The effect of vericiguat on sudden cardiac death: insights from the VICTOR trial

Sudden cardiac death constitutes a significant risk in patients with heart failure and reduced ejection fraction (HFrEF). This risk is proportionally higher in those with less advanced disease and is not confined to periods of clinical instability. Previous studies have shown that although the absolute risk of sudden cardiac death has declined over the past two decades with the use of evidence-based therapies, a sizable residual risk remains at ∼10% at 3 years in ambulatory patients with HF.1 Vericiguat, an oral soluble guanylyl cyclase stimulator, is currently recommended to reduce the risk of cardiovascular death or hospitalizations for heart failure (HHF) in patients with HFrEF and recent worsening, defined as either HHF within 6 months or need for outpatient intravenous diuretics within 3-months before screening. The Vericiguat Global Study in Participants with Chronic Heart Failure (VICTOR) trial addressed the role of vericiguat in ambulatory HFrEF patients without recent worsening.2 VICTOR was notable for the high use of guideline-directed medical therapy and implantable cardiac defibrillator (ICD) use at baseline.3 In VICTOR, while vericiguat did not statistically significantly reduce the primary composite endpoint of cardiovascular death or HHF, the risk for cardiovascular death (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.71–0.97) and all-cause death (HR 0.84, 95% CI 0.74–0.97) were lowered with vericiguat.2,4 Importantly, vericiguat lowered the risk of sudden cardiac death (1.6 versus 2.2 events per 100 patient-years; HR 0.75, 95% CI 0.56–0.99 in vericiguat versus placebo group, respectively). The sudden cardiac death benefit was observed early, at a median follow-up of 5.4 months after an accrual of 21 events (6 [0.4%] in vericiguat versus 15 [1.1%] in placebo group; HR 0.40, 95% CI 0.155–1.032; P = .0497) and persisted throughout the follow-up. In this exploratory sub-analysis of the VICTOR trial, we assessed the consistency of vericiguat effect on sudden cardiac death across demographics characteristics, comorbidities, estimated glomerular filtration rate (≥15–≤30 mL/min/1.73 m2 vs ≥30–≤60 mL/min/1.73 m2 vs ≥60 mL/min/1.73 m2), and mean left ventricular ejection fraction (<31% vs ≥31%). The impact of baseline guideline-directed medical therapy and ICD individually, and the number of guideline-directed medical therapy drugs (0–2 vs 3 vs 4) on mortality outcomes were also assessed. Separately for each subgroup level, we used Cox proportional hazard models, controlling for the stratification factor New York Heart Association class to evaluate heterogeneity of sudden cardiac death risk and competing modes of death. Forest plots were then used to display the results. Subgroup by treatment interaction P-values were derived from likelihood ratio tests based on Cox proportional hazard models, where the reduced models included treatment group, New York Heart Association class, and the subgroup as covariates. Among 6105 patients with HFrEF, the benefit of vericiguat on sudden cardiac death versus placebo was consistent across subgroups studied. In particular, consistency was shown between patients with ICD (HR 0.51, 95% CI 0.24–1.09) and without an ICD (HR 0.79, 95% CI 0.58–1.07; interaction P = .301), those with history of ischaemic heart disease (HR 0.70, 95% CI 0.49–1.01) and without (HR 0.82, 95% CI 0.52–1.30; interaction P = .600), and irrespective of baseline medical therapy with angiotensin receptor neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonists, or sodium-glucose cotransporter inhibitor-2 (all treatment-by-outcome interaction P > .18). The benefit across the number of guideline-directed medical therapy drugs at baseline was also consistent (HR 0.81, 95% CI 0.44–1.49 for 0–2 drugs, HR 0.70, 95% CI 0.47–1.04 for 3 drugs, and HR 0.79, 95% CI 0.46–1.35 for 4 drugs, respectively; treatment-by-subgroup interaction P = .896). There was no evidence of heterogeneity across key subgroups (Figure 1). In an exploratory analysis of upstream clinical trajectory preceding sudden cardiac death, the latter was infrequently preceded by worsening HF events. Across 193 SCD events, only 26 patients (13.5%) had ≥1 HHF before death. Among those with prior HHF, the most recent HHF occurred a median of 132.5 days