Beta blocker treatment in heart failure

https://doi.org/10.1053/pcad.1999.0410301Get rights and content

Abstract

The sympathetic nervous system occupies a prominent role in heart failure both as a marker of severity of disease and also as an important factor in its progression. Beta blocker therapy, once thought heretical in heart failure, has consistently improved cardiac function and slowed progression of disease. Large clinical trials of mild to moderate heart failure show improved survival as well as reduction in hospitalization. Beta blockers now have stronger data in heart failure than converting enzyme inhibitors, and should be considered standard therapy in mild-moderate heart failure. Ongoing trials are addressing beta blocker therapy in advanced heart failure and comparisons between agents. Copyright © 1999 by W.B. Saunders Company

Progress in Cardiovascular Diseases, Vol. 41, No. 4 (January/February), 1999: pp 301-322

Section snippets

Pathophysiology

The body responds to the presence of heart failure with a number of mechanisms. The failing myocardium has increased wall stress prompting a remodeling process involving the addition of sarcomeres, classically elaborated in parallel in response to systolic overload (eg, aortic stenosis), and, in series in response to diastolic volume overload (eg, mitral regurgitation).2 This myocardial remodeling occurs postmyocardial infarction as well as in heart failure.3 One important early mechanism is

Properties differentiating among beta blockers

The pharmocologic properties of beta blockers differ in important ways that could influence clinical response and tolerability in heart failure. The most prominent features involve the selectivity of β1- and β2-receptor blockade. Other important features include whether an agent is lipophilic or hydrophilic, or has vasodilating properties. Other characteristics include intrinsic symptomatic activity (ISA), partial agonist activity, or membrane stabilizing activity. In heart failure, there is

Clinical trials

Early investigation with beta blockers in heart failure were initially undertaken in Europe. Waagstein evaluated practolol in seven postmyocardial infarction patients with cardiac failure in 1976.31 The agent was well tolerated and some clinical improvement was noted. This use expanded into heart failure.32 Later Swedberg reported a series in which heart failure patients treated with a beta blocker, in addition to digitalis and diuretic, had survival at 1, 2, and 3 years of 83%, 66%, and 52%,

Hemodynamics

Beta blockers characteristically improve ejection fraction while reducing cardiac filling pressure-cardiac stroke work commonly improves; at a lower volume indicating an inotropic effect as noted by Woodley et al39 (Fig 5) with bucindolol and Eichhorn et al with metoprolol.40This effect appears similar whether a nonselective or cardioselective agent is used or whether vasodilating properties are present. Gilbert et al43 has shown a similar improvement with metoprolol as with carvedilol Table 3.

Exercise

The exercise data with beta blockers has been mixed. In part this is because of the fact that, as in other clinical circumstances such as angina and hypertension, beta blockers often do not improve maximal exercise response. This is largely caused by the blunting of maximal heart rate. The effect of this blunting was particularly notable with bucindolol as reported by Bristow et al20; maximal exercise was actually decreased by this agent and this correlated with a decrease in maximal heart

Quality of life

Symptoms and quality of life assessment have been a source of controversy in heart failure. The complexity of the syndrome is one issue, but the instruments used to make the measurements present challenges also. The New York Heart Association (NYHA) classification has been widely used but is limited by subjectivity, particularly between class II and III. Quality of life assessment has been even more difficult as disagreement exists over what the instruments are measuring. The most validated

Morbidity and mortality

Morbidity and mortality has been reported in six trials. Four were small to medium size trials that could not assess mortality effects but could provide combined morbidity and mortality results, MDC,44 CIBIS-I,57 US Carvedilol Trials26 and ANZ.47 Two completed trials qualify as mega trials and contain enough statistical power to assess mortality alone as well as morbidity data: they are CIBIS-II23 and MERIT-HF.24

CIBIS I

CIBIS I has some similarity to MDC. It tested a cardioselective beta blocker, bisoprolol, against placebo in a mild-moderate heart failure population (95% NYHA III) of modest size, consisting of 641 patients. However, the population was both ischemic and idiopathic in origin and the primary endpoint was overall mortality. This trial also did not require a test dose run-in phase. Like MDC, CIBIS I did not show a significant reduction in mortality Table 7. (P = .22).Also as in MDC, the beta

US carvedilol trials

This evaluation of carvedilol involved a ″stratified program” that included common inclusion/exclusion criteria such as ejection fraction less than or equal to 35% and symptoms despite standard therapy. The program was composed of four separate protocols with entry based on the following 6-minute exercise criteria: (1) 426 to 550 m-mild heart failure protocol; (2) 150 to 425 m moderate heart failure protocol (PRECISE)55 or a dose ranging study (MOCHA)41; (3) less than 150 metersMsevere heart

ANZ

The ANZ trial tested carvedilol in a cohort of ischemic cardiomyopathy patients with mild symptoms (predominantly NYHA class I and II). These patients had a average ejection fraction of 29%. The primary endpoints were a change in LVEF and treadmill exercise duration. Multiple secondary endpoints assessed symptoms as well as morbidity and mortality.

This trial also contained a run-in period. Four hundred and twenty-two patients were eligible while 415 were randomized and followed up an average of

CIBIS II

CIBIS II can be seen as a larger, more comprehensive, and finally, conclusive study of bisoprolol in heart failure. This trial terminated early because of positive findings in March 1998, and was the first of the larger megatrials to report results. This is particularly important because, in contrast to most previously reported beta blocker trials, CIBIS II tested a beta blocker without a run-in phase. Also, because there were 274 centers, it also tested beta blocker use outside of heart

MERIT-HF

The even larger MERIT-HF trial tested long-acting metoprolol against placebo in addition to standard therapy in a mild-moderate heart failure population of NYHA II to IV patients. This trial was prematurely terminated in October 1998 after approximately 4,000 patient years of exposure with 3,991 enrolled patients.

