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OBJECTIVE In patients with moderate to severe albuminuric kidney disease, sodium–glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk. RESEARCH DESIGN AND METHODS In the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to RESULTS Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38–0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001). CONCLUSIONS Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease.

Heart failure (HF) is a growing public health problem and ischemic heart disease is an important risk factor. Understanding the epidemiology of HF in patients with atherosclerosis may help identify subgroups at greater risk who have the potential to derive greater benefit from preventive strategies.The TRA 2°P-TIMI 50 trial randomized 26,449 patients with stable atherosclerosis to the antiplatelet agent vorapaxar versus placebo. Hospitalization for HF (HHF) endpoints were adjudicated from serious adverse events by blinded structured review using established definitions. HHF incidence was estimated using Kaplan-Meier analysis. Independent predictors of HHF risk were identified using multivariable logistic regression. The effect of vorapaxar on HHF risk was explored using Cox regression. The estimated incidence of HHF at 3 years was 1.6%. Independent predictors of HHF included prior HF (adjusted odds ratio [adj-OR]: 8.31; 95% confidence interval [CI]: 6.56-10.54), age (adj-OR [per 10 years]: 1.67; 95% CI: 1.47-1.89), type 2 diabetes mellitus (T2DM; adj-OR: 2.55; 95% CI: 2.01-3.24), polyvascular disease (two-territory disease, adj-OR: 1.89; 95% CI: 1.46-2.44; three-territory disease, adj-OR: 2.68; 95% CI: 1.94-3.70), chronic kidney disease (CKD; adj-OR: 1.65; 95% CI: 1.30-2.11), body mass index (BMI; adj-OR [per 5 kg/mIn patients with stable atherosclerosis, prior HF, age, T2DM, polyvascular disease, CKD, BMI, prior MI, and hypertension are important predictors of HHF risk.

ImportanceSodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown.ObjectiveTo assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR).Design, setting, and participantsThis secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (InterventionsDapagliflozin vs placebo.Main outcomes and measuresThe dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF.ResultsAt baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher.Conclusions and relevanceThe effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria.Trial registrationClinicalTrials.gov Identifier: NCT01730534.

Background: Dapagliflozin improved heart failure and kidney outcomes in patients with type 2 diabetes (T2DM) with or at high risk for atherosclerotic cardiovascular disease in the DECLARE-TIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58). Here, the aim was to analyze the efficacy and safety of dapagliflozin stratified according to baseline systolic blood pressure (SBP). Methods: The DECLARE-TIMI 58 trial randomly assigned patients with T2DM and either previous atherosclerotic cardiovascular disease or atherosclerotic cardiovascular disease risk factors to dapagliflozin or placebo. Patients were categorized by baseline SBP levels: Results: The trial comprised 17 160 patients; mean age, 64.0±6.8 years; 37.4% women; median duration of T2DM, 11 years; 40.6% with prevalent cardiovascular disease. Overall, dapagliflozin reduced SBP by 2.4 mm Hg (95% CI, 1.9–2.9; P P interactions =0.28 and 0.52, respectively). Among normotensive patients, the hazard ratios were 0.66 (95% CI, 0.42–1.05) and 0.39 (95% CI, 0.19–0.78), respectively, for hospitalization for heart failure and the renal-specific outcome. Events of volume depletion, amputation, and acute kidney injury did not differ with dapagliflozin overall or within any baseline SBP group. Conclusions: In patients with T2DM with or at high atherosclerotic cardiovascular disease risk, dapagliflozin reduced risk for hospitalization for heart failure and renal outcomes regardless of baseline SBP, with no difference in adverse events of interest at any level of baseline SBP. These results indicate that dapagliflozin provides cardiorenal benefits in patients with T2DM at high atherosclerotic cardiovascular disease risk independent of baseline blood pressure. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01730534.

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

AimsCeramide (Cer) and phosphatidylcholine (PC) lipids are associated with pathophysiological processes in cardiovascular (CV) diseases. A previously derived and validated plasma Cer-PC risk score (CERT2) was associated with CV death risk in patients with stable disease, but its prognostic value has not been evaluated in patients early post-acute coronary syndrome (ACS).Methods and resultsPrespecified plasma Cer and PC species in the CERT2 risk score were measured in 4871 subjects from SOLID-TIMI 52, which enrolled patients ≤30 days after ACS (median follow-up 2.5 years). The CERT2 score (scale 0–12 points) was calculated as previously defined. The primary outcome was CV death; Coronary heart disease death, all-cause death, hospitalization for heart failure (HF), myocardial infarction (MI) and stroke were also analyzed. Poisson models included baseline characteristics and established biomarkers. Patients with higher CERT2 risk scores were more likely to be older, female, current smokers, presenting with STEMI, and to have impaired renal function and higher LDL-C. After multivariable adjustment, patients in the highest risk score category remained at a nearly two-fold higher risk of CV death (adj relative risk [RR] 1.92, 95% CI 1.01–3.66, P = 0.047). Patients in the highest risk score category were also at higher risk of all-cause death (adj RR 2.01, 95% CI 1.21–3.35, P = 0.007), whereas the relationships with HF, MI, and stroke were attenuated with multivariable adjustment.ConclusionsA plasma ceramide and phospholipid-based risk score is associated with the risk of CV death independent of established clinical risk factors and biomarkers in patients after ACS.

