Abstract
Left ventricular dysfunction is an established marker in heart failure (HF) patients predicting poor clinical outcomes, sudden death, and overall mortality. 1 Over the last few decades, various pharmacological agents as guideline directed medical treatment (GDMT) have been introduced serially in the management of HF resulting in incremental benefit in HF hospitalizations, quality of life, symptom alleviation, and mortality. Large data has established the use of beta blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor–neprilysin inhibitors, and mineralocorticoid receptor antagonists, in these patients. The ongoing battle against HF was consolidated by amalgamation of sacubitril–valsartan and SGLT-2 inhibitors in the GDMT by data from large trials—PARDIGM HF, DAPA HF, EMPEROR Reduced. 2, 3, 4 Despite the scintillating advances in pharmacotherapy in this area, the twin clinical problems of worsening HF and renal failure continue to cause abundant frustration in patient management. Patients with a recent HF hospitalization or worsening HF constitute a particularly vulnerable cohort as they are associated with high subsequent event rates and mortality. Moreover HF is frequently associated with impaired renal function and/or high serum potassium concentrations. Kidney is truly the Achilles heel in the management of HF as almost all the routine medications used in these patients require monitoring of renal function and electrolytes. 5 Impaired estimated glomerular filtration rate (eGFR), with HF, presents a serious therapeutic challenge as it precludes prescription of all components of GDMT, makes it difficult to up-titrate them to optimal doses, and frequently results in their discontinuation. The most difficult cohort of patients to initiate and maintain GDMT are patients with a lower eGFR, higher N-terminal probrain natriuretic peptide (NTproBNP), and elevated serum potassium concentrations. These are the patients who have a higher risk of cardiovascular death and hospitalizations for HF and in a greater need for these treatments. Accordingly, an unmet need exists for effective therapies in patients with severe heart failure with reduced ejection fraction (HFrEF) and advanced chronic kidney disease that do not adversely influence renal function and/or potassium concentrations.
Vericiguat is a soluble guanylate cyclase (sGC) stimulator for the treatment of chronic HF. It binds to the sGC and stimulates cGMP production in the absence of Nitic Oxide (NO). It also stabilizes the NO-sGC binding and enhances the effect of endogenous NO on cGMP production. Vericiguat received its first approval on 19 January 2021 in the USA to reduce the risk of cardiovascular death and HF hospitalization following a hospitalization for HF or need for outpatient IV diuretics in adults with symptomatic chronic HF and ejection fraction. The recommended initial dose of vericiguat is 2.5 mg orally, once daily, taken with food, doubled approximately every two weeks to a target maintenance dose of 10 mg once daily, according to tolerability.
Clinical evidence of this molecule in patients with HFrEF has been obtained from VICTORIA(Vericiguat Global Study in Subjects with HFrEF)—a phase III placebo controlled study. 6 In this multi-center study, patients with chronic HF (98.6% in New York Heart Association class II or III) and mean left ventricular ejection fraction of about 29% who had been recently hospitalized or received outpatient treatment with IV diuretics were randomized to guideline-based medical therapy plus vericiguat (n = 2519) or guideline-based medical therapy plus placebo (n = 2515). Notably 60% of the patients received triple therapy (a beta-blocker and a mineralocorticoid antagonist combined with an angiotensin-converting–enzyme inhibitor, an angiotensin-receptor blocker, or sacubitril–valsartan). After a median 10.8 months, 897 (35.5%) vericiguat, and 972 (38.5%) placebo, recipients reached the primary outcome of cardiovascular death or hospitalization for HF (hazard ratio 0.90; 95% CI 0.82–0.98; P = .02). There was 10% reduction in the primary end point and an absolute reduction of events (4%) paralleling PARADIGM and DAPA HF trials. Cardiovascular death occurred in 414 (16.4%) and 441 (17.5%) of vericiguat and placebo recipients, respectively (hazard ratio, 0.93; 95% CI 0.81–1.06). There were 1,223 and 1,336 total hospitalizations (first and recurrent events) in vericiguat and placebo treatment groups, respectively (hazard ratio 0.91; 95% CI 0.84–0.99; P = .02). Secondary outcome of all-cause mortality or HF hospitalization occurred in 957 (37.9%) and 1,032 (40.9%) patients, respectively (hazard ratio, 0.90; 95% CI 0.83–0.98; P = .02). Importantly, adherence to the drug was >80% in 93.8% of patients which was no different from placebo demonstrating drug tolerance.
VICTORIA Trial was unique in including patients with higher NTProBNP ( (2816 pg/mL; nearly twice as compared to PARADIGM & DAPAHF) and patients with GFR < 30. In these patients, decline in renal function over follow-up period was no different between vericiguat and placebo treated patients. In addition, vericiguat reduced the primary composite endpoint of cardiovascular death or HF hospitalization across the full range of baseline eGFR from 15 mL/min/1.73 m2 and higher. Importantly, the beneficial effects observed were similar in patients with low and normal eGFR. Worsening renal function was associated with worse outcomes, but the beneficial effects of the drug were similar in patients with and without worsening renal function. Therefore, vericiguat can likely be safely provided to patients with elevated serum potassium concentrations, including those with hyperkalemia in whom renin–angiotensin–aldosterone system blockers are contraindicated.
Vericiguat is a new addition to the armamentarium of pharmacotherapy of HF with reduced ejection fraction, with encouraging clinical data in patient subsets with severe HF, renal impairment, and hyperkalemia.