Verquvo (Vericiguat)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Reduce risk of CV death and HF hospitalization following a hospitalization for heart failure or need for outpatient IV diuretics, in symptomatic chronic HF with ejection fraction <45% | Adults ≥18 years with symptomatic chronic HFrEF after a worsening HF event | Adjunctive — added to other heart failure therapies | FDA Approved |
Vericiguat is positioned as an additional pharmacotherapy for patients who remain at high residual risk after a worsening heart failure event despite optimization on guideline-directed medical therapy (GDMT). The pivotal VICTORIA trial enrolled patients with a recent HF decompensation (HF hospitalization within 6 months or outpatient IV diuretic therapy within 3 months), a high-risk population in which the addition of vericiguat to background therapy reduced the composite primary endpoint of CV death or first HF hospitalization (HR 0.90; 95% CI 0.82–0.98; p=0.02). Notably, the cardiovascular death component alone did not reach statistical significance, with the benefit driven primarily by reduction in HF hospitalizations. Clinicians should reserve vericiguat for patients matching this enrichment profile, where the supporting evidence base is most robust.
Stable chronic HFrEF without recent decompensation: The phase 3 VICTOR trial (presented ESC 2025; published Lancet 2025) evaluated vericiguat in this broader population and did not meet its primary endpoint of CV death or HF hospitalization, although a pre-specified pooled analysis of VICTOR plus VICTORIA suggested possible benefit on the composite endpoint. Evidence quality: low — not currently recommended outside selected high-risk individuals.
HF with preserved ejection fraction (HFpEF): The VITALITY-HFpEF trial of vericiguat in HFpEF was negative for its primary endpoint of KCCQ physical limitation score. Evidence quality: low — not recommended.
Pediatric HFrEF: Not approved; safety and efficacy not established in patients under 18 years. Evidence quality: very low.
Dosing
The current FDA-approved dosing of vericiguat reflects a label update incorporating the VELOCITY study, which demonstrated tolerability of a 5 mg once-daily starting dose. Always administer with food — fasting administration produces lower and more variable exposure.
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| HFrEF after worsening HF event — initiation (per current FDA label) | 5 mg PO once daily with food | — | — | Confirm SBP ≥100 mmHg and patient is not symptomatically hypotensive before first dose Take with food for predictable absorption |
| Titration step | — | Double to 10 mg once daily at ~2 weeks | — | Up-titrate if SBP ≥100 mmHg and no symptoms of hypotension If SBP is too low or symptoms occur, hold or step down |
| Target maintenance dose | — | 10 mg once daily | 10 mg/day | Continue indefinitely while tolerated and clinically appropriate |
| Patient cannot swallow whole tablet | Tablet may be crushed and mixed with water immediately before administration | Same | Same | Bioequivalence of crushed tablet demonstrated in clinical pharmacology studies |
| Missed dose | Take as soon as remembered on the same day | — | — | Do not take two doses on the same day to make up for a missed dose Resume normal once-daily schedule the following day |
The original FDA-approved regimen used a 2.5 mg starting dose, doubled at ~2 weeks to 5 mg, then doubled at ~4 weeks to the 10 mg target — the regimen actually used in VICTORIA. Following the VELOCITY study, the U.S. label was updated to recommend initiation at 5 mg once daily, simplifying titration to a single step. The 2.5 mg starting dose remains a reasonable option for clinicians who prefer a more cautious approach in patients with borderline blood pressure, lower body weight, advanced age, or other concerns regarding hemodynamic tolerability.
Population-Specific Considerations
| Population | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Mild–moderate renal impairment (eGFR 15–89) | Standard initiation | Up to 10 mg daily | 10 mg/day | No dose adjustment specified by the label; titrate by tolerability |
| Severe renal impairment (eGFR <15) or on dialysis | Not studied — use is not recommended | Insufficient PK and safety data | ||
| Mild–moderate hepatic impairment (Child-Pugh A or B) | Standard initiation | Up to 10 mg daily | 10 mg/day | No specific dose adjustment required per the label |
| Severe hepatic impairment (Child-Pugh C) | Not studied — use is not recommended | Glucuronidation capacity not characterized in this group | ||
| Older adults (≥65 y) | Standard initiation | Up to 10 mg daily | 10 mg/day | No mandated reduction; consider 2.5 mg start in frail patients given a small initial SBP decline observed in those over 75 years |
| Pediatric (<18 y) | Not approved — safety and efficacy not established | — | ||
The mortality and hospitalization benefit of vericiguat in VICTORIA was associated with reaching the 10 mg target dose, which approximately 89% of trial participants achieved. If hypotension limits up-titration, audit the rest of the regimen first — overaggressive diuresis, recently up-titrated ARNI, or unnecessary vasodilators are common contributors that, once adjusted, often allow vericiguat to reach target.