before death (interquartile range 75.0–230.0). Furthermore, 27 patients (14.0%) had a non-HF cardiovascular hospitalization (median 32.0 days from the most recent event to death), 14/193 (7.3%) had a non-cardiovascular hospitalization (median 198.5 days), and 53/193 (27.5%) had any all-cause hospitalization (median 86.0 days). Median baseline NT-proBNP was 1979 pg/mL (Q1–Q3: 1142–3223) and the most recent pre-death NT-proBNP was 1969 pg/mL (Q1–Q3: 1159–4306), with a median change from baseline of 0 pg/mL (−136 to 880). The proportions with ≥30% increase (32.1%) and any decrease (28.9%) were similar. Time to sudden cardiac death and risk reduction across subgroups. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor/neprilysin inhibitor; CI, confidence interval; eGFR, estimated glomerular filtration rate; GDMT, guideline-directed medical therapy; HFH, heart failure hospitalization; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; SGLT2i, sodium-glucose cotransporter-2 inhibitor In VICTOR, HHF was uncommon before sudden cardiac death, as only 26 sudden cardiac death events were preceded by at least 1 HHF, and when the latter happened, the most recent HHF typically occurred months before death. Consistent with this trajectory, other upstream causes of hospitalization were also infrequent before sudden cardiac death, and the time from the most recent all-cause hospitalization to sudden cardiac death remained relatively long. Taken together, upstream trajectory data preceding sudden cardiac death suggest that, in the VICTOR trial, sudden cardiac death was often not temporally coupled to a recent worsening HF event, demonstrating that the observed reduction in SCD with vericiguat is unlikely to be explained solely by prevention of clinical HF progression. NT-proBNP was mostly unchanged from baseline to the most recent assessment before death among patients experiencing sudden cardiac death. These data do not support a dominant pattern of escalating neurohormonal and haemodynamic stress immediately preceding sudden cardiac death in this cohort of stable HF patients. Therefore, vericiguat may reduce vulnerability to sudden cardiac death through mechanisms that are at least partially independent of immediate pre-terminal congestion. The benefit of risk reduction for sudden cardiac death is especially notable considering the overall lower risk population that was enrolled in VICTOR, including a high proportion of patients without a history of past HHF or remote HHF, almost a third of the participants were not on diuretics at baseline, almost 80% had New York Heart Association class II symptoms, and were receiving excellent guideline directed medical therapy at baseline, all of which have been associated with reduction in the risk of sudden cardiac death. Moreover, the magnitude of risk reduction (25% relative risk reduction) was clinically meaningful. The VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA), which enrolled a higher-risk population with recent HF decompensation, did not demonstrate a statistically significant reduction in cardiovascular death with vericiguat (HR for cardiovascular death 0.93, 95% CI 0.81–1.06).1 However, in a pre-specified post hoc analysis limited to the lower three natriuretic peptide quartiles, there was a nominally significant cardiovascular death benefit. Specifically, among patients with NT-proBNP levels below the highest quartile (≤5314 pg/mL), vericiguat was associated with an HR for cardiovascular death of 0.75 (95% CI: 0.60–0.94), while this effect was not observed in the highest quartile.5 In contrast with our findings, another post hoc analysis of VICTORIA showed a statistically significant reduction in sudden cardiac death risk (adjusted HR 0.64, 95% CI 0.43–0.96) in patients with ICD at baseline, which was consistent regardless of HF aetiology (ischaemic vs non-ischaemic HF).6 Pooled analyses of VICTORIA and VICTOR showed a reduction in cardiovascular death and SCD with vericiguat across the HFrEF risk spectrum.3 These benefits were seen consistently in patients with or without an ICD, history of coronary artery disease, or degree of baseline medical therapy for HFrEF. Although the point estimate for sudden cardiac death reduction was numerically larger in patients with ICD than in those without, there was no evidence of heterogeneity by ICD status (interaction