β blockers for heart failure: which works best?
BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f480 (Published 24 January 2013) Cite this as: BMJ 2013;346:f480
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I picked up a recent hard copy of BMJ from my local medical library while resting from studying and noticed this article in print, something I would have passed over in web-media. Reading up the topic stirred deep feelings on learning new medicine in the age of informatics in the rapidly changing medical world.
I recalled some equivalent of a lifetime ago (for some of the younger readers) in early 1990s; yes the last millennium, I was taught the Vaughan-Williams classification of Antiarrhythmic Drugs and anti-hypertensives (anti-HTs) were in encompassed in the mnemonics ABCD drugs (Alpha-adrenergic blocker, Beta-blocker, Calcium-channel-blockers, Diuretics).
Towards the end of medical school training the list expanded to 10 classes: Alpha-adrenergic blocker, Beta-blocker, Calcium-channel-blockers, Diuretics, ACE inhibitors, Angiotensin 2 receptor antagonist, aldosterone antagonists, magnesium sulphate, alpha2 agonist, vasodilators(nitrous/hydralazine)
It took at least 5 years for the results of drugs trials like CAST and ISIS-1/2 to filter through the medical school cirriculum and even as I graduate, we were still debating on the implication of the US Carvedilol Heart Failure Program and ANZ Carvedilol Heart Failure Trial. "Acute coronary syndrome" was a new catchphrase for cardiac conditions not readily fitting the classic MI criteria.
Now we are constantly bombarded with medical information, consciously and subconsciously like it or not, with increasingly competitive researchers advocating opposing views. We are no longer naive readers of evidence-based medicine (EBM) as we learn of incredible lapse in study designs causing selection bias, and lament of lost data from research withheld by pharmaceutical companies.
Thank you, BMJ, for allowing casual readers like me to catch up with the greater world of medicine with your quick-read format.
Competing interests: No competing interests
Re: β blockers for heart failure: which works best?
We commend the timely publication of Chatterjiee et al 1 and subsequent editorial by Mentz 2 on which β-blocker is more efficacious in patients with heart failure. We also acknowledge the significant strides made in the treatment of heart failure in recent times3. Treatment of heart failure is among the controversial medical therapies with regards to differences in response by race/ethnicity4. A number of studies have shown significant differences in response to heart failure therapies between black and white patients.
Retrospective analyses of the Valsartan Heart Failure Trial (V-HeFT) data revealed differences in heart failure mortality between white and African American patients4 5. In one such analysis, enalapril was found to provide survival benefit to whites than blacks whereas Isosorbide dinitrate -Hydralazine (I-H) significantly improved survival in African Americans compared with white patients in another. This was confirmed in the African American Heart Failure Trial (A-HeFT), which enrolled only self-declared African Americans to test the efficacy of I-H versus placebo6. The Food and Drugs Association eventually approved I-H for treatment of African Americans with heart failure, after it improved survival in A-HeFT. Our concern is the inadequate or lack of emphasis on differences in racial/ethnic response to β-blockers in the recent publications.
The efficacy of bisoprolol, metoprolol CR/XL, nebivolol and carvedilol in heart failure are well established7-10. But surprisingly a large clinical trial (β-Blocker Evaluation of Survival Trial [BEST] ) with bucindolol failed to improve survival11. The authors suggested that the failure could be due to the ancillary pharmacological properties of bucindolol and differences in the patient population. Among the beta-blocker trials, BEST had the most notable differences in study populations as it enrolled substantially more blacks than any of the trials. The black population in the metoprolol CR/XL and carvedilol trials were about 5% and less than 1% in the bisoprolol trial while the BEST had about 23%12. A subgroup analysis of the BEST data, reported no benefit in blacks [Hazard ratio (HR) 1.17, 95% confidence interval (CI): 0.89-1.53] whereas non blacks had a significant reduction in mortality (HR 0.82; 95% CI: 0.70-0.96). Earlier, a secondary analysis of the carvedilol data reported no ethnic differences in outcomes, with blacks having similar estimates of risk reduction to whites13. However, only 5% of the study population were blacks and thus a lack of, or reduced efficacy in blacks cannot be overlooked. A subgroup analysis of the metoprolol CR/XL data shows whites have marginally better survival compared to black patients. The hazard ratios in blacks were less than 1.0 but statistically not significant. For overall mortality the hazard ratio point estimate was 0.79 in blacks and 0.67 in whites and for mortality and heart failure hospitalization, point estimate was about 0.98 in blacks and 0.70 in whites. Furthermore, the metoprolol CR/XL trial did not improve survival in participants from the United States (US) population. Almost all the black participants in the trial came from the US, and thus it is possible that the reduced efficacy in this population led to the lack of benefit observed among the US population in this trial 14 15. Although in conclusion, no differences exist between blacks and whites, it may not be the case as the studies may be inadequately powered to detect significant ethnic differences.
In a recent study, the relationship between β-blocker exposure and outcomes in self-identified white and African Americans with heart failure was assessed using administrative and pharmacy claims data. A total of 1094 (476 white and 618 African American) patients who were hospitalized for HF with ejection fraction <50% were followed for approximately 2 years. Β-blocker exposure was associated with lower risk of death or hospitalization in white individuals (HR, 0.40; 95% CI: 0.27-0.60) compared with African American individuals (HR, 0.67; 95% CI: 0.48-0.94). However, risk reduction with β-blocker exposure was statistically significant in both groups. The authors found β-blockers to be 40–50% less effective in preventing death or hospitalization among African Americans as compared with whites with heart failure16. Nonetheless, this evidence comes from a retrospective analysis, liable to confounding and bias and needs to be confirmed in a prospective study.
Clinicians and researchers appear uncertain about which β-blocker is more efficacious in black patients with heart failure. β-blockers are the cornerstone pharmacological agents for the treatment of heart failure. But the lack of clarity surrounding their efficacy in black patients is still worrying. Thus there is the need for further research to ascertain whether β-blockers have failed as class or individual drugs may have superior efficacy over others in black patients with HF.
Acknowledgement
None
Conflict of interest
There are no competing interests.
References
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2. Mentz RJ. beta blockers for heart failure: which works best? BMJ 2013;346:f480.
3. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. European journal of heart failure 2012;14(8):803-69.
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Competing interests: No competing interests