The β Blockers: Are They as Protective in Hypertension as in other Cardiovascular Conditions?

Abstract

Beta blockers are frequently used to treat hypertension because of their well established safety and efficacy. Large clinical trials yield a 12%–20% decline in cardiovascular end points in hypertensive patients treated with β blockers. However, β blockers account for only 11% of antihypertensive prescriptions, and their use appears to be declining as newer agents with fewer side effects become available. The metabolic side effects of β blockers have recently been examined. While they may raise triglycerides, lower high‐density lipoprotein cholesterol, induce glucose intolerance, and possibly unmask diabetes, these effects have not been shown to impact their clinical effectiveness. For hypertension, β blockers are still recommended as first‐line therapy in many patients, particularly those at high risk for cardiovascular disease. They are also indicated for other cardiovascular disorders, such as congestive heart failure and postmyocardial infarction, in which mortality reductions exceed that seen with hypertension treatment in patients without cardiovascular complications.

In the United States, β‐adrenergic blockers are prescribed to more than 3 million hypertensive patients because of their well established efficacy and safety. ¹ In 1997, the Sixth Report by the Joint National Committee (JNC VI) for the Prevention, Detection, Evaluation, and Treatment of Hypertension recommended β blockers, along with diuretics, as first line therapy for the treatment of uncomplicated hypertension. ² However, despite these recommendations, the use of β blockers has declined with the increasing availability of other agents. In 1992, 18% of prescriptions for antihypertensive medications in the U.S. were for β blockers, but they accounted for only 11% in 1995. ³

Despite the less frequent use of β blockers in hypertension, there has been an emergence of their use in patients with other cardiovascular disorders. Patients with congestive heart failure (CHF) and diabetes, who were previously thought to have contraindications to β blockade, experience significant mortality reductions with β‐blocker therapy. ⁴ , ⁵ Consequently, the spectrum of β‐blocker indications and use has shifted, in part, from the treatment of hypertension to other cardiovascular conditions. The rationale for these patterns in association with our current understanding of the protective mechanisms of these agents is discussed in this paper.

BETA BLOCKERS AS ANTIHYPERTENSIVE DRUGS

Beta blockers have been used extensively in the treatment of hypertension as single agents or in combination with other classes of antihypertensive medications. Response rates of 50% are comparable to other drug classes, although in the elderly (β blockers may be less effective than diuretics or calcium channel blockers (CCBs). ⁶

Properties to consider when selecting a β blocker are lipophilicity, intrinsic sympathomimetic activity (ISA), and β selectivity (Table I). Lipophilic agents may penetrate the central nervous system (CNS) and, although this is controversial, may cause more CNS side effects. Agents with increased ISA (which simultaneously block and stimulate β receptors) can cause less of a decrease in cardiac output, heart rate and renin release than β blockers without ISA, but may have less of an effect on blood pressure. Beta blockers with increased ISA also have less effect on bronchospasm, exercise tolerance, and lipid metabolism. However, only β blockers without ISA have been demonstrated to reduce morbidity and mortality from recurrent myocardial infarctions (MIs). ⁷

Table I.

Properties of Commonly Used β‐Adrenergic Blocking Agents

Agent	Cardioselectivity	ISA	Lipid Solubility
Acebutolol	+	+	+
Atenolol	+	−	−
Bisoprolol	+	−	++
Esmolol	+	−	−
Labetalol	−	+	+++
Metoprolol	+	−	+++
Nadolol	−	−	−
Propranolol	−	−	+++
−=none; +=weak; ++=moderate; +++=high; ISA=intrinsic sympathetic activity

Nonselective β blockers block both cardiac β₁ receptors and peripheral β₂ receptors. Both nonselective and cardioselective drugs lower blood pressure, but the cardioselective agents are less likely to exacerbate chronic obstructive lung disease, peripheral vasospasm, and metabolic disturbances. Nonselective agents are more efficacious for the treatment of tremors and migraines. ⁶

MECHANISM OF PROTECTION

The mechanisms of action of β blockers can be categorized into physiologic and clinical effects (Table II). Most β blockers reduce cardiac output by inhibition of cardiac β‐adrenergic receptors. However, this effect does not appear to correlate with the antihypertensive properties. Moreover, long‐term cardiovascular protection with their use in other conditions demonstrates beneficial effects not necessarily associated with reduction in blood pressure.

Table II.

