Beta blockade in patients with congestive heart failure

Why, who, and how

Robert P. Frantz, MD

VOL 108 / NO 3 / SEPTEMBER 1, 2000 / POSTGRADUATE MEDICINE

CME learning objectives

• To understand the pathophysiologic rationale for use of beta blockers in congestive heart failure (CHF)
• To recognize the appropriate timing for addition of beta blockers in CHF
• To become familiar with proper dosing and titration of beta blockers in CHF

Dr Frantz has received research support from SmithKline Beecham.

Preview: The use of beta blockers in patients with left ventricular systolic dysfunction and congestive heart failure represents the most important advance in management of these conditions since the advent of angiotensin-converting enzyme inhibitors. It is critical that physicians caring for patients with these ailments fully incorporate beta blockade into their treatment regimen. In this article, Dr Frantz summarizes the benefits of beta blockers, appropriate recipients, and effective methods of initiating such therapy.
Frantz RP. Beta blockade in patients with congestive heart failure: why, who, and how. Postgrad Med 2000:108(3):103-18

Regardless of its underlying cause, left ventricular (LV) systolic dysfunction is a chronic condition that easily becomes progressive and self-perpetuating. Fortunately, agents are available to interrupt advance of the disease and produce significant improvement in symptoms.

Why to use beta blockers

Progression of LV dysfunction is driven by a combination of mechanical and neurohumoral processes. For example, LV cavity enlargement results in increased wall stress and mitral valve incompetence caused by mitral annular dilatation. LV dysfunction is a form of chronic circulatory stress that is also associated with activation of numerous neurohumoral systems. The renin-angiotensin-aldosterone system and the beta-adrenergic adenylate cyclase system are two of the most important.

ACE inhibitors are now a standard component of CHF therapy on the basis of favorable results from randomized trials, such as Studies of Left Ventricular Dysfunction (SOLVD) (1,2) and the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) (3). ACE inhibitors achieve their benefits through reduction in mechanical stress via reduced afterload and are associated with some improvement in neurohumoral markers, such as plasma norepinephrine.

ACE inhibitors are not enough
Although ACE inhibitors are useful in treatment of CHF, on their own, they are not enough. Unfortunately, patients with CHF who are treated with ACE inhibitors still have unacceptably high morbidity and mortality. For example, the SOLVD treatment trial randomized patients with mild to moderate CHF and LV ejection fractions (LVEFs) of less than 35% to receive either enalapril or placebo. Enalapril treatment resulted in lower morbidity and mortality. However, during a 3 1/2 year follow-up period, nearly one third (31%) of patients receiving enalapril died; nearly half (48%) either died or were hospitalized for CHF. Available therapies must (and can) do better.

In patients with LV dysfunction, a cauldron of dangerous sympathetic activation smolders beneath the surface. ACE inhibitors will not fix that. Sympathetic activation, with increased release and diminished reuptake of norepinephrine from myocardial sympathetic nerve terminals, is an acute response to circulatory stress. In a teleological sense, an acute increase in sympathetic drive was advantageous for our ancestors. When they were being pursued by a tiger or bleeding from a wound, increasing heart rate, peripheral tone, and myocardial contractility allowed them to reach safety or maintain central perfusion.

However, sustained sympathetic activation, as occurs in LV dysfunction, is a maladaptation of what was intended as an acute response. Chronic sympathetic activation is ultimately a highly deleterious process. Excessive norepinephrine is directly toxic to the myocyte. It also causes down-regulation of the beta-adrenergic receptor and uncoupling of it from the post-receptor pathway, resulting in progressive deterioration in contractility. Furthermore, sympathetic surges increase the risk of fatal arrhythmia.

