Senni, Michele

Abstract Background Ventricular arrhythmias (VA) are common complications of acute coronary syndromes (ACS) and can cause cardiac arrest and adverse outcomes. However, the prognostic impact of VA according to their timing in relation to percutaneous coronary intervention (PCI) remains unclear. Purpose To assess the prognostic significance of VA in patients with ACS undergoing PCI according to the timing of occurrence (before, during, or after PCI). Methods We performed a systematic review and meta-analysis of observational studies reporting all-cause mortality with and without VA (sustained VT/VF) in ACS patients undergoing PCI. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using random-effects models for short-term (30 days/in-hospital) and long-term (1 year) mortality. Between-study heterogeneity was assessed using the I² statistic. We conducted subgroup analyses for studies that stratified VA according to timing, defined as VA before PCI (prior to arrival in the catheterization laboratory), VA during PCI (in the catheterization laboratory or immediately after reperfusion), VA after PCI (following completion of PCI). Each timing category was compared to patients who did not develop VA within the same time window (before, during or after PCI). Results Twelve studies comprising 49306 patients were included, of whom 4320 (8.76%) experienced VA. The mean age of the patients ranged from 60 to 70 years, and the follow-up ranged from hospital discharge to 8 years. VA was associated with increased short-term (OR 5.02 [3.91-6.44]) and long-term mortality (OR 3.00 [2.86-3.82]). However, in patients alive at discharge/30 days, subsequent long-term mortality risk did not differ between those with and without VA (OR 1.21 [0.70-2.09]) (Figure 1). The subgroup analyses showed that patients with VA were associated with higher short-term mortality compared to patients without VA within each time window: before (OR 4.32 [3.29-5.66]), during (OR 4.29 [2.08-8.84]), and after PCI (OR 9.29 [3.12-27.63]) (Figure 2). VA after PCI was associated with the highest OR for short-term mortality. Conclusions VA significantly worsens short-term outcomes in ACS patients undergoing PCI. Subgroup analysis shows that VA increases mortality in each timing category, before, during and after PCI, with the poorest prognosis observed for arrhythmias developed after reperfusion, in whom reversible acute ischemia may play a lesser role and underlying arrhythmic substrate may predominate.Figure 1Figure 2

Abstract Aims The efficacy and safety of vericiguat in patients with chronic heart failure with reduced ejection fraction (HFrEF) on contemporary heart failure (HF) therapies and without recent worsening was investigated in the VICTOR trial, yet some subgroups may be more susceptible to symptomatic hypotension. Methods and results Among VICTOR trial participants that received at least one dose of study drug or placebo, we describe the systolic blood pressure (SBP) trajectories over time (mean change from baseline), symptomatic hypotension events and efficacy of vericiguat in potentially vulnerable patient subgroups: lower baseline blood pressure (SBP ≤110 mmHg), older patients (>75 years) and those taking angiotensin receptor–neprilysin inhibitors (ARNI) or sodium–glucose co-transporter 2 inhibitors (SGLT2i) at baseline. The efficacy outcomes of cardiovascular death and HF hospitalization and cardiovascular death alone across baseline SBP were examined using Cox proportional hazards models. Overall SBP trajectories showed a small initial decline from baseline in vericiguat-treated patients compared with placebo (placebo-corrected differences of −1.17 [−1.84, −0.50], p = 0.0007) that was relatively stable throughout follow-up. This trajectory was similar in those >75 years (vs. younger) as well as those receiving ARNI or SGLT2i (as compared with those not receiving these) or those with SBP ≤110 mmHg at baseline (compared with >110 mmHg). Symptomatic hypotension occurred in 11.3% of vericiguat-treated patients compared with 9.2% of placebo-treated patients with an adjusted hazard ratio of 1.24 (95% confidence interval 1.06–1.46), which was similar across age, SBP, SGLT2i and ARNI groups (all interaction p >0.05). The treatment effect of vericiguat compared with placebo on the efficacy outcomes was similar across the spectrum of baseline SBP (both interaction p >0.15). Conclusions Vericiguat showed a slight adjusted decrease in SBP and resulted in more symptomatic hypotension compared with placebo but was overall well-tolerated in a broad population with HFrEF on contemporary therapy even among those predisposed to hypotension. Treatment effects on efficacy outcomes were consistent regardless of baseline SBP.

