usually ventricular fibrillation [24]. It has been clearly shown that ß-blockers reduce the incidence of sudden death. Recent evidence [9] also suggests that simvastatin has a beneficial effect in patients with hypercholesterolemia. Aspirin and aspirin-like drugs have been found to reduce early and late mortality after myocardial infarction [25], but no evidence shows any effects on sudden death. An average reduction in total mortality of about 20% has been shown from pooled data from 18 000 patients during long-term treatment after myocardial infarction with ß-blockers [26]. This translates into an absolute reduction in risk for death from about 10% to about 8%. Even more impressive is that ß-blocker treatment reduces sudden death among these patients by 32% to 50% [27-30].

The results of three long-term, placebo-controlled trials of ß-blockers administered after infarction were published in 1981 and 1982 [27-29], providing, for the first time, evidence that medical therapy could reduce mortality after myocardial infarction. The three drugs used—the non-selective agents timolol and propranolol and the ß₁-selective agent metoprolol—reduced total mortality by 26% to 36%. In the Norwegian Multicenter Study Group trial [27], the most pronounced effects of timolol were on the sudden cardiac death rate, which was almost halved. In the ß-Blocker Heart Attack Trial (BHAT) [28], propranolol reduced the incidence of sudden cardiac death from 4.6% (in participants receiving placebo) to 3.3% (P < 0.05), a reduction of almost 30%. In the Goteborg metoprolol trial [29], a 40% reduction in the number of deaths occurring within 24 hours and within 1 hour of onset of symptoms was seen. An analysis of pooled data from five different trials in which long-term metoprolol therapy was used after myocardial infarction [30] suggested that the reduction in total mortality was due primarily to a 40% reduction in the incidence of sudden cardiac death, a Figure that held true for both men and women (Figure 2).

View larger version (15K): [in this window] [in a new window]   Figure 2. Cumulative number of sudden deaths reported in five postinfarction trials. Reproduced with permission from the European Heart Journal [30].

Two large, short-term, prospective trials of ß-blockers administered soon after the onset of myocardial infarction have also confirmed the efficacy of these agents in reducing mortality in the acute setting [31, 32]. The First International Study of Infarct Survival (ISIS-1) [31] included approximately 16 000 patients and found that atenolol reduced early cardiovascular mortality by 14% after 7 days. The study did not specifically analyze sudden death rates. In the Metoprolol in Acute Myocardial Infarction (MIAMI) trial [32], randomly assigning 6000 patients to metoprolol or placebo produced a 13% difference in mortality at 15 days in favor of metoprolol, but the effect was not statistically significant. On the basis of pooled data from trials of early intervention with a ß-blocker [33], it has been calculated that ß-blockers reduce mortality by about 15% in the first week.

It is not possible to say from these results that all ß-blockers will produce similar results in the treatment of myocardial infarction. Although there appears to be a class effect in lowering blood pressure, reducing ischemia, and inhibiting the development of infarction, only a few ß-blockers have been shown to reduce the risk for sudden cardiac death. This is true of the lipophilic (and hence central nervous system-active) ß-blockers timolol [27], metoprolol [30], and propranolol [28], but a long-term prophylactic effect has not been shown for the hydrophilic ß-blockers atenolol [31] and sotalol [34]. The clinical evidence appears to confirm experimental observations that the reduction in sudden cardiac death is, at least in part, mediated through activity in the central nervous system.

Little evidence supports the efficacy of other antihypertensive or anti-ischemic agents in the secondary prevention of sudden cardiac death. Although good theoretical reasons exist for the use of calcium-channel blockers, particularly in reducing ischemia, the data so far have been inconclusive or even suggestive of a detrimental effect on mortality [35, 36]. Angiotensin-converting enzyme inhibitors appear to have an important role in the long-term reduction of cardiovascular death after infarction [37, 38], but the improvement they cause occurs primarily in patients with impaired cardiac function and is due to slowed progression to overt congestive heart failure rather than to a reduction in sudden death. Finally, results from the Fourth International Study of Infarct Survival (ISIS-4) [39] are disappointing: They show no clear benefit, in terms of mortality reduction, from the routine use of magnesium or nitrates in myocardial infarction.

