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

Résumé fourni par la source

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 highes

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.