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IMPORTANCE: Myocardial infarction is a frequent cause of out-of-hospital cardiac arrest (OHCA). The long-term effect of early coronary angiography on patients with OHCA with possible coronary trigger but no ST-segment elevation remains unclear. OBJECTIVE: To compare the clinical outcomes of early unselective angiography with the clinical outcomes of a delayed or selective approach for successfully resuscitated patients with OHCA of presumed cardiac origin without ST-segment elevation at 1-year follow-up. DESIGN, SETTING, AND PARTICIPANTS: The TOMAHAWK trial was a multicenter, international (Germany and Denmark), investigator-initiated, open-label, randomized clinical trial enrolling 554 patients between November 23, 2016, to September 20, 2019. Patients with stable return of spontaneous circulation after OHCA of presumed cardiac origin but without ST-segment elevation on the postresuscitation electrocardiogram were eligible for inclusion. A total of 554 patients were randomized to either immediate coronary angiography after hospital admission or an initial intensive care assessment with delayed or selective angiography after a minimum of 24 hours. All 554 patients were included in survival analyses during the follow-up period of 1 year. Secondary clinical outcomes were assessed only for participants alive at 1 year to account for the competing risk of death. INTERVENTIONS: Early vs delayed or selective coronary angiography and revascularization if indicated. MAIN OUTCOMES AND MEASURES: Evaluations in this secondary analysis included all-cause mortality after 1 year, as well as severe neurologic deficit, myocardial infarction, and rehospitalization for congestive heart failure in survivors at 1 year. RESULTS: A total of 281 patients were randomized to the immediate angiography group and 273 to the delayed or selective group, with a median age of 70 years (IQR, 60-78 years). A total of 369 of 530 patients (69.6%) were male, and 268 of 483 patients (55.5%) had a shockable arrest rhythm. At 1 year, all-cause mortality was 60.8% (161 of 265) in the immediate angiography group and 54.3% (144 of 265) in the delayed or selective angiography group without significant difference between the treatment strategies, trending toward an increase in mortality with immediate angiography (hazard ratio, 1.25; 95% CI, 0.99-1.57; P = .05). For patients surviving until 1 year, the rates of severe neurologic deficit, myocardial infarction, and rehospitalization for congestive heart failure were similar between the groups. CONCLUSIONS AND RELEVANCE: This study found that a strategy of immediate coronary angiography does not provide clinical benefit compared with a delayed or selective invasive approach for patients 1 year after resuscitated OHCA of presumed coronary cause and without ST-segment elevation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02750462

Graphical abstract(A) Cumulative incidence curves for all-cause death stratified by the top quartile (Q) vs. Q1–Q3 of mid-regional pro-adrenomedullin (MR-proADM). Patients with MR-proADM levels in the top quartile vs. those in Q1–Q3 had significantly higher death rates at 7 days (55.2 vs. 19.0%, P< 0.001) and at 28 days (75.9 vs. 45.4%, P< 0.001). (B) Kaplan–Meier event rates at 28 days stratified by MR-proADM and lactate levels for all-cause death. Patients with both markers in the top quartile had significantly higher rates of death. This risk persisted after multivariable adjustment (adjusted hazard ratio 3.50; 95% confidence interval 1.92–6.39).

