Risk Assessment of Kidney Disease Progression and Efficacy of SGLT2 Inhibition in Patients With Type 2 Diabetes.

OBJECTIVE: To develop a risk assessment tool to identify patients with type 2 diabetes (T2D) at higher risk for kidney disease progression and who might benefit more from sodium-glucose cotransporter 2 (SGLT2) inhibition. RESEARCH DESIGN AND METHODS: A total of 41,204 patients with T2D from four Thrombolysis In Myocardial Infarction (TIMI) clinical trials were divided into derivation (70%) and validation cohorts (30%). Candidate predictors of kidney disease progression (composite of sustained ≥40% decline in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney death) were selected with multivariable Cox regression. Efficacy of dapagliflozin was assessed by risk categories (low: <0.5%; intermediate: 0.5 to <2%; high: ≥2%) in Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58. RESULTS: There were 695 events over a median follow-up of 2.4 years. The final model comprised eight independent predictors of kidney disease progression: atherosclerotic cardiovascular disease, heart failure, systolic blood pressure, T2D duration, glycated hemoglobin, eGFR, urine albumin-to-creatinine ratio, and hemoglobin. The c-indices were 0.798 (95% CI, 0.774-0.821) and 0.798 (95% CI, 0.765-0.831) in the derivation and validation cohort, respectively. The calibration plot slope (deciles of predicted vs. observed risk) was 0.98 (95% CI, 0.93-1.04) in the validation cohort. Whereas relative risk reductions with dapagliflozin did not differ across risk categories, there was greater absolute risk reduction in patients with higher baseline risk, with a 3.5% absolute risk reduction in kidney disease progression at 4 years in the highest risk group (≥1%/year). Results were similar with the 2022 Chronic Kidney Disease Prognosis Consortium risk prediction model. CONCLUSIONS: Risk models for kidney disease progression can be applied in patients with T2D to stratify risk and identify those who experience a greater magnitude of benefit from SGLT2 inhibition.

Assessment of Atherothrombotic Risk in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Risk of atherothrombotic events is not uniform in patients with type 2 diabetes mellitus (T2DM). Tailored risk assessment may help guide selection of pharmacotherapies for cardiovascular primary and secondary prevention. OBJECTIVES: The purpose of this study was to develop a risk model for atherothrombosis in patients with T2DM. METHODS: We developed and validated a risk model for myocardial infarction (MI) or ischemic stroke (IS) in a pooled cohort of 42,181 patients with T2DM from 4 TIMI (Thrombolysis In Myocardial Infarction) clinical trial cohorts. Candidate variables were assessed with multivariable Cox regression, and independent variables (P < 0.05) were retained in the final model. Discrimination and calibration were assessed. Treatment interactions with dapagliflozin (sodium-glucose cotransporter-2 inhibitor) and evolocumab (proprotein convertase subtilisin/kexin type 9 inhibitor) were explored in the DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis In Myocardial Infarction 58) and FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trials, respectively. RESULTS: Sixteen variables were independent predictors of MI or IS. The model identified a >8-fold gradient of MI or IS rates between the top vs bottom risk quintiles in the validation cohort (3-year Kaplan-Meier rate: 14.9% vs 1.4%; P < 0.0001). C-indexes were 0.704 and 0.706 in the derivation and validation cohorts, respectively. The model was well-calibrated in both primary and secondary prevention. Absolute reduction in the rates of MI or IS tended to be greater in patients with higher baseline predicted risk for both dapagliflozin (absolute risk reduction: 2.1% vs 0.2%) and evolocumab (absolute risk reduction: 3.2% vs 1.0%). CONCLUSIONS: We developed and validated a risk score for atherothrombotic events, leveraging 16 routinely assessed clinical variables in patients with T2DM. The score has the potential to improve risk assessment and inform clinical decision-making.

Race and Sex Differences in Management and Outcomes of Patients After ST-Elevation and Non-ST-Elevation Myocardial Infarct: Results From the NCDR.