Background: Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular complications. The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk for hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes mellitus. An increased risk of amputation has been observed with canagliflozin in 1 previous trial. We examined cardiovascular and kidney efficacy and the risk of limb-related events in patients with and without PAD in an exploratory analysis. Methods: A total of 17 160 patients with type 2 diabetes mellitus, including 1025 (6%) with PAD, were randomized. Key efficacy outcomes were MACE (cardiovascular [CV] death, myocardial infarction, stroke), CV death/HHF, and progression of kidney disease. Amputations, peripheral revascularization, and limb ischemic adverse events were site-reported and categorized by a blinded reviewer. Results: Patients in the placebo arm with PAD versus those without tended to have higher adjusted risk of CV death, myocardial infarction, or stroke (adjusted hazard ratio [HR], 1.23 [95% CI, 0.97–1.56], P =0.094) and significantly higher adjusted risk of CV death/HHF (adjusted HR, 1.60 [95% CI, 1.21–2.12], P =0.0010) and progression of kidney disease (adjusted HR, 1.51 [95% CI, 1.13 – 2.03], P =0.0058), and limb adverse events (adjusted HR, 8.37, P P -interaction=0.79) and progression of kidney disease (HR, 0.78, PAD; HR, 0.76, no-PAD; P -interaction=0.84) were consistent regardless of PAD. There were 560 patients who had at least 1 limb ischemic event, 454 patients with at least 1 peripheral revascularization, and 236 patients with at least 1 amputation, with a total of 407 amputations reported. Overall, there were no significant differences in any limb outcome with dapagliflozin versus placebo including limb ischemic adverse events (HR, 1.07 [95% CI, 0.90–1.26]) and amputation (HR, 1.09 [95% CI, 0.84–1.40]), with no significant interactions by a history of PAD versus not ( P -interactions=0.30 and 0.093, respectively). Conclusions: Patients with versus without PAD are at a higher risk of CV death of CV death, HHF, and kidney outcomes, and have a consistent benefits for CV death/HHF and progression of kidney disease with dapagliflozin. Patients with PAD had a higher risk of limb events, with no consistent pattern of incremental risk observed with dapagliflozin. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01730534.

Background Patients with peripheral artery disease are at increased risk of both major adverse cardiovascular events (MACEs) and limb events. The pathobiology of limb events is likely multifactorial. Observational studies suggest a benefit of statin therapy for reducing the risk of limb ischemic events while randomized trials demonstrate a benefit with more potent antithrombotic therapies, particularly those targeting thrombin. Whether the effects of these therapeutic pathways are independent and complementary is not known. Methods and Results The TRA 2°P‐TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50) trial demonstrated that vorapaxar significantly reduced MACEs and limb events. The purpose of the current analysis was to evaluate the association of statin use and intensity and the occurrence of MACEs and limb events in 5845 patients with symptomatic peripheral artery disease randomized in TRA 2°P‐TIMI 50 and then to understand whether statin use modified the benefits of vorapaxar for MACEs or limb ischemic events. We found that statin therapy was associated with significantly lower risk of MACEs (hazard ratio [HR], 0.77; 95% CI, 0.66–0.89; P P =0.002). The benefit of vorapaxar for reducing MACEs and limb events was consistent regardless of background statin ( P ‐interaction=0.715 and 0.073, respectively). Event rates were lowest in patients receiving the combination of statin therapy and vorapaxar. Conclusions In conclusion, statin use and intensity is associated with significantly lower rates of MACEs and limb ischemic events. Thrombin inhibition with vorapaxar is effective regardless of background statin therapy. These results suggest that targeting both lipid and thrombotic risk in peripheral artery disease is necessary in order to optimize outcomes.

OBJECTIVE Heart failure (HF) is an impactful complication of type 2 diabetes mellitus (T2DM). We aimed to develop and validate a risk score for hospitalization for HF (HHF) incorporating biomarkers and clinical factor(s) in patients with T2DM. RESEARCH DESIGN AND METHODS We derived a risk score for HHF using clinical data, high-sensitivity troponin T (hsTnT), and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) from 6,106 placebo-treated patients with T2DM in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using Cox regression. The strongest indicators of HHF risk were included in the score using integer weights. The score was externally validated in 7,251 placebo-treated patients in DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events–Thrombolysis in Myocardial Infarction 58). The effect of dapagliflozin on HHF was assessed by risk category in DECLARE-TIMI 58. RESULTS The strongest indicators of HHF risk were NT-proBNP, prior HF, and hsTnT (each P < 0.001). A risk score using these three variables identified a gradient of HHF risk (P-trend CONCLUSIONS We developed and validated a risk score for HHF in T2DM that incorporated NT-proBNP, prior HF, and hsTnT. The risk score identifies patients at higher risk of HHF who derive greater absolute benefit from dapagliflozin.

OBJECTIVE Current guidelines recommend prescribing SGLT2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c. RESEARCH DESIGN AND METHODS In the Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomly assigned to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population and with dapagliflozin versus placebo in HbA1c subgroups were studied by Cox regression models. RESULTS In the overall population, higher baseline HbA1c was associated with a higher risk of cardiovascular death or hospitalization for heart failure (HHF); major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and ischemic stroke; and cardiorenal outcomes (adjusted hazard ratios 1.12 [95% CI 1.06–1.19], 1.08 [1.04–1.13], and 1.17 [1.11–1.24] per 1% higher level, respectively). Elevated HbA1c was associated with a greater increased risk for MACE and cardiorenal outcomes in patients with multiple risk factors (MRF) than in established ASCVD (P-interaction = 0.0064 and 0.0093, respectively). Compared with placebo, dapagliflozin decreased the risk of cardiovascular death/HHF, HHF, and cardiorenal outcomes, with no heterogeneity by baseline HbA1c (P-interaction > 0.05). CONCLUSIONS Higher HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c

