Optimized HF Meds May Lessen MR Severity, Perhaps Avoiding MV Repair

October 03, 2022

Among the benefits of fully optimized medical therapy in heart failure with reduced ejection fraction (HFrEF) may be, indirectly, lessened severity of associated mitral regurgitation (MR) that might render invasive mitral valve (MV) repair unnecessary for some patients.

That's one implication, at least, from an analysis of HFrEF patients who showed significantly less moderate-to-severe MR a year after starting on sacubitril-valsartan (Entresto), apparently due to its reverse-remodeling effects. The nearly 800 patients in the 2019 single-arm PROVE-HF study received the drug on top of other guideline-directed medical therapy (GDMT).

The prevalence of moderate-to-severe (grade 3+ or 4+) MR fell from about 15% at baseline to 8.2%, indicating a "substantial shift" to MR of lesser severity after a year of sacubitril-valsartan, researchers said. Indeed, the benefit emerged as early as 6 months after starting the drug.

About three fourths of the patients had been switched from an ACE inhibitor or angiotensin receptor blocker (ARB) to sacubitril-valsartan at the start of the trial. It seems likely, therefore, that the drug's reverse-remodeling effects were behind the substantial overall improvement in MR severity, even though the nonrandomized study wasn't equipped to show it, observed James L. Januzzi, MD, Massachusetts General Hospital and Harvard Medical School, Boston.

Another way to look at it, he told theheart.org | Medscape Cardiology, is that the study's overall improvement in MR severity "is what a clinician might expect when changing a patient from an ACE inhibitor or ARB over to sacubitril-valsartan."

The reduction in MR was substantial, Januzzi noted, and in theory may have obviated invasive procedures like transcatheter MV repair for some patients. "Nearly half of the patients with mitral regurgitation that would have been considered eligible for MitraClip [Abbott] placement, for example, were no longer eligible after only six months of treatment."

Moreover, the patients who improved in MR severity showed substantial cardiac reverse remodeling by echocardiography and "significant reductions in natriuretic peptides and improved health status," the latter assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ).

Januzzi is lead author on the study's October 2 publication in Circulation, timed to coincide with its live presentation at the Heart Failure Society of America Annual Scientific Meeting (ASM) 2022, held outside Washington, DC, by co-author G. Michael Felker, MD, Duke University, Durham, North Carolina. 

"The Power of GDMT"

The PROVE-HF findings "reinforce how effective GDMT is at actually improving remodeling and diminishing the severity of MR," Felker said during his presentation. "We often think that patients whom we diagnose with relatively new-onset heart failure, and are starting on therapy, are those who will have favorable remodeling," he noted. The current patients had been on medical therapy a median of 50 months, yet even after that long, "half the patients, almost, improved their MR significantly."

In the setting of a clinical trial, Felker observed, "we were very aggressive about titrating sacubitril-valsartan." The highest recommended dosage was achieved in 60% of patients, "which is not what we see in clinical practice."

That underscores "the power of GDMT to remodel the ventricle, even in people who've had heart failure a long time," he said, "and the necessity for continuing to be aggressive about titrating that therapy to get the greatest effects."

Undoubtedly, Stefan D. Anker, MD, PhD, told theheart.org | Medscape Cardiology, "optimized therapy of HFrEF with all foundational therapies, not only sacubitril-valsartan, can preserve and most likely also improve valvular function in heart-failure patients."

The current analysis is "interesting and supports the notion that optimized heart failure therapy in patients with moderate-to-severe functional MR is beneficial for them," said Anker, of the German Center for Cardiovascular Research and Charité Universitätsmedizin, Berlin, and not involved in PROVE-HF.  

However, he said, "valid efficacy conclusions, including on the relative value of different therapies," which would include transcatheter devices, "cannot be made as there was no control group."

"Responders" and "Nonresponders"

As previously reported, PROVE-HF primarily saw significant cardiac reverse remodeling in 794 patients with HFrEF within 12 months of initiating sacubitril-valsartan. The current analysis excluded 70 patients with missing baseline MR data or who had prior MV procedures.

