Indication: For the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilized after a recent heart failure decompensation event requiring hospitalization and/or IV diuretic therapy. Vericiguat should be used in combination with standard of care therapy for heart failure.
Sponsor: Bayer Inc.
Final recommendation: Reimburse with conditions
Summary
What Is the CADTH Reimbursement Recommendation for Verquvo?
CADTH recommends that Verquvo be reimbursed by public drug plans for the treatment of chronic heart failure (HF) as an adjunct to standard of care therapy if certain conditions are met.
Which Patients Are Eligible for Coverage?
Verquvo should only be covered to treat adult patients: whose heart is unable to pump enough blood to keep up with the body’s needs because the heart is too weak (i.e., HF with reduced ejection fraction); who are considered to be symptomatic (e.g., slight limitation in physical activity, defined as New York Heart Association [NYHA] functional classification class II; a marked limitation in physical activity, defined as NYHA class III; or symptoms even at rest, defined as NYHA class IV); and who had a recent hospitalization or needed to receive IV medicines.
What Are the Conditions for Reimbursement?
Verquvo should only be reimbursed if the price of Verquvo is reduced.
Why Did CADTH Make This Recommendation?
Evidence from 1 clinical trial (VICTORIA) demonstrated that patients with symptomatic chronic HF who were treated with Verquvo were less likely to die from cardiovascular (CV) events or be hospitalized due to HF compared to those who were treated with standard of care alone.
Patients identified a need for new therapies to treat HF with reduced ejection fraction that work and improve their quality of life. Verquvo has the potential to meet some of these needs as the evidence from the VICTORIA trial showed that Verquvo worked for some patients.
Based on CADTH’s assessment of the health economic evidence, Verquvo does not represent good value to the health care system at the public list price. A price reduction is therefore required.
Based on public list prices, Verquvo is estimated to cost the public drug plans approximately $18 million over the next 3 years.
Additional Information
What Is Heart Failure?
HF is a condition whereby the heart is unable to pump enough blood to keep up with the body’s needs. HF can be considered acute (no previous signs or symptoms of HF) or chronic (slowly over time, the heart weakens and has difficulties pumping enough blood throughout the body). The severity of HF is classified in 4 stages, ranging from patients with no HF symptoms (NYHA class I) to patients with HF symptoms even at rest (NYHA class IV).
Unmet Needs in HF
For patients with HF with reduced ejection fraction, Verquvo can be used in those who are not eligible for standard of care therapy, or those who experience disease progression while on standard therapy.
How Much Does Verquvo Cost?
Treatment with Verquvo is expected to cost approximately $1,763 per patient per year.
There is a potential for vericiguat to be prescribed to patients outside of the population used in the VICTORIA trial. The associated impact, in terms of cost and value for money, is not known.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that vericiguat be reimbursed for the treatment of symptomatic chronic HF in adult patients with reduced ejection fraction who are stabilized after a recent HF decompensation event requiring hospitalization and/or IV diuretic therapy only if the conditions listed in Table 1 are met.
One phase III, multicentre, double-blind, randomized placebo-controlled trial (VICTORIA; N = 5,050) demonstrated that treatment with vericiguat when added to dual or triple background HF therapy resulted in added clinical benefit for patients with symptomatic chronic HF with a reduced ejection fraction who are stabilized after a recent HF decompensation event. Compared with placebo, treatment with vericiguat was associated with a statistically significant and clinically meaningful reduction in the hazard of a first event of CV death or hospitalization for heart failure (HHF) (hazard ratio [HR] = 0.90; 95% confidence interval [CI], 0.82 to 0.98). The hazard of total HHF events (first and recurrent) was lower in the vericiguat group relative to placebo in the VICTORIA trial (HR = 0.91; 95% CI, 0.84 to 0.99). Compared to placebo, the hazard of the first event of all-cause mortality or HHF was lower in the vericiguat group (HR = 0.90; 95% CI, 0.83 to 0.98). Patients identified an unmet need for new therapies to treat HF with reduced ejection fraction that were effective and improved their quality of life. CDEC concluded that vericiguat potentially meets some of these needs.