BACKGROUND: Race and sex have been shown to affect management of myocardial infarction (MI); however, it is unclear if such disparities exist in contemporary care of ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI). HYPOTHESIS: Disparities in care will be less prevalent in more heavily protocol-driven management of STEMI than the less algorithmic care of NSTEMI. METHODS: Data were collected from the ACTION Registry-GWTG database to assess care differences related to race and sex of patients presenting with NSTEMI or STEMI. For key treatments and outcomes, adjustments were made including patient demographics, baseline comorbidities, and markers of socioeconomic status. RESULTS: Key demographic variables demonstrate significant differences in baseline comorbidities; black patients had higher incidences of hypertension and diabetes, and women more frequently had diabetes. With few exceptions, rates of acute and discharge medical therapy were similar by race in any sex category in both STEMI and NSTEMI populations. Rates of catheterization were similar by race for STEMI but not for NSTEMI, where both black men and women had lower rates of invasive therapy. Rates of revascularization were significantly lower for black patients in both the STEMI and NSTEMI groups regardless of sex. Rates of adverse events differed by sex, with disparities for death and major bleeding; after adjustment, rates were similar by race within sex comparisons. CONCLUSIONS: In this contemporary cohort, although there are differences by race in presentation and management of MI, heavily protocol-driven processes seem to show fewer racial disparities.

Coronary CT angiography versus standard evaluation in acute chest pain.

BACKGROUND: It is unclear whether an evaluation incorporating coronary computed tomographic angiography (CCTA) is more effective than standard evaluation in the emergency department in patients with symptoms suggestive of acute coronary syndromes. METHODS: In this multicenter trial, we randomly assigned patients 40 to 74 years of age with symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic changes or an initial positive troponin test to early CCTA or to standard evaluation in the emergency department on weekdays during daylight hours between April 2010 and January 2012. The primary end point was length of stay in the hospital. Secondary end points included rates of discharge from the emergency department, major adverse cardiovascular events at 28 days, and cumulative costs. Safety end points were undetected acute coronary syndromes. RESULTS: The rate of acute coronary syndromes among 1000 patients with a mean (±SD) age of 54±8 years (47% women) was 8%. After early CCTA, as compared with standard evaluation, the mean length of stay in the hospital was reduced by 7.6 hours (P<0.001) and more patients were discharged directly from the emergency department (47% vs. 12%, P<0.001). There were no undetected acute coronary syndromes and no significant differences in major adverse cardiovascular events at 28 days. After CCTA, there was more downstream testing and higher radiation exposure. The cumulative mean cost of care was similar in the CCTA group and the standard-evaluation group ($4,289 and $4,060, respectively; P=0.65). CONCLUSIONS: In patients in the emergency department with symptoms suggestive of acute coronary syndromes, incorporating CCTA into a triage strategy improved the efficiency of clinical decision making, as compared with a standard evaluation in the emergency department, but it resulted in an increase in downstream testing and radiation exposure with no decrease in the overall costs of care. (Funded by the National Heart, Lung, and Blood Institute; ROMICAT-II ClinicalTrials.gov number, NCT01084239.).

Safety and efficacy of prasugrel compared with clopidogrel in different regions of the world.

BACKGROUND: Among patients with acute coronary syndrome (ACS), demographics, procedural characteristics and adjunctive medications differ globally. We examined whether there were differential effects of prasugrel compared with clopidogrel in the multinational TRITON-TIMI 38 study. METHODS: We divided the enrollment into 5 pre-specified geographic regions. Patients were randomized to prasugrel or clopidogrel without regard to country of enrollment. End points are expressed as Kaplan-Meier failure estimates through 15 months. Heterogeneity was evaluated using Cox proportional hazards model. Additional sensitivity analyses were performed by dividing countries into categories based on the Human Development Index (HDI), which is a composite measure of social and economic development. RESULTS: 13,608 patients were enrolled. Clinical characteristics including age, comorbidities, ACS presentation, stent types, and adjunctive medications differed broadly among regions. Despite these differences, no regional heterogeneity was observed with prasugrel compared to clopidogrel in the reduction of ischemic events (HR range: 0.76-0.87, p(interaction)>0.10 for each) and stent thrombosis (HR range: 0.34-0.72, p(interaction)>0.10 for each) or in the increased rate of non-CABG TIMI major bleeding (HR range: 1.16-1.76, p(interaction)>0.10 for each). There was a consistent trend in net clinical benefit (all cause death/MI/stroke/non-CABG TIMI major bleeding) favoring prasugrel (HR range: 0.81-0.97, p(interaction)>0.10 for each). Consistent results were also observed regarding the safety and efficacy of prasugrel compared with clopidogrel in both developed and developing countries. CONCLUSIONS: Despite differences in patient demographics, procedural techniques and adjunctive medications, consistent reduction in ischemic events and increased bleeding were seen with prasugrel compared with clopidogrel throughout the world.

