The trial showed that patients taking this novel therapy, an oral soluble guanylate cyclase stimulator, were 10% less likely to experience the primary outcome—a composite of death from cardiovascular (CV) causes or first hospitalization for HF—than those taking placebo. The drug could address the sickest patients through a mechanism that would take on HF progression.
For the sickest heart failure (HF) patients—those with reduced ejection fraction who show signs of decline while taking standard medication—the investigational drug vericiguat may stem the tide, based on results of an international trial presented online this morning.
The trial, VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) showed that patients taking this novel therapy, an oral soluble guanylate cyclase stimulator, were 10% less likely to experience the primary outcome—a composite of death from cardiovascular (CV) causes or first hospitalization for HF—than those taking placebo.
The presentation led the first late-breaking session of the 2020 American College of Cardiology/World Congress of Cardiology virtual meeting, which had been set for Chicago but shifted to a virtual format due to coronavirus disease 2019. Results were simultaneously published in the New England Journal of Medicine.1
About 6.5 million people in the United States have HF—a debilitating condition in which the heart cannot pump enough blood through the body. Health systems and Medicare have focused more closely on HF in the past decade not only because of its effects on patients, but also because it costs the healthcare system about $31 billion a year. About 1 in 8 deaths are linked to HF, which tends to accompany conditions like diabetes or hypertension.
As a group, patients in VICTORIA were sicker than the typical patients in clinical trials; they had to demonstrate worsening HF to enroll in the trial. All had been hospitalized within the previous 6 months or treated with an intravenous diuretic; most had been hospitalized within the past 3 months. Patients were taking guideline-indicated therapy. Their average age was 67.3 years.
During an online press conference after the presentation, lead study author Paul W. Armstrong, MD, said up to 1 in 4 HF patients could benefit from vericiguat, and that they represented a new population whose needs would be addressed through a new drug and a new mechanism. Vericiguat is aimed not just at treating symptoms but at addressing HF progression.
“For a group of patients with this form of high-risk heart failure, where other heart failure drugs have rarely been studied, vericiguat provides a significant novel addition to usual treatment,” said Armstrong, cardiologist and distinguished university professor of medicine at the Canadian VIGOUR Centre, University of Alberta, in a statement. “I think it’s a gratifying result in high-risk heart failure patients that not only opens up a new avenue for them, but also a pathway for future discovery in cardiovascular heart disease.”
Results showed the following:
The results could offer an option for a group of patients who currently lack them, according to one of the study’s authors, Javed Butler, MD, MPH, MBA, professor and chairman of the Department of Medicine, University of Mississippi Medical Center in Jackson, Mississippi. In an interview with The American Journal of Managed Care®, Butler explained that there is an unmet need among these high-risk patients with worsening heart failure.
“These are the patients who have been stable in the outpatient setting on whatever the medication that you were giving them, but now that therapy is not enough,” he said. “Now they're developing worsening heart failure symptoms requiring escalation of therapy or hospitalization in many, many cases.”
Once this group is hospitalized, the 1-year mortality rates are 25% to 30%, Butler said. For this group, the results show “the primary endpoint for combined HF hospitalization and cardiovascular mortality was a benefit that was beneficial.”
Just how much of a much of a benefit? Both in the NEJM paper and in an editorial published in Circulation,2 the study authors explained at length how the results relate to a pair of recent trials, PARADIGM-HF, (sacubitril / valsartan) and DAPA-HF (dapagliflozin), which yielded much higher relative risk reductions, albeit with different study populations.
“Although both of these trials showed more substantial relative reductions in the primary composite outcome of VICTORIA (a composite of death from cardiovascular causes or first hospitalization for heart failure), the annualized reductions in absolute risk are similar,” the authors wrote in the main study.
They wrote that patients in VICTORIA had much higher values of NT-proB-type Natriuretic Peptide (BNP), a hormone that indicates worsening heart heart failure. In the interview, Butler pointed out that a patient’s NT-proBNP levels were an important signal of how much vericiguat helped—up to a certain threshold, there was a benefit, but for those with the highest hormone values, things got worse. Which, Butler noted, “raises the question whether the sickest of the sick … are too sick to benefit.”
During the press conference, Armstrong said this an area that will be explored in greater detail, and leading to heart failure treatment that is "more personalized and precise."
How Vericiguat Works
Vericiguat was well-tolerated and easy to titrate up to its 10 mg dose, the study authors reported.
As Butler explained in the interview, in HF there is generalized endothelial dysfunction and a resulting decrease in nitric oxide production. Normally, nitric oxide enters a cell and binds to an enzyme called soluble guanylate cyclase. Once binding occurs, this leads to increased production of cyclic guanosine monophosphate (GMP). Cyclic GMP has many benefits, but for the cardiovascular system, it improves endothelial function and decreases fibrosis of the heart.
When there is oxidative stress, there is substantial reduction in nitric oxide and subsequently the action of the soluble guanylate cyclase. Vericiguat, Butler explained, bypasses that nitric oxide step and directly binds to stimulate the soluble guanylate cyclase. This boosts the solid CGMP production and creates the downstream beneficial effects on the cardiovascular system.
Just who will get this therapy remains to be seen. Clyde Yancy, MD, of Northwestern University, commented during the presentation that it would be a new challenge to have multiple therapeutic options in HF, and during the press briefing ACC President Richard Kovacs, MD, said that the questions of cost and prior authorization still have to be addressed.
“It’s evident the benefit occurs quickly, which is both a benefit and a challenge," Kovacs said.
Drug sponsors Merck and Bayer supported the study.