Heart failure Complex clinical syndrome caused by any structural or functional impairment of ventricular filling or ejection of blood Estimated prevalence of ~2.4% (NHANES)
Etiology Generally divided into two major categories: Ischemic causes non ischemic causes Coronary artery disease still remains as the leading cause of heart failure, accounting for more than 50% of the heart failure cases in the Framingham study
Survival Survival is grim 5 year survival rate = 59%
Current Treatment Current recommendations B blockers on top of an ACEi or ARB for the treatment of heart failure Trials that support treatment include a majority of ischemic heart failure patients
Evidence Lacking the trials that enroll mostly non-ischemic heart failure patients are small and underpowered to analyze mortality endpoints
Research Question Among patients with non-ischemic causes of heart failure, how effective are in reducing all cause mortality and beta-blockers hospitalization for worsening heart failure?
Objective To determine the effectiveness of betablockers in heart failure patients with non-ischemic etiologies in decreasing: All cause mortality Hospitalization for worsening heart failure
METHODOLOGY
Search Database: PUBMED MEDLINE Cochrane Controlled Trial Register Search Terms: Beta blockers, heart failure, mortality, hospitalization, RCT and placebo. Other sources Review of all trials included in a recent Metaanalysis on beta blockers
Identification Potentially relevant records identified through database searching: 94 Records after duplicates removed: 106 Relevant records identified through other sources: 20 Screening Records screened: 106 Eligibility Full-text articles assessed for eligibility: 18 Full-text articles excluded based on: no results reported on non-ischemic sub-group: 13 Included Studies included in the meta-analysis: 5
Identification Potentially relevant records identified through database searching: 94 Records after duplicates removed: 106 Relevant records identified through other sources: 20 Screening Records screened: 106 Eligibility Full-text articles assessed for eligibility: 18 Full-text articles excluded based on: no results reported on non-ischemic sub-group: 13 Included Studies included in the meta-analysis: 5
Identification Potentially relevant records identified through database searching: 94 Records after duplicates removed: 106 Relevant records identified through other sources: 20 Screening Records screened: 106 Eligibility Full-text articles assessed for eligibility: 18 Full-text articles excluded based on: no results reported on non-ischemic sub-group: 13 Included Studies included in the meta-analysis: 5
Selection Criteria Inclusion Criteria randomized trials comparing beta blockers with placebo patients with heart failure with nonischemic etiology ejection fraction 40% reported on mortality and/or hospitalizations for worsening heart failure Exclusion Criteria non-randomized compared beta blockers with other betablockers or other heart failure treatment did not specify results of mortality and hospitalizations for the non-ischemic subgroup
Identification Potentially relevant records identified through database searching: 94 Records after duplicates removed: 106 Relevant records identified through other sources: 20 Screening Records screened: 106 Eligibility Full-text articles assessed for eligibility: 18 Full-text articles excluded based on: no results reported on non-ischemic sub-group: 13 Included Studies included in the meta-analysis: 5
Identification Potentially relevant records identified through database searching: 94 Records after duplicates removed: 106 Relevant records identified through other sources: 20 Screening Records screened: 106 Eligibility Full-text articles assessed for eligibility: 18 Full-text articles excluded based on: no results reported on non-ischemic sub-group: 13 Included Studies included in the meta-analysis: 5
Study Participants Patients Overall # CIBIS I Age 18-75 yrs, with chronic heart failure NYHA III or IV. On diuretic and vasodilator therapy w/ EF 40% CIBIS II Age 18-80 yrs, with chronic heart failure NYHA III or IV. On diuretic and ACEi therapy w/ EF 40% MDC Age 16-75 years, with idiopathic dilated cardiomyopathy w/ EF 40% Merit-HF Age 40-80 yrs, with chronic heart failure NYHA II or IV. On optimal treatment w/ EF 40% US Carvedilol Symptomatic failure w/ EF 35% heart 641 (321 placebo 320 bisoprolol) 2647 (1320 placebo 1327 bisoprolol) 383 (194 placebo 189 metoprolol) 3991 (2001 placebo 1990 metoprolo l) 1094 (398 placebo 696 bisoprolol ) Nonischemic 350 (115 placebo 117 bisoprolol) 317 (157 placebo 160 bisoprolol) 1397 (701 placebo 696 metoprolol) 350 (115 placebo 117 bisoprolol) Intervention treatment Bisoprolol vs placebo Bisoprolol vs placebo Metoprolol vs placebo Metoprolol vs placebo Carvedilol vs placebo mean ffup 1.9 yrs 1.3 yrs 1.5 yrs Outcome Method BIAS Bias Mortality, Bisoprolol tolerability Mortality, hospitalizati on Cardiac Death Cardiac hospitalizati on Mortality and need for transplantat 1 yr Mortality, hospitalizati on 6-12 mos Mortality, safety RCT, double blind RCT, double blind RCT, double blind RCT, double blind RCT, double blind A A A A A A A A A A
Data Collection and Analysis Data on total mortality as well as hospitalizations were extracted from each trial using a standardized data collection form Analysis was done using Cochrane Review Manager software version 5.2 Heterogeneity was tested using chi-square test as well as I 2 statistics p value < 0.1 and I 2 value of 50% considered to have significant heterogenity
Total Mortality
Hospitalizations
Discussion Treatment with beta-blockers shows improved outcomes Consistent results in multiple trials Independent of the type of beta blocker Chatterjee, S., Biondi-Zoccai, G., Abbate, A., et al. Benefits Of Β Blockers In Patients With Heart Failure And Reduced Ejection Fraction: Network Meta-Analysis. BMJ 2013;346:f55
Discussion The results of this analysis: Beta blockers reduce mortality and hospitalizations in non-ischemic heart failure patients Risk reduction of 28% for mortality, comparable to 34% risk reduction for mortality of the entire cohort.
Discussion Possible mechanisms: Restoration of the low and high frequency oscillation of the muscle sympathetic nerve activity variability Restoration of baroreceptor tone and increasing vagal tone Both contributes to decreasing sudden death and disease progression Kubo, T, Azevedo, E.R., Newton, G.E., et al. Beta-Blockade Restores Muscle Sympathetic Rhythmicity in Human Heart Failure. Circulation Journal 2011. Vol.75, 1400-1408 Sanderson, J. E., Yeung, L.Y., Chan, S., et al. Effect of β-blockade on Baroreceptor and Autonomic Function in Heart Failure.Clinical Science (1999) 96, 137 146
LIMITATION This meta-analysis was limited to the data reported by the included studies. Unpublished studies and those whose access is restricted, may not have been included.
CONCLUSION The mortality benefit and decrease in hospitalization seen with the addition of beta-blockers to maximal medical therapy among patients is not limited to ischemic causes alone.
RECOMMENDATION Patients with non ischemic heart failure should be started on beta blockers in the absence of contraindications