Using the sponsor-submitted price for vericiguat and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio for vericiguat in combination with background therapy was $62,778 per quality-adjusted life-year compared with background therapy alone. Vericiguat is not cost-effective at a willingness-to-pay threshold of $50,000 per quality-adjusted life-year for adults with chronic HF and reduced ejection fraction who are stabilized after a recent HF decompensation event. A price reduction is required for vericiguat to be considered cost-effective at this threshold.
Table 1: Reimbursement Conditions and Reasons
Reimbursement condition | Reason | Implementation guidance |
|---|---|---|
Initiation | ||
1. Patients with symptomatic chronic HF with reduced ejection fraction | In the VICTORIA trial, treatment with vericiguat demonstrated a clinical benefit in patients who were at least 18 years of age and with symptomatic chronic HF and reduced ejection fraction (LVEF < 45%). | Vericiguat should be prescribed in combination with standard of care HF therapy. |
2. Patients must have a recent HF decompensation event requiring hospitalization and/or IV diuretic therapy | Patients enrolled in the VICTORIA trial had a recent HF decompensation event, defined as previous HHF within 6 months or IV diuretic treatment for HF (without hospitalization) within 3 months before randomization. | — |
Pricing | ||
3. A reduction in price | The ICER for vericiguat in combination with BT is $62,778 when compared with BT alone. A price reduction of 14% would be required for vericiguat in combination with BT to achieve an ICER of $50,000 per QALY compared to BT alone. | — |
Feasibility of adoption | ||
4. Organizational feasibility | Potential exists for vericiguat to be prescribed to patients outside the eligible population for the VICTORIA trial. Consequently, the value represented to the full indicated population is unclear. | — |
BT = background therapy; HHF = hospitalization for heart failure; HF = heart failure; ICER = incremental cost-effectiveness ratio; LVEF = left ventricular ejection fraction.
CDEC acknowledged that the VICTORIA trial demonstrated that vericiguat can be beneficial in combination with dual or triple HF therapy in adult patients with symptomatic HF, including NYHA classes II to IV. In the VICTORIA trial, background therapy included beta blockers, angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), or an angiotensin receptor–neprilysin inhibitor (ARNI), and mineralocorticoid receptor antagonists (MRAs). In the VICTORIA trial, 91.4% of patients were receiving at least 2 medications, 60% of patients were receiving 3 medications, and 14% of patients were receiving sacubitril-valsartan.
CDEC identified an evidence gap between the treatment regimens in the VICTORIA trial and current standard quadruple therapy, which includes sodium-glucose cotransporter 2 (SGLT2) inhibitors. No patients received background therapy with SGLT2 inhibitors in the VICTORIA trial; therefore, the cumulative benefit and potential harms of adding vericiguat to standard quadruple therapy or adding vericiguat instead of SGLT2 inhibitors to triple therapy remains unknown.
CDEC further noted the cost-effectiveness, incremental benefit, and incremental cost of vericiguat either added to standard quadruple therapy or added instead of SGLT2 inhibitors to triple therapy remains unknown.
CDEC noted that there was no evidence from the VICTORIA trial that demonstrated whether patients who are intolerant to 1 or more of the classes of medications included in standard HF therapy may benefit from the addition of vericiguat.
The potential misclassification of CV deaths in the VICTORIA trial may overestimate the true incidence by including undetermined cause of death (27% [112 of 414 CV deaths] and 23% [101 of 441 CV deaths] in the vericiguat and placebo groups respectively); therefore, there is a possibility that stopping the trial early may have overestimated the effect of vericiguat compared to placebo. The presence and extent of any overestimation, however, is uncertain.
In the VICTORIA trial, 26.4% of patients were not screened into the study, mostly because of below-threshold N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. The clinical expert consulted indicated that NT-proBNP testing is not widely available in Canada; thus, this patient selection criterion would be difficult to implement in clinical practice.
Improvement in health-related quality of life (HRQoL) has been identified by both patients and the clinical expert as an important outcome and goal in the treatment of patients with HF. In the VICTORIA trial, no clinically meaningful differences were found between treatment groups in change from baseline Kansas City Cardiomyopathy Questionnaire (KCCQ) scores (i.e., less than a minimal important difference of at least 5 points) and 5-Level EQ-5D (EQ-5D-5L) index scores at week 32. These results should be interpreted as supportive evidence only, as this outcome was not part of the statistical testing hierarchy and there was a high rate of attrition at later follow-up periods.