P = .30). The absence of a statistically significant interaction should be interpreted cautiously, given limited event counts within subgroups. In addition, baseline ICD and cardiac resynchronization therapy prevalences among participants who experienced sudden cardiac death were 15.5% (30/193) and 6.7% (13/193), respectively, compared with 32.9% (1741/5288) and 14.5% (767/5288) in those who survived, suggesting that many sudden cardiac death events occurred in patients without device protection. However, the lack of interaction is clinically plausible because ICD do not prevent arrhythmia occurrence or non-shockable terminal rhythms, and in this context vericiguat may reduce arrhythmic burden/substrate, providing incremental benefit regardless of device status, as supported by emerging preclinical and clinical data.3,6–10 A limitation of our analysis is that outpatient worsening HF events were not available. Therefore, we were not able to evaluate subclinical congestion or non-hospitalized deterioration preceding sudden cardiac death. Nevertheless, the strong contrast in both frequency and proximity of HHF before sudden cardiac death provides clinically relevant context for interpreting the clinical trajectories before sudden cardiac death in the VICTOR trial. In conclusion, this analysis shows that even in the lower risk population of participants with HFrEF with high use of guideline-directed medical and device therapy at baseline, residual sudden cardiac death risk is considerable and is modifiable with vericiguat. The observed reduction in sudden cardiac death with vericiguat was mostly consistent across demographic characteristics, baseline comorbidities, and background medical and device therapy. Vericiguat may provide incremental benefit in reducing sudden cardiac death in ambulatory HFrEF patients, complementing foundational therapies. FF has nothing to disclose. FZ reports personal fees from 89bio, Applied Therapeutics, Bayer, Betagenon, Biopeutics, Boehringer, BMS, CVRx, Cardior, Cambrian, Cereno pharmaceutical, Cellprothera, CEVA, Merck, Northsea, Novartis, Novo Nordisk, Otsuka, Owkin, and Salubri; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Boehringer, CVRx, Cellprothera, CEVA, and Merck; participates in a data safety monitoring board or advisory board for Merck/Acceleron; has equities at G3Pharmaceutical, Cereno, Cardiorenal, and Eshmoun Clinical Research; and is founder of Global CardioVascular Clinical Trialists. IB and AX are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. SC is employee of Bayer AG and may own stock and/or stock optionsin Bayer AG. JAE has received research grants and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim-Lilly, Merck, Amgen, CSL-Vifor, Carduirion, American Regent, Otsuka, Novo Nordisk, and Applied Therapeutics. CSPL has received research grants from the National Medical Research Council of Singapore, Novo Nordisk, and Roche Diagnostic; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; has patent PCT/SG2016/050217 pending and patent US Patent No. 10702, 247; is a co-founder and non-executive director of Us2.ai; and has received stock or stock options from Us2.ai. RJM has received research support and honoraria from Bayer and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; and consulting fees from Abbott, Alleviant Medical, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Lexicon, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Reprieve Cardiovascular, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily, Vifor, Windtree Therapeutics, and Zoll. CMO has received consulting fees from Abiomed, Merck, and Zealcare. IB is an employee of Bayer AG. JB has received consulting fees from Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, Cardiorem, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis, Boehringer Ingelheim-Lilly, AstraZeneca, Impulse Dynamics, and Vifor. The data sharing policy, including procedures and restrictions, of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD), is available at https://externaldatasharing-msd.com/ The VICTOR trial was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and Bayer AG. VICTOR Primary Site Investigators / Primary Study Coordinators Argentina: Angela Romero Zarante / Yenisca Zambrano; Miguel Hominal / Martin Suarez; Ezequiel Vottero / Marcia Lopez; Oscar Montaña / Gloria