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Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.

Background: Metformin and sulfonylureas are frequently prescribed to patients with diabetes for glycemic control. The impact of these drugs on cardiovascular outcomes among patients with heart failure (HF) and diabetes is unclear. Methods: We evaluated Medicare beneficiaries hospitalized for HF in the Get With The Guidelines-HF Registry between 2006 and 2014 who had diabetes and Part D prescription coverage (n=29,181). Patients with glomerular filtration rate 2 or prescribed metformin or sulfonylurea prior to admission were excluded. In separate analyses for metformin and sulfonylurea, patients filling new prescriptions for each therapy within 90 days of discharge were compared with patients not prescribed therapy. Multivariable models landmarked at 90 days evaluated associations between therapy and mortality and hospitalization for HF (HHF) outcomes over the following 12 months. Secondary analyses were stratified by ejection fraction (EF) ≤40% vs >40%. Results: Of 5,852 patients, 454 (7.8%) were newly prescribed metformin and 504 (8.6%) were newly prescribed sulfonylurea. After adjustment, metformin prescription was associated with reduced risk of composite mortality/HHF, but not individual components (Table) . Associations with mortality/HHF and HHF endpoints were driven by reduced risk among patients with EF>40% (all p for interaction ≤0.04). Sulfonylurea prescription was independently associated with increased risk of mortality, HHF, and the composite. Associations between sulfonylurea prescription and endpoints were consistent regardless of EF (all p for interaction >0.12). Conclusion: Among US patients hospitalized for HF with comorbid diabetes, initiation of metformin was independently associated with improved clinical outcomes, driven by improvements among patients with preserved EF. In contrast, sulfonylurea initiation was associated with adverse clinical outcomes regardless of EF.

Introduction: Coronary Computed Tomography Angiography (CCTA) and SPECT myocardial perfusion imaging (SPECT-MPI) are equally safe in evaluating patients presenting to the emergency department with acute chest pain. However, no study has compared the use of CCTA with Fractional Flow Reserve (FFR-CT) to SPECT-MPI in a chest pain observation unit (OU). We compared the performance of CCTA (with FFR-CT as needed) to SPECT-MPI for change in coronary artery disease (CAD) specific treatment (statins, antianginals, antiplatelets, and coronary revascularization) as well its impact on length of hospital stay (LOS). Methods: In 2020, our institution implemented an algorithm-based protocol in the OU to select patients appropriate for CCTA with explicit guidelines for management based on the results. We performed a retrospective analysis of 105 patients (52 SPECT-MPI patients from the period prior to initiation of the OU CCTA protocol who met criteria for CCTA, and 53 CCTA patients after CCTA protocol initiation). We performed two-tailed t-tests and chi-squared analyses to compare changes in treatment and LOS in both groups. Results: Patients in the CCTA group were younger (61 vs. 67 years, p=0.007), but there were no significant differences in CAD risk factors amongst the two groups. CCTA led to significant increase in statin, antianginal, and antiplatelet therapies, cardiac catheterization and revascularization within 6 months. There was no increase in LOS. Finally, CCTA did not increase acute kidney injury at follow up (Table 1). Conclusion: CCTA with FFR-CT significantly improved patient care by increasing appropriate preventative CAD treatment compared to SPECT-MPI while increasing the rate of revascularization without compromising length of stay or kidney function. In conclusion, protocol-based use of CCTA with FFR-CT is a more effective tool when compared to SPECT-MPI for chest pain patients admitted to the OU.

The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.

Background: The effect of menopausal status on the risk factors of cardiovascular (CV) disease is not well ascertained. We aimed to evaluate the impact of menopause on several traditional and non-traditional cardiovascular (CV) risk factors. Methods: The CARTaGENE study was a prospective cohort study with random sampling of individuals in Quebec, Canada. We completed a seven-year follow-up in 2016. For this analysis, we included only subjects without prior cardiovascular (CV) events (CVE) or CV interventions (CVI). We defined the primary endpoint as CVE which can be any of the following events: acute coronary syndromes, heart failure, strokes, CV deaths, and peripheral vascular events. The secondary endpoint was CVI which included coronary, carotid, or peripheral artery revascularization. We used Cox proportional hazard stepwise multivariate analyses to identify independent predictors of the primary endpoint separately in pre- and post-menopausal women. Results Of 9,529 women without prior CV disease, 57% were post-menopausal. The mean age was 47.4 years and 58.6 years for pre-menopausal and post-menopausal women, respectively. There were 793 CVEs and 83 CVIs with a median time to event of 6.6 years. Hypertension, active smoking, increased waist to hip ratio, and glycosylated hemoglobin were independent predictors of the primary endpoint in both pre- and post-menopausal women. Furthermore, advanced age, family history of myocardial infarction, prior cancer, increased gamma-glutamyl transferase, and hyperuricemia also predicted increased riks of the primary endpoint in post-menopausal women. Conclusion: Hypertension, active smoking, increased waist to hip ratio, and high glycosylated hemoglobin were associated with increased CV risk in pre-menopausal women. The impact of hypertension was markedly amplified in pre-menopausal women compared to postmenopausal women. Intensive blood pressure control should be considered in pre-menopausal women.