Physiologic Actions of β Blockers

• Decrease peripheral vascular resistance

• Inhibit central sympathetic outflow

• Reduce cardiac output

• Reduce heart rate

• Inhibit renin release

Proposed antihypertensive modes of action of (β blockers include: 1) stimulation of β₂ receptors in vascular smooth muscle, with a subsequent reduction in peripheral vascular resistance; 2) inhibition of sympathetic outflow from the CNS; 3) reduction in cardiac output and heart rate; and 4) inhibition of renin release. ⁶ The latter mechanism parallels angiotensin‐converting enzyme (ACE) inhibitor therapy by reducing angiotensin II generation, increasing atrial natriuretic peptide levels, and improving renal sodium and water excretion. Beneficial clinical effects consequent to blood pressure reduction include the regression of left ventricular (LV) hypertrophy and, possibly, improvement of endothelial dysfunction (due to vasodilatory agents). ⁸ , ⁹ , ¹⁰ , ¹¹ Beta blockers also reduce the likelihood of diuretic‐induced hypokalemia.

Reduction of Heart Rate

There is substantial evidence that an elevated heart rate is independently associated with atherosclerosis and cardiovascular morbidity and mortality, possibly by increasing cardiac workload and oxygen consumption. ¹² In the Framingham population, the predictive power of heart rate for all‐cause mortality was equal to that of smoking or of systolic blood pressure. ¹³ Similar results have been reported from numerous epidemiologic studies. Whether an increased heart rate is an independent risk factor or merely an epiphenomenon associated with other well established risk factors is a matter of debate. Indeed, more rapid heart rates have been associated with hypertension, hypercholesterolemia, erythrocytosis, hyperinsulinemia, increased body mass index, and increased glucose. ¹³ It is possible that the heightened adrenergic stimulation in these disorders elevates heart rate and exposes patients to excess risk by reducing the threshold for arrhythmias. Nonetheless, there is experimental evidence indicating that elevated heart rates alone reduce arterial compliance and promote atherosclerosis, although there are no data at this time indicating that reduction of heart rate with β blockers causes regression of atherosclerosis. ¹²

Leary et al. ¹⁴ recently demonstrated that, in addition to reducing exercise‐induced increases in heart rate, β blockers significantly attenuate the morning surge in blood pressure and heart rate that is associated with the onset of physical activity. This effect may be important insofar as this time period is associated with the highest rates of MI.

REDEFINING THE ROLE OF β BLOCKERS AS FIRST‐LINE THERAPY

The JNC VI report recommended thiazide diuretics, or β blockers in combination with thiazide diuretics, for the older person with hypertension, as their use was associated with a reduction in morbidity and mortality in multiple randomized, controlled trials. Furthermore, based on evidence for cardiovascular protection with CCBs (from the Systolic Hypertension in Europe [Syst‐Eur] and other trials) in the elderly hypertensive with isolated systolic hypertension, JNC VI suggests diuretics or long‐acting dihydropyridine calcium antagonists as initial therapy. ² , ¹⁵

Benefits in the Elderly?

For several years, the beneficial effects of β blockers for hypertension have come under intense scrutiny by a number of investigators. Messerli et al. ¹⁶ , ¹⁷ examined 10 trials involving 16,164 elderly patients randomized to diuretics and/or β blockers. Diuretic therapy was found to be superior to β blockers in this patient population for controlling blood pressure and reducing cardiovascular events. Specifically, diuretic therapy was associated with a 39% reduction in cerebrovascular events, a 33% reduction in fatal stroke, a 26% reduction in coronary heart disease (CHD), a 25% reduction in cardiovascular mortality, and a 14% reduction in all‐cause mortality. In this analysis, β blockers in elderly patients were only effective in reducing cerebrovascular events and heart failure (odds ratio, 0.75). Unfortunately, this meta‐analysis has been questioned, since 52%–60% of the patients were taking concurrent diuretics and β blockers, (limiting the power of the study to detect significant class differences) and much of the difference between agents was seen in the Medical Research Council‐Elderly trial, ¹⁸ in which there was a high drop‐out rate. Nevertheless, as in the JNC VI report, many experts would not use β blockers as monotherapy in the elderly hypertensive patient.

