Breakthrough Clinical Results
Merck announced results from the Phase 3 VICTOR trial and a pooled analysis of VICTOR and VICTORIA trials evaluating VERQUVO (vericiguat) in chronic heart failure with reduced ejection fraction (HFrEF). VICTOR, focusing on patients without recent worsening heart failure, did not meet its primary endpoint of reduced cardiovascular death or heart failure hospitalization. However, a pooled analysis of VICTOR and VICTORIA, which included patients with a broader range of disease severity, showed a statistically significant reduction in the primary composite endpoint. VERQUVO remains approved for patients with HFrEF following a recent heart failure event and with ejection fraction less than 45%, based on the positive VICTORIA trial results.
Key Highlights
- The Phase 3 VICTOR trial of VERQUVO in stable chronic heart failure patients did not meet its primary endpoint.
- A pooled analysis of VICTOR and VICTORIA trials showed a statistically significant reduction in cardiovascular death or heart failure hospitalization across a broader range of HFrEF patients.
- VERQUVO's approval for patients with HFrEF following a recent heart failure event and with ejection fraction less than 45% remains unchanged.
- The overall safety profile of VERQUVO was consistent with previous trials.
Additional Indications for VERQUVO (Vericiguat) Beyond Chronic Heart Failure
Heart Failure with Preserved Ejection Fraction (HFpEF)
One of the primary additional indications being explored for vericiguat is heart failure with preserved ejection fraction (HFpEF). This differs from its FDA-approved use for heart failure with reduced ejection fraction (HFrEF). The SOCRATES-PRESERVED trial has shown promising results, demonstrating improvement in quality of life and health status in HFpEF patients. However, it's important to note that the beneficial effects with vericiguat are still limited in this population, and further studies are needed to fully define its role in HFpEF management.
Optimized Therapy in Heart Failure
The VICTOR study is currently evaluating the efficacy and safety of vericiguat in heart failure patients who are on optimized therapy and have no recent episodes of stabilization. This represents an expansion of the drug's application within the heart failure spectrum, targeting a specific subpopulation with different characteristics than those in the original VICTORIA trial.
Potential Anti-Arrhythmic Applications
Research in a rabbit model of myocardial infarction (MI) has revealed promising anti-ventricular arrhythmia effects of vericiguat. The therapy has demonstrated ability to: - Reduce ventricular ectopic beats - Suppress cardiac alternans - Prevent conduction block and reentry circuits
These findings suggest potential for anti-arrhythmic applications beyond the current heart failure indications, though clinical trials in humans for this specific indication are not detailed in the available information.
The specific intervention models for these trials are not comprehensively described in the available information, with limited details provided about study designs beyond the general heart failure applications. The research community acknowledges that further research is warranted to determine additional applications of vericiguat beyond its current approved indication.
Incidence and Prevalence
Global Prevalence of Chronic Heart Failure
The prevalence of chronic heart failure (CHF) varies significantly across different populations and age groups worldwide, with recent studies providing important insights into this growing health concern.
According to a comprehensive 2013 German population-based study, the overall age-standardized prevalence of symptomatic CHF was 7.7% (95%CI 6.0-9.8) for men and 9.0% (95%CI 7.0-11.5) for women. This study demonstrated that CHF strongly increases with age, rising dramatically from 3.0% among 45-54-year-old subjects to 22.0% among 75-83-year-old subjects.
When examining types of heart failure, the German study found that symptomatic heart failure with reduced ejection fraction (HFREF) accounted for 48% of CHF cases, while symptomatic heart failure with normal ejection fraction (HFNEF) represented 52% of cases. The age-standardized prevalence of HFREF was 3.8% (95%CI 2.4-5.8) for women and 4.6% (95%CI 3.6-6.3) for men. Interestingly, the age-standardized prevalence of HFNEF showed a gender difference, with 5.1% (95%CI 3.8-7.0) for women and 3.0% (95%CI 2.1-4.5) for men, indicating that more women were affected by HFNEF than men.
