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BACKGROUND There are concerns that Asian patients respond differently to some medications. This study evaluated the efficacy and safety of evolocumab among Asian vs. other subjects in the FOURIER trial, which randomized stable atherosclerosis patients to receive either evolocumab or placebo.Methods and Results:Effects of adding evolocumab vs. placebo to background statin therapy on low-density lipoprotein cholesterol (LDL-C) reductions, cardiovascular outcomes, and adverse events were compared among 27,564 participants with atherosclerotic disease, according to self-reported Asian (n=2,723) vs. other (n=24,841) races followed for a median of 2.2 years in the FOURIER trial. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. At randomization, Asians had slightly lower LDL-C (median 89 [IQR 78-104] mg/dL vs. 92 [80-109] mg/dL; P

Aims We assessed the impact of the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab on acute arterial events across all vascular territories, including coronary, cerebrovascular, and peripheral vascular beds, in patients with established atherosclerotic cardiovascular disease (ASCVD). Methods and results In the FOURIER trial, 27 564 patients with stable ASCVD on statin therapy were randomly assigned to evolocumab or placebo. Acute arterial events were a composite of acute coronary (coronary heart disease death, myocardial infarction, or urgent coronary revascularization), cerebrovascular (ischaemic stroke, transient ischaemic attack, or urgent cerebral revascularization), or peripheral vascular (acute limb ischaemia, major amputation, or urgent peripheral revascularization) events. Of the 2210 first acute arterial events, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced first acute arterial events by 19% (hazard ratio [HR] 0.81 [95% confidence interval 0.74–0.88]; P Conclusion The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced acute arterial events across all vascular territories with a robust effect over time, indicating a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.

Aims We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM). Methods and results DECLARE–TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to Conclusions In DECLARE–TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM. Clinical trial registration URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534.

Women remain underrepresented in clinical trials and those with type 2 diabetes mellitus are at high risk for cardiovascular (CV) events. The sodium–glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin reduces the risk of CV death or heart failure hospitalisations in individuals with type 2 diabetes. Here, we performed a pre-specified analysis to examine whether sex modifies these effects. The DECLARE-TIMI 58 trial randomised 17,160 patients with type 2 diabetes with or at risk for atherosclerotic disease to dapagliflozin or placebo (median follow-up 4.2 years). The dual efficacy outcomes were CV death or heart failure hospitalisations, and major adverse cardiovascular events (MACE; CV death, myocardial infarction or ischaemic stroke). The renal-specific composite outcome was a sustained ≥40% drop in eGFR to

Supplemental Digital Content is available in the text., Background: Female sex is an independent risk factor for stroke and systemic embolic events in patients with atrial fibrillation. This study aimed to examine the efficacy and safety profile of edoxaban in women versus men. Methods: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) randomly assigned 21 105 patients (8040 women) with atrial fibrillation and CHADS2 score ≥2 either to a higher-dose edoxaban regimen, a lower-dose edoxaban regimen, or warfarin. The primary end points of the trial were the composite of stroke or systemic embolic events (efficacy), and International Society on Thrombosis and Haemostasis–defined major bleeding (safety). Results: In comparison with men, women were older, had lower body weight, were more likely to have hypertension and renal dysfunction, but less likely to smoke, drink alcohol, or have diabetes or coronary artery disease. Pretreatment endogenous factor Xa activity was significantly higher in women than in men (92.5% versus 86.1%, P

AIMS Dapagliflozin reduced the risk of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus in DECLARE-TIMI 58. We hypothesized that baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels would help identify patients who are at higher baseline risk and we describe the treatment effects of dapagliflozin in patients according to their baseline NT-proBNP and hsTnT levels. METHODS AND RESULTS This was a pre-specified biomarker study from DECLARE-TIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Clinical Trials Laboratory in 14 565 patients. Among the included patients, 9143 patients (62.8%) were male, 1464 (10.1%) had a history of heart failure and the mean age was 63.9 years. The median baseline NT-proBNP and hsTnT levels were 75 pg/mL [interquartile range (IQR) 35-165] and 10.2 pg/mL (IQR 6.9-15.5), respectively. Patients with higher NT-proBNP and hsTnT quartiles had higher rates of CV death/HHF (Q4 vs. Q1: NT-proBNP: 4-year Kaplan-Meier event rates 13.7% vs. 1.0%; hsTnT: 11.8% vs. 1.4%; P-trend

Background: Dual antiplatelet therapy with aspirin and a P2Y 12 inhibitor has been shown to reduce the risk of major adverse cardiovascular events (MACE) compared with aspirin alone after percutaneous coronary intervention (PCI) or acute coronary syndrome but with increased risk of bleeding. The safety of discontinuing aspirin in favor of P2Y 12 inhibitor monotherapy remains disputed. Methods: A meta-analysis was conducted from randomized trials (2001–2020) that studied discontinuation of aspirin 1 to 3 months after PCI with continued P2Y 12 inhibitor monotherapy compared with traditional dual antiplatelet therapy. Five trials were included; follow-up duration ranged from 12 to 15 months after PCI. Primary bleeding and MACE outcomes were the prespecified definitions in each trial. Results: The study population included 32 145 patients: 14 095 (43.8%) with stable coronary artery disease and 18 046 (56.1%) with acute coronary syndrome. In the experimental arm, background use of a P2Y 12 inhibitor included clopidogrel in 2649 (16.5%) and prasugrel or ticagrelor in 13 408 (83.5%) patients. In total, 820 patients experienced a primary bleeding outcome and 937 experienced MACE. Discontinuation of aspirin therapy 1 to 3 months after PCI significantly reduced the risk of major bleeding by 40% compared with dual antiplatelet therapy (1.97% versus 3.13%; hazard ratio [HR], 0.60 [95% CI, 0.45–0.79]), with no increase observed in the risk of MACE (2.73% versus 3.11%; HR, 0.88 [95% CI, 0.77–1.02]), myocardial infarction (1.08% versus 1.27%; HR, 0.85 [95% CI, 0.69–1.06]), or death (1.25% versus 1.47%; HR, 0.85 [95% CI, 0.70–1.03]). Findings were consistent among patients who underwent PCI for an acute coronary syndrome, in whom discontinuation of aspirin after 1 to 3 months reduced bleeding by 50% (1.78% versus 3.58%; HR, 0.50 [95% CI, 0.41–0.61]) and did not appear to increase the risk of MACE (2.51% versus 2.98%; HR, 0.85 [95% CI, 0.70–1.03]). Conclusions: Discontinuation of aspirin with continued P2Y 12 inhibitor monotherapy reduces risk of bleeding when stopped 1 to 3 months after PCI. An increased risk of MACE was not observed after discontinuation of aspirin, including in patients with acute coronary syndrome.

Intensive antithrombotic therapy reduces major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with peripheral artery disease (PAD). Recent studies have suggested heterogeneity in risk and benefit in those with and without concomitant coronary artery disease (CAD) and peripheral revascularization. We evaluated the risk of MACE and MALE in patients with PAD stratified by history of concomitant CAD and prior peripheral revascularization and whether the efficacy and safety of vorapaxar were similar in these subgroups. The TRA 2°P-TIMI 50 trial randomized 26,449 patients with prior MI, ischemic stroke, or PAD to vorapaxar or placebo. This analysis examined the effect of vorapaxar in a broad population of 6136 patients with PAD. Overall, vorapaxar significantly reduced MACE (HR 0.85, 95% CI 0.73, 0.99; p = 0.034) and MALE (HR 0.70, 95% CI 0.53, 0.92; p = 0.011) in patients with PAD. The absolute risk reduction (ARR) for MACE was greater in patients with PAD and CAD versus those with PAD alone (–2.2% vs 0.1%: number needed to treat (NNT) 45 vs 1000). Conversely, the ARR for MALE was higher in those with prior lower extremity revascularization (2.5% vs 0.2%: NNT 40 vs 500). Vorapaxar increased major bleeding (HR 1.39, 95% CI 1.12, 1.71; p = 0.003). The net clinical outcome in all patients with PAD was reduced with vorapaxar (HR 0.82, 95% CI 0.72, 0.94; p = 0.004), with benefits driven by reductions in MACE for those with CAD and by reductions in MALE for those with prior peripheral revascularization. Among patients with PAD, vorapaxar resulted in a net clinical benefit; however, the drivers of benefit were heterogeneous, with greater reductions in MACE in those with concomitant CAD and greater reductions in MALE in those with prior lower extremity revascularization, and unclear benefit in patients with neither. These clinical characteristics may be useful in identifying the subgroups of patients with PAD most likely to benefit from potent antithrombotic therapies. ClinicalTrials.gov Identifier: NCT00526474

