CADTH Reimbursement Review

Vericiguat (Verquvo)

Sponsor: Bayer Inc.

Therapeutic area: Heart failure

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNi = angiotensin receptor and neprilysin inhibitor; MRA = mineralocorticoid receptor antagonist; NOC = Notice of Compliance; NYHA = New York Heart Association.

Introduction

Heart failure (HF), sometimes referred to as congestive heart failure, is a clinical condition in which the heart is unable to adequately pump blood throughout the body to maintain the metabolic needs of tissues and organs. HF results from structural or functional impairment of ventricular filling or ejection of blood.^1,2 HF is classified based on the percentage of blood that is being pumped out of the left ventricle, otherwise known as the left ventricular ejection fraction (LVEF).² HF with reduced ejection fraction is defined as HF with an LVEF of 40% or less, whereas having an LVEF of 50% or greater is termed HF with preserved ejection fraction. There are an estimated 669,000 people in Canada older than 40 years with HF, with an age-standardized prevalence of 3.5%.³ Between 2001 and 2013, the age-standardized incidence rate of HF in Canada declined, as did the age-standardized all-cause mortality rate among people living with HF.³ However, people in Canada older than 40 years with HF are 6 times more likely to die than those without a HF diagnosis.³ The economic burden due to HF is substantial, with costs associated with health care services, medications, and lost productivity.

Common symptoms of HF include dyspnea (breathlessness) and fatigue, exercise intolerance, and fluid build-up, which in turn may lead to pulmonary congestion and peripheral edema (mainly in the feet, ankles, or legs) that can have a significant effect on a patient’s quality of life.¹ Depending on symptom severity, HF may go unnoticed, only causing minor symptoms, but patients with advanced HF may find it difficult to carry out normal everyday activities.⁴ HF leads to a progressive decline in cardiac function over time, with persistent signs and symptoms interspersed with acute episodes of decompensation. Acute decompensated HF is a sudden worsening of the signs and symptoms of HF that often lead to hospitalization or an emergency department visit.⁵ Worsening HF and hospitalization for heart failure (HHF) portend a poor prognosis and are associated with an increased risk of mortality and hospital readmission.⁶ Hospitalizations due to HF are frequent, with 83% of patients hospitalized at least once and 43% hospitalized 4 or more times after a diagnosis of HF.⁷ It is generally accepted that hospitalization for acute decompensated HF is a powerful predictor of readmission and death after discharge in patients with chronic HF, with postdischarge mortality rates as high as 20%.^5,8 The current foundational pharmaceutical management of HF with reduced ejection fraction encompasses combination therapy (in the absence of contraindications), including 1 evidence-based medication from each of the following categories: (1) sacubitril-valsartan, either as first-line therapy or switching from an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), (2) beta-blockers, (3) mineralocorticoid receptor antagonists (MRAs), and (4) sodium-glucose cotransporter-2 (SGLT2) inhibitors.⁶ Recently, new therapies have emerged, such as soluble guanylate cyclase (sGC) stimulators or ivabradine (a sinus node inhibitor), that are taken in conjunction with well-established therapies and have shown benefit in patients with HF with reduced ejection fraction.⁶

Vericiguat is a stimulator of sGC. HF is associated with impaired nitric oxide (NO) synthesis and decreased activity of its receptor, sGC. Vericiguat restores the relative deficiency in this signalling pathway by directly stimulating sGC, independently and synergistically with NO, to increase the level of intracellular cyclic guanosine monophosphate (cGMP), which may improve both myocardial and vascular function. According to the proposed Health Canada indication, vericiguat is indicated for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilized after a recent HF decompensation event requiring hospitalization and/or IV diuretic therapy. Vericiguat should be used in combination with standard-of-care (SOC) therapy for HF. Vericiguat should be initiated under the supervision of a health care professional who is experienced in the management of HF. The recommended starting dose of vericiguat is 2.5 mg administered orally once daily, followed by doubling the dose every 2 weeks to the target maintenance dose of 10 mg, as tolerated by the patient.⁹

The objective of this report is to perform a systematic review of the beneficial and harmful effects of vericiguat 10 mg once daily to reduce the risk of cardiovascular (CV) death and HHF in adults with symptomatic chronic HF and an ejection fraction of less than 45% who are stabilized after a recent worsening HF event in combination with other HF therapies.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups that responded to CADTH’s call for patient input and from the clinical expert consulted by CADTH for the purpose of this review.

Patient Input

Two patient groups, the HeartLife Foundation and the Heart Function Clinic in Vancouver General Hospital, St. Paul’s Hospital, British Columbia, provided input for the review of vericiguat. The HeartLife Foundation is a patient-driven federal charity whose mission is to transform the quality of life for people living with HF by engaging, educating, and empowering a global community to create lasting solutions and build healthier lives. The input was informed by interviews with 3 HF specialists (British Columbia, Ontario, and Quebec), 1 researcher (Alberta), and 2 patients with HF (British Columbia and Ontario), as well as a review of study material and online literature.

The HeartLife Foundation indicated that patients with HF experience a wide range of physical, social, and emotional challenges. Symptoms include shortness of breath, extreme fatigue, low blood pressure, dizziness, edema, bloating, palpitations, and arrhythmia. The HeartLife Foundation highlighted that access to care, medical therapies, and support services vary widely across Canada, and that every individual’s experience with HF is unique. Two patient interviews (aged 33 and 44 years; 1 male and 1 female) highlighted the impact of HF on their quality of life, including being unable to pursue their desired career or exercise regularly. A recurring theme in the 2 patient interviews was the need to find a “new normal” for life following their diagnosis of HF. The Heart Function Clinic highlighted the following gaps in the treatment of HF: not all patients respond to available treatments and patients become refractory to existing treatment options. The HeartLife Foundation indicated that patients with HF seek to improve their quantitative and qualitative outcomes. The HeartLife Foundation further emphasized that it is imperative to provide equitable access to high-quality care and services for all patients with HF, including access to diagnostics, medical therapy, mental health support, cardiac rehabilitation, and advanced care. The HeartLife Foundation advocated for vericiguat to be approved for the indication under review and suggested that vericiguat will help alleviate the gaps in current therapy.

Clinician Input

Input From the Clinical Expert Consulted by CADTH

The clinical expert consulted by CADTH for this review indicated that HF with reduced ejection fraction is still associated with increased rates of death and need for hospitalization despite standard therapy. The clinical expert noted that not all patients are eligible for the standard quadruple therapy due to side effects or comorbidities. It was further highlighted by the clinical expert that some patients who experience disease progression while on standard therapy may require de-escalation of therapy to become restabilized. The clinical expert consulted indicated that vericiguat can be added to foundational quadruple HF therapy, as its mechanism of action differs from that of the foundational treatment. However, the impact or role of vericiguat in the context of current quadruple therapy is unknown because the VICTORIA trial was designed and completed before the current therapeutic paradigm, which now includes SGLT2 inhibitors, was widely adopted. The clinical expert consulted indicated that patients included in the VICTORIA trial received foundational therapy and generally tended to be “sicker” than those included in HF trials with other therapies. The clinical expert noted that the response to therapy in clinical practice is assessed based on the reduction in burden of symptoms, the need for escalation of diuretic therapy, hospitalization, or death. The clinical expert indicated that vericiguat should be prescribed by a practitioner with expertise in the management of HF in specialty clinics with a focus on the assessment and management of HF. It was further mentioned by the clinical expert that the addition of this medication is expected to have a positive impact on the management of these patients.

Clinician Group Input

The clinician group input was obtained from 3 clinician groups, including Oakville Cardiologists, represented by 9 clinicians; 1 clinician from the Division of Cardiology, University of Alberta; and 1 clinician representing the North Shore Heart Centre in Vancouver. The clinician from the Division of Cardiology, University of Alberta, identified the following as key goals of new therapies for HF: reducing recurrent symptoms and the need for hospitalization or emergency department visits. All clinician groups agreed that morbidity and mortality rates remain high in patients with HF with reduced ejection fraction despite advancements in therapies, and many patients cannot be titrated to the optimal doses of the medications due to hypotension, hyperkalemia, bradycardia, or renal dysfunction. The clinician groups agreed that vericiguat represents an additional approach to the treatment of HF with reduced ejection fraction, which is not targeted by current guideline-directed medical therapy (GDMT). The clinician from the Division of Cardiology, University of Alberta, also suggested that because vericiguat does not cause hyperkalemia or impair renal function, patients who cannot tolerate angiotensin receptor–neprilysin inhibitors (ARNis) or ACEis (e.g., patients with diabetes or renal impairment) would be good candidates for vericiguat. The clinical groups pointed out several reasons that may lead to the discontinuation of vericiguat, including a decline in the glomerular filtration rate to less than 15 mL/min/1.73 m², severe hypotension, and syncope. The Oakville Cardiologists indicated that physician assessment of clinical stability and patient-reported symptoms continue to be the cornerstone of evaluating response to therapy in patients with HF with reduced ejection fraction in the outpatient setting. The clinical groups advocated for vericiguat to be an accessible treatment option in the high-risk HF patient population, as it is safe, well tolerated, and taken once daily.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially affect the implementation of a CADTH recommendation for vericiguat:

• relevant comparators

• considerations for initiation of therapy

• considerations for prescribing therapy

• system and economic issues.

The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

The VICTORIA trial was a phase III, randomized, multicentre, double-blind, event-driven, placebo-controlled trial designed to assess the efficacy and safety of vericiguat versus placebo as an adjunct to SOC therapy in adults with symptomatic chronic HF and an ejection fraction of less than 45% who are stabilized after a recent worsening HF event. Previous HF decompensation (or worsening) was defined as HHF within 6 months before randomization or the use of an IV diuretic for HF (without hospitalization) within 3 months before randomization. A total of 5,050 patients with symptomatic chronic HF with reduced ejection fraction were enrolled across 694 sites in 42 countries in North America (560 patients), Eastern Europe, Western Europe, the Asia-Pacific region, and Latin and South America. The primary efficacy end point was the time to first event of the adjudicated CV death or HHF; the key secondary end points were time to CV death, time to first event of HHF, time to total events (first and recurrent) of HHF, time to first event of all-cause mortality or HHF, and time to all-cause mortality events. Health-related quality of life (HRQoL) was assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EQ-5D instrument. Futility and efficacy interim analyses were planned for the time when approximately 75% (587 events) of the planned number of CV death events were reached and data safety monitoring board could recommend early termination of the trial for overwhelming efficacy or futility. The database lock was executed on October 31, 2019.

Overall, baseline characteristics were well balanced between treatment groups in the VICTORIA trial. The mean age of all randomized patients in the VICTORIA trial was 67.3 years (standard deviation [SD] = 12.2 years). A total of 76.1% of patients were male, and 24.0% were female. About 64.1% of patients were white, while 27.0% were Asian or multiracial. A total of 81.4% of patients were non-Hispanic or non-Latino, and 16.1% were Hispanic or Latino. The mean LVEF was 28.9% (SD = 8.30%), and nearly half of patients had an LVEF of less than 30% (49.3%). Most patients had a New York Heart Association (NYHA) functional class II or III (98.6%) at baseline. The mean N-terminal probrain natriuretic peptide (NT-proBNP) was 4,741.90 pg/mL (SD = 6,845.60 pg/mL), the mean brain natriuretic peptide (BNP) was ||||||| pg/mL (SD = |||||||| pg/mL), and the mean estimated glomerular filtration rate (eGFR) was 61.5 mL/min/1.73 m² (SD = 27.2 mL/min/1.73 m²). Approximately 70% of patients had HHF within 3 months before randomization, 17.2% had HHF within 3 to 6 months, and 15.9% had outpatient treatment with IV diuretics for worsening HF within 3 months before hospitalization. A total of 91.2% of patients received 2 or more HF medications, and only 60% of patients received triple therapy, including ACEis or ARBs, beta-blockers, and MRAs.

Efficacy Results

A summary of the results for the main efficacy and safety outcomes of the VICTORIA trial is presented in Table 2.

Time to First Event of CV Death or HHF

A composite of time to first event of adjudicated CV death or HHF occurred in 897 patients (35.5%) in the vericiguat group and 972 patients (38.5%) in the placebo group. The annual event rate was lower in the vericiguat group compared with the placebo group (33.6% and 37.8%, respectively), with a hazard ratio (HR) of 0.90 (95% confidence interval [CI], 0.82 to 0.98; P = 0.019) in favour of the vericiguat group. The median follow-up duration was 11.1 months in the vericiguat group and 10.4 months in the placebo group. The proportion of HHF as the first event was lower in the vericiguat group (27.4%) compared with the placebo group (29.6%), whereas proportion of CV death was similar between the treatment groups (8.2% versus 8.9% in the vericiguat and placebo groups, respectively).

Table 2: Summary of Key Results From Pivotal Study

AE = adverse event; CEC = Clinical Events Committee; CI = confidence interval; CV = cardiovascular; EQ VAS = EQ-5D visual analogue scale; EQ-5D-5L = 5-Level EQ-5D; HHF = hospitalization for heart failure; HR = hazard ratio; KCCQ = Kansas City Cardiomyopathy Questionnaire; KM = Kaplan-Meier; LS = least squares; SAE = serious adverse event; SD = standard deviation.

Notes: For patients with multiple events, only the first event contributing to the composite end point is counted in the table.

Based on data up to the primary completion date (June 18, 2019).

^aTotal events per 100 patient-years at risk.

^bKM estimate and CI at 2 years.

^cHR (vericiguat over placebo) and CI from Cox proportional hazard model, controlled for stratification factors (defined by region and race).

^dFrom log-rank test stratified by the stratification factors defined by region and race.

^eP value was not adjusted for multiplicity.

^fBased on a longitudinal analysis of the covariance model, with change in score as the dependent variable, including categorical terms for stratification factor, week, treatment group, and week-by-treatment-group interaction, with the baseline value as a continuous covariate and including all postrandomization time points through week 96. For baseline and week 32, N is the number of patients with nonmissing assessments at the specific time point. For change from baseline, N is the number of patients with nonmissing assessment in both baseline and week 32.

^gIncludes AEs associated with a fatal outcome but does not reflect all deaths reported in the study.

^hDefined as a dose reduction, drug interruption, or drug withdrawal.

Source: Clinical Study Report for VICTORIA.¹⁰

Time to CV Death

This secondary outcome was tested in a nonhierarchical sequence without adjustments for multiplicity and was exploratory in nature. The number of CV death events was 414 (16.4%) in the vericiguat group and 441 (17.5%) in the placebo group. The proportion of patients who died of HF was 6.5% and 7.6% in the vericiguat and placebo groups, respectively; sudden cardiac event 4.2% and 4.5% in the vericiguat and placebo groups, respectively; and undetermined cause of death 4.4% and 4.0% in the vericiguat and placebo groups, respectively. The HR for time to CV death was 0.93 (95% CI, 0.81 to 1.06; P = 0.269).

Time to All-Cause Mortality

A total of 512 (20.3%) patients in the vericiguat group and 534 (21.2%) patients in the placebo group died of any cause. The annual event rate was similar between the treatment groups (16.0% and 16.9% in the vericiguat and placebo groups, respectively), with an HR of 0.95 (95% CI, 0.84 to 1.07; P = 0.377).

Time to First Event of All-Cause Mortality or HHF

A composite of time to first event of all-cause mortality or HHF occurred in 957 patients (37.9%) in the vericiguat group and 1,032 patients (40.9%) in the placebo group. The annual event rate was 35.9% and 40.1% in the vericiguat and placebo groups, respectively, with an HR of 0.90 (95% CI, 0.83 to 0.98; P = 0.021). This difference was likely driven primarily by a lower proportion of HHF events, although individual components of this composite end point were not formally tested for significance.

Time to CV Hospitalization

This secondary outcome was tested in a nonhierarchical sequence without adjustments for multiplicity and was exploratory in nature. A total of ||| |||||||| ||||||| in the vericiguat group and ||||| |||||||| ||||||| in the placebo group had CV hospitalizations. The annual event rate was lower in the vericiguat group (|||||) compared with the placebo group (|||||), with an HR of |||| |||| || |||| || ||||| | | |||||||.

Time to First Event of HHF

This secondary outcome was tested as a component of the primary composite end point in a nonhierarchical sequence without adjustments for multiplicity and was exploratory in nature. The number of patients with HHF events was 691 (27.4%) in the vericiguat group and 747 (29.6%) in the placebo group. The annual event rate was 25.9% in the vericiguat group and 29.1% in the placebo group, with an HR of 0.90 (95% CI, 0.81 to 1.00; P = 0.048).

Time to Total Events (First and Recurrent) of HHF

The total number of HHF events was lower in patients who received vericiguat (n = 1,223) compared with those who received placebo (n = 1,336). The annual event rate was 38.3% in the vericiguat group and 42.4% in the placebo group, with an HR of 0.91 (95% CI, 0.84 to 0.99; P = 0.023).

Health-Related Quality of Life

No strong conclusions could be drawn about the effect of vericiguat compared with placebo on HRQoL due to an increased risk of type I error and a high risk of attrition bias.

KCCQ Score

For the analysis of the KCCQ score based on the intention-to-treat (ITT) population, week 32 data were missing for ||||| || ||||| of patients in the vericiguat group and for ||||| || ||||| of patients in the placebo group. No clinically meaningful differences were found between treatment groups in change from baseline in KCCQ scores at week 32 (less than minimally important difference [MID] of 5 or more points).

KCCQ Overall Summary Score: The KCCQ overall summary score combines the physical limitation, total symptom, social limitation, and HRQoL domains into a single score. The analysis showed a slight improvement from baseline of ||| |||||| (SD = ||||) in the vericiguat group and ||| points (SD = ||||) in the placebo group in the KCCQ overall summary score at week 32, with a least squares (LS) mean difference of ||| |||| || |||| || |||| | | ||||||.

KCCQ Total Symptom Score: The KCCQ total symptom score combines the symptom burden and symptom frequency domains into a single score. The analysis showed a slight improvement from baseline of ||| |||||| || |||||| in the vericiguat group and ||| |||||| || |||||| in the placebo group in the KCCQ total symptom score at week 32, with an LS mean difference of ||| |||| || |||| || |||| | | |||||||.

KCCQ Clinical Summary Score: The KCCQ clinical summary score combines the physical limitation and total symptom domains into a single score. The analysis showed a slight improvement from baseline of ||| |||||| || |||||| in the vericiguat group and ||| |||||| || |||||| in the placebo group in the KCCQ clinical summary score at week 32, with an LS mean difference of ||| |||| || |||| || |||| | | |||||||.

