European Journal of Heart Failure (2014) EDITORIALdoi:10.1002/ejhf.108
Convergence in findings from randomizedtrials and elaborately analysed observationaldata on mortality reduction with carvedilolin heart failure in comparison with metoprololAnasua Chakraborty1 and Saurav Chatterjee2*1Division of Pulmonary and Critical Care Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA; and 2Division of Cardiology, St. Lukes-Roosevelt HospitalCenter, Mount Sinai Health System, New York, NY, USA
The opinions expressed in this article are not necessarily thoseof the Editors of the European Journal of Heart Failure or of theEuropean Society of Cardiology.
This editorial refers to ‘Comparison of the clinical outcomeof different beta-blockers in heart failure patients: a retrospectivenationwide cohort study’, by R. Bølling et al., on page 678
Beta-blockers have been shown to reduce ‘clinically meaningful’endpoints such as mortality, sudden cardiac arrest, and ventriculararrhythmias, and to lead to a decrease in rehospitalizations due tosymptomatic heart failure with reduced ejection fraction (HFrEF);as well as to improve LV systolic function in both well-designedrandomized trials1,2 and observational studies,3 including largemeta-analyses.4 However, the choice of the optimal beta-blockerfor management of HFrEF, in the midst of multiple available optionsof beta-blockers with varying properties and effects on the differentadrenergic receptors, remains contentious. A recent, comprehen-sive meta-analysis5 had sought to evaluate this problem by meansof a network meta-analysis of published, large randomized trialsof beta-blockers in HFrEF, and found a ‘class effect’ for the clinicalbenefits seen with the different beta-blockers in HFrEF.
In this issue of the European Journal of Heart Failure, Bøllinget al. have performed an elaborate analysis to compare survival ondifferent beta-blockers in heart failure.6 They analysed all Danishpatients ≥35 years of age who were hospitalized with a firstadmission for HFrEF, and were initiated with a beta-blocker within60 days of discharge. The analysis included 58 634 patients followedup for a mean period of 4.1 years. They found that patientsreceiving high dose carvedilol (≥50 mg/day) had a significantlylower risk of all-cause mortality than patients receiving high dose(≥200 mg/day) metoprolol. Risk of all-cause hospitalization wasalso reduced with use of high dose carvedilol, in comparison withhigh dose metoprolol. Also, in contrast to randomized data fromthe CIBIS group of trials,7 patients on a ≥10 mg/day dosage of
*Corresponding author. St Luke’s-Roosevelt Hospital Center, Cardiovascular Medicine Division, 1111 Amsterdam Avenue, Clark Building, New York, NY 10025, USA. Tel: +1 484988 0084, Fax: +1 347 244 7148, Email: [email protected]
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.... bisoprolol had worse all-cause mortality risk than patients on high
dose metoprolol.This is an important and elaborately analysed study6 with var-
ious facets for deliberation. There is validation of the trend insuperiority seen with carvedilol in comparison with metoprolol inthe recent network meta-analysis of randomized trials.5 There, aBayesian ‘credible’ reduction in pooled odds for all-cause mortal-ity of 20% was noted—whereas in the analysis of Bølling et al.6
a 13% reduction in all-cause mortality was seen, with overlapping95% confidence intervals—indicating that there may be no statis-tically significant difference in the two separate analyses (Table 1).Any minor differences noted may have been due to random sta-tistical chance. The mortality advantages seen with carvedilol incomparison with metoprolol5 do not reach statistical significance,probably due to underpowered analysis for that specific compari-son. The results of Bølling et al. also corroborate the findings fromthe only head-to-head randomized comparison of carvedilol andmetoprolol (tartrate)—the COMET trial.8 While that trial8 wasplagued with concerns of underdosing of the metoprolol arm (100mg/day)9 —the analysis by Bølling et al. shows that even contrastedagainst a comparably high dosage of metoprolol, carvedilol hadsuperior mortality outcomes in HFrEF. Interestingly, the currentstudy does not specify the formulation of the metoprolol used—asonly the long-acting, ‘succinate’ variety has been shown to have afavourable mortality benefit in randomized trials.10
The study also found significantly lower mortality with carvediloluse in comparison with metoprolol in men at 3 months. However,overlapping confidence intervals in the absence of a robust testfor interaction, and wide confidence intervals may indicate thisto be a chance finding, or one because of sample size disparity,representing a relatively smaller proportion of women among thesubjects under consideration. The issue of tolerability at 1 year offollow-up was also representative of the results from randomized
controlled trials,5 with carvedilol having the best adherence totherapy at 1 year. However, an alternative explanation for thisfinding, other than mortality advantage with carvedilol itself, mayalso have been due to the fact that the patients in the carvedilolgroup were younger, less sick, with fewer co-morbidities—andhence had better survival and compliance at follow-up—probablyreflective of carvedilol being a newer drug. This finding may alsohave been confounded by the changes in guidelines over the yearsand progressive greater emphasis on the use of beta-blockers inHFrEF for reduction in mortality.
Apart from the favourable mortality seen with use of carvedilolover metoprolol, high dose carvedilol was also seen to reducerehospitalizations to a significantly greater extent than high dosemetoprolol. Leaving the limitations of the analysis of observationaldata aside—this finding may have great significance for the currentmodels of healthcare, emphasizing the need for avoidance ofrehospitalizations for medical, as well as economic reasons. Alsoresults from the study of Bølling et al.6 provide evidence forbisoprolol to be relegated to being a ‘third-line’ option, only forconsideration after carvedilol and metoprolol have been excludedfor mortality reduction in HFrEF.
Notwithstanding the shortcomings of a registry-based anal-ysis, and diagnostic identifications derived from ICD (Interna-tional Classifications of Diseases) codes,11 the study of Bøllinget al. reinforces the mortality advantages seen with carvedilolover metoprolol in a predominantly western European, possiblylargely Caucasian population. Previous studies12 have contendedthat beta-blockers had a more favourable mortality benefit in tri-als conducted outside of the USA. However, the US Carvediloltrials13 have established quite conclusively the mortality benefitsseen with carvedilol in the USA. Coupled with the results ofthis current analysis, there appears to be a robust reduction inmortality globally, seen at least with carvedilol, as corroboratedby another recent large analysis of beta-blocker use in HFrEFacross different regions of the world.14 Of note, the previousstudy12 had indicated that a reason for the poorer mortality out-comes in the US population may have been because of the impactof having enrolled a significantly larger group of African Ameri-can patients in the USA compared with the rest of the world.The present study did not report outcomes in this potentiallyinteresting subgroup, if any were included, of African Americansubjects.
Several other limitations have been acknowledged by theauthors—and may impact the conclusions drawn—the absence ..
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.. of NYHA class at baseline and at follow-up, EF, blood pres-sure data, and paucity of laboratory values weaken thestudy—however, if replicated in other populations, a clearlysuperior option for beta-blockade in HFrEF may have beenidentified with this analysis. The mechanism of such superior-ity of carvedilol over metoprolol in the reduction of mortalityin HFrEF needs to be identified,15 and an adequately pow-ered head-to-head randomized trial of high doses of carvediloland metoprolol succinate is imperative to settle the debatedefinitively.
Conflicts of interest: none declared.
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