Associate Professor of Medicine
Department of Cardiovascular Medicine
Center for Advanced Heart Disease
Harvard Medical School
Director, Heart Failure Disease Management Program
Brigham and Women's Hospital
Dr. Desai has disclosed that he has received funds for research support from Abbott, Alnylam, AstraZeneca, Bayer, and Novartis and consulting fees from Abbott, Amgen, Alnylam, AstraZeneca, Bayer, Boston Scientific, Boehringer Ingelheim, Biofourmis, Corvidia, DalCor Pharma, Merck, Novartis, Regeneron, and Relypsa.
Although the 2020 American College of Cardiology/World Congress of Cardiology Scientific Sessions were cancelled due to social distancing precautions necessitated by the COVID-19 pandemic, a robust virtual meeting (ACC.20/WCC Virtual) took place online with the release of important new data relevant to the care of patients with heart failure. Key among these new findings were principal results of the VICTORIA trial as well as important secondary analyses from the PARAGON-HF and DAPA-HF trials.
Soluble Guanylate Cyclase Stimulation for Patients With HFrEF
Despite the availability of an expanding array of effective therapies for patients with chronic heart failure and reduced ejection fraction (HFrEF), patients with recent episodes of worsening heart failure requiring hospital admission or ambulatory IV treatment continue to represent a group at high risk for readmission and death. Of current pharmacologic treatments recommended for HFrEF by treatment guidelines, few have been studied in patients with recent heart failure decompensation, other than the angiotensin-receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, which reduced natriuretic peptides and clinical events at 8 weeks compared with enalapril among patients stabilized after hospitalization for acute decompensated heart failure enrolled in the PIONEER-HF trial.
Vericiguat is a novel oral soluble guanylate cyclase (sGC) stimulator that enhances cyclic GMP and nitric oxide signaling both by directly stimulating sGC and by sensitizing sGC to endogenous nitric oxide. Preliminary evidence of a dose-dependent reduction in levels of NTproBNP seen at 12 weeks among patients with worsening HFrEF who received vericiguat in the SOCRATES-REDUCED trial fueled interest in examining the potential benefits of adding vericiguat to standard guideline-directed medical therapy for HFrEF.
The randomized, double-blind VICTORIA trial randomly assigned 5050 patients with chronic heart failure to treatment with vericiguat or placebo. Participants had New York Heart Association (NYHA) Class II-IV symptoms, left ventricular ejection fraction < 45%, elevated natriuretic peptide levels, and evidence of worsening heart failure (requiring recent hospitalization or IV diuretic therapy) despite guideline-directed medical therapy. Patients with systolic blood pressure < 100 mm Hg and concomitant or anticipated use of nitrates or phosphodiesterase-5 inhibitors were excluded. The primary study outcome was the composite of cardiovascular death or heart failure hospitalization.
As per the study design, the enrolled study population (23.9% female, 59% NYHA Class II, median NTproBNP 2816 pg/mL) was well treated according to guidelines (including 15% on ARNI) and at high overall risk for clinical events. At a median follow-up of 10.8 months, the primary composite outcome occurred in 35.5% of those assigned to vericiguat vs 38.5% of those assigned to placebo (HR 0.90; 95% CI: 0.82-0.98; P = .02). These benefits of vericiguat were driven principally by effects on heart failure hospitalization, which was reduced by 10% vs placebo (HR: 0.90; 95% CI: 0.81-1.00; P = .048). By contrast, the effect of vericiguat on cardiovascular death was neutral vs placebo (P = .27).
Vericiguat was well tolerated, with lower overall rates of serious adverse events reported during study follow-up and, of note, no increase in the rates of symptomatic hypotension and syncope compared with placebo.
Overall, the results of VICTORIA suggest that vericiguat reduces cardiovascular death and heart failure hospitalization (principally the latter) among high-risk patients with worsening HFrEF. Additional data are needed to better understand the incremental benefits of vericiguat according to background medical therapy and in key subgroups (particularly those defined by age and NTproBNP at baseline where variable effects were noted).
Additional Updates Regarding Pharmacologic Therapy for Patients With HFrEF and HFpEF
Other key updates presented at the ACC.20/WCC Virtual were related to secondary analyses of previously presented trials of chronic heart failure.
New data from the randomized, placebo-controlled DAPA-HF trial emphasized the consistent benefits of the SGLT2 inhibitor dapagliflozin across the full range of patients with HFrEF enrolled in the trial, including subgroups defined by the intensity and type of background pharmacologic therapy, presence of implantable cardiac rhythm devices, systolic blood pressure, body mass index, and baseline NTproBNP levels. Analyses of recurrent heart failure events, which were frequent in DAPA-HF, also suggested a significant reduction with dapagliflozin compared with placebo, even after accounting for the competing risk of cardiovascular death.
For patients with heart failure and preserved ejection fraction (HFpEF), similar follow-up analyses were presented from the randomized, double-blind PARAGON-HF trial, which had previously suggested a modest reduction in the composite of cardiovascular death and total heart failure hospitalizations with sacubitril/valsartan vs valsartan alone, which just missed the margin for statistical significance. A novel putative placebo analysis pooling data from this trial and the previously completed CHARM program estimated that, had a placebo comparator been used in the trial, a statistically significant 29% reduction in primary composite outcome might have been seen with sacubitril/valsartan. Subgroup analyses suggest that benefits of sacubitril/valsartan in patients with HFpEF appear to be independent of background mineralocorticoid receptor antagonist use, age, and systolic blood pressure at baseline.
An additional analysis of the PARAGON-HF trial highlighted the importance of NTproBNP as a prognostic marker in patients with HFpEF and noted that rapid reduction in NTproBNP levels were seen during treatment with sacubitril/valsartan compared with valsartan. One caveat to this analysis is that NTproBNP reduction in PARAGON-HF appeared to be a less perfect surrogate for clinical event reduction than previously seen in the PARADIGM-HF study of patients with HFrEF, highlighting the need for additional biomarkers of treatment benefit in this population.
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