HF, sometimes referred to as congestive HF, is a clinical condition whereby 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 and 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). HF with reduced ejection fraction (HFrEF) 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 aged older than 40 years with HF, with an age-standardized prevalence of 3.5%. Between 2001 and 2013, the age-standardized incidence rate of HF in Canada has declined, as has the age-standardized all-cause mortality rate among people living with HF. However, people in Canada aged older than 40 years with HF are 6 times more likely to die than those without an HF diagnosis. 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 is significantly affecting a patient’s quality of life. Depending on severity, HF may go unnoticed, only causing minor symptoms, but patients with advanced HF may find it difficult to carry out normal everyday activities. 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 leads to hospitalization or an emergency department visit. Worsening HF and hospitalizations for HF portend a poor prognosis and are associated with an increased risk of mortality and readmissions. Hospitalizations due to HF are frequent, with 83% of patients hospitalized at least once, and 43% of patients hospitalized 4 or more times after a diagnosis of HF. 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%. The current foundational pharmaceutical management of HFrEF encompasses combination therapy (in the absence of contraindications), including 1 evidence-based medication from each of the following categories: sacubitril-valsartan, either as first-line therapy or switching from ACEis, or ARBs; beta blockers; MRAs; and SGLT2 inhibitors. More recently, new therapies such as soluble guanylate cyclase (sGC) or ivabradine (a sinus node inhibitor), have emerged to be taken in conjunction with well-established therapies and have shown benefit for those with HFrEF.
Vericiguat is a stimulator of sGC. HF is associated with impaired nitric oxide 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 nitric oxide, to increase the level of intracellular cyclic guanosine monophosphate, which may improve both myocardial and vascular function. According to the proposed Health Canada indication, vericiguat is indicated for the treatment of symptomatic chronic HF in adults with reduced ejection fraction who are stabilized after a recent HF decompensation event requiring hospitalization and/or IV diuretic therapy. Verquvo should be used in combination with standard of care therapy for HF and should be initiated under the supervision of a health care professional who is experienced in the management of HF. The recommended starting dosage 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.
To make its recommendation, the committee considered the following information:
a review of 1 clinical trial in adults with symptomatic chronic HF and reduced ejection fraction
patients’ perspectives gathered by 2 patient groups: the HeartLife Foundation, and the Heart Function Clinic in Vancouver General Hospital, St. Paul’s Hospital
input from the public drug plans that participate in the CADTH review process
input from 1 clinical specialist with expertise diagnosing and treating patients with HF
input from 3 clinician groups, including Oakville Cardiologists, University of Alberta, Division of Cardiology, and the North Shore Heart Centre
a review of 4 published indirect treatment comparisons retrieved from the literature
a review of the pharmacoeconomic model and report submitted by the sponsor.
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.
Two patient groups, the HeartLife Foundation and the Heart Function Clinic in Vancouver General Hospital, St. Paul’s Hospital, 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 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 varies widely across Canada and that every individual’s experience with HF is unique. Two patient interviews (ages were 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 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, and 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.
The clinical expert consulted by CADTH for this review indicated that HFrEF 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 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 reduction in burden of symptoms, 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 that focus on the assessment and management of HF. It was further mentioned by the clinical expert that the addition of this medication to the current treatment paradigm is expected to have a positive impact on the management of these patients.
The clinician group input was obtained from 3 clinician groups, including Oakville Cardiologists, which was represented by 9 clinicians, 1 from the Division of Cardiology, University of Alberta, and 1 representing the North Shore Heart Centre. 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 room visits. All clinician groups agreed that morbidity and mortality remain high in patients with HFrEF 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 clinician groups agreed that vericiguat represents an additional approach to the treatment of HFrEF, which is not targeted by the current guideline-directed medical therapy. 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 and/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 glomerular filtration rate of less than 15 mL/min/1.73 m2, severe hypotension, and syncope. 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 HFrEF in the outpatient setting. The clinical groups advocated for vericiguat to be an accessible treatment option to the high-risk HF population as it is safe, well-tolerated, and taken once daily.