IMPORTANCE: Dapagliflozin reduces the risk of hospitalizations for heart failure and the progression of chronic kidney disease in patients with and without type 2 diabetes (T2D), whereas the effects on reducing atherosclerotic events appear less clear. OBJECTIVE: To explore whether N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) levels can identify a subset of patients with T2D at higher risk and who might benefit more from dapagliflozin with regard to atherosclerotic events. DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of the DECLARE-TIMI 58 trial, a randomized clinical trial of dapagliflozin in patients with T2D and either multiple risk factors for atherosclerotic cardiovascular disease (ASCVD; approximately 60%) or established ASCVD (approximately 40%). All patients with available blood samples at randomization were included in these analyses. Data were collected from May 2013 to September 2018, and data were analyzed from May 2019 to June 2022. INTERVENTIONS: Dapagliflozin vs placebo. MAIN OUTCOMES AND MEASURES: Major adverse cardiovascular events (MACE), the composite of myocardial infarction, ischemic stroke, or cardiovascular death, which was one of dual primary outcomes of the main trial. RESULTS: Of 14 565 included patients, 9143 (62.8%) were male, and the mean (SD) age was 63.9 (6.8) years. When tested individually in a multivariable model for MACE risk, NT-proBNP and hsTnT were each significantly associated with the risk of MACE (adjusted hazard ratio [aHR] per 1 SD in log-transformed biomarker: NT-proBNP, 1.62; 95% CI, 1.49-1.76; hsTnT: 1.59; 95% CI, 1.46-1.74). The magnitude of the association was similar in patients with ASCVD (NT-proBNP: aHR, 1.60; 95% CI, 1.45-1.77; hsTnT: aHR, 1.62; 95% CI, 1.45-1.81) and multiple risk factors for ASCVD (NT-proBNP: aHR, 1.62; 95% CI, 1.40-1.88; hsTnT: aHR, 1.51; 95% CI, 1.29-1.77). Moreover, both biomarkers remained independently associated with MACE when both were included in the multivariable model (NT-proBNP: aHR, 1.46; 95% CI, 1.34-1.60; hsTnT: aHR, 1.39; 95% CI, 1.26-1.53). Modeled as a continuous variable, baseline biomarker levels did not modify the relative treatment effect of dapagliflozin vs placebo with MACE. However, the relative risk reduction numerically grew with higher biomarker levels, as did the baseline risk. Thus, MACE event rates were nominally lower in dapagliflozin-treated vs placebo-treated patients with biomarker concentrations in the top quartile (NT-proBNP: HR, 0.83; 95% CI, 0.71-0.97; absolute risk reduction [ARR], 2.4%; hsTnT: HR, 0.85; 95% CI, 0.72-0.99; ARR, 2.7%), whereas there was no significant treatment effect in patients with biomarkers levels in quartiles 1 to 3 (NT-proBNP: HR, 1.02; 95% CI, 0.88-1.18; ARR, 0%; hsTnT: HR, 0.97; 95% CI, 0.84-1.13; ARR, 0.2%). CONCLUSIONS AND RELEVANCE: In this study, NT-proBNP and hsTnT levels were associated with the risk for future cardiovascular events in both primary and secondary prevention patients with T2D. Both cardiac biomarkers were helpful to identify patients at very high risk for atherosclerotic events that may derive reduction in risk of MACE with dapagliflozin. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01730534

In people with type 2 diabetes at high risk of cardiovascular or kidney disease, sodium-glucose co-transporter 2 (SGLT2) inhibitors consistently reduce the risk of hospitalisations for heart failure. Less is known about their effects on hospitalisation from any cause, especially in people with type 2 diabetes without atherosclerotic cardiovascular disease, which includes most of the global population of people with type 2 diabetes. We aimed to assess the effect of the SGLT2 inhibitor, dapagliflozin, on the risks of hospitalisations for any cause and for specific causes in people with type 2 diabetes with and without atherosclerotic cardiovascular disease.

Diabetes mellitus (DM) stellt eine wichtige Komorbidität bei Patienten mit Herzinsuffizienz dar, die maßgeblich die Prognose determiniert. Von entscheidender Bedeutung zur Verbesserung der Prognose dieser Hochrisikopatienten ist daher eine frühzeitige Diagnostik und differenzierte medikamentöse Therapie mit Ausschöpfung aller möglichen Therapieoptionen und Absetzen potenziell schädlicher Substanzen. Das gemeinsame Positionspapier der Deutschen Gesellschaft für Kardiologie (DGK) und der Deutschen Diabetes Gesellschaft (DDG) fasst die vorhandene wissenschaftliche Evidenz zusammen und gibt Empfehlungen, was bei der Diagnose und Therapie der Herzinsuffizienz und des DM zu beachten ist, um die Prognose zu verbessern.

