New in Heart Failure:

Vericiguat
Ashley Logan, PharmD
PGY1 Pharmacy Resident
Parkview Health
Objectives

Discuss
• Discuss vericiguat and information regarding the
medication

Review
• Review novel mechanism of action of this
medication

Evaluate
• Evaluate primary literature regarding vericiguat and
its use in heart failure

Determine
• Determine vericiguat’s place in therapy for the
treatment of heart failure
Vericiguat Overview
Indication, Mechanism of Action, and Concerns with Use
 Vericiguat (Verquvo)
FDA approved in 2021

Class:

• Soluble Guanylate Cyclase (sGC) Stimulator

Indication:

• Heart failure with reduced ejection fraction (<

45%)
• Symptomatic patients already optimized on goal
directed medical therapy (GDMT)
Vericiguat. Package insert. 2021.
Vericiguat. Lexicomp. http://online.lexi.com.
https://www.medchemexpress.com/Vericiguat.html
Mechanism of Action
Mechanism of Action

Lang NN, et al. Cardiovasc Res. 2020.

Dosing
Initial
• 2.5 mg once daily taken with food

Titration in 2-week intervals to a goal of 10 mg once daily

• Based on blood pressure and symptoms

• Systolic blood pressure > 100 mmHg: consider increasing dose if not already
at 10 mg maximum
• Systolic blood pressure > 90 and < 100 mmHg: maintain current dosing
• Systolic blood pressure < 90 mmHg: decrease dose or interrupt therapy (if
dosing 2.5 mg once daily or patient with symptomatic hypotension)

Vericiguat. Package insert. 2021.

Vericiguat. Lexicomp. http://online.lexi.com.
Dosing Adjustments
 Dose adjustments
 Renal impairment
 eGFR > 15 mL/minute/1.73 m^2:
no adjustments needed
 eGFR < 15 mL/minute/1.73 m^2 or
hemodialysis: has not yet been
studied
 Hepatic impairment:
 Mild to moderate impairment: no
adjustments needed
 Severe: has not yet been studied

Vericiguat. Package insert. 2021.

Vericiguat. Lexicomp. http://online.lexi.com.
 Adverse reactions

• Most common: Hypotension (frequency > 10%)

• Frequency < 10%:
• Dyspepsia (3%)
• Nausea (4%)
Concerns • Anemia (10%)
with
Vericiguat Warnings
Use • Concomitant use with long-acting nitrates or
PDE-5 inhibitors

Contraindications

• Pregnancy

Vericiguat. Package insert. 2021.

Vericiguat. Lexicomp. http://online.lexi.com.
 Cost
Vericiguat Sacubitril/valsartan (Entresto)*

Tablet Size Average Wholesale

Tablet Size Average Wholesale
Price
Price
24-26 mg
2.5 mg $11.66
$23.32 (per each)
(per each)
49-51 mg
5 mg (per each) $11.66
$23.32 (per each)
97-103 mg
$11.66
10 mg (per each)
(per each) $23.32
*Entresto is dosed twice daily

Vericiguat. Lexicomp. http://online.lexi.com.

Literature Regarding
Vericiguat
Vericiguat in Patients with
Heart Failure and Reduced
Ejection Fraction
(VICTORIA)

Armstrong PW, et al. N Engl J Med. 2020.

Study Overview
Objective
• Assess the efficacy and safety of vericiguat in patients with heart failure
with reduced ejection fraction (HFrEF) and chronic heart failure with
recent decompensated heart failure

Methods
• Multinational, randomized, double-blinded, placebo-controlled trial
• Initial dosing: 2.5 mg
• Titration based on systolic blood pressure up to maximum dose of 10
mg
• Patients were evaluated every 4 months after titration period
• Screening period (0 to 30 days)

Armstrong PW, et al. N Engl J Med. 2020.

 Inclusion/Exclusion Criteria
Inclusion Exclusion
• CHF (MYHA class II, III, IV) • SBP < 100 mmHg
• Reduced EF (< 45%) within past 12 • Concurrent use of long-acting nitrates,
months soluble guanylate cyclase stimulators, or
• Elevated natriuretic peptide levels PDE-5 inhibitors
within past 30 days • Use of intravenous inotropes or left
• Normal sinus rhythm ventricular assist devices (LVADs)
• BNP: > 300 pg/mL
• NT-proBNP: > 1000 pg/mL
• Atrial fibrillation
• BNP: > 500 pg/mL
• NT-proBNP: > 1600 pg/mL
• Evidence of worsening heart failure

Armstrong PW, et al. N Engl J Med. 2020.

