Marc S. Sabatine

BackgroundConventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being into a single outcome.MethodsWe examined the effect of dapagliflozin on an integrated measure that included days lost from death and hospitalization, and additional days of full health lost through diminished well-being in patients with HFrEF in the DAPA-HF trial.ResultsOver 360 days, patients in the dapagliflozin group (n= 2127) lost 10.6±1.0 [mean±SE](2.9%) of potential days of full health through CV death and HF hospitalization, compared with 14.4±1.2 days (4.0%) in the placebo group (n= 2108), and these accounted for the greatest between-treatment difference (Figure). Patients receiving dapagliflozin also lost fewer days due to death and hospitalization from all causes, versus placebo [15.5±1.1 days (4.3%) vs. 20.3±1.3 days (5.6%)]. When remaining days of full health lost due to …

BackgroundPatients recently hospitalized for heart failure (HF) are at a higher risk of adverse clinical outcomes, but they may experience a greater absolute and relative benefit from effective therapies than individuals who are considered more “stable.”ObjectivesThe authors examined the effects of dapagliflozin according to the timing of prior HF hospitalization in a patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure).MethodsA total of 11,007 patients were randomized in DAPA-HF and DELIVER. The primary outcome was the composite of worsening HF or cardiovascular death.ResultsIn total, 12.4% were hospitalized for HF within 3 months of randomization, 14.2% between 3 and 12 months, and 16.8% more than 1 year before …

Background The sodium glucose cotransporter‐2 inhibitors are guideline‐recommended to treat heart failure across the spectrum of left ventricular ejection fraction; however, economic evaluations of adding sodium glucose cotransporter‐2 inhibitors to standard of care in chronic heart failure across a broad left ventricular ejection fraction range are lacking. Methods and Results We conducted a US‐based cost‐effectiveness analysis of dapagliflozin added to standard of care in a chronic heart failure population using pooled, participant data from the DAPA‐HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. The 3‐state Markov model used estimates of transitional probabilities, effectiveness of dapagliflozin, and utilities from the pooled trials. Costs estimates were …

BackgroundThe Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial was a non-inferiority trial that compared percutaneous coronary intervention (PCI) using first-generation paclitaxel-eluting stents with coronary artery bypass grafting (CABG) in patients with de-novo three-vessel and left main coronary artery disease, and reported results up to 5 years. We now report 10-year all-cause death results.MethodsThe SYNTAX Extended Survival (SYNTAXES) study is an investigator-driven extension of follow-up of a multicentre, randomised controlled trial done in 85 hospitals across 18 North American and European countries. Patients with de-novo three-vessel and left main coronary artery disease were randomly assigned (1:1) to the PCI group or CABG group. Patients with a history of PCI or CABG, acute myocardial infarction, or an indication for concomitant cardiac surgery were excluded. The primary …

BackgroundSGLT2i improve HF and kidney outcomes. The effects on major adverse cardiovascular events (MACE) across different pt populations are less clear.MethodsThe SGLT2i meta-analysis cardio-renal trialists consortium (SMART-C) includes all placebo-controlled RCTs of SGLT2i across 3 groups of pts: DM at high risk for ASCVD, HF, and CKD. Outcomes of interest were the MACE composite (CV death, MI or stroke), individual components, all-cause mortality (ACM) and death subtypes. Trial effect estimates were meta-analyzed in each of the 3 pt groups using fixed-effects (FE) and pooled using random-effects (RE).Results78,607 pts across 11 RCTs were included (54%, 26% & 19% from high-risk DM, HF & CKD RCTs respectively), w/7,976 experiencing MACE. SGLT2i reduced the risk of MACE w/o heterogeneity across the 3 pt populations (HR 0.91 [0.87-0.96]; Fig 1A). This effect was primarily driven by …