IMPORTANCE: Sodium-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. OBJECTIVE: To 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 PARTICIPANTS: This 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 (&lt;60 vs ≥60 mL/min/1.73 m2), urinary albumin to creatinine ratio (UACR; &lt;30 vs ≥30 mg/g), and of chronic kidney disease (CKD) markers using these subgroups (0, 1, or 2). The study was conducted from May 2013 to September 2018. INTERVENTIONS: Dapagliflozin vs placebo. MAIN OUTCOMES AND MEASURES: The dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF. RESULTS: At 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 RELEVANCE: The 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 REGISTRATION: ClinicalTrials.gov Identifier: NCT01730534

Background: Early risk stratification remains an unmet clinical need in patients with in out-of-hospital cardiac arrest. We hypothesised that soluble neprilysin may represent a promising biomarker in patients with out-of-hospital cardiac arrest of non-traumatic origin and provide new pathobiological insight.Methods: This pilot study was a biomarker analysis from the Heidelberg Resuscitation Registry. Serum soluble neprilysin levels on admission were measured in 144 patients with successful return of spontaneous circulation after out-of-hospital cardiac arrest of non-traumatic origin. The primary endpoint was time to all-cause mortality. KM Event Rates are reported. Cox models were adjusted for age, bystander resuscitation, initial ECG rhythm, baseline estimated glomerular filtration rate, baseline lactate, left ventricular function at baseline, and targeted temperature management.Results: In total, 90 (62.5%) patients died over a follow-up of at least 30 days. Soluble neprilysin correlated weakly with high-sensitivity troponin T (r=0.18, P=0.032) but did not correlate significantly with estimated glomerular filtration rate (r=−0.12) or lactate (r=0.11). Patients with elevated soluble neprilysin levels on admission were at significantly higher risk of all-cause mortality (Q4 69.1% vs. Q1 48.4%). After multivariable adjustment, soluble neprilysin in the top quartile (Q4) was significantly associated with all-cause mortality (Q4 vs. Q1: adjusted hazard ratio 2.48 (1.20–5.12)). In an adjusted multimarker model including high-sensitivity troponin T and high-sensitivity C-reactive protein, soluble neprilysin and high-sensitivity troponin T remained independently associated with all-cause mortality (soluble neprilysin: adjusted hazard ratio 2.27 (1.08–4.78); high-sensitivity troponin T: adjusted hazard ratio 3.40 (1.63–7.09)).Conclusion: Soluble neprilysin, measured as early as on hospital admission, was independently associated with all-cause mortality in patients with out-of-hospital cardiac arrest of non-traumatic origin and may prove to be useful in the estimation of risk in these patients.

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Background: Patients with atrial fibrillation and concomitant coronary artery disease (CAD) are at higher risk for myocardial infarction or cardiovascular death, often require antiplatelet therapy and are therefore exposed to an increased risk of bleeding. This meta-analysis aimed to compare the efficacy and safety profile of non-vitamin K antagonist oral anticoagulants (NOACs) with warfarin in patients with atrial fibrillation and concomitant CAD.Materials and methods: We performed a trial-level meta-analysis of CAD subgroups from four trials of NOAC versus warfarin in patients with atrial fibrillation, comparing the primary trial endpoints (efficacy: stroke or systemic embolic event; safety: International Society on Thrombosis and Haemostasis major bleeding) in patients with versus those without CAD, and used interaction testing to assess for treatment effect modification.Results: In total, 58,606 patients with established CAD were included in this meta-analysis. NOACs reduced the risk of stroke/systemic embolic event irrespective of presence of CAD (CAD: 0.76 (0.56–1.04); no CAD: hazard ratio 0.77 (0.56–1.06); p-INT 0.93). Similarly, there was no effect modification by presence of CAD for major bleeding (CAD: hazard ratio 0.92 (0.65–1.32), no CAD: 0.83 (0.61–1.12); p-INT 0.46) or myocardial infarction (CAD: hazard ratio 0.95 (0.62–1.44); no CAD: hazard ratio 0.95 (0.60–1.50); p-INT = 0.98). While NOACs reduced all-cause mortality in patients without CAD compared with warfarin (hazard ratio 0.85 (0.71–1.02)), there was no difference in mortality between NOACs and warfarin in the CAD group (hazard ratio 0.99 (0.82–1.20); p-INT 0.01).Conclusion: The present meta-analysis of four trials supports that NOACs are safe and at least as effective as warfarin in patients with atrial fibrillation and established CAD.