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 Vorapaxar inhibits the thrombin-mediated activation of platelets, reduces thrombotic events in patients with myocardial infarction or peripheral arterial disease while increasing bleeding. In the TRA 2°P-TIMI 50 trial, we observed a nominally significant interaction between low body weight and the reduced efficacy of vorapaxar. Methods We investigated the relationship between body weight and the efficacy and safety of vorapaxar within a multinational, randomized, double-blind, placebo-controlled trial of vorapaxar in patients with atherosclerosis. This analysis was performed among 20,138 patients with a clinical indication for vorapaxar. Results Compared with patients weighing 60 kg or more, patients weighing less than 60 kg were older, more frequently women, Asian and had renal insufficiency (each P0.05). Conclusions Vorapaxar reduced vascular events and improved net clinical outcome regardless of body weight in younger patients. Elderly patients with low weight may not be good candidates for aggressive secondary prevention with vorapaxar added to standard therapy. Clinical Trial Registration URL: http://www.clinicaltrials.gov Unique identifier: NCT00526474

Dapagliflozin was shown to reduce the cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes. However, data are limited on the relationship of the effect and safety with the concurrent use of CV medications in patients with type 2 diabetes.To assess whether the cardiorenal efficacy and safety of dapagliflozin were consistent with and without background use of CV medications commonly used for heart failure (HF) and kidney disease in patients with type 2 diabetes.This study is a prespecified secondary analysis of DECLARE-TIMI 58, which was a randomized trial of dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and either atherosclerotic disease or multiple risk factors for CV disease. Patients were stratified by baseline use of the following CV medications: angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACEI/ARBs), β-blockers, diuretics, and mineralocorticoid receptor antagonists (MRAs). The study was conducted from May 2013 to September 2018, and data were evaluated for this analysis from February 2021 to May 2022.Dapagliflozin or placebo.The outcomes of interest were the composite of CV death or hospitalization for HF (HHF), HHF alone, and a kidney-specific composite outcome (persistent ≥40% decrease in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney-related death).Among 17 160 patients, 13 950 (81%) used ACEI/ARBs, 9030 (53%) used β-blockers, 6205 (36%) used diuretics, and 762 (4%) used MRAs at baseline. Changes in blood pressure and eGFR at 48 months with dapagliflozin compared with placebo did not differ regardless of concurrent therapy (placebo-corrected change, -1.6 mm Hg [95% CI, -4.2 to 1.0] to -2.6 mm Hg [95% CI, -3.3 to -2.9]; P .05 for each interaction). Dapagliflozin consistently reduced the risk of CV death/HHF, HHF alone, and the kidney-specific composite outcome regardless of background use of selected medications (hazard ratio [HR] range: HR, 0.50; 95% CI, 0.39-0.63; to HR, 0.82; 95% CI, 0.72-0.95; P .05 for each interaction). In patients receiving ACEI/ARBs + β-blockers + diuretics (n = 4243), dapagliflozin reduced the risk of CV death/HHF and of the kidney-specific outcome by 24% (HR, 0.76; 95% CI, 0.62-0.93) and 38% (HR, 0.62; 95% CI, 0.44-0.87), respectively. There were no significant treatment interactions with the concomitant CV medications for adverse events of volume depletion, acute kidney injury, or hyperkalemia (range: HR, 0.12; 95% CI, 0.02-0.99; to HR, 1.04; 95% CI, 0.83-1.32; P .05 for each interaction).Dapagliflozin consistently reduced the risk of CV and kidney outcomes irrespective of background use of various CV medications without any treatment interaction for key safety events. These data show the clinical benefit and safety of dapagliflozin in a broad range of patients with type 2 diabetes regardless of background therapy.ClinicalTrials.gov Identifier: NCT01730534.

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

Background Patients with stable atherothrombotic disease vary in their risk of developing heart failure (HF). Circulating cardiovascular biomarkers may improve HF risk assessment and identify patients who may benefit from emerging HF preventive therapies. Methods and Results We measured high‐sensitivity cardiac troponin I and BNP (B‐type natriuretic peptide) in 15 833 patients with prior myocardial infarction, ischemic stroke, or peripheral artery disease from the TRA 2°P‐TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events‐Thrombolysis in Myocardial Infarction 50) trial, excluding patients with recent myocardial infarction (P LRT Conclusions Biomarkers of myocardial injury and hemodynamic stress are independent predictors of HHF risk in patients with stable atherothrombotic disease, with and without prior HF and/or type 2 diabetes mellitus. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00526474.

Introduction: In DECLARE-TIMI 58, the SGLT-2 inhibitor, dapagliflozin reduced the risk of the composite of cardiovascular death (CVD) or hospitalization for heart failure (HHF), and renal-specific outcomes in a broad range of patients with type 2 diabetes mellitus (T2DM). The TIMI Risk Score for Secondary Prevention (TRS 2°P) is a clinical risk score developed in patients with atherosclerotic cardiovascular disease (ASCVD) that provides risk stratification. Hypothesis: We hypothesized that the TRS 2°P would provide risk stratification in this population and that dapagliflozin would provide cardiovascular protection regardless of risk. Methods: DECLARE-TIMI 58 included patients with T2DM and either multiple risk factors or established ASCVD. Patients were stratified into 3 risk categories based on the 10-point TRS 2°P (see Figure , low: 1 or 2 points, intermediate: 3 points, or high: ≥4 points). Outcomes were major adverse cardiovascular events (MACE) (CVD, myocardial infarction, or ischemic stroke), CVD/HHF, components for MACE, and renal-specific composite outcomes. Results: Low, intermediate, or high risk, comprised respectively 49.8%, 31.2%, and 19.0% of the total of 17159 patients. In the placebo arm, increasing risk category was associated with a higher risk of all the outcomes of interest across risk categories (P-trendFigure ). The C-statistics were 0.67 for MACE and 0.72 for CVD/HHF in the placebo arm. Relative risk reductions in CVD/HHF and renal-specific composite outcomes with dapagliflozin were consistent for patients across the spectrum of TRS 2°P (P>0.05 for each interaction). Conclusions: Cardiovascular risk stratification using TRS 2°P identifies high-risk patients with T2DM for MACE, CVD/HHF, individual components for MACE, and renal-specific outcomes. Reductions in CVD/HHF and renal-specific outcomes with dapagliflozin versus placebo were consistent across the range of TRS 2°P.