5-Level EQ-5D

For the analysis of the 5-Level EQ-5D (EQ-5D-5L) index score based on the ITT population, week 32 data were missing for ||||| || ||||| of patients in the vericiguat and placebo groups, respectively. No difference was found between the 2 treatment groups in mean change from baseline in EQ-5D-5L score at week 32. For the EQ-5D-5L UK and US index scores, the LS mean differences at week 32 for vericiguat versus placebo were ||||| |||||| || |||||| | | |||||| and 0.01 (95% CI, –0.01 to 0.03; P = 0.257), respectively.

Harms Results

A total of 2,027 (80.5%) patients in the vericiguat group and 2,036 (81.0%) patients in the placebo group experienced 1 or more adverse events (AEs). The most common AEs that occurred in the vericiguat or placebo groups were hypotension (15.4% and 14.1%, respectively), cardiac failure (8.9% and 9.9%, respectively), anemia (7.6% and 5.7%, respectively), and pneumonia (6.4% and 7.2%, respectively). A total of 653 (25.9%) patients in the vericiguat group and 606 (24.1%) patients in the placebo group experienced 1 or more AEs leading to dose modification. The proportion of fatal AEs during the double-blind treatment phase was similar between the treatment groups (3.3% and 3.4% in the vericiguat and placebo groups, respectively). A total of 826 (32.8%) patients in the vericiguat group and 876 (34.8%) in the placebo groups experienced 1 or more serious adverse event (SAE). Withdrawal of study treatment due to AEs was required in 167 (6.6%) patients in the vericiguat group and 158 (6.3%) patients in the placebo group. The most common reasons for discontinuation in the vericiguat and placebo groups were hypotension (1.9% and 1.3%, respectively), chronic kidney disease (0.3% and 0.6%, respectively), pneumonia (0.1% and 0.2%, respectively), cardiac failure (0.2% and 0.2%, respectively), and dyspepsia (0.2% and 0.1%, respectively). In the VICTORIA trial, symptomatic hypotension was the most commonly reported notable AE (9.1% and 7.9% in the vericiguat and placebo groups, respectively), followed by syncope (4.0% and 3.5% in the vericiguat and placebo groups, respectively), and hepatic AEs (0.9% and 0.5% in the vericiguat and placebo groups, respectively).

Critical Appraisal

Internal Validity

The VICTORIA trial used accepted methods for blinding, allocation concealment, and randomization with stratification by race and geographic region. An Interactive Voice Response System and Integrated Web Response System methodology was used, and randomization with stratification was performed centrally, which typically has a low risk of bias. The baseline demographic and disease characteristics of patients were generally balanced between the treatment groups, so randomization was successful. A relatively high proportion of patients prematurely discontinued the trial medication (38.7%), but the cause of discontinuations occurred at a similar frequency between the treatment groups. The clinical expert consulted by CADTH for this review noted that the main reason for treatment discontinuation was fatal events, reflecting the natural course of HF. In accordance with the exclusion criteria, patients in the trial were randomized starting 24 hours after IV diuretic treatment, which may not be enough time to achieve clinically stability after a worsening HF event and may lead to an underestimation or overestimation of the treatment effect. Furthermore, there was no run-in period in the trial to initiate or maintain optimal doses of HF medications to achieve clinical stability after worsening HF. However, the clinical expert consulted noted that sometimes only 1 dose of a diuretic is required to achieve clinical stability, and sometimes it takes several days or weeks before the patient becomes stable.

An independent blinded Clinical Events Committee (CEC) performed an adjudication of efficacy and safety end points a priori. The clinical expert consulted indicated that the primary and key secondary outcomes were appropriate for the disease setting. The analyses of primary and key secondary outcomes were conducted using the ITT population, which maintains randomization and minimizes the risk of bias by comparing groups with similar prognostic factors. Both interim and final analyses were planned a priori and adequately described; however, the decision was made to cancel the interim analysis because there were more than expected CV death events. Given the potential misclassification of CV deaths, which may overestimate the true incidence of CV death events, as they include undetermined causes of death, there is a possibility that the trial was stopped earlier than planned. Therefore, there is a risk that the effect of vericiguat, compared to placebo, is overestimated, but the presence and extent of any estimation in uncertain.^11-13 The median primary composite end point, all-cause survival, total HHF, and a composite of all-cause mortality and HHF was not estimable because insufficient follow-up time had elapsed for these outcomes; thus, the long-term efficacy of vericiguat is unknown. Subgroup analyses were not adjusted for multiplicity and may not have been powered to detect a treatment difference; as such, any inferences or interpretations based on subgroups should be made with caution. Although improvement in HRQoL was of primary importance for both patients and physicians, this was an exploratory outcome and was tested outside the statistical testing hierarchy. The KCCQ is generally a valid and reliable questionnaire for HF, but there is no evidence for the validity or reliability of the EQ-5D instrument in patients with HF. Clinical experts consulted indicated that these tools are not commonly used in clinical practice. No strong conclusions could be drawn about the effect of vericiguat, compared with placebo, on HRQoL due to an increased risk of type I error and a high risk of attrition bias, especially with longer follow-up.

External Validity

In general, the clinical expert consulted by CADTH for this review confirmed that the population of the VICTORIA trial was similar to patients seen in Canadian clinics, and the study results would be generalizable to patients with HF in Canada with some limitations. CADTH was unable to draw conclusions about patients with NYHA class I or IV HF because the VICTORIA trial excluded patients who had NYHA class I HF and only included a very small proportion of patients who had NYHA class IV HF (1.1%). Furthermore, the clinical expert consulted indicated that patients with NYHA class IV HF are more likely to be clinically unstable than those with NYHA class II or class III HF. About 26.4% of patients in the trial did not pass the screening, predominantly because the NT-proBNP level of those patients was below the prespecified threshold. According to the clinical expert consulted, NT-proBNP testing is not widely available in Canada because some jurisdictions have limited access to it; thus, this patient selection criterion would be difficult to implement in clinical practice. The clinical expert further noted that the enrolment of patients with elevated NT-proBNP levels likely created an enriched population in the trial because these patients appeared to be sicker and more likely to benefit from treatment with vericiguat than the population in the real-world setting. The clinical expert consulted indicated that the population in the VICTORIA trial was younger than the typical adult population in Canada with symptomatic chronic HF with reduced ejection fraction (mean age is 75 to 77 years). Most patients were white and non-Hispanic or non-Latino, and only 11% of patients were recruited from North America. The clinical expert consulted noted that the lack of representation of Canadian patients does not reduce the generalizability of the results to Canadian clinical practice.

About 91% of patients in the trial received 2 or more background HF treatments, and only 60% of patients received triple therapy for HF, representing a large majority of patients whose treatment was suboptimal. In addition, a small proportion of patients (14.4%) received sacubitril-valsartan and none of the patients received SGLT2 inhibitors for the treatment of HF. According to the clinical expert consulted, SGLT2 inhibitors became available for the treatment of chronic HF with reduced ejection fraction after the VICTORIA trial was conducted (between 2016 and 2019). Therefore, it is unclear whether the population included in the VICTORIA study is reflective of the population that would be eligible for treatment with vericiguat in current Canadian clinical practice. The clinical expert consulted indicated that vericiguat may be added to foundational quadruple HF therapy (including ACEis or ARBs, beta-blockers, MRAs, and SGLT2 inhibitors), as its mechanism of action is different from quadruple therapy medications. However, the cumulative benefit of vericiguat added to quadruple therapy remains unknown. According to the clinical expert consulted by CADTH for this review, most clinicians will choose to prescribe SGLT2 inhibitors over vericiguat in combination with triple HF therapy unless contraindicated,⁶ and only after failure of standard quadruple therapy would they prescribe vericiguat to patients who are stabilized after worsening HF.

Indirect Comparisons

No sponsor-submitted network meta-analysis (NMA) was identified for this review. A focused literature search for indirect treatment comparisons dealing with HF was run in MEDLINE All (1946–) on November 9, 2022. No limits were applied to the search. The literature search identified 7 potential citations, of which 4 were included for consideration for the following reasons: in the VICTORIA trial, vericiguat was compared to placebo plus standard triple therapy; only 14% of patients in the VICTORIA trial received sacubitril-valsartan; and none of the patients received SGLT2 inhibitors for HF treatment because they became available only after completion of the VICTORIA trial. The 4 studies identified through the literature search aimed to compare the efficacy of vericiguat in the treatment of patients with HF with reduced ejection fraction with SGLT2 inhibitors, sacubitril-valsartan, ivabradine, and a standard triple therapy, which were considered to be comparators in the systematic review protocol.

Aimo et al. (2021) NMA

The NMA by Aimo et al. (2021)¹⁴ was identified from the literature. The objective of the analysis was to compare vericiguat with sacubitril-valsartan and with SGLT2 inhibitors in the treatment of patients with HF with reduced ejection fraction. Databases, including PubMed, Embase, and clinicaltrials.gov, were searched for articles of interest on September 25, 2020. The systematic review included 6 studies for analysis that compared sacubitril-valsartan, vericiguat, or SGLT2 inhibitors with SOC therapy. A random-effects NMA with the DerSimonian-Laird estimator and a fixed-effects model were performed separately for the primary and secondary outcomes of interest. The primary end point of interest was a composite of CV death and HHF, and the secondary end points included CV death alone and HHF alone.

The pooled results of the NMA showed for a composite of CV death and HHF, the HR for SGLT2 inhibitors versus vericiguat and sacubitril-valsartan was 0.83 (95% CI, 0.73 to 0.94) and 0.92 (95% CI, 0.88 to 1.24), respectively. For CV death, the HR for SGLT2 inhibitors versus vericiguat and sacubitril-valsartan was 0.88 (95% CI, 0.63 to 1.22) and 1.04 (95% CI, 0.88 to 1.24), respectively. For HHF, the HR for SGLT2 inhibitors versus vericiguat and sacubitril-valsartan was 0.77 (95% CI, 0.66 to 0.89) and 0.87 (95% CI, 0.75 to 1.02), respectively.

De Marzo et al. (2022) NMA

The NMA by De Marzo et al. (2022)¹⁵ was identified from the literature The objective of the analysis was to compare the efficacy of vericiguat, ivabradine, and SGLT2 inhibitors in the treatment of patients with HF with reduced ejection fraction. Databases, including PubMed, Embase, SCOPUS, and the Cochrane Library, were searched for articles of interest on November 30, 2020. The NMA comprised both a fixed-effects model and a random-effects model within a Bayesian framework. The primary end point of interest was all-cause death, and the secondary end points included CV death, HHF, and all-cause hospitalization. The systematic review included 69 randomized controlled trials (RCTs) for all-cause death, 56 RCTs for CV death, 45 RCTs for HHF, and 26 RCTs for all-cause hospitalization.

The results of the NMA showed that for the primary end point of all-cause death, the HR for ivabradine and SGLT2 inhibitors versus vericiguat was 0.97 (95% credible interval [CrI], 0.60 to 1.60) and 0.94 (95% CrI, 0.62 to 1.40), respectively. For CV death, the HR for ivabradine and SGLT2 inhibitors versus vericiguat was 1.00 (95% CrI, 0.61 to 1.50) and 0.94 (95% CrI, 0.61 to 1.50). For HHF, the HR for ivabradine and SGLT2 inhibitors versus vericiguat was 0.89 (95% CrI, 0.50 to 1.70) and 0.88 (95% CrI, 0.56 to 1.60). The results for all-cause hospitalizations were not reported, as this information was not available in 63% of the RCTs examined.

Luo et al. (2022) NMA

The NMA by Luo et al. (2022)¹⁶ was identified from the literature. The objective of the analysis was to compare sGC stimulators, ARNis, and SGLT2 inhibitors in the treatment of patients with HF with reduced ejection fraction. Databases, including PubMed, Embase, the Cochrane Library, and Web of Science, were searched for articles of interest on September 1, 2021. A random-effects model was constructed based on frequency theory. The efficacy outcomes included HF rehospitalization, all-cause mortality, CV death, and CV death or HF rehospitalization. A total of 15 RCTs were included for HF rehospitalization, 14 RCTs for all-cause mortality, 12 RCTs for CV death, and 16 RCTs for CV death or HF rehospitalization.

The results of the NMA for HF rehospitalization, the odds ratio (OR) for SGLT2 inhibitors versus sGC stimulators was 0.79 (95% CI, 0.68 to 0.93), whereas the OR for ARNis versus sGC stimulators was 0.87 (95% CI, 0.75 to 1.01). For all-cause mortality, the OR for SGLT2 inhibitors versus sGC stimulators was 0.98 (95% CI, 0.70 to 1.38), whereas for ARNis versus sGC stimulators was 0.87 (95% CI, 0.61 to 1.25). For CV death, the OR for SGLT2 inhibitors versus sGC stimulators was 0.96 (95% CI, 0.74 to 1.25), whereas for ARNis versus sGC stimulators was 0.88 (95% CI, 0.68 to 1.15). For CV death or HF rehospitalization, the OR for SGLT2 inhibitors versus sGC stimulators was 0.87 (95% CI, 0.76 to 1.00), whereas for ARNis versus sGC stimulators was 0.88 (95% CI, 0.77 to 1.01).

Pagnesi et al. (2022) NMA

The NMA by Pagnesi et al. (2022)¹⁷ was identified from the literature .The objective of the analysis was to compare vericiguat with SGLT2 inhibitors in the treatment of patients with HF with reduced ejection fraction. Databases, including PubMed, Embase, Google Scholar, and the Cochrane Central Register of Controlled Trials, were searched for articles of interest on March 18, 2021. A random-effects NMA was performed on the cumulative event rates for primary and secondary end points based on a frequentist approach with the DerSimonian-Laird estimator. The primary end point was the composite of CV death and HHF, and secondary end points were CV death, all-cause death, and HHF. The systematic review included 7 studies for the composite of CV death and HHF, 10 studies for CV death, 12 studies for all-cause mortality, and 10 studies for HHF.

The results of the NMA For a composite of CV death or HHF, the relative risk (RR) for SGLT2 inhibitors versus vericiguat was 0.84 (95% CI, 0.75 to 0.96). For all-cause mortality, the RR for SGLT2 inhibitors versus vericiguat was 0.90 (95% CI, 0.77 to 1.04). For CV death, the RR for SGLT2 inhibitors versus vericiguat was 0.91 (95% CI, 0.91 to 0.96). For HHF, the RR for SGLT2 inhibitors versus vericiguat was 0.79 (95% CI, 0.69 to 0.91).

Critical Appraisal of Published NMA Articles

The results of the NMA are highly uncertain, given the heterogeneity across the studies included in the networks, heterogeneity in the baseline characteristics of patients within the included trials, and limited information related to definitions of end points. Furthermore, ivabradine and vericiguat were restricted to selected patients who were stabilized after an episode of worsening HF. Results in efficacy estimates were imprecise (i.e., wide CIs including HR = 1) in many comparisons and end points, which adds to the uncertainty in the effect estimates. Therefore, no definitive conclusions can be drawn from the published NMAs for many outcome comparisons due to methodological limitations and impression in the effect estimates. Furthermore, safety outcomes were not analyzed in the published NMAs, and no justification was provided, which precludes a balanced judgment of comparative benefits relative to comparative harms. Outcomes important to patients, such as HRQoL, were also not analyzed in the published NMAs.

Other Relevant Evidence

No other relevant evidence was identified for this review.

Conclusions

Based on data from the VICTORIA trial, vericiguat demonstrated a statistically significant and clinically meaningful benefit compared to placebo in reducing the hazard rates of first event of CV death or HHF, occurrence of first and recurrent HHF, and the composite of all-cause mortality and HHF in adult patients with symptomatic chronic HF with reduced ejection fraction. The median composite primary end point, total events of HHF, and composite of all-cause mortality and HHF were not estimable in either treatment group because insufficient follow-up time had elapsed for these outcomes; thus, the longer-term efficacy of vericiguat is unknown. In addition, the estimates of the benefit of vericiguat may be overestimated because of the possibility that the trial was stopped earlier than planned due to the potential misclassification of CV death; however, the presence and extent of any overestimation is uncertain. Strong conclusions could not be drawn about the effect of vericiguat on HRQoL due to the high risk of attrition bias and increased risk of type I error in the analyses of these outcomes. No new safety signals were identified in patients with HF with reduced ejection fraction. Owing to its superiority over placebo, vericiguat may be another treatment option for patients with HF with reduced ejection fraction who are stabilized after a recent HF decompensation event. According to the clinical expert consulted by CADTH, vericiguat may be added to foundational quadruple HF therapy (including ACEis or ARBs, beta-blockers, MRAs, and SGLT2 inhibitors); however, the cumulative benefit of vericiguat added to the current model of quadruple therapy remains unknown. No conclusions could be drawn from the published NMAs about the efficacy of vericiguat relative to SGLT2 inhibitors, ivabradine, and sacubitril-valsartan for the treatment of patients with HF with reduced ejection fraction due to methodological limitations and imprecision in the effect estimates.

Introduction

Disease Background

HF, sometimes referred to as congestive HF, is a clinical condition in which the heart is unable to adequately pump blood throughout the body to maintain the metabolic needs of tissues and organs. HF results from structural or functional impairment of ventricular filling or ejection of blood.^1,2 HF is classified based on the percentage of blood that is being pumped out of the left ventricle, otherwise known as the LVEF.² HF with reduced ejection fraction is defined as HF with an LVEF of 40% or less, whereas HF with preserved ejection fraction is defined as an LVEF of 50% or greater. HF with an LVEF in the range of 41% to 49% is defined as HF with midrange LVEF, which may represent a variety of phenotypes, including patients transitioning to and from HF with preserved ejection fraction.² There is uncertainty regarding management strategies, including surveillance, treatment, and prognosis, for patients with HF with midrange ejection fraction.² Additionally, HF with “recovered” or “improved” ejection fraction is defined as an LVEF of more than 40% but with a previously documented LVEF of less than 40%.¹⁸ Assessment of LVEF is a routine part of the diagnosis and management of HF and can be carried out using a variety of techniques, the most common being 2D echocardiography, as well as nuclear medicine, angiography, and MRI; however, LVEF estimates may vary depending on the patient, technical factors, and clinical deterioration.² Natriuretic peptide (NP) tests may be useful in identifying individuals at increased risk of developing HF in whom preventive strategies have been studied.² In addition, the monitoring of NP levels can provide important information about response to therapy and residual risk.^19,20 Another common classification system is the NYHA functional classification, which is based on HF symptoms and a patient’s ability to perform physical activities. Patients with NYHA class I HF have no symptoms (asymptomatic), and those with class IV HF have symptoms at rest or with any minimal activity.²

There are an estimated 669,000 people in Canada older than 40 years with HF, with an age-standardized prevalence of 3.5%.³ Between 2001 and 2013, the age-standardized incidence rate of HF in Canada declined, as did the age-standardized all-cause mortality rate among people living with HF.³ However, people in Canada older than 40 years with HF are 6 times more likely to die than those without a HF diagnosis.³ The economic burden due to HF is substantial, with costs associated with health care services, medications, and lost productivity. Common symptoms of HF include dyspnea (breathlessness) and fatigue, exercise intolerance, and fluid build-up, which in turn may lead to pulmonary congestion and peripheral edema (mainly feet, ankles, or legs), which significantly affect patients’ quality of life.¹ Other possible symptoms include a rapid heartbeat, frequent urination at night, difficulties concentrating, weight gain, and a dry cough, although these symptoms are present in other conditions, making it difficult to distinguish HF from other medical conditions, particularly during the early stages.