Study Outcomes
Primary

• Composite of death from cardiovascular causes or first hospitalization for heart failure

Secondary

• First and subsequent hospitalizations for heart failure

• Composite of death from any cause or first hospitalization for heart failure
• Death from any cause

Safety Outcomes

• Symptomatic hypotension
• Syncope

Armstrong PW, et al. N Engl J Med. 2020.

Baseline Characteristics
Characteristic Total (N = 5050)

Index Event (Defining worsening heart failure)

HF hospitalization w/in 3 months 3378 (66.9%)
HF hospitalization w/in 3-6 months 871 (17.2%)
IV diuretic w/in 3 months 801 (15.9%)

NYHA Heart Failure Classification

II 2975 (59.0%)
III 2003 (39.7%)
IV 66 (1.3%)

Concomitant Medications
ACE-Inhibitor or ARB 3704 (73.5%)
Beta-Blocker 4691 (93.1%)
MRA 3548 (70.4%)
ARNI (sacubitril/valsartan) 731 (14.5%)
Triple Therapy (MRA + BB + ACE-I/ARB/ARNI) 3013 (59.8%)

Armstrong PW, et al. N Engl J Med. 2020.

Pieke B, et al. Eur J Heart Fail. 2019.
Results
Outcome Vericiguat Placebo Hazard Ratio P-Value
(N = 2526) (N = 2524) (95% CI)
Primary Outcome
Death from CV causes or
first hospitalization for 897 (35.5%) 972 (38.5%) 0.90 (0.82 – 0.98) 0.02
heart failure
Secondary Outcomes
Total Hospitalizations* 1223 1336 0.91 (0.84 – 0.99) 0.02
Death from any cause or
first hospitalization for 957 (37.9) 1032 (40.9) 0.90 (0.83 – 0.98) 0.02
heart failure
Death from any cause 512 (20.3) 534 (21.2) 0.95 (0.84 – 1.07) 0.38

Armstrong PW, et al. N Engl J Med. 2020.

Safety Results
Vericiguat (N = Placebo Estimate (95%
Adverse Reaction P-Value
2519) (N = 2515) CI)

Symptomatic
Hypotension 229 (9.1%) 198 (7.9%) 1.2 (-0.3 to 2.8) 0.121

Syncope
101 (4.0%) 87 (3.5%) 0.6 (-0.5 to 1.6) 0.303

Gastrointestinal
Disorders 637 (25.3%) 546 (21.7%) --- ---

Anemia
192 (7.6%) 143 (5.7%) --- ---

Armstrong PW, et al. N Engl J Med. 2020.

Conclusion
Conclusion

• At around 11 months of therapy, the outcome of death from cardiovascular causes or first
hospitalization for heart failure was significantly lower in the vericiguat group compared to
the placebo group.

Limitations

• Short study duration (10.8 months)

• Small number of patients on either sacubitril/valsartan or an SGLT2 inhibitor

Strengths

• High-risk population included in the study

• Very few patients lost to follow-up, as well as high adherence rate to the study medication

Armstrong PW, et al. N Engl J Med. 2020.

Effect of Vericiguat vs Placebo
on Quality of Life in Patients
with Heart Failure and Preserved
Ejection Fraction
(VITALITY-HFpEF)

Armstrong PW, et al. JAMA. 2020.

Study Overview
Objective
• To determine if vericiguat improved the physical limitation score
(PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ)
when compared to placebo in patients with HFpEF after 24 weeks.

Methods
• Multicenter, randomized, double-blinded, placebo-controlled, phase
2b trial
• Randomized on 1:1:1 to receive either placebo, vericiguat 10 mg,
or vericiguat 15 mg

Armstrong PW, et al. JAMA. 2020.

KCCQ
23-item self-administered questionnaire

Measures patient’s perception of their health status

• Heart failure symptoms

• Impact on physical and social function
• How heart failure impacts their quality of life (QOL)

Consists of 6 domains and 2 summary scores

• Symptom domain
• Physical function domain
• Quality of life domain
• Social limitation domain
• Self-efficacy domain
• Symptom stability domain
• Clinical summary score
• Overall summary score

Armstrong PW, et al. JAMA. 2020.