Abstract Background and Aims In the VICTOR trial (NCT05093933), vericiguat was neutral for the primary composite endpoint of cardiovascular death or hospitalization for heart failure (HF). VICTOR was powered to independently assess cardiovascular death. This study reports detailed analysis on the effects of vericiguat on mortality. Methods VICTOR, a double-blind, placebo-controlled, randomized trial, enrolled 6105 ambulatory patients with HF and reduced ejection fraction (HFrEF) without recent worsening and randomized them to vericiguat or placebo. The main outcome for this analysis was the pre-specified secondary endpoint of cardiovascular death. All-cause death, sudden cardiac death, and death related to HF were also assessed. Results Over a median of 19.7 months (inter-quartile range 14.6–25.4), cardiovascular deaths occurred in 292 patients (5.7 deaths per 100 patient-years) and 346 patients (6.8 deaths per 100 patient-years) in the vericiguat and placebo groups, respectively (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.71–0.97; P = .020). Risk of death from any cause was lower with vericiguat vs placebo (377 [7.3 deaths per 100 patient-years] vs 440 [8.6 deaths per 100 patient-years]; HR 0.84, 95% CI 0.74–0.97; P = .015). Sudden cardiac death and HF-related deaths were lower with vericiguat vs placebo (1.6 vs 2.2 events per 100 patient-years; HR 0.75, 95% CI 0.56–0.99; P = .042 and 1.7 vs 2.4 events per 100 patient-years; HR 0.71, 95% CI 0.54–0.94; P = .016, respectively). Lower mortality rates were consistent across subgroups including baseline therapy. Consistent cardiovascular and all-cause mortality benefit was seen across baseline N-terminal pro-B-type natriuretic peptide levels. Conclusions In ambulatory well-treated participants with HFrEF, vericiguat was associated with clinically meaningful reductions in the key secondary outcome of cardiovascular death, as well as all-cause mortality.

Abstract Aims To describe the baseline characteristics of the participants in the VICTOR (Vericiguat Global Study in Patients with Chronic Heart Failure; NCT05093933) trial and compare them to recent trials in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results Baseline characteristics were evaluated in 6105 patients randomized to vericiguat or placebo. The mean age of the participants was 67 ± 11 years, 23.6% were women, 64.4% were White, and 10.7% were self-identified Black. Overall, 29.1% of participants were enrolled in Latin and South America, 27.8% and 18.5% in Eastern and Western Europe, 14.0% in Asia-Pacific and 10.6% in North America. The mean left ventricular ejection fraction was 30 ± 7% and 79% had New York Heart Association class II symptoms. Mean estimated glomerular filtration rate was 70.9 ± 24.0 ml/min/1.73 m2. Median N-terminal pro-B-type natriuretic peptide level was 1476 (970–2495) pg/ml and 47.5% of participants had no prior hospitalization for heart failure. Baseline therapy included 94.4% beta-blockers, 94.3% renin–angiotensin system modulation (including 56.0% on an angiotensin receptor–neprilysin inhibitor), 77.7% mineralocorticoid receptor antagonists, 59.1% sodium–glucose cotransporter 2 inhibitors, and 32.9% implantable cardioverter-defibrillators. Overall characteristics were relatively similar to other recent HFrEF trials but the VICTOR trial enrolled a higher proportion of participants receiving contemporary drug and device therapy. Conclusion The VICTOR trial enrolled the most optimally treated population in a phase III heart failure trial. These features will facilitate assessment of the benefit of vericiguat and elucidate the outcomes of patients on up-to-date medical therapy.

Abstract Aims In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure (HF) and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent worsening HF remains unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with ejection fraction ≤40% without recent worsening HF on a background of current foundational HFrEF therapy. Methods The primary endpoint for VICTOR is time to first event for the composite of HHF or cardiovascular death. The trial will also assess the effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all-cause death. As an event-driven trial, at least 1080 primary events are expected, but follow-up will continue until the targeted number of at least 590 cardiovascular deaths has been reached. Approximately 6000 participants will be randomized to vericiguat or placebo. Conclusion VICTOR is the first large event-driven HFrEF trial performed in the contemporary era of quadruple foundational guideline-directed medical therapy, in a compensated ambulatory HF population. VICTOR will add important information to the evidence of the effects of vericiguat across the spectrum of patients with HFrEF.

Background Little is known about the impact of chronic obstructive pulmonary disease (COPD) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We examined outcomes in patients with heart failure with preserved ejection fraction, according to COPD status, in the PARAGON‐HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and cardiovascular death. Of 4791 patients, 670 (14%) had COPD. Patients with COPD were more likely to be men (58% versus 47%; P <0.001) and had worse New York Heart Association functional class (class III/IV 24% versus 19%), worse Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (69 versus 76; P <0.001) and more frequent history of heart failure hospitalization (54% versus 47%; P <0.001). The decrement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores with COPD was greater than for other common comorbidities. Patients with COPD had echocardiographic right ventricular enlargement, higher serum creatinine (100 μmol/L versus 96 μmol/L) and neutrophil‐to‐lymphocyte ratio (2.7 versus 2.5), than those without COPD. After multivariable adjustment, COPD was associated with worse outcomes: adjusted rate ratio for the primary outcome 1.51 (95% CI, 1.25–1.83), total heart failure hospitalization 1.54 (95% CI, 1.24–1.90), cardiovascular death (adjusted hazard ratio [HR], 1.42; 95% CI, 1.10–1.82), and all‐cause death (adjusted HR, 1.52; 95% CI, 1.25–1.84). COPD was associated with worse outcomes than other comorbidities and Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores declined more in patients with COPD than in those without. Conclusions Approximately 1 in 7 patients with heart failure with preserved ejection fraction had concomitant COPD, which was associated with greater functional limitation and a higher risk of heart failure hospitalization and death. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711 .