BACKGROUND: The optimal revascularisation strategy for patients with left main coronary artery disease is uncertain. We therefore aimed to evaluate long-term outcomes for patients treated with percutaneous coronary intervention (PCI) with drug-eluting stents versus coronary artery bypass grafting (CABG).METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane database using the search terms "left main", "percutaneous coronary intervention" or "stent", and "coronary artery bypass graft*" to identify randomised controlled trials (RCTs) published in English between database inception and Aug 31, 2021, comparing PCI with drug-eluting stents with CABG in patients with left main coronary artery disease that had at least 5 years of patient follow-up for all-cause mortality. Two authors (MSS and BAB) identified studies meeting the criteria. The primary endpoint was 5-year all-cause mortality. Secondary endpoints were cardiovascular death, spontaneous myocardial infarction, procedural myocardial infarction, stroke, and repeat revascularisation. We used a one-stage approach; event rates were calculated by use of the Kaplan-Meier method and treatment group comparisons were made by use of a Cox frailty model, with trial as a random effect. In Bayesian analyses, the probabilities of absolute risk differences in the primary endpoint between PCI and CABG being more than 0·0%, and at least 1·0%, 2·5%, or 5·0%, were calculated.FINDINGS: Our literature search yielded 1599 results, of which four RCTs-SYNTAX, PRECOMBAT, NOBLE, and EXCEL-meeting our inclusion criteria were included in our meta-analysis. 4394 patients, with a median SYNTAX score of 25·0 (IQR 18·0-31·0), were randomly assigned to PCI (n=2197) or CABG (n=2197). The Kaplan-Meier estimate of 5-year all-cause death was 11·2% (95% CI 9·9-12·6) with PCI and 10·2% (9·0-11·6) with CABG (hazard ratio 1·10, 95% CI 0·91-1·32; p=0·33), resulting in a non-statistically significant absolute risk difference of 0·9% (95% CI -0·9 to 2·8). In Bayesian analyses, there was an 85·7% probability that death at 5 years was greater with PCI than with CABG; this difference was more likely than not less than 1·0% (INTERPRETATION: Among patients with left main coronary artery disease and, largely, low or intermediate coronary anatomical complexity, there was no statistically significant difference in 5-year all-cause death between PCI and CABG, although a Bayesian approach suggested a difference probably exists (more likely than not FUNDING: No external funding.

Background In the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trial, adding the PCSK9 inhibitor evolocumab to statin therapy reduced low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk. Although atherosclerotic coronary, cerebrovascular, and peripheral vascular events share a related pathobiology, the effect of aggressive LDL-C lowering with PCSK9 inhibition on the risk of acute arterial events across all three vascular beds is not well-described. Purpose To assess the efficacy of evolocumab on acute arterial events in all vascular territories including coronary, cerebral, and peripheral vascular beds. Methods In the FOURIER trial, patients (n=27,564) with stable atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on a statin were randomly assigned to evolocumab versus placebo and followed for a median of 2.2 years (1.8–2.5). Acute arterial events were defined as a composite of coronary (coronary heart disease [CHD] death, myocardial infarction [MI], or urgent coronary revascularization), cerebrovascular (ischemic stroke, transient ischemic attack [TIA], or urgent cerebral revascularization), or peripheral vascular (acute limb ischemia, major amputation, or urgent peripheral revascularization) events. Cox proportional-hazard models were used to assess the efficacy of evolocumab on these outcomes. Landmark and total event analyses were also done. Results Of the 2,210 first acute arterial events occurring during follow-up, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced the risk of a first acute arterial event by 19% (HR 0.81, 95% CI 0.74–0.88; P Conclusions The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced the risk of acute arterial events across all vascular territories with a robust effect over time. These findings indicate a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): The FOURIER trial was supported by Amgen.

OBJECTIVE Sodium–glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk. RESEARCH DESIGN AND METHODS DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to 300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to RESULTS Baseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to 300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35–1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, Pinteraction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups (P < 0.05, Pinteraction = 0.480). CONCLUSIONS In DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease.

Background: Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing heart failure. Sodium-glucose cotransporter-2 inhibitors reduce the risk of hospitalization for heart failure (HHF) in patients with T2DM. We aimed to develop and validate a practical clinical risk score for HHF in patients with T2DM and assess whether this score can identify high-risk patients with T2DM who have the greatest reduction in risk for HHF with a sodium-glucose cotransporter-2 inhibitor. Methods: We developed a clinical risk score for HHF in 8212 patients with T2DM in the placebo arm of SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using multivariable Cox regression, and independent clinical risk indicators achieving statistical significance of P Results: Five clinical variables were independent risk predictors of HHF: prior heart failure, history of atrial fibrillation, coronary artery disease, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. A simple integer-based score (0–7 points) using these predictors identified a >20-fold gradient of HHF risk ( P for trend P for trend=0.04), with high-risk (2 points) and very-high-risk (≥3 points) patients having 1.5% and 2.7% absolute reductions in Kaplan-Meier estimates of HHF risk at 4 years, respectively. Conclusions: Risk stratification using a novel clinical risk score for HHF in patients with T2DM identifies patients at higher risk for HHF who derive greater absolute benefit from sodium-glucose cotransporter-2 inhibition. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01107886 and NCT01730534.

Background Addition of ezetimibe to statin therapy reduces the risk of recurrent cardiovascular (CV) events in patients with prior acute coronary syndrome (ACS). The role of biomarkers in identifying subsets of patients who may derive greater clinical benefit with ezetimibe is unknown. Objectives This study sought to evaluate the role of established CV biomarkers in assessing likely benefit with ezetimibe added to statin therapy in post-ACS patients. Methods In a pre-specified nested analysis within a randomized, double-blind trial of ezetimibe/simvastatin versus placebo/simvastatin (IMPROVE-IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), high-sensitivity troponin T, N-terminal pro–B-type natriuretic peptide, growth-differentiation factor-15, and high-sensitivity C-reactive protein was measured in 7,195 patients stabilized (1 month post-randomization) after ACS. A multimarker approach based on biomarker values was used to examine the risk of recurrent CV events and clinical benefit with ezetimibe. Results Elevated levels of each biomarker were independently associated with higher risks of CV death/myocardial infarction/stroke and CV death/heart failure (ptrend Conclusions A biomarker-based strategy identifies a gradient of risk among patients post-ACS, offering the potential to identify higher-risk patients with a correspondingly high absolute benefit from the addition of ezetimibe to statin therapy.

Background Patients with liver disease have increased risk of thrombosis and bleeding but are typically excluded from trials of direct oral anticoagulant agents. Objectives This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation (AF) and history of liver disease. Methods ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction Study 48) was a randomized, double-blind trial comparing edoxaban with warfarin in patients with AF followed for 2.8 years. History of liver disease was defined as investigator-reported liver disease or >2-fold transaminase elevation at randomization. The primary efficacy and safety endpoints of stroke or systemic embolic event (SSEE) and major bleeding were assessed stratified by history of liver disease. PK/PD assessments of edoxaban included endogenous and extrinsic factor Xa activity and edoxaban concentration. Results Among 21,105 patients, 1,083 (5.1%) had a history of liver disease; they had a higher prevalence of many comorbidities. The adjusted risks of SSEE were similar (adjusted hazard ratio [HRadj]: 0.90; 95% confidence interval [CI]: 0.67 to 1.22; p = 0.50), but major bleeding was more common in patients with liver disease (HRadj: 1.38; 95% CI: 1.10 to 1.74; p = 0.005). There were no significant differences in PK/PD assessment of edoxaban in patients with versus without liver disease. The HRs for higher-dose edoxaban versus warfarin for SSEE were 0.86 (95% CI: 0.73 to 1.01) in patients without and 1.11 (95% CI: 0.54 to 2.30) with liver disease (p for interaction [pint] = 0.47), major bleeding 0.80 (95% CI: 0.70 to 0.91) in patients without and 0.91 (95% CI: 0.56 to 1.47) with liver disease (pint = 0.63). There were no significant differences in hepatic adverse events between the 2 treatment groups. Conclusions Among patients with AF receiving oral anticoagulation, bleeding, but not thromboembolic events, was increased in patients with liver disease. A history of liver disease did not alter the relative efficacy and safety of edoxaban compared with warfarin. Hepatic adverse events were similar between edoxaban and warfarin.

Background: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. Methods: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF Results: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45–0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76–1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66–1.17]) and those without HF (HR, 0.88 [95% CI, 0.74–1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43–0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62–0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34–0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89–1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40–0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86–1.10]; P for interaction=0.016). Conclusions: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

Background: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. Results: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72–0.99; P =0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88–1.13; P =0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81–1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65–1.00; P =0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72–1.00; P =0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). Conclusions: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

Background: Obesity is thought to increase renal hyperfiltration, thereby increasing albuminuria and the progression of renal disease. The effect of pharmacologically mediated weight loss on renal outcomes is not well-described. Lorcaserin, a selective serotonin 2C receptor agonist that promotes appetite suppression, led to sustained weight loss without any increased risk for major adverse cardiovascular (CV) events in the CAMELLIA-TIMI 61 trial (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61). Methods: CAMELLIA-TIMI 61 randomly assigned 12 000 overweight or obese patients with or at high risk for atherosclerotic CV disease to lorcaserin or placebo on a background of lifestyle modification. The primary renal outcome was a composite of new or worsening persistent micro- or macroalbuminuria, new or worsening chronic kidney disease, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death. Results: At baseline, 23.8% of patients had an estimated glomerular filtration rate (eGFR) −1 ·1.73 m −2 and 19.0% had albuminuria (urinary albumin:creatinine ratio ≥30 mg/g). Lorcaserin reduced the risk of the primary renal composite outcome (4.2% per year versus 4.9% per year; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79–0.96; P =0.0064). The benefit was consistent across subpopulations at increased baseline CV and renal risk. Lorcaserin improved both eGFR and urinary albumin:creatinune ratio within the first year after randomization. The effect of lorcaserin on weight, hemoglobin A1c, and systolic blood pressure was consistent regardless of baseline renal function. Likewise, there was no excess in cardiovascular events in patients assigned to lorcaserin in comparison with placebo, regardless of renal function. After adjustment for baseline characteristics, those with evidence of kidney disease were at increased risk of major CV events. Compared with patients with an eGFR ≥90 mL·min −1 ·1.73 m −2 , those with an eGFR 60-90 and those −1 ·1.73 m–2 had HRs of 1.25 (95% CI, 1.01, 1.56) and 1.51 (95% CI, 1.17, 1.95), respectively ( P for trend 0.0015). Likewise, compared with patients with no albuminuria (P for trend Conclusions: Renal dysfunction was associated with increased CV risk in overweight and obese patients. When added to diet and lifestyle, lorcaserin reduced the rate of new-onset or progressive renal impairment in comparison with placebo. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02019264.

