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Aims: In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF. Methods and results: We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1–39, 41–80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post‐randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1–39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41–80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all pinteraction > 0.5). Post‐randomization diuretic dose changes for vericiguat and placebo showed similar rates of up‐titration (19.6 and 20.2/100 person‐years), down‐titration (16.8 and 18.1/100 person‐years), and stopping diuretics (22.9 and 24.2/100 person‐years). Conclusions: Loop diuretic TDD at randomization was independently associated with worse outcomes in this high‐risk population. The efficacy of vericiguat was consistent across the range of diuretic doses. [ABSTRACT FROM AUTHOR]

Aims: Whether electrocardiographic (ECG) measurements predict mortality in chronic heart failure with reduced ejection fraction (HFrEF) is unknown. Methods and results: We studied 4880 patients from the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial with a baseline 12‐lead ECG. Associations between ECG measurements and mortality were estimated as hazard ratios (HR) and adjusted for the Meta‐Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score, N‐terminal pro‐B‐type natriuretic peptide, and index event. Select interactions between ECG measurements, patient characteristics and mortality were examined. Over a median of 10.8 months, there were 824 cardiovascular (CV) deaths (214 sudden) and 1005 all‐cause deaths. Median age was 68 years (interquartile range [IQR] 60–76), 24% were women, median ejection fraction was 30% (IQR 23–35), 41% had New York Heart Association class III/IV, and median MAGGIC score was 24 (IQR 19–28). After multivariable adjustment, significant associations existed between heart rate (per 5 bpm: HR 1.02), QRS duration (per 10 ms: HR 1.02), absence of left ventricular hypertrophy (HR 0.64) and CV death, and similarly so with all‐cause death (HR 1.02; HR 1.02; HR 0.61, respectively). Contiguous pathologic Q waves were significantly associated with sudden death (HR 1.46), and right ventricular hypertrophy with all‐cause death (HR 1.44). The only sex‐based interaction observed was for pathologic Q waves on CV (men: HR 1.05; women: HR 1.64, pinteraction = 0.024) and all‐cause death (men: HR 0.99; women: HR 1.57; pinteraction = 0.010). Whereas sudden death doubled in females, it did not differ among males (male: HR 1.25, 95% confidence interval [CI] 0.87–1.79; female: HR 2.50, 95% CI 1.23–5.06; pinteraction = 0.141). Conclusion: Routine ECG measurements provide additional prognostication of mortality in high‐risk HFrEF patients, particularly in women with contiguous pathologic Q waves. [ABSTRACT FROM AUTHOR]

Aim: Vericiguat significantly reduced the primary composite outcome of heart failure (HF) hospitalization or cardiovascular death in the VICTORIA trial. It is unknown if these outcome benefits are related to reverse left ventricular (LV) remodelling with vericiguat in patients with HF with reduced ejection fraction (HFrEF). The aim of this study was to compare the effects of vericiguat versus placebo on LV structure and function after 8 months of therapy in patients with HFrEF. Methods and results: Standardized transthoracic echocardiography (TTE) was performed at baseline and after 8 months of therapy in a subset of HFrEF patients in VICTORIA. The co‐primary endpoints were changes in LV end‐systolic volume index (LVESVI) and LV ejection fraction (LVEF). Quality assurance and central reading were performed by an echocardiographic core laboratory blinded to treatment assignment. A total of 419 patients (208 vericiguat, 211 placebo) with high‐quality paired TTE at baseline and 8 months were included. Baseline clinical characteristics were well balanced between treatment groups and echocardiographic characteristics were representative of patients with HFrEF. LVESVI significantly declined (60.7 ± 26.8 to 56.8 ± 30.4 ml/m2; p < 0.01) and LVEF significantly increased (33.0 ± 9.4% to 36.1 ± 10.2%; p < 0.01) in the vericiguat group, but similarly in the placebo group (absolute changes for vericiguat vs. placebo: LVESVI −3.8 ± 15.4 vs. −7.1 ± 20.5 ml/m2; p = 0.07 and LVEF +3.2 ± 8.0% vs. +2.4 ± 7.6%; p = 0.31). The absolute rate per 100 patient‐years of the primary composite endpoint at 8 months tended to be lower in the vericiguat group (19.8) than the placebo group (29.6) (p = 0.07). Conclusions: In this pre‐specified echocardiographic study, significant improvements in LV structure and function occurred over 8 months in both vericiguat and placebo in a high‐risk HFrEF population with recent worsening HF. Further studies are warranted to define the mechanisms of vericiguat's benefit in HFrEF. [ABSTRACT FROM AUTHOR]