ß-Blockers and Prevention of Ventricular Fibrillation: Mode of Action

The efficacy of ß-blockers in preventing sudden cardiac death has been presumed to result from the antiarrhythmic properties of these agents. Animal studies [40-45] show that they can prevent ventricular fibrillation but that they are only moderately effective in suppressing common ventricular arrhythmias in patients who receive standard therapeutic doses [46]. One trial of metoprolol after infarction showed that the drug had relatively small effects on less serious arrhythmias, such as ventricular premature complexes, although it markedly reduced the incidence of ventricular fibrillation [46, 47]. In a study of patients with previous ventricular tachyarrhythmias [48], intravenous propranolol appeared to effectively suppress the inducibility of fast, electrically unstable ventricular tachyarrhythmias. In contrast, the ß-blocker was ineffective in suppressing the inducibility of stable, monomorphic ventricular tachyarrhythmias. These findings suggest that the mechanisms of initiation of ventricular premature complexes and stable, monomorphic ventricular tachyarrhythmias differ from those of electrically unstable ventricular tachyarrhythmias. If this is so, then effective suppression of the former will not necessarily predict successful protection from ventricular fibrillation.

ß-blockers are now thought to have a beneficial effect on many factors that predispose to reduced electrical stability of the heart [46], including myocardial ischemia, high cardiac sympathetic tone, and stress-induced reduction of cardiac vagal tone.

ß-blockers cause a major anti-ischemic effect by decreasing heart rate, systolic blood pressure, and myocardial contractility and thus decreasing myocardial oxygen demand [49]. They may also increase myocardial blood supply relative to oxygen demand by prolonging diastolic perfusion time and, after acute administration, by maintaining diastolic perfusion pressure. Beneficial effects on myocardial metabolism, subendocardial blood flow, and microvascular injury during ischemia may also be seen [4].

High catecholamine levels, and thus high cardiac sympathetic tone, are seen in association with stress, exercise, and infarction and probably play a role in the generation of ventricular fibrillation by decreasing the threshold for such arrhythmias. This hypothesis has been confirmed in animal studies [50], in which the role of ß-blockers in increasing the arrhythmia threshold has also been shown. The action of ß-blockers in anesthetized, open-chest dogs appears to be a class effect: It has been seen with timolol, pindolol, propranolol, metoprolol, and labetalol [50].

Although the reduction of myocardial ischemia and cardiac sympathetic activation appear to be effects common to most ß-blockers, the attenuation of stress-induced vagal withdrawal, and hence a beneficial increase in cardiac vagal tone, is probably mediated from within the central nervous system [43]. Ablad and colleagues [43] studied this hypothesis in stressed rabbit models in which 3 weeks of treatment with ß-blockers (metoprolol or atenolol) was followed by coronary artery occlusion under anesthesia. After coronary occlusion, most controls (89%) and most rabbits treated with atenolol (83%) died from ventricular fibrillation compared with a minority of the rabbits treated with metoprolol (33%). The degree of myocardial ischemia, as measured by ST-segment elevation, and the levels of cardiac sympathetic activation, as measured by heart rate, were both reduced by about the same degree by the two ß-blockers. In contrast, the level of vagal tone as measured by respiratory sinus arrhythmia was significantly higher in the group treated with metoprolol. A clear inverse relation was shown between cardiac vagal tone and the development of ventricular fibrillation.

Although the relation between respiratory sinus arrhythmia and cardiac vagal tone requires further clarification, Ablad and coworkers [43] showed that cholinergic blockade by methylscopolamine caused a more pronounced increase in heart rate in rabbits treated with metoprolol than in those treated with atenolol. It appears from these studies that both metoprolol and atenolol reduce myocardial ischemia and cardiac sympathetic activation, whereas their effects on vagal tone during acute stress seem to differ. The attenuation of stress-induced vagal withdrawal is probably mediated at the level of the central nervous system, into which metoprolol is well distributed but atenolol is not. This is of interest when noting that the long-term reduction of sudden cardiac death has only been clearly shown with central nervous system-active ß-blockers.