The clinical expert consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Table 2: Responses to Questions From the Drug Programs
Implementation issues | Response |
|---|---|
Relevant comparators | |
Issues with the choice of comparator in the submitted trial The pivotal phase III VICTORIA trial demonstrated that vericiguat had a significant reduction in CV death and HHF with a comparable safety profile to placebo on top of background therapy. The background therapy included ACEis, ARBs, ARNis, beta blockers, and/or MRAs, which represented the SOC at the time of the trial’s conclusion and continue to represent fundamental pillars of the new SOC. The Canadian Cardiovascular Society defines 4 key therapeutic drug classes as standard therapy for most patients: ARNIs (as first-line therapy or after ACEis or ARBs titration), beta blockers, MRAs, and SGLT2 inhibitors. How can vericiguat be integrated into the current treatment paradigm with drugs such as dapagliflozin, empagliflozin, or ivabradine? | Vericiguat may be added to foundational quadruple HF therapy as its mechanism of action is different from current quadruple therapy medications. However, given that SGLT2 inhibitors are also now an option, the cumulative benefit of vericiguat added to quadruple therapy remains unknown. Not all patients are eligible for standard quadruple therapy because of side effects, contraindications, or comorbidities; vericiguat could be a treatment option for these patients. |
Considerations for initiation of therapy | |
Disease diagnosis, scoring or staging for eligibility In the VICTORIA trial, evidence of worsening HF was categorized based on the timing of the HF decompensation — those hospitalized within 3 to 6 months before randomization, or those receiving IV diuretics for HF, without hospitalization, within the previous 3 months. How is worsening HF defined in clinical practice? | HF decompensation event or progressive HF is most commonly defined as worsening symptoms while on conventional therapy, resulting in treatment escalation and hospitalization or outpatient IV diuretic treatment. The laboratory and diagnostic tests to define worsening HF include elevated BNP or NT-proBNP, or reduction in ejection fraction. |
Eligibility to re-treatment What is the expected treatment duration for vericiguat? | HF is a chronic disease, and given the mechanism of action of vericiguat, the duration of treatment is indefinite. |
Considerations for prescribing of therapy | |
Dosing, schedule and frequency, dose intensity The recommended starting dosage 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. | Comment from the drug programs to inform CDEC deliberations |
Consistency with prescribing criteria associated with other drugs reviewed by CADTH in the same therapeutic space Per the indication and sponsor request, vericiguat “should be initiated under the supervision of a healthcare professional who is experienced in the management of HF.” | Comment from the drug programs to inform CDEC deliberations |
System and economic issues | |
Concerns regarding the anticipated budget impact and sustainability The list price of vericiguat 2.5 mg, 5 mg, and 10 mg is anticipated to be $4.83 per tablet in Canada, which corresponds to a total cost of $4.83 per day (once daily dosage). The BIA estimates that listing vericiguat will lead to an incremental budget impact of $2,469,604 in year 1, $5,010,977 in year 2, and $7,625,827 in year 3, for a total of $15.1 million over 3 years. | Comment from the drug programs to inform CDEC deliberations |
Presence of confidential negotiated prices for comparators The negotiated prices for Inspra (eplerenone), Entresto (sacubitril-valsartan), and Forxiga (dapagliflozin) for HF were considered. Generics are available for other comparators. | Comment from the drug programs to inform CDEC deliberations |
ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor antagonist; ARNi = angiotensin receptor–neprilysin inhibitor; BIA = budget impact analysis; BNP = brain natriuretic peptide; CV = cardiovascular; HF = heart failure; HHF = hospitalization for heart failure; NT-proBNP = N-terminal pro-brain natriuretic peptide; MRA = mineralocorticoid receptor antagonist; SOC = standard of care; SGLT2 = sodium-glucose cotransporter 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 standard of care 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 use of IV diuretic for HF (without hospitalization) within 3 months before randomization. A total of 5,050 patients with symptomatic chronic HFrEF were enrolled across 694 sites in 42 countries in North America (560 patients), Eastern Europe, Western Europe, Asia Pacific, and Latin and South America. The primary efficacy end point was the time to first event of the adjudicated 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 EQ-5D instrument. Futility and efficacy interim analyses were scheduled for the time when approximately 75% (587 events) of the planned number of CV death events were reached, and a 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) and most patients were male (76.1%), white (64.1%), and not Hispanic or Latino (81.4%). 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 were classified as NYHA functional class II and III (98.6%) at baseline. The mean NT-proBNP was ||||||| pg/mL (SD = ||||||| pg/mL), the mean brain natriuretic peptide was ||||||| pg/mL (SD = |||||||| pg/mL), and the mean estimated glomerular filtration rate was |||| mL/min/1.73 m2 (SD = ||||| mL/min/1.73 m2). Approximately 70% of patients had HHF within 3 months before randomization, 30% 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 91.4% of patients had received 2 or more HF medications, and only 60% of patients had received triple therapy, including ACEis or ARBs, beta blockers, and MRAs.