BackgroundData are sparse on long-term benefits of PCSK9 inhibition in elderly pts. Concerns about the relative efficacy and safety, have led to weaker recommendations in lipid guidelines for aggressive LDL-C lowering in the elderly.MethodsFOURIER randomized 27,564 pts with stable ASCVD to evolocumab (evo) vs placebo (pbo) over 2.2 yrs median f/u. In the open-label extension (FOURIER-OLE), 6635 completing FOURIER on study drug were transitioned to open-label evo (median f/u 5 yrs). Primary end point (PEP: CV death, MI, stroke, unstable angina, coronary revasc) and secondary end point (SEP: CV death, MI, stroke) were compared by age:< 75 vs>= 75yrs. Annualized incidence rates (IR) for adverse events were compared in pbo pts in FOURIER with evo pts during FOURIER+ FOURIER-OLE.ResultsOf 27,564 pts, 2526 (9%) were>= 75 yrs at entry into FOURIER (median 78 [IQR 77, 80] yrs, max 86 …

ImportanceElevated lipoprotein(a) (Lp[a]) is a putative causal risk factor for atherosclerotic cardiovascular disease (ASCVD). There are conflicting data as to whether Lp(a) may increase cardiovascular risk only in the presence of concomitant inflammation.ObjectiveTo investigate whether Lp(a) is associated with cardiovascular risk independent of high-sensitivity C-reactive protein (hs-CRP) in both primary and secondary prevention populations.Design, Setting, and ParticipantsThis cohort study uses data from 3 distinct cohorts, 1 population-based cohort and 2 randomized clinical trials. Participants included individuals from the UK Biobank (data from 2006-2010) without prevalent ASCVD, participants in the FOURIER (TIMI 59) trial (data from 2013-2017) who had baseline Lp(a) and hs-CRP data, and participants in the SAVOR-TIMI 53 trial (data from 2010-2013) who had prevalent ASCVD and baseline values for Lp …

BackgroundThe reduction of low-density lipoprotein cholesterol (LDL-C) with evolocumab, a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9i), reduces the risk of major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease (ASCVD) with a prior MI, prior stroke, or symptomatic peripheral artery disease, with no offsetting safety concerns. The effect of evolocumab on CV outcomes in lower risk patients without a history of MI or stroke has not been explored.Study designVESALIUS-CV is a randomized, double-blind, placebo-controlled, global clinical trial designed to evaluate the effect of evolocumab on the risk of major cardiovascular events in patients at high cardiovascular risk but without a prior ischemic event. The study population consists of 12,301 patients with atherosclerosis or high-risk diabetes mellitus without a prior …

Inflammation is central to the pathogenesis of atherosclerotic cardiovascular disease (ASCVD) and is further amplified in the setting of myocardial infarction (MI). C-reactive protein (CRP) is a downstream inflammatory protein that is associated with increased cardiovascular risk in stable ASCVD and acute coronary syndromes, including ST-segment elevation myocardial infarction (STEMI). 1 Given these links, upstream proteins in the central immune pathway linking interleukin (IL)-1, tumor necrosis factor (TNF) a, and IL-6 are of interest as potential targets for therapeutic interventions across the spectrum of ASCVD. 2 In the CANTOS trial, 3 antiinflammatory therapy targeting IL-1b reduced cardiovascular events in patients with stable coronary artery disease, and in an ongoing trial (NCT05021835), anti-IL-6 therapy is being evaluated for cardiovascular protection in stable ASCVD. Whether directly targeting this …

BackgroundST2 is involved in inflammation and fibrosis, and its soluble form (sST2) is associated with heart failure (HF) and cardiovascular (CV) outcomes. These associations have not been evaluated in large cohorts of patients (pts) with type 2 diabetes mellitus (T2DM).MethodssST2 was measured at baseline (Ella, Protein Simple) in 14,572 pts enrolled in DECLARE-TIMI 58, a randomized, placebocontrolled trial of dapagliflozin in pts with T2DM with or at high risk for atherosclerotic CV disease (median f/u= 4.2 years). Outcomes included adjudicated CV death (CVD) or hospitalization for HF (HHF) and MACE (CV death, myocardial infarction, or ischemic stroke). Hazard ratios were adjusted for age, sex, race, BMI, hypertension, prevalent CV disease, prior HF, eGFR, hs-cTnT, and NT-proBNP. Comparative effects of dapagliflozin vs. placebo were assessed by baseline sST2 quartiles.ResultsMedian baseline sST2 …