Pharmacology
Mechanism of Action
Vericiguat is a stimulator of soluble guanylate cyclase (sGC), a key enzyme in the nitric oxide (NO) signaling pathway. In healthy physiology, NO binds to sGC and the activated enzyme catalyzes synthesis of intracellular cyclic GMP (cGMP), a second messenger that regulates vascular tone, cardiac contractility, and cardiac remodeling. Heart failure is associated with impaired NO synthesis and decreased sGC activity, which contributes to myocardial and vascular dysfunction. Vericiguat stimulates sGC directly — independently of and synergistically with NO — augmenting intracellular cGMP and producing smooth muscle relaxation and vasodilation alongside potential favorable effects on cardiac and vascular function.
This positions vericiguat differently from related vasoactive agents. Unlike organic nitrates, it does not depend on functional NO synthesis. Unlike PDE-5 inhibitors, it acts upstream by augmenting cGMP production rather than slowing its breakdown. Pharmacologically it is in the same class as riociguat (approved for pulmonary hypertension), but with PK and PD properties tailored for chronic heart failure use; co-administration with riociguat or other sGC stimulators is contraindicated due to additive hypotension.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Median Tmax ~1 hour with food; oral bioavailability ~93% with food. BCS class 2 — solubility is the rate-limiting step | Always dose with food; fasting administration leads to lower and more variable exposure |
| Distribution | Steady-state Vd ~44 L in healthy subjects; protein binding ~98% (mainly serum albumin) | Modest distribution volume; high but reversible protein binding does not produce clinically meaningful displacement interactions |
| Metabolism | Glucuronidation by UGT1A9 (primary) and UGT1A1 (minor), forming an inactive N-glucuronide; CYP-mediated metabolism is a minor pathway (<5%) | Low risk of CYP-mediated drug interactions; the pathway is unusually clean for a cardiovascular agent |
| Elimination | Half-life ~30 hours in HF patients; ~53% urinary excretion (primarily as inactive metabolite) and ~45% fecal (primarily as unchanged drug) | Long half-life supports once-daily dosing; balanced renal and fecal clearance gives predictable PK across mild-to-moderate organ impairment |
Side Effects
The adverse effect profile of vericiguat is dominated by hemodynamic effects related to its vasodilatory mechanism (hypotension, syncope) and a modest signal of anemia. Frequencies below are drawn from the FDA prescribing information (incidences ≥5% in vericiguat group with rate ≥ placebo) and the VICTORIA primary publication (NEJM 2020; n=5,050).
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hypotension (any) | 16% vs 15% placebo (FDA PI) | Includes all hypotension events captured in VICTORIA. Symptomatic hypotension specifically occurred in 9.1% on vericiguat vs 7.9% on placebo (p=0.12). Most events occur during titration; review concomitant antihypertensives and diuretic dose before holding vericiguat. |
| Anemia | 10% vs 7% placebo (FDA PI) | Adverse-event-defined anemia in VICTORIA was 7.6% vs 5.7%; mean Hb dropped ~0.24 g/dL by 16 weeks then plateaued. Mechanism not fully established; check baseline and follow-up Hb. |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Symptomatic hypotension (subset) | 9.1% vs 7.9% placebo (NEJM 2020) | Pre-specified VICTORIA endpoint; difference not statistically significant (p=0.12). Higher numerical risk in ARNI users and patients >75 years. |
| Syncope | 4.0% vs 3.5% placebo (p=0.30) | Reflects underlying HFrEF risk as much as drug effect; reassess for arrhythmic causes when it occurs. |
| Dizziness, headache, nausea | Reported specific incidence rates not detailed in PI | Typical of vasodilator class; usually mild and frequently improve with continued therapy. Not among the ≥5% adverse reactions specified in the FDA PI. |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Severe symptomatic hypotension | Uncommon | During titration; first 2–4 weeks | Hold dose; reassess fluid status, antihypertensives, and diuretic dose; re-initiate at lower step when stable |
| Embryo-fetal toxicity | Animal data — boxed warning | Any time during pregnancy | Pregnancy testing before initiation and effective contraception throughout treatment and for 1 month after the final dose; report exposures to the pregnancy registry (1-877-888-4231) |