Depending on symptom severity, HF may go unnoticed or cause only minor symptoms; however, patients with advanced HF may find it difficult to carry out normal everyday activities.⁴ HF leads to a progressive decline in cardiac function over time, with persistent signs and symptoms interspersed with acute episodes of decompensation. Acute decompensated HF is a sudden worsening of the signs and symptoms of HF that often lead to hospitalization or an emergency department visit.⁵ Worsening HF and hospitalization for HF portend a poor prognosis and are associated with an increased risk of mortality and readmissions.⁶ Hospitalizations due to HF are frequent, with 83% of patients hospitalized at least once and 43% of patients are hospitalized 4 or more times after a diagnosis of HF.⁷ Approximately half of patients with HF have a reduced ejection fraction; it is in this population that the evidence base regarding treatment is well established.⁷ It is generally accepted that hospitalization for acute decompensated HF is a powerful predictor of readmission and death after discharge in patients with chronic HF; postdischarge mortality rates are as high as 20%.^5,8 Patients with HF are often afflicted with multiple comorbid conditions, such as hypertension, atrial fibrillation, renal disease, and diabetes mellitus, which contribute to increased morbidity and mortality rates and an impaired quality of life.²¹

Standards of Therapy

The current foundational pharmaceutical management of HF with reduced ejection fraction encompasses combination therapy (in the absence of contraindications), including 1 evidence-based medication from each of the following categories: (1) sacubitril-valsartan, either as first-line therapy or switching from ACEis or ARBs, (2) beta-blockers, (3) MRAs, and (4) SGLT2 inhibitors.⁶ These drug classes, individually and together, have shown improvement in clinical outcomes, including worsening, rehospitalizations and mortality, in patients with HF with reduced ejection fraction. In addition to this standard quadruple therapy, complementary medications benefit important subgroups of patients with HF with reduced ejection fraction, and should be initiated and titrated when indicated.⁶ Recently, new therapies that have emerged, such as sGC stimulators and ivabradine (a sinus node inhibitor), are taken in conjunction with well-established therapies and have shown benefit in HF with reduced ejection fraction.⁶ Other potential therapies for HF with reduced ejection fraction, depending on the situation, include diuretics, digoxin, temporary inotropic therapy, cardiac resynchronization therapy, and implantable cardioverter defibrillators.^2,6 Nonpharmacological measures include lifestyle recommendations for HF with reduced ejection fraction, such as fluid restriction, avoiding salt and alcohol, and regular exercise.^2,6 In general, patients with HF with reduced ejection fraction benefit from lifestyle changes, cardiac rehabilitation attendance, coordinated management with a multidisciplinary team, and pharmacotherapy. According to the clinical expert and clinician groups consulted by CADTH, the goal of HF therapy is to reduce the risk of CV death and HHF, and to improve quality of life.

Drug

Vericiguat is an sGC. HF is associated with impaired NO synthesis and decreased activity of its receptor, sGC. sGC catalyzes the synthesis of intracellular cGMP, an important signalling molecule that regulates critical physiological processes, such as cardiac contractility, vascular tone, and cardiac remodelling. Deficiency in cGMP derived from sGC contributes to myocardial and vascular dysfunction. Vericiguat restores the relative deficiency in this signalling pathway by directly stimulating sGC, independent from and synergistically with NO, to increase the level of intracellular cGMP, which may improve both myocardial and vascular function. Thus, the complementary cardiovascular benefits of vericiguat in patients with HF are associated with the active restoration of the deficient NO-sGC-cGMP pathway.

The vericiguat dossiers were submitted to CADTH as a pre–Notice of Compliance submission, with an anticipated Notice of Compliance date of April 10, 2023. Verquvo (vericiguat) underwent a standard review at Health Canada and obtained a Notice of Compliance on April 28, 2023, for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilized after a recent HF decompensation event requiring hospitalization and/or IV diuretic therapy. Vericiguat should be used in combination with SOC therapy for HF. Vericiguat should be initiated under the supervision of a health care professional who is experienced in the management of HF.⁹ The sponsor’s requested reimbursement criteria for vericiguat are generally aligned with the Health Canada–proposed indication; however, the sponsor added the following initiation criteria to the reimbursement request: in adult patients with chronic HF with NYHA class II to class IV HF; other patients taking other HF therapies that include ACEis or ARNis, ARBs, beta-blockers, and MRAs, if tolerated; and vericiguat should be initiated under the supervision of a health care professional who is experienced in the management of HF.²² Vericiguat is available as 2.5 mg, 5 mg, and 10 mg tablets. The recommended starting dose of vericiguat is 2.5 mg, followed by a doubling of the dose every 2 weeks up to the target maintenance dose of 10 mg administered orally once daily, as tolerated by the patient.⁹

Vericiguat received approval from the FDA in January 2021 to reduce the risk of CV death and HHF after hospitalization for heart failure or the need for outpatient IV diuretics in adults with symptomatic chronic HF and an ejection fraction less than 45%.²³ Vericiguat received approval from the European Medicines Agency in May 2021 for the treatment of symptomatic chronic HF in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event requiring IV therapy.²⁴

Key characteristics of commonly used medical treatments for HF are presented in Table 3.

Table 3: Key Characteristics of Pharmacotherapies for HF (by Drug Class)

ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNi = angiotensin receptor and neprilysin inhibitor; AT1 = angiotensin type 1; bpm = beats per minute; cGMP = cyclic guanosine monophosphate; CV = cardiovascular; HCN = hyperpolarization and cyclic nucleotide; HF = heart failure; HHF = hospitalization for heart failure; I_f = pacemaker current; NA = not applicable; NT-proBNP = N-terminal probrain natriuretic peptide; NYHA = New York Heart Association; PDE-5 = phosphodiesterase type 5; RAAS = renin-angiotensin-aldosterone system; SGLT2 = sodium-glucose cotransporter-2; SOC = standard of care; sGC = soluble guanylate cyclase.

^aHealth Canada–approved indication.

Sources: Product monographs for Verquvo (Bayer Inc.),⁹ Jardiance (Boehringer Ingelheim Ltd.),²⁵ Forxiga (Novartis),²⁶ Entresto,²⁷ Lancora,²⁸ and Canadian Pharmacists Association.^29,30

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full original patient inputs received by CADTH have been included in the stakeholder section at the end of this report.

Two patient groups, the HeartLife Foundation and the Heart Function Clinic in Vancouver General Hospital, St. Paul’s Hospital, British Columbia, provided input for the review of vericiguat. The HeartLife Foundation is a patient-driven federal charity whose mission is to transform the quality of life of people living with HF by engaging, educating, and empowering a global community to create lasting solutions and build healthier lives. The input was informed by interviews with 3 HF specialists (British Columbia, Ontario, and Quebec), 1 researcher (Alberta), and 2 patients with HF (British Columbia and Ontario), as well as the review of study material and online literature.

The HeartLife Foundation indicated that patients with HF experience a wide range of physical, social, and emotional challenges. Symptoms include shortness of breath, extreme fatigue, low blood pressure, dizziness, edema, bloating, palpitations, and arrhythmia. Moreover, HF is associated with comorbidities, including anxiety, depression, and a decline in cognitive function, that can have a negative impact on mental health. The HeartLife Foundation highlighted that access to care, medical therapies, and support services vary widely across Canada, and that every individual’s experience with HF is unique.

Two patient interviews (ages 33 and 44 years; 1 male and 1 female) highlighted the impact of HF on their quality of life, including being unable to pursue their desired career and exercise regularly. A recurring theme in the 2 patient interviews was the need to find a “new normal” for life after their diagnosis of HF. The HeartLife Foundation stated that there is currently no cure for HF and, if left untreated, the condition will progress over time; however, medical therapies and lifestyle changes can help patients manage their HF. The Heart Function Clinic highlighted the following gaps in the treatment of HF: not all patients respond to available treatments and patients become refractory to existing treatment options. Respondents from the HeartLife Foundation noted that the current standard therapy includes ARNis (as first-line therapy or after ACEi or ARB titration), beta-blockers, MRAs, and SGLT2 inhibitors.

An interview with 1 patient whose HF treatment included a medication plan (beta-blocker, Lasix, and Entresto), a healthy diet, and cardiac rehabilitation, reported that his HF worsens 40% of the time. The patient expressed a desire to be stable 100% of the time and avoid the 40% of the time he feels unwell and has to be hospitalized. No patient interviewees reported experience with vericiguat. The HeartLife Foundation indicated that patients with HF seek to improve their quantitative and qualitative outcomes. The HeartLife Foundation further emphasized that it is imperative to provide equitable access to high-quality care and services for all patients with HF, including access to diagnostics, medical therapy, mental health support, cardiac rehabilitation, and advanced care. The HeartLife Foundation advocated for vericiguat to be approved for the indication under review and suggested that vericiguat will help alleviate the gaps in current therapy.

Clinician Input

Input From Clinical Expert Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of HF.

Unmet Needs

The clinical expert consulted by CADTH for this review indicated that HF with reduced ejection fraction is associated with increased rates of death and the need for hospitalization even with standard quadruple therapy. The clinical expert highlighted that not all patients are eligible for standard quadruple therapy due to side effects, contraindications, or comorbidities, and some patients who experience disease progression while on standard therapy may require de-escalation of therapy to become restabilized.

Place in Therapy

The clinical expert consulted indicated that vericiguat can be added to foundational quadruple HF therapy, as its mechanism of action differs from that of the foundational medications. It was further noted by the clinical expert that the impact or role of vericiguat in the context of current quadruple therapy is unknown because the VICTORIA trial was designed and completed before the current therapeutic paradigm, such as SGLT2 inhibitors, was widely adopted.

Patient Population

The clinical expert consulted indicated that patients included in the VICTORIA trial received background dual or triple HF therapy and generally tended to be “sicker” than those included in HF trials with other therapies. The clinical expert noted that patients with more advanced disease may benefit the most.

Assessing Response to Treatment

The clinical expert indicated that the response to therapy in clinical practice is assessed based on reduction in burden of symptoms, need for IV diuretic therapy, hospitalization, or death.

Discontinuing Treatment

The clinical expert identified the following factors to consider when deciding to discontinue treatment with vericiguat: symptomatic hypotension and disease progression (need for transplant, left ventricular assist device [LVAD], or palliation).

Prescribing Conditions

The clinical expert indicated that vericiguat should be prescribed by a practitioner with expertise in the management of HF in specialty clinics with a focus on the assessment and management of HF.

Additional Considerations

The clinical expert noted that although the role of vericiguat in the management of HF with reduced ejection fraction in patients receiving quadruple therapy is uncertain, given the mechanism of action of vericiguat, the addition of this medication is expected to have a positive impact on the management of patients who have worsened while taking foundational quadruple therapy.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by the clinician group. The full original clinician group inputs received by CADTH have been included in the stakeholder section at the end of this report.

The clinician group input was obtained from 3 sources: Oakville Cardiologists, represented by 9 clinicians; 1 clinician from the Division of Cardiology, University of Alberta; and 1 clinician representing the North Shore Heart Centre in Vancouver. The Oakville Cardiologists is a cardiology group practising in Oakville, Ontario, that meets regularly to share best practices and collaborate on research and educational projects to improve the care of patients with cardiovascular disease.

The Oakville Cardiologists and the clinician from the Division of Cardiology, University of Alberta, indicated that patients with HF with reduced ejection fraction should be treated with 4 standard therapies: ARNis either as first-line therapy or switching from ACEis or ARBs; beta-blockers; MRAs; and SGLT2 inhibitors. This GDMT is indicated to reduce morbidity and mortality, as well as improve quality of life. The clinician groups agreed that for patients with HF with reduced ejection fraction who are in sinus rhythm (heart rate greater than 70 beats per minute) and remain symptomatic despite treatment with GDMT, ivabradine is also prescribed to prevent CV death and HHF. In addition, 2 nonpharmacologic interventions are often considered for patients with HF with reduced ejection fraction, including implantable cardioverter defibrillator therapy and cardiac resynchronization therapy.

The clinician from the Division of Cardiology, University of Alberta, identified the following as key goals of new therapies in HF: reducing recurrent symptoms and the need for hospitalization or emergency department visits. All clinical groups agreed that morbidity and mortality rates remain high in patients with HF with reduced ejection fraction despite advancements in therapies, and many patients cannot be titrated to the optimal doses of the medications due to hypotension, hyperkalemia, bradycardia, and renal dysfunction. The clinical groups agreed that vericiguat represents an additional approach to the treatment of HF with reduced ejection fraction, which is not targeted by the current GDMT. The clinician from the Division of Cardiology, University of Alberta, also suggested that because vericiguat does not cause hyperkalemia or impair renal function, patients who cannot tolerate ARNis or ACEis (e.g., patients with diabetes or renal impairment) would be good candidates for vericiguat.

The clinician groups consulted noted that vericiguat would be prescribed for patients with HF with reduced ejection fraction on optimal therapy who develop worsening symptoms or who needed HHF in the past 6 months to reduce CV death or first HHF; this was identified as a high-risk patient population by the clinician groups. The clinician groups pointed out several reasons that may lead to the discontinuation of vericiguat, including a decline in the glomerular filtration rate to less than 15 mL/min/1.73 m², severe hypotension, and syncope. The Oakville Cardiologists indicated that physician assessment of clinical stability and patient-reported symptoms continue to be the cornerstone of evaluating response to therapy in patients with HF with reduced ejection fraction in the outpatient setting. The clinical groups advocated for vericiguat to be an accessible treatment option for the high-risk HF patient population, as it is safe, well tolerated, and taken once daily.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical expert consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNi = angiotensin receptor–neprilysin inhibitor; BIA = budget impact analysis; BNP = brain natriuretic peptide; CDEC = CADTH Canadian Drug Expert Committee; CV = cardiovascular; HF = heart failure; HHF = hospitalization for heart failure; MRA = mineralocorticoid receptor antagonist; NT-proBNP = N-terminal pro-brain natriuretic peptide; SGLT2 = sodium-glucose cotransporter-2; SOC = standard of care.

Clinical Evidence

The clinical evidence included in the review of vericiguat is presented in 2 sections. The first section, the Systematic Review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as studies that were selected according to an a priori protocol. The second section includes indirect evidence selected from the literature that met the selection criteria specified in the review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

A systematic review was performed to assess the beneficial and harmful effects of vericiguat 10 mg once daily when used to reduce the risk of CV death and HHF in adults with symptomatic chronic HF and an ejection fraction of less than 45% who are stabilized after a recent worsening HF event, in combination with other HF therapies.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

ACEi = angiotensin-converting enzyme inhibitor; AE = adverse event; ARB = angiotensin receptor blocker; BNP = brain natriuretic peptide; CV = cardiovascular; HF = heart failure; HHF = hospitalization for heart failure; HRQoL = health-related quality of life; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; NT-proBNP = N-terminal probrain natriuretic peptide; NYHA = New York Heart Association; RCT = randomized controlled trial; SAE = serious adverse event; SGLT2 = sodium-glucose cotransporter-2; WDAE = withdrawal due to adverse event.

^aHF hospitalization within 6 months before randomization.

^bIV diuretic treatment for HF (without hospitalization) within 3 months before randomization.

The literature search was performed by an information specialist using a peer-reviewed search strategy in accordance with the PRESS Peer Review of Electronic Search Strategies checklist.³¹

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Verquvo (vericiguat) and heart failure. The following clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

If filters were used, CADTH-developed search filters were applied to limit retrieval to RCTs or controlled clinical trials. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on November 10, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee (CDEC) on March 22, 2023.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.³² Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy. These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Findings From the Literature

A total of 195 studies were identified from the literature for inclusion in the systematic review (Figure 1). A total of 3 reports^10,33,34 of 1 study were included in the systematic review. The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Table 6: Details of the VICTORIA Trial

AE = adverse event; BNP = brain natriuretic peptide; CABG = coronary artery bypass grafting; CV = cardiovascular; eGFR = estimated glomerular filtration rate; HF = heart failure; HHF = hospitalization for heart failure; KCCQ = Kansas City Cardiomyopathy Questionnaire; LV = left ventricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; NSTEMI = non–ST elevation myocardial infarction, NT-proBNP = N-terminal probrain natriuretic peptide; NYHA = New York Heart Association; PCI = percutaneous coronary intervention; PDE5 = phosphodiesterase type 5; SBP = systolic blood pressure; STEMI = ST elevation myocardial infarction; TIA = transient ischemic attack.

^aNo more than approximately 20% of patients will be randomized with a qualifying HF hospitalization > 3 months before randomization.

^bBNP cannot be used to determine eligibility for inclusion in patients on sacubitril-valsartan because sacubitril-valsartan led to an increase of approximately 15% in median BNP in the PARADIGM-HF trial. NT-proBNP must be used to confirm eligibility for patients taking sacubitril-valsartan.

^cMost recent measurement must be used to determine eligibility.

^dCoadministration of short-acting nitrates (i.e., sublingual nitroglycerin spray as indicated for angina attacks) is allowed.

^eNo more than approximately 15% of patients will be enrolled with an eGFR in the 15 mL/min/1.73 m² to 30 mL/min/1.73 m² range.

^fThis wording is from original study.

^gScreening could start as early as at time of hospitalization or upon IV diuretic treatment for HF. Screening visit and randomization (visit 2) could occur on the same day if the patient is clinically stable, defined as having not received IV treatment for more than 24 hours and having SBP greater than or equal to 100 mm Hg. In this case, all procedures specified for visit 2 were done after informed consent was given and replaced screening visit procedures.

^hIt was an event-driven trial and was to stop once the required number of CV death events was reached.

ⁱAll patients were contacted by phone within 14 days ( + 1 week) of the final visit to assess for clinical events, AEs, and vital status (if applicable).

Source: Clinical Study Report for VICTORIA.¹⁰

Description of the VICTORIA Trial

One sponsor-conducted trial (VICTORIA)¹⁰ that met the CADTH review protocol criteria was included in this systematic review (Table 5). Study-specific details are included in Table 6. A schematic of the trial is presented in Figure 2.