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.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Background: The relative efficacy and safety profile of the oral Factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation and established coronary artery disease (CAD) has not been analyzed.Materials and methods: In the ENGAGE AF–TIMI 48 trial, two edoxaban regimens were compared with warfarin in 21,105 patients with atrial fibrillation and CHADS2⩾2. We analyzed the primary trial endpoints (efficacy: stroke or systemic embolic event, safety: International Society on Thrombosis and Haemostasis major bleeding) in patients with versus without CAD, and used interaction testing to assess for treatment effect modification.Results: The 4510 patients (21.4%) with known CAD were older, more likely male, on aspirin, with lower creatinine clearance and higher CHADS2and HAS-BLED scores (p<0.001 for each). Treatment with the higher-dose edoxaban regimen (versus warfarin) in patients with known CAD tended to have a greater reduction in stroke/systemic embolic event compared with patients without CAD (CAD: hazard ratio 0.65 (0.46–0.92) versus no CAD: hazard ratio 0.94 (0.79–1.12), p-INT 0.062) and also in myocardial infarction (CAD: hazard ratio 0.69 (0.49–0.98) versus no CAD: hazard ratio 1.24 (0.89–1.72), p-INT 0.017), while there was a similar reduction in bleeding irrespective of CAD status (hazard ratio 0.81 and 0.80, p-INT 0.97). Presence or absence of CAD did not modify the efficacy or safety profile of the lower-dose edoxaban regimen (versus warfarin).Conclusion: The reduction in ischemic events with the higher-dose edoxaban regimen versus warfarin was greater in patients with CAD, while bleeding was significantly reduced with edoxaban regardless of CAD status. The efficacy and safety profile of the lower-dose edoxaban regimen relative to warfarin was unaffected by CAD status.

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.

Introduction:Adrenomedullin (ADM) is a free circulating peptide that regulates endothelial barrier function and vascular tone. Here, we sought to study the relationship of adrenomedullin in combination with lactate and the risk of death in patients with out-of-hospital cardiac arrest (OHCA) of non-traumatic origin.Methods:Mid-regional pro-ADM (MR-proADM) concentrations were measured in OHCA patients after successful ROSC on admission. The outcome of interest was all-cause death. Patients were characterized by quartiles (Q) of MR-proADM and lactate concentrations. Cox models were adjusted for age, sex, shockable rhythm, bystander resuscitation, and baseline eGFR.Results:A total of 232 patients were included in the present study (28% women, 67 years, SAPS II score 80). In total, 132 patients (56.9%) died, and 24 patients had an unfavorable neurologic outcome (i.e., a CPC score of 3-4). The median MR-proADM and lactate levels were 1.4 nmol/L (IQR 0.8 to 2.8 nmol/L) and 4.8 mmol/L (IQR 2.8 to 7.4 mmol/L), respectively. MR-proADM concentrations correlated weakly with lactate levels (r=0.23, P<0.001). High (Q4) versus low (Q1-Q3) MR-proADM concentration was associated with an increased rate of death at 28 days (45.4% vs. 75.9%; P<0.001; Fig A). After multivariable adjustment (including baseline lactate levels), higher MR-proADM levels were significantly associated with an increased risk of death (Q4 vs. Q1-Q3: adjusted HR 1.84, 95% CI 1.21 to 2.77; adjusted HR for 1 unit increase in standardized biomarker 1.55, 95% CI 1.28 to 1.86). The combination of high MR-proADM and high lactate (Q4) concentration identified patients at particularly elevated risk (adjusted HR 3.99; 95% CI 1.67-9.56; Fig B).Conclusions:Higher MR-proADM concentration are associated with an increased risk of death in patients with OHCA of non-traumatic origin. The combination of high MR-proADM and high lactate levels identifies patients at distinctly elevated risk.