In the United States, it was estimated in 2015 that approximately 6 million people have ischemic cardiomyopathies and CHF. A 2010 study focusing on older adults found that among 32.5 million US adults aged ≥65 years, 67% (21.8 million) are dyslipidemic, and among these dyslipidemic subjects, the prevalence of congestive heart failure is 9.9% (2.2 million).
Earlier data from 1998 indicated that the prevalence of CHF ranges from 3-20 per 1,000 in the general population and increases steeply with age.
Regarding underlying causes, coronary heart disease is the primary cause in 50% of CHF cases, while idiopathic cardiomyopathy accounts for 20% of cases. Persons with CHF were more likely to have hypertension (PR = 3.4; 95%CI 1.6-7.3) or to have had a previous myocardial infarction (PR = 2.5, 95%CI 1.8-3.5).
Based on population attributable risks, hypertension has the greatest impact on CHF, accounting for 39% of CHF events in men and 59% in women. Despite its lower prevalence in the population (3-10%), myocardial infarction also has a high attributable risk in men (34%) and women (13%). Valvular heart disease only accounted for 7-8% of CHF cases, while diabetes increased CHF risk 2-8 fold with risk ratios twice as large in women as men, with about 19% of CHF cases having diabetes.
In Canada, based on the 2000/2001 Canadian Community Health Survey, among Canadians 12 years of age and older, 1.0% (n=264,000) have CHF.
The quality of life of heart failure patients is severely impaired, with studies showing moderate to poor QOL depending on the assessment tools used.
Study Design Parameters
Study Design Parameters and Endpoints in Key Chronic Heart Failure Trials
Trial Designs
Key chronic heart failure (CHF) trials have employed various study designs including multicenter observational studies (BIOSTAT-CHF), prospective interventional pilot studies, and randomized controlled trials. The BIOSTAT-CHF prospectively enrolled patients with acute or worsening heart failure across Europe. Other notable designs include cross-sectional comparative analyses with interventions like computer-based reminder systems for guideline implementation. Biventricular pacing studies such as MIRACLE and COMPANION trials have provided valuable insights. Recent trials like the Qishen Taohong Granule study used a single-center, prospective, randomized, controlled design with 1:1 randomization ratio.
Patient Populations
Trials typically included patients with mild-to-moderate heart failure, some specifically targeting those with congestive heart failure and intraventricular conduction delay. The KCHF registry enrolled 4,056 consecutive patients with acute decompensated heart failure using an all-comer design. Patient classifications often used left ventricular ejection fraction (LVEF) categories: HFrEF (<40%), HFmrEF (40-49%), and HFpEF (≥50%). Sample sizes varied widely, from smaller studies with 32 patients to larger registries with thousands of participants.
Primary Endpoints
Primary endpoints in major trials consistently included: - All-cause mortality and survival benefit - Heart failure hospitalization - Composite endpoints combining cardiovascular mortality and hospitalization - Exercise capacity measurements - Cardiac function evaluated by NYHA classification and LVEF - Quality of life assessments using validated tools
The BIOSTAT-CHF developed risk models to predict mortality and heart failure hospitalization using clinical data and biomarkers. Recent studies have used composite endpoints including HF hospitalization, left ventricular assist device implantation, heart transplantation, and cardiovascular death.
Secondary Endpoints
Secondary endpoints frequently included: - Improvements in cardiac index - Systolic blood pressure changes - Functional class progression - Quality of life measurements using tools like Minnesota Living with Heart Failure Questionnaire - 6-minute walking test (6MWT) performance - Biomarker levels such as NT-proBNP and BNP - Left ventricular parameters including LVEDD - TIMI flow grade and myocardial perfusion grade in some studies
Outcome Measurements
Studies have demonstrated that beta-blocker therapy saves 1 life of every 35 patients treated with mild-to-moderate heart failure. Biventricular pacing improved cardiac index, systolic blood pressure, and functional class both acutely and long-term. Guideline-based therapy implementation improved prescription rates of key medications. Health-related quality of life (HRQOL) was measured using standardized tools like EQ-5D-5L. Recent studies show major polypharmacy due to guideline-directed medical therapy is associated with significant improvement in survival across heart failure phenotypes.