The VICTORIA trial was a phase III, randomized, multicentre, double-blind, event-driven, placebo-controlled trial designed to assess the efficacy and safety of vericiguat versus placebo as an adjunct to SOC therapy in adults with symptomatic chronic HF and ejection fraction less than 45% who are stabilized after a recent worsening HF event. A previous HF decompensation (or worsening) event was defined as HHF within 6 months before randomization or the use of an IV diuretic for HF (without hospitalization) within 3 months before randomization. No more than 20% of patients with previous HF decompensation that occurred more than 3 months before randomization were to be enrolled in the VICTORIA trial. A total of 5,050 patients with symptomatic chronic HF with reduced ejection fraction were enrolled across 694 sites in 42 countries in North America (560 patients), Eastern Europe, Western Europe, the Asia-Pacific region, and Latin and South America. The primary efficacy end point was the time to first event of CV death or HHF, and the key secondary end points were time to CV death, time to first event of HHF, time to total events (first and recurrent) of HHF, time to first event of all-cause mortality or HHF, and time to all-cause mortality. HRQoL was assessed using the KCCQ and the EQ-5D instrument. Futility and efficacy interim analyses were planned at the time when approximately 75% of the planned number of CV death events (587 events) was reached, and the data safety monitoring board could recommend early termination of the trial for overwhelming efficacy or futility. The database lock was executed on October 31, 2019.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Randomization, Treatment Allocation, and Blinding

An Interactive Voice Response System and Integrated Web Response System methodology was used to randomly assign patients in a 1:1 ratio to receive vericiguat at a dose of 2.5 mg, 5.0 mg, or 10 mg once daily (N = 2,526) or to receive matching placebo (N = 2,524). Randomization was stratified by geographic region and race. The stratification variable race was nested within the North America region as North America (Black) and North America (non-Black). As a result of the combination of these 2 stratification variables, patients were randomized into 6 different strata, as follows: Eastern Europe (including Israel and South Africa), Western Europe, North America (Black), North America (non-Black), Latin and South America, and the Asia-Pacific region (including Australia). Both patients and investigators were blinded to the study treatments administered during the trial.

Study Phases

Screening Phase

In the VICTORIA trial, patients were randomized within 30 days of the screening period. The screening visit could begin at the time of hospitalization (or after IV diuretic treatment for HF without hospitalization) and up to 30 days before randomization (visit 2). The screening visit and randomization (visit 2) could occur on the same day if the patient was clinically stable, defined as not receiving IV treatment for more than 24 hours and having systolic blood pressure greater than or equal to 100 mm Hg. In addition, evidence was provided that LVEF was less than 45% within 12 months before randomization (the most recent measurement should be used).

Treatment Phase

The VICTORIA trial was an event-driven trial and was to stop once the required number of CV death events was reached. Thus, the duration of the double-blind treatment phase was different for each patient. After the 4-week titration phase, during which the starting dose (2.5 mg) of the study medication was up-titrated to the target dose of 10 mg, patients were assessed at week 16 and then every 4 months until the end of the trial. The final visit was conducted for all patients when the planned number of CV death events was reached and the efficacy cut-off was announced. If applicable, patients continued to take the study medication until the final visit and were asked to stop taking the study drug medication during that visit. An independent data and safety monitoring committee was responsible for reviewing the safety and efficacy data approximately every 3 to 6 months throughout the trial. Discontinuation visits were conducted at the time of permanent treatment discontinuation to collect information on clinical events, AEs, and other clinical and laboratory procedures.

Follow-Up Safety Phase

Within 14 days after the last dose of study medication, all patients who discontinued the study drug prematurely had an in-clinic safety follow-up visit. Thus, patients who permanently discontinued the study drug were still followed up for clinical events and vital status until study completion. If the patients did not attend the study visit, a telephone contact would be made to collect information on protocol-defined end point events.

Protocol Amendments

Several modifications were made to the study protocol after the start of patient recruitment that were documented in the Clinical Study Report. The amendments dated June 15, 2016, included: exclusion of patients with intestinal lung disease, exclusion of patients who are breastfeeding or plan to breastfeed during the course of the trial, and addition of echocardiography and cardiac MRI assessments. The amendments dated December 20, 2017, included: addition of the indication that futility analysis would be performed at 75% of CV death events, revision of the futility analysis approach and bounds, addition of the minimal NP cut-off points for sinus rhythm and atrial fibrillation, clarification of the inclusion and exclusion criteria related to pregnancy, addition of the Canadian Cardiovascular Society functional classification of angina to trial flow chart, and addition of instruction regarding the pulse rate assessment at the randomization visit.

Figure 2: Study Schema for the VICTORIA Trial

HF = heart failure.

Source: Clinical Study Report for VICTORIA.¹⁰

There were several modifications to the statistical analysis plan for the study that were documented in the statistical analysis plan amendments. The amendments dated March 8, 2017, included addition of the days alive and out of HHF as an additional exploratory end point, addition of subgroup analyses for CV death and HHF, and addition of baseline ejection fraction as a subgroup. The amendments dated October 22, 2019, included addition of the exploratory end point of time to the first occurrence of the composite of CV death, myocardial infarction (MI) hospitalization, and stroke hospitalization; addition of a subsection to describe intention to withdraw analysis; addition of a subsection to discuss the approaches for randomization errors; addition of the censoring rule for time-to-event end points; addition of the imputation rule for partial death dates; addition of a description of on-treatment analysis of efficacy end points; and removal of subsections related to interim analysis approaches.

Populations

Inclusion and Exclusion Criteria

The key inclusion and exclusion criteria applied to the VICTORIA trial are summarized in Table 6. Briefly, patients eligible for enrolment in the VICTORIA trial were adults with symptomatic chronic HF with reduced ejection fraction; NYHA class II, class III, or class IV HF; and receipt of guideline-recommended SOC therapy. Patients were also required to have elevated levels of NPs (i.e., NT-proBNP ≥ 1,000 pg/mL or BNP ≥ 300 pg/mL for patients in sinus rhythm), previous HF decompensation defined as HHF within 6 months before randomization or receiving IV diuretic therapy for HF within 3 months before randomization. No more than 20% of patients were to be randomized with a qualifying HHF more than 3 months before randomization. Patients were excluded from the VICTORIA trial if they were clinically unstable within 24 hours before randomization, defined as the administration of any IV treatment and/or systolic blood pressure less than 100 mm Hg, or symptomatic hypotension. Patients with cardiac comorbidities (i.e., hypertrophic obstructive or post–heart transplant cardiomyopathy, acute coronary syndrome) or noncardiac comorbidities (i.e., chronic dialysis, hepatic insufficiency, malignancy) were excluded from the VICTORIA trial.

Baseline Characteristics

A summary of baseline characteristics is presented in Table 7. Baseline characteristics were well balanced between the treatment arms. The mean age of all randomized patients in the VICTORIA trial was 67.3 years (SD = 12.2 years). A total of 76.1% of patients were male, and 24.0% were female. About 64.1% of patients were white, and 27.0% were Asian or multiracial. A total of 81.4% of patients were non-Hispanic or non-Latino, and 16.1% were Hispanic or Latino. The mean LVEF was 28.9% (SD = 8.30%), and nearly half of patients had an LVEF of less than 30% (49.3%). Most patients had NYHA functional class II and class III HF (98.6%) at baseline. The mean NT-proBNP was 4,741.90 pg/mL (SD = 6,845.60 pg/mL), the mean BNP was ||||||| pg/mL (SD = |||||||| pg/mL), and the mean eGFR was 61.5 mL/min/1.73 m² (SD = 27.2 mL/min/1.73 m²). Approximately 70% of patients had HHF within 3 months before randomization, 17.2% had HHF within 3 to 6 months before randomization, and 15.9% received outpatient treatment with IV diuretics for worsening HF within 3 months before hospitalization. The mean time from a diagnosis of HF to randomization was 4.8 years (SD = 5.4 years), and the mean time from the index event (hospitalization or use of an IV diuretic for HF) to randomization was 50.2 days (SD = 46.57 days). Patients received the following previous HF medications at the start of the VICTORIA trial: ACEis or ARBs (73.4%), beta-blockers (93.1%), MRAs (70.3%), and sacubitril-valsartan (14.5%). A total of 91.2% of patients received 2 or more HF medications, and only 60% of patients received triple therapy, including ACEis or ARBs, beta-blockers, and MRAs. Almost half of the patients were diagnosed with diabetes mellitus (46.9%) at baseline, and about 52.8% had a history of atrial fibrillation or flutter.

Table 7: Summary of Baseline Characteristics — ITT Population

ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BNP = brain natriuretic peptide; CCSA = Canadian Cardiovascular Society Functional Classification of Angina; eGFR = estimated glomerular filtration rate; HF = heart failure; HHF = hospitalization for heart failure; ICD = implantable cardioverter defibrillator; ITT = intention to treat; MRA = mineralocorticoid receptor antagonist; NT-proBNP = N-terminal prohormone brain natriuretic peptide; NYHA = New York Heart Association; SD = standard deviation; SOC = standard of care.

^aIV diuretic for HF (without hospitalization).

Source: Clinical Study Report for VICTORIA.¹⁰

Interventions

All eligible patients were randomized in a 1:1 ratio to receive vericiguat or matching placebo, administered orally once daily with food. The vericiguat and placebo tablets were identical in packaging and labelling. Treatment was started with a starting dose of 2.5 mg, followed by 2 dose doublings every 2 weeks to the target dose of 10 mg. In the phase IIb SOCRATES-REDUCED trial,³⁵ vericiguat doses from 1.25 mg up to a target dose of 10 mg were examined in patients with worsening chronic HF with reduced ejection fraction. Vericiguat at a dose of 1.25 mg was confirmed as a “no effective dose” and had an overall profile comparable to placebo. Vericiguat at a dose of 2.5 mg was associated with a first-dose systolic blood pressure–lowering effect of approximately 3 mm Hg, and was defined as the “minimally effective dose.” The 10 mg target dose of vericiguat reduced NT-proBNP level and was well tolerated, compared to placebo.³⁵ The blood pressure criterion for dose up-titration was a systolic blood pressure greater than or equal to 100 mm Hg. The titration steps included a sham titration in the placebo group. Dose assessments were performed at all scheduled and unscheduled visits when blood pressure was assessed. Dose modifications were based on mean systolic blood pressure, the absence of symptoms indicative of hypotension, and the investigator’s discretion (Table 8). Reasons for dose modifications were recorded at all scheduled and unscheduled visits. All attempts were made to resume the study treatment after a temporary interruption (during the titration phase or after 28 days) and to reach and maintain the target dose of the study treatment when deemed medically appropriate by the investigator. There was no defined maximum time limit for temporary treatment interruption.

Table 8: SBP Criteria for Study Treatment Dose Modification

SBP = systolic blood pressure.

Source: Clinical Study Report for VICTORIA.¹⁰

All patients should receive guideline-recommended SOC therapy for HF, including beta-blockers, ACEis, ARBs, MRAs, sacubitril-valsartan, and cardiac device therapies, such as implantable cardioverter defibrillators and biventricular pacemakers. Prohibited concomitant treatments included long-lasting nitrates or NO donors (i.e., isosorbide 5-mononitrate, pentaerythritol tetranitrate), phosphodiesterase type 5 (PDE5) inhibitors (i.e., vardenafil, tadalafil, or sildenafil), and sGC stimulators (i.e., riociguat).

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 9. These end points are also further summarized subsequently. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Efficacy Outcomes

The primary composite end point of the VICTORIA trial was the time to first event of adjudicated CV death or HHF.

The CEC performed an adjudication of the following outcomes occurring after randomization: reported death (CV and non-CV death), CV hospitalizations, and urgent HF visits.

CV death included:

• death due to HF, which refers to a death associated with clinically worsening symptoms and/or signs of HF, regardless of HF etiology

• death due to acute MI, which refers to a death from any CV mechanism (e.g., arrhythmia, sudden death, HF, stroke, pulmonary embolus, peripheral arterial disease) at least 30 days after an MI related to the immediate consequences of the MI, such as progressive HF or recalcitrant arrhythmia. Death resulting from a procedure to treat an MI, (e.g., percutaneous coronary intervention, coronary artery bypass grafting) or to treat a complication resulting from an MI was also considered a death due to acute MI.

• sudden cardiac death, which refers to a death

  • occurring without new or worsening symptoms

  • witnessed within 60 minutes of the onset of new or worsening cardiac symptoms, unless the symptoms suggest acute MI

  • witnessed and attributed to an identified arrhythmia

  • after unsuccessful resuscitation from cardiac arrest

  • after successful resuscitation from cardiac arrest and without identification of a specific cardiac or noncardiac etiology

  • unwitnessed death in a person seen alive and clinically stable at least 24 hours before being found dead without any evidence supporting a specific non-CV cause of death.

• death due to stroke, which refers to a death after a stroke that is either a direct consequence of the stroke or a complication of the stroke

• other CV causes, which refer to a CV death not included in the previous categories but with a specific, known cause

• undetermined cause of death, which refers to a death not attributable to any of the previous categories of CV death or to a non-CV cause.

Secondary end points in the VICTORIA trial included time to CV death, time to first event of HHF, time to total (first and recurrent) HHF events, time to all-cause mortality or HHF, and time to all-cause mortality.

Non-CV death was defined as any death with a specific cause that is not thought to be CV in nature.

CV hospitalization: The duration of the patient's stay in the hospital or emergency department was at least 24 hours and was unplanned. If death occurred within 24 hours after hospitalization, that event was considered a death and not a hospitalization.

CV hospitalization was defined as an event that met all the following criteria:

• HHF

  • the patient was admitted to the hospital or emergency department with a primary diagnosis of HF

  • the patient’s length of stay in hospital or emergency department extended for at least 24 hours

  • the patient exhibited new or worsening symptoms due to HF on presentation

  • the patient had objective evidence of new or worsening HF, consisting of at least 2 physical examination findings or 1 physical examination finding and at least 1 laboratory criterion

  • the patient received initiation or intensification of treatment specifically for HF (i.e., IV diuretic, mechanical or surgical intervention).

• Hospitalization for MI, defined as a patient demonstrating at least 1 biochemical indicator of myocardial necrosis.

• Hospitalization for stroke, defined as an acute episode of focal or global neurologic dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction —

  • ischemic stroke

  • hemorrhagic stroke

  • undetermined stroke.

• Other CV hospitalizations, defined as urgent and unscheduled hospitalization for CV causes that do not meet the criteria for the specific events listed here.

Table 9: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

CV = cardiovascular; HF = heart failure; HHF = hospitalization for heart failure; KCCQ = Kansas City Cardiomyopathy Questionnaire, NT-proBNP = N-terminal probrain natriuretic peptide; NYHA = New York Heart Association.

Source: Clinical Study Report for VICTORIA.¹⁰

Patient-Reported Outcomes

In addition to the clinical end points, HRQoL was measured in the VICTORIA trial using the KCCQ and EQ-5D instrument.

Kansas City Cardiomyopathy Questionnaire

The KCCQ is a self-administered, 23-item, disease-specific questionnaire used to measure HRQoL in patients with HF over a 2-week recall period. Items are categorized into the following 7 domains: symptom frequency; symptom burden; symptom stability; physical limitations; social limitations; quality of life; and self-efficacy. The questionnaire is scored by assigning each item an ordinal value, beginning with 1 as the lowest level of functioning, then summing all items within each domain and transforming the value to a 0- to 100-point scale. Missing values are assigned the average score of the answered items in the same domain.³⁶ Lower scores indicate greater symptom severity and limitations, whereas a score of 100 would indicate no symptoms, no limitations, and excellent HRQoL. Additionally, the KCCQ scores can be summarized in 25-point health status ranges, where 0 to 24 represent very poor to poor, 25 to 49 represent poor to fair, 50 to 74 represent fair to good, and 75 to 100 represent good to excellent health status.³⁷ To improve the interpretation of the questionnaire results, summary scores were developed. The KCCQ total symptom score comprises the symptom frequency and symptom severity domains. The KCCQ clinical summary score comprises the physical limitation, symptom frequency, and symptom severity domains. The KCCQ overall summary score comprises the physical limitation, symptom frequency, symptoms severity, HRQoL, and social limitation domains.^36,37

The KCCQ questionnaire is generally a valid, reliable, and responsive instrument for CV diseases, including HF. Convergent validity was demonstrated in patients with HF with reduced ejection fraction (defined as an LVEF of less than 40%) (N = 129).³⁶ The Spearman’s rank correlation coefficient for the KCCQ physical limitation domain ranged from 0.48 for the 6-minute walk test (6MWT) to 0.84 for the 36-Item Short Form Survey (SF-36) physical limitation domain; for the KCCQ quality-of-life domain, the correlation ranged from 0.45 for the SF-36 general health perception domain to –0.64 for NYHA class; for the KCCQ social limitation domain, the correlation was –0.57 for NYHA class and 0.62 for the SF-36 social functioning domain.³⁶ Construct validity of the KCCQ physical limitation domain in patients with HF was demonstrated by the correlation coefficient that ranged from 0.48 for the 6MWT to 0.84 for the SF-36 physical functioning domain, and for the KCCQ social limitation domain, the correlation coefficient was 0.59 to 0.62 for the SF-36 social functioning domain.³⁸ For internal consistency, the Cronbach alpha was 0.62 for the KCCQ self-efficacy score, 0.78 for the KCCQ quality-of-life score, 0.86 for the KCCQ social limitation score, 0.88 for the KCCQ total symptoms score, 0.90 for the KCCQ physical limitation score, 0.93 for the KCCQ clinical summary score, and 0.95 for the KCCQ overall summary score in patients with HF with reduced ejection fraction (defined as an LVEF of less than 40%) (N = 39).³⁶ For test-retest reliability, no differences were found in the mean domain or summary scores between baseline and 3-month follow-up.³⁶ Guyatt’s responsiveness statistic was 0.62 for the KCCQ social limitation domain, 0.83 for the KCCQ self-efficacy domain, 0.86 for the KCCQ quality-of-life score, 1.48 for the KCCQ physical limitation score, 1.74 for the KCCQ overall summary score, 2.62 for the KCCQ symptom stability score, 2.77 for the KCCQ clinical summary score, and 3.19 for the KCCQ symptom frequency and severity domain.³⁶

The relationship between KCCQ and 6MWT and peak oxygen consumption (VO₂) in patients with HF with reduced ejection fraction (defined as LVEF of less than 35%) (N = 2,331) was assessed in Flynn et al. (2009).³⁹ The authors of that study by Flynn et al. (2009)³⁹ concluded that the results generally supported the need for a 5-point difference in the KCCQ between patients to be clinically meaningful. In another study, Spertus et al. (2005)⁴⁰ described the relationship between measures of disease status, and clinically observed changes in patients with HF with reduced ejection fraction (defined as LVEF of less than 40%) using clinical change assessed by a cardiologist on a 15-point Likert scale, which ranged from extremely worse to extremely better, and grouped into categories of change (N = 476).⁴⁰ When the KCCQ overall summary score was assessed at baseline and at 6 weeks, a mean improvement of 5.7 points (SD = 16) was associated with a small improvement in HF, and a mean decline of 5.3 points (SD = 11) was associated with a small deterioration in HF.⁴⁰

5-Level EQ-5D Instrument

The EQ-5D-5L is a generic self-reported HRQoL outcome measure that can be applied to a variety of health conditions and treatments. The EQ-5D-5L was developed by the EuroQol Group as an improvement to the 3-Level EQ-5D (EQ-5D-3L) to measure small and medium health changes and reduce ceiling effects.³⁹ The instrument comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on 5 levels: level 1 “no problems,” level 2 “slight problems,” level 3 “moderate problems,” level 4 “severe problems,” and level 5 “extreme problems” or “unable to perform.”^41,42 A total of 3,125 unique health states are possible, with 55555 representing the worst health state and 11111 representing the best state. The corresponding scoring of EQ-5D-5L health states is based on a scoring algorithm derived from preference data obtained from interviews using choice-based techniques (e.g., time trade-off) and discrete choice experiment tasks.^41,42 The lowest and highest scores vary depending on the scoring algorithm used. Scores less than 0 represent health states that are valued by society as being worse than dead, whereas scores of 0 and 1.00 are assigned to the health states “dead”’ and “‘perfect health,” respectively. As an example, a Canadian scoring algorithm results in a score of –0.148 for health state 55555 (worst health state) and a score of 0.949 for health state 11111 (best health state).^41,42 Another component of the EQ-5D-5L is a visual analogue scale (EQ VAS), which asks respondents to rate their health on a visual scale from 0 (worst health imaginable) to 100 (best health imaginable).