| Serious anemia (in VICTORIA) | 1.6% vs 0.9% placebo | Weeks to months | Investigate alternative causes (GI bleed, iron deficiency, hemolysis); consider drug hold if no other cause and Hb falls progressively |
| Hypersensitivity reactions | Frequency not established | Any time | Discontinue; treat per standard protocols; document reaction in chart |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Symptomatic hypotension | Predominant drug-related driver | Most events occurred during the titration phase; verify rates against the current FDA PI before quoting specific numbers |
| Syncope | Comparable to placebo | Reflects baseline HFrEF risk more than drug effect |
| Anemia | Numerically higher than placebo | Usually managed by dose hold rather than permanent discontinuation |
| Worsening HF | Reflects natural history | VICTORIA was an enriched cohort with a high underlying event rate; not a drug-attributable signal |
If a patient becomes hypotensive (SBP <100 mmHg or symptomatic), the first move is rarely to stop vericiguat. Audit the rest of the regimen: is the loop diuretic dose now too high in a euvolemic patient? Has ARNI just been up-titrated? Are unnecessary vasodilators (long-acting nitrates, alpha-blockers) still on the chart? Vericiguat’s benefit in VICTORIA was greatest in patients reaching 10 mg, so preserving the up-titration pathway by adjusting other agents is usually the right strategy.
Drug Interactions
Vericiguat is metabolized predominantly by glucuronidation (UGT1A9 > UGT1A1) and CYP-mediated metabolism is a minor pathway (<5%). The drug shows low potential for cytochrome- or transporter-mediated interactions; no clinically relevant PK or PD interactions have been observed with warfarin, digoxin, aspirin, or sacubitril/valsartan. The interactions of clinical importance are pharmacodynamic — additive vasodilation with other modulators of the NO–cGMP pathway.
Monitoring
Monitoring of vericiguat is mostly hemodynamic and is built around the titration step. Outside of titration, the schedule is light and overlaps with routine HF follow-up labs.
-
Blood Pressure
Before initiation, at the titration visit (~2 weeks), then at routine HF follow-up
Routine Confirm SBP ≥100 mmHg and absence of symptomatic hypotension before initiation and before up-titration. Check both seated and standing readings if the patient reports lightheadedness. Hold or step down if SBP is too low or symptoms occur. -
CBC (Hemoglobin)
Baseline; with routine HF labs
Routine Anemia signal in VICTORIA; investigate any meaningful Hb drop. Concurrent iron deficiency in HFrEF is common and may warrant workup or IV iron rather than stopping vericiguat. -
Renal Function (creatinine, eGFR)
Baseline; with routine HF labs
Routine No direct nephrotoxicity. Avoid initiation if eGFR is below 15 mL/min/1.73 m² or the patient is on dialysis (not studied). A falling eGFR may indicate that the rest of the GDMT cocktail needs review. -
Pregnancy Test (β-hCG)
Before initiation; while on therapy as needed; report exposures to the registry
Routine Required in females of reproductive potential per the boxed warning. Effective contraception is required throughout therapy and for one month after the final dose. Document the contraception plan in the chart. Pregnancy exposures should be reported to the Verquvo pregnancy registry (1-877-888-4231). -
Symptom Review (Hypotension)
At every visit; targeted check around the titration step
Routine Ask specifically about lightheadedness on standing, falls, and near-syncope. A useful screening question: “Have you felt unsteady when you first stand up since the dose changed?” -
LFTs
Not routinely required
Trigger-based No vericiguat-specific surveillance schedule. Re-check if jaundice, RUQ symptoms, or unexplained fatigue. Hepatic safety in VICTORIA was unremarkable. -
ECG
No vericiguat-driven schedule
Trigger-based Vericiguat does not have a recognized clinically significant effect on QT interval. ECG follow-up is dictated by underlying HFrEF management, not the drug itself. -
NT-proBNP / BNP
Per HF protocol
Trigger-based Useful for tracking HF trajectory but is not a vericiguat-specific monitoring parameter; do not titrate the drug to BNP.
Contraindications & Cautions
Based on data from animal reproduction studies, VERQUVO may cause fetal harm when administered to a pregnant woman. In pregnant rabbits, vericiguat at exposures approximately 4 times the human exposure at the maximum recommended human dose produced cardiac and major vessel malformations (ventricular septal defect, truncus arteriosus communis) along with increased abortions and resorptions.