Spertus J. KCCQ. Saint Luke’s Mid American Heart Institute.
 Inclusion/Exclusion Criteria
Inclusion Exclusion
• Age > 45 years • Clinically unstable
• HFpEF (EF > 45%) • SBP > 160 mmHg or < 110 mmHg
• NYHA class II to III • DBP < 40 mmHg
• HF decompensation within 6 months • Symptomatic hypotension
prior to randomization • Resting heart rate < 50 BPM or > 100
• Elevated natriuretic peptide levels w/in PM
30 days • Use of IV inotropes between
• Sinus rhythm hospitalization and randomization
• BNP > 100 pg/mL • Previous HFrEF diagnosis
• NT-proBNP > 300 pg/mL • Use of nitrates, PDE-5 inhibitors, or
• Atrial fibrillation soluble guanylate cyclase inhibitors
• BNP > 200 pg/mL • eGFR < 30 mL/minute/1.73m^2
• NT-proBNP > 600 pg/mL

Armstrong PW, et al. JAMA. 2020.

Study Outcomes
Primary

• Change from baseline to week 24 in physical limitation as measure by KCCQ PLS

Secondary

• Change from baseline in 6-minute walking distance (6MWD) at 24 weeks

Exploratory Outcomes

• Cardiovascular and non-cardiovascular deaths

• Cardiovascular hospitalizations including HF, non-HF, and non-HF cardiovascular
hospitalizations

Armstrong PW, et al. JAMA. 2020.

Results

• No significant
difference in KCCQ
PLS changes from
baseline to 24 weeks
between the three
groups

Armstrong PW, et al. JAMA. 2020.

Results

• No difference in
6MWD between the
three groups.

Armstrong PW, et al. JAMA. 2020.

Safety Results
Vericiguat 15 Vericiguat
Placebo
Adverse Reaction mg 10 mg
(N = 262)
(N = 264) (N = 262)
> 1 Adverse Events
172 (65.2%) 163 (62.2%) 172 (65.6%)

Symptomatic
Hypotension 17 (6.4%) 11 (4.2%) 9 (3.4%)

Syncope
4 (1.5%) 2 (0.8%) 1 (0.4%)

Armstrong PW, et al. JAMA. 2020.

Conclusion
Conclusion

• Treatment with vericiguat 10 mg or 15 mg did not improve the physical limitation

score of the KCCQ in patient with HFpEF and recent decompensation

Limitations

• Study was not powered to make a conclusion regarding CV deaths or HF

hospitalizations
• Patient –reported outcomes
• No mention of method to account for missing data

Strengths

• First study involving vericiguat and patients with HFpEF

Armstrong PW, et al. JAMA. 2020.

Relative Efficacy of Sacubitril-
Valsartan, Vericiguat, and SGLT2
Inhibitors in Heart Failure with
Reduced Ejection Fraction: a
Systemic Review and Network Meta-
Analysis

Aimo A, et al. Cardiovasc Drugs Ther. 2020.

Study Overview
Objective

• Explore the relative efficacy of sacubitril/valsartan, vericiguat, and SGLT2

inhibitors in heart failure with reduced ejection fraction

Methods

• Network meta-analysis
• Six trials included:
• PARADIGM-HF 2014 – sacubitril/valsartan
• VICTORIA 2020 – vericiguat
• SOCRATES-REDUCED 2015 – vericiguat
• DAPA-HF 2019 – dapagliflozin
• DECLARE-TIMI 58 – dapagliflozin
• EMPEROR-Reduced – empaglifozin

Aimo A, et al. Cardiovasc Drugs Ther. 2020.

Results

Aimo A, et al. Cardiovasc Drugs Ther. 2020.

Results
Outcome Treatment SOC* Sacubitril/ Vericiguat SGLT2i*
HR (95% CI) Valsartan HR (95% CI) HR (95% CI)
HR (95% CI)

CV death or HF SOC 1 0.8 (0.73 to 0.87) 0.89 (0.82 to 0.98) 0.74 (0.67 to 0.81)
hospitalization Sacubitril/ Valsartan
0.8 (0.73 to 0.87) 1 --- ---

Vericiguat 0.89 (0.82 to 0.98) 1.12 (0.98 to 1.27) 1 1.21 (1.06 to 1.38)
SGLT2i 0.74 (0.67 to 0.81) 0.92 (0.81 to 1.05) 0.83 (0.73 to 0.94) 1
CV death SOC 1 0.8 (0.71 to 0.9) 0.93 (0.81 to 1.06) 0.84 (0.74 to 0.95)
Sacubitril/ Valsartan
0.8 (0.71 to 0.9) 1 --- ---