The literature search completed by CADTH did not find any evidence on the validity, reliability, responsiveness, and MID of the EQ-5D-5L questionnaire in patients with HF, although a Canadian-specific MID of 0.037 has been reported for the EQ-5D-5L.^41,42

Harms

The safety outcomes assessed in the VICTORIA trial were:

• AEs

• SAEs

• AEs leading to discontinuation of the investigational drug

• AEs of special interests, including syncope, symptomatic hypotension, and elevated aspartate aminotransferase and alanine transaminase values

• pharmacokinetic and pharmacodynamic measurements.

Statistical Analysis

The statistical analysis of efficacy end points conducted in the VICTORIA trial is summarized in Table 9.

Sample Size Calculations

In the VICTORIA trial, the sample size calculation was driven by the CV death component of the composite primary end point. At least 782 CEC-confirmed CV death events in the ITT population were required to achieve an 80% power at a study-wise 1-sided significance level of 0.025. The sponsor estimated that at least 4,872 patients needed to be enrolled to achieve the required number of events, assuming a yearly CV death event rate in the placebo group of 11%,⁴³ an accrual period of approximately 30 months, and a median follow-up period of 10 months. With this sample size, 1,561 patients with a primary end point event were expected to be followed, with a power of approximately 98%, to test the primary hypothesis. The yearly dropout rate was assumed to be 2%. In addition, approximately 10% of patients per year were expected to discontinue the study drug, but they could be followed after discontinuation of treatment for the primary end point. A true HR of 0.8 between vericiguat and placebo was considered to be a clinically relevant treatment effect for the primary composite end point in the planned high-risk population.

Interim and Final Analyses

One futility interim analysis to assess lack of efficacy was to be performed approximately 27 months after the start of the study, when approximately 50% (781 events) of the planned number of primary end point events was observed. One efficacy interim analysis was to be performed approximately 33 months after the start of the study, with a median follow-up of 10 months, when approximately 75% of the planned number of CV death events (587 events) as a component of the composite primary end point was observed. The Hwang, Shih, and DeCani alpha spending function was to be used to assess the superiority of vericiguat. However, the decision was made to cancel the interim analysis because the number of CV death events was higher than expected. Accordingly, no multiplicity adjustment for the interim analysis was applied, and a 1-sided significance level of 0.025 was used for all hypothesis testing at the final analysis. A final analysis was to be performed approximately 39 months after the start of the study, with a median follow-up of 10 months, when approximately 782 CV deaths were observed.

Analysis of Outcomes

Primary Outcome

In the VICTORIA trial, the analysis of the composite end point of time to first event of CV death or HHF was performed using a 1-sided stratified log-rank test, stratified by geographic region and race considered for randomization. Only the adjudicated and confirmed events were included in the primary analysis. This analysis was based on the ITT population (described subsequently), comprised of all randomized patients. The overall study-wise 1-sided type I error rate was controlled at 0.025. Kaplan-Meier estimates of the primary composite end point (95% CI) survival curves were presented for each treatment group. HR, RR reduction, and corresponding 95% CIs were estimated using a Cox proportional hazards model, controlled by stratification factors (geographic region and race). The proportional hazards assumption between treatments in the models were assessed with ZPH tests for nonproportional hazards, and no evidence of any nonproportional hazard of treatments was found for any of the transitions. The number and proportion of patients with CV death or HHF events and rates per 100 patient-years were provided by treatment group. The time to event was derived from the date of randomization. A patient with at least 1 event (CV death or HHF) was considered to have an event, and the date of the first event was used for the composite end point analysis. Patients without a specific end point event were censored based on the date of their non-CV death, last available information for the primary end point event, or the primary completion date (June 18, 2019), whichever was earliest. The component of the primary end point was also summarized. If a patient’s first HHF and CV death occurred on the same day, the CV death was considered to be the component that contributed to the primary end point.

Of the subgroups listed in the CADTH review protocol, the following subgroups were prespecified in the VICTORIA trial:

• ejection fraction (LVEF < 35% versus ≥ 35%, and LVEF < 40% versus ≥ 40%)

• NYHA class (class I or II or class III or IV)

• renal function (eGFR ≤ 30 mL/min/1.73 m² versus eGFR between 31 and 60 mL/min/1.73 m² and versus eGFR > 60 mL/min/1.73 m²)

• index event (IV diuretic within 3 months of randomization versus hospitalization within 3 months of randomization, and versus hospitalization within 3 to 6 months before randomization)

• prior use of sacubitril-valsartan (yes versus no)

• baseline NT-proBNP by quartiles.

The subgroup analyses for the primary composite end point and its components, time to CV death and time to first HHF, were performed using a Cox proportional hazards model. There were no adjustments made for multiplicity; as such, all subgroup analyses are exploratory in nature. A between-group treatment effect with a nominal 95% CI for these end points was estimated within each category. Forest plots were created, including interaction P values for treatment-by-subgroup interactions.

Sensitivity Analysis

On-treatment analyses were performed on the primary composite end point, as approximately half of the patients were no longer receiving the study drug by the end of the trial. This analysis included all randomized patients who received the study drug. Efficacy measurement or follow-up from the date of first dose of the study drug to 14 days after the last dose of the study drug was included in the on-treatment analysis.

Secondary Outcomes

The secondary end points were separated into 2 families. The first family included the time to CV death and time to first HHF, and these were tested without multiplicity adjustment.

The end points of the second family, including time to total events (first and recurrent) of HHF, time to first event of all-cause mortality or HHF, and time to all-cause mortality, were analyzed using a 1-sided stratified log-rank test. The time to total events of HHF was analyzed using the Andersen-Gill model, and treatment group and the stratification factors used for randomization were included in the model as fixed effects. In addition, the marginal approach of Wei, Lin, and Weissfeld method was used for analysis of the time to total events of HHF, including all patients included in the ITT analysis, assuming each patient is simultaneously at risk for each type of event (sensitivity analysis). A Cox regression model with covariates for treatment and stratification factors was used to estimate the HR for each type of event. Subgroup analyses were carried out; however, there were no adjustments made for multiplicity. The sensitivity on-treatment analysis of the secondary outcomes included all randomized patients who received the study drug.

For end points defined as time to a nonfatal event or composite end points defined as time to both fatal and nonfatal events, censoring time was the date of last study follow-up (excluding follow-up for vital status only). If a patient died during the study but the death was not part of the end point (i.e., non-CV death for the primary end point), and the death occurred in the 4 months after the last study follow-up (excluding vital status only follow-up), the date of the non–end point death was considered as the last follow-up date. If the non–end point death occurred more than 4 months after the last study follow-up (excluding vital status only follow-up), the date of follow-up before death was considered as last follow-up date. For end points defined as time to a fatal event, the censoring time was the date of the last study follow-up, including follow-ups for vital status only.

A fixed-sequence hierarchical resting approach was used to test the secondary end points from the second family to control the study-wise type I error. In particular, the secondary end points were only tested if the primary composite end point was significant. The time to total events of HHF was tested only if the primary composite end point was significant, the time to the first event of all-cause mortality or HHF was only tested if the time to total events of HHF was significant, and the time to all-cause mortality was tested only if the time to the first event of all-cause mortality or HHF was significant (Figure 3).

Exploratory Outcomes

In the VICTORIA trial, end points listed as exploratory were tested in a nonhierarchical fashion without adjustments for multiplicity. The following time-to-event end points were analyzed using a Cox proportional hazard model, as they were in the primary outcome analysis: time to first HF event (defined as a composite of HHF or urgent HF visit, time to first CV hospitalization, and total number of HHFs, and time to the first event of CV death, MI hospitalization, or stroke hospitalization.

In the VICTORIA trial, the changes from baseline in KCCQ physical limitation score, KCCQ symptom frequency score, KCCQ total symptom score, KCCQ clinical summary score, KCCQ overall summary score, EQ-5D-5L index, and EQ-5D VAS score at week 32 were analyzed in the ITT population using a repeated-measures covariance model with region, study group, stratification factors, study visit, and the interaction between study visit and study treatment group as covariates. For patients who died during the trial, the worst score (0) was used for each of these scores from the time of death onward (Table 10).

Missing Data

In the VICTORIA study, patients who discontinued study treatment early were followed up for further data collection; thus, the amount of missing data was expected to be minor. Because the analysis of the primary end point is the time-to-event analysis, patients with missing follow-up data were included in the analysis, with time to event censored at the last visit date with full assessment of efficacy end points. Lost follow-up time was calculated as the time from the last visit with full evaluation of efficacy end points to the last visit in the study.

In addition, missing follow-up data on the primary end point were planned to simulate based on the assumption that the time to first primary event will have similar survival distribution pattern as the observed data and would include 2 scenarios: missing at random and missing not at random. The time-to-event analysis on the combined data (observed plus imputed) using the same 1-sided log-rank test for primary efficacy analysis was planned; however, it was not conducted because the amount of missing follow-up data was low.

Figure 3: Summary of Hierarchical Testing

CV = cardiovascular; HF = heart failure.

Sources: Clinical Study Report for VICTORIA,¹⁰ Statistical Analysis Plan.⁴⁴

Table 10: Statistical Analysis of Efficacy End Points

CV = cardiovascular; EQ-5D-5L = 5-Level EQ-5D; EQ VAS = EQ visual analogue scale; HF = heart failure; HHF = hospitalization for heart failure; KCCQ = Kansas City Cardiomyopathy Questionnaire; NT-proBNP = N-termina probrain natriuretic peptide; NYHA = New York Heart Association.

^aOn-treatment analysis helped to establish the treatment effect for patients who remained on the study drug. This analysis included all randomized patients who received the study drug. Efficacy measurement or follow-up from the date of first dose of study drug to 14 days after the last dose of study drug was included in the on-treatment analysis.

^bKCCQ scores include KCCQ physical limitation score, KCCQ symptom frequency score, KCCQ total symptom score, KCCQ clinical summary score, and KCCQ overall summary score.

Source: Clinical Study Report for VICTORIA.¹⁰

Harms

The CEC reviewed each suspected clinical end point event without unblinding treatment. All safety end points were reported using descriptive statistics and were carried out on the safety (or all subjects as treated [ASaT]) population, including patients who had received at least 1 dose of the trial medication. Separate summaries were provided for the 2 most notable safety end points: syncope, and symptomatic hypotension. The incidence of these end points was analyzed by treatment, as well as by subgroups.

Analysis Populations

All patient populations were defined and documented before the database lock.

The ITT population (N = 5,050) consisted of all randomized patients. Patients were analyzed according to their randomized group. Unless otherwise specified, all efficacy end points were summarized and analyzed using the ITT population.

The ASaT, or safety, population (N = 5,034) consisted of all randomized patients who received at least 1 dose of the study drug. Patients were analyzed according to their randomized group. The summary for the safety analysis set was based on subjects “as treated.” A total of 7 patients, 4 of whom were randomized to the placebo group, received both placebo and vericiguat during the trial and were analyzed according to their planned treatment.

Results

Patient Disposition

As of the primary completion date (June 18, 2019), 6,857 individuals were screened, of whom 1,807 (26.4%) did not pass screening. The main reason was not meeting eligibility criteria, predominantly because patients’ NT-proBNP levels were below the prespecified thresholds at screening (59.7%), patients were clinically unstable (14.7%), or patients withdrew consent (10.6%). In total, 5,050 patients were randomized in the treatment period (Table 11). Vital status for the primary end point was known for 2,524 (99.9%) patients in the vericiguat group and 2,520 (99.8%) patients in the placebo group. Of the 5,034 patients treated with the study medication, 38.2% of patients in the vericiguat group and 37.4% of patients in the placebo group discontinued treatment. The most frequently reported reasons for discontinuation were AEs (7.0% and 6.3% in the vericiguat and placebo groups, respectively), death (14.0% and 15.0% in the vericiguat and placebo groups, respectively), and withdrawal by patient (7.7% and 7.6% in the vericiguat and placebo groups, respectively).

Table 11: Patient Disposition — ITT Population

ASaT = all subjects as treated; ITT = intention to treat.

Note: Based on data up to the primary completion date (June 18, 2019).

^aComplete follow-up for vital status was defined as meeting either of the following criteria:

• the patient died during the study

• the patient’s last known vital status was on or after the primary completion date.

^bComplete follow-up for the primary end point was defined as meeting any of the following criteria:

• the patient had a primary end point event before the primary completion date

• the patient died during the study

• the patient’s last follow-up date occurred on or after the primary completion date.

Source: Clinical Study Report for VICTORIA.¹⁰

Exposure to Study Treatments

Treatment compliance was assessed based on the amount of study drug returned at the end of the treatment period. Compliance with the study treatment regimen was high and similar across the treatment groups. Most patients (86.8% and 85.6% in the vericiguat and placebo groups, respectively) were between 90% and 100% compliant with the study medications during the trial.

As of the primary completion date (June 18, 2019), the mean duration of exposure to any dose of vericiguat was 375.5 days (range = 1 to 964 days), and to vericiguat at a dose of 10 mg was 362.0 days (range = 1 to 935 days) (Table 12). The mean duration of exposure to any dose of placebo was 374.7 days (range = 1 to 966 days). The mean dose of the study intervention was similar between the vericiguat and placebo groups (7.8 mg and 8.0 mg, respectively). A total of 218 (8.9%) of patients in the vericiguat group required a dose decrease at 1 or more visits, compared to 181 (7.4%) patients in the placebo group (Table 12). The proportion of patients requiring a study drug dose interruption was similar in the vericiguat and placebo groups (17.0% and 16.4%, respectively).

Protocol Deviation

Protocol deviations in the VICTORIA trial are summarized in Table 13. Overall, 114 (11.3%) patients had at least 1 major protocol deviation, with similar frequencies across the treatment groups. A total of 75 (3.0%) patients in the vericiguat group and 71 (2.8%) in the placebo group had at least 1 clinically important protocol deviation. The most common were related to safety reporting (1.4%), study intervention (0.9%), and inclusion or /exclusion criteria (3.8%).

Table 12: Treatment Exposure — ASaT Population

ASaT = all subjects as treated; SD = standard deviation.

Notes: Each patient is counted once in each specific dose category row, corresponding to the actual dose(s) received.

Based on data up to the primary completion date (June 18, 2019).

^aEach patient who received at least 1 dose of vericiguat (including doses other than 2.5 mg, 5 mg, or 10 mg).

^bDuration of exposure is calculated assuming 1 day of dosing on days of exposure.

Source: Clinical Study Report for VICTORIA.¹⁰

Table 13: Protocol Deviations — ITT Population

ITT = intention to treat.

Source: Clinical Study Report for VICTORIA.¹⁰

Concomitant Medications

Reported concomitant medication use was generally balanced between treatment arms. The most frequently reported concomitant medication categories included diuretics (98.9%), beta-blocking agents (95.1%), agents acting on the renin-angiotensin system (91.2%), and antithrombotic agents (90.5%). According to the study protocol, patients requiring treatment with long-acting nitrates or NO donors were excluded from participation in the study; however, concomitant use of short-acting nitrates for the treatment of angina attacks was permitted. During the VICTORIA trial, the proportion of patients that used nitrates at 1 or more visits was similar between the vericiguat and placebo groups (10.8% and 12.9%, respectively).

Duration of Follow-Up

The median duration of follow-up for the primary end point of time to first event of adjudicated CV death or HHF in the ITT population was 11.1 months (quartile [Q]1 to Q3, 6.5 to 19.1 months) in the vericiguat group and 10.4 months (Q1 to Q3, 6.1 to 18.7 months) in the placebo group (Table 14). The median duration of follow-up for all-cause mortality in the ITT population was |||| |||||| |||| || || || |||| ||||||| in the vericiguat group and |||| |||||| |||| || || || |||| ||||||| in the placebo group. The percentage of follow-up for the primary end point and all-cause mortality, out of the total potential follow-up, was greater than 99% in both treatment groups.

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported here. Refer to Appendix 3 for detailed efficacy data. Only clinical end points adjudicated by the CEC were used in the efficacy analyses.

Table 14: Follow-Up Duration — ITT Population

CV = cardiovascular; HHF = hospitalization for heart failure; Q1 = 25th percentile; Q3 = 75th percentile; SD = standard deviation.

^aComputed for each patient as the day of randomization to the day of death, the last available information on vital status, or the primary completion date (June 18, 2019).

^bComputed for each patient as the day of randomization to the day of the earlier instance of death or the primary completion date (June 18, 2019)

^cPercentage of follow-up = (patient-years of follow-up / potential patient-years of follow-up) × 100.