VERQUVO is contraindicated in pregnancy. In females of reproductive potential, exclude pregnancy before starting therapy and use effective contraception throughout treatment and for one month after the final dose. Healthcare providers should report any prenatal exposure to VERQUVO via the pregnancy registry at 1-877-888-4231 or pregnancyreporting.verquvo-us.com.
Absolute Contraindications
- Pregnancy — embryo-fetal toxicity (boxed warning)
- Concomitant use of other soluble guanylate cyclase (sGC) stimulators such as riociguat — risk of severe hypotension
- Known hypersensitivity to vericiguat or any tablet excipient
Relative Contraindications (Specialist Input Recommended)
- Concurrent use of PDE-5 inhibitors — concomitant use is not recommended per the FDA label, with limited data in HF; co-prescription should be avoided when possible
- Symptomatic hypotension at baseline or SBP <100 mmHg — defer initiation; reassess diuretic burden and other antihypertensives first
- Severe renal impairment (eGFR <15 mL/min/1.73 m²) or dialysis — not studied; if used, decision should involve nephrology and cardiology
- Severe hepatic impairment (Child-Pugh C) — not studied
Use with Caution
- Concurrent long-acting nitrates — co-administration was studied without clinically significant BP changes in CAD patients per the FDA PI, but data in HF are limited; clinical judgement applies in frail patients
- Baseline anemia — initiate cautiously, investigate cause, and correct iron deficiency if present
- Older or frail patients with high fall risk — favor a more cautious initiation (e.g., 2.5 mg start) and bedside BP checks; small initial SBP declines have been reported in those over 75 years and patients on ARNIs
- Patients on aggressive diuretic regimens — risk of intravascular volume depletion can amplify hemodynamic effects during titration
- Patients of reproductive potential not on reliable contraception — counsel and document contraception plan before any prescription is issued
Vericiguat is contraindicated in pregnancy. Animal studies showed teratogenicity at exposures comparable to the human therapeutic dose. There are no human data establishing safety in pregnancy. Excretion into human milk is not characterized; vericiguat is present in the milk of lactating rats. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during therapy with VERQUVO.
Patient Counselling
Purpose of Therapy
Frame vericiguat as an additional medicine layered on top of the patient’s existing heart failure regimen — not a replacement. Its specific role is to lower the chance of being readmitted to hospital with worsening heart failure and to reduce the risk of dying from cardiovascular causes, in patients who have recently had a heart failure flare-up. The benefit accrues over months of consistent use, and missed doses or premature stops blunt that benefit.
How to Take
Vericiguat is taken once daily with a meal — the morning meal is usually most reliable. Tablets must be taken with food because absorption is variable on an empty stomach. Tablets should be swallowed whole; if swallowing whole tablets is difficult, the tablet may be crushed and mixed with water immediately before drinking. Under the current label, treatment typically begins at 5 mg once daily and is doubled to the 10 mg target dose at approximately two weeks, provided blood pressure and tolerance allow. Patients should never adjust their own dose without instruction from the prescriber. Mild side effects often improve with continued use.
Sources
- Merck Sharp & Dohme LLC. VERQUVO (vericiguat) tablets — full prescribing information. merck.com/product/usa/pi_circulars/v/verquvo/verquvo_pi.pdf Current U.S. prescribing information including the boxed warning, indication, dosing (5 mg starting dose per the updated label), adverse reactions, and clinical pharmacology.
- U.S. Food and Drug Administration. VERQUVO drug approval package — NDA 214377. accessdata.fda.gov/drugsatfda_docs/nda/2021/214377Orig1s000lbl.pdf Original FDA approval label and review documents (January 2021), useful for the regulatory history and review-level safety analyses.
- European Medicines Agency. Verquvo: EPAR — product information (vericiguat). ema.europa.eu/en/medicines/human/EPAR/verquvo EMA SmPC and assessment report — useful for European-aligned dosing language and pharmacovigilance updates.
- Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med. 2020;382(20):1883–1893. doi.org/10.1056/NEJMoa1915928 VICTORIA — pivotal Phase 3 RCT (n=5,050) demonstrating reduction in the composite of CV death and HF hospitalization in worsening HFrEF; the basis for FDA approval.
- Butler J, McMullan CJ, Anstrom KJ, et al; VICTOR Investigators. Vericiguat in patients with chronic heart failure and reduced ejection fraction (VICTOR): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2025. doi.org/10.1016/S0140-6736(25)01665-4 VICTOR — Phase 3 trial in stable ambulatory HFrEF without recent decompensation; did not meet the primary composite endpoint, though pooled analysis with VICTORIA suggested possible benefit.
