By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

The FDA has approved a treatment for patients with severe heart failure (HF) with reduced ejection fraction. Vericiguat is a soluble guanylate cyclase stimulator that relaxes smooth muscle and promotes vasodilation.1 The FDA granted priority review. It is distributed as Verquvo.

INDICATIONS

Vericiguat is indicated to lower the risk of cardiovascular death and HF hospitalization in adults with symptomatic chronic HF and an ejection fraction less than 45%. The drug should be prescribed for these patients who also have been hospitalized recently for HF or need outpatient intravenous diuretics.1

DOSAGE

The patient should take 2.5 mg orally every day with a meal.1 Double the dose about every two weeks to a target dose of 10 mg once daily, as tolerated. Vericiguat is sold as 2.5-mg, 5-mg, and 10-mg tablets.

POTENTIAL ADVANTAGES

Vericiguat provides a treatment option with a different mode of action to reduce the composite risk of death from cardiovascular causes or first hospitalization in patients with high-risk HF.

POTENTIAL DISADVANTAGES

Vericiguat may cause embryo-fetal toxicity. It should not be prescribed to pregnant women. Patients with reproductive potential should use an effective method of contraception.1 Concomitant administration of a phosphodiesterase type 5 inhibitor is not recommended because of a higher risk of hypotension.1 The most common adverse reactions vs. placebo are hypotension (16% vs. 15%) and anemia (10% vs. 7%).1

COMMENTS

Soluble guanylate cyclase is a key enzyme of the nitric oxide signaling pathway.2 Impairment or dysregulation of this pathway has been implicated in the development and progression of HF. Vericiguat stimulates guanylate cyclase, resulting in smooth muscle relaxation and vasodilatation. Researchers evaluated efficacy in a randomized, placebo-controlled, double-blind study of subjects with symptomatic chronic HF and left ventricular ejection fraction less than 45% following a worsening HF event, the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA).1,3 An HF event was defined as HF hospitalization within six months before randomization or use of outpatient intravenous diuretics within three months before randomization. Subjects mainly were white (64%) and male (76%). A total of 22.4% were Asian. Fifty-nine percent were New York Heart Association (NYHA) class II and 40% were class III. The mean left ventricular ejection fraction was 29%, and 67% had been hospitalized for HF in the previous three months. The median biomarker, N-terminal prohormone B-type natriuretic peptide (NT-proBNP), level was 2,816 pg/mL. Ninety-three percent were on two or more standard drugs for HF. Subjects were randomized to vericiguat (n = 2,526) or placebo (n = 2,524). The primary endpoint was a composite of time to first event of cardiovascular death or hospitalization for HF.

The median follow-up was 11 months. The median dose of trial medication was 9.2 mg. The event rate percentage of patients/year was 33.6 for vericiguat vs. 37.8 for placebo, a 10% reduction in risk (HR, 0.90; 95% CI, 0.82-0.96; P = 0.019), an absolute rate reduction of 4.2 per 100 patient years. A reduction in hospitalization for HF, rather than death from cardiovascular causes, was the primary driver. Subjects in the highest baseline NT-proBNP quartile, compared to the other three quartiles, did not respond favorably to vericiguat. The benefit of vericiguat, relative to placebo, tended to be greater with longer duration since hospitalization, with less benefit in the subgroup randomized within three months of HF hospitalization when the risk for primary outcome was the highest.4

CLINICAL IMPLICATIONS

HF affects about 6.5 million adults, with approximately 1 million hospitalizations annually.5 Approximately 50% of these are caused by HF with reduced ejection fraction. There are numerous pharmacological treatment options, including sodium-glucose cotransporter 2 inhibitors, angiotensin-converting enzyme inhibitors, beta-blockers, vasodilators, angiotensin receptor blockers, mineralocortisone receptor antagonists, and angiotensin receptor-neprilysin inhibitors.5,6 Vericiguat provides a vasodilator with a different mode of action, producing benefit mainly in reducing HF hospitalization. The benefit appears to be modest; however, VICTORIA included sicker patients, with a higher percent with NYHA class III and higher median levels of NT-proBNP compared to previous HF studies with sacubitril/valsartan and dapagliflozin that showed a lower risk of cardiovascular death and HF hospitalization or HF worsening.7,8 The role of vericiguat remains to be determined, particularly when it comes to identifying which patients are more likely to benefit. The cost for vericiguat 10 mg is $583 for a 30-day supply.

REFERENCES

  1. Merck & Co., Inc. Verquvo prescribing information. January 2021.
  2. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 2011;123:2263-2273.
  3. 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.
  4. Lam CSP, Giczewska A, Sliwa K, et al. Clinical outcomes and response to vericiguat according to index heart failure event: Insights from the VICTORIA trial. JAMA Cardiol 2020; Nov 13;e206455. doi: 10.1001/jamacardio.2020.6455. [Online ahead of print].
  5. Murphy SP, Ibrahim NE, Januzzi JL Jr. Heart failure with reduced ejection fraction: A review. JAMA 2020;324:488-504.
  6. Writing Committee; Maddox TM, Januzzi JL Jr, Allen LA, et al. 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: Answers to 10 pivotal issues about heart failure with reduced ejection fraction: A report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021;77:772-810.
  7. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
  8. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.