Source: Clinical Study Report for VICTORIA.¹⁰

Time to First Event of Adjudicated CV Death or HHF

The results of the primary efficacy end point are presented in Table 15. A composite of time to first event of adjudicated CV death or HHF occurred in 897 patients (35.5%) in the vericiguat group and 972 patients (38.5%) in the placebo group. The annual event rate was lower in the vericiguat group compared to placebo group (33.6% and 37.8%, respectively), with an HR of 0.90 (99.5% CI, 0.82 to 0.98; P = 0.019) in favour of vericiguat. The median follow-up duration was 11.1 months in the vericiguat group and 10.4 months in the placebo group (Table 14). The Kaplan-Meier plot of the primary composite end point for the ITT is presented in Figure 4. The proportion of HHF as the first event was lower in the vericiguat group (27.4%) than in the placebo group (29.6%), whereas the proportion of CV death as the first event was similar across the vericiguat and placebo groups (8.2% and 8.9%, respectively). The on-treatment analysis results for the primary composite end point showed that the HR was |||| |||| || |||| || ||||| | | |||||| (Appendix 3, Table 33, Figure 11).

Subgroup Analysis

The primary end point subgroup analysis is presented in Table 16. The analyses may not have been powered to detect a treatment difference and there were no adjustments made for multiplicity. Although the treatment effects for prespecified subgroups in the CADTH protocol were generally consistent with the main effect, a potential difference was noted, depending on NT-proBNP at baseline (P value for interaction < 0.05).

Time to CV Death

This secondary outcome was tested in a nonhierarchical sequence without adjustments for multiplicity and was exploratory in nature. The number of CV death events was 414 (16.4%) in the vericiguat group and 441 (17.5%) in the placebo group (Table 17). The proportion of patients who died of HF was 6.5% and 7.6% in the vericiguat and placebo groups, respectively, sudden cardiac event 4.2% and 4.5% in the vericiguat and placebo groups, respectively, and undetermined cause of death 4.4% and 4.0% in the vericiguat and placebo groups, respectively. The HR for the time to CV death was 0.93 (99.5% CI, 0.81 to 1.06; P = 0.269). The Kaplan-Meier plot of the time to CV death is presented in Figure 5. The results of the on-treatment analysis were consistent with those of the primary analysis (HR = 0.93; 95% CI, 0.78 to 1.12; P = 0.469) (Appendix 3, Table 34, Figure 12).

Table 15: Time to First Event of CEC-Confirmed CV Death or HHF — ITT Population

CEC = Clinical Events Committee; CI = confidence interval; CV = cardiovascular; HHF = hospitalization for heart failure; HR = hazard ratio; ITT = intention to treat; KM = Kaplan-Meier.

Notes: For patients with multiple events, only the first event contributing to the composite end point is counted in the table.

Based on data up to the primary completion date (June 18, 2019).

^aTotal events per 100 patient-years at risk.

^bKM estimate and CI at 2 years.

^cHR (vericiguat over placebo) and CI from Cox proportional hazard model, controlled for stratification factors (defined by region and race).

^dFrom log-rank test stratified by the stratification factors defined by region and race.

Table 16: Subgroup Analyses of the Primary Composite End Point — ITT Population

CEC = Clinical Events Committee; CI = confidence interval; eGFR = estimated glomerular filtration rate; HR = hazard ratio; ITT = intention to treat; KM = Kaplan-Meier; NT-proBNP = N-terminal probrain natriuretic peptide; NYHA = New York Heart Association; Q1 = 25th percentile; Q2 = 50th percentile; Q3 = 75th percentile; Q4 = 100th percentile.

^aHR, CI, and P value for treatment-by-subgroup interaction from Cox proportional hazard model, with covariates of the stratification factors (defined by region and race), treatment, subgroup, and treatment-by-subgroup interaction.

^bP value was not adjusted for multiplicity.

Table 17: Time to CEC-Confirmed CV Death — ITT Population

CEC = Clinical Events Committee; CI = confidence interval; CV = cardiovascular; HR = hazard ratio; ITT = intention to treat; KM = Kaplan-Meier.

Note: Based on data up to the primary completion date (June 18, 2019).

^aTotal events per 100 patient-years at risk.

^bKM estimate and CI at 2 years.

^cHR (vericiguat over placebo) and CI from Cox proportional hazard model, controlling for stratification factors (defined by region and race).

^dFrom log-rank test stratified by the stratification factors, defined by region and race. P value was not adjusted for multiplicity.

Source: Clinical Study Report for VICTORIA.¹⁰

Source: Clinical Study Report for VICTORIA.¹⁰

Figure 4: Kaplan-Meier Plot for CEC-Confirmed Primary Composite End Point — ITT Population

CEC = Clinical Events Committee; ITT = Intention to treat.

Note: Based on data up to the primary completion date (June 18, 2019).

Source: Clinical Study Report for VICTORIA.¹⁰

Subgroup analyses for time to CV death is presented in Appendix 3, Table 35. The analyses may not have been powered to detect a treatment difference and there were no adjustments made for multiplicity. The treatment effects for all prespecified subgroups in the CADTH protocol were consistent with the main effect.

Figure 5: Kaplan-Meier Plot for Time to CEC-Confirmed CV Death — ITT Population

CEC = Clinical Events Committee; CV = cardiovascular; ITT = intention to treat; KM = Kaplan-Meier.

Note: Based on data up to the primary completion date (June 18, 2019).

Source: Clinical Study Report for VICTORIA.¹⁰

Table 18: Time to CEC-Confirmed All-Cause Mortality — ITT Population

CEC = Clinical Events Committee; CI = confidence interval; HR = hazard ratio; ITT = intention to treat; KM = Kaplan-Meier.

Note: Based on data up to the primary completion date (June 18, 2019).

^aTotal events per 100 patient-years at risk.

^bKM estimate and CI at 2 years.

^cHR (vericiguat over placebo) and CI from Cox proportional hazard model, controlling for stratification factors (defined by region and race).

^dFrom log-rank test stratified by the stratification factors, defined by region and race. P value was not adjusted for multiplicity.

Source: Clinical Study Report for VICTORIA.¹⁰

Time to All-Cause Mortality

A total of 512 (20.3%) patients in the vericiguat group and 534 (21.2%) patients in the placebo group died of any cause (Table 18). The annual event rate was similar across the treatment groups (16.0% and 16.9% in the vericiguat and placebo groups, respectively), with an HR of 0.95 (95% CI, 0.84 to 1.07; P = 0.377). The Kaplan-Meier plot of time to all-cause mortality is presented in Figure 6. Results of the on-treatment analysis of time to all-cause mortality were consistent with those of the primary analysis (HR = 0.98; 95% CI, 0.83 to 1.16; P = 0.878) (Appendix 3, Table 36, Figure 13).

Time to First Event of All-Cause Mortality or HHF

A composite of time to first event of all-cause mortality or HHF occurred in 957 patients (37.9%) in the vericiguat group and 1,032 patients (40.9%) in the placebo group (Table 19). The annual event rate was 35.9% and 40.1% in the vericiguat and placebo groups, respectively, with an HR of 0.90 (95% CI, 0.83 to 0.98; P = 0.021). This difference was likely driven primarily by a lower proportion of HHF events, although individual components of this composite end point were not formally tested for significance. The Kaplan-Meier plot of the time to all-cause mortality or HHF is presented in Figure 7. The results of the on-treatment analysis were consistent with those of the primary analysis, with an HR of 0.92 (95% CI, 0.83 to 1.01; P = 0.082) (Appendix 3, Table 37, Figure 14).

Figure 6: Kaplan-Meier Plot for Time to CEC-Confirmed All-Cause Mortality — ITT Population

Note: This figure has been redacted per the sponsor’s request.

||||| ||||||||| |||||| |||||||||| || |||||||||||||||||||| || |||||||||||||||||||| || |||| || || || ||||||| |||||||||| |||| ||||| || |||||||||||||| |||||||| ||||| |||||| || ||||||||

Figure 7: Kaplan-Meier Plot for Time to First Event of CEC-Confirmed All-Cause Mortality or HHF — ITT Population

Note: This figure has been redacted per the sponsor’s request.

||||| ||||||||| |||||| |||||||||| || |||||||||||||||| || ||||| |||||||| || |||||||||||||||||||| || |||||||||||||||||||| || |||| || || || ||||||| |||||||||| |||| ||||| || |||||||||||||| |||||||| ||||| |||||| || ||||||||||| || ||||| ||||| || || |||||||||||||||

Table 19: Time to First Event of CEC-Confirmed All-Cause Mortality or HHF — ITT Population

CEC = Clinical Events Committee; CI = confidence interval; HHF = hospitalization for heart failure; HR = hazard ratio; ITT = intention to treat; KM = Kaplan-Meier.

Notes: Based on data up to the primary completion date (June 18, 2019).

For patients with multiple events, only the first event contributing to the composite end point is counted in the table.

^aTotal events per 100 patient-years at risk.

^bKM estimate and CI at 2 years.

^cHR (vericiguat over placebo) and CI from Cox proportional hazard model, controlling for stratification factors (defined by region and race).

^dFrom log-rank test stratified by the stratification factors defined by region and race.

Source: Clinical Study Report for VICTORIA.¹⁰

This secondary outcome was tested in a nonhierarchical sequence without adjustments for multiplicity and was exploratory in nature. A total of ||| |||||||| ||||||| in the vericiguat group and ||||| |||||||| ||||||| in the placebo group had CV hospitalizations (Table 20). The annual event rate was lower in the vericiguat group ||||||| compared to the placebo group |||||||, with an HR of |||| |||| || |||| || ||||| | | ||||||. The Kaplan-Meier plot of time to CV hospitalization is presented in Figure 8. The results of the on-treatment analysis for CV hospitalizations were consistent with those of the primary analysis ||| |||||| || |||| |||| || ||||| | | |||||| ||||||||| || |

Table 20: Time to First Event of CEC-Confirmed CV Hospitalization — ITT Population

CEC = Clinical Events Committee; CI = confidence interval; CV = cardiovascular; HR = hazard ratio; ITT = intention to treat; KM = Kaplan-Meier.

Notes: For patients with multiple events, only the first event contributing to the composite end point is counted in the table.

Based on data up to the primary completion date (June 18, 2019).

^aTotal events per 100 patient-years at risk.

^bKM estimate and CI at 2 years.

^cHR (vericiguat over placebo) and CI from Cox proportional hazard model, controlling for stratification factors (defined by region and race).

^dFrom log-rank test stratified by the stratification factors defined by region and race. P value was not adjuster for multiplicity.

Source: Clinical Study Report for VICTORIA.¹⁰

Figure 8: Kaplan-Meier Plot for Time to First Event of CEC-Confirmed CV Hospitalization — ITT Population

Note: This figure has been redacted per the sponsor’s request.

||| ||||||||| |||||| |||||||||| || |||||||||||||||| || |||||| ||||||| |||||||||||||||| || |||||||||||||||||||| || |||||||||||||||||||| || |||| || || || ||||||| |||||||||| |||| ||||| || |||||||||||||| |||||||| ||||| |||||| || ||||||||^||

Time to First Event of HHF

This secondary outcome was tested as a component of the primary composite end point in a nonhierarchical sequence without adjustments for multiplicity and was exploratory in nature. The number of patients with HHF events was 691 (27.4%) in the vericiguat group and 747 (29.6%) in the placebo group (Table 21). The annual event rate was 25.9% in the vericiguat group and 29.1% in the placebo group, with an HR of 0.90 (0.81 to 1.00; P = 0.048). The Kaplan-Meier plot for time to the first event of HHF is presented in Figure 9. The results of the on-treatment analysis for this end point were consistent with those of the primary analysis (HR = 0.89; 95% CI, 0.81 to 0.97; P = 0.012) (Appendix 3, Table 39, Figure 16). Although the treatment effects of vericiguat on the HHF for prespecified subgroups in the CADTH protocol were generally consistent with the main effect, a potential difference was noted depending on NT-proBNP at baseline (P value for interaction < 0.05) (Appendix 3, Table 40).

Table 21: Time to First Event of CEC-Confirmed HHF — ITT Population

CEC = Clinical Events Committee; CI = confidence interval; HHF = hospitalization for heart failure; HR = hazard ratio; ITT = intention to treat; KM = Kaplan-Meier.

Note: Based on data up to the primary completion date (June 18, 2019).

^aTotal events per 100 patient-years at risk.

^bKM estimate and CI at 2 years.

^cHR (vericiguat over placebo) and CI from Cox proportional hazard model, controlling for stratification factors (defined by region and race).

^dFrom log-rank test stratified by the stratification factors defined by region and race. P value was not adjuster for multiplicity.

Source: Clinical Study Report for VICTORIA.¹⁰

Figure 9: Kaplan-Meier Plot for Time to CEC-Confirmed HHF — ITT Population

Note: This figure has been redacted per the sponsor’s request.

||| ||||||||| |||||| |||||||||| || |||||||||||||||| || ||||| |||||||| || |||||||||||||||||||| || |||||||||||||||||||| || |||| || || || ||||||| |||||||||| |||| ||||| || |||||||||||||| |||||||| ||||| |||||| || |||||||

Time to Total Events (First and Recurrent) of HHF

The total number of HHF events was lower in patients who received vericiguat (n = 1,223) compared to those who received placebo (n = 1,336) (Table 22). The annual event rate was 38.3% in the vericiguat group and 42.4% in the placebo group, with an HR of 0.91 (95% CI, 0.84 to 0.99; P = 0.023). The results of the sensitivity analysis using the Wei, Lin, and Weissfeld method and supportive on-treatment analyses were consistent with those of the primary analysis (Appendix 3, Table 41 and Table 42).

Table 22: Time to Total Events of CEC-Confirmed HHF — ITT Population

CEC = Clinical Events Committee; CI = confidence interval; HHF = hospitalization for heart failure; HR = hazard ratio; ITT = intention to treat.

Note: Based on data up to the primary completion date (June 18, 2019).

^aTotal number of HHFs (first and recurrent).

^bTotal events per 100 patient-years of follow-up.

^cCalculated based on the Andersen-Gill model, controlling for stratification factors (defined by region and race). Robust standard errors are used to account for correlations of event times for a patient.

^dCalculated based on Andersen-Gill model controlling for stratification factors (defined by region and race). Robust standard errors are used to account for correlations of event times within a subject.

Source: Clinical Study Report for VICTORIA.¹⁰

Change From Baseline in NT-proBNP

This additional outcome was tested in a nonhierarchical sequence without adjustments for multiplicity and was exploratory in nature. The reduction in NT-proBNP from baseline to week 32 was greater in the vericiguat group compared to placebo group, with a of geometric mean ratio LS means of 0.90 (95% CI, 0.85 to 0.96; P = 0.001) (Table 23).

Change From Baseline in NYHA Class

The number of patients with NYHA class I to class IV HF and the net change from baseline in NYHA class at week 32 in the vericiguat and placebo groups are presented in Table 24.

Time to First Event of CV Death, MI Hospitalization, or Stroke Hospitalization

This exploratory outcome was tested in a nonhierarchical sequence without adjustments for multiplicity. The number of patients with a composite end point was ||| ||||||| in the vericiguat group and ||| ||||||| in the placebo group (Table 25). The annual event rate was ||||| in the vericiguat group and ||||| in the placebo group, with an HR of |||| |||| || |||| || ||||| | | ||||||. The Kaplan-Meier plot for time to CV death, MI, or stroke hospitalization is presented in Figure 10. The results of the on-treatment analysis were consistent with those of the primary analysis (Appendix 3, Table 46, Figure 17).

Table 23: Change From Baseline in NT-proBNP at Week 32— ITT Population

CI = confidence interval, GMR = geometric mean ratio; ITT = intention to treat; LS = least squares, NT-proBNP = N-terminal probrain natriuretic peptide; SD = standard deviation (back-transformed from SD of log of NT-proBNP value).

Notes: Based on data up to the primary completion date (June 18, 2019).

For baseline and week 32, N is the number of patients with nonmissing assessments at the specific time point. For change from baseline, N is the number of patients with nonmissing assessment in both baseline and week 32.

^aBased on a longitudinal analysis of the covariance model, with the change from baseline in log-transformed value as the dependent variable, including categorical terms for stratification factor, week, treatment group, and the week-by-treatment group interaction, with the log-transformed baseline value as a continuous covariate, and including all postrandomization time points through week 96.

^bP value was not adjusted for multiplicity.

Source: Clinical Study Report for VICTORIA¹⁰

Table 24: Change From Baseline in NYHA Class at Week 32 — ITT Population

HF = heart failure; ITT = intention to treat; NYHA = New York Heart Association.

Notes: Percentages are computed based on the number of patients with nonmissing assessments at the specific time point.

Based on data up to the primary completion date (June 18, 2019).

Source: Clinical Study Report for VICTORIA.¹⁰

Table 25: Time to First Event of CEC-Confirmed CV Death, MI, or Stroke Hospitalization — ITT Population

CEC = Clinical Events Committee; CI = confidence interval; CV = cardiovascular; HR = hazard ratio; ITT = intention to treat; KM = Kaplan-Meier; MI = myocardial infarction.

Notes: For patients with multiple events, only the first event contributing to the composite end point is counted in the table.

Based on data up to the primary completion date (June 18, 2019).

^aTotal events per 100 patient-years at risk.

^bKM estimate and CI at 2 years.

^cHR (vericiguat over placebo) and CI from Cox proportional hazard model, controlling for stratification factors (defined by region and race).

^dFrom log-rank test stratified by the stratification factors defined by region and race. P value was not adjuster for multiplicity.

Source: Clinical Study Report for VICTORIA.¹⁰

Figure 10: Kaplan-Meier Plot for Time to First Event of CEC-Confirmed CV Death, MI, or Stroke Hospitalization — ITT Population

Note: This figure has been redacted per the sponsor’s request.

||| ||||||||| |||||| |||||||||| || |||||||||||||||||| |||||||||||||||||||| || |||||||||||||| || ||||||||||| ||||||||||||||||| || |||| || || || ||||||| |||||||||| |||| ||||| || |||||||||||||| |||||||| ||||| |||||| || ||||||||

Health-Related Quality of Life

HRQoL was tested in a nonhierarchical sequence without adjustments for multiplicity and was exploratory in nature.

KCCQ Score

The results for change from baseline in KCCQ scores are presented in Table 26. For the analysis of the KCCQ score based on the ITT population, week 32 data were missing for ||||| || ||||| of patients in the vericiguat group and for ||||| || ||||| of patients in the placebo group. No clinically meaningful differences were found between treatment groups in change from baseline in KCCQ scores at week 32 (less than MID of at least 5 points).

KCCQ Overall Summary Score: The KCCQ overall summary score combines the physical limitation, total symptom, social limitation, and quality-of-life domains into a single score with a range of 0 to 100, where larger scores represent a better outcome. The analysis showed a slight improvement from baseline of ||| points (SD = ||||) in the vericiguat group and ||| points (SD = ||||) in the placebo group in the KCCQ overall summary score at week 32, with an LS mean difference of ||| (||| || |||| || |||| | | |||||).