Background:Patients with hypertrophic cardiomyopathy (HCM) frequently have diastolic dysfunction (DD) characterized by elevated filling pressures. Speckle-tracking analysis of the left atrium (LA) is an imaging tool for quantifying DD, however, its value in HCM is not well established.Methods.Transthoracic echocardiographic images of consecutive HCM patients with a septal thickness ≥15 mm and no aberrant loading conditions at an academic tertiary care center were evaluated. Peak atrial longitudinal strain (PALS) was determined by averaging the atrial strain over all segments in the 4- and 2-chamber views (Figure).Results.Among 205 HCM patients, 108 patients (52 years, 40% female) had sinus rhythm and sufficient image quality to be included. The median interventricular wall thickness was 20 mm (IQR 17-23), the relative wall thickness ratio was 0.65 mm (IQR 0.46-0.87), and the LV mass index was 164.0 g/m2(IQR 131.5-188.5). The mean PALS was 18.5% (± 8.8%) and did not differ between men and women. PALS significantly (all p <0.05) correlated with septal thickness (r=-0.31), LA volume index (r=-0.60), E/A ratio (r=-0.25), E/E’ (r=-0.63), systolic pulmonary pressure (r=-0.31), and high sensitivity troponin-T levels (r=-0.43). Moreover, PALS correlated with resting gradients in patients with relevant LV outflow tract obstruction (n=53 [49%]; r=-0.29). Among patients who underwent cardiac magnetic resonance imaging (81%), PALS was significantly correlated with LA ejection fraction (r=0.59) and late gadolinium enhancement of the total LV mass (r=-0.42). In addition, PALS was the only echocardiographic parameter reflecting DD that was significantly associated with the presence of LGE (Odds Ratio 0.93, 95%CI 0.88-0.99).Conclusion.PALS is a useful tool for quantifying DD in HCM patients and is associated with the presence of LGE. Future research will need to evaluate its significance in early identification of HCM patients at risk of sudden cardiac death.

Background:Aspirin is the most frequently used antiplatelet monotherapy for secondary prevention in patients with established ASCVD. Trials comparing monotherapy with a P2Y12i versus aspirin have shown variable results.Methods:Medline, Embase, & Cochrane Central databases were searched to identify RCTs comparing monotherapy with a P2Y12i versus aspirin for secondary prevention in patients with established ASCVD (ischemic stroke, coronary, or peripheral artery disease). The primary outcome of interest was major adverse cardiac events (MACE). Secondary outcomes were myocardial infarction (MI), stroke, all-cause mortality, & major bleeding. The DerSimonian and Laird random-effects model was used to calculate risk ratios (RR) & the corresponding 95% confidence interval (CI). Heterogeneity among studies was assessed using the Higgins I2value.Results:9 eligible RCTs (5 with clopidogrel & 4 with ticagrelor) with 62,336 patients were included in our analyses. Monotherapy with P2Y12i significantly reduced the risk of MACE by 11% (0.89, 95% CI 0.84 - 0.95, I2=0), & MI by 19% (0.81, 95% CI 0.71 - 0.92, I2=0) as compared with aspirin monotherapy (Figure). There was no significant difference in the risk of stroke (0.85, 95% CI 0.73-1.01), & all-cause mortality (1.01, 95% CI 0.92 - 1.11) between the 2 treatment groups. There was no significant difference in the risk of major bleeding with P2Y12i monotherapy as compared with aspirin (0.97, 95% CI 0.66 - 1.43, I2=0). Results were consistent irrespective of the P2Y12i.Conclusion:P2Y12i monotherapy is associated with a significant reduction in atherothrombotic events as compared with aspirin alone without an increased risk of major bleeding.

