- ACRONYMS AND DEFINITIONS
- AHA - American Heart Association
- EF - Ejection Fraction
- HFrEF - Heart failure with reduced ejection fraction
- NYHA - New York Heart Association heart failure classification
- SBP - systolic blood pressure
- sGC - soluble guanylate cyclase
- DRUGS IN CLASS
- Vericiguat is a soluble guanylate cyclase (sGC) stimulator that is approved to treat heart failure with reduced ejection fraction. It is the only sGC stimulator approved for this indication.
- Another sGC stimulator called riociguat (Adempas®) is approved to treat pulmonary hypertension
- MECHANISM OF ACTION
- Soluble guanylate cyclase stimulator
- Soluble guanylate cyclase (sGC) is an enzyme in the nitric oxide signaling pathway. When nitric oxide binds sGC, it increases the amount of intracellular cyclic guanosine monophosphate (cGMP). cGMP plays an important role in regulating processes that control vascular tone, proliferation, fibrosis, and inflammation. Patients with heart failure have decreased levels of nitric oxide and cGMP.
- Vericiguat directly stimulates sGC, independently of and synergistically with nitric oxide. This leads to increased levels of cGMP which promote smooth muscle relaxation and vasodilation.
- FDA-APPROVED INDICATION
- Heart failure with reduced ejection fraction
- Vericiguat is indicated to reduce the risk of cardiovascular death and heart failure hospitalization following a hospitalization for heart failure or need for outpatient IV diuretics, in adults with symptomatic chronic heart failure and ejection fraction less than 45%
- HEART FAILURE WITH REDUCED EJECTION FRACTION (HFrEF)
- Overview
- The effects of vericiguat on heart failure with reduced ejection fraction were evaluated in VICTORIA study detailed below
- The VICTORIA study enrolled 5050 patients with NYHA class II - IV heart failure and an ejection fraction < 45%
Main inclusion criteria
- NYHA class II - IV heart failure
- Ejection fraction < 45%
- NT-proBNP ≥ 1000 pg/ml (sinus rhythm) , ≥ 1600 pg/ml (A fib)
- Hospitalization for HF within 6 months or outpatient IV diuretics
Main exclusion criteria
- SBP < 100 mmHg
- Long-acting nitrate use
- Phosphodiesterase type 5 inhibitor use
- Implantable left ventricular assist device
Baseline characteristics
- Average age 67 years
- Average ejection fraction - 28.9%
- Median NT-proBNP - 2816 pg/ml
- Average SBP - 121 mmHg
- NYHA class: II - 59% | III - 39.7% | IV - 1.3%
Randomized treatment groups
- Group 1 (2526 patients) - Vericiguat with a target dose of 10 mg once daily (median dose in trial was 9.2 mg)
- Group 2 (2524 patients) - Placebo
- Vericiguat was started at 2.5 mg once daily and the dose was doubled every two weeks as tolerated to a target dose of 10 mg
- 60% of patients in both groups were taking concomitant triple therapy (ACE/ARB + Beta blocker + Aldosterone antagonist)
- 15% of patients in both groups were taking concomitant sacubitril–valsartan (Entresto)
Primary outcome: Composite of death from cardiovascular causes or first hospitalization for heart failure
Results
| Duration: Median 10.8 months | |||
| Outcome | Vericiguat | Placebo | Comparisons |
|---|---|---|---|
| Primary outcome | 35.5% | 38.5% | HR 0.90, 95%CI [0.82 – 0.98], p=0.02 |
| Death from cardiovascular causes | 16.4% | 17.5% | HR 0.93, 95%CI [0.81 – 1.06] |
| Hospitalization for heart failure | 27.4% | 29.6% | HR 0.90, 95%CI [0.81 – 1.0] |
| Overall mortality | 20.3% | 21.2% | HR 0.95, 95%CI [0.84 – 1.07], p=0.38 |
| Symptomatic hypotension | 9.1% | 7.9% | p=0.12 |
| Syncope | 4.0% | 3.5% | p=0.30 |
| Anemia | 7.6% | 5.7% | N/A |
| Change in hemoglobin at 16 weeks | -0.38 g/dl | -0.14 g/dl | N/A |
Findings: Among patients with high-risk heart failure, the incidence of death from cardiovascular causes or hospitalization for heart failure was lower among those who
received vericiguat than among those who received placebo.
- AHA recommendations
- Vericiguat was FDA-approved to treat heart failure in 2021. It has not been included in AHA recommendations yet.
- See AHA HFrEF treatment recommendations
- SIDE EFFECTS
- Hypotension
- Vericiguat promotes vasodilation so it has the potential to cause hypotension. In the Victoria study, hypotension was reported in 16% of vericiguat-treated patients and 15% of placebo-treated patients, and symptomatic hypotension occurred in 9.1% and 7.9%, respectively.
- Anemia
- In the Victoria study, 10% of vericiguat-treated patients experienced anemia compared to 7% of placebo-treated patients, and average hemoglobin levels decreased by 0.38 g/dl and 0.14 g/dl, respectively.
- CONTRAINDICATIONS
- Concomitant soluble guanylate cyclase (sGC) stimulators (e.g. riociguat, Adempas)
- PRECAUTIONS
- Kidney disease
- CrCl ≥ 15 ml/min - no dose adjustment necessary
- CrCl < 15 ml/min or dialysis - has not been studied. Manufacturer makes no specific recommendation.
- Liver disease
- Mild to moderate (Child-Pugh A or B) - no dose adjustment necessary
- Severe (Child-Pugh C) - has not been studied. Manufacturer makes no specific recommendation.
- Pregnancy
- Based on data from animal reproduction studies, vericiguat may cause fetal harm when administered to a pregnant woman. Women who may become pregnant should be warned about the potential risk of fetal harm and advised to use contraception during use and for at least 1 month after the final dose.
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Vericiguat
- Other soluble guanylate cyclase stimulators (e.g. riociguat, Adempas) - DO NOT COMBINE
- Phosphodiesterase type 5 (PDE-5) Inhibitors (e.g. Viagra, Cialis) - DO NOT COMBINE. May increase the risk of severe hypotension.
- Metabolism and clearance
- Vericiguat primarily undergoes glucuronidation by UGT1A9 and to a lesser extent, by UGT1A1 to form an inactive N-glucuronide metabolite. CYP-mediated metabolism is a minor clearance pathway (<5%).
- DOSING
- Dosage form (tablet)
- 2.5 mg
- 5 mg
- 10 mg
- Dosing
- Starting: 2.5 mg once daily with food
- Target: 10 mg once daily with food
- Double the dose every 2 weeks as tolerated to a target of 10 mg
- Food slows the rate of absorption and increases the extent of absorption
- Tablets may be crushed and mixed with water
- LONG-TERM SAFETY
- Vericiguat was FDA-approved in 2021. There is no long-term data on its use.
- BIBLIOGRAPHY
- 1 - Verquvo PI
- 2 - PMID 32222134 - Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction, NEJM (2020)