Current guidelines recommend prescribing SGLT2 inhibitors to patients (pts) with type 2 diabetes (T2D) and established or at high risk for cardiovascular (CV) disease, irrespective of HbA1c levels. We assessed whether the CV and renal benefits of dapagliflozin vary by baseline HbA1c. In the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 study 17160 pts with T2D were randomized to dapagliflozin (DAPA) or placebo (PBO) for a median follow up of 4.2 years. Baseline HbA1c was 0.05, figure). In a pre-specified subgroup analysis, high HbA1c levels posed greater CV and renal risk, yet the benefits of DAPA were observed irrespective of baseline HbA1c including those with HbA1c Disclosure A. Cahn: Advisory Panel; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Eli Lilly and Company, Novo Nordisk, Consultant; Self; Glucome, Medial Early Sign, Speaker’s Bureau; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk. I. A. Gause-nilsson: Employee; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. M. S. Sabatine: Consultant; Self; Althera, Amgen Inc., Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Research Support; Self; Amgen Inc., Anthos Therapeutics, AstraZeneca, Daiichi Sankyo, Eisai Inc., Intarcia Therapeutics, Inc., Medicines Company , MedImmune, LLC, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc. I. Raz: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi, Consultant; Self; AstraZeneca, BOL, Camereyes, Concenter BioPharma Ltd., DarioHealth, Diabot, Exscopia, GlucoMe, Insuline Medical, Medial EarlySIgn, Orgenesis Inc., Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi, Stock/Shareholder; Self; BOL, Camereyes, DarioHealth, Diabot, GlucoMe, Orgenesis Inc. S. D. Wiviott: Consultant; Self; Aegerion Pharmaceuticals Inc., Allergan, AngelMed, Arena Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Boston Clinical Research Institute, LLC., Bristol-Myers Squibb Company, Daiichi Sankyo, Eisai Inc., Eli Lilly and Company, ICON Clinical, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Servier, St. Jude Medical, Xoma, Employee; Spouse/Partner; Merck & Co., Inc., Research Support; Self; Amgen Inc., Arena Pharmaceuticals, Inc., AstraZeneca, Bristol-Myers Squibb Company, Daiichi Sankyo, Eisai Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi-Aventis. O. Mosenzon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., BOL Pharma, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. S. Murphy: Research Support; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Daiichi Sankyo, Eisai Co., Ltd., Intarcia Therapeutics, Inc., MedImmune, LLC, Merck & Co., Inc., Novartis AG. E. L. Goodrich: Research Support; Self; AstraZeneca. D. L. Bhatt: Research Support; Self; Afimmune Limited, Amarin Corporation plc, Amgen Inc., AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Idorsia Pharmaceuticals Ltd, Lexicon Pharmaceuticals, Inc., PLx Pharma Inc., Sanofi-Aventis. L. A. Leiter: Advisory Panel; Self; Abbott Diabetes, Amgen Inc., AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Esperion, Janssen Pharmaceuticals, Inc., Funding AstraZeneca

Importance Dapagliflozin has been shown to reduce the risk of cardiovascular death or worsening heart failure (HF) in patients with chronic HF and reduced ejection fraction (HFrEF). However, clinical inertia often underlies deferred initiation of effective therapies. Objective To examine timing of onset of clinical benefit with dapagliflozin and magnitude as a function of proximity to prior HF hospitalization. Design, Setting, and Participants This is a secondary analysis of a completed multinational trial. The Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure trial was a double-blind, placebo-controlled randomized clinical trial of dapagliflozin in patients with chronic HFrEF (n = 4744). From February 2017 to August 2018, the study enrolled patients in New York Heart Association classes II through IV and with left ventricular ejection fraction of 40% or less; the median (range) follow-up time was 18.2 (0-27.8) months. Hazard ratios (HRs) were calculated for the primary efficacy outcome with dapagliflozin vs placebo by time following randomization. Efficacy and safety of dapagliflozin were assessed according to the timing of the most recent HF hospitalization prior to trial enrollment. Exposures None. Main Outcomes and Measures Composite of cardiovascular death or worsening HF. Results A total of 4744 patients were included (1109 women [23.4%]; mean [SD] age, 66.3 [10.9] years). The reduction in the primary outcome with dapagliflozin was rapidly apparent, with a sustained statistically significant benefit by 28 days after randomization (HR at 28 days, 0.51 [95% CI, 0.28-0.94];P = .03). A total of 2251 patients (47.4%) had been previously hospitalized for HF, and 1301 (27.4%) had been hospitalized within 12 months prior to enrollment. Among patients treated with placebo, there was a stepwise gradient of risk for the primary outcome according to timing of most recent HF hospitalization, with 2-year Kaplan-Meier rates of 21.1%, 25.3%, and 33.8% (adjustedP = .003) for patients with a prior HF hospitalization never, more than 12 months ago, and 12 or fewer months ago, respectively. Across these subgroups, dapagliflozin reduced the relative risk of the primary outcome by 16% (HR, 0.84 [95% CI, 0.69-1.01]), 27% (HR, 0.73 [95% CI, 0.54-0.99]), and 36% (HR, 0.64 [95% CI, 0.51-0.80]), respectively (P = .07 for trend). Accordingly, patients with a more recent HF hospitalization tended to experience greater absolute risk reductions with dapagliflozin at 2 years: 2.1% (95% CI, −1.9% to 6.1%), 4.1% (95% CI, −3.6% to 11.7%), and 9.9% (95% CI, 3.3%-16.5%), respectively (P = .05 for trend). Conclusions and Relevance In this study, treatment with dapagliflozin was associated with rapid reduction in the risk of cardiovascular death or worsening HF, with a sustained statistically significant benefit emerging very early after randomization. Patients with a more recent HF hospitalization were at particularly high risk and experienced greater relative and absolute risk reductions with dapagliflozin. Trial Registration ClinicalTrials.gov IdentifierNCT03036124

Introduction The efficacy and safety of the oral factor Xa inhibitor edoxaban compared to warfarin stratified by CHA2DS2VASc scores have not been described. Methods The ENGAGE AF-TIMI 48 trial randomized patients with atrial fibrillation to once-daily edoxaban or warfarin. We classified patients based on CHA2DS2VASc score and compared pharmacokinetics (edoxaban concentration), pharmacodynamics (anti-factor Xa [FXa] with edoxaban, time-in-therapeutic range for warfarin), efficacy (stroke or systemic embolism [SSE]), safety (major bleeding [MB], intracranial hemorrhage), and cardiovascular mortality, for the approved edoxaban regimen vs warfarin. Results The distribution CHA2DS2VASc score were:≤3, N = 4159 (29.6%); 4, N = 4066 (28.9%); 5, N = 3165 (22.5%); and ≥6, N = 2681 (19.1%). Increasing rates of SSE (1.05 to 2.99%/year) and MB (2.27 to 4.66%/year) were observed in the warfarin arm as the CHA2DS2VASc score increased. The hazard ratios per unit increase of CHA2DS2VASc score were 1.29 (1.21-1.38) and 1.26 (1.17-1.36) for SSE, and 1.20 (1.13-1.27) and 1.19 (1.12-1.27) for MB, with warfarin and edoxaban, respectively. Time-in-therapeutic range in warfarin-treated patients was similar and high (median 68%-69%) across CHA2DS2VASc scores, whereas edoxaban trough concentration, exogenous anti-FXa activity and %inhibition of endogenous FXa were higher at increasing CHA2DS2VASc scores. Edoxaban reduced SSE, MB, intracranial hemorrhage, and cardiovascular mortality vs warfarin to a similar degree across the range of CHA2DS2VASc scores (P-int = 0.90, 0.96, 0.21, and 0.37, respectively). Because of higher event rates the number of events prevented with edoxaban tended to be greater in patients with higher CHA2DS2VASc scores. Conclusion The benefit and safety of edoxaban versus warfarin is maintained across CHA2DS2VASc scores. While the relative risk reductions remain similar, edoxaban provides incrementally larger absolute reductions in outcomes over warfarin in patients with higher CHA2DS2VASc scores.

Introduction: Among patients with atherosclerotic cardiovascular disease (ASCVD), those with history of PCI represent an important population for potential high risk for cardiovascular (CV) events. We examined the clinical efficacy of the PCSK9 inibitor evolocumab in patients with prior PCI. Methods: FOURIER randomized 27,564 patients with ASCVD on statin therapy to evolocumab or placebo with a median follow-up of 2.2 yrs. The primary end point (PEP) was the composite of CV death, MI, stroke, unstable angina, or coronary revascularization; major coronary events were the composite of coronary death, MI, or coronary revascularization. The risk of events in patients with and without a history of PCI were compared in the placebo arm. The clinical benefit of evolocumab vs. placebo was compared using a Cox proportional hazards model. Results: 17,073 (62%) patients had prior PCI at baseline. Among patients in the placebo arm, those with prior PCI (N=8563) had a 1.6x higher rate of the PEP (16.8 vs 10.7%; adjusted HR 1.61; 95% CI 1.42-1.84 P Conclusions: In a contemporary cohort with ASCVD on statin therapy, patients with prior PCI were at heightened risk for coronary events. Evolocumab was highly effective in this group, reducing major coronary events by 18% with a NNT at 3 years of only 36.