BackgroundPrevious meta-analyses of summary data from randomised controlled trials have shown that statin therapy increases the risk of diabetes, but less is known about the size or timing of this effect, or who is at greatest risk. We aimed to address these gaps in knowledge through analysis of individual participant data from large, long-term, randomised, double-blind trials of statin therapy.MethodsWe conducted a meta-analysis of individual participant data from randomised controlled trials of statin therapy that participated in the CTT Collaboration. All double-blind randomised controlled trials of statin therapy of at least 2 years' scheduled duration and with at least 1000 participants were eligible for inclusion in this meta-analysis. All recorded diabetes-related adverse events, treatments, and measures of glycaemia were sought from eligible trials. Meta-analyses assessed the effects of allocation to statin therapy …

Background In FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), during a median follow-up of 2.2 years, risk reduction for major adverse cardiovascular event with evolocumab was greater in patients with multivessel disease (MVD). The FOURIER Open-Label Extension (FOURIER-OLE) provides an additional median follow-up of 5 years. Objectives The purpose of this study was to assess the long-term benefit of evolocumab in patients with and without MVD. Methods FOURIER randomized 27,564 patients to evolocumab vs placebo; 6,635 entered FOURIER-OLE. Patients with coronary artery disease were categorized based on the presence of MVD (≥40% stenosis in ≥2 large vessels). The primary endpoint was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary …

BackgroundSleep apnea is more common in patients with heart failure (HF) than in the general population, but little is known about its association with clinical outcomes in various HF phenotypes or how it might modify the effect of HF therapy.ObjectivesTo examine the prevalence of sleep apnea, its association with outcomes and the effects of dapagliflozin in patients with HF with and without sleep apnea in a pooled analysis of 2 trials comparing dapagliflozin to placebo in HFrEF (DAPA-HF trial) and HFmrEF/HFpEF (DELIVER trial).MethodsA history of sleep apnea was investigator-reported. The primary outcome was a composite of worsening HF or cardiovascular death.ResultsThe prevalence of sleep apnea was 5.7% and 7.8% in patients with HFrEF and HFmrEF/HFpEF, respectively. The primary outcome occurred at a rate of 16.0 in participants with sleep apnea compared to 10.6 per 100 person-years in those …

BackgroundConventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome.ObjectivesTo overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being.MethodsThe effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA class II-IV HF and a LVEF ≤40%.ResultsOver 360 days, patients in the dapagliflozin group (n=2,127) lost 10.6±1.0 [mean±SE] (2.9%) of potential follow-up days through cardiovascular death and HF hospitalization, compared with 14.4±1.0 days (4.0%) in the placebo group (n=2,108), and this component of all measures of days lost accounted for the greatest between-treatment difference [-3.8 …

BackgroundPatients with autoimmune or inflammatory diseases (AIID) have higher CV risk due to systemic inflammation. In FOURIER, the PCSK9i evolocumab (evo) reduced LDL-C and the risk of CV events, but had no effect on CRP, vs. placebo in ASCVD pts on statins.MethodsWe compared evo vs. placebo in FOURIER pts with or without AIID, ie, any autoimmune or chronic inflammatory condition. The primary endpoint (PEP) was CV death, MI, stroke, UA, or coronary revasc; key secondary EP (SEP) was CV death, MI, or stroke. Cox models, adjusted for screening LDL-C and region, were used.ResultsOf 27,564 pts (mean 63 yrs; 75% male), 889 (3.2%) had an AIID. The most common diseases were rheumatoid arthritis (34%) and psoriasis (16%). Baseline LDL-C (mean 97 vs. 98 mg/dL) and reduction with evo (62% vs. 61%) were similar in pts with vs. without an AIID. Baseline hsCRP was higher in AIID vs. non …