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 the placebo group (33.6% and 37.8%, respectively), with an HR 0.90 (95% 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 first event was lower in the vericiguat group (27.4%) compared to the placebo group (29.6%), while the proportion of CV death was similar across the treatment groups (8.2% versus 8.9% in the vericiguat and placebo groups, respectively).
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 due to HF was 6.5% and 7.6% in the vericiguat and placebo groups, respectively; the proportion of patients who died of a sudden cardiac event was –4.2% and 4.5% in the vericiguat and placebo groups, respectively; and the proportion of patients with an 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 (95% CI, 0.81 to 1.06; P = 0.269).
A total of 512 (20.3%) patients in the vericiguat group and 534 (21.2%) patients in the placebo group died from any cause. 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).
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 the individual components of this composite end point were not formally tested for significance.
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 (|||||) than in the placebo group (|||||), with an HR || |||| |||| ||| |||| || ||||| | ||||||| .
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).
The total number of HHF events was lower in patients who received vericiguat (1,223) than in those who received placebo (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).
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.
For the analysis of the KCCQ score based on the intention-to-treat population (ITT), week 32 data were missing for 22.8% to 30.4% of the patients in the vericiguat group, and for 23.8% to 32.0% of the patients in the placebo group. No clinically meaningful differences were found between the treatment groups in change from baseline in KCCQ scores at week 32 (i.e., less than a minimal important difference of 5 or more points).
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 2.6 points (SD = 28.4) in the vericiguat group and 0.8 points (SD = 30.0) in the placebo group in the KCCQ overall summary score at week 32, with a least squares (LS) mean difference of 1.2 (95% CI, –0.5 to 2.9; P = 0.180).
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 ||| |||| ||| |||| || |||| || ||||||.
The KCCQ total symptom score incorporates the 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 ||| |||| ||| |||| || |||| || ||||||.
For the analysis of the EQ-5D-5L index score based on the ITT population, week 32 data were missing for 23.1% and 24.8% of the patients in the vericiguat and placebo groups, respectively. No difference was found between the 2 treatment groups in mean change of 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 (–0.01 to 0.03; P = 0.257), respectively.
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 event (AE). The most common AEs occurring 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 across 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 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).
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 were 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, which led to successful randomization. A relatively high proportion of patients prematurely discontinued the trial medication (38.7%), though 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, which reflects the natural course of HF. In accordance with the exclusion criteria, patients in the trial were randomized starting 24 hours after IV diuretic treatment, and this period may not be enough to achieve clinical stability after a worsening HF event, which 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 diuretics is required to achieve clinical stability, and sometimes it takes several days or weeks to become stable.
An independent blinded clinical events committee 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 deaths. Given the potential misclassification of CV deaths, which may overestimate the true incidence of CV death events as they include undetermined cause 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, though the presence and extent of any estimation is uncertain.11-13 Median primary composite end point, all-cause survival, total hospitalization for HF, and a composite of all-cause mortality or hospitalization for HF were 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. While 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, while 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.