Introduction: Although PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall, their ability to specifically reduce the risk of complex coronary atherosclerosis requiring revascularization has not been explored. Methods: FOURIER was a randomized trial of the PCSK9 inhibitor evolocumab vs. placebo in 27,564 patients with ASCVD on statin therapy (median achieved LDL-C 32 mg/dL vs. 89 mg/dL) followed for a median of 2.2 years. The study database was blindly reviewed to assess characteristics of coronary revascularization procedures. Complex revascularization was the composite of complex PCI (per GLOBAL LEADERS criteria, at least one of: multivessel PCI, 3 or more stents implanted, 3 or more lesions treated, bifurcation PCI with 2 or more stents, or total stent length >60 mm) or CABG. PCI complications included no-reflow, side branch loss, thrombus formation, major dissection, or perforation. The effects of evolocumab on types of revascularization and PCI complications were evaluated using Cox proportional hazards models. Results: 1724 patients underwent revascularization procedures during follow-up. Evolocumab reduced the risk of non-complex PCI by 22% (HR 0.78; 95%CI 0.70-0.88; P Conclusions: Adding evolocumab to statin therapy reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. Together with prior coronary imaging findings, these data suggest very aggressive LDL-C lowering to

In the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, the lower dose edoxaban regimen (LDER) and the higher dose edoxaban regimen (HDER) were noninferior to well-managed warfarin for stroke prevention in atrial fibrillation.The objective of the present analysis of the ENGAGE AF TIMI-48 trial was to comprehensively compare the net clinical outcome (NCO) of LDER (30 mg once daily, dose reduced to 15 mg in selective patients) versus HDER (60 mg once daily, dose reduced to 30 mg in selective patients).This study performed a pre-specified analysis of the ENGAGE AF-TIMI 48 trial, comparing patients on LDER versus HDER.The pre-defined primary NCO (stroke/systemic embolism [SEE], major bleeding, death) was less frequent with LDER (7.26% vs. 8.01%; hazard ratio: 0.90; 95% confidence interval: 0.84 to 0.98; p = 0.014). The secondary (disabling stroke, life-threatening bleeding, or all-cause mortality) and tertiary pre-defined NCOs (stroke, SEE, life-threatening bleeding, or all-cause mortality) were similar between the 2 dosing regimens. Patients randomized to LDER versus HDER had a significantly higher risk of stroke/SEE (2.04% vs. 1.56%; hazard ratio: 1.31; 95% confidence interval: 1.12 to 1.52; p 0.001). Conversely, major bleeding, intracranial hemorrhage, major gastrointestinal bleeding, and life-threatening bleeding occurred significantly less frequently with LDER compared with those of HDER. These findings were supported by multiple pharmacokinetic findings.In the ENGAGE AF-TIMI 48 trial, the primary NCO was reduced with LDER versus HDER, whereas the secondary and tertiary NCOs were similar between the 2 dosing regimens. These results may aid physicians in evidence-based individualization of edoxaban dosing. However, the approved HDER remains the standard therapy among the available edoxaban dosing regimens for stroke prevention in atrial fibrillation. (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48 [ENGAGE AF-TIMI 48]; NCT00781391).

Background Patients with atrial fibrillation (AF) have progressive cardiac structural changes that may be manifest by biomarkers of myocardial injury and hemodynamic stress. Baseline values of hsTnT (high-sensitivity troponin T), and NT-proBNP (N-terminal pro-brain natriuretic peptide) are associated with stroke risk and GDF-15 (growth differentiation factor-15) is associated with bleeding risk in patients with AF. However, the variability of these biomarkers over time and their associations with stroke or systemic embolism events (S/SEE) and bleeding in patients with AF remain unclear. Purpose We examined whether patients with AF demonstrate detectable changes in these biomarkers over 12 months and whether such changes from baseline to 12 months are associated with the subsequent risk of S/SEE (hsTnT, NT-proBNP) and bleeding (GDF-15). Methods ENGAGE AF-TIMI 48 was a multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS2 score ≥2. We performed a nested prospective biomarker study in 6062 patients, analyzing hsTnT, NT-proBNP, and GDF-15 at baseline and 12 months. Event rates were estimated and displayed with annualized event rates after 12 months. Results Of 6062 patients, hsTnT was dynamic in 46.9% (≥2 ng/L change), NT-proBNP in 51.9% (≥200 pg/L change), GDF-15 in 45.6% (≥300 pg/L change) between baseline and 12 months. In addition, 7.7% in hsTnT shifted from low->high categories, 9.4% in NT-proBNP from low->high, 10.6% in GDF-15 from low->high over 12 months (Figure). Elevated hsTnT (≥14 ng/L) and NT-proBNP (≥900 pg/L) either at baseline or at 12 months were independently associated with higher rates of subsequent S/SEE, and elevated GDF-15 (≥1800 pg/L) either at baseline or at 12 months were independently associated with higher rates of subsequent bleeding (P Conclusions Serial assessment of hsTnT, NT-proBNP, and GDF-15 revealed a substantial proportion of patients with AF had dynamic values. Patients with either persistently elevated or dynamic values were at higher risk of adverse clinical outcomes. Those biomarkers may play a role in personalizing preventive strategies in patients with AF based on risk. Change in biomarkers and event rate Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo Pharma Development

Background In the phase 3 RCT ENGAGE AF-TIMI 48, both the higher-dose (HDER/edoxaban 60/30mg) and lower-dose edoxaban regimen (LDER/edoxaban 30/15mg) were non-inferior to well-managed warfarin for the prevention of stroke or systemic embolic events in patients with atrial fibrillation (AF). While LDER was associated with a 41% relative increase in ischemic stroke as compared to warfarin, LDER showed a larger relative reduction in bleeding events than HDER. An interaction tree analysis was performed to identify subgroups of patients likely to derive greater benefit from LDER vs. HDER based on a serious net outcome (SNO) that combines the most serious stroke and bleeding events: disabling/fatal ischemic stroke or life-threatening/fatal bleeding. Methods and results LDER (N=7002) had a higher risk for disabling/fatal ischemic stroke (HR 1.37, 95% CI 1.06–1.77; p=0.017), but fewer life-threatening/fatal bleeds (0.61 (0.44, 0.84), p=0.002) than HDER (N=7012). The SNO was similar with LDER vs HDER in the total population (0.95 (0.78–1.16), p=0.61). In the 30% of patients who had either malignancy or paroxysmal AF (Figure) the SNO was significantly lower with LDER vs HDER (HR 0.59 (0.40–0.86)), driven by large reductions in bleeding without an increase in ischemic stroke in this subgroup (figure). Meanwhile the remaining 70% of patients with neither malignancy nor paroxysmal AF tended to have a higher risk with LDER vs. HDER (HR 1.15 (0.91–1.46), P-interaction 0.003). Conclusions In our current post-hoc analysis we were able to demonstrate that the combined rate of serious stroke and bleeding events was similar in patients treated with LDER and HDER. Moreover, patients with a malignancy as well as those with paroxysmal AF derived a greater net benefit from LDER vs. HDER regarding serious AF-/anticoagulation-related outcome events. These results need to be viewed as hypothesis-generating which may, if confirmed, aid physicians in individualizing edoxaban dosing. Funding Acknowledgement Type of funding source: None

Aims We investigated whether patients with atrial fibrillation (AF) demonstrate detectable changes in biomarkers including high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) over 12 months and whether such changes from baseline to 12 months are associated with the subsequent risk of stroke or systemic embolic events (S/SEE) and bleeding. Methods and results ENGAGE AF-TIMI 48 was a randomized trial of the oral factor Xa inhibitor edoxaban in patients with AF and a CHADS2 score of ≥2. We performed a nested prospective biomarker study in 6308 patients, analysing hsTnT, NT-proBNP, and GDF-15 at baseline and 12 months. hsTnT was dynamic in 46.9% (≥2 ng/L change), NT-proBNP in 51.9% (≥200 pg/mL change), GDF-15 in 45.6% (≥300 pg/mL change) during 12 months. In a Cox regression model, upward changes in log2-transformed hsTnT and NT-proBNP were associated with increased risk of S/SEE [adjusted hazard ratio (adj-HR) 1.74; 95% confidence interval (CI) 1.36–2.23 and adj-HR 1.27; 95% CI 1.07–1.50, respectively] and log2-transformed GDF-15 with bleeding (adj-HR 1.40; 95% CI 1.02–1.92). Reassessment of ABC-stroke (age, prior stroke/transient ischaemic attack, hsTnT, and NT-proBNP) and ABC-bleeding (age, prior bleeding, haemoglobin, hsTnT, and GDF-15) risk scores at 12 months accurately reclassified a significant proportion of patients compared with their baseline risk [net reclassification improvement (NRI) 0.50; 95% CI 0.36–0.65; NRI 0.42; 95% CI 0.33–0.51, respectively]. Conclusion Serial assessment of hsTnT, NT-proBNP, and GDF-15 revealed that a substantial proportion of patients with AF had dynamic values. Greater increases in these biomarkers measured over 1 year are associated with important clinical outcomes in anticoagulated patients with AF.