Antiarrhythmic Drug Therapy in Reducing Sudden Death

Given the frequency of ventricular fibrillation and sudden cardiac death in patients with coronary artery disease, antiarrhythmic drug therapy appears to be a rational approach to the prevention of these events. A survey of cardiologists in the United States, reported in 1990 [51], suggested that ventricular arrhythmias were frequently treated when they produced even minor symptoms or were thought to be prognostically significant. The publication of the results of the Cardiac Arrhythmia Suppression Trial (CAST) [52, 53] led to a dramatic reevaluation of these practices. These publications confirmed that well-tolerated drugs (encainide, flecainide, and moricizine) known to effectively suppress acute ventricular arrhythmias actually increased late arrhythmic mortality. Several meta-analyses have suggested increased late mortality with other agents, such as quinidine and mexiletine [54, 55].

Unlike CAST, most trials with ß-blockers have not evaluated effects on arrhythmias. However, a review of patients participating in CAST (both those who were actively treated and those who received placebo) showed that those treated with ß-blockers [56] were less likely to have sudden death than were those receiving only an antiarrhythmic drug. Moreover, these patients also had a significantly lower mortality from new or worsened congestive heart failure. Thus, it appears that ß-blocker therapy prevented the adverse effects seen in CAST and may indeed have an effective antiproarrhythmic action.

Similar conclusions may be drawn from the Seattle cardiac arrest survivor group trial [57], in which ß-blocker therapy significantly improved survival during long-term follow-up, independent of the use of antiarrhythmic agents. In contrast, unadjusted comparisons suggest a significant negative effect on survival when antiarrhythmic drug therapy was used independent of ß-blockers.

In attempting to predict drug efficacy in the treatment of ventricular arrhythmias, the Electrophysiologic Study versus Electrocardiographic Monitoring (ESVEM) investigators [58] studied patients, most of whom had sustained ventricular tachycardia associated with coronary artery disease. They found that those patients treated with sotalol, a ß-blocker with marked class III antiarrhythmic properties, were less likely to die or have recurrence of arrhythmia than were patients treated with any of six other antiarrhythmic drugs [58]. It must be stated, however, that the beneficial effect of sotalol may have been due to the fact that the other antiarrhythmic agents increased the incidence of serious arrhythmias and caused a higher mortality rate, as in CAST.

Recent interim analysis of the SWORD (Survival with Oral D-Sotalol) study [59], in which a higher mortality rate was seen in the treated group than in the placebo group, suggests that any benefits of sotalol in the ESVEM study may have been due to the ß-blocking action of the L-isomer rather than to the class III antiarrhythmic action of the D-isomer. It should also be noted that sotalol is associated with proarrhythmic effects, notably torsades de pointes [60], and that, in a large trial of patients who had infarction in the United Kingdom, sotalol did not significantly reduce mortality and had no effect on sudden cardiac death [34].

Some evidence indicates that amiodarone, a class III antiarrhythmic agent with a heart-rate-lowering effect similar to that of ß-blockers, may be effective in reducing mortality after myocardial infarction [61] and in patients with severe heart failure [62]. This will be further clarified when the results of several large-scale trials of amiodarone in patients after myocardial infarction become available.