Aim: We assessed a subset of the 5040 patients in VICTORIA receiving sacubitril/valsartan, either at randomization (n = 731) or post-randomization drop-in use (n = 425), to evaluate the relationship between the efficacy and safety of combination therapy with vericiguat.Methods and Results: The efficacy of vericiguat on the primary composite endpoint, heart failure (HF) hospitalization, and all-cause mortality was assessed. Safety outcomes included symptomatic hypotension, syncope, worsening renal function, and hyperkalaemia. At randomization, 731 patients received sacubitril/valsartan; they were more frequently from Western Europe or North America, had lower ejection fraction and systolic blood pressure, and more use of triple background HF therapy (65.9% vs. 58.6%), biventricular pacemakers (17.9% vs. 14.1%), or implantable cardioverter defibrillators (42.3% vs. 25.3%). For patients on versus not on sacubitril/valsartan at randomization, adjusted hazard ratios (95% confidence intervals) for vericiguat's treatment effect on the primary composite outcome, cardiovascular death, and HF hospitalization were 0.92 (0.71-1.19) versus 0.89 (0.80-0.98), 0.71 (0.45-1.12) versus 0.95 (0.82-1.11), and 0.98 (0.74-1.29) versus 0.87 (0.78-0.98), respectively. No significant interaction existed between sacubitril/valsartan and vericiguat's treatment effect (p-values for interaction: 0.81, 0.23 and 0.47, respectively). Post-randomization, more drop-in sacubitril/valsartan use occurred in those assigned to placebo (n = 238) versus vericiguat (n = 187) (p = 0.007). Symptomatic hypotension (21.0% vs. 23.1%; p = 0.41), renal dysfunction (29.9% vs. 31.9%; p = 0.50), and hyperkalaemia (10.3% vs. 7.9%; p = 0.20) in patients receiving sacubitril/valsartan (n = 992) for ≥3 months were not different by treatment arm.Conclusions: Concomitant use of sacubitril/valsartan for at least 3 months did not alter the efficacy of vericiguat and was similarly safe and tolerated in both study arms. Sacubitril/valsartan was initiated more frequently after randomization in patients assigned to placebo versus vericiguat.Clinical Trial Registration: ClinicalTrials.gov NCT02861534. [ABSTRACT FROM AUTHOR]

Objective: Phenotypic heterogeneity among patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) is ill defined. We used cluster analysis machine-learning algorithms to identify phenotypes among trial participants with T2DM and ASCVD.Research Design and Methods: We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular outcome safety trial comparing sitagliptin with placebo in patients with T2DM and ASCVD (median follow-up 3.0 years). Cluster analysis using 40 baseline variables was conducted, with associations between clusters and the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) assessed by Cox proportional hazards models. We replicated the results using the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial.Results: Four distinct phenotypes were identified: cluster I included Caucasian men with a high prevalence of coronary artery disease; cluster II included Asian patients with a low BMI; cluster III included women with noncoronary ASCVD disease; and cluster IV included patients with heart failure and kidney dysfunction. The primary outcome occurred, respectively, in 11.6%, 8.6%, 10.3%, and 16.8% of patients in clusters I to IV. The crude difference in cardiovascular risk for the highest versus lowest risk cluster (cluster IV vs. II) was statistically significant (hazard ratio 2.74 [95% CI 2.29-3.29]). Similar phenotypes and outcomes were identified in EXSCEL.Conclusions: In patients with T2DM and ASCVD, cluster analysis identified four clinically distinct groups. Further cardiovascular phenotyping is warranted to inform patient care and optimize clinical trial designs. [ABSTRACT FROM AUTHOR]

Aims: Whether glycaemic control is associated with cardiovascular outcomes in patients with type 2 diabetes (T2D) is unclear. Consequently, we assessed the relationship between glycated haemoglobin (HbA1c) and cardiovascular outcomes in a placebo‐controlled randomized trial which demonstrated no cardiovascular effect of sitagliptin in patients with T2D and atherosclerotic vascular disease. Methods and results: Secondary analysis of 14 656 TECOS participants with time to event analyses using multivariable Cox proportional hazard models. During a median 3.0 (interquartile range 2.3–3.8) year follow‐up, 456 (3.1% of 14 656) patients had first hospitalization for heart failure (HF), 1084 (11.5%) died, 1406 (9.6%) died or were hospitalized for HF, and 1689 (11.5%) had a non‐HF cardiovascular event (cardiovascular death, non‐fatal stroke, non‐fatal myocardial infarction, or hospitalization for unstable angina). Associations between baseline or time‐varying HbA1c and cardiovascular outcomes were U‐shaped, with the lowest risk when HbA1c was around 7%. Each one‐unit increase in the time‐varying HbA1c above 7% was associated with an adjusted hazard ratio (HR) of 1.21 [95% confidence interval (CI) 1.11–1.33] for first HF hospitalization, 1.11 (1.03–1.21) for all‐cause death, 1.18 (1.09–1.26) for death or HF hospitalization, and 1.10 (1.02–1.17) for non‐HF cardiovascular events. Each one‐unit decrease in the time‐varying HbA1c below 7% was associated with an adjusted HR of 1.35 (95% CI 1.12–1.64) for first HF hospitalization, 1.37 (1.16–1.61) for death, 1.42 (1.23–1.64) for death or HF hospitalization, and 1.22 (1.06–1.41) for non‐HF cardiovascular events. Conclusion: Glycated haemogobin exhibits a U‐shaped association with cardiovascular outcomes in patients with T2D and atherosclerotic vascular disease, with nadir around 7%. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT00790205. [ABSTRACT FROM AUTHOR]