HF hospitalization
Vericiguat 0.93 (0.81 to 1.06) 1.16 (0.98 to 1.39) 1 1.11 (0.92 to 1.34)
SGLT2i 0.84 (0.74 to 0.95) 1.04 (0.88 to 1.24) 0.88 (0.63 to 1.22) 1
SOC 1 0.79 (0.71 to 0.88) 0.9 (0.81 to 1) 0.69 (0.62 to 0.77)
Sacubitril/ Valsartan
0.79 (0.71 to 0.88) 1 --- ---

Vericiguat 0.9 (0.81 to 1) 1.14 (0.98 to 1.33) 1 ---

SGLT2i 0.69 (0.62 to 0.77) 0.87 (0.75 to 1.02) 0.77 (0.66 to 0.89) 1
*SOC (standard of care); SGLT2i (sodium-glucose co-transporter-2 inhibitors)
Aimo A, et al. Cardiovasc Drugs Ther. 2020.
Conclusion
Conclusion

• There was no difference between the risk of CV death or HF hospitalization or CV death

among the three groups; however, dapagliflozin was statistically significantly better at
reducing HF hospitalizations when compared to vericiguat but not different then
sacubitril/valsartan.

Limitations

• Indirect versus direct evidence

• Different patient populations across trials due to inclusion/exclusion criteria
• Small number of studies included

Strengths

• Compares newer treatment options in heart failure

Aimo A, et al. Cardiovasc Drugs Ther. 2020.

Vericiguat: Place in
Therapy
Current
Guideline
Therapies

Maddox TM, et al. J Am Coll Cardiol. 2021.

Lee A, et al. American College of Cardiology.
 Conclusion
• Vericiguat is a novel oral soluable guanylate cyclase stimulator that enhances
cGMP production and is associated with vasodilatory effects
• This medication is currently approved for heart failure with reduced ejection
fraction
• Studies have shown:
 A reduction in CV deaths and first hospitalizations in patients with HFrEF
 No difference in physical limitations or 6MWD in patients with HFpEF

• Patient specific factors will likely be used to help determine vericiguat’s place in
therapy until more data is published regarding its comparison to other GDMT
References
1. Vericiguat. Package insert. Merck Sharp & Dohme Corp; 2021.

2. Vericiguat. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Accessed April 15, 2021. http://online.lexi.com.

3. Lang NN, Dobbin SJH, Petrie MC. Vericiguat in worsening heart failure: agonizing over, or celebrating, agonism in the VICTORIA
trial. Cardiovasc Res. 2020;116;e152-e155.

4. Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med.
2020;382:1883-1893.

5. Pieske B, Patel MJ, Westerhout CM, et al. Baseline features of VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with
Reduced Ejection Fraction) trial. Eur J Heart Fail. 2019;21:1596-1604.

6. Armstrong PW, Lam CS, Anstrom, et al. Effect of Vericiguat vs Placebo on Quality of Life in Patients with Heart Failure and Preserved
Ejection Fraction. JAMA. 2020;324:1-10.

7. Spertus J. Medical Device Development Tool (MDDT) Qulification Decision Summary for Kansas City Cardiomyopathy Questionnaire
(KCCQ). Saint Luke’s Mid America Heart Institute. Accessed April 29, 2021. https://www.fda.gov/media/108301/download.

8. Aimo A, Pateras K, Stamatelopoulos K, et al. Relative Efficacy of Sacubitril-Valsartan, Vericiguat, and SGLT2 Inhibitors in Heart
Failure with Reduced Ejection Fraction: a Systemic Review and Network Meta-Analysis. Cardiovasc Drugs Ther. 2020; DOI:
https://doi.org/10.1007/s10557-020-07099-2.
9. Maddox TM, Januzzi JL Jr., Allen LA, et al. 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure
treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology
Solution Set Oversight Committee. J Am Coll Cardiol 2021.

10. Lee A, Natarajan PP, Cheng RKH, et al. The Roler of Vericiguat in the Expanding Realm of Heart Failure Pharmacotherapy: An Overview of
the VICTORIA Trial. American College of Cardiology. Accessed April 25, 2021. https://www.acc.org.
New in Heart Failure:
Vericiguat
Ashley Logan, PharmD
PGY1 Pharmacy Resident
Parkview Health
ashley.logan@parkview.com