VICTORIA - Vericiguat in heart failure with reduced ejection fraction

in

Armstrong PW, et al. Vericiguat in patients with heart failure and reduced ejection fraction. NEJM 2020

Bottom line: In patients with heart failure (HF) with reduced ejection fraction, vericiguat compared with placebo:

  • decreased the risk of HF hospitalization from 30% to approximately 27% over a median ~11 months

  • did not reduce deaths

  • increased the incidence of anemia (by 2%)

Participants (n=5050)

  • Included:

    • Heart failure (NYHA functional class 2-4)

    • Left ventricular ejection fraction (LVEF) <45%

    • Elevated natriuretic peptides within 30 days before randomization

      • Sinus rhythm: NT-proBNP >1000 or BNP >300

      • Atrial fibrillation: NT-proBNP >1600 or BNP >500

    • HF hospitalization within 6 months (could be randomized during HF hospitalization) OR received IV diuretics without hospitalization within 3 months

  • Key exclusion

    • Concurrent medications: Long-acting nitrates, phosphodiesterase-5 inhibitors (eg sildenafil), or riociguat

    • Receiving IV inotropes; received IV treatment within last 24 hours; LVAD in situ or anticipated; pre- or post-heart transplant

    • Cardiac comorbidities:

      • ACS or coronary revascularization within 2 months

      • Tachycardia-related cardiomyopathy or uncontrolled tachyarrhythmia

      • Primary valvular disease or within 3 months after valve surgery

      • Acute myocarditis, amyloidosis, sarcoidosis, Takotsubo cardiomyopathy

      • HCM

      • Symptomatic carotid stenosis, TIA or stroke within 2 months

    • Non-cardiac comorbidities: Home O2 for severe pulmonary disease; interstitial lung disease; severe liver disease

    • SBP <100 mm Hg or symptomatic hypotension

    • eGFR-MDRD <15 mL/min/1.73m^2

  • 6857 screened -> 5050 randomized from September 2016 to December 2018

    • Of 1807 excluded: 1978 due to NT-proBNP or BNP below inclusion criteria, 265 unstable, 191 declined consent

  • Baseline

    • Age 67, male 76%, white 64%/Asian 22%, North America 11%

    • HF duration 4.8 years

    • HF hospitalization within 3 months 67%

    • NYHA 2 (59%), 3 (40%), 4 (1%)

    • LVEF 29% (<40% in 86%)

    • NT-proBNP median ~2800

    • Comorbidities: AF 45%, CAD 58%, diabetes 47%, HTN 79%

    • SBP 121 mm Hg, HR 73 bpm

    • Hemoglobin 134 g/L, eGFR 61 (15-30: 10%)

    • HF therapies: ACEI/ARB 73%, ARNI 15%, beta-blocker 93%, MRA 70% - triple therapy 60%, ICD 28%, CRT 15%

Intervention: Vericiguat

  • Starting dose: 2.5 mg once daily (taken with food)

    • Then 2 weeks later, uptitrated to 5 mg once daily

    • Then 2 weeks later, uptitrated to 10 mg once daily (target dose)

  • Median achieved dose: 9.2 mg/d (90% receiving 10 mg/d)

  • Dose modification criteria

    • SBP >=100 mm Hg & not on target dose: Increase dose

    • SBP 90-99: Maintain current dose

    • SBP <90

      • Asymptomatic: Decrease dose 1 level (if 2.5 mg, hold)

      • Symptomatic: Hold regardless of dose

  • Adherence: 94% of patients took >80% of doses

Comparator: Matching placebo

Outcomes @ median 10.8 months

  • Primary outcome (CV death or HF hospitalization): Vericiguat 35.5%, placebo 38.5%

    • Hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.82-0.98

    • Consistent across all subgroups, except baseline NT-proBNP (possible harm/lack of benefit with baseline NT-proBNP >5300)

  • Death from any cause: 20.3% vs 21.2% (HR 0.95, 95% CI 0.84-1.07)

  • HF hospitalization: 27.4% vs 29.6% (HR 0.90, 95% CI 0.81-1.00)

  • Adverse effects

    • Anemia: 7.6% vs 5.7% (p<0.01)

    • Symptomatic hypotension: 9.1% vs 7.9% (p=0.12)

    • Syncope: 4.0% vs 3.5% (p=0.3)

Internal validity: Low risk of bias overall

  • Allocation bias: Low risk

    • Randomization & allocation concealment via interactive voice/web response system

  • Performance bias: Low risk

    • Matching placebo for blinding of participants

  • Detection bias: Low risk

    • Outcomes adjudicated by committee unaware of group assignment

  • Attrition bias: Low risk

    • Analyzed intention-to-treat (ITT) population

    • 0.3% lost-to-follow-up with no difference between groups

Other considerations

  • Generalizability

    • Enrolled a very high-risk HFrEF population since inclusion required both very recent HF hospitalization + elevated NT-proBNP/BNP

      • Other HFrEF RCTs have traditionally selected higher-risk patients by requiring either recent HF hospitalization OR elevated NT-proBNP/BNP (e.g. DAPA-HF or PARADIGM-HF for the latter)

      • Furthermore, cutoff for natriuretic peptides higher than prior trials (NT-proBNP in sinus rhythm >400-600 in DAPA-HF & PARADIGM-HF)

    • As a result of this higher-risk population, the absolute risk of HF hospitalization/death (& therefore absolute benefit from adding another therapy) is greater

  • Comparison to other recent therapies

    • In this trial, vericiguat was added to standard HFrEF triple therapy

    • Trials of other therapies, including dapgliflozin & ivabradine have followed this similar add-on approach, whereas sacubitril-valsartan replaced the ACEI/ARB component

    • Although HFrEF therapies generally work by complementary mechanisms & likely have additive benefit, not all patients will be able to afford or tolerate the combination of all of these medications. Therefore, clinicians will need to help patients find a balance between efficacy & safety/cost/polypharmacy

      • In the absence of head-to-head comparisons from RCTs, indirect comparison using relative risk reduction (which can be combined with estimate of the patient’s prognosis) can be helpful to estimate the benefit of the different options

Indirect comparison of relative efficacy of different HFrEF pharmacotherapeutic options

Indirect comparison of relative efficacy of different HFrEF pharmacotherapeutic options