KCCQ Total Symptom Score: The KCCQ total symptom score combines the symptom burden and symptom frequency domains into a single score with a range of 0 to 100, where larger scores represent a better outcome. The analysis showed a slight improvement from baseline of ||| points (SD = ||||) in the vericiguat group and ||| points (SD = ||||) in the placebo group in the KCCQ total symptom score at week 32, with an LS mean difference of ||| (||| || |||| || |||| | | |||||).

KCCQ Clinical Summary Score: The KCCQ total symptom score combines the physical limitation and total symptom domains into a single score with a range of 0 to 100, where larger scores represent a better outcome. The analysis showed a slight improvement from baseline of ||| points (| |||||) in the vericiguat group and ||| points (SD = ||||) in the placebo group in the KCCQ clinical summary score at week 32, with an LS mean difference of ||| (||| || |||| || |||| | | |||||).

Table 26: Change From Baseline in KCCQ Scores at Week 32 — ITT Population

CI = confidence interval; ITT = intention to treat; KCCQ = Kansas City Cardiomyopathy Questionnaire; LS = least squares; SD = standard deviation.

Notes: Patients who died during the study were assigned the worst possible score for all post-death visits until the primary completion date.

Based on data up to the primary completion date (June 18, 2019).

^aBased on a longitudinal analysis of the covariance model, with the change score as the dependent variable, including categorical terms for stratification factor, week, treatment group, and the week-by-treatment group interaction, with the baseline value as a continuous covariate, and including all postrandomization time points through week 96. For baseline and week 32, N is the number of patients with nonmissing assessments at the specific time point. For change from baseline, N is the number of patients with nonmissing assessments at both baseline and week 32.

^bP value was not adjusted for multiplicity.

Source: Clinical Study Report for VICTORIA.¹⁰

5-Level EQ-5D

For the analysis of the EQ-5D-5L index score based on the ITT population, week 32 data were missing for ||||| and ||||| of patients in the vericiguat and placebo groups, respectively. No difference was found between the 2 treatment groups for mean changes in EQ-5D-5L index and EQ VAS scores from baseline at week 32. (Table 27). For the EQ-5D-5L UK and US index scores, the LS mean differences at week 32 for vericiguat versus placebo were ||||| |||||| || |||||| | | |||||| and 0.01 (95% CI, –0.01 to 0.03; P = 0.257), respectively.

Table 27: Change From Baseline in EQ-5D-5L US Score at Week 32 — ITT Population

CI = confidence Interval; EQ VAS = EQ visual analogue scale; EQ-5D-5L = 5-Level EQ-5D; ITT = intention to treat; LS = least squares, SD = standard deviation.

Notes: Patients who died during the study were assigned the worst possible score for all postdeath visits until the primary completion date.

Based on data up to the primary completion date (June 18, 2019).

^aBased on a longitudinal analysis of the covariance model, with the change score as the dependent variable, including categorical terms for stratification factor, week, treatment group, and the week-by-treatment group interaction, with the baseline value as a continuous covariate, and including all postrandomization time points through week 96. For baseline and week 32, N is the number of patients with nonmissing assessments at the specific time point. For change from baseline, N is the number of patients with nonmissing assessments at both baseline and week 32.

^bP value was not adjusted for multiplicity.

Source: Clinical Study Report for VICTORIA.¹⁰

All-Cause Hospitalization

All-cause hospitalization was not measured or reported in the VICTORIA trial.

Change From Baseline in BNP

Change from baseline in BNP was not measured or reported in the VICTORIA trial.

Harms

Only those harms identified in the review protocol are reported here. Refer to Table 28 for detailed harms data.

Adverse Events

A total of 2,027 (80.5%) patients in the vericiguat group and 2,036 (81.0%) patients in the placebo group experienced 1 or more AE (Table 27). Common AEs by the preferred term are summarized in Table 29. The most common AEs occurring in the vericiguat and placebo groups were hypotension (15.4% and 14.1%, respectively), cardiac failure (8.9% and 9.9%, respectively), anemia (7.6% and 5.7%, respectively), and pneumonia (6.4% and 7.2%, respectively). A total of 653 (25.9%) patients in the vericiguat group and 606 (24.1%) patients in the placebo group experienced 1 or more AE leading to dose modification (Table 28). The proportion of fatal AEs during the double-blind treatment phase was similar in the vericiguat and placebo groups (3.3% and 3.4%, respectively).

Serious Adverse Events

A total of 826 (32.8%) patients in the vericiguat group and 876 (34.8%) patients in the placebo group experienced 1 or more SAE (Table 29). The most common SAEs occurring in the vericiguat and placebo groups were pneumonia (4.0% and 4.5%, respectively), cardiac failure (93.2% and 4.4%, respectively), acute kidney injury (2.5% and 2.0%, respectively), and syncope (1.7% and 1.3%, respectively).

Withdrawals Due to Adverse Events

In the VICTORIA trial, withdrawal of study treatment due to AEs was required in 167 (6.6%) patients in the vericiguat group and 158 (6.3%) patients in the placebo group (Table 28). The most common reasons for discontinuation were hypotension (1.9% and 1.3% in the vericiguat and placebo groups, respectively), chronic kidney disease (0.3% and 0.6% in the vericiguat and placebo groups, respectively), pneumonia (0.1% and 0.2% in the vericiguat and placebo groups, respectively), cardiac failure (0.2% and 0.2% in the vericiguat and placebo groups, respectively), and dyspepsia (0.2% and 0.1% in the vericiguat and placebo groups, respectively).

Notable Harms

In the VICTORIA trial, symptomatic hypotension was the most commonly reported notable AE (9.1% and 7.9% in the vericiguat and placebo groups, respectively), followed by syncope (4.0% and 3.5% in the vericiguat and placebo groups, respectively), and hepatic AEs (0.9% and 0.5% in the vericiguat and placebo groups, respectively).

Table 28: Summary of Harms — ASaT Population

AE = adverse event; ASaT = all subjects as treated; SAE = serious adverse event.

Notes: Based on data up to the primary completion date (June 18, 2019).

Includes events and/or measurements from the day of the first dose of the study drug to 14 days after the last dose of the study drug.

^aIncludes AEs associated with a fatal outcome but does not reflect all deaths reported in the study.

^bDefined as a dose reduction, drug interruption, or drug withdrawal.

Source: Clinical Study Report for VICTORIA.¹⁰

Table 29: AEs Reported in at Least 2% of Patients in Either Treatment Arm — ASaT Population

AE = adverse event, ASaT = all subjects as treated; SAE = serious adverse event.

Source: Clinical Study Report for VICTORIA.¹⁰

Table 30: SAEs and Notable Harms — ASaT Population

AE = adverse event; ASaT = all subjects as treated; SAE = serious adverse event.

Source: Clinical Study Report for VICTORIA.¹⁰

Critical Appraisal

Internal Validity

The VICTORIA trial used accepted methods for blinding, allocation concealment, and randomization with stratification by race and geographic region. An Interactive Voice Response System and Integrated Web Response System methodology was used, and randomization with stratification was performed centrally, which typically has a low risk of bias. The baseline demographic and disease characteristics of patients were generally balanced between the treatment groups, so randomization was successful. Although the VICTORIA trial was double-blinded and the investigators were blinded to treatment assignment, risk of bias from unblinding of treatment assignment cannot be ruled out. In the vericiguat group, about 80.5% of patients experienced at least 1 AE, which may have made the investigators and/or patients aware of the treatment assignment. Knowledge of the assigned treatment could have led to bias in the reporting and measurement of subjective outcomes, including patient-reported outcomes (i.e., HRQoL) and subjective AEs. However, the extent and direction of bias due to treatment knowledge is uncertain. A relatively high proportion of patients prematurely discontinued the trial medication (38.7%), although causes of discontinuation occurred at a similar frequency in the treatment groups. The main reason for treatment discontinuation was a fatal event, which, according to the clinical expert consulted by CADTH for this review, reflects the natural course of HF. In addition, patients who withdrew from the study and those who discontinued the study medication early continued to be followed and were included in outcome analyses. Protocol deviations were reported in 17% to 18% of patients in the 2 treatment groups, and the proportion of protocol deviations was comparable between groups and identified before the database lock.

In accordance with the exclusion criteria, patients in the VICTORIA trial were randomized starting 24 hours after IV treatment, which may not have been long enough to achieve clinical stability after acute treatment for worsening HF, and could have led to an underestimation or overestimation of the treatment effect. In addition, there was no run-in period in the trial to initiate or maintain optimal doses of HF medications to achieve clinical stability after worsening HF. However, the clinical expert consulted noted that although sometimes only 1 dose of a diuretic is required to achieve clinical stability, it can take several days or weeks to regain stability. The clinical expert further indicated that stable HF lacks a consensus definition, and, in clinical practice, it reflects the physician's perception of the patient's condition. According to the Canadian Cardiovascular Society, the term “stable HF” is not considered to be clinically appropriate, given the inherent risk for future clinical events related to a progressive disease.²

An independent CEC performed an adjudication of CV death, HHF, and urgent HF visit events based on criteria defined a priori. The clinical expert consulted indicated that the primary and key secondary outcomes were appropriate for the disease setting. The primary composite outcome in the trial was the time to the first event of CV death or HHF. The FDA-issued guidance for industry for Multiple Endpoints in Clinical Trials⁴⁵ indicated that a composite end point may be needed when more than 1 clinical end point in a clinical trial is important and when treatment is expected to affect all outcomes. However, although the overall statistical analysis of the primary outcome indicates a benefit of treatment, it is important to analyze the individual components of the composite end point for a greater depth of understanding of the treatment’s effects.⁴⁵ In the VICTORIA trial, CV death as an individual component of the primary composite end point (which was defined based on time to first event) was not formally tested, whereas HHF was tested with a hierarchical testing strategy without adjustment for multiplicity and is exploratory in nature. Also, composite outcomes, although commonly used in trials of CV therapies, assume that each component has equal clinical importance, which is unlikely to be true when comparing hospitalization and death. Given that HF hospitalizations occurred at a greater frequency (and at earlier time points) than deaths in the composite outcome, the time to first event definition means that the measurement of the effect of vericiguat on CV death is likely imprecise, based on the composite outcome analysis. CV death was evaluated as a secondary outcome; however, given the criteria for interim efficacy assessment and stopping the trial prematurely, the longer-term effects of vericiguat on this outcome are difficult to determine.

Non-CV death was not considered a competing risk in the analysis of the primary composite end point, which could lead to a biased effect of vericiguat compared to placebo. In addition, the clinical expert consulted indicated that the list of criteria used to define CV deaths in the trial appeared to be too comprehensive, as it included undetermined causes of death, which could have resulted in a similar proportion of CV deaths in the 2 treatment groups. Secondary end points were separated into 2 families. The first family included time to CV death and time to HHF, which were tested in nonhierarchical sequence without adjustments for multiplicity and were exploratory in nature. The second family consisted of the end points of time to total hospitalizations for HF, time to all-cause mortality, and a composite of time to the first occurrence of the composite of HHF or all-cause mortality, and was tested hierarchically using a fixed-sequence approach to reduce the risk of type I error across these analyses.

The statistical analysis methods appear to be acceptable. The analyses of primary and key secondary outcomes were conducted using the ITT population, which maintains randomization and minimizes the risk of bias by comparing groups with similar prognostic factors. Both the interim and final analyses were planned a priori and adequately described. However, a decision was made to cancel the interim analysis because there were more CV deaths than expected. Given the potential misclassification of CV deaths, which may overestimate the true incidence of CV death events, as they include undetermined causes of death, there is a possibility that the trial was stopped earlier than planned. Therefore, there is a risk that the effect of vericiguat, compared to placebo, is overestimated, but the presence and extent of any overestimation is uncertain.^11-13 The sponsor commented on a draft version of this review report and noted that outcomes were aligned with those proposed by the Standardized Data Collection for Cardiovascular Trials Initiative and the FDA and were prespecified in the CEC charter.⁴⁶ An independent CEC blinded to treatment allocation throughout the trial assessed all reported deaths, CV hospitalizations, and urgent HF visits. The sponsor also highlighted that the inclusion of undetermined deaths as CV deaths is an accepted approach by the Standardized Data Collection for Cardiovascular Trials Initiative, is standard for large cardiometabolic trials,^47,48 and is a conservative approach to the analyses. CADTH reviewers acknowledge that the approach of classifying deaths from an undetermined cause as CV deaths has been used in other CV trials and may be a conservative approach if the criteria are applied equally to the treatment groups. The CEC charter⁴⁶ provided by the sponsor indicated that “death not attributable to CV death or to a non-CV cause” should not be used and should apply to few patients in well-run clinical trials. It is noteworthy that undetermined causes of death accounted for 25% (213 of 855) of CV deaths. Even though this approach may generally be conservative, given the relatively high percentage of patients with deaths of undetermined cause and, as already discussed, CV deaths were used in criteria for determining early efficacy stopping decisions and that classifying patients with an undetermined cause of death as CV death may have influenced the early efficacy claims, this approach may not have been as conservative as planned because of the potentially overestimated benefit of the treatment effect, versus placebo, at an earlier point in the study’s treatment period.

The clinical expert consulted noted that the results of the primary and key secondary outcomes were modest but clinically meaningful, based on the absolute event rate reduction in the selected study population. The sensitivity analysis for missing data was not performed, as about 0.4% of patients were lost to follow-up for the primary end point and vital status was known for more then 99% of patients. The median primary composite end point, all-cause survival, total HHF, and a composite of all-cause mortality and HHF was not estimable because insufficient follow-up time had elapsed for these outcomes; thus, the long-term efficacy of vericiguat is unknown. The Cox regression models were controlled for stratification factors (geographic region and race), and no rationale was provided for the lack of adjustment for important clinical variables, such as SOC therapy and comorbidities. Subgroup analyses by ejection fraction at screening, NYHA class, renal function, index event, prior use of sacubitril-valsartan, and NT-proBNP level were prespecified in the VICTORIA trial. Subgroup analyses were reported only for the primary composite end point, time to CV deaths, and time to HHF. Subgroups were not included as a stratification variable in the randomization scheme, and there may have been imbalances in the distribution of these variables within the subgroups. Subgroup analyses were not adjusted for multiplicity and may not have been powered to detect a treatment difference; as such, any inferences or interpretations based on subgroups should be made with caution.

Although improvement in HRQoL was of primary importance of both patients and physicians, this was an exploratory outcome and was tested outside the statistical testing hierarchy. HRQoL was assessed using the KCCQ and EQ-5D instruments. The KCCQ is generally a valid and reliable questionnaire for HF, but there is no evidence for the validity and reliability of the EQ-5D instrument in patients with HF. The clinical expert consulted indicated that these tools are not commonly used in clinical practice. No strong conclusions could be drawn about the effect of vericiguat, compared with placebo, on HRQoL due to an increased risk of type I error and a high risk of attrition bias, especially at longer follow-up. Because treatment discontinuation rates were relatively high in both treatment groups, there is a risk of bias, as patients who completed the questionnaires may be completely different than those who did not (e.g., differences in treatment response, AEs). Although HRQoL was measured, there were methodological issues that precluded the drawing of any strong conclusions, so there remains a knowledge gap.

External Validity

In general, the clinical expert consulted by CADTH for this review confirmed that the population in the VICTORIA trial was similar to patients seen in Canadian clinics, and the study results would be generalizable to patients with HF in Canada, with some limitations. Previous HF decompensation (or worsening) was defined as HHF within 3 to 6 months before randomization or the use of IV diuretics for HF (without hospitalization) within 3 months before randomization. The clinical expert consulted noted that the definition of worsening HF was reflective of clinical practice. Although the proposed Health Canada indication for vericiguat is for the treatment of patients with symptomatic chronic HF with reduced ejection fraction, regardless of NYHA class, CADTH was unable to draw conclusions related to patients with NYHA class I and class IV HF, because the trial excluded patients who had NYHA class I HF and had only a very small proportion of patients who had NYHA class IV HF (1.1%). The clinical expert consulted indicated that patients with NYHA class IV HF are more likely to be clinically unstable than those with NYHA class II or class III HF. About 26.4% of patients in the trial were screening failures, predominantly because patients’ NT-proBNP levels were below the prespecified threshold at screening. The clinical expert consulted indicated that NT-proBNP testing is not widely available in Canada, as some jurisdictions have limited access to it; thus, this patient selection criterion would be difficult to implement in clinical practice. The clinical expert further noted that the enrolment of patients with elevated NT-proBNP levels likely created an enriched population in the trial, with patients who appeared to be sicker and who may benefit from treatment with vericiguat more than the population in the real-world setting.

About 14% of patients had midrange LVEF (41% to 45%); however, the clinical expert consulted did not expect this to be an issue with the generalizability of the trial results to HF patients with reduced ejection fraction. According to the Canadian Cardiovascular Society, uncertainty often occurs in the measurement of LVEF, as estimates may vary, depending on the patient, technical factors, and clinical deterioration.² The clinical expert consulted indicated that the population in the VICTORIA trial was younger than the typical adult population in Canada with symptomatic chronic HF with reduced ejection fraction (in which the mean age is 75 to 77 years). Most patients were white, non-Hispanic or non-Latino, and only 11% of patients were recruited from North America. The clinical expert consulted noted that the lack of representation of Canadian patients does not reduce the generalizability of results to Canadian clinical practice. Protocol deviations were reported in 16.7% to 18.3% of patients in the 2 treatment groups, and the proportion of protocol deviations was comparable between groups and identified before the database lock in a blinded manner.

About 91% of patients in the trial received 2 or more background HF treatments, but only 60% of patients received triple HF therapy, representing patients whose treatment was suboptimal. In addition, a small proportion of patients (14.4%) received sacubitril-valsartan and none of the patients received SGLT2 inhibitors for the treatment of HF. The clinical expert consulted indicated that SGLT2 inhibitors became available for the treatment of chronic HF with reduced ejection fraction after the VICTORIA trial was conducted (between 2016 and 2019). Therefore, it is unclear whether the population included in the VICTORIA study is reflective of the population that would be eligible for treatment with vericiguat in current Canadian clinical practice. The clinical expert consulted indicated that vericiguat may be added to foundational quadruple HF therapy (including ACEis or ARBs, beta-blockers, MRAs, and SGLT2 inhibitors), as its mechanism of action is different from quadruple therapy medications. However, the cumulative benefit of vericiguat added to quadruple therapy remains unknown.