Introduction: Biomarkers of hemodynamic stress and myocardial injury are associated with the risk of CV death & heart failure in patients with atherosclerotic vascular disease (ASCVD). Here we explore the association between cardiac biomarkers and ASCVD outcomes in patients with type 2 diabetes (T2DM). Methods: This was a nested biomarker study in DECLARETIMI 58, a randomized, blinded, placebo-controlled trial of dapagliflozin in T2DM and either multiple risk factors (MRF, ~60%) or established ASCVD (~40%). The relationship between baseline NT-proBNP and hsTnT levels (TIMI Biomarker Laboratory, n=14,565) and the composite of myocardial infarction, ischemic stroke, and CV death (MACE), was modeled within the placebo arm using Cox models adjusted for age, sex, race, smoking, baseline eGFR, BMI, T2DM duration, insulin use, history of CAD, MI, ischemic stroke, PAD, HF, dyslipidemia & hypertension. Interaction testing was applied to assess the effect of dapagliflozin according to baseline biomarker value. Results: NT-proBNP and hsTnT were significantly associated with MACE (Adjusted hazard ratio (aHR) per 1-SD in log-transformed biomarker, NT-proBNP: aHR 1.62; hsTnT aHR 1.59). The magnitude of the relationship was similar in patients with ASCVD (NT-proBNP aHR 1.60; hsTnT aHR 1.62) and MRF (NT-proBNP aHR 1.62; hsTnT: aHR 1.51) [Fig A] . Moreover, both biomarkers remained independently associated with MACE when combined in the multivariable model (NT-proBNP aHR 1.46, hsTnT aHR 1.39). The risk of MACE by baseline biomarker level and stratified by treatment arm is shown in Fig B. Conclusions: In patients with T2DM both with and without ASCVD, higher baseline NT-proBNP or hsTnT levels identified patients at increased risk of MACE. The difference in MACE rates between dapagliflozin and placebo tended to be more pronounced in ASCVD patients with higher baseline or NT-proBNP or hsTnT levels.

Introduction: Heart failure (HF) is a prognostically important complication of T2DM, the risk of which can be reduced by SGLT2 inhibitors. Clinical factors and circulating biomarkers of myocardial injury and hemodynamic stress predict risk of hosp for HF (HHF) in pts with T2DM. Aim: We aimed to develop and validate a biomarker-based risk score for HHF in pts with T2DM and to assess whether this score can identify high-risk pts with T2DM who have the greatest reduction in HHF risk with SGLT2 inhibition. Methods: Blood samples were prospectively collected from pts enrolled in SAVOR-TIMI 53 and DECLARE-TIMI 58 at randomization; high-sensitivity troponin T (hsTnT) and N-terminal B-type natriuretic peptide (NT-proBNP) were measured. We derived a risk score in 6106 pts with T2DM in the placebo arm of SAVOR-TIMI 53. Candidate variables (n=27) were assessed using Cox regression. The strongest indicators of HHF risk (based on Wald χ;2 values) were selected for inclusion and assigned integer weights. We externally validated the score in 7251 T2DM pts in the placebo arm of DECLARE-TIMI 58. Hazard ratios (HR) and absolute risk reductions (ARR) in HHF with the SGLT2 inhibitor dapagliflozin were assessed by baseline risk group. Results: The strongest independent indicators of HHF risk were NT-proBNP and hsTnT concentrations, and prior HF (each pFig ). Conclusions: A novel biomarker-based risk score for HHF in pts with T2DM identifies pts at higher risk of HHF who derive greater absolute benefit from SGLT2 inhibitors.

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.

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.

SGLT2 inhibitors may lead to short term decrease in eGFR, with later stabilization and long-term reduction in the risk for end stage kidney disease. Fast decline (FD) in eGFR can be defined as a reduction of ≥3 ml/min/1.73m2/year and is associated with poor long-term renal prognosis. In this post-hoc analysis we studied the effect of dapagliflozin (dapa) on the risk for FD in the DECLARE-TIMI 58 trial. In DECLARE-TIMI 58, 17,160 patients with T2D and established or increased risk for CVD, with mean baseline eGFR of 85.2 ml/min/1.73m2, were randomized to dapa vs. placebo and followed for a median of 4.2 years. The risk for FD was compared between treatment arms. In the time frame of 0.5 years (after stabilization) to 4 years, the proportion of patients with FD was reduced with dapa vs. placebo (26.8% vs. 37.1% respectively, p Disclosure 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. 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. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. J.P. Dwyer: Advisory Panel; Self; Bayer AG, Bird Rock Bio. Consultant; Self; US Food and Drug Administration (FDA). Employee; Self; Vanderbilt University Medical Center. Other Relationship; Self; Akcea Therapeutics, AstraZeneca, CSL Behring, Lexicon Pharmaceuticals, Inc., Praetego, Sanofi. 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. E.L. Goodrich: Other Relationship; Self; AstraZeneca. 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. A. Rozenberg: None. I. Yanuv: 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. R.C. Ma: Advisory Panel; Self; AstraZeneca. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Tricida Inc. T. Tankova: Board Member; Self; Amgen, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Sanofi, Servier. M. Fredriksson: Employee; Self; AstraZeneca. I.A. Gause-Nilsson: 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. 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. Funding AstraZeneca

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.