OBJECTIVE International guidelines propose prescribing sodium–glucose cotransporter 2 (SGLT2) inhibitors to patients with type 2 diabetes (T2D) as secondary prevention in patients with established atherosclerotic cardiovascular disease (ASCVD) or for primary prevention of cardiovascular events in high-risk patients with multiple risk factors (MRF) for ASCVD. The current analyses expand on the cardiovascular renal and metabolic effects of SGLT2 inhibitors in MRF patients. RESEARCH DESIGN AND METHODS In DECLARE-TIMI 58, 17,160 patients with T2D and MRF (59.4%) or established ASCVD (40.6%) were randomized to dapagliflozin versus placebo; patients were followed for a median of 4.2 years. The cardiovascular and renal outcomes in the MRF cohort were studied across clinically relevant subgroups for treatment effect and subgroup-based treatment interaction. RESULTS Among patients with MRF, the reduction with dapagliflozin in risk of cardiovascular death or hospitalization for heart failure (CVD/HHF) (hazard ratio [HR] 0.84, 95% CI 0.67–1.04) and the renal-specific outcome (HR 0.51, 95% CI 0.37–0.69) did not differ from that for patients with ASCVD (Pinteraction 0.99 and 0.72, respectively). The effect on CVD/HHF was entirely driven by a reduction in HHF (HR 0.64, 95% CI 0.46–0.88). The benefits of dapagliflozin on HHF and on the renal-specific outcome, among the subset with MRF, were directionally consistent across clinically relevant subgroups. At 48 months, HbA1c, weight, systolic blood pressure, and urinary albumin–to–creatinine ratio were lower with dapagliflozin versus placebo and estimated glomerular filtration rate was higher (P < 0.001). CONCLUSIONS In patients with T2D and MRF, dapagliflozin reduced the risk of HHF and adverse renal outcomes regardless of baseline characteristics. These analyses support the benefit of dapagliflozin for important outcomes in a broad primary prevention population.

This study sought to evaluate the ability of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab to reduce the risk of complex coronary atherosclerosis requiring revascularization.PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall.FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was a randomized trial of the PCSK9 inhibitor evolocumab versus placebo in 27,564 patients with stable atherosclerotic cardiovascular disease on statin therapy followed for a median of 2.2 years. Clinical documentation of revascularization events was blindly reviewed to assess coronary anatomy and procedural characteristics. Complex revascularization was the composite of complex percutaneous coronary intervention (PCI) (as per previous analyses, ≥1 of: multivessel PCI, ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length60 mm) or coronary artery bypass grafting surgery (CABG).In this study, 1,724 patients underwent coronary revascularization, including 1,482 who underwent PCI, 296 who underwent CABG, and 54 who underwent both. Complex revascularization was performed in 632 (37%) patients. Evolocumab reduced the risk of any coronary revascularization by 22% (hazard ratio [HR]: 0.78; 95% CI: 0.71 to 0.86; p 0.001), simple PCI by 22% (HR: 0.78; 95% CI: 0.70 to 0.88; p 0.001), complex PCI by 33% (HR: 0.67; 95% CI: 0.54 to 0.84; p 0.001), CABG by 24% (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.019), and complex revascularization by 29% (HR: 0.71; 95% CI: 0.61 to 0.84; p 0.001). The magnitude of the risk reduction with evolocumab in complex revascularization tended to increase over time (20%, 36%, and 41% risk reductions in the first, second, and beyond second years).Adding evolocumab to statin therapy significantly reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER); NCT01764633.).

Importance: Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a life-threatening condition with no proven disease-modifying therapy. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS. The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab reduces circulating LDL-C concentrations by 50% to 60% and Lp(a) by 20% to 30%. Objective: To determine whether evolocumab reduces the risk of AS events in patients with atherosclerotic cardiovascular disease. Interventions: Patients were randomized 1:1 to evolocumab or placebo. Design, Setting, and Participants: Exploratory analysis of the FOURIER trial, which enrolled 27564 patients with stable atherosclerotic cardiovascular disease who were taking statin therapy at 1242 sites in 49 countries from February 2013 to November 2016. Patients were randomized to evolocumab or placebo and followed up for a median (interquartile range) of 2.2 (1.8-2.5) years. This post hoc analysis was performed from September 2019 to February 2020. Main Outcomes and Measures: Site-reported adverse events of new or worsening AS or aortic valve replacement (termed AS events). The adjusted risk of AS events was calculated with a multivariable model including concentrations of Lp(a) and LDL-C corrected for Lp(a) content, plus age, sex, diabetes, hypertension, current smoking, and estimated glomerular filtration rate. Evolocumab efficacy was tested using a Cox proportional hazards model. Results: Aortic stenosis events occurred in 63 patients (48 men [76%]; mean [SD] age, 69 [9] years) over a median of 2.2 years. Elevated Lp(a) concentration was associated with higher rates of AS events (adjusted hazard ratio [aHR], 1.55 [95% CI, 1.17-2.05] per SD; P =.002), including aortic valve replacement (aHR, 2.22 [95% CI, 1.38-3.58] per SD; P =.001), after multivariable adjustment. The corrected LDL-C concentration was not significantly associated with AS events (aHR, 1.23 [95% CI, 0.93-1.61] per SD; P =.14). The overall HR for AS events with evolocumab was 0.66 (95% CI, 0.40-1.09), with no apparent association in the first year (HR, 1.09 [95% CI, 0.48-2.47]) but an HR of 0.48 (95% CI, 0.25-0.93) after the first year of treatment. Conclusions and Relevance: In this exploratory analysis of the FOURIER trial, higher Lp(a) levels, but not Lp(a)-corrected LDL-C levels, were associated with a higher risk of subsequent AS events, including aortic valve replacement. Long-term therapy with evolocumab may reduce AS events, and this raises the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS. These exploratory findings merit further investigation with a dedicated randomized clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.

In the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 study 17160 patients (pts) with T2DM were randomized to the SGLT2 inhibitor dapagliflozin (DAPA) or placebo (PBO) for a median follow up of 4.2 years. At baseline 14068 pts used metformin, 7322 sulfonylureas, 2888 DPP-4 inhibitors, 750 GLP-1 receptor agonist (GLP-1 RA) and 7013 insulin. DAPA reduced the composite of CV death and hospitalization for heart failure (CVD/HHF) vs. PBO regardless of baseline glucose lowering agents (GLA), though the effect appeared to be particularly large in the small group of pts with baseline use of GLP-1 RA (Figure). The overall HR for major adverse cardiovascular events (MACE; CVD, myocardial infarction, ischemic stroke) was 0.93 (95% CI 0.84-1.03) with DAPA vs. PBO, with no interaction by non-insulin GLA, yet a tendency toward greater benefit with DAPA vs. PBO was observed in baseline insulin users (Figure). The renal specific outcome (sustained decrease of ≥40% in eGFR to 0.05). The effects of DAPA on CV and renal outcomes were generally consistent regardless of baseline GLA. Use or non-use of metformin did not alter outcomes. Additional studies defining the clinical benefit of combining CV risk reducing GLAs will be helpful. Disclosure A. Cahn: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. Consultant; Self; GlucoMe, Medial EarlySign. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. S.D. Wiviott: Consultant; Self; Aegerion Pharmaceuticals, Allergan, Angelmed, Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Boston Clinical Research Institute, Bristol-Myers Squibb, Daiichi Sankyo, Eisai Inc., Eli Lilly and Company, ICON Clinical, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Servier, St. Jude Medical, XOMA Corporation. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Amgen, Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eisai Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi-Aventis. Other Relationship; Self; See other relationships for list. O. Mosenzon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Teva Pharmaceutical Industries Ltd. S. Murphy: Research Support; Self; AstraZeneca. Other Relationship; Self; Abbott, Amgen, Aralez, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharma. E.L. Goodrich: Other Relationship; Self; AstraZeneca. I. Yanuv: None. A. Rozenberg: None. J. Wilding: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Mundipharma International, Napp Pharmaceuticals, Novo Nordisk A/S, Wilmington Healthcare. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. L.A. Leiter: Advisory Panel; Self; Abbott, Amgen, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Amgen, AstraZeneca, Kowa Pharmaceuticals America, Inc., Medicines Company. Speaker’s Bureau; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Medscape, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. D.L. Bhatt: Research Support; Self; Abbott, Afimmune, Amarin Corporation, Amgen, AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Cardax, Chiesi USA, Inc., CSL Behring, Ferring Pharmaceuticals, Fractyl Laboratories, Inc., Idorsia, Ironwood Pharmaceuticals, Ischemix, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PLx Pharma Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis, Synaptic. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp & Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. L. Litwak: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk Inc., Sanofi. A. Kooy: Advisory Panel; Self; Eli Lilly and Company, Novartis Pharma K.K. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Research Support; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Daiichi Sankyo, Mundipharma International. I.A. Gause-Nilsson: Employee; Self; AstraZeneca. M. Fredriksson: Employee; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. M.S. Sabatine: Consultant; Self; Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor Pharmaceuticals, Dyrnamix Inc., Esperion Therapeutics, Inc., IFM Therapeutics, Intarcia Therapeutics, Ionis Pharmaceuticals, Inc., Medicines Company, MedImmune, Merck & Co., Inc. Research Support; Self; Amgen, AstraZeneca, Bayer U.S., Daiichi Sankyo, Eisai Inc., Intarcia Therapeutics, Janssen Research and Development, Medicines Company, MedImmune, Merck & Co., Inc., Novartis AG, Pfizer Inc., Quark Pharmaceuticals. I. Raz: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Consultant; Self; AstraZeneca, BOL, CamerEyes Ltd, Concenter BioPharma, DarioHealth, Diabot, Exscopia, GlucoMe, Insuline Medical, Medial EarlySIgn, Orgenesis Inc. Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Stock/Shareholder; Self; BOL, CamerEyes Ltd, DarioHealth, Diabot, GlucoMe, Orgenesis Inc.