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 related to patients classified as NYHA class I and IV, because the VICTORIA trials excluded patients who were NYHA class I, and only a very small proportion of patients who were NYHA class IV (1.1%) were included. Furthermore, the clinical expert consulted indicated that patients classified as NYHA class IV are more likely to be clinically unstable than those who are NYHA class II or III. About 26.4% of patients in the trial did not pass the screening, predominantly because the patients’ NT-proBNP level were below the prespecified threshold at screening. According to the clinical expert consulted, 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 enrolment of patients with elevated NT-proBNP levels likely created an enriched population in the trial because these patients appear to be sicker and may benefit more 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 HFrEF (where the mean age of patients is 75 to 77 years). Most patients were white and not Hispanic or Latino, and only 11% were recruited from North America. The clinical expert consulted noted that the lack of representation of patients living in Canada does not reduce the generalizability of results to Canadian clinical practice.
About 91% of patients in the trial received 2 or more background HF treatment, 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 HFrEF 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, 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.
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: first, in the VICTORIA trial, vericiguat was compared to placebo plus standard triple therapy; second, only 14% of patients received sacubitril-valsartan; and third, none of the patients received SGLT2 inhibitors for HF treatment, as they became available after completion of this trial. Four studies identified through the literature search aimed to compare the efficacy of vericiguat in the treatment of patients with HFrEF with SGLT2 inhibitors, sacubitril-valsartan, ivabradine, and a standard triple therapy, which were considered as comparators in the systematic review protocol.
The NMA was identified from the literature included in the publication from Aimo et al. (2021). The objective of the analysis was to compare vericiguat with sacubitril-valsartan and SGLT2 inhibitors in the treatment of patients with HFrEF. 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 comparing sacubitril-valsartan, vericiguat, or SGLT2 inhibitors versus standard of care therapy. A random-effects NMA using 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 or HHF, and the secondary end points included CV death alone and HHF alone.
The pooled results of the NMA showed a composite of CV death or HHF, and the HRs for SGLT2 inhibitors versus vericiguat and sacubitril-valsartan were 0.83 (95% CI, 0.73 to 0.94) and 0.92 (95% CI, 0.88 to 1.24), respectively. For CV death, the HRs for SGLT2 inhibitors versus vericiguat and sacubitril-valsartan were 0.88 (95% CI, 0.63 to 1.22) and 1.04 (95% CI, 0.88 to 1.24), respectively. For HHF, the HRs for SGLT2 inhibitors versus vericiguat and sacubitril-valsartan were 0.77 (95% CI, 0.66 to 0.89) and 0.87 (95% CI, 0.75 to 1.02), respectively.
The NMA identified from the literature was included in the publication from De Marzo et al. (2022). The objective of the analysis was to compare the efficacy of vericiguat, ivabradine, and SGLT2 inhibitors in the treatment of patients with HFrEF. 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 HRs for ivabradine and SGLT2 inhibitors versus vericiguat were 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 HRs for ivabradine and SGLT2 inhibitors versus vericiguat were 1.00 (95% CrI, 0.61 to 1.50) and 0.94 (95% CrI, 0.61 to 1.50). For HHF, the HRs for ivabradine and SGLT2 inhibitors versus vericiguat were 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.
The NMA was identified from the literature included in the publication from Luo et al. (2022). The objective of the analysis was to compare sGCs, ARNIs, and SGLT2 inhibitors in the treatment of patients with HFrEF. Databases including PubMed, EMBASE, 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.
In the results of the NMA for HF rehospitalization, the odds ratio (OR) for SGLT2 inhibitors versus sGCs was 0.79 (95% CI, 0.68 to 0.93), while the OR for ARNIs versus sGCs it was 0.87 (95% CI, 0.75 to 1.01). For all-cause mortality, the OR for SGLT2 inhibitors versus sGCs was 0.98 (95% CI, 0.70 to 1.38), while for ARNIs versus sGCs it was 0.87 (95% CI, 0.61 to 1.25). For CV death, the OR for SGLT2 inhibitors versus sGCs was 0.96 (95% CI, 0.74 to 1.25), while for ARNIs versus sGCs it was 0.88 (95% CI, 0.68 to 1.15). For CV death or HF rehospitalization, the OR for SGLT2 inhibitors versus sGCs was 0.87 (95% CI, 0.76 to 1.00), while for ARNIs versus sGCs it was 0.88 (95% CI, 0.77 to 1.01).
