[beta]-Blocker survival benefit outweighs side-effect risks - Patient-Oriented Evidence that Matters

Journal of Family Practice, Oct, 2002 by Lisa P. Easterling, Peter G. Koval, Todd McDiarmid

Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. [beta]-Blocker therapy and symptoms of depression, fatigue and sexual dysfunction. JAMA 2002; 288:351-7.

* BACKGROUND Despite mortality benefits, [beta]-blockers are often underused, possibly because of concerns of developing side effects. The authors systematically reviewed trials with patients receiving [beta]-blockers for myocardial infarction, heart failure, or hypertension that assessed for symptoms of depression, fatigue, and sexual dysfunction.

* POPULATION STUDIED Researchers identified controlled trials completed before December 2001 using a MEDLINE search. Reference lists of published trials were reviewed for additional studies. The authors identified 475 articles that matched keyword searches and found 15 randomized placebo-controlled trials meeting inclusion criteria of enrollment of at least 100 patients with a minimum 6-month follow-up. This evaluation included 6 post-myocardial infarction, 3 heart failure, and 6 hypertension trials totaling more than 35,000 patients.

* STUDY DESIGN AND VALIDITY The authors compared [beta]-blockers with placebo in relation to patient-reported depression, fatigue, and sexual dysfunction, and withdrawal due to these agents. Propranolol and timolol were classified as early-generation drugs and the remaining tested [beta]-blockers classified as late-generation agents. Bucindolol, carvedilol, and propranolol were categorized as highly lipid soluble agents, with the rest as low-to-moderately lipid soluble.

The evaluation lacked a dose-response assessment and was inconsistent in the methods for assessing symptoms of depression, fatigue, and sexual dysfunction. The criteria used to identify and select trials were appropriate and consistent.

* OUTCOMES MEASURED The main outcomes measured were number of patient-reported symptoms and withdrawal of therapy related to each of the evaluated side effects--depression, fatigue, or sexual dysfunction--compared with placebo.

* RESULTS Seven of the 15 trials evaluated the overall frequency of reported depressive symptoms. Combining the result of these 7 trials identified no difference compared with placebo. Withdrawal of medication attributed to depression was assessed in 4 trials (N = 5800) with an average follow up of 14 months. No difference was noted between b-blocker therapy and placebo for risk of withdrawal due to depression (relative risk [RR] = 0.94; 95% confidence interval [CI], 0.44-2.01). Early-generation and highly lipid soluble b-blockers were studied in 3 and 5 trials, respectively, with an average follow-up of 16 months. The comparisons for generation and solubility revealed no difference in the incidence of depression.

Fatigue was assessed in 10 studies. The combined analysis showed an increase in the number of reported symptoms (32%) versus placebo (28%) (RR = 1.15; 95% CI, 1.05-1.26; number needed to harm [NNH] = 57 per year). However, of 29,400 patients followed for an average of 29 months with fatigue-related symptoms, only 2.4% withdrew from therapy (RR = 3.8; 95% CI, 1.16-5.94; NNH = 225 per year). Five trials studied early-generation [beta]-blockers (N = 24000) over an average of 25 months and found a small but statistically significantly higher risk for fatigue when compared with the 5 trials of late-generation [beta]-blocker use (N = 12,200). No difference was noted in fatigue when agents were assessed by lipid solubility.

In assessing patient-reported sexual dysfunction, 6 trials showed no difference between [beta]-blocker and placebo. Withdrawal of medication due to sexual dysfunction was evaluated in 4 trials (N = 11260) with an average follow-up 33 months. A small significant increase in withdrawal from [beta]-blockers due to sexual dysfunction was found (RR = 4.89; 95% CI, 2.98-8.03; NNH = 438 per year). No significant differences were shown in risk estimates of sexual dysfunction between early- and late-generation [beta]-blockers. No differences were noted between high or low-to-moderate degrees of solubility, although only propranolol and bucindolol were studied.

RECOMMENDATIONS FOR CLINICAL PRACTICE

[beta]-Blockers are not associated with a significant increase in depressive symptoms. They do cause a slightly higher incidence of withdrawal because of fatigue and sexual dysfunction. Propranolol is associated with an increased risk of experiencing fatigue. Later-generation b-blockers (metoprolol, atenolol, pindolol, carvedilol, and sotalol) should be used to minimize the potential for fatigue. Lipid solubility made no difference in the risks of side effects. The fear of these side effects should not deter prescribers from initiating b-blockers where mortality benefit has been documented. Close follow-up observation for the infrequent cases of fatigue and sexual dysfunction is appropriate.

Lisa P. Easterling, PharmD
Peter G. Koval, PharmD, BCPS
Todd McDiarmid, MD
Moses Cone Health System
Greensboro, NC
E-mail: Lisa.Easterling@mosescone.com