Background: Sodium glucose co-transporter 2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. Methods: This was a collaborative trial-level meta-analysis from the SGLT2i meta-analysis cardio-renal trialists consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across three patient populations (diabetes at high risk for atherosclerotic cardiovascular disease [ASCVD], heart failure [HF], or chronic kidney disease [CKD]). The outcomes of interest were MACE (composite of CV death, myocardial infarction [MI], or stroke), individual components of MACE (inclusive of fatal and non-fatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i vs. placebo were meta-analyzed across trials and examined across key …

Lipoprotein (a)(Lp (a)) is a subtype of apolipoprotein B (apoB)-containing lipoproteins that can be distinguished from low-density lipoprotein (LDL) particles by its additional glycoprotein apolipoprotein (a). Lp (a) levels appear to carry risk beyond that of apoB levels, but a challenge in the field has been putting the risk of Lp (a) into context. 1The preferred unit of measurement for Lp (a) is nmol/L. Although apoB is typically reported in mg/dL, it can be converted into nmol/L using its estimated molecular weight (513 kDa). 2 With molar measurements of both, one can quantify the individual cardiovascular (CV) risk associated with an Lp (a) particle compared with a non-Lp (a) apoB-containing particle. Such an approach may become relevant with the ongoing development of new therapies targeting Lp (a) or apoB.

Diabetes-associated atherosclerosis involves excessive immune cell recruitment and plaque formation. However, the mechanisms remain poorly understood. Transcriptomic analysis of the aortic intima in Ldlr−/− mice on a high-fat, high-sucrose-containing (HFSC) diet identifies a macrophage-enriched nuclear long noncoding RNA (lncRNA), MERRICAL (macrophage-enriched lncRNA regulates inflammation, chemotaxis, and atherosclerosis). MERRICAL expression increases by 249% in intimal lesions during progression. lncRNA-mRNA pair genomic mapping reveals that MERRICAL positively correlates with the chemokines Ccl3 and Ccl4. MERRICAL-deficient macrophages exhibit lower Ccl3 and Ccl4 expression, chemotaxis, and inflammatory responses. Mechanistically, MERRICAL guides the WDR5-MLL1 complex to activate CCL3 and CCL4 transcription via H3K4me3 modification. MERRICAL deficiency in …

Aims Patients with heart failure (HF) and history of myocardial infarction (MI) face a higher risk of disease progression and clinical events. Whether sodium–glucose cotransporter 2 inhibitors may modify clinical trajectory in such individuals remains incompletely understood. Methods and results The DAPA‐HF and DELIVER trials compared dapagliflozin with placebo in patients with symptomatic HF with left ventricular ejection fraction (LVEF) ≤40% and > 40%, respectively. In this pooled participant‐level analysis, we assessed efficacy and safety outcomes by history of MI. The primary outcome in both trials was the composite of cardiovascular death or worsening HF. Of the total of 11 007 patients, 3731 (34%) had a previous MI and were at higher risk of the primary outcome across the spectrum of LVEF in covariate‐adjusted models (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.02–1.24). Dapagliflozin …

BackgroundHigh sensitivity troponin T (hsTnT) & I (hsTnI) have similar diagnostic performance in patients with AMI, but their comparative association with prognosis in stable ASCVD is unclear.MethodsWe assessed the correlation, concordance, & predictive association of hsTnT and hsTnI in patients with ASCVD from PEGASUS-TIMI 54 and HPS3 TIMI 55-REVEAL. HsTn was modeled both continuously and categorically (< LOQ, LOQ-99% ile,> 99% ile URL). Log-transformed hazard ratios (adjusted for age, sex, and comorbidities) and categorical C-indices for the primary endpoint (PEP; CV death, MI, or stroke) and all-cause mortality (ACM) were calculated over 3 years.ResultsAmong the 37,886 patients, mean age was 66 years, 82% were men, and 70% had CAD. The median hsTnT level was 9 ng/L (IQR 6-14), with 78%≥ LOQ and 24%≥ URL. The median hsTnI was 4 ng/L (2-7), with 55%≥ LOQ and 5%≥ URL …