Of those remaining, 5.8% and 9.1% had baseline MR grade 3+ and 4+, respectively, for a 14.9% initial prevalence of moderate-to-severe MR.

That prevalence fell to 8.2% by 6 months and held at 8.4% at 12 months, for a 1-year relative reduction of 44.7%, the group reported.

The 52 patients who entered the study with moderate to severe MR but were in grade 2+ or better after a year, considered "responders," were at baseline not easily distinguishable from the 33 "nonresponder" patients who ended the follow-up with persistent grade 3+ or 4+ MR.

The two groups were initially similar with respect to baseline GDMT, clinical features, and echo features such as left ventricular ejection fraction (LVEF) and ventricular volumes, the report notes. Their mean sacubitril-valsartan dosages during the study were essentially the same.

By 12 months, responders showed marginally greater improvement in LVEF compared with nonresponders, with a gain of 11 vs 7.6 percentage points, respectively (P = .05). They also benefited with significantly greater reductions in left ventricular end-systolic and end-diastolic volumes and improved E/e', an indirect echo measure of diastolic function.

A strength of the study, Januzzi said, was that echocardiograms were interpreted blindly in "temporally randomized" order. That is, the readers didn't know whether a given echo was obtained at baseline or at 6 or 12 months.

Responders also ended the 12-month follow-up with lower median natriuretic peptide levels (P = .01) and higher median KCCQ scores (P = .04), "despite similar results for both measures at baseline," the published report states.

There really wasn't a good way to predict which patients would show substantially improved MR severity, the researchers noted. "Baseline clinical and echocardiographic characteristics did not identify those who would or would not improve their severity of mitral regurgitation," Felker said.

"That has important implications, I think, for how long we want to try optimizing GDMT prior to considering the possibility of mitral intervention," he said.

"There's been rapid growth of percutaneous approaches to mitral regurgitation therapy in HFrEF since the COAPT trial," Felker said. "I think these study results reinforce the importance of optimizing GDMT before committing patients to a mitral procedure."

"The data really do argue for a trial of optimized GDMT before turning to an invasive procedure to manage MR," Januzzi said, and suggest that "at least 6 months of sacubitril-valsartan should be placed before making a decision."

Transcatheter MV repair for MR "is a critically important tool in our armamentarium," Januzzi said. "But so is guideline-directed medical therapy, and one should always precede the other."

Novartis, which had initially funded PROVE-HF, did not provide support for the current analysis, said Januzzi, who discloses being a Trustee of the American College of Cardiology and a board member of Imbria Pharmaceuticals; receiving research support from Abbott, Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Roche Diagnostics and consulting income from Abbott, Beckman, Bristol Myers, Boehringer Ingelheim, Janssen, Novartis, Pfizer, Merck, Roche Diagnostics, and Siemens; and serving on clinical endpoint committees or data safety monitoring boards for Abbott, AbbVie, Bayer, CVRx, Intercept, Janssen, and Takeda.

Felker discloses receiving research grants from the National Heart, Lung, and Blood Institute, the American Heart Association, Amgen, Bayer, Bristol-Myers Squibb, Merck, Cytokinetics, and CSL-Behring; acting as a consultant to Novartis, Amgen, Bristol-Myers Squibb, Cytokinetics, Medtronic, Cardionomic, Boehringer Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, Myovant, Sequana, Windtree Therapuetics, and Whiteswell; and serving on clinical endpoint committees or data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma.

Disclosures for the other authors are in the report. Anker discloses consulting for Bayer, Boehringer Ingelheim, Abbott, Bioventrix, Edwards, Novartis, Occlutech, Vifor, V-Wave, Cardiac Dimension, and Servier; and receiving grants or research support from Abbott and Vifor.

Circulation. Published online October 2, 2022. Full Text

Heart Failure Society of America Annual Scientific Meeting 2022. Late Breaking Clinical Trials Session I.  Effect of Sacubitril/valsartan on Mitral Regurgitation in Heart Failure with Reduced Ejection Fraction. The PROVE-HF Study. Presented October 2, 2022.

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