One of the initiation criteria in the sponsor’s submitted reimbursement request indicates that vericiguat will be prescribed in combination with ACEis, ARBs, or ARNis; beta-blockers; and MRAs, if tolerated. The clinical expert consulted by CADTH for this review noted that clinicians will choose to prescribe SGLT2 inhibitors over vericiguat in combination with triple therapy unless contraindicated,⁶ and only after the failure of standard quadruple therapy will they prescribe vericiguat to patients who are stabilized after a worsening HF event.

Indirect Evidence

No sponsor-submitted NMA was identified for this review.

A focused literature search for indirect treatment comparisons dealing with HF was run in MEDLINE All (1946–) on November 9, 2022. No limits were applied to the search. The literature search identified 7 potential citations, of which 4 were included for consideration for the following reasons: in the VICTORIA trial, vericiguat was compared to placebo plus standard triple therapy, only 14% of patients received sacubitril-valsartan, and none of the patients received SGLT2 inhibitors for HF treatment, as they became available after completion of this trial. The studies identified through the literature search aimed to compare the efficacy of vericiguat for the treatment of patients with HF with reduced ejection fraction with SGLT2 inhibitors, sacubitril-valsartan, ivabradine, and triple HF therapy, which were considered comparators in the systematic review protocol.

Aimo et al. (2021) NMA

An NMA by Aimo et al. (2021)¹⁴ was identified from the literature. The objective of the analysis was to compare vericiguat, sacubitril-valsartan, and SGLT2 inhibitors in the treatment of patients with HF with reduced ejection fraction. Databases, including PubMed, Embase, and clinicaltrials.gov, were searched for articles of interest on September 25, 2020. The systematic review included 6 studies for analysis that compared sacubitril-valsartan, vericiguat, or SGLT2 inhibitors with SOC therapy. A random-effects NMA with the DerSimonian-Laird estimator and a fixed-effects model were performed separately for the primary and secondary outcomes of interest. The primary end point of interest was a composite of CV death and HHF, and the secondary end points included CV death alone and HHF alone.

The pooled results of the NMA showed that for a composite of CV death and HHF, the HR for SGLT2 inhibitors versus vericiguat and versus sacubitril-valsartan was 0.83 (95% CI, 0.73 to 0.94) and 0.92 (95% CI, 0.88 to 1.24), respectively. For CV death, the HR for SGLT2 inhibitors versus vericiguat and versus sacubitril-valsartan was 0.88 (95% CI, 0.63 to 1.22) and 1.04 (95% CI, 0.88 to 1.24), respectively. For HHF, the HR for SGLT2 inhibitors versus vericiguat and versus sacubitril-valsartan was 0.77 (95% CI, 0.66 to 0.89) and 0.87 (95% CI, 0.75 to 1.02), respectively.

De Marzo et al. (2022) NMA

An NMA by De Marzo et al. (2022)¹⁵ was identified from the literature. The objective of the analysis was to compare vericiguat, ivabradine, and SGLT2 inhibitors in the treatment of patients with HF with reduced ejection fraction. Databases, including PubMed, Embase, SCOPUS, and the Cochrane Library, were searched for articles of interest on November 30, 2020. The NMA comprised both a fixed-effects model and a random-effects model within a Bayesian framework. The primary end point of interest was all-cause death, and the secondary end points included CV death, HHF, and all-cause hospitalization. The systematic review included 69 RCTs for all-cause death, 56 RCTs for CV death, 45 RCTs for HHF, and 26 RCTs for all-cause hospitalization.

In the NMA for the primary end point of all-cause death, the HR for ivabradine and for SGLT2 inhibitors versus vericiguat was 0.97 (95% CrI, 0.60 to 1.60) and 0.94 (95% CrI, 0.62 to 1.40), respectively. For CV death, the HR for ivabradine and for SGLT2 inhibitors versus vericiguat was 1.00 (95% CrI, 0.61 to 1.50) and 0.94 (95% CrI, 0.61 to 1.50), respectively. For HHF, the HR for ivabradine and for SGLT2 inhibitors versus vericiguat was 0.89 (95% CrI, 0.50 to 1.70) and 0.88 (95% CrI, 0.56 to 1.60), respectively. The results for all-cause hospitalizations were not reported, as this information was not available in 63% of the RCTs examined.

Luo et al. (2022) NMA

An NMA by Luo et al. (2022)¹⁶ was identified from the literature. The objective of the analysis was to compare sGC stimulators, ARNis, and SGLT2 inhibitors in the treatment of patients with HF with reduced ejection fraction. Databases, including PubMed, Embase, the Cochrane Library, and the Web of Science, were searched for articles of interest on September 1, 2021. A random-effects model was constructed based on frequency theory. The efficacy outcomes included rates of HF rehospitalization, all-cause mortality, CV death, and rates of CV death or HF rehospitalization. A total of 15 RCTs were included for HF rehospitalization, 14 RCTs for all-cause mortality, 12 RCTs for CV death, and 16 RCTs for rates of CV death or HF rehospitalization.

In the NMA for HF rehospitalization, the OR for SGLT2 inhibitors versus sGC stimulators was 0.79 (95% CI, 0.68 to 0.93) and the OR for ARNis versus sGC stimulators was 0.87 (95% CI, 0.75 to 1.01). For all-cause mortality, the OR for SGLT2 inhibitors versus sGC stimulators was 0.98 (95% CI, 0.70 to 1.38) and for ARNis versus sGC stimulators was 0.87 (95% CI, 0.61 to 1.25). For CV death, the OR for SGLT2 inhibitors versus sGC stimulators was 0.96 (95% CI, 0.74 to 1.25) and for ARNis versus sGC stimulators was 0.88 (95% CI, 0.68 to 1.15). For rates of CV death or HF rehospitalization, the OR for SGLT2 inhibitors versus sGC stimulators was 0.87 (95% CI, 0.76 to 1.00) and for ARNis versus sGC stimulators was 0.88 (95% CI, 0.77 to 1.01).

Pagnesi et al. (2022) NMA

An NMA by Pagnesi et al. (2022)¹⁷ was identified from the literature. The objective of the analysis was to compare vericiguat with SGLT2 inhibitors in the treatment of patients with HF with reduced ejection fraction. Databases, including PubMed, Embase, Google Scholar, and the Cochrane Central Register of Controlled Trials, were searched for articles of interest on March 18, 2021. A random-effects NMA was performed on the cumulative event rates for primary and secondary end points based on a frequentist approach with the DerSimonian-Laird estimator. The primary end point was the composite of CV death andHHF, and the secondary end points were CV death, all-cause death, and HHF. The systematic review included 7 studies for the primary end point of CV death or HHF, 10 studies for CV death, 12 studies for all-cause mortality, and 10 studies for HHF.

The results of the NMA for a composite of CV death and HHF, the RR for SGLT2 inhibitors versus vericiguat was 0.84 (95% CI, 0.75 to 0.96). For all-cause mortality, the RR for SGLT2 inhibitors versus vericiguat was 0.90 (95% CI, 0.77 to 1.04). For CV death, the RR for SGLT2 inhibitors versus vericiguat was 0.91 (95% CI, 0.91 to 0.96). For HHF, the RR for SGLT2 inhibitors versus vericiguat was 0.79 (95% CI, 0.69 to 0.91).

Critical Appraisal of Published NMA Articles

The results of the NMAs are highly uncertain, given the heterogeneity across the studies included in the networks, the heterogeneity in the baseline characteristics of patients in the included trials, and the limited information related to definitions of end points. Furthermore, ivabradine and vericiguat were restricted to selected patients who were stabilized after an episode of worsening HF. Results in efficacy estimates were imprecise (i.e., wide CIs, including HR = 1) in many comparisons and end points, which adds to uncertainty in the effect estimates. Therefore, no definitive conclusions can be drawn from the published NMAs for many outcome comparisons due to methodological limitations and imprecision in the effect estimates. Furthermore, safety outcomes were not analyzed in the published NMAs, and no justification was provided, which precludes a balanced judgment of comparative benefits relative to comparative harms. Outcomes important to patients, such as HRQoL, were also not analyzed in the published NMAs.

Other Relevant Evidence

No other relevant evidence was identified for this review.

Discussion

Summary of Available Evidence

The VICTORIA trial¹⁰ was a phase III, randomized, multicentre, double-blind, event-driven, placebo-controlled trial designed to assess the efficacy and safety of vericiguat versus placebo, as an adjunct to SOC therapy in adults with symptomatic chronic HF with reduced ejection fraction who are stabilized after a recent worsening HF event. The trial was initiated on September 20, 2016, at 694 sites in 42 countries in North America (560 patients), Latin and South America, Eastern Europe, Western Europe, and the Asia-Pacific region. In the VICTORIA trial, 5,050 patients were randomized in a 1:1 ratio to receive either vericiguat (N = 2,526) or placebo (N = 2,524). The mean age of all randomized patients in the VICTORIA trial was 67.3 years (SD = 12.2 years). A total of 76.1% of patients were male, and 24.0% were female. About 64.1% of patients were white, and 27.0% were Asian or multiracial. A total of 81.4% of patients were non-Hispanic or non-Latino, and 16.1% were Hispanic or Latino. The mean LVEF was 28.9% (SD = 8.30%), and nearly half of patients had an LVEF of less than 30% (49.3%).

Approximately 70% of patients had an HHF within 3 months prior randomization, 17.2% had an HHF within 3 to 6 months, and 15.9% had received outpatient treatment with IV diuretics for worsening HF within 3 months before hospitalization. A total of 91.2% of patients received 2 or more HF medications, but only 60% of patients received a triple therapy regimen that included an ACEi or ARB, a beta-blocker, and an MRA. The primary efficacy end point was the time to first event of CV death or HHF, and the secondary end points were time to CV death, time to first HHF, time to total events (first and recurrent) of HHF, time to first event of all-cause mortality or HHF, and time to all-cause mortality. HRQoL was assessed using the KCCQ and EQ-5D instruments. Harms and notable harms (identified in the CADTH systematic review protocol) were assessed.

There were 4 published NMAs identified from the literature search that aimed to compare the efficacy of vericiguat with that of SGLT2 inhibitors, sacubitril-valsartan, and ivabradine in patients with HF with reduced ejection fraction. These NMAs had significant methodological limitations, and the results were highly uncertain.

Interpretation of Results

Efficacy

The VICTORIA trial appeared to have appropriate methods for blinding, allocation concealment, randomization with stratification to minimize bias, and the type I error was adequately accounted for in the primary and key secondary outcomes. Definitive conclusions could not be drawn for HRQoL data due to the lack of adjustment for multiplicity and the high risk of attrition bias. Other key limitations of the pivotal trials include the large proportion of screening failures due to the trial’s criterion that directed the inclusion of patients only with elevated NT-proBNP levels, and limited clinical evidence on the benefit of vericiguat in patients with NYHA class I and class IV HF. Thus, it is difficult to draw strong conclusions and generalize the results to all patients with symptomatic chronic HF who may be treated in a Canadian setting. Furthermore, given the potential misclassification of CV deaths, there is a possibility that the trial was stopped earlier than planned. Therefore, there is a risk that the effect of vericiguat, compared to placebo is, overestimated, but the presence and extent of any overestimation is uncertain.^11-13 Additionally, there was no run-in period in the trial to initiate or maintain optimal doses of HF medications to achieve clinical stability after worsening HF.

The superiority of vericiguat over placebo in the time to first event of CV death or HHF was demonstrated with the median follow-up duration of 10.8 months (HR = 0.90; 95% CI, 0.82 to 0.98). However, the median composite of CV death or HHF was not estimable because insufficient follow-up time had elapsed for this outcome. The clinical expert consulted noted that the results of the primary outcome were modest but clinically meaningful, based on the absolute event rate reduction of 4.2% within the selected study population. This difference was likely driven primarily by a lower proportion of HHF events in the vericiguat group compared to placebo group. However, CV death as an individual component within the primary composite end point was not formally tested, and HHF alone was tested out of the hierarchical testing strategy without adjustment for multiplicity and is exploratory in nature. Therefore, a deep understanding of which components of the primary composite end point contributed more to the overall significance remains unclear. The treatment effects for prespecified subgroups in the CADTH protocol were generally consistent with the main effect, whereas a potential difference was noted that depended on NT-proBNP at baseline.

The study demonstrated the superiority of vericiguat over placebo in terms of time to first event of HHF or all-cause mortality, with an absolute event rate reduction of 4.2%. Although individual components of this composite end point were not formally tested for significance, the difference was likely driven by a lower rate of HHF events. The median composite of all-cause mortality and HHF was not estimable because insufficient follow-up time had elapsed for this outcome. Subgroup analyses did not identify a particular group of patients who experienced a considerably higher or lower benefit from empagliflozin on the primary composite end point. The study also demonstrated the superiority of vericiguat over placebo in terms of time to total events (first and recurrent) of HHF, with an absolute event rate reduction of 4.1%. The clinical expert consulted highlighted that the HHF is the most important outcome for assessing treatment response in patients with HF.

There were no differences between the treatment groups in the time to all-cause mortality and the time to adjudicated CV death. The time to CV death tested as part of the secondary analysis captured all CV death events observed during the trial (N = 855) and differed from CV death as a component of the primary composite end point (N = 431). The clinical expert consulted indicated that the list of criteria used to identify CV death was too comprehensive due to inclusion of undetermined causes of death, which could have resulted in the similar number of CV deaths across treatment groups. The clinical expert further noted that the mean duration of treatment exposure and the mean follow-up period were likely short to observe the beneficial effect of vericiguat on mortality, as reducing the number of hospitalizations will lead to a decrease in mortality in the long-term. Other additional end points, such as CV hospitalizations, change in NYHA class, and change in NT-proBNP, were tested as part of the exploratory outcomes. The clinical expert consulted noted that the clinical results of the trial are consistent with biochemical findings, such as change in NT-proBNP.

In their input, patients highlighted HRQoL as important outcome and important treatment goal. The clinical expert consulted indicated that quality of life is probably most important to patients with HF, as it worsens with each hospitalization. HRQoL was assessed using the KCCQ and EQ-5D-5L instruments. Although the KCCQ has been reported to be a generally valid, reliable, and responsive tool, psychometric properties of the EQ-5D-5L instrument have not been assessed in the HF population. In the VICTORIA trial, no clinically meaningful differences were found between treatment groups in change from baseline in KCCQ scores at week 32 (less than the prespecified clinically meaningful threshold of an improvement or deterioration of at least 5 points). Furthermore, for the analysis of KCCQ scores, week 32 scores were missing for about 31% of patients. The results from the EQ-5D-5L analysis showed no difference between the 2 treatment arms, suggesting that vericiguat neither improves nor impedes the HRQoL of patients with chronic HF. In addition, for the analysis of EQ-5D-5L scores, week 52 scores were missing for about 28% of patients.

Overall, the efficacy of vericiguat for use as an adjunct to standard dual or triple therapy for the treatment of adult patients with symptomatic chronic HF with reduced ejection fraction has been demonstrated. However, the generalizability to the current SOC, which includes SGLT2 inhibitors as part of a quadruple drug regimen, is currently unknown because patients enrolled in the VICTORIA trial received dual or triple therapy as background therapy. It is acknowledged that the VICTORIA trial was undertaken at the same time as trials for the recently approved SGLT2 inhibitors for HF with reduced ejection fraction, which likely prevented it from capturing the current SOC. Strong conclusions could not be drawn for HRQoL due to the high risk of attrition bias and increased risk of type I error. Four published NMAs identified from the literature search compared vericiguat with SGLT2 inhibitors, ivabradine, and sacubitril-valsartan for the treatment of patients with HF with reduced ejection fraction. No conclusion could be drawn from the published NMAs due to methodological limitations and imprecision in the effect estimates (i.e., wide 95% CIs, including HR = 1).

Harms

AE profile in the VICTORIA trial was comparable between treatment group, with similar frequencies of AEs, SAEs, and withdrawals due to AEs. Most patients in the 2 treatment groups (80.5% of patients in the vericiguat group and 81.0% of patients in the placebo group) experienced 1 or more AE. The most common AEs were hypotension, anemia, and pneumonia. The clinical expert consulted noted that hypotension would be the most expected AE related to treatment with vericiguat in clinical practice, whereas the incidence of hyperkalemia in the VICTORIA trial is slightly lower than in the real-world setting. There were no notable differences between vericiguat and placebo regarding the overall frequencies of any AE or SAE leading to treatment discontinuation. The incidence of symptomatic hypotension, syncope, and hepatic AEs were considered notable harms for this review, all of which appeared in similar frequencies in both treatment groups in the trial. The clinical experts consulted noted that more AEs would be expected in the vericiguat group compared with the placebo group, given that an additional treatment was added to the regimen in the selected study population. The clinical expert was of the opinion that vericiguat should be prescribed by specialists who have expertise in the management of HF in specialty clinics that focus on the assessment and management of HF to ensure that the drug is prescribed to appropriate patients and side effects or AEs associated with the disease or drug are prevented or managed in a timely manner. However, the sponsor highlighted that patients with HF with reduced ejection fraction in rural settings may not have access to specialty clinics, which are predominantly found in urban city centres. It was further noted by the clinical expert that treatment with vericiguat generally revealed no new safety concerns in the VICTORIA trial.

Conclusions

Based on data from the VICTORIA trial, vericiguat demonstrated a statistically significant and clinically meaningful benefit, compared to placebo, in reducing the hazard rates of the first event of CV death or HHF, occurrence of the first and recurrent HHF event, and the composite of all-cause mortality and HHF in adult patients with symptomatic chronic HF with reduced ejection fraction. The median composite primary end point, total events of HHF, and the composite of all-cause mortality and HHF were not estimable in either treatment group because insufficient follow-up time had elapsed for these outcomes; thus, the longer-term efficacy of vericiguat is unknown. In addition, the estimates of the benefit of vericiguat may be overestimated because of the possibility that the trial was stopped earlier than planned due to the potential misclassification of CV deaths; however, the presence and extent of any overestimation is uncertain. Strong conclusions could not be drawn related to the effect of vericiguat on HRQoL due to the high risk of attrition bias and increased risk of type I error in the analyses of these outcomes. No new safety signals were identified in patients with HF with reduced ejection fraction. Owing to its superiority over placebo, vericiguat may be another treatment option for patients with HF with reduced ejection fraction who are stabilized after a recent HF decompensation event. According to the clinical expert consulted by CADTH, vericiguat may be added to foundational quadruple HF therapy (which includes ACEis or ARBs, beta-blockers, MRAs, and SGLT2 inhibitors); however, the cumulative benefit of vericiguat added to the current model of quadruple therapy remains unknown. No conclusions could be drawn from the published NMAs about the efficacy of vericiguat, relative to SGLT2 inhibitors, ivabradine, or sacubitril-valsartan for the treatment of patients with HF with reduced ejection fraction due to methodological limitations and imprecision in the effect estimates.

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