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: Sodium-glucose co-transporter-2 inhibitors were previously shown to improve renal parameters. In this predefined analysis of DECLARE-TIMI 58, we report the effects of dapagliflozin (dapa) on albuminuria in a broad population of patients with type 2 diabetes (T2DM) and either multiple risk factors (MRF) for or atherosclerotic cardiovascular disease (ASCVD), according to patients’ baseline albuminuria status. Methods: We randomized 17,160 patients with T2DM and either MRF 10,186 (59%) or ASCVD 6974 (41%) to dapa 10 mg or placebo in addition to standard of care, including 13,950 (81%) patients on ACEI/ARB. We report urinary albumin-to-creatinine ratio (UACR) change over the median follow-up of 4 years for dapa vs. placebo, according to albuminuria at baseline. Results: At baseline there were 11,644 (69%) patients w/normo-albuminuria (UACR 300 mg/g). Dapa blunted the increase in UACR over time by -29.0 mg/g (95% CI -44.0, -14.0; P=0.0002). This benefit was observed in patients with normo-, micro-, and macro-albuminuria: 3.2 mg/g (95% CI -6.4 to 0.03; P=0.052), -51.3 mg/g (95% CI -67.6 to -35.1; P Conclusion: In a broad population of patients with T2DM, long-term treatment with dapagliflozin blunts the rise in urinary albumin excretion, in all stratum of baseline albuminuria. Disclosure I. Raz: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Consultant; Self; AstraZeneca, BOL, Bristol-Myers Squibb Company, CameraEyes Ltd, DarioHealth, Diabot, Exscopia, GlucoMe Ltd., Insuline Medical, Medial EarlySign, Orgenesis Ltd. Speaker's Bureau; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Stock/Shareholder; Self; BOL, CameraEyes Ltd, DarioHealth, Diabot, GlucoMe Ltd., Orgenesis Ltd. S.D. Wiviott: Consultant; Self; Aegerion Pharmaceuticals, Allergan, Angel Medical Systems, Inc., Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Boston Clinical Research Institute, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, 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 Inc., Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Eisai Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi-Aventis. I. Yanuv: Research Support; Self; AstraZeneca. A. Rozenberg: Research Support; Self; AstraZeneca. T.A. Zelniker: None. A. Cahn: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, GlucoMe Ltd., Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Stock/Shareholder; Self; GlucoMe Ltd. H.L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation. J.P. Dwyer: Consultant; Self; Akcea Therapeutics, AstraZeneca, Bird Rock Bio, Eisai Inc., Goldfinch Bio, Sanofi-Aventis. E. Goodrich: None. D.L. Bhatt: Research Support; Self; Abbott, Amarin Corporation, Amgen Inc., AstraZeneca, Bayer Vital GmbH, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Chiesi USA, Inc., Eisai Inc., Eli Lilly and Company, Ethicon, Inc., FlowCo, Forest Laboratories, Inc., Idorsia, Ironwood Pharmaceuticals, Inc., Ischemix, Medicines Company, Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PLx Pharma, Regeneron Pharmaceuticals, Roche Pharma, Sanofi, Synaptic, Takeda Pharmaceutical Company Limited. L.A. Leiter: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. D.K. McGuire: Consultant; Self; Eisai Co., Ltd., Eli Lilly and Company, Pfizer Inc. Research Support; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. J.P. Wilding: Consultant; Self; Astellas Pharma Europe Ltd., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, NAPP Pharmaceuticals Limited, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company, WebMD. I.A. Gause-Nilsson: Employee; Self; AstraZeneca. M. Fredriksson: Employee; Self; AstraZeneca. P.A. Johansson: None. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. M.S. Sabatine: Consultant; Self; Amgen Inc., AstraZeneca, Bristol-Myers Squibb Company, CVS/Caremark, Dyrnamix, Esperion, Intarcia Therapeutics, Inc., Janssen Research and Development, Medicines Company, MedImmune, Merck & Co., Inc., Novartis. Research Support; Self; Amgen Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eisai Co., Ltd., GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Janssen Research and Development, Medicines Company, MedImmune, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Takeda. O. Mosenzon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. Funding 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.

Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as 2 new classes of antihyperglycemic agents that also reduce cardiovascular risk. The relative benefits in patients with and without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs remain undefined.We performed a systematic review and trial-level meta-analysis of GLP1-RA and SGLT2i cardiovascular outcomes trials using the PubMed and EMBASE databases (Excerpta Medica Database). The primary outcomes were the composite of myocardial infarction, stroke, and cardiovascular death (MACE); hospitalization for heart failure; and progression of kidney disease.In total, data from 8 trials and 77 242 patients, 42 920 (55.6%) in GLP1-RA trials, and 34 322 (44.4%) in SGLT2i trials, were included. Both drug classes reduced MACE in a similar magnitude with GLP1-RA reducing the risk by 12% (hazard ratio [HR], 0.88; 95% CI, 0.84-0.94; P0.001) and SGLT2i by 11% (HR, 0.89; 95% CI, 0.83-0.96; P=0.001). For both drug classes, this treatment effect was restricted to a 14% reduction in those with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.80-0.93; P=0.002), whereas no effect was seen in patients without established atherosclerotic cardiovascular disease (HR, 1.01; 95% CI, 0.87-1.19; P=0.81; P interaction, 0.028). SGLT2i reduced hospitalization for heart failure by 31% (HR, 0.69; 95% CI, 0.61-0.79; P0.001), whereas GLP1-RA did not have a significant effect (HR, 0.93; 95% CI, 0.83-1.04; P=0.20). Both GLP1-RA (HR, 0.82; 95% CI, 0.75-0.89; P0.001) and SGLT2i (HR, 0.62; 95% CI, 0.58-0.67; P0.001) reduced the risk of progression of kidney disease including macroalbuminuria, but only SGLT2i reduced the risk of worsening estimated glomerular filtration rate, end-stage kidney disease, or renal death (HR, 0.55; 95% CI, 0.48-0.64; P0.001).In trials reported to date, GLP1-RA and SGLT2i reduce atherosclerotic MACE to a similar degree in patients with established atherosclerotic cardiovascular disease, whereas SGLT2i have a more marked effect on preventing hospitalization for heart failure and progression of kidney disease. Their distinct clinical benefit profiles should be considered in the decision-making process when treating patients with type 2 diabetes mellitus.