Benefits offset inotropic effects
When first initiated, beta blockers impair contractility, but if they are started at a low dose and gradually increased, impairment is usually tolerable and manageable. If contractility is evaluated 3 months or more after initiation of beta blockade, it is found to have actually improved. This reflects enhanced coupling of the beta receptor to the postreceptor pathway, improved energetics, related in part to decreased heart rate and, in patients with coronary artery disease, potentially less myocardial ischemia (4,5). Ultimately, the negative inotropic effects of beta blockade are more than offset by the improvements described.

Trial results support their use
More than 12,000 patients with LV dysfunction and CHF have participated in placebo-controlled, randomized trials of beta blockers (6-16). This is considerably more than the number who had participated in trials of ACE inhibitors before their widespread application. It is now nearly 25 years since Waagstein and colleagues first reported their favorable experience with beta blockade in CHF. Results of subsequent randomized trials are consistent, compelling, and dramatic.

When added to a regimen of ACE inhibitors, diuretics, and digoxin (Lanoxicaps, Lanoxin) if needed, beta blockers improve LVEF, reduce the risk of death (both sudden death and that caused by progressive CHF), reduce the risk of hospitalization for CHF and, in the long run, improve symptoms in patients with LV dysfunction and New York Heart Association (NYHA) class II or III CHF.

Patients who should receive beta blockers

Beta blockers are not a treatment for acute heart failure. Patients tolerate initiation of beta blockade best when CHF is reasonably compensated.

Beta blockade is an important secondary prevention measure in patients with LV dysfunction, aimed at averting progression of heart failure and death. The perfect time to add a beta blocker to treatment is when a patient with LV dysfunction comes in for a recheck and seems to be getting along well, having only modest exertional dyspnea. Such patients may, for example, have dyspnea on walking briskly or climbing stairs but often are free of overt edema. Compensation may seem adequate, but the adverse effects of chronic sympathetic activation are occurring under the surface, ready to cause progressive LV failure or even sudden death.

If the effort to optimize therapy is delayed until rest dyspnea or overt congestion develops, a golden opportunity may be missed. In fact, adding a beta blocker to the regimen of a patient with decompensated CHF makes things worse, because getting through that initial period of impaired contractility may not be possible. Beta blockade is usually considered beneficial in patients with an LVEF of less than 40%. Indications for beta blockade are shown in table 1.

Table 1. Indications for beta blockade in patients with left ventricular dysfunction
Severity of congestive heart failure	Ischemic cause?	Idiopathic cause?
No symptoms	Yes	Yes*
Mild (NYHA class II)	Yes	Yes
Moderate (NYHA class III)	Yes	Yes
Severe (NYHA class IV)	No**	No**
NYHA, New York Heart Association. *Supported by clinical experience; effect on survival not yet known. **Carefully selected patients may benefit; additional studies are required.

Some patients with stable NYHA class IV symptoms (orthopnea but no acute decompensation, such as pulmonary edema and overt congestion) may tolerate beta blockade. However, additional studies are required to define the possible role of beta blockers in these patients.

Patients who should not receive beta blockers

Diabetic patients usually have a worse prognosis than do nondiabetics with similar degrees of LV dysfunction. The potential for beta blockers to mask hypoglycemic symptoms has not turned out to be a clinically relevant concern for most diabetic patients, and denying them the major benefits of beta blockade is rarely necessary. Carvedilol (Coreg) may be the agent of choice in diabetic patients, because its alpha-blocking effects actually improve insulin sensitivity, hyperglycemia, and lipid profile (17).

However, patients with brittle diabetes and frequent hypoglycemic episodes should not, in general, receive beta blockers. Most beta blockers may worsen hyperglycemia, insulin resistance, and dyslipidemia. Additional contraindications to beta blockade are listed in table 2.