In contrast, Staessen et al. ¹⁹ suggest that β blockers are suitable first‐line therapy for elderly hypertensives. Their conclusion is based upon the evidence that they are effective for the primary prevention of stroke, MI, and sudden death. ²⁰ At present, it appears that β blockers are effective for many hypertensive elderly patients, particularly those with comorbid conditions and tachycardia, but they do not appear to be as effective as diuretics or CCBs as first‐line therapy in uncomplicated hypertension in the elderly. ²¹ This conclusion must be interpreted with caution, as no direct head‐to‐head comparisons have been made between these agents. Such comparisons are particularly difficult since β blockers are most often used with other agents.

It should be emphasized that the controversy about the use of β blockers in the elderly may lead to a reluctance to use these agents in appropriate situations, including uncomplicated hypertension. Krumholz et al. ²² found that early β blocker therapy was omitted in 51% of elderly patients who were hospitalized for an MI, despite a lack of contraindication to their use. Of 58,165 elderly patients analyzed, those with the greatest risk for in‐hospital death received β blockers less frequently, even though patients who received β blockers had a 19% lower in‐hospital mortality rate than those who did not. Thus, while they may not be the preferred first‐line therapy for hypertension in the elderly, β‐blocker use in elderly patients with clear indications must not be ignored.

POTENTIAL PITFALLS

Deleterious Effects on Glucose Metabolism

Hypertension intervention studies consistently reveal a less than expected decrease in CHD events (4%–9%), in contrast to stroke reduction. ²⁰ Alternatively, the shortfall in CHD event reduction may be more closely correlated with the shorter 3–5‐year duration of the trials.

Proposed explanations for the former discrepancy have focused on the impact of concomitant cardiovascular risk factors, such as diabetes mellitus, and impaired glucose tolerance, and dyslipidemia. Beta blockers may increase metabolic risk by reducing lipoprotein lipase activity and high‐density lipoprotein (HDL) cholesterol, promoting weight gain, attenuating insulin clearance, and impairing β₂‐stimulated vasodilation and insulin secretion (Table III). ²³ Gress et al. ²⁴ recently conducted a prospective study of 12,560 adults to determine the incidence of new cases of diabetes in patients treated with various antihypertensive therapies. Hypertensive patients who were taking (β blockers had a 28% higher risk of having diabetes than those not taking medication. However, in similar analyses, no difference in the incidence of diabetes has been demonstrated with β blockers compared to other treatments. It is of interest that in the Gress et al. ²⁴ analysis, type 2 diabetes mellitus was almost 2.5 times as likely to develop in hypertensive than in normotensive patients.

Table III.

Impact of β blockers on Metabolic Risk Factors

• Reduce lipoprotein lipase activity

• Reduce high‐density lipoproteins

• Promote weight gain

• Decrease insulin clearance

• Impair insulin secretion

Despite these critical observations, for many patients the proven benefits of β blockers in reducing cardiovascular events outweighs this potential risk. Indeed, β blockers have been shown to decrease morbidity and mortality from cardiovascular causes in diabetics, as demonstrated in the United Kingdom Prospective Diabetes Study (UKPDS). ⁵ This trial was designed to evaluate the impact of more intensive blood pressure control with either a β blocker‐based or ACE inhibitor‐based medical regimen in patients with type 2 diabetes and hypertension. Of the patients, 1148 were randomized to either a “tight control” group, with a target blood pressure <150/85 mm Hg, or to the “less tight” control group (target blood pressure <180/105 mm Hg). The mean follow‐up was 8.4 years. Overall, the “tight control” group achieved a mean blood pressure of 144/82 mm Hg, approximately 10/5 mm Hg lower than the “less tight” group. This better blood pressure reduction resulted in substantial reductions in both microvascular and macrovascular end points. Interestingly, there were equivalent reductions in mortality and diabetes‐related end points with the β blocker‐based and ACE inhibitor‐based medical regimens (Fig. 1). As in many studies, multiple medications were needed to reach the target blood pressure, diminishing the power of the study to detect significant differences between primary drug classes. The importance of this study and others in demonstrating the safety and beneficial impact of β blockers on mortality in diabetic patients should be emphasized.

Figure 1.

Data represent equivalency of β blockers and ACE inhibitors in reducing cardiovascular end points in diabetics. ACE=angiotensin‐converting enzyme; MI=myocardial infarction; CHF=congestive heart failure. Reprinted with permission from BMJ. 1998;317:703–713. ⁵

Effects of β Blockers on Lipids

Regular administration of β blockers may increase triglyceride levels and decrease HDL‐cholesterol to varying degrees. Frishman et al. ²⁵ recently reviewed 42 studies examining the effects of different agents on lipids. Beta blockers with increasing cardioselectivity, such as bisoprolol or agents with ISA, appear to have the most neutral effect on the lipid profile. Nonselective β blockers without ISA may decrease HDL cholesterol up to 20% and increase triglycerides by up to 50%, whereas cardioselective β blockers without ISA may decrease HDL cholesterol by 10% and increase triglycerides by up to 20%.