The design of the trial was similar to CIBIS II in that it did not require a run-in period.23 It tested two primary endpoints: (1) all cause mortality and (2) combined all cause

Resolvd

The only beta blocker trial with unfavorable clinical outcomes has been The randomized evaluation of strategies for left ventricular dysfunction (RESOLVD)60 pilot study. This study had a very complicated design with two phases: stage I-three arms comparing the angiotensin II antagonist candesartan, the angiotensin converting enzyme inhibitor enalapril, and the combination of enalapril and candesartan; stage II-at five months eligible patients received metoprolol or placebo for 6 more months.

Meta analysis

Two major meta analyses have been undertaken on beta-blocker studies in heart failure patients. Both studies were undertaken before the CIBIS II and MERIT-HF study results and therefore some of their conclusions have been supplanted by the data from these new trials.

Heidenreich et al published their work first in 1997.61 Analyzing 17 trials on 3,039 patients with mortality data beyond 3 months, these authors showed that beta blockade significantly reduced all cause mortality (RR = 0.69, 95%

Clinical differentiation

As discussed above, pharmacological properties differ among beta blockers. How are physicians to decide which agent to use? Based on available data, most of the above properties do not strongly influence clinical outcome. No agent without ISA is usable in heart failure, and the ancillary properties such as antioxidant actions are unproven. Hydrophilic beta blockers may not effect sudden death but all beta blockers in clinical trials are lipophilic and therefore could effect vagal tone.

Who should receive beta blockers?

The combined data from beta blocker trials, including CIBIS II and MERIT-HF, strongly support the concept that heart failure patients with mild-to-moderate heart failure symptoms and systolic dysfunction should receive these agents. The data is now as strong or stronger than the data for converting enzyme inhibitors on reducing morbidity and mortality. An analysis from Cleland et al64 indicates that, even before the data from the mega trial data is considered, beta blocker treatment result in

Conclusion

The data on morbidity and mortality for beta blockers use in mild-moderate heart failure should make these agents mandated therapy. The specific mechanism by which they improve ventricular function and prognosis is not entirely elucidated, but appears to relate to antiadrenergic cardioprotective effects and ventricular remodeling. Beta blockers should be prescribed with great caution in advanced or decompensated heart failure where, at present, there is no data supporting their use. Further

References (68)

  • EM Gilbert et al.

    Long-term beta blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: A double-blind, randomized study of bucindolol versus placebo

    Am J Med

    (1990)
  • F Waagstein et al.

    Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy

    Lancet

    (1993)
  • SG Pollock et al.

    Usefulness of bucindolol in congestive heart failure

    Am J Cardiol

    (1990)
  • M Metra et al.

    Effects of short-term and long-term carvedilol administration on rest and exercise hemodynamic variable, with idiopathic dilated cardiomyopathy

    J Am Coll Cardiol

    (1994)
  • SL Olsen et al.

    Carvedilol improves symptoms and left ventricular function in chronic heart failure. A double-blind randomized study

    Am Coll of Cardiol

    (1995)
  • T Wisenbaugh et al.

    Long-term (3 month) effects of a new beta-blocker (nebivolol) on cardiac performance in dilated cardiomyopathy

    J Am Coll Cardiol

    (1993)
  • ML Fisher et al.

    Beneficial effects of metoprolol in heart failure associated with coronary artery disease: A randomized trial

    J Am Coll Cardiol

    (1994)
  • JN Cohn et al.

    Safety and efficacy of carvedilol in severe heart failure

    J Card Fail

    (1997)
  • PA Heidenreich et al.

    Effect of beta-blockade on mortality in patients with heart failure: A meta-analysis of randomized clinical trials

    JACC

    (1997)
  • Burden of heart failure. American Heart Association

    (1997)
  • AM Katz

    The cardiomyopathy of overload: An unnatural growth response in the hypertrophied heart

    Ann Intern Med

    (1994)
  • NJ Cohn et al.

    Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure

    N Engl J Med

    (1984)
  • B Rundquist et al.

    Increased cardiac adrenergic drive precedes generalized sympathetic activation in human heart failure

    Circulation

    (1997)
  • DL Mann et al.

    Adrenergic effects on the biology of the adult mammalian cardiocyte

    Circulation

    (1992)
  • T Yoshikawa et al.

    Cardiac adrenergic receptor effects of carvedilol

    Eur Heart J

    (1996)
  • MR Bristow et al.

    Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts

    N Engl J Med

    (1982)
  • MR Bristow et al.

    Beta 1 and Beta 2-adrenergic subpopulations in non-failing human ventricular myocardium: Coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor downregulation in heart failure

    Cir Res

    (1986)
  • GE Newton et al.

    Acute effects of β1-selective and nonselective β-adrenergic receptor blockade on cardiac sympathetic activity in congestive heart failure

    Circulation

    (1996)
  • EM Gilbert et al.

    Comparative hemodynamic, left ventricular functional, and anti-adrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart

    Circulation

    (1996)
  • EJ Eichhorn et al.

    Practical guidelines for initiation of beta-adrenergic blockade in patients with chronic heart failure

    Am J of Cardiol

    (1997)
  • BD Lowes et al.

    Clinical relevance of inverse agonism and guanine nucleotide modulate binding properties of β adrenergic receptor blocking agent

    Circulation

    (1994)
  • The xamoterol in severe heart failure study group

    Xamoterol in severe heart failure

    Lancet

    (1990)
  • TJ Rimele et al.

    Pharmacology of bucindolol in isolated canine vascular smooth muscle

    J Pharmacol Exp Ther

    (1984)
  • Cited by (0)

    View full text