Perceived Problems with ß-Blockers

Some physicians regularly elect not to use ß-blockers because of several perceived problems with these drugs. Certainly, patients with definite bronchospastic disease and those in cardiogenic shock should not receive them. However, the decision to use other agents is frequently made because of a misunderstanding of the available clinical evidence or because newer classes of drugs are thought to be effective substitutes. For example, in CAST [52], approximately 30% of patients who had infarction received ß-blockers, and more than 50% received calcium-channel blockers, which have no proven efficacy in reducing sudden cardiac death. Baseline data suggest that these figures were reversed in the Scandinavian Simvastatin Survival Study [9]. In a study of almost 5000 patients hospitalized with validated acute myocardial infarction, Gurwitz and colleagues [63] showed that reluctance to use ß-blockers increased with patient age: Patients older than 65 years of age were approximately half as likely to receive ß-blockers as were patients younger than 55 years of age. When the evidence is properly examined, it is clear that ß-blockers, particularly those with cardioselectivity, are associated with few effects that would preclude their use.

Blood Lipid Levels

ß-blockers have been found to produce small changes in blood lipid levels [64], including modest increases in triglyceride levels and, in some patients, decreases in high-density lipoprotein (HDL) cholesterol levels. These changes in lipid metabolism are seen particularly with nonselective ß-blockers such as propranolol, whereas ß₁-selective antagonists, such as metoprolol and atenolol, may have a lesser effect [65]. Although such changes to the lipid profile in untreated patients are associated with an increased risk for atherosclerotic disease, it is unclear whether a drug-induced alteration has the same implications for coronary health. Indeed, in cholesterol-fed animals, ß-blockers have a well-documented inhibitory effect on the development of atherosclerosis [66, 67].

Evidence also indicates that ß-blocker therapy has a beneficial effect on the blood components involved in atherogenesis. In one study, volunteers treated with ß-blockers showed a decrease in the affinity of low-density lipoprotein (LDL) cholesterol for arterial proteoglycans [68]. This may be of particular importance because the strong interaction of LDL cholesterol with arterial proteoglycans appears to play a major role in lipid accumulation in atherogenesis [69]. Endothelial wall damage often precedes the formation of an atherosclerotic plaque, which can become the site of subsequent thrombus formation. Tissue plasminogen activator can reverse this process and may, in turn, be inhibited by plasminogen activator inhibitor-1. Treatment with ß-blockers has been shown to reduce plasminogen activator inhibitor-1 activity [70]. Finally, the use of ß-blockers increases the biosynthesis of prostacyclin in stressed rabbits [71] and may have similar effects in humans [72]. Prostacyclin has important vasodilatory, antithrombotic, and antiatherogenic actions [69].

Events at the vessel wall are probably as important as the composition of blood in the genesis of atherosclerosis. Pressure-induced wall stresses are 4 to 6 times greater at branch than at nonbranch regions of the blood vessel [73]. Thus, it is not surprising that atherosclerotic lesions commonly develop in areas of vessel bifurcation and branching [74]. Thubrikar and colleagues have provided evidence indicating that endothelial cell structure differs [75] and that lipid uptake is greater [76] in branch than in nonbranch regions. These investigators have also shown that reducing arterial intramural stress in rabbits may inhibit the progression of atherosclerosis [77]. They found that uptake of LDL cholesterol from blood into the wall of the rabbit aorta is reduced after treatment with ß-blockers [78]. These effects were attributed primarily to vessel protection.

Atheroma formation is a complex process involving both blood components and mechanical effects on the vessel wall. ß-blockers appear to affect several processes, including lipid deposition, coagulation profiles, and vessel-wall stress. The clinical importance of most of these changes is uncertain. Although concerns about an adverse effect of ß-blocker therapy on atherogenesis are frequently voiced, no animal or human data confirm this, and most evidence supports an antiatherosclerotic effect.

Diabetes

ß-blockers may theoretically inhibit catecholamine-induced glycogenolysis and glucose mobilization, and such effects may prolong an episode of hypoglycemia in patients with diabetes. This has been seen in patients treated with propranolol, although it is less noticeable in those treated with a cardioselective agent [79]. ß-blockers may also mask the tachycardia that is characteristic of the hypoglycemic state. These possible risks need to be weighed against the benefits of cardioprotection in patients with diabetes.