Background: Patients with type 2 diabetes mellitus (T2DM) are at an increased risk for developing heart failure (HF), and clinical models are needed to identify patients with a greater risk for HF hospitalization (HHF). The Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (TRS-HFDM) was recently developed and validated to predict HHF in patients with T2DM in two large clinical trials (SAVOR-TIMI 53 and DECLARE-TIMI 58). We aimed to validate the TRS-HFDM in another cohort of patients with T2DM. Methods: We validated the TRS-HFDM score in 5,123 patients with T2DM for fatal or non-fatal HHF in the placebo arm of the ACCORD (Action to Control Cardiovascular Risk in Diabetes Study Group). The TRS-HFDM included: prior HF, history of atrial fibrillation, coronary artery disease, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. We evaluated discrimination with the Harrell C index, and calibration by comparing observed event rates for HHF with predicted risk, and the Nam-D’Agostino statistic. Results: During a mean follow up of 4.8 years, 212 patients (4.14%) experienced at least one HHF. The mean age was 63 ±6.7 years, and 38% were female. The baseline hemoglobin A1C was 8.3%, and 36% were on insulin. The ACCORD patients had less comorbidities with a lower proportion of patients with renal dysfunction (8% vs. 16% vs. 17%), established cardiovascular disease (35% vs.79% vs. 41%) and pre-existing HF (5% vs. 13% vs. 10%) compared to patients enrolled in the SAVOR-TIMI 53 and DECLARE TIMI-58 trials respectively. In our cohort, the TRS-HFDM score predicted well HHF events with a Harrel C index of 0.78. The integer-based score was well calibrated, with the observed Kaplan-Meier HHF rates closely predicting the Kaplan-Meier event rates at the end follow up (Nam D`Agostino test: 65.39 (p Discussion: Our findings confirm the applicability of the TRS-HFDM in a large cohort of patients with T2DM with less high-risk features than the SAVOR-TIMI 53 and DECLARE-TIMI 58 populations. Future validation of this risk score in observational cohort studies is needed to evaluate its external validity in a general clinical setting.

Background: Atrial fibrillation is associated with an increased risk of death. High-sensitivity troponin T, growth differentiation factor-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and interleukin-6 levels are predictive of cardiovascular events and total cardiovascular death in anticoagulated patients with atrial fibrillation. The prognostic utility of these biomarkers for cause-specific death is unknown. Methods: The ARISTOTLE trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients (1.9 years median follow-up). Cox models were used to identify clinical variables and biomarkers independently associated with each specific cause of death. Results: In total, 1272 patients died: 652 (51%) cardiovascular, 32 (3%) bleeding, and 588 (46%) noncardiovascular/nonbleeding deaths. Among cardiovascular deaths, 255 (39%) were sudden cardiac deaths, 168 (26%) heart failure deaths, and 106 (16%) stroke/systemic embolism deaths. Biomarkers were the strongest predictors of cause-specific death: a doubling of troponin T was most strongly associated with sudden death (hazard ratio [HR], 1.48; P P P =0.028). Prior stroke/systemic embolism (HR, 2.58; P >0.001) followed by troponin T (HR, 1.45; P Conclusions: Biomarkers were some of the strongest predictors of cause-specific death and may improve the ability to discriminate among patients’ risks for different causes of death. These data suggest a potential role of biomarkers for the identification of patients at risk for different causes of death in patients anticoagulated for atrial fibrillation. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00412984.

Atrial fibrillation is associated with an increased risk of death. High-sensitivity troponin T, growth differentiation factor-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and interleukin-6 levels are predictive of cardiovascular events and total cardiovascular death in anticoagulated patients with atrial fibrillation. The prognostic utility of these biomarkers for cause-specific death is unknown.The ARISTOTLE trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients (1.9 years median follow-up). Cox models were used to identify clinical variables and biomarkers independently associated with each specific cause of death.In total, 1272 patients died: 652 (51%) cardiovascular, 32 (3%) bleeding, and 588 (46%) noncardiovascular/nonbleeding deaths. Among cardiovascular deaths, 255 (39%) were sudden cardiac deaths, 168 (26%) heart failure deaths, and 106 (16%) stroke/systemic embolism deaths. Biomarkers were the strongest predictors of cause-specific death: a doubling of troponin T was most strongly associated with sudden death (hazard ratio [HR], 1.48; P0.001), NT-proBNP with heart failure death (HR, 1.62; P0.001), and growth differentiation factor-15 with bleeding death (HR, 1.72; P=0.028). Prior stroke/systemic embolism (HR, 2.58; P0.001) followed by troponin T (HR, 1.45; P0.0029) were the most predictive for stroke/ systemic embolism death. Adding all biomarkers to clinical variables improved discrimination for each cause-specific death.Biomarkers were some of the strongest predictors of cause-specific death and may improve the ability to discriminate among patients' risks for different causes of death. These data suggest a potential role of biomarkers for the identification of patients at risk for different causes of death in patients anticoagulated for atrial fibrillation.URL: https://www.clinicaltrials.gov . Unique identifier: NCT00412984.