Yusuf, Salim

Abstract Background and Aims Clinical models incompletely capture the molecular pathways driving heart failure (HF) progression. This study evaluated whether molecular risk stratification provides incremental prognostic information beyond established clinical predictors in patients with HF. Methods A total of 2432 patients from the Global Congestive Heart Failure (G-CHF) registry with available genotyping, DNA methylation, and proteomic profiling were analysed. Three molecular scores were assessed: a composite cardiovascular polygenic risk score (PRS) from DNA sequence polymorphisms, a methylation risk score (MRS) derived from epigenome-wide associations, and a 23-protein-based score (ProteomicDeath23). Each score was tested individually and in combination with the clinical Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels for mortality prediction. Validation was performed in an HF subset of the UK Biobank (UKB). Results Over a median follow-up of 3.0 years in G-CHF, 523 patients died from any cause (7.64 per 100 person-years [PY]). In multivariable analyses, ProteomicDeath23 was the strongest independent predictor of all-cause mortality (hazard ratio [HR] per 1 standard deviation, 2.23), outperforming NT-proBNP (HR 2.00), MRSMortality (HR 1.66), PRSmetaCVD (HR 1.10), and the MAGGIC score (HR 1.70). A model combining ProteomicDeath23 with MAGGIC and NT-proBNP achieved the highest discrimination for mortality (C-index, 0.77). Addition of MRSMortality to this proteomic-clinical model resulted in only small improvements in discrimination (ΔC-index, +0.004, P = .0039), while the PRSmetaCVD provided no incremental benefit. Among patients with low NT-proBNP/MAGGIC score, mortality rates increased from 1.71 to 8.12 per 100 PY across ProteomicDeath23 tertiles. Consistent results were observed in the UKB-HF validation cohort. Conclusion A proteomic score was the strongest molecular predictor of mortality in HF. Integrating proteomic signatures with clinical risk factors significantly improved risk prediction.

Background— Antiplatelet therapy and antithrombin therapy have been demonstrated to reduce the risk of cardiac events in patients presenting with acute coronary syndrome, yet all effective therapies also increase the risk of bleeding. Methods and Results— In the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial, 12 562 patients were randomized to clopidogrel or placebo in addition to aspirin, and the primary outcome was cardiovascular (CV) death, myocardial infarction (MI), or stroke. The benefits were consistent among those undergoing percutaneous coronary intervention (PCI) [9.6% for clopidogrel, 13.2% for placebo; relative risk (RR), 0.72; 95% CI, 0.57 to 0.90], coronary artery bypass grafting (CABG) surgery (14.5% for clopidogrel 16.2% for placebo; RR, 0.89; 95% CI, 0.71 to 1.11), and medical therapy only (8.1% for clopidogrel, 10.0% for placebo; RR, 0.80; 95% CI, 0.69 to 0.92; test for interaction among strata, 0.53). For CABG during the initial hospitalization (530 for placebo, 485 for clopidogrel), the frequency of CV death, MI or stroke before CABG was 4.7% for placebo and 2.9% for clopidogrel (RR, 0.56; 95% CI, 0.29 to 1.08). For the entire study, there was a 1% excess of major bleeding but no significant excess of life-threatening bleeding. Among patients undergoing CABG, the rates of life-threatening bleeding were 5.6% for clopidogrel and 4.2% for placebo (RR, 1.30; 95% CI, 0.91 to 1.95; both nonsignificant). Conclusions— The benefits versus risks of early and long-term clopidogrel therapy (freedom from CV death, MI, stroke, or life-threatening bleeding) are similar in those undergoing revascularization (CABG or PCI) and in the study population as a whole. Overall, the benefits of starting clopidogrel on admission appear to outweigh the risks, even among those who proceed to CABG during the initial hospitalization.

Background— We studied the benefits and risks of adding clopidogrel to different doses of aspirin in the treatment of patients with acute coronary syndrome (ACS). Methods and Results— In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, 12 562 patients with ACS using aspirin, 75 to 325 mg daily, were randomized to clopidogrel or placebo for up to 1 year. In this analysis, patients were divided into the following 3 aspirin dose groups: ≤100 mg, 101 through 199 mg, and ≥200 mg. The combined incidence of cardiovascular death, myocardial infarction, or stroke was reduced by clopidogrel regardless of aspirin dose, as follows: ≤100 mg, 10.5% versus 8.6% (relative risk [RR], 0.81 [95% CI, 0.68 to 0.97]); 101 to 199 mg, 9.8% versus 9.5% (RR, 0.97 [95% CI 0.77 to 1.22]); and ≥200 mg, 13.6% versus 9.8% (RR, 0.71 [95% CI, 0.59 to 0.85]). The incidence of major bleeding increased with increasing aspirin dose both in the placebo group (1.9%, 2.8%, and 3.7%, respectively; P =0.0001) and the clopidogrel group (3.0%, 3.4%, and 4.9%, respectively; P =0.0009); thus, the excess risk with clopidogrel was 1.1%, 1.2%, and 1.2%, respectively. The adjusted hazard ratio for major bleeding for the highest versus the lowest dose of aspirin was 1.9 (95% CI 1.29 to 2.72) in the placebo group, 1.6 (95% CI 1.19 to 2.23) in the clopidogrel group, and 1.7 (95% CI 1.36 to 2.20) in the combined group. Conclusions— In patients with ACS, adding clopidogrel to aspirin is beneficial regardless of aspirin dose. Bleeding risks increase with increasing aspirin dose, with or without clopidogrel, without any increase in efficacy. Our findings suggest that the optimal daily dose of aspirin may be between 75 and 100 mg, with or without clopidogrel.

Background— The risk of ischemic events is high, both early and late after acute coronary syndromes (ACS). We examine the benefits and risks associated with the use of adding clopidogrel to aspirin within the first 30 days and later (31 days to 12 months) in 12 562 patients with ACS. Methods and Results— A total of 12 562 ACS patients were randomized to receive clopidogrel (300 mg initially followed by 75 mg/d) or placebo for 3 to 12 months. The proportion of patients experiencing cardiovascular death, myocardial infarction, or strokes (primary outcome) at 30 days was 5.4% in the placebo group and 4.3% in the active group (relative risk 0.79, 95% CI 0.67 to 0.92). Beyond 30 days, the corresponding rates were 6.3% versus 5.2% (relative risk 0.82, 95% CI 0.70 to 0.95). There was no significant excess in life-threatening bleeds in each period (0.97% versus 1.28%, relative risk 1.32, 95% CI 0.95 to 1.84 for 0 to 30 days; 0.83% versus 0.91%, relative risk 1.09, 95% CI 0.75 to 1.59 for 31 days to 12 months). Further subdivision of the early data indicates benefits within 24 hours with consistently lower rates of the primary outcome in combination with refractory or severe ischemia. Conclusions— Clopidogrel reduces the risk of ischemic vascular events, with the benefits emerging within 24 hours of initiation of treatment and continuing throughout the 12 months (mean 9 months) of the study.