The risks for cardiovascular disease and premature death are known to be significantly higher in patients with diabetes mellitus than in the general population [80-82]. In one national survey, the age-adjusted death rates for men and women with diabetes were twice those seen in patients without diabetes [83]; 75% of the excess mortality was a result of coronary disease. Moreover, this increased risk is independent of other known risk factors present in diabetic persons [81]. Because diabetes potentiates other risk factors for coronary artery disease [81], it seems sensible to make a particular effort to modify any identified risk factors in these patients.

It has been suggested that an elevated heart rate is associated with an increased risk for cardiovascular death after myocardial infarction [84]. In patients with coronary artery disease, impaired cardiac autonomic function has been shown to predict sudden cardiac death [85, 86]. Diabetic patients with autonomic dysfunction have a substantial excess of cardiovascular mortality [87, 88]. Benefit from ß-blockers would thus seem particularly likely to occur in diabetic patients with elevated heart rates.

Interestingly, the negative chronotropic properties of ß-blockers appear to be preserved among diabetic patients with autonomic dysfunction and thus would be expected to be particularly effective in secondary prevention. This has been borne out in clinical trials. The pooled results of early treatment of myocardial infarction with ß-blockers [31, 32, 89] indicate a 13% mortality reduction in all patients compared with a 37% mortality reduction in diabetic patients [90, 91]. Long-term studies show mortality reductions of 33% in all patients treated with ß-blockers and 48% in patients with diabetes [90] (Table 1). These findings are also similar to those for rates of reinfarction: Patients without diabetes who were treated with ß-blockers had a 21% reduction, whereas similarly treated patients with diabetes had a 55% reduction [90] (Figure 3). Similar effects were also obtained during the early phase of myocardial infarction [93]; in the Goteborg metoprolol trial and the MIAMI trial, intravenous metoprolol followed by oral treatment in patients with acute myocardial infarction decreased mortality by 50%, with similar effects on late infarction. Reassuringly, the incidence of hypoglycemia has not been reported to increase among diabetic patients treated with ß-blockers after myocardial infarction [27, 28].

View larger version (23K): [in this window] [in a new window]   Figure 3. Effect of ß-blocker therapy on mortality and reinfarction rates in patients with and without diabetes after myocardial infarction, expressed as percentage reduction compared with patients receiving placebo. Adapted from data in references 90 and 91.

The risk for prolonged hypoglycemia in the diabetic patient treated with ß-blockers is real, although its occurrence appears to be rare, especially when cardioselective ß-blockers are used [79]. The benefits of such therapy for cardioprophylaxis are particularly well established in diabetic patients, and, consequently, ß-blocker use should not be withheld because of the possibility of hypoglycemia.

A Cause of Heart Failure?

The pharmacology of nethalide, one of the first ß-blocking agents developed for the treatment of hypertension, was reviewed by Black and Stephenson in 1962 [94]. They showed that the administration of nethalide limited myocardial contractility in response to adrenaline. They also observed that rapid intravenous administration of nethalide depressed contractility. It was concluded from these results that ß-blockers were effective in reducing hypertension but that they had the potential to decrease cardiac function and thus to cause or exacerbate congestive heart failure.

Controlled studies of the management of myocardial infarction have not confirmed that patients treated with normal therapeutic doses of ß-blockers are particularly prone to the development of heart failure. In one study [95], the rate of congestive heart failure was similar in both the group treated with metoprolol and the control group, and the control group required much more furosemide for the treatment of pulmonary edema. In the Norwegian propranolol trial [96], the group treated with propranolol had an increased withdrawal from the study because of heart failure compared with the control group in the first 2 weeks of therapy but had a similar withdrawal rate thereafter. Similarly, the Norwegian Multicenter Study Group [27] showed that the occurrence of heart failure in patients receiving timolol was similar to that in the control group [27], although there was a trend toward increasing pulmonary edema in those receiving timolol.

The incidence of heart failure was also examined in BHAT [97, 98], in which patients were randomly assigned to receive propranolol or placebo. After the exclusion of patients with shock or overt heart failure, follow-up over an average of 25 months indicated that the occurrence of definite heart failure was similar in both groups. This was true of patients with or without a previous history of heart failure (Figure 4).

