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Author: Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA
Heralded as a breakthrough in the management of heart failure, the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibition with ACE Inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial demonstrated that LZC696, a combination of the neprilysin inhibitor sacubitril and angiotensin receptor blocker valsartan (now marketed as Entresto), reduced cardiovascular death and heart failure hospitalizations compared to the ACE inhibitor enalapril.1 Benefits were so compelling that the trial had to be terminated early after a median follow-up of only 27 months.
The results of PARADIGM-HF are certainly impressive and may signal a major change in how we manage patients with heart failure, but there’s still one thing about the trial that bothers me: it enrolled very few black patients.
With nearly 8400 patients randomized to either LCZ696 or enalapril, PARADIGM-HF represents one of the largest heart failure trials to date. However, fewer than 500 of those patients (approximately 5%) were black. When results were compared across subgroups, a difference in the primary endpoint was not observed in black patients, although it is not clear whether this was due to a lack of efficacy or simply the small size of the black subgroup. The fact that blacks are underrepresented in PARADIGM-HF is not completely surprising given that the trial was mostly conducted in Central and Western Europe. Even in North America, under-representation of blacks in clinical trials has been well-documented.2
So why is this particularly a problem for PARADIGM-HF?
First, we have a substantial body of evidence to suggest that black patients respond less favorably to a number of therapies in heart failure. The limited efficacy of ACE inhibitors in black patients is well-known, but we also have evidence of a tempered effect with beta blockers and aldosterone antagonists.3-5 Only with the combination of isosorbide and hydralazine have we found a more robust effect in black patients compared to whites, indicating that they may respond more favorably to drugs that target nitric oxide rather than the renin-angiotensin-aldosterone system (RAAS).6 Given the connection between the natriuretic peptide system – where neprilysin inhibitors exert their effects – and RAAS, it is not too irrational to think that black patients may not respond as well to LCZ696 as whites.
Finally, we also have evidence to suggest that blacks are at greater risk of angioedema with inhibitors of the RAAS system.7 The high rates of angioedema observed in trials of omapatrilat, a predecessor of LCZ696 that inhibited both neprilysin and ACE, are partly to blame for its failure to gain much traction for the management of heart failure or hypertension.8 Although the rates of angioedema with LCZ696 are much lower than those observed with omapatrilat, the low enrollment of black patients in PARADIGM-HF prevents us from assessing its risk in this high-risk population.
LCZ696 may truly represent a breakthrough in the management of patients with heart failure but I am hesitant to broadly recommend its use in black patients until data are available. I do not think a trial that exclusively enrolls black patients is necessary, but I think one that more broadly represents a North American population is warranted prior to its widespread use in the United States. Given the potential clinical and financial implications of a drug that could replace ACE inhibitors in a significant number of patients with heart failure, I do not think a request of this nature is too unreasonable.
Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA
Dr. Reed is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in advanced heart failure at the University of Maryland Medical Center in Baltimore, MD. Follow him on Twitter @brentnreed
- McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004.
- Zhang T, et al. Reporting and representation of ethnic minorities in cardiovascular trials: a systematic review. Am Heart J. 2013 Jul;166(1):52-7.
- Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail. 1999 Sep;5(3):178-87.
- Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001 May 31;344(22):1659-67.
- Vardeny O, Cavallari LH, Claggett B, et al; Randomized Aldactone Evaluation Study (RALES) Investigators. Race influences the safety and efficacy of spironolactone in severe heart failure. Circ Heart Fail. 2013 Sep 1;6(5):970-6.
- Taylor AL, Ziesche S, Yancy C, et al; African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004 Nov 11;351(20):2049-57.
- Weber MA, Messerli FH. Angiotensin-converting enzyme inhibitors and angioedema: estimating the risk. Hypertension. 2008 Jun;51(6):1465-7.
- Kostis JB, Packer M, Black HR, et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004 Feb;17(2):103-11.
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