Beta-Blockers to Reduce Mortality in Patients with Systolic Dysfunction A Meta-Analysis

Relative contraindications to b-blocker use are reflected in the exclusion criteria used in the trials discussed and include clinical instability,^3,11-13,14 second- or third-degree heart block in the absence of an implantable pacemaker,^3,9,13 low blood pressure,^3,9,12 low heart rate,^9,12,13 or treatment-requiring obstructive airway disease.^9,12,14 All the trials we reviewed indicated that b-blocker therapy in patients with heart failure does not result in a clinically significant decrease in systolic or diastolic blood pressure. As expected, however, a decrease in heart rate of approximately 10 to 15 beats per minute is likely to occur.^3,9,11-14 It is important to note that in US Carvedilol, increased dizziness in the carvediloltreated patients was noted compared with placebo. Dizziness was most pronounced after a dosage increase and dissipated with continued use.¹³ Target doses reached with b-blocker and placebo therapies were similar,^9,13,14 further confirming the tolerability of these agents with progressive dose titration.

Patients with Heart Failure

On the basis of studies reviewed, it is reasonable to anticipate a 15% to 20% withdrawal rate from b-blocker therapy in patients with systolic heart failure. The reasons for withdrawal will most commonly be worsening heart failure or side effects, such as fatigue and dyspnea. It is reassuring that the rates of withdrawal in the trials were similar for placebo and active therapies, suggesting that b-blocker therapy was not the primary cause of withdrawal.

Questions remain concerning the effects of b-blockade in patients with heart failure. The Carvedilol Prospective Randomized Cumulative Survival Trial was designed to evaluate the mortality effect of carvedilol versus placebo in patients with severe heart failure.^4,21,22 Although not published at the time of this review, the trial was discontinued early as a result of a large and consistent decrease in mortality in patients receiving carvedilol.²³ The Carvedilol ACE Inhibitors Remodeling Mild Heart Failure Evaluation trial is designed to evaluate carvedilol in asymptomatic patients with left ventricular dysfunction.^12,21 Also, the Betablocker Evaluation Survival Trial evaluated bucindilol versus placebo in patients with moderate to severe heart failure.^4,15,21 This trial was discontinued early because of lack of mortality benefit.²⁴

Heart failure primarily affects the elderly population older than 65 years.¹ Currently published trials have not included large numbers of elderly patients,^12,21,22 and therefore, extrapolation of the data to this patient population should be done with caution. Also, the effects of race and ethnicity have yet to be systematically addressed.²¹ Studies designed to assess the impact of b-blockade in patients with heart failure depending on the etiology of their disease would allow for further maximization of benefit. The Carvedilol Post-Infarction Survival Control in Left Ventricular Dysfunction trial²² was designed to evaluate patients with heart failure following an acute myocardial infarction.^12,22 Clinical trials are needed to determine optimal dosing regimens.³

Comparative clinical trials with a mortality end point have not been conducted. Efficacy comparisons between selective and nonselective b-blockers are necessary to quantify the survival benefit.³ The Betaxolol Versus Carvedilol in Chronic Heart Failure study is designed to compare betaxolol with carvedilol in patients with NYHA class II or III heart failure.⁴ The comparative efficacy of carvedilol with the b1-selective agent metoprolol is being assessed in the Carvedilol and Metoprolol European Trial.^4,21,22

Conclusions

All stable patients with NYHA class II and III heart failure should be considered for b-blocker therapy. Therapy should be initiated only in stable patients using a low dose of a b-blocker. This dose may be subsequently gradually titrated upward by doubling the current dose every 1 to 2 weeks on the basis of clinical response and patient tolerability.

Acknowledgments

We would like to acknowledge the assistance of Deborah S. Carson, PharmD, BCPS, and Ché Jordan, PharmD.

Related Resources

• American Heart Association-congestive heart failure www.americanheart.org/chf
• WebMD-Heart Disease Center www.my.webmd.com/condition_center/cvd
• Heart Failure Society of America www.hfsa.org Organizers describe the site as “a forum for all those interested in heart function, heart failure, and congestive heart failure (CHF) research and patient care.”