Background and Purpose— The PCSK9 (proprotein convertase subtilisin-kexin type 9) monoclonal antibody evolocumab lowered LDL (low-density lipoprotein) cholesterol by 59% to 0.8 (0.5–1.2) mmol/L and significantly reduced major vascular events in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk). Herein, we report the results of a prespecified analysis of cerebrovascular events in the overall trial population and in patients stratified by prior stroke. Methods— FOURIER was a randomized, double-blind trial comparing evolocumab versus placebo in patients with established atherosclerosis, additional risk factors, and LDL cholesterol levels ≥1.8 (or non-HDL [high-density lipoprotein] ≥2.6 mmol/L) on statin therapy. The median follow-up was 2.2 years. We analyzed the efficacy of evolocumab to reduce overall stroke and stroke subtypes, as well as the primary cardiovascular composite end point by subgroups according to a history of stroke. Results— Among the 27 564 patients, 469 (1.7%) experienced a total of 503 strokes of which 421 (84%) were ischemic. Prior ischemic stroke, diabetes mellitus, elevated CRP (C-reactive protein), history of heart failure, older age, nonwhite race, peripheral arterial disease, and renal insufficiency were independent predictors of stroke. Evolocumab significantly reduced all stroke (1.5% versus 1.9%; hazard ratio, 0.79 [95% CI, 0.66–0.95]; P =0.01) and ischemic stroke (1.2% versus 1.6%; hazard ratio, 0.75 [95% CI, 0.62–0.92]; P =0.005), with no difference in hemorrhagic stroke (0.21% versus 0.18%; hazard ratio, 1.16 [95% CI, 0.68–1.98]; P =0.59). These findings were consistent across subgroups, including among the 5337 patients (19%) with prior ischemic stroke in whom the hazard ratios (95% CIs) were 0.85 (0.72–1.00) for the cardiovascular composite, 0.90 (0.68–1.19) for all stroke, and 0.92 (0.68–1.25) for ischemic stroke ( P interactions, 0.91, 0.22, and 0.09, respectively, compared with patients without a prior ischemic stroke). Conclusions— Inhibition of PCSK9 with evolocumab added to statin in patients with established atherosclerosis reduced ischemic stroke and cardiovascular events in the total population and in key subgroups, including those with prior ischemic stroke. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01764633.

Aims To evaluate comprehensively the safety of dapagliflozin in patients with type 2 diabetes (T2DM), with emphasis placed on potential safety concerns related to the sodium-glucose co-transporter-2 inhibitor class. Methods In the Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) study, 17 160 patients with T2DM were randomized to dapagliflozin or placebo and followed for a median of 4.2 years. Safety was evaluated in 17 143 patients receiving at least one dose of study drug. Results Acute kidney injury occurred less frequently with dapagliflozin, and adverse events suggestive of volume depletion were balanced between treatment groups, both irrespective of baseline estimated glomerular filtration rate, blood pressure, diuretic or loop diuretic use (interaction P values >0.05). Fractures and malignancies were balanced between the groups, irrespective of sex, diabetes duration or smoking (interaction P values >0.05) and fewer cases of bladder cancer occurred in the dapagliflozin versus the placebo group. Diabetic ketoacidosis was very rare, but more frequent with dapagliflozin versus placebo (27 vs. 12 patients with events; P = 0.02), yet signs, symptoms and contributing factors were similar in the two groups. Major hypoglycaemia occurred less frequently with dapagliflozin versus placebo, regardless of baseline use of either insulin or sulphonylureas (interaction P values >0.05). There were more adverse events of genital infections leading to discontinuation of study drug in the dapagliflozin versus the placebo group, but serious genital infections were few and balanced between treatment groups. Urinary tract infections, acute pyelonephritis and urosepsis were also balanced between treatment groups. Conclusions Dapagliflozin was well tolerated. The long duration and large number of patient-years in DECLARE-TIMI 58 comprehensively addressed previous safety questions, confirming the robust safety profile of dapagliflozin.

OBJECTIVE Data regarding the effects of sodium–glucose cotransporter 2 inhibitors in the elderly (age ≥65 years) and very elderly (age ≥75 years) are limited. RESEARCH DESIGN AND METHODS The Dapagliflozin Effect on Cardiovascular Events (DECLARE)–TIMI 58 assessed cardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. Efficacy and safety outcomes were studied within age subgroups for treatment effect and age-based treatment interaction. RESULTS Of the 17,160 patients, 9,253 were CONCLUSIONS The overall efficacy and safety of dapagliflozin are consistent regardless of age.

Background: Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes mellitus and its related comorbidities, including hypertension, obesity, and heart failure (HF). SGLT2 (sodium-glucose cotransporter 2) inhibitors have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling, and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes mellitus. We therefore investigated whether SGLT2 inhibitors could also reduce the risk of AF/AFL. Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) studied the efficacy and safety of the SGLT2 inhibitor dapagliflozin versus placebo in 17 160 patients with type 2 diabetes mellitus and either multiple risk factors for atherosclerotic cardiovascular disease (n=10 186) or known atherosclerotic cardiovascular disease (n=6974). We explored the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using MedDRA preferred terms (“atrial fibrillation,” “atrial flutter”). Results: Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events; 7.8 versus 9.6 events per 1000 patient-years; hazard ratio [HR], 0.81 [95% CI, 0.68–0.95]; P =0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (previous AF/AFL: HR, 0.79 [95% CI, 0.58–1.09]; no AF/AFL: HR, 0.81 [95% CI, 0.67–0.98]; P for interaction 0.89). Similarly, presence of atherosclerotic cardiovascular disease (HR, 0.83 [95% CI, 0.66–1.04]) versus multiple risk factors (HR, 0.78 [95% CI, 0.62–0.99]; P for interaction 0.72) or a history of HF (HF: HR, 0.78 [95% CI, 0.55–1.11]; No HF: HR, 0.81 [95% CI, 0.68–0.97]; P for interaction 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, glycated hemoglobin A 1c , body mass index, blood pressure, or estimated glomerular filtration rate (all P for interaction >0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio, 0.77 [95% CI, 0.64–0.92]; P =0.005). Conclusions: Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with type 2 diabetes mellitus. This effect was consistent regardless of the patient’s previous history of AF, atherosclerotic cardiovascular disease, or HF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01730534.

Patients with renal disease are often undertreated with antiplatelet therapy due to concerns about bleeding. Vorapaxar blocks platelet activation via the PAR-1 receptor and reduces cardiovascular events in patients with stable atherosclerosis, but with increased bleeding. We examined the efficacy and safety of vorapaxar in patients with impaired renal function. TRA2°P-TIMI 50 randomized patients with stable atherosclerosis to vorapaxar or. We analyzed patients with eGFR assessed who qualified with a history of MI or PAD (without stroke or TIA) (n = 19,932). Cox models assessed the risk of CV events and bleeding by quartile of baseline eGFR in the placebo arm and then by randomized assignment. Net clinical outcome (NCO) was predefined as CV death, MI, stroke, or GUSTO severe bleeding. Patients with lower eGFR tended to be older, female, have hypertension, hyperlipidemia or prior PAD. In the placebo arm, baseline eGFR in the lowest quartile was associated with a 26% higher risk of CV death, MI or stroke (Q1:Q4 HRadj 1.26, 1.03–1.55) and 73% higher risk of GUSTO moderate or severe bleeding (HRadj 1.73, 1.12–2.65). Vorapaxar reduced the risk of MACE to a similar extent (14–26%) across quartiles of baseline eGFR (P interaction = 0.70) and increased the relative risk of GUSTO moderate or severe bleeding (P interaction = 0.54). NCO was similar across quartiles of eGFR (P interaction = 0.65). Intensification of antiplatelet therapy with vorapaxar offers comparable net clinical benefit regardless of baseline renal function. These data support the use of more potent antiplatelet regimens in patients with renal dysfunction.

