Author + information
- Marcus D. Flather, MBBS∗ ( and )
- Nicholas D. Gollop, MBBCh
- Norwich Medical School, University of East Anglia, and Norfolk and Norwich University Hospitals, Norwich, United Kingdom
- ↵∗Reprint requests and correspondence:
Dr. Marcus Flather, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR7 7TJ, United Kingdom.
Heart failure (HF) is a global health challenge due to ageing populations and increasing burden of disease (1). Older HF patients have higher rates of preserved ejection fraction (HFpEF) and higher numbers of females and comorbidities (2). There are uncertainties in diagnosis of HF in the elderly, who may present with atypical symptoms, and the evidence base for conventional treatments is weaker especially for HFpEF (3).
The exact pathophysiologic mechanisms responsible for HFpEF are not clear. The condition is thought to be mediated by diastolic dysfunction (including myocardial hypertrophy, increased ventricular stiffness, and prolonged ventricular relaxation), but a simple and universal definition of HFpEF is lacking (4). Unfortunately, the therapeutic paradigm that has been successful in heart failure with reduced ejection fraction (HFrEF) has yet to be convincingly demonstrated in HFpEF. Without effective therapies, hospitalizations for HFpEF have increased, and risk of death and hospitalization appear similar to those of HFrEF (5). As a result, a dichotomy in outcomes has emerged between these 2 seemingly related pathophysiological states.
The physiological mechanisms of beta blockers appear to be well understood in HFrEF, blocking sympathetic neural activity, preventing catecholamine elevation, reducing heart rate, and reducing proapoptotic and cardiotoxic effects of cyclic adenosine monophosphate-mediated calcium overload (6). Several large trials and an individual patient data meta-analysis confirm an overall absolute reduction in the risk of death with beta blockers compared to placebo (7). However there was little evidence of benefit in patients with atrial fibrillation (hazard ratio: 0.97 compared to 0.73 for sinus rhythm). The apparent benefit of the composite of all-cause mortality and cardiovascular hospitalization in the SENIORS trial in patients with EF >35% (mean EF: 49%) was found to be similar to that in patients with EF ≤35% (mean: 28%), but mortality benefits appeared to be attenuated with higher EF (8). Other subgroups in whom there are doubts about efficacy of beta blockers are the elderly, women, and those with diabetes, and further analyses from the Beta Blockers Heart Failure Collaborative Group will help to clarify effects in these important subgroups.
CIBIS-ELD (Comparison of Bisoprolol and Carvedilol in elderly heart failure [HF] patients: a randomised, double-blind multicentre study; ISRCTN34827306) randomized 883 patients (mean: 73 years of age; 39% women; mean EF: 42%) to receive bisoprolol or carvedilol, to assess safety and tolerability over a 12-week titration period (9). Only one-fourth of patients in both groups achieved the target (10 mg of bisoprolol or 25 mg of carvedilol [which was twice the daily carvedilol dose]) with approximately 90% of subjects tolerating the starting or a higher dose. Adverse bradycardia was more common with bisoprolol, whereas pulmonary events were more common with carvedilol.
The paper by Edelman et al. (10) in this issue of JACC: Heart Failure extended these findings by stratifying the CIBIS-ELD cohort into HFpEF (EF: >45%) and HFrEF (10). HFpEF was diagnosed in 29% of patients with a mean EF of 59% compared to 35% in HFrEF. HFpEF patients were slightly older, more likely to be female, have lower heart rate, higher systolic BP, higher body mass index and less likely to have atrial fibrillation compared to the HFrEF group. Overall tolerability and safety of bisoprolol and carvedilol were similar in the 2 groups, but there were more likely to be delays to increased titration in the HFpEF group. Although there were similar reductions in heart rate from baseline to end of titration in both groups (approximately 7 beats/min), HFpEF patients showed greater reductions in systolic blood pressure while N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentrations showed elevation compared to HFrEF patients, who showed no detectable changes. Increases in New York Heart Association functional class, 6-min walk test results, and SF-36 questionnaire responses were greater in HFrEF patients than in HFpEF patients, and echocardiographic measurements, including EF and end-systolic and end-diastolic results, were improved in HFrEF patients, with no observable change in HFpEF patients (10).
CIBIS-ELD was a well conducted study and one of the few direct comparisons of beta-blockers in HF (9). The current analysis stratified by EF is important for several reasons. First, HFrEF patients tolerate speedier up-titration of beta-blockers than HFpEF, which seems counterintuitive. Second, there are differential mechanistic effect of beta-blockers in HF stratified by EF, as HFrEF responds better in terms of cardiac function, walking ability, and subjective measurements assessed by SF-36. Third, there is evidence that NT-proBNP shows little change or a potential rise in response to beta-blockers in HF, which again is counterintuitive but has been seen in previous studies (11). This opens up the question of the role of NT-proBNP in monitoring response to beta-blocker therapy in HF. These findings also suggest that HFpEF is a heterogeneous and poorly understood condition with various definitions in clinical trials. The analysis presented is not randomized and we should be cautious about overinterpretation. However the study provides a sound basis for future randomized trials of beta-blockers in elderly patients with HFpEF, to resolve an unmet need.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. Flather was a member of the SENIORS trial steering committee (2002–2007); is a principal investigator for the Beta Blockers in Heart Failure Collaborative Group; served on the Steering Committee for Novartis Sponsored Trials; is on an advisory board for AstraZeneca; has received research grants from Menarini International; and has received honoraria from AstraZeneca, Novartis, and Pfizer. Dr. Gollop has reported that he has no relationships relevant to the contents of this paper to disclose.
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