View larger version (15K): [in this window] [in a new window]   Figure 4. Cumulative history (Hx) of congestive heart failure (CHF) by previous history of CHF and by treatment group. Adapted with permission from Circulation [98].

The use of the calcium-channel blocker diltiazem has been studied after myocardial infarction [36] and may have an adverse effect on mortality, particularly in patients with left ventricular dysfunction. In this trial [36], patients receiving ß-blockers had a lower mortality than did those not receiving ß-blockers, especially if they also had a low ejection fraction [99]. The improved mortality figures of patients treated with ß-blockers who had previous heart failure had been shown in BHAT [98], in which the incidence of sudden death was 10.4% in the placebo group and 5.5% in patients treated with propranolol (Figure 5).

View larger version (20K): [in this window] [in a new window]   Figure 5. Effect of propranolol on morbidity and mortality related to the presence or absence of congestive heart failure (CHF). Adapted with permission from Circulation [98].

Although there seems to be a potential for early worsening of baseline left ventricular function in patients treated with ß-blockers, these studies indicate little danger when the drugs are used with care. This is true in the presence or absence of previous heart failure. Moreover, in those patients with previous heart failure, treatment with ß-blockers after myocardial infarction has been shown to improve overall mortality and to dramatically reduce the incidence of sudden death [98].

A Treatment for Heart Failure?

In 1975, Waagstein and colleagues [100] first reported the benefits of ß-blocker therapy in congestive heart failure caused by idiopathic dilated cardiomyopathy. Further studies [101] have confirmed these findings. Hjalmarson and coworkers [102] have now given ß-blockers to more than 600 patients with idiopathic dilated cardiomyopathy for 1 to 2 years with favorable results. A trial in which 33 patients with idiopathic dilated cardiomyopathy were treated with metoprolol showed that withdrawal of the ß-blocker led to worsening of symptoms and indices of cardiac function. Survivors after withdrawal of metoprolol benefited from the readministration of the drug [103].

Most recently, the multicenter Metoprolol in Dilated Cardiomyopathy (MDC) trial has assessed the effect of metoprolol on deaths or the need for heart transplantation [104]. A risk reduction of 34% in these events did not quite reach statistical significance (P = 0.058), although a significant improvement in cardiac function and exercise capacity was shown. The drug was well tolerated at a starting dose of 5 mg twice daily that was increased gradually to 100 to 150 mg/d.

The mechanism of beneficial action of ß-blockers appears to be multifactorial: Reduced myocardial oxygen demand, improved diastolic relaxation, and reduction in sympathetically mediated vasoconstriction are probably all important. Reduction of catecholamine-induced myocardial damage and ß-receptor desensitization may also help [105].

Positive results of ß-blocker therapy have also been seen in studies of congestive heart failure from other causes, including coronary artery disease [106, 107]. It appears that the efficacy of ß-blockers in heart failure may not be limited to idiopathic dilated cardiomyopathy. The issue of ß-blocker therapy in heart failure is complicated; however, it has become clear that past or present heart failure is not the absolute contraindication to ß-blocker use that it was once thought to be. Indeed, recent results indicate that particularly strong benefit may be gained from ß-blocker therapy in patients with past or present heart failure, provided that the starting dose is extremely low and that the drug is given with great care.

Quality of Life

Although the primary aim of the medical practitioner in treating hypertension is to reduce cardiovascular risk, it is particularly important to the patient that quality of life be maintained. As a result, commonly reported adverse effects of antihypertensive therapy, such as depression, fatigue, headache, anxiety, and sleep disturbance, are frequently the focus of quality-of-life studies. The interest in such studies has increased considerably since Croog and colleagues [108] published results that favorably compared captopril with propanolol and methyldopa.

Although hypertension is generally considered to be an asymptomatic condition, various symptoms may occur in its presence, including headache, dizziness, sexual problems, and cognitive impairment [109]. Similar symptoms may also be described during placebo treatment [110], suggesting that useful evaluation of drug side effects requires placebo-controlled studies. Moreover, blood pressure reduction may indeed produce a beneficial effect on the quality of life [109].

