Contributor: Emily Cendrowski
VITALITY-HFPEF is a trial underway which will evaluate the efficacy of vericiguat in HFpEF patients by using the KCCQ-PLS (Kansas City Cardiomyopathy Questionnaire Physical Limitation Score) as a primary endpoint. The choice of this primary endpoint will make it the first HF trial utilizing a quality of life, patient-reported outcome (PRO) as a primary endpoint. There remains a need for medications which improve mortality and functional status for patients with HFpEF. An ongoing area of research involves the cyclic guanosine monophosphate (cGMP) pathway.
Prior studies attempting to increase cGMP signaling either directly with nitrates/nitrites or indirectly with phosphodiesterase type 5 (PDE) inhibition have shown no benefit. Vericiguat is a direct oral sGC stimulator, which activates the same pathways via a different mechanism. Although the recent phase II dose-finding trial for vericiguat, SOCRATES-PRESERVED, did not find significant changes in its primary endpoints of NT-pro BNP or LA volume, post hoc analyses showed significant improvements in several domains of the KCCQ, most notably in the physical limitation score (PLS) sub-domain. Based on these post hoc findings from SOCRATES-PRESERVED, VITALITY-HFPEF hypothesizes that vericiguat in doses of 10mg or a novel higher dose of 15mg will improve physical functioning in ADLs due to reduced symptoms of dyspnea and fatigue, and will produce at least a 5 point improvement in KCCQ-PLS compared to placebo in patients with HFpEF after 24 weeks of treatment. This will be a prospective, randomized, parallel-group, placebo-controlled, double-blind, multi-center, phase IIb trial, which will include 200 sites in 21 countries. Currently, it is estimated that 735 patients will be enrolled and randomized 1:1:1 to placebo, 10mg daily, or 15mg daily dose of vericiguat.
The primary endpoint will be change in KCCQ PLS from baseline to week 24, and a secondary endpoint will be change in six minute walk test from baseline to week 24. To be included, patients must have an EF of at least 45%, NYHA class II or III HF symptoms, age > 45 years, NT-proBNP > 300 or BNP > 100, and hospitalization or outpatient IV diuretic treatment for heart failure within 6 months prior to randomization. Among those excluded from the study are patients with a prior diagnosis of HFrEF (EF < 40%), use of IV inotropes at any time between qualifying heart failure event and randomization, SBP < 110 mmHg or >160mmHg, renal impairment (eGFR < 30), hepatic impairment, or obesity with BMI > 45 (Table 2).
The trial will employ a novel method of quantifying the clinical importance of KCCQ PLS improvements in patients through an anchor-based approach using the Patient Global Impression of Change (PGIC); all patient self assessments will take place before un-blinding. Mean changes from baseline in KCCQ PLS scores will be calculated to define clinically meaningful within-patient change thresholds.
No study is perfect, but given the extensive exclusion criteria, it may be possible that the study could underestimate the efficacy of vericiguat in the real world heterogenous HFpEF population.
In a heartbeat… VITALITY-HFPEF will serve both as a pivotal trial for vericiguat and will be the first HF trial to use patient-reported quality of life measures as a primary endpoint. This may pave the way for future drug development trials using patient-centered outcomes and quality of life as mechanisms of drug approval.
Study Link: Rationale and Design of the VITALITY-HFpEF Trial