Background: Patients who experience an acute coronary syndrome are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after acute coronary syndrome. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), with a focus on patients with a stroke before randomization. Methods: Patients who experienced acute coronary syndrome were randomized to a placebo/simvastatin or ezetimibe/simvastatin regimen and followed for a median of 6 years. Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the end points of stroke of any etiology, stroke subtypes, and the primary trial end point at 7 years. Results: Of 18 144 patients, 641 (3.5%) experienced at least 1 stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes mellitus, myocardial infarction, and renal dysfunction. There was a nonsignificant reduction in the first event of stroke of any etiology (4.2% versus 4.8%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.73–1.00; P =0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% versus 4.1%; HR, 0.79; 95% CI, 0.67–0.94; P =0.008) and a nonsignificant increase in hemorrhagic stroke (0.8% versus 0.6%; HR, 1.38; 95% CI, 0.93–2.04; P =0.11). Evaluating total events, including the first and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR, 0.83; 95% CI, 0.70–0.98; P =0.029) and ischemic stroke (HR, 0.76; 95% CI, 0.63–0.91; P =0.003). Patients who had experienced a stroke prior to randomization were at a higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% versus 18.8%; number needed to treat=12; HR, 0.60; 95% CI, 0.38–0.95; P =0.030) and 7.6% for ischemic stroke (8.7% versus 16.3%; number needed to treat=13; HR, 0.52; 95% CI, 0.31–0.86; P =0.011) with ezetimibe added to simvastatin therapy. Conclusions: The addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00202878.

Summary Background The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab reduced LDL cholesterol and cardiovascular events in the FOURIER trial. In this prespecified analysis of FOURIER, we investigated the efficacy and safety of evolocumab by diabetes status and the effect of evolocumab on glycaemia and risk of developing diabetes. Methods FOURIER was a randomised trial of evolocumab (140 mg every 2 weeks or 420 mg once per month) versus placebo in 27 564 patients with atherosclerotic disease who were on statin therapy, followed up for a median of 2·2 years. In this prespecified analysis, we investigated the effect of evolocumab on cardiovascular events by diabetes status at baseline, defined on the basis of patient history, clinical events committee review of medical records, or baseline HbA 1c of 6·5% (48 mmol/mol) or greater or fasting plasma glucose (FPG) of 7·0 mmol/L or greater. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularisation. The key secondary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. We also assessed the effect of evolocumab on glycaemia, and on the risk of new-onset diabetes among patients without diabetes at baseline. HbA 1c was measured at baseline then every 24 weeks and FPG was measured at baseline, week 12, week 24, and every 24 weeks thereafter, and potential cases of new-onset diabetes were adjudicated centrally. In a post-hoc analysis, we also investigated the effects on glycaemia and diabetes risk in patients with prediabetes (HbA 1c 5·7–6·4% [39–46 mmol/mol] or FPG 5·6–6·9 mmol/L) at baseline. FOURIER is registered with ClinicalTrials.gov, number NCT01764633. Findings At study baseline, 11 031 patients (40%) had diabetes and 16 533 (60%) did not have diabetes (of whom 10 344 had prediabetes and 6189 had normoglycaemia). Evolocumab significantly reduced cardiovascular outcomes consistently in patients with and without diabetes at baseline. For the primary composite endpoint, the hazard ratios (HRs) were 0·83 (95% CI 0·75–0·93; p=0·0008) for patients with diabetes and 0·87 (0·79–0·96; p=0·0052) for patients without diabetes (p interaction =0·60). For the key secondary endpoint, the HRs were 0·82 (0·72–0·93; p=0·0021) for those with diabetes and 0·78 (0·69–0·89; p=0·0002) for those without diabetes (p interaction =0·65). Evolocumab did not increase the risk of new-onset diabetes in patients without diabetes at baseline (HR 1·05, 0·94–1·17), including in those with prediabetes (HR 1·00, 0·89–1·13). Levels of HbA 1c and FPG were similar between the evolocumab and placebo groups over time in patients with diabetes, prediabetes, or normoglycaemia. Among patients with diabetes at baseline, the proportions of patients with adverse events were 78·5% (4327 of 5513 patients) in the evolocumab group and 78·3% (4307 of 5502 patients) in the placebo group; among patients without diabetes at baseline, the proportions with adverse events were 76·8% (6337 of 8256 patients) in the evolocumab group and 76·8% (6337 of 8254 patients) in the placebo group. Interpretation PCSK9 inhibition with evolocumab significantly reduced cardiovascular risk in patients with and without diabetes. Evolocumab did not increase the risk of new-onset diabetes, nor did it worsen glycaemia. These data suggest evolocumab use in patients with atherosclerotic disease is efficacious and safe in patients with and without diabetes. Funding Amgen.

Background Atrial fibrillation (AF) ablation procedures are increasingly being performed in patients receiving direct oral anticoagulants (DOACs). Experience regarding the safety of edoxaban in this context is limited. In an exploratory analysis we therefore investigated the outcome of patients undergoing transcatheter AF ablation in the ENGAGE AF-TIMI 48 trial. Methods & results During the trial, 193 transcatheter AF ablation procedures were performed in 169 patients. For the majority of ablations (n=157, 81%), study drug was interrupted >3days (median time of interruption: 18days, interquartile range 3–30days); 86 ablations were performed with ≤10days, and 36 ablations with ≤3days study drug interruption. During the first 30days after the ablation, one ischemic stroke was observed in the warfarin group and none in the higher-dose edoxaban regimen (HDER) or lower-dose edoxaban regimen (LDER) group. Three clinically relevant non-major (CRNM) bleeding events were observed in the warfarin group; one major bleed was seen in the HDER group; one minor bleed occurred in the LDER group. All bleeding events occurred among the patients with ≤10days study drug interruption; in contrast, no ischemic events or deaths were observed in these patients. Conclusions In this pilot evaluation of the ENGAGE AF-TIMI 48 trial, treatment with edoxaban was associated with a low risk of ischemic and bleeding events during the first 30days post ablation.

Residual cardiovascular risk persists despite statins, yet outcome studies of lipid-targeted therapies beyond low-density lipoprotein cholesterol (LDL-C) have not demonstrated added benefit. Triglyceride elevation is an independent risk factor for cardiovascular events. High-dose eicosapentaenoic acid (EPA) reduces triglyceride-rich lipoproteins without raising LDL-C. Omega-3s have postulated pleiotropic cardioprotective benefits beyond triglyceride-lowering. To date, no large, multinational, randomized clinical trial has proved that lowering triglycerides on top of statin therapy improves cardiovascular outcomes. The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT; NCT01492361) is a phase 3b randomized, double-blinded, placebo-controlled trial of icosapent ethyl, a highly purified ethyl ester of EPA, vs placebo. The main objective is to evaluate whether treatment with icosapent ethyl reduces ischemic events in statin-treated patients with high triglycerides at elevated cardiovascular risk. REDUCE-IT enrolled men or women age ≥45 years with established cardiovascular disease or age ≥50 years with diabetes mellitus and 1 additional risk factor. Randomization required fasting triglycerides ≥150 mg/dL and 40 mg/dL and ≤100 mg/dL with stable statin (± ezetimibe) ≥4 weeks prior to qualifying measurements. The primary endpoint is a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Several secondary, tertiary, and exploratory endpoints will be assessed. Approximately 8000 patients have been randomized at approximately 470 centers worldwide. Follow-up will continue in this event-driven trial until approximately 1612 adjudicated primary-efficacy endpoint events have occurred.

Background Sex-specific differences in response to antiplatelet therapies have been described. Whether women and men derive comparable benefit from intensification of antiplatelet therapy remains uncertain. Objectives The study investigated the efficacy and safety of the potent P2Y12 inhibitors in patients with coronary artery disease. Methods A collaborative sex-specific meta-analysis was conducted of phase III or IV randomized trials of potent P2Y12 inhibitors, including prasugrel, ticagrelor, and intravenous cangrelor. Seven trials were included that enrolled a total of 24,494 women and 63,346 men. Major adverse cardiovascular events (MACE) were defined as the primary endpoint for each trial. Results Potent P2Y12 inhibitors significantly reduced the risk of MACE by 14% in women (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.78 to 0.94) and by 15% in men (HR: 0.85; 95% CI: 0.80 to 0.90; p interaction = 0.93). Treatment reduced the risk of myocardial infarction by 13% in women (HR: 0.87; 95% CI: 0.78 to 0.96) and 16% in men (HR: 0.84; 95% CI: 0.77 to 0.91; p interaction = 0.65), and the risk of stent thrombosis by 51% in women (HR: 0.49; 95% CI: 0.37 to 0.65) and 41% in men (HR: 0.59; 95% CI: 0.42 to 0.84; p interaction = 0.85). Directional consistency was seen for cardiovascular death in women (HR: 0.87; 95% CI: 0.76 to 1.01) and men (HR: 0.85; 95% CI: 0.77 to 0.95; p interaction = 0.86). The potent P2Y12 inhibitors increased major bleeding in women (HR: 1.28; 95% CI: 0.87 to 1.88) and men (HR: 1.52; 95% CI: 1.12 to 2.07; p interaction = 0.62). Conclusions In randomized trials, the efficacy and safety of the potent P2Y12 inhibitors were comparable between men and women. Given these data, sex should not influence patient selection for the administration of potent P2Y12 inhibitors.