Table 2. Contraindications to beta blockade in patients with congestive heart failure
Condition	Concern
NYHA class IV disease; overt fluid overload	Initial negative inotropic effects
Heart rate <60 beats/min*	Risk of excess bradycardia
Chronotropic incompetence; AV block*	Risk of excess bradycardia
Systolic blood pressure <100 mm Hg	Risk of symptomatic hypotension
Asthma	Risk of provoking bronchospasm
COPD with asthmatic component	Risk of provoking bronchospasm
Severe peripheral vascular disease	Worsening claudication, ischemia
Cardiac amyloidosis	Risk of heart block
Severe diabetic hypoglycemic spells	Masking symptoms of hypoglycemia
Orthostatic hypotension	Aggravation of orthostatic symptoms
Severe depression	Risk of exacerbating the condition
AV, atrioventricular; COPD, chronic obstructive pulmonary disease; NYHA, New York Heart Association. *Selected patients may receive a pacemaker and then beta blockade.

How to administer beta blockers

Beta blocker therapy in patients with congestive heart failure can usually be effectively and safely initiated with use of the following tips.

Have a system for managing chronic disease.
In a busy practice, it is easy to get in the routine of managing acute symptomatic episodes of disease rather than preventing exacerbations in the first place (ie, the squeaky wheel gets the grease). Being proactive is much more beneficial, especially in the case of serious disease, such as LV dysfunction.

Often, patients come to the office only when they have increasing symptoms. If they happen to be seen at a time when symptoms are controlled, they usually are not interested in starting an additional medication because they believe they are doing fine. Patients should be given a clear explanation of the risks they face by receiving suboptimal therapy. Physicians would not allow hypertension to go untreated just because a patient is not complaining, and LV dysfunction should be considered in the same way. In other words, manage the disease, not just the symptoms.

An algorithm for treating patients with LV dysfunction is provided in figure 1 (not shown).

Optimize the basic CHF treatment regimen.
The consensus guidelines for CHF management may be helpful in determining that the basic CHF treatment program is satisfactory (18). Regular, often brief, office visits over the course of a month or two may be necessary to achieve the compensated state that is ideal for subsequent addition of beta blockade. The following tips may be helpful in ensuring the best compensation:

• Be sure the patient is receiving an appropriate dose of ACE inhibitor, angiotensin-receptor antagonist, or nitrate and hydralazine hydrochloride (Apresoline).
• Optimize the diuretic dose. If the patient has fluid overload, increase the dose. If the patient is lightheaded and hypotensive and exhibits worsening renal insufficiency because of excess diuresis, lower the diuretic dose to allow addition of the beta blocker.
• Use digoxin if appropriate for background inotropic support. This is most appropriate in patients with NYHA class III or IV CHF, and it is helpful in many patients with class II disease.

Consider possible contraindications.
The risk-benefit ratio of beta blockade is influenced by diseases and comorbid conditions listed in table 2. In general, patients with the disorders listed were excluded from randomized trials of beta blockers in CHF because of concern that treatment would worsen their condition. Use of beta blockers in such patients should usually be avoided.

Involve patients in their therapy.
Patients with idiopathic dilated cardiomyopathy often have dramatic improvement in LVEF after 3 to 6 months of beta-blocker therapy, assuming they follow the treatment regimen. Including them in decisions and successes and celebrating with them as their LVEF improves on follow-up is a wonderful way to reduce their fears about the disease and promote long-term compliance.

To get patients involved in their therapy, clarify the rationale for starting beta blockade. Explain that worsening of dyspnea or fatigue is usually temporary and that some lightheadedness may occur. Emphasize the importance of fluid and salt restriction. Tell them to weigh themselves daily as the dose is being adjusted so any fluid retention can be detected early. Patients may have a temporary tendency toward increased fluid retention on initiation of beta blockade because of negative inotropic effects.

Select the proper agent.
Beta blockers vary from one another much more than do ACE inhibitors. It is important to recognize that the principle of beta blockade in CHF appears not to be simply a class effect, in which any beta blocker is useful. Even among agents that appear helpful in patients with LV dysfunction, there are significant differences.