The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains undefined.We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function.We included data from three identified trials and 34 322 patients (60·2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation sfor heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0·89 [95% CI 0·83-0·96], p=0·0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0·86 [0·80-0·93]) and not in those without (1·00 [0·87-1·16], p for interaction=0·0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77 [0·71-0·84], p0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0·55 [0·48-0·64], p0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0·0073) and lesser reductions in progression of renal disease (p for interaction=0·0258) in patients with more severe kidney disease at baseline.SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure.None.

Objectives The aim of this study was to determine whether the reduction in peripheral revascularization with vorapaxar in patients with peripheral artery disease (PAD) is directionally consistent across indications, including acute limb ischemia, progressively disabling symptoms, or both. Background The protease-activated receptor–1 antagonist vorapaxar reduces peripheral revascularization in patients with PAD. Methods The TRA 2°P–TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50) trial randomized 26,449 patients with histories of myocardial infarction, stroke, or symptomatic PAD to vorapaxar or placebo on a background of standard therapy. A total of 5,845 patients had a known history of PAD at randomization. Peripheral revascularization procedures reported by the site were a pre-specified outcome. We explored whether the benefit of vorapaxar was consistent across indication and type of procedure. Results Of the 5,845 patients with known PAD, a total of 934 (16%) underwent at least 1 peripheral revascularization over 2.5 years (median). More than one-half (55%) were for worsening claudication, followed by critical limb ischemia (24%), acute limb ischemia (16%), and asymptomatic severe stenosis (4%). Vorapaxar significantly reduced peripheral revascularization (19.3% for placebo, 15.4% for vorapaxar; hazard ratio: 0.82; 95% confidence interval: 0.72 to 0.93; p = 0.003), with a consistent pattern of efficacy across indication. Conclusions Vorapaxar reduces peripheral revascularization in patients with PAD. This benefit of vorapaxar is directionally consistent across type of procedure and indication. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2°P - TIMI 50] [P04737]; NCT00526474)

The 2018 American Heart Association/American College of Cardiology (AHA/ACC) cholesterol management guidelines identified 2 distinct groups of patients with atherosclerotic cardiovascular disease (ASCVD) prompting different treatment recommendations.To investigate whether the addition of high-sensitivity troponin (hsTn) testing to guideline-derived ASCVD risk can improve risk classification and downstream treatment recommendations.A prospective cohort biomarker substudy was performed that included 8635 patients enrolled in the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial. Patients were assigned to risk groups of either very high-risk ASCVD or lower-risk ASCVD based on their cardiovascular history and comorbidities, in line with the 2018 AHA/ACC cholesterol management guidelines criteria. Patients were also classified on the basis of hsTnI level (ARCHITECT assay; Abbott) using cut points of 2 ng/L (limit of detection) and 6 ng/L (risk threshold), followed by joint classification on the basis of clinical features and hsTnI level. The setting was a nested prospective cohort study in a completed multinational trial. Participants were all patients who had a myocardial infarction 1 to 3 years before enrollment, were at least 50 years of age, and had at least 1 high-risk feature. The study dates were October 2010 to December 2014. The dates of analysis were June 2019 to January 2020.The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke.Among 8635 patients enrolled in the PEGASUS-TIMI 54 trial, the median age was 65 years (interquartile range, 58-71 years), and 6614 (76.6%) were men; 8340 (96.6%) were White individuals and 176 (2.0%) were Black individuals. Patients meeting clinical criteria for the very high-risk ASCVD group had a primary end point 3-year event rate of 8.8% compared with 5.0% in the lower-risk ASCVD group (hazard ratio, 2.01; 95% CI, 1.58-2.57; P .001). When patients in the very high-risk ASCVD group were further risk stratified by hsTnI level, 614 of 6789 patients (9.0%) with an undetectable hsTnI level had a 3-year event rate of 2.7% (1% per year), which was less than the overall rate in the lower-risk ASCVD group. Analogously, in the lower-risk ASCVD group, 417 of 1846 patients (22.6%) with an hsTnI level exceeding 6 ng/L had an event rate of 9.1%, comparable to the overall rate in the very high-risk ASCVD group. The addition of hsTnI to guideline-derived ASCVD risk led to a net reclassification index at event rate of 0.15 (95% CI, 0.10-0.21). Overall, use of hsTnI reclassified 1031 of 8635 patients (11.9%) (1 in 11 with very high-risk ASCVD and 1 in 4 with lower-risk ASCVD).The findings of this cohort substudy suggest that a strategy incorporating hsTn into a guideline-derived ASCVD risk algorithm provides enhanced risk stratification and reclassifies 11.9% of patients into a more appropriate risk group. This application of hsTn testing might be used to optimize the care of patients with ASCVD.

Background It is unknown whether short sleep duration, obstructive sleep apnea, and overnight shift work are associated with the risk of recurrent cardiovascular events in patients after an acute coronary syndrome. Methods and Results SOLID ‐ TIMI 52 (The Stabilization of PLaques UsIng Darapladib‐Thrombolysis in Myocardial Infarction 52 Trial) was a multinational, double‐blind, placebo‐controlled trial that enrolled 13 026 patients ≤30 days of acute coronary syndrome. At baseline, all patients were to complete the Berlin questionnaire to assess risk of obstructive sleep apnea and a sleep and shift work survey. Median follow‐up was 2.5 years. The primary outcome was major coronary events ( MCE ; coronary heart disease death, myocardial infarction, or urgent revascularization). Cox models were adjusted for clinical predictors. Patients who reported MCE (adjusted hazard ratio, 1.29; 95% confidence interval, 1.12–1.49; P MCE (1.12; 1.00–1.24; P =0.04) than those who did not screen positive. Overnight shift work (≥3 night shifts/week for ≥1 year) was associated with a 15% higher risk of MCE (1.15; 1.03–1.29; P =0.01). A step‐wise increase in cardiovascular risk was observed for individuals with more than 1 sleep‐related risk factor. Individuals with all 3 sleep‐related risk factors had a 2‐fold higher risk of MCE (2.01; 1.49–2.71; P Conclusions Short sleep duration, obstructive sleep apnea, and overnight shift work are under‐recognized as predictors of adverse outcomes after acute coronary syndrome. Increased efforts should be made to identify, treat, and educate patients about the importance of sleep for the potential prevention of cardiovascular events. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01000727.