Background Ezetimibe improves cardiovascular (CV) outcomes in patients stabilized after acute coronary syndrome (ACS) when added to statin therapy. After ACS, patients vary considerably in their risk for recurrent CV events. Objectives This study tested the hypothesis that atherothrombotic risk stratification may be useful to identify post-ACS patients who have the greatest potential for benefit from the addition of ezetimibe to statin therapy. Methods The TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention (TRS 2°P) is a simple 9-point risk stratification tool, previously developed in a large population with atherothrombosis to predict CV death, myocardial infarction (MI), and ischemic stroke (CV death/MI/ischemic cerebrovascular accident [iCVA]). The current study applied this tool prospectively to 17,717 post-ACS patients randomized either to ezetimibe and simvastatin or to placebo and simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Treatment efficacy was assessed by baseline risk for CV death/MI/iCVA, the IMPROVE-IT composite endpoints (CE), and individual component endpoints at 7 years. Results All 9 clinical variables in the TRS 2°P were independent risk indicators for CV death/MI/iCVA (p Conclusions Atherothrombotic risk stratification using the TRS 2°P identifies high-risk patients who derive greatest benefit from the addition of ezetimibe to statin therapy for secondary prevention after ACS. (Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878)

Recent emphasis on reduced duration and/or intensity of antiplatelet therapy following percutaneous coronary intervention (PCI) irrespective of indication for PCI may fail to account for the substantial risk of subsequent nontarget lesion events in acute coronary syndrome (ACS) patients.The authors sought to examine the effect of more potent antiplatelet therapy on the basis of the timing and etiology of recurrent myocardial infarction (MI) or cardiovascular death following PCI for ACS.In the TRITON-TIMI 38 study (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38), which randomized patients to prasugrel or clopidogrel, 12,844 patients with ACS received at least 1 stent. MI and cardiovascular death were categorized as: 1) procedural (related to revascularization); 2) definite or probable stent thrombosis (ST); or 3) spontaneous (non-ST or non-procedure-related). Median follow-up was 14.5 months.Among the first events occurring within 30 days, 584 (69.0%) were procedural, 126 (14.9%) ST-related, and 136 (16.1%) spontaneous. After 30 days, 22 (4.7%) were procedural, 63 (13.5%) were ST-related, and 383 (81.8%) spontaneous. Prasugrel significantly reduced the incidence of MI or cardiovascular death for ST-related (1.0% vs. 2.1%; p 0.001) and spontaneous events (3.9% vs. 4.8%; p = 0.012), with a directionally consistent numerical reduction for procedural events (4.4% vs. 5.1%; p = 0.078). Prasugrel increased spontaneous, but not procedural, major bleeding.Long-term potent antithrombotic therapy reduces de novo (spontaneous) atherothrombotic events in addition to preventing complications associated with stenting of the culprit lesion following ACS. In patients undergoing PCI for ACS, spontaneous events predominate after 30 days, with the later-phase cardiovascular benefit of potent dual antiplatelet therapy driven largely by reducing de novo atherothrombotic ischemic events. (Comparison of Prasugrel [CS-747] and Clopidogrel in Acute Coronary Syndrome Subjects Who Are to Undergo Percutaneous Coronary Intervention; NCT00097591).

Background Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing heart failure (HF). Treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors reduces the risk of hospitalization for HF (HHF) in patients with T2DM. Purpose To develop and validate a practical, multivariable clinical risk score for HHF in patients with T2DM and assess whether this score can identify high-risk patients with T2DM who have the greatest reduction in risk for HHF with an SGLT2 inhibitor. Methods We developed a clinical risk score for centrally-adjudicated HHF using independent clinical risk indicators of HHF in 8212 patients with T2DM in the placebo arm of SAVOR-TIMI 53. Candidate variables were assessed using multivariable Cox regression and independent clinical risk indicators achieving statistical significance of p Results The 5 independent clinical risk indicators were prior heart failure, atrial fibrillation, coronary artery disease, estimated glomerular filtration rate (eGFR), and urine albumin/creatinine ratio (UACR) (Figure, left). A simple integer-based scheme using these predictors identified a strong >16-fold gradient of HHF risk (p-trend Conclusion(s) Risk stratification using a novel clinical risk score for HHF in patients with T2DM identifies patients at higher risk for HHF who derive greater benefit from treatment with the SGLT2 inhibitor dapagliflozin. Acknowledgement/Funding SAVOR-TIMI 53 and DECLARE-TIMI 58 were sponsored by AstraZeneca.

Summary Background Sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown beneficial effects on renal outcomes mainly in patients with established atherosclerotic cardiovascular disease. Here we report analyses of renal outcomes with the SGLT2 inhibitor dapagliflozin in the DECLARE–TIMI 58 cardiovascular outcomes trial, which included patients with type 2 diabetes both with and without established atherosclerotic cardiovascular disease and mostly with preserved renal function. Methods In DECLARE–TIMI 58, patients with type 2 diabetes, HbA1c 6·5–12·0% (47·5–113·1 mmol/mol), with either established atherosclerotic cardiovascular disease or multiple risk factors, and creatinine clearance of at least 60 mL/min were randomly assigned (1:1) to 10 mg dapagliflozin or placebo once daily. A prespecified secondary cardiorenal composite outcome was defined as a sustained decline of at least 40% in estimated glomerular filtration rate [eGFR] to less than 60 mL/min per 1·73m2, end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR ClinicalTrials.gov , number NCT01730534 . Findings The trial took place between April 25, 2013, and Sept 18, 2018; median follow-up was 4·2 years (IQR 3·9–4·4). Of the 17 160 participants who were randomly assigned, 8162 (47·6%) had an eGFR of at least 90 mL/min per 1·73 m2, 7732 (45·1%) had an eGFR of 60 to less than 90 mL/min per 1·73 m2, and 1265 (7·4%) had an eGFR of less than 60 mL/min per 1·73 m2 at baseline (one participant had missing data for eGFR); 6974 (40·6%) had established atherosclerotic cardiovascular disease and 10 186 (59·4%) had multiple risk factors. As previously reported, the cardiorenal secondary composite outcome was significantly reduced with dapagliflozin versus placebo (hazard ratio [HR] 0·76, 95% CI 0·67–0.87; p Interpretation Dapagliflozin seemed to prevent and reduce progression of kidney disease compared with placebo in this large and diverse population of patients with type 2 diabetes with and without established atherosclerotic cardiovascular disease, most of whom had preserved renal function. Funding AstraZeneca.

Importance: The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and first cardiovascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, but patients remain at high risk of recurrent cardiovascular events. Objective: To evaluate the effect of evolocumab on total cardiovascular events, given the importance of total number of cardiovascular events to patients, clinicians, and health economists. Design, Setting, and Participants: Secondary analysis of a randomized, double-blind clinical trial. The FOURIER trial compared evolocumab or matching placebo and followed up patients for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Data were analyzed between May 2017 and February 2019. Main Outcomes and Measures: The primary end point (PEP) was time to first cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary end point was time to first cardiovascular death, myocardial infarction, or stroke. In a prespecified analysis, total cardiovascular events were evaluated between treatment arms. Results: The mean age of patients was 63 years, 69% of patients were taking high-intensity statin therapy, and the median LDL-C at baseline was 92 mg/dL (to convert to millimoles per liter, multiply by 0.0259). There were 2907 first PEP events and 4906 total PEP events during the trial. Evolocumab reduced total PEP events by 18% (incidence rate ratio [RR], 0.82; 95% CI, 0.75-0.90; P

Aims Pacemaker, implantable cardioverter-defibrillator, and cardiac resynchronization therapy device implantations and generator changes are frequently performed in patients receiving direct oral anticoagulants. In an exploratory analysis, we investigated the outcome of patients undergoing such device procedures in the ENGAGE AF-TIMI 48 trial. Methods and results During the trial, 1217 device procedures were performed in 1145 patients, with intervention dates available for 1203 procedures. Two hundred and twenty-five procedures (in 212 patients) were performed >30 days after study drug was stopped and are not included in the event analysis. For most interventions (n = 728, 74%), study drug was interrupted >3 days (median for the entire cohort: 5 days, interquartile range 0-11 days); 250 interventions were performed with ≤3 days study drug interruption. During the first 30 days after the procedure, six strokes/systemic embolic events (SEEs) (three each in the lower-dose edoxaban and warfarin arm) and one major bleeding event (in the lower-dose edoxaban arm) occurred; no stroke/SEEs or major bleeds occurred around the 295 device procedures in the higher-dose edoxaban arm. Two ischaemic and one major bleeding event occurred after the 288 device procedures performed with ≤3 days periprocedural interruption of study drug. Conclusion In this first experience of patients undergoing device surgery with edoxaban, a low risk of ischaemic and bleeding events was observed during the first 30 days post-procedure. Our data are in line with current recommendations of no or only brief interruption of non-vitamin K antagonist oral anticoagulants prior to cardiac device surgery.

IMPORTANCE: The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER randomized clinical trial. Patients with metabolic syndrome (MetS) are at increased cardiovascular risk. OBJECTIVE: To investigate outcomes with evolocumab in patients with and without MetS. DESIGN, SETTING, AND PARTICIPANTS: The FOURIER trial randomized patients worldwide with stable atherosclerotic cardiovascular disease receiving statin to evolocumab vs placebo with follow-up for a median of 2.2 years. Data were collected February 2013 to November 2016. For this prespecified analysis, patients with the requisite data were stratified based on the National Cholesterol Education Program Adult Treatment Panel III MetS criteria; in secondary analyses, patients were further substratified by diabetes at baseline. Analysis was intention to treat. Analysis began March 2018 and ended April 2020. INTERVENTIONS: Patients were randomized to evolocumab or placebo. MAIN OUTCOMES AND MEASURES: The primary end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary end point was cardiovascular death, myocardial infarction, or stroke. RESULTS: Of 27 342 patients (mean [SD] age, 63 [9] years; 20 623 men [75.4%]) included in this analysis, 16 361 (59.8%) with baseline MetS were, when compared with patients without MetS, at higher risk of cardiovascular events (adjusted hazard ratio [95% CI], 1.31 [1.18-1.46]; P