Weir and Moser ²⁶ reviewed the potential mechanisms by which β blockers may induce lipid changes. Unopposed α‐adrenergic stimulation that may occur after β blockade inhibits lipoprotein lipase activity. This reduces clearance of very low‐density lipoproteins and triglycerides and enables enhanced catabolism of HDL cholesterol. This theory is supported by the fact that the cardioselective β blockers, which may not produce the peripheral imbalance favoring a stimulation have much less impact on these lipoproteins.

At this time, no studies have demonstrated a clinically important impact of changes in lipids on overall mortality. In fact, in one study ²⁷ the calculated risk reduction was 60% for mortality and 50% for stroke in patients being treated with atenolol for hypertension. This benefit was achieved despite the fact that those patients who survived had higher triglyceride levels than those who did not, suggesting that hypertriglyceridemia may contribute less to cardiovascular disease than other lipids.

Effects on Vascular Integrity

The lesser than expected reduction in cardiovascular events with β blockers in large clinical trials may also be due to the inability of some β blockers to normalize vascular structure and endothelial function, even if they slow progression of atherosclerosis. ACE inhibitors and other antihypertensive medications have been demonstrated to improve endothelial function. Schiffrin et al. ²⁸ recently demonstrated that antagonism of the angiotensin II, subtype I receptor with losartan corrected the hypertrophic arterial vascular wall, normalizing the wall media‐to‐lumen ratio, and improved endothelium‐dependent vasodilation in patients with mild hypertension. The β blocker atenolol had no effect on arterial structure or endothelial function despite equivalent reductions in blood pressure. Experimental evidence suggests that drugs of the vasodilatory subclass of β blockers, such as carvedilol, may be more prone to improving endothelial function due to the antioxidant properties (and possibly, greater attenuation of the renin‐angiotensin system). ¹⁰ , ¹¹

THE CHANGING SPECTRUM OF β BLOCKER USE

Patients with cardiovascular conditions other than hypertension may benefit to an even greater degree from β blockade than hypertensive patients (Table IV). The attributable risk reduction in cardiovascular mortality for hypertensive patients treated with β blockers is 12%–21% in most randomized trials. In contrast, patients with other cardiovascular conditions, such as those associated with overactivity of the sympathetic nervous system, experience up to a 60% reduction in mortality, as discussed in the following text.

Table IV.

Reduction in Mortality with [3 Blockers in Patients with Cardiovascular Conditions

Condition	% Reduction	Reference
Hypertension	12–20	16,20
Congestive heart failure	19–34	4,34
Myocardial infarction	40	7,21
Perioperative CABG	60	31
Diabetes mellitus	40	5,30
Sudden death	40–50	28
CABG=coronary artery bypass graft surgery

Sudden Death

Hjalmarson ²⁹ recently analyzed more than 50 randomized trials involving more than 55,000 patients. The reduction in sudden cardiac death in patients with prior MI, CHF, and hypertension ranged from 30%–50% with β blocker therapy. This impressive protection exceeded that of ACE inhibitors and was most pronounced for the lipopholic β blockers, such as metoprolol, bisoprolol, and carvedilol. The mechanism for this benefit may be the ability of the β blocker to restore the heart rate variability that is frequently diminished during the sympathoexcitation stage preceding ventricular arrhythmias. ³⁰ Based on such analysis, it is suggested that β blockers be prescribed for all patients at risk for sudden death.

Myocardial Infarction

Numerous trials confirm the benefits of β blockers in uncomplicated MI, making this a compelling use in the JNC VI report (Fig. 2). ² , ⁹ This benefit has recently been confirmed in older patients, diabetics, and patients with chronic obstructive pulmonary disease and left ventricular dysfunction. On review of more than 200,000 patients, Gottleib et al. ³¹ found that mortality in those patients experiencing non‐Q wave infarctions who were treated with β blockers experienced a 40% mortality reduction, including patients with chronic obstructive pulmonary disease. Black patients, patients >80 years of age, patients with LV ejection fractions <20%, patients with serum creatinine >1.4 mg/dL, and diabetics, experienced lower, but significant, risk reductions (28%–30%) as well. Given their overall higher risk, the absolute risk reduction was at least equivalent to patients without these comorbid conditions.

