By Jamie L. W. Kennedy, MD, FACC

Associate Professor, Division of Cardiology, Advanced Heart Failure & Transplant Cardiology, University of California, San Francisco

Dr. Kennedy reports no financial relationships relevant to this field of study.

SYNOPSIS: Vericiguat reduced cardiovascular death and heart failure hospitalization, although no reduction in overall mortality was observed over a short follow-up period.

SOURCE: Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med 2020;382:1883-1893.

Cyclic guanosine monophosphate (cGMP) is an intracellular second messenger molecule active in many biochemical pathways throughout the body. In smooth muscle cells, it leads to vasodilation in both the pulmonary and systemic vasculature.

In cardiomyocytes, cGMP prevents maladaptive hypertrophy, protects against ischemia/reperfusion injury, and blunts the effects of catecholamines. cGMP is produced by particulate guanylate cyclase when triggered by natriuretic peptides, and by soluble guanylate cyclase in response to nitric oxide (NO). Sacubitril inhibits neprilysin and increases levels of natriuretic peptides, ultimately increasing intracellular cGMP with beneficial effects in chronic heart failure patients.

Vericiguat also targets the cGMP pathway as a stimulator of soluble guanylate cyclase. Preliminary data revealed beneficial effects in animal models of heart failure and reduction in NT-proBNP in patients with heart failure. VICTORIA was a randomized, double-blind, placebo-controlled trial of vericiguat in patients with recent worsening of chronic systolic heart failure. Enrolled patients were New York Heart Association (NYHA) class II-IV with left ventricular ejection fraction (LVEF) less than 45% and elevated brain natriuretic peptide BNP (300 pg/mL if sinus or 500 pg/mL if atrial fibrillation) or NT-proBNP (1,000 pg/mL if sinus or 1,600 pg/mL if atrial fibrillation). Additionally, patients had either been hospitalized for heart failure in the last six months or required intravenous diuretics in the past three months. Unstable patients were excluded, such as patients with systolic blood pressure less than 100 mmHg, intravenous treatment within 24 hours, patients listed at high urgency for heart transplant, and patients awaiting or following left ventricular assist device implantation. Vericiguat is teratogenic; there were strict contraception requirements for women of childbearing potential. Combination treatment with long-acting nitrates or PDE5 inhibitors was not allowed.

Armstrong et al enrolled 5,050 patients, drawn primarily from Eastern Europe (33%) and Asia-Pacific (23%); 11% were North American. The population was otherwise fairly typical for heart failure trials (76% male, mean ejection fraction 29%, and only 1.3% NYHA class IV). On average, patients had been diagnosed with heart failure 4.8 years prior to enrollment. Comorbid conditions were common, including coronary artery disease (58%), atrial fibrillation or flutter (53%), diabetes mellitus (47%), chronic kidney disease stage 3 or worse (53%), and chronic obstructive pulmonary disease (17%). Guideline-directed medical therapy was excellent, with 93% receiving beta-blockers, 70% aldosterone antagonists, 73% angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), and 14.5% angiotensin receptor plus neprilysin inhibitor (ARNI). Overall, 60% were treated with all three medication classes (ACE/ARB/ARNI, beta-blocker, and aldosterone antagonist), 28% had an implantable cardioverter-defibrillator, and 15% had a biventricular pacemaker. Median NT-proBNP was 2,816 pg/mL. Patients started with 2.5 mg daily of vericiguat and titrated up to 10 mg over four weeks, if blood pressure permitted. The median dose achieved was 9.2 mg in both vericiguat and placebo arms.

The primary endpoint was a composite of cardiovascular death or first heart failure hospitalization, which occurred in 35.5% of patients in the vericiguat group and 38.5% in the control group (P = 0.02) at a median follow-up of just 10.8 months. Cardiovascular death occurred in 16.4% in the vericiguat group and 17.5% in the control group. First heart failure hospitalization occurred in 27.4% in the vericiguat group and 29.6% in the control group (confidence intervals for both included 1.00). Total heart failure hospitalizations were lower in the treatment arm (38.3 vs. 42.4 per 100 patient-years; P = 0.02). Overall mortality was similar between the two groups (20.3% in the vericiguat group and 21.2% in the control group; P = 0.38). The results of a subgroup analysis suggested patients with higher NT-proBNP levels did not benefit from vericiguat treatment. Hypotension and syncope were more common in the treatment arm, although the difference was not statistically significant. Anemia also was more common in the treatment arm. Hemoglobin decreased an average of 0.38 with vericiguat vs. 0.14 with placebo. For patients with high-risk heart failure, the authors concluded patients who took vericiguat experienced less cardiovascular death or hospitalization for heart failure vs. those who took placebo.

COMMENTARY

The VICTORIA investigators are to be congratulated for enrolling so many patients with severe heart failure, as demonstrated by the advanced NYHA class (41% III or IV), high NT-proBNP levels, and high event rate. Vericiguat was well tolerated in this high-risk population, with most patients achieving the target dose and similar adverse event rates between the treatment and control arms.

For comparison, the PARADIGM-HF authors found the use of sacubitril/valsartan reduced the combined endpoint of cardiovascular death and heart failure hospitalization from 26.5% to 21.8% (P < 0.001). With a median follow-up of 27 months, sacubitril/valsartan also led to a significant reduction in overall mortality (19.8% to 17%). The authors of DAPA-HF used a combined primary endpoint of worsening heart failure and cardiovascular death, resulting in an overall mortality reduction from 21.2% to 16.2% (P < 0.001) over 18.2 months. There also was a significant reduction in overall mortality from 13.9% to 11.6%. Finally, the COAPT authors found percutaneous mitral valve repair reduced heart failure hospitalizations from 67.9% to 35.8% over 24 months (the primary endpoint), and also demonstrated mortality reduction from 46.1% to 29.1% (both P < 0.001). The slight differences in primary endpoints among these trials does complicate interpretation, but it is noteworthy that VICTORIA did not demonstrate overall reduction in mortality, while PARADIGM-HF, DAPA-HF, and COAPT did. Perhaps this is a reflection of the short duration of follow-up in VICTORIA, and mortality benefit would have been seen over a longer period.

Where does vericiguat fit into the increasingly complex systolic heart failure treatment algorithm? Patients should be optimally medically managed with ACE/ARB/ARNI (preferably ARNI), beta-blockers, and aldosterone antagonists. The CHAMP-HF registry, an outpatient study of U.S. systolic heart failure patients, revealed 22% were prescribed triple therapy. Just 1% were receiving target doses of all three medication classes. There certainly is room for improvement on this front. After achieving maximally tolerated doses of all three of these foundational therapies, I would favor additional treatments with proven mortality benefit, such as dapagliflozin and percutaneous mitral repair in appropriate candidates. Treatment with vericiguat could be considered after that. In my practice, I imagine I will be deciding between vericiguat and hydralazine/isosorbide. In A-HeFT, hydralazine/isosorbide demonstrated mortality benefit in African Americans; this combination may be the better choice in patients who can take it. However, many patients struggle with medication compliance or cannot tolerate hydralazine/isosorbide because of its side effects. In these situations, vericiguat may be a good choice.