Charles Shea 6/30/15740 Block 1Clinical Inquiry

Final Question: How does carvedilol compare with metoprolol for reduction of all-cause mortality in patients with reduced ejection fraction heart failure?P: Patients with reduced ejection fraction heart failureI: carvedilolC: metoprololO: reduction in all-cause mortality

Evidence-based Answer: Carvedilol and metoprolol extended release reduce all-cause mortality equally for heart failure patients with reduced ejection fraction. (Strength of Recommendation = A, based on a 2015 clinical inquiry that assessed three meta-analyses containing randomized control trials (RCTs), a 2015 systematic review using cohort and prospective control studies, and consensus from professional guidelines with evidence levels referencing RCTs and meta-analyses)

Evidence Summary: A 2015 clinical inquiry compared multiple beta-blockers against each other for superiority in reduction of mortality for patients with class III or IV heart failure with reduced ejection fraction (HFrEF).1 Three meta-analyses (37,762 patients) were included. The first meta-analysis, comprising 21 RCTs found no statistically significant difference in mortality benefit for patients with a median ejection fraction of 25% at baseline between carvedilol and metoprolol after a median follow-up of one year (odds ratio 0.80; 95% CI, 0.59 to 1.08; no p-value). The second meta-analysis compared data between one RCT of carvedilol versus placebo (2289 patients) against one RCT of metoprolol succinate versus placebo (985 patients). No statistically significant difference in reduction of mortality was found between carvedilol (relative risk reduction [RRR] 35%; 95% CI, 19-48; p = 0.0014) and metoprolol succinate (RRR 39%; 95% CI 11-58; p = 0.0086). The third meta-analysis compared carvedilol with beta-blockers selective for beta-1 (8 RCTs containing a total of 4,563 patients) and concluded there is a statistically significant mortality benefit for carvedilol compared to beta-1 selective beta-blockers (relative risk = 0.85; 95% CI, 0.78-0.93). This result is confounded by potentially sub-therapeutic maximum titration of the tartrate form of metoprolol used in four of the RCTs. The clinical inquiry notes that both the 2010 Heart Failure Society of America Comprehensive Heart Failure Practice Guidelines and the 2013 American College of Cardiology Foundation/American Heart Association Heart Failure Guidelines recommend either carvedilol or metoprolol succinate for HFrE using their highest evidence level recommendation which are based on RCTs and meta-analyses.

A 2015 meta-analysis compared carvedilol against metoprolol for benefits in all-cause mortality in HFrEF under 40%.2 Four prospective control studies and six observational cohort studies were chosen. Overall, 30,942 patients received carvedilol and 69,925 metoprolol with a mean follow-up of 36.4 months. Doses of metoprolol 100 mg or below per day were excluded. The prospective controlled studies revealed a statistically significant mortality benefit of carvedilol compared to metoprolol tartrate (odds ratio 0.80; 95% CI, 0.70-0.91; p