Hjemdahl and Wiklund [109] have pointed out that the design of many comparative studies of quality of life in hypertension fails to meet a standard that would allow worthwhile conclusions to be made about the relative benefits of one or another drug. Indeed, unblinded studies based on physicians' assessments of symptoms are commonly influenced by negative expectations of ß-blockers and positive expectations of drugs such as angiotensin-converting enzyme inhibitors and calcium-channel blockers.

The anecdotal experiences of many clinicians suggest that patients often feel slightly less well when receiving ß-blockers than when receiving some other agents. Relatively little clinical trial evidence, however, supports this belief. Indeed, when valid methods to assess quality of life have been used in double-blind, controlled trials, treatment with ß₁-selective antagonists has produced a level of well-being similar to that seen with angiotensin-converting enzyme inhibitors and calcium channel blockers [109] (Table 2). In contrast, adverse effects on well-being appear to result from treatment with methyldopa and the nonselective ß-blocker propranolol [108, 111, 112]. Although no clinical difference is apparent between hydrophilic and lipophilic ß-blockers in terms of effects on well-being and psychomotor ability, ß₁-selective blockers seem to produce fewer and less severe adverse effects than do nonselective ß-blockers [113].

When hypertension is being treated, evidence of a beneficial effect on mortality and morbidity is clearest for ß-blockers and diuretics. Consideration of such hard end points should be a priority when an antihypertensive agent is being chosen. Fortunately, when aspects of quality of life are being considered, treatment with ß₁-selective ß-blockers is as well tolerated as treatment with angiotensin-converting-enzyme inhibitors and calcium-channel blockers. Such treatment has, as a result, established efficacy in improving both quantity and quality of life.

Conclusion

Top Conclusion Author & Article Info References

Our goal was to emphasize the continuing importance of coronary artery disease as a cause of death, particularly sudden death. Advances in the management of patients presenting with myocardial infarction have been impressive, but the most convincing data showing reduction of coronary events still support the use of ß-blockers. Despite this, the medical profession has increasingly used the newer antihypertensive drugs, usually with little evidence that these can prevent myocardial infarction and with no evidence that they can prevent sudden death. In patients after infarction, appreciation of the frequency with which ventricular fibrillation occurs has led to the investigation of many antiarrhythmic drugs, which have invariably had no effect. In contrast, the data supporting the efficacy of ß-blocker therapy in preventing sudden cardiac death are consistently strong.

The arguments against using ß-blockers are well known, and these drugs are clearly contraindicated in some patients. However, we argue that most of these concerns do not warrant the withholding of ß-blockers. The effects of these agents on lipids are theoretical rather than real, and patients with diabetes probably stand to receive benefit rather than harm from ß-blocker therapy. Although recognizing the negative inotropic properties of these agents remains important, the idea that ß-blockers are absolutely contraindicated in patients with heart failure is no longer acceptable. Finally, adverse effects on quality of life have not been well established in objective, double-blind trials, and any unwanted effects of ß₁-selective ß-blockers are modest, particularly when these drugs are given in low doses.

When the issue of cardioprotection is addressed, it is important for the clinician to recognize the strength of the evidence supporting ß-blockers and consider the hard end points of morbidity and mortality before withholding these agents or substituting newer, less established drugs in their place. If contraindications to ß-blockers do exist, it should be established whether these are absolute; if they are not, a careful trial of their use should be done. If we wish to reduce cardiovascular mortality, a reappraisal of the role of ß-blockers in cardiovascular disease is now due.

Dr. Hjalmarson: Wallenberg Laboratory for Cardiovascular Research, Sahlgren's Hospital, S-413 45 Gothenburg, Sweden.

Dr. Kjekshus: Section of Cardiology, The National Hospital, University of Oslo, Piolstredet 32, 0027 Oslo, Norway.