Figure 1.

Risk reduction with β blockers in the post‐MI patient MI=myocardial infarction. Adapted with permission from Moser M. Clinical Management of Hypertension. 4th ed. Caddo, OK; Professional Comm.; 1999:78–91.

Perioperative Risk for MI with Coronary Artery Bypass Graft Surgery

Perhaps the patients who benefit the most from β blockade are those undergoing coronary artery surgery. Weightman et al. ³² assessed the association between preoperative drug therapy and in‐hospital mortality in 1593 patients undergoing coronary artery bypass graft (CABG) surgery. The risk reduction of in‐hospital mortality associated with β blockers was 60%. Use of CCBs, ACE inhibitors, or nitrates was not significantly associated with in‐hospital mortality. These findings are consistent with other studies examining the use of β blockers in perioperative patients, and support the commonly accepted practice of continuing or initiating β blockade in the perioperative patient undergoing CABG surgery.

CHF

Systolic Dysfunction

There is now substantial evidence that β blockers limit the progression and improve survival in patients with CHF. ³³ The Cardiac Insufficiency Bisoprolol Study II (CIBIS II) trial ⁴ demonstrated a 20% reduction in mortality in patients with moderate heart failure. In bisoprolol‐treated patients, hospitalizations for heart failure were reduced by 36% and sudden death was reduced by 44%. In this large study of 2647 patients, those randomized to bisoprolol experienced an 11.8% mortality rate vs. a 17.3% mortality rate in the placebo group (Fig. 3). These benefits occur in patients with New York Heart Association (NYHA) functional class II/III, who are the same patients in whom sudden death is the predominant mode of death. Moreover, these are benefits achieved with β blockers added to a medical regimen containing ACE inhibitor therapy.

Figure 1.

Kaplan‐Meier survival plots for CHF patients treated with β blockers. CHF=congestive heart failure. Reprinted with permission from Lancet. 1999;353:9–13. ⁴

The recently completed Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT‐HF) randomized 3991 patients with CHF to long‐acting metoprolol or placebo. ³⁴ , ³⁵ This study confirmed a 34% risk reduction with β‐blocker use, 41% risk reduction for sudden death, an improved sense of well‐being, and improved NYHA functional class. Moreover, the withdrawal rate from metoprolol was only 10%, compared to a 25% withdrawal rate in placebo‐treated patients. This finding is particularly important insofar as acute clinical deterioration in patients with heart failure initiated on β‐blocker therapy does not interfere significantly with long‐term tolerability.

Several potential mechanisms have been postulated to account for the beneficial effects of β blockers in patients with CHF. Over the long‐term, they improve exercise tolerance, LV geometry, and LV structure, and reduce myocardial oxygen demand. ³⁶ Beta blockers lower mortality in heart failure to a large extent by reducing the incidence of sudden death. This effect results from dampening of the underlying neurohumoral activation. It is conceivable that protection from hypokalemia also protects against sudden death, particularly in the majority of patients on digoxin. However, despite this demonstrated benefit, only 42% of patients with systolic heart failure are currently treated with β blockers. ³⁷

After initiating standard therapy with ACE inhibitors or angiotensin receptor antagonists, diuretics, and possibly digoxin, physicians should select β blockers that are β‐selective and that have been shown to be effective (i.e., bisoprolol, carvedilol, or metoprolol). Titration should start with a low dose and proceed slowly, with close monitoring for clinical deterioration in the early period.

CONCLUSIONS

For three decades, physicians have been encouraged to select β blockers and diuretics as first‐line agents for the treatment of hypertension. However, the evidence supporting these recommendations has recently come under scrutiny. This has occurred in concert with the rapidly expanding availability of other antihypertensive agents. The result has been a reduction in the use of β blockers for hypertension, and a reluctance to use them in some clinical situations. On the basis of available evidence, β blockers are suitable first‐line agents, for nonelderly hypertensive patients or in combination with diuretics in the elderly, and are clearly indicated for patients with a history of MI, coronary artery disease, heart failure, and in the perioperative period for CABG surgery. Their benefits likely stem from attenuation of the adrenergic nervous system. Additional coexisting disorders that warrant β blockade include systolic dysfunction, exercise‐induced arrhythmias, migraine, glaucoma, hypertrophic cardiomyopathy, thyrotoxicosis, and tremor. ²¹