The NMA was identified from the literature included in the publication from Pagnesi et al. (2022). The objective of the analysis was to compare vericiguat with SGLT2 inhibitors in the treatment of patients with HFrEF. 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 or HHF, while secondary end points were CV death, all-cause death, and HHF. The systematic review included 7 studies for the composite of CV death or HHF, 10 studies for CV death, 12 studies for all-cause mortality, and 10 studies for HHF.
In 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, 0.90 to 0.96). For HHF, the RR for SGLT2 inhibitors versus vericiguat was 0.79 (95% CI, 0.69 to 0.91).
The results of the NMA are highly uncertain given the heterogeneity across the studies included in the networks, the 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 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.
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 or HHF in adult patients with symptomatic chronic HFrEF. The median composite primary end point, total events of hospitalization for HF, and the composite of all-cause mortality or hospitalization for HF 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 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 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 HFrEF. Owing to its superiority over placebo, vericiguat may be another treatment option for patients with HFrEF 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, ARBs, beta blockers, MRAs, and SGLT2 inhibitors); however, the cumulative benefit of vericiguat added to the current modal 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 HFrEF due to methodological limitations and imprecision in the effect estimates.
Table 3: Cost and Cost-Effectiveness
Component | Description |
|---|---|
Type of economic evaluation | Cost-utility analysis Markov model |
Target population | Adult patients with chronic HF and an EF of < 45% who are stabilized after a recent HF decompensation event who:
|
Treatment | Vericiguat and BTs, including ACEis, ARBs, ARNIs, BBs, and MRAs |
Dose regimen | The recommended starting dose of vericiguat is 2.5 mg once daily. Patients are up-titrated to 5 mg and then to the target dose of 10 mg of vericiguat at 2-week intervals. |
Submitted price | Vericiguat 2.5 mg, 5 mg, or 10 mg: $4.83 per tablet |
Treatment cost | At the submitted price of $4.83 per 2.5 mg, 5 mg, or 10 mg tablet, the annual per-patient cost of vericiguat is $1,763. This resulted in an annual per-patient cost of $2,567 for vericiguat plus BT. |
Comparator | BT alone |
Perspective | Canadian publicly funded health care payer |
Outcomes | QALYs, LYs |
Time horizon | 15 years |
Key data source | VICTORIA (phase III clinical trial) |
Key limitations |
|
CADTH reanalysis results |
|
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor antagonist; ARNI = angiotensin receptor and neprilysin inhibitor; BB = beta blocker; BT = background therapy; COPD = chronic obstructive pulmonary disease; EF = ejection fraction; HF = heart failure; HFH = heart failure hospitalization; HFrEF = heart failure with reduced ejection fraction; ICER = incremental cost-effectiveness ratio; LY = life-year; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; OS = overall survival; QALY = quality-adjusted life-year; SGLT2I = sodium-glucose cotransporter 2; vs. = versus; WTP = willingness to pay.
CADTH identified the following limitations in the sponsor’s base case: the proportion of patients who would experience an HF decompensation event annually is underestimated, and the proportion of patients with chronic HF and an EF of less than 45% is uncertain. CADTH performed a reanalysis, in line with clinician expert opinion, by increasing the proportion of patients expected to experience an HF decompensation event annually to 36.8%, in accordance with the relevant literature.
Based on the CADTH reanalysis, the budget impact from the introduction of vericiguat is expected to be $2,979,718 in year 1, $6,046,031 in year 2, and $9,200,998 in year 3, with a 3-year total of $18,226,748.
CADTH conducted scenario analyses to assess the impact of different assumptions regarding the prevalence of HF with an ejection fraction of less than 45%. This led to an increase in the estimated 3-year budget impact to $20,728,458 when assuming 58% prevalence and a decrease in the estimated 3-year budget impact to $16,082,424 when assuming 45% prevalence.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed
Meeting date: March 23, 2023
Regrets: One expert committee member did not attend.
Conflicts of interest: None
ISSN: 2563-6596
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