Cendali; Marisa Vico / Erica Giozzi; Diego Aizenberg / Santiago Coussio; Diego Arakaki / Miriam Gelersztein. Australia: Scott McKenzie / Kathryn Stibilj; David Colquhoun / Gemma Macdonald; John Atherton / Lydia Lilwall; Carmine De Pasquale / Simeoni Thomas; Alicia Chan / Denise Healy; Brendan McQuillan / Natalya Beer. Austria: Dirk von Lewinski / Viktoria Rausch; Andreas Schober / Maria-Christine Leitgeb; Christopher Adlbrecht / Cordula Koehler; Johann Auer / Manuela Rossmaier; Moritz Mirna / Kristen Kopp. Brazil: Jose Saraiva / Carla Cristina Vicente; Pedro Schwartzmann / Gabriela Ilana; Aguinaldo Freitas / Sandra Costa; Lidia Moura / Fernanda de Liz; Ricardo Mourilhe Rocha / Roberta Coelho; Fabiana Marcondes-Braga / Talita Antunes; Marcus Simoes / Veronica Silva; Joao Souza / Grazielle Freire; Fábio Silveira / Tamyres Galvão; Euler Manenti / Carollainy Silva. Canada: Ronald Bourgeois / Karen Boyd; Thao Huynh / Caroline Boudreault; Michael Hartleib / Rebecca Otis; James Cha / Judy Otis; Michael Heffernan / Marie Birch; A. Shekhar Pandey / Samantha Armstrong; Ashok Mukherjee / Lubna Zakria; Marie-Claude Parent / Helene Brown; Doug Hayami / Deborah Keller; Stephen Allan Schaffer / Wendy Janz; Yves Pesant / Yanick Sardin-Laframboise; Justin Ezekowitz / Quentin Kushnerik; Annie Roy / Caroline Boudreault; Gilbert Gosselin / Nathalie Leblanc; Yaariv Khaykin / Debbie Nemtean; Gordon Moe / Carlos Fernando; Ying Sia / Amelie Bujold; Jonathan Howlett / Anusha Sasikumar; Elizabeth Swiggum / Noreen Lounsbury; Serge Lepage / Carl Fortier; Subodh Verma / Debbie Chen. Chile: Fernando Lanas / Pamela Figueroa; Gabriel Maluenda / Maria Vergara; Juan Prieto / Viviana Noriega; Luis Morales / Jessica Zapata; Patricio Yovaniniz / Marcela Grandon; Franco Appiani / Tatiana del Rio; Sergio Mellado / Claudia Alvarez; German Cruz / Sebastian Mino; Juan Carlos Palma Carvajal / Veronica Olguin; Paz Bourke / Maribel Toledo Grell; Hugo Marin / Sebastian Rios; Manuel Novajas / Macarena Carcamo Medina. China: Jingmin Zhou / Mingfeng Lu; Jiyan / / / / / / / / / / / / / / / / / Lu; / / / / / / / / / / / / / / / / / / / / / / / / / / / / Claudia Jose / / / Jessica Miguel / / de / Maria Juan Carvajal / Luis / Karen Juan / / / / / Martin / / / Martin / / / / / / / / / / / / / / / / / / / Nathalie / / / / / / / / / / / / / / Martin / / / / von / / / / Martin / / / / Maria de / / Johann / / Maria / / / / / / / / / / de / Juan / / / / / / Chan / / / / / / / / / / / / / Maria / / / / / / / / / / / / / / / / / / / / / / / / Roberta / / / / / De / / / / / / / / / / / / Maria / / Carlos / / de / Wendy / / Maria / / / Claudia Lopez; Pedro / Sergio del / Ricardo / / / / / / / New / / / Deborah / James / / / / / / / / Jose / del / Maria / / Maria / Luis / / / Lidia / / / / / / / / / / / / / / Jose / / / Luis / / / / / / / / / / Natalya / / / / / / Maria / Maria / / David / / / / / / / Deborah / / / / / / / / / De / / / / / / / / / / Diego / Jose / / / / / Paz / Cristina / / / de / Maria / / / / / / / Marcus / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / Sandra / / / / / Brown; Justin / Christopher / / / / / / Deborah / / Rebecca / Angela / / David / / / / / / David / / Jose / James / / / Marie / Luis / / / Marcus / / / / / / / / / / / John / / / / / Alicia / / / / / / / / / / / / / David / / / / / / / / / / / Christopher / / / / / / Christopher / Armstrong; / / / / / / / / / / Scott and Research of Medical Bayer AG Justin of Merck & Co., James Medical of Scott and Research of Medical of Global of of Bayer AG Justin of National Heart Singapore, Medical Medical Merck & Co., Clinical Research of Christopher Heart and Medical of James Medical of A. Heart Failure Research of Merck Global Clinical Development Merck Global Clinical Development Merck Global Clinical Development Merck Global Clinical Development Vericiguat Merck Global Clinical Study Merck Global Clinical Clinical Merck Global Clinical Merck and Research Merck and Research Vericiguat Medical Merck Global Clinical De Merck Global Clinical Merck Global Clinical Lydia Clinical Bayer AG Maria of and Bayer AG Bayer AG Argentina: Marisa Australia: Scott Austria: Dirk von Brazil: Fabiana Canada: Chile: Fernando China: Juan New Jose David Karen Marisa of Diego Medical of & Medical of Research of Association of of and Clinical of of Maria Medical Heart Heart Michael Karen David Clinical Research