The heart expresses both beta₁and beta₂ receptors, both of which are linked to the contractile pathway. Since beta₁ receptors are substantially down-regulated in CHF, the relative importance of the beta₂ pathway increases. Highly beta₁-selective blockers, such as bisoprolol fumarate (Zebeta), leave the beta₂ pathway unblocked, whereas nonselective beta blockers obstruct both receptor pathways. The importance of this difference is not clear at this point. In theory, nonselective beta blockers might provide more complete cardioprotection, but adequate clinical studies to prove this hypothesis have not been completed.

Some beta blockers, such as carvedilol, also incorporate alpha-receptor antagonist activity, which results in vasodilation. Carvedilol also has antioxidant properties; whether this is a clinically significant characteristic is unknown. Some beta blockers, such as pindolol (Visken), have intrinsic sympathomimetic activity, which may be deleterious in patients with LV dysfunction.

A limited number of beta blockers have been studied in patients with CHF; using other agents that have not been subjected to randomized trials puts the physician on unproved ground. Carvedilol is the only beta blocker currently approved by the US Food and Drug Administration (FDA) for treatment of CHF. This may change, considering recent results with use of sustained-release metoprolol succinate (Toprol XL) and bisoprolol. Beta blockers that have been carefully studied in patients with CHF are listed in table 3.

Table 3. Properties of the beta blockers that have been studied for use in congestive heart failure
Beta blocker	Beta1 selectivity	Vasodilating?	Comments
Carvedilol (Coreg)	None	Yes; alpha blocker	Only agent approved by FDA for this use
Metoprolol succinate (Toprol XL)	++ (diminishes as dose increases)	No	Once-daily dosing
Metoprolol tartrate (Lopressor)	++ (diminishes as dose increases)	No	Generic agent
Bisoprolol (Zebeta)	+++	No	Once-daily dosing
Bucindolol	None	Mild direct dilator	Investigational agent
FDA, US Food and Drug Administration.

Carvedilol therapy

Carvedilol has been shown to improve survival, ejection fraction, NYHA class, and need for hospitalization in patients with class II and III CHF. It is supplied in tablets of 3.125, 6.25, 12.5, and 25 mg. Therapy should start with 3.125 mg taken twice a day--with morning and evening meals to slow absorption and reduce risk of excess hypotension. If necessary, vasodilator doses can be staggered until it is clear that the addition of carvedilol is tolerated. If there is any doubt or concern regarding heart failure or carvedilol's effects on blood pressure and heart rate, the initial dose should be given in the office setting so the patient can be observed and have periodic blood pressure and heart rate checks for an hour after administration.

After the patient has been taking 3.125 mg twice daily for about 2 weeks, recheck vital signs, including weight, blood pressure (sitting and standing), and heart rate, and ask the patient about signs and symptoms of CHF, such as lightheadedness and fatigue. Briefly reexamine the patient for evidence of worsening CHF. If all seems satisfactory, the dose may be increased to 6.25 mg twice daily for another 2 weeks, then raised to 12.5 mg twice daily, and then increased to 25 mg twice daily. A dose up to 50 mg twice daily may be considered in patients weighing more than 85 kg (187 lb) who have adequate heart rate and blood pressure and are tolerating the drug well.

If lightheadedness develops during dose increases, consider reducing the vasodilator dose, and if symptoms persist, reduce the carvedilol dose. If fluid retention worsens, temporarily increase the diuretic dose, and if symptoms persist, decrease or discontinue carvedilol. If bradycardia (heart rate <55 beats/min) or greater than first-degree atrioventricular block occurs, decrease or discontinue carvedilol. Consideration of pacemaker implantation may be necessary.