Background Interleukin‐6 ( IL ‐6) is an inflammatory cytokine implicated in plaque instability in acute coronary syndrome ( ACS ). We aimed to evaluate the prognostic implications of IL ‐6 post‐ ACS . Methods and Results IL ‐6 concentration was assessed at baseline in 4939 subjects in SOLID ‐ TIMI 52 (Stabilization of Plaque Using Darapladib—Thrombolysis in Myocardial Infarction 52), a randomized trial of darapladib in patients ≤30 days from ACS . Patients were followed for a median of 2.5 years for major adverse cardiovascular events; cardiovascular death, myocardial infarction, or stroke) and cardiovascular death or heart failure hospitalization. Primary analyses were adjusted first for baseline characteristics, days from index ACS , ACS type, and randomized treatment arm. For every SD increase in IL ‐6, there was a 10% higher risk of major adverse cardiovascular events (adjusted hazard ratio [adj HR ] 1.10, 95% confidence interval [ CI ] 1.01‐1.19) and a 22% higher risk of cardiovascular death or heart failure (adj HR 1.22, 95% CI 1.11‐1.34). Patients in the highest IL ‐6 quartile had a higher risk of major adverse cardiovascular events (adj HR Q4:Q1 1.57, 95% CI 1.22‐2.03) and cardiovascular death or heart failure (adj HR 2.29, 95% CI 1.6‐3.29). After further adjustment for biomarkers (high‐sensitivity C‐reactive protein, lipoprotein‐associated phospholipase A 2 activity, high‐sensitivity troponin I, and B‐type natriuretic peptide), IL ‐6 remained significantly associated with the risk of major adverse cardiovascular events (adj HR Q4:Q1 1.43, 95% CI 1.09‐1.88) and cardiovascular death or heart failure (adj HR 1.79, 95% CI 1.22‐2.63). Conclusions In patients after ACS , IL ‐6 concentration is associated with adverse cardiovascular outcomes independent of established risk predictors and biomarkers. These findings lend support to the concept of IL ‐6 as a potential therapeutic target in patients with unstable ischemic heart disease.

Background: Observational studies suggest that symptomatic atherosclerosis may be associated with risk of venous thromboembolism (VTE). Prior randomized studies have demonstrated a significant reduction in recurrent VTE with aspirin monotherapy. Whether VTE risk is associated with more severe symptomatic atherosclerosis and more intensive antiplatelet therapy reduces VTE risk beyond aspirin monotherapy is unknown. Methods: TRA2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction) (vorapaxar) and PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54) (ticagrelor) were blinded, randomized placebo-controlled trials of antiplatelet therapy for the prevention of ischemic events in stable patients with symptomatic atherosclerosis. Two blinded vascular specialists systematically identified symptomatic venous thromboembolic events in both trials. Results: Of 47 611 patients with stable vascular disease followed for 3 years in both studies there were 343 VTE events in 301 patients (Kaplan-Meier rate at 3 years, 0.9% for placebo). The risk of VTE was independently associated with age, body mass index, polyvascular disease, chronic obstructive pulmonary disease, and malignancy. The burden of atherosclerosis manifested as an increasing number of symptomatic vascular territories was associated with a graded increase in the 3-year rates of VTE (0.76% for 1, 1.53% for 2, and 2.45% for 3 territories). More intensive antiplatelet therapy (vorapaxar and ticagrelor pooled) significantly reduced the risk of VTE by 29% compared with background antiplatelet therapy, from 0.93% to 0.64% at 3 years (hazard ratio, 0.71; 95% confidence interval, 0.56–0.89; P =0.003). Conclusions: The rate of VTE in patients with atherosclerosis is ≈0.3% per year while on treatment with ≥1 antiplatelet agent, with increased risk independently associated with the number of symptomatic vascular territories. More intensive antiplatelet therapy reduces the risk of VTE. These data suggest a relationship between atherosclerosis burden and VTE risk, and they support inclusion of VTE as a prospective end point in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with atherosclerosis. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01225562.

Background High‐potency statins reduce cardiovascular events after acute coronary syndromes but remain underused in clinical practice. We examined predictors of nonuse of high‐potency statins after acute coronary syndromes. Methods and Results The Stabilization of pLaques usIng Darapladib‐Thrombolysis in Myocardial Infarction (SOLID‐TIMI 52) trial enrolled patients after an acute coronary syndrome in 36 countries between 2009 and 2011. Statin use was strongly encouraged throughout the trial, and statin potency was at the discretion of the treating physician. A high‐potency statin was defined as ≥40 mg atorvastatin, ≥20 mg rosuvastatin, or 80 mg simvastatin daily. Predictors of nonuse of high‐potency statins were examined using logistic regression. Of the patients included (n=12 446), 11 850 (95.2%) were treated with a statin at baseline after acute coronary syndrome (median 14 days), but only 5212 (41.9%) were on a high‐potency statin. Selected patient factors associated with nonuse of high‐potency statins included age ≥75 years (odds ratio 1.39, 95% CI 1.24–1.56), female sex (odds ratio 1.11, 95% CI 1.02–1.22), renal dysfunction (odds ratio 1.17, 95% CI 1.03–1.32), and heart failure during hospital admission (odds ratio 1.43, 95% CI 1.27–1.62). At 3 months after baseline, only 49% of patients had low‐density lipoprotein cholesterol CI 1.11–1.19). Conclusion Despite the widespread use of statins after acute coronary syndromes, most patients are not treated with high‐potency statins early and late after the event, including patients at the highest risk of recurrent cardiovascular events. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01000727.