- Greene SJ, Lam CSP, Mentz RJ, et al. Safety and tolerability of a 5 mg starting dose of vericiguat among patients with heart failure: the VELOCITY study. Eur J Heart Fail. 2025;27(7):1180–1191. doi.org/10.1002/ejhf.3699 VELOCITY — single-arm Phase 2b study (n=106) supporting the updated label change to a 5 mg starting dose, with one-step titration to 10 mg.
- Gheorghiade M, Greene SJ, Butler J, et al. Effect of vericiguat, a soluble guanylate cyclase stimulator, on natriuretic peptide levels in patients with worsening chronic heart failure and reduced ejection fraction: the SOCRATES-REDUCED randomized trial. JAMA. 2015;314(21):2251–2262. doi.org/10.1001/jama.2015.15734 Phase 2 dose-finding study in worsening HFrEF — established the 10 mg target dose later confirmed in VICTORIA.
- Armstrong PW, Lam CSP, Anstrom KJ, et al. Effect of vericiguat vs placebo on quality of life in patients with heart failure and preserved ejection fraction: the VITALITY-HFpEF randomized clinical trial. JAMA. 2020;324(15):1512–1521. doi.org/10.1001/jama.2020.15922 Negative HFpEF trial — supports restricting clinical use to HFrEF and clarifies the off-label evidence base.
- Lam CSP, Mulder H, Lopatin Y, et al. Blood pressure and safety events with vericiguat in the VICTORIA trial. J Am Heart Assoc. 2021;10(22):e021094. doi.org/10.1161/JAHA.121.021094 Detailed analysis of SBP trajectory and safety events in vulnerable subgroups (≥75 years, baseline SBP 100–110 mmHg, ARNI users) — supports the gentle hemodynamic profile observed clinically.
- Ezekowitz JA, O’Connor CM, Troughton RW, et al. Hemoglobin and clinical outcomes in the Vericiguat Global Study in Patients with Heart Failure and Reduced Ejection Fraction (VICTORIA). Circulation. 2021;144(18):1489–1499. doi.org/10.1161/CIRCULATIONAHA.121.056797 Pre-specified hemoglobin sub-analysis from VICTORIA showing a small early Hb decrease that did not affect treatment benefit.
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation. 2022;145(18):e895–e1032. doi.org/10.1161/CIR.0000000000001063 U.S. guideline placing vericiguat as a Class 2b recommendation in selected HFrEF patients with worsening HF despite GDMT.
- McDonagh TA, Metra M, Adamo M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023;44(37):3627–3639. doi.org/10.1093/eurheartj/ehad195 European guideline framework situating vericiguat alongside the four pillars of HFrEF therapy and refining the worsening-HF management pathway.
- Sandner P, Zimmer DP, Milne GT, et al. Soluble guanylate cyclase stimulators and activators. Handb Exp Pharmacol. 2021;264:355–394. doi.org/10.1007/164_2018_197 Pharmacology review of the sGC modulator class — explains the dual stimulator mechanism shared by vericiguat and riociguat.
- Fritsch A, Meyer M, Blaustein RO, et al. Clinical pharmacokinetic and pharmacodynamic profile of vericiguat. Clin Pharmacokinet. 2024;63(6):751–771. doi.org/10.1007/s40262-024-01371-6 Comprehensive review of the absorption, distribution, metabolism, and elimination of vericiguat, including the food effect, BCS class 2 behavior, and special-population PK.
- Boettcher M, Thomas D, Mueck W, et al. Safety, pharmacodynamic, and pharmacokinetic characterization of vericiguat: results from six phase I studies in healthy subjects. Eur J Clin Pharmacol. 2021;77(4):527–537. doi.org/10.1007/s00228-020-03023-7 Aggregated Phase 1 PK/PD data in healthy volunteers — source for absorption, food effect, and metabolic disposition data.
- Boettcher M, Loewen S, Gerrits M, Becker C. Pharmacokinetic interaction studies of the soluble guanylate cyclase stimulator vericiguat. Clin Pharmacol Drug Dev. 2021;10(11):1245–1255. doi.org/10.1002/cpdd.974 Dedicated DDI program covering UGT-mediated interactions, antacids, warfarin, digoxin, and key CYP probe substrates — the empirical basis for the interaction profile.