Metoprolol and bisoprolol therapy

Metoprolol tartrate (Lopressor), metoprolol succinate, and bisoprolol are not currently approved by the FDA for use in CHF. Studies of short-acting metoprolol (metoprolol tartrate) have usually initiated treatment with 6.25 mg twice daily, with increases every 2 weeks to a maximum total daily dose of 100 to 150 mg if tolerated. The 6.25-mg dose form is best prepared by a pharmacist by dividing 50-mg tablets. Whether metoprolol tartrate improves survival is unknown, because no trials large enough to answer this question have yet been completed. The drug's shorter half-life requires twice-daily dosing, and whether the 24-hour control of sympathetic tone is as complete as it is with use of sustained-release metoprolol is uncertain. A trial comparing benefits of metoprolol tartrate and carvedilol is ongoing (the COMET trial).

The Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) (14) used metoprolol succinate and initiated therapy at a dose of 12.5 mg daily for NYHA classes III and IV CHF and 25 mg daily for class II CHF, with doubling of the dose every 2 weeks to a maximum of 200 mg daily if tolerated. A target dose of 200 mg daily was achieved in 64% of patients, and 87% received 100 mg or more daily (mean dose, 159 mg/day). Metoprolol succinate was well tolerated. Fewer patients in the metoprolol group than in the placebo group withdrew from the study. Withdrawal because of worsening CHF was 25% lower in the metoprolol group than in the placebo group, emphasizing the tolerability and efficacy of sustained-release metoprolol. Use of the drug improved survival, need for hospitalization, and NYHA class. (Too few class IV patients were enrolled to allow conclusions about that group.)

Trials of bisoprolol therapy started with a dose of 1.25 mg daily and increased to a maximum of 10 mg daily if tolerated. In the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II) (12), use of bisoprolol therapy improved survival (11.8% in the bisoprolol group compared with 17% in the placebo group). However, at present, bisoprolol is unavailable in the United States in a tablet small enough to initiate a dose of 1.25 mg daily.

The Beta Blocker Survival Trial (BEST), which was examining the effects of bucindolol in patients with NYHA class III or IV CHF, was recently terminated. Findings of the trial suggest some benefit, but not as great as was hoped. This may reflect the more advanced heart failure in patients enrolled in this trial or may indicate particular attributes of bucindolol. Results of the BEST trial have not yet been published.

Treatment overview

Many patients do not reach the maximum recommended dose of beta blocker. Tailoring the program to meet the characteristics of a given patient is critical. These patients are often following complex multidrug regimens that require periodic adjustment to achieve the best possible outcome. Heart rate less than 60 beats per minute, symptomatic hypotension, excessive fatigue, and progressive signs and symptoms of CHF may all be indicators that the beta blocker dose needs to be reduced and certainly not escalated.

Even if dose reduction is necessary, it appears preferable to continue beta blockade, if tolerated, rather than discontinue the drug altogether. This recommendation is based on dose-response studies that found beneficial effects of beta blockade (eg, improvement in ejection fraction) even at lower-than-recommended doses. Even greater benefits were noted in patients who were able to tolerate the higher recommended doses.

Summary

In patients with CHF, physicians should aim to treat the LV dysfunction, not just the CHF symptoms. LV dysfunction is a chronic disease that is usually progressive, even when it seem compensated. The risk of sudden death or progressive CHF is very real. Adding a beta blocker to the treatment regimen while the disease is still compensated or after resolution of an acute exacerbation can stabilize or reverse the LV dysfunction and improve survival. Beta blockade is now a vital part of the standard of care for most patients with LV dysfunction.

References

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2. 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(10):685-91
3. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316(23):1429-35
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12. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353(9146):9-13
13. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993;342(8885):1441-6
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17. Giugliano D, Acampora R, Marfella R, et al. Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension: a randomized, controlled trial. Ann Intern Med 1997;126(12):955-9
18. Packer M, Cohn JN, eds. Consensus recommendations for the management of chronic heart failure. Am J Cardiol 1999;83(2A):1-38A

Dr Frantz is assistant professor of medicine, Mayo Medical School, and a consultant in cardiovascular diseases and internal medicine, Mayo Clinic, Rochester, Minnesota. Correspondence: Robert P. Frantz, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail: frantz.robert@mayo.edu.

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