Introduction:Atrial fibrillation (AF) and atrial flutter (AFL) are associated with diabetes and its comorbidities including hypertension, obesity, and heart failure (HF). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) 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 (T2D). We therefore hypothesized that SGLT2i may reduce the risk of AF/AFL.Methods:DECLARE-TIMI 58 studied the efficacy and safety of the SGLT2i dapagliflozin in 17160 patients with T2D and either multiple risk factors for (MRF, n=10186) or known atherosclerotic cardiovascular disease (ASCVD, n=6974). Here, we explore the effect of dapagliflozin on the first and total number of AF/AFL events using Cox and negative binomial models, respectively. AF events were identified using a MedDRA preferred term search (?Atrial Fibrillation?, ?Atrial Flutter?) in the safety database.Results:Dapagliflozin reduced the risk of incident AF/AFL by 19% (264 versus 325 events; hazard ratio 0.81, 95% CI 0.68 to 0.95, P=0.009, Fig A). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (Prior AF/AFL (n=1116): HR 0.79, 95% CI 0.58 to 1.09, No AF/AFL: HR 0.81, 95% CI 0.67 to 0.98; P-INT 0.89). Similarly, presence of ASCVD (HR 0.78, 95% CI 0.62 to 0.99) versus MRF (HR 0.83, 95% CI 0.66 to 1.04; P-INT 0.72), or a history of HF (HF: HR 0.78, 95% CI 0.55 to 1.11, No HF: HR 0.81, 95% CI 0.68 to 0.97; P-INT 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Dapagliflozin also reduced the total number of AF/AFL events (337 versus 432; rate ratio 0.77, 95% CI 0.64 to 0.92, P=0.005; Fig B).Conclusions:Dapagliflozin appears to reduce both incident AF/AFL as well as the total number of AF/AFL events in patients with T2D. This effect was consistent regardless of the patients? prior history of AF, ASCVD, or HF.

Introduction:Dapagliflozin reduced the risk of the composite of cardiovascular death or hospitalization for heart failure (CVD/HHF) in patients (pts) with type 2 diabetes (T2D) in DECLARE-TIMI 58. We hypothesized that cardiac biomarkers may help to identify pts who are at higher baseline risk and thus may benefit more from treatment with SGLT2i.Aim:To evaluate the association of baseline hsTnT and NT-proBNP levels with CVD/HHF and with the magnitude of benefit with dapagliflozin.Methods:This was a prespecified biomarker study from DECLARETIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin in pts with. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Biomarker Core Laboratory in 14,565 pts (median follow-up 4.2 y). Patients were stratified by baseline biomarker levels. Relative risk ratios using hazard ratios and absolute risk reductions using Kaplan-Meier event rates at 4 years with dapagliflozin were calculated for CVD/HHF within biomarker quartiles.Results:The median baseline NT-proBNP and hsTnT levels were 75 pg/mL (IQR 35-165) and 10.2 pg/mL (IQR 6.9-15.5), respectively. Patients with higher levels of NT-proBNP and hsTnT had higher KM event rates of CVD/HHF (Q4 vs Q1: NT-proBNP: 13.7% vs 1.0%; hsTnT: 11.8% vs 1.4%; P-trend <0.001). Dapagliflozin consistently reduced the relative risk of CVD/HHF regardless of baseline NT-proBNP (P INT 0.72) or hsTnT quartiles (P INT 0.93). However, given their higher baseline risk, pts with elevated levels of NT-proBNP and/or hsTnT tended to derive even greater absolute risk reduction with dapagliflozin [ARR in Q4 for NT-proBNP 2.9% (NNT 35); hsTnT 2.4% (NNT 42)] [Figure].Conclusions:Patients with higher NT-proBNP or hsTnT levels are at increased risk of CV death and HHF. Dapagliflozin reduced the risk of CV death/HHF irrespective of NT-proBNP and hsTnT levels, with greater absolute risk reductions seen in pts with higher baseline biomarker levels.