Background: Very few long-term data are available on patients undergoing mitral valve surgery for chronic ischemic mitral regurgitation (CIMR). Objective:to identify determinants of survival and adverse cardiovascular events, at very long-term outcome. Methods and Results: We reviewed complete left and right ventricular echocardiographic data, six-minute walking test (6-MWT) and BNP levels at pre, peri and follow-up, on 137 consecutive patients who underwent restrictive mitral annuloplasty (RMA) or mitral valve replacement (MVR) and CABG, for CIMR. Combined adverse cardiovascular events were defined as composite of death, heart failure, angina, myocardial infarction and re-hospitalization. Mean age was 67±0.7. Preoperative EF was 35±06%. Among 137 patients, 46% underwent RMA and 54% had MVR. Median follow- up was 7 years (range: 0.3-15.4). Early mortality was 7% (p=NS). In the RMA 42% of patients experienced MR recurrence. Overall survival at 5, 10 and 15 years were 84, 76 and 62% in RMA, and 87, 62 and 54% in MVR (p=0.65). At univariate analysis, preop B-blocker, 6-MWT, mean transmitral gradients and RV size were predictors of adverse events.The Cox Hazard multivariate analysis identified preoperative atrial fibrillation (p=0.005), preop BNP (p=0.025) as independent predictors of long-term mortality.Freedom from cardiovascular events at 5, 10 and 15 years were 90, 75 and 48% in RMA, and 90, 62 and 45% in MVR (p=0.57). . The Cox Hazard multivariate analysis identified preop B-blocker therapy (p=0.001), atrial fibrillation (p=0.01), postoperative mean transmitral gradients (p=0.047 ) and indexed effective orifice area (p=0.02) as independent predictors of adverse cardiovascular events. Conclusions: Our study confirms an high rate of true MR recurrence, at very long-term follow-up. Among collected variables, preoperative BNP and atrial fibrillation were independent predictors of survival, whereas B-blocker therapy, atrial fibrillation, postoperative mean transmitral gradients and indexed effective orifice area were independent predictors of adverse cardiovascular events. Type of surgery did not affect the very long-term outcome.

Introduction: Whether echocardiographic (echo) markers of left ventricular (LV) remodeling and diastolic dysfunction contribute incremental and independent prognostic information to clinical risk markers in patients (Pts) with coronary artery disease and severe LV systolic dysfunction is unclear. We sought to determine which echo variables provide the greatest prognostic value in the Surgical Treatment for Ischemic Heart Failure (STICH) population. Methods: Pts enrolled in STICH for whom transmitral Doppler (E/A ratio) was available on a baseline echo interpreted by an echo core laboratory blinded to treatment and outcomes formed the analysis cohort. Comprehensive datasets to account for missing echo data were created by multiple imputation and the impact on all-cause mortality was determined with the Cox’s regression model. Results: E/A ratio could be measured in 1511 of the 2136 Pts enrolled in STICH. Amongst markers of diastolic dysfunction, E/A ratio was the most significant predictor of mortality (χ 2 41.05, p <0.001) with a non-linear, u-shaped, relationship. Mortality was lowest with E/A ratio = 1.0, and increased for E/A ratio <0.6 and >1.0 up to 2.3, beyond which there was no further increase in risk. The combination of larger LV end-systolic volume index (LVESVI), low or high E/A ratio, and mitral regurgitation severity grade, had highly significant incremental negative effects on mortality (χ 2 69.65, p<0.001) when added to a multivariable model with clinical risk markers. Overall, creatinine (χ 2 30.00, p <0.001), followed by LVESVI (χ 2 27.26, p<0.001), age, and E/A ratio (χ 2 12.46, p<0.001) were among the most significant predictors of mortality and accounted for 74% of the total prognostic information. LVESVI and E/A ratio were stronger predictors of poor prognosis than New York Heart Association (NYHA) functional class, hemoglobin, diabetes, stroke, or atrial fibrillation. Conclusions: Echo markers of advanced LV remodeling and diastolic dysfunction add incremental prognostic value to clinical risk markers and are more predictive of poor prognosis than advanced NYHA functional class or anemia. LVESVI and E/A ratio outperformed other echo markers and should be considered standard in assessing risk in Pts with ischemic LV dysfunction.