Assessment of adiponectin and the risk of recurrent cardiovascular events in patients presenting with an acute coronary syndrome: observations from the Pravastatin Or atorVastatin Evaluation and Infection Trial-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22).

BACKGROUND: Adiponectin, an adipocytokine, is secreted by fatty cells and exerts a regulatory role in atherogenesis, modulating foam cell formation and cellular adhesion. In stable atherosclerosis, plasma adiponectin has been reported to be associated with both increased and decreased cardiovascular risk. Recent data have suggested a possible discordant adverse risk relationship in acute coronary syndrome (ACS). Therefore, we investigated the association between adiponectin and cardiovascular events in patients with ACS. METHODS: We measured plasma adiponectin in 3,931 patients stabilized following ACS and assessed the relationship with 2-year outcome. Patients were followed for all-cause death and major cardiovascular events. Using multivariable Cox regression, we adjusted for age, sex, race, ACS type, diabetes, smoking status, triglycerides, blood pressure, body mass index, estimated glomerular filtration rate, treatment group (atorvastatin), B-type natriuretic peptide, and C-reactive protein. RESULTS: Adiponectin correlated negatively with age, diabetes, body mass index, and triglycerides (each, P < .001) but showed a positive relationship with the risk of death (P = .01), myocardial infarction (P = .01), and heart failure (P < .001). After adjusting for clinical risk factors, B-type natriuretic peptide, and C-reactive protein, adiponectin greater than the median (4,477 ng/mL) was independently associated with an increased risk of death or myocardial infarction (hazard ratio 1.58, 95% CI 1.10-2.28, P = .013) and congestive heart failure (hazard ratio 2.17, 95% CI 1.21-3.89, P = .010). CONCLUSIONS: Higher adiponectin concentrations early after ACS are independently associated with a higher risk of recurrent cardiovascular events. This finding is directionally opposite to that observed in patients at risk for atherosclerosis and reveals the need for investigation to elucidate differences in the pathobiology of adiponectin in stable versus unstable coronary artery disease.

Streptokinase and enoxaparin as an alternative to fibrin-specific lytic-based regimens: an ExTRACT-TIMI 25 analysis.

BACKGROUND: Enoxaparin was superior to unfractionated heparin (UFH), regardless of fibrinolytic agent in ST-elevation myocardial infarction (STEMI) patients receiving fibrinolytic therapy in ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment - Thrombolysis in Myocardial Infarction 25) trial. OBJECTIVE: This post hoc analysis compared outcomes with streptokinase plus enoxaparin to the standard regimen of fibrin-specific lytic (FSL) plus UFH and to the newer combination of FSL plus enoxaparin. METHODS: In ExTRACT-TIMI 25, STEMI patients received either streptokinase or a FSL (alteplase, reteplase or tenecteplase) at the physician's discretion and were randomized to enoxaparin or UFH, stratified by fibrinolytic type. Thirty-day outcomes were adjusted for baseline characteristics, region, in-hospital percutaneous coronary intervention (PCI) and a propensity score for the choice of lytic. RESULTS: The primary trial endpoint of 30-day death/myocardial infarction (MI) occurred in fewer patients in the streptokinase-enoxaparin cohort (n = 2083) compared with FSL-UFH (n = 8141) [10.2% vs 12.0%, adjusted odds ratio [OR(adj)] 0.76; 95% CI 0.62, 0.93; p = 0.008]. Major bleeding was significantly increased with streptokinase-enoxaparin compared with FSL-UFH (OR(adj) 2.74; 95% CI 1.81; 4.14; p < 0.001) but intracranial haemorrhage (ICH) was similar (OR(adj) 0.90; 95% CI 0.40, 2.01; p = 0.79). Net clinical outcomes, defined as either death/MI/major bleeding or as death/MI/ICH tended to favour streptokinase-enoxaparin compared with FSL-UFH (OR(adj) 0.88; 95% CI 0.73, 1.06; p = 0.17; and OR(adj) 0.77; 95% CI 0.63, 0.93; p = 0.008, respectively). Patients receiving FSL-enoxaparin (n = 8142) and streptokinase-enoxaparin therapies experienced similar adjusted rates of the primary endpoint (OR(adj) 1.08; 95% CI 0.87, 1.32; p = 0.49) and net clinical outcomes. CONCLUSIONS: Our results suggest that fibrinolytic therapy with the combination of streptokinase and the potent anticoagulant agent enoxaparin resulted in similar adjusted outcomes compared with more costly regimens utilizing a FSL.

Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial.

AIMS: To examine the extent of platelet inhibition by prasugrel vs. clopidogrel in a TRITON-TIMI 38 substudy. METHODS AND RESULTS: TRITON-TIMI 38 randomized acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) to prasugrel or standard dose clopidogrel. Selected sites prospectively enrolled TRITON-TIMI 38 patients to evaluate adenosine diphosphate (ADP)-attenuated phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) (n = 125 patients) and, in a subset (n = 31 patients), ADP-stimulated platelet aggregation. VASP platelet reactivity index (PRI) was lower in prasugrel-treated patients than in clopidogrel-treated patients at 1-2 h post-PCI (>or=1 h after loading dose) (P < 0.001) and at 30 days (P < 0.001). Maximal platelet aggregation to 20 microM ADP was lower in prasugrel-treated patients than in clopidogrel-treated patients at 1-2 h (P = 0.004) and 30 days (P = 0.03). Results were similar with 5 microM ADP. Thienopyridine hyporesponsiveness, prespecified as VASP PRI >50%, was more frequent in clopidogrel-treated patients than in prasugrel-treated patients at 1-2 h (P < 0.001) and 30 days (P = 0.03). CONCLUSIONS: The TRITON-TIMI 38 platelet substudy shows that prasugrel results in greater inhibition of ADP-mediated platelet function in ACS patients than clopidogrel, supporting the hypothesis that greater platelet inhibition leads to a lower incidence of ischaemic events and more bleeding both early and late following PCI.

Differential expression of cardiac biomarkers by gender in patients with unstable angina/non-ST-elevation myocardial infarction: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18) substudy.

BACKGROUND: Diagnosis of coronary artery disease in women is more difficult because of lower specificity of symptoms and diagnostic accuracy of noninvasive testing. We sought to examine the relationship between gender and cardiac biomarkers in patients with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI). METHODS AND RESULTS: In the TACTICS-TIMI 18, OPUS-TIMI 16, and TIMI 11 studies, baseline samples were analyzed in the Thrombolysis In Myocardial Infarction (TIMI) biomarker core laboratory. We examined the relationship between gender and elevated biomarkers. Of 1865 patients from TACTICS-TIMI 18, 34% were women. Fewer women had elevated creatine kinase-MB or troponins, whereas more had elevated high-sensitivity C-reactive protein or brain natriuretic peptide. Presence of ST-segment deviation and TIMI risk scores were not significantly different. This pattern was confirmed in TIMI 11 and OPUS-TIMI 16. The prognostic value of the markers in TACTICS-TIMI 18 was similar in women and men. When a multimarker approach was examined, a greater proportion of high-risk women were identified. Marker-positive patients of both genders had improved outcome with an invasive strategy; however, marker-negative women appeared to have improved outcomes with a conservative strategy. CONCLUSIONS: In patients with UA/NSTEMI, there was a different pattern of presenting biomarkers. Men were more likely to have elevated creatine kinase-MB and troponins, whereas women were more likely to have elevated C-reactive protein and brain natriuretic peptide. This suggests that a multimarker approach may aid the initial risk assessment of UA/NSTEMI, especially in women. Further research is necessary to elucidate whether gender-related pathophysiological differences exist in presentation with acute coronary syndromes.