Introduction:Sodium glucose transporter 2 inhibitors (SGLT2i) reduce the risk of major adverse cardiovascular events (MACE), including myocardial infarction (MI), in patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD). In DECLARE-TIMI 58, this benefit was seen in patients with ASCVD and particularly in those ones with prior MI. The effect of SGLT2i in reducing MIs of different types and sizes has not previously been reported.Hypothesis:In patients with T2DM and prior MI, dapagliflozin consistently reduces recurrent MI events across a range of infarct types & sizes.Methods:This was a pre-specified sub-analysis from DECLARE-TIMI 58, which randomized 17,160 patients with T2DM to dapagliflozin 10 mg vs. placebo, of whom, 3584 had a history of prior MI at enrollment. All MI events were prospectively adjudicated and classified according to: (1) Universal Definition types 1-5, (2) the presenting electrocardiogram (STEMI vs. NSTEMI), and (3) size based on peak troponin [as multiples of the upper limit of normal (ULN)]. Cox proportional hazards model was used to generate HR and 95 % CI.Results:From the total incident MIs (489) in patients with prior MI from DECLARE-TIMI 58, 316 (65%) were type 1 MIs and 403 (82%) were NSTEMI. From those with biomarkers available (456), 241 (53%) had peak troponin ? 10 X ULN. Besides reducing recurrent MI (HR 0.78; 95 % CI 0.63-0.95; p = 0.016), dapagliflozin appeared to favorably affect the risk of both type 1 (HR 0.80; 95 % CI 0.63-1.02) and type 2 (HR 0.64; 95 % CI 0.42-0.97) MIs. There also appeared to be a favorable reduction across all ranges of infarct sizes based on peak troponin (Figure).Conclusions:In patients with T2DM and prior MI, dapagliflozin consistently reduced recurrent MI across the spectrum of different infarct sizes and types, including those ones caused by a myocardial oxygen supply/demand mismatch. The mechanisms that explain reductions in MI with SGLT2i remain to be determined.

Background:We previously observed early aspirin (ASA) use after orthotopic heart transplantation (OHT) to be associated with lower rates of moderate to severe cardiac allograft vasculopathy (CAV). Antibody-mediated rejection (AMR) and acute cellular rejection (ACR) are important risk factors for CAV. As ASA has anti-inflammatory and antithrombotic actions, we hypothesized that the inverse association between ASA use and CAV incidence may be most pronounced in patients with allograft rejection.Methods:Patients receiving OHT at a single center (N=120) were categorized by the presence of early ASA use post-transplant (ASA treatment >6 months in the first year) and the presence of ACR and/or AMR during 5-year follow-up. Propensity scores for ASA treatment were estimated using boosting models and applied by inverse probability of treatment weighting. The association between ASA use and time to angiographic moderate/severe CAV (International Society for Heart and Lung Transplantation grade ? 2) was investigated and interaction tested with rejection status.Results:Patients with rejection (N=77) were younger and less likely hypertensive with no imbalance in aspirin use. Patients with both AMR and ACR had higher rates of CAV >2 at 5 years than those with either isolated AMR or ACR or no rejection (24.0 vs 14.9 v 5.3%; ptrend=0.028). Among patients with rejection, ASA therapy was associated with significantly lower rates of CAV >2 (3.3 vs 30.1%; p=0.001; HRadj0.07; 95% CI 0.01-0.52; Fig.), whereas ASA therapy was not associated with lower rates of CAV in patients with no rejection (5.6 vs 5.3%; p=0.900; pinteraction=0.094).Conclusions:Early ASA use after OHT was associated with lower rates of moderate to severe CAV among patients with allograft rejection. This observation supports the need for a prospective randomized evaluation of ASA therapy after heart transplantation.