Patients with stable atherothrombotic disease vary in their risk of developing heart failure (HF). Circulating cardiovascular biomarkers may improve assessment of incident HF risk. We measured high-sensitivity troponin I (hsTnI) and brain natriuretic peptide (BNP) (Abbott ARCHITECT) in 14,603

Background: In the PEGASUS-TIMI 54 trial (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54), ticagrelor reduced the risk of major adverse cardiovascular events when added to low-dose aspirin in stable patients with prior myocardial infarction, resulting in the approval of ticagrelor 60 mg twice daily for long-term secondary prevention. We investigated the incidence of stroke, outcomes after stroke, and the efficacy of ticagrelor focusing on the approved 60 mg twice daily dose for reducing stroke in this population. Methods: Patients were followed for a median of 33 months. Stroke events were adjudicated by a central committee. Data from similar trials were combined using meta-analysis. Results: Of 14 112 patients randomly assigned to placebo or ticagrelor 60 mg, 213 experienced a stroke; 85% of these strokes were ischemic. A total of 18% of strokes were fatal and another 15% led to either moderate or severe disability at 30 days. Ticagrelor significantly reduced the risk of stroke (hazard ratio, 0.75; 95% confidence interval, 0.57–0.98; P =0.034), driven by a reduction in ischemic stroke (hazard ratio, 0.76; 95% confidence interval, 0.56–1.02). Hemorrhagic stroke occurred in 9 patients on placebo and 8 patients on ticagrelor. A meta-analysis across 4 placebo-controlled trials of more intensive antiplatelet therapy in 44 816 patients with coronary disease confirmed a marked reduction in ischemic stroke (hazard ratio, 0.66; 95% confidence interval, 0.54–0.81; P =0.0001). Conclusions: High-risk patients with prior myocardial infarction are at risk for stroke, approximately one-third of which are fatal or lead to moderate-to-severe disability. The addition of ticagrelor 60 mg twice daily significantly reduced this risk without an excess of hemorrhagic stroke but with more major bleeding. In high-risk patients with coronary disease, more intensive antiplatelet therapy should be considered not only to reduce the risk of coronary events, but also of stroke. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique Identifier: NCT01225562.

Peripheral artery disease (PAD) is associated with heightened ischemic and bleeding risk in patients with prior myocardial infarction (MI).This study evaluated the efficacy and safety of ticagrelor on major cardiovascular (CV) events and major adverse limb events in patients with PAD and a prior MI.PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) randomized 21,162 patients with prior MI (1 to 3 years) to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all on a background of low-dose aspirin. History of PAD was obtained at baseline. Occurrences of major adverse cardiovascular events (MACE) (defined as CV death, MI, or stroke) and major adverse limb events (MALE) (defined as acute limb ischemia or peripheral revascularization for ischemia) were recorded in follow-up.A total of 1,143 patients (5%) had known PAD. In the placebo arm, those with PAD (n = 404) had higher rates of MACE at 3 years than those without (n = 6,663; 19.3% vs. 8.4%; p 0.001), which persisted after adjusting for baseline differences (adjusted hazard ratio: 1.60; 95% confidence interval: 1.20 to 2.13; p = 0.0013), and higher rates of acute limb ischemia (1.0% vs. 0.1%) and peripheral revascularization procedures (9.15% vs. 0.46%). Whereas the relative risk reduction in MACE with ticagrelor was consistent, regardless of PAD, patients with PAD had a greater absolute risk reduction of 4.1% (number needed to treat: 25) due to their higher absolute risk. The absolute excess of TIMI major bleeding was 0.12% (number needed to harm: 834). The 60-mg dose had particularly favorable outcomes for CV and all-cause mortality. Ticagrelor (pooled doses) reduced the risk of MALE (hazard ratio: 0.65; 95% confidence interval: 0.44 to 0.95; p = 0.026).Among stable patients with prior MI, those with concomitant PAD have heightened ischemic risk. In these patients, ticagrelor reduced MACE, with a large absolute risk reduction, and MALE. (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS-TIMI 54]; NCT01225562).

The aim of this study was to determine whether the reduction in peripheral revascularization with vorapaxar in patients with peripheral artery disease (PAD) is directionally consistent across indications, including acute limb ischemia, progressively disabling symptoms, or both.The protease-activated receptor-1 antagonist vorapaxar reduces peripheral revascularization in patients with PAD.The TRA 2°P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50) trial randomized 26,449 patients with histories of myocardial infarction, stroke, or symptomatic PAD to vorapaxar or placebo on a background of standard therapy. A total of 5,845 patients had a known history of PAD at randomization. Peripheral revascularization procedures reported by the site were a pre-specified outcome. We explored whether the benefit of vorapaxar was consistent across indication and type of procedure.Of the 5,845 patients with known PAD, a total of 934 (16%) underwent at least 1 peripheral revascularization over 2.5 years (median). More than one-half (55%) were for worsening claudication, followed by critical limb ischemia (24%), acute limb ischemia (16%), and asymptomatic severe stenosis (4%). Vorapaxar significantly reduced peripheral revascularization (19.3% for placebo, 15.4% for vorapaxar; hazard ratio: 0.82; 95% confidence interval: 0.72 to 0.93; p = 0.003), with a consistent pattern of efficacy across indication.Vorapaxar reduces peripheral revascularization in patients with PAD. This benefit of vorapaxar is directionally consistent across type of procedure and indication. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2°P - TIMI 50] [P04737]; NCT00526474).