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Sacubitril/valsartan promotes cardiac structure, function improvement in HFrEF
PARIS — Sacubitril/valsartan was associated with improvements in cardiac structure and function as well as N-terminal pro-B natriuretic peptide in patients with HF with reduced ejection fraction, according to the PROVE-HF and EVALUATE-HF studies presented at the European Society of Cardiology Congress.
In PROVE-HF, sacubitril/valsartan (Entresto, Novartis) was found to promote reverse cardiac remodeling, correlated with improvements in NT pro-BNP. In EVALUATE-HF, sacubitril/valsartan did not significantly reduce central aortic stiffness compared with enalapril, but was shown to significantly improve left atrial volume index and other structural parameters compared with enalapril.
Both studies were published simultaneously in JAMA.
“We continue to have discussions with the medical community and our advisors about what information gaps exist with our medicines,” David Soergel, MD, global head of cardiovascular, renal and metabolic drug development at Novartis, told Cardiology Today. “What we heard about Entresto was ... it would be great if we understood how the improvements shown in PARADIGM-HF actually happened, if we could draw a mechanistic line between Entresto’s pharmacology and the benefits that were demonstrated in PARADIGM-HF.”
PROVE-HF
For PROVE-HF, a single-arm, open-label study of 794 patients with HFrEF (mean age, 65 years; 29% women), James L. Januzzi Jr., MD, Hutter Family Professor of Medicine at Harvard Medical School and cardiologist and director of the Dennis and Marilyn Barry Fellowship in Cardiovascular Research at Massachusetts General Hospital, and colleagues assessed the correlation between changes in log2 NT pro-BNP concentration and parameters including left ventricular ejection fraction, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index and E/e’ ratio at 12 months.
“Correlating these measures would allow us and the medical community to be more confident that that we can draw a line between Entresto’s pharmacology and the outcomes from PARADIGM-HF,” Soergel told Healio.
Median NT pro-BNP concentration improved from baseline to 12 months among the 82.4% of the cohort who completed the study (from 816 pg/nL to 455 pg/nL; P < .001).
The researchers found that changes in log2 NT pro-BNP concentration were correlated with changes in the following parameters at 12 months:
LVEF (r = –0.381; P < .001);
LVEDVI (r = 0.32; P < .001);
LVESVI (r = 0.405; P < .001);
Left atrial volume index (r = 0.263; P < .001); and
E/e’ ratio (r = 0.269; P < .001).
During the study period, LVEF rose from 28.2% to 37.8% (difference, 9.4%; 95% CI, 8.8- 9.9%; P < .001), and LVEDVI, LVESVI, left atrial volume index and E/e’ ratio all declined, according to the researchers.
The most frequent adverse events reported were hypotension (17.6%), dizziness (16.8%), hyperkalemia (13.2%) and declining kidney function (12.3%).
EVALUATE-HF
For EVALUATE-HF, Akshay S. Desai, MD, MPH, associate professor of medicine at Harvard Medical School and medical director of the cardiomyopathy and heart failure program, advanced heart disease section, Brigham and Women’s Hospital, and colleagues randomly assigned 464 patients with HF and EF 40% or less (mean age, 67 years; 24% women) to sacubitril/valsartan or enalapril.
The primary outcome was change in aortic characteristic impedance, a measure of central aortic stiffness, at 12 weeks. Secondary outcomes included 12-week changes in NT pro-BNP and various structural parameters.
At 12 weeks, the sacubitril/valsartan group had a decrease in aortic characteristic impedance and the enalapril group had an increase, but the difference was not statistically significant (–2.2 dyne × s/cm5; 95% CI, –17.6 to 13.2), Desai and colleagues found.
The difference in change in LVEF was also not significant.
However, the sacubitril/valsartan group had significantly greater reductions in LVEDVI, LVESVI, left atrial volume index and mitral E/e’ ratio compared with the enalapril group, according to the researchers.
“In PROVE-HF, we saw a very strong effect on cardiac remodeling and a very strong correlation between improvements in NT pro-BNP and improvements in remodeling,” Soergel said in an interview. “EVALUATE-HF supports that. We saw similar types of effects as we did in PROVE-HF. We now have two trials in slightly different populations for slightly different durations with concordant results with respect to reverse remodeling.” – by Erik Swain
References:
Desai AS, et al.
Januzzi JL, et al. Late-Breaking Science in Heart Failure 1. Both presented at: European Society of Cardiology Congress; Aug. 31 to Sept. 4, 2019; Paris.
Desai AS, et al. JAMA. 2019;doi:10.1001/jama.2019.12843.
Januzzi AS, et al. JAMA. 2019;doi:10.1001.jama.2019.12821.
Disclosures: The studies were funded by Novartis. Desai reports he received research support from Alnylam, AstraZeneca and Novartis and consultant fees from AstraZeneca, Abbott, Alnylam, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma, Novartis and Regeneron. Januzzi reports he received personal fees from AbbVie, the American College of Cardiology, Amgen, Boehringer Ingelheim, Merck, Pfizer and Takeda; grants and personal fees from Abbott, Janssen, Novartis and Roche; and grants from Prevencio and Singulex. Soergel is an employee of Novartis. Please see the studies for the other authors’ relevant financial disclosures.
Editor’s Note: This article was updated on Sept. 6, 2019 to change the headline and make other modifications at the request of Dr. Soergel.