Patient selection for long-term secondary prevention with ticagrelor: insights from PEGASUS-TIMI 54.

AIM: In patients with prior myocardial infarction (MI) on aspirin, the addition of ticagrelor reduces ischaemic risk but increases bleeding risk. The simultaneous assessment of baseline ischaemic and bleeding risk may assist clinicians in selecting patients who are most likely to have a favourable risk/benefit profile with long-term ticagrelor. METHODS AND RESULTS: PEGASUS-TIMI 54 randomized 21 162 prior MI patients, 13 956 of which to the approved 60 mg dose or placebo and who had all necessary data. The primary efficacy endpoint was cardiovascular death, MI, or stroke, and the primary safety outcome was TIMI major bleeding; differences in Kaplan-Meier event rates at 3 years are presented. Post-hoc subgroups based on predictors of bleeding and ischaemic risk were merged into a selection algorithm. Patients were divided into four groups: those with a bleeding predictor (n = 2721, 19%) and then those without a bleeding predictor and either 0-1 ischaemic risk factor (IRF; n = 3004, 22%), 2 IRF (n = 4903, 35%), or ≥3 IRF (n = 3328, 24%). In patients at high bleeding risk, ticagrelor increased bleeding [absolute risk difference (ARD) +2.3%, 95% confidence interval (CI) 0.6, 3.9] and did not reduce the primary efficacy endpoint (ARD +0.08%, 95% CI -2.4 to 2.5). In patients at low bleeding risk, the ARDs in the primary efficacy endpoint with ticagrelor were -0.5% (-2.2, 1.3), -1.5% (-3.1, 0.02), and -2.6% (-5.0, -0.24, P = 0.03) in those with ≤1, 2, and 3 risk factors, respectively (P = 0.076 for trend across groups). There were significant trends for greater absolute risk reductions for cardiovascular death (P-trend 0.018), all-cause mortality (P-trend 0.027), and net outcomes (P-trend 0.037) with ticagrelor across these risk groups. CONCLUSION: In a post-hoc exploratory analysis of patients with prior MI, long-term ticagrelor therapy appears to be best suited for those with prior MI with multiple IRFs at low bleeding risk. CLINICAL TRIAL REGISTRATION: NCT01225562 ClinicalTrials.gov.

Technology-Enabled Clinical Trials: Transforming Medical Evidence Generation.

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.

Grenada Heart Project-Community Health ActioN to EncouraGe healthy BEhaviors (GHP-CHANGE): A randomized control peer group-based lifestyle intervention.

BACKGROUND: The incidence of cardiovascular (CV) risk factors is increasing globally, with a disproportionate burden in the low and low-middle income countries (L/LMICs). Peer support, as a low-cost lifestyle intervention, has succeeded in managing chronic illness. For global CV risk reduction, limited data exists in LMICs. AIM: The GHP-CHANGE was designed as a community-based randomized trial to test the effectiveness of peer support strategy for CV risk reduction in the island of Grenada, a LMIC. METHODS: We recruited 402 adults from the Grenada Heart Project (GHP) Cohort Study of 2827 subjects with at least two CV risk factors. Subjects were randomized in a 1:1 fashion to a peer-group based intervention group (n = 206) or a self-management control group (n = 196) for 12 months. The primary outcome was the change from baseline in a composite score related to Blood pressure, Exercise, Weight, Alimentation and Tobacco (FBS, Fuster-BEWAT Score), ranging from 0 to 15 (ideal health = 15). Linear mixed-effects models were used to test for intervention effects. RESULTS: Participants mean age was 51.4 years (SD 14.5) years, two-thirds were female, and baseline mean FBS was 8.9 (SD 2.6) and 8.5 (SD 2.6) in the intervention and control group, respectively (P = .152). At post intervention, the mean FBS was higher in the intervention group compared to the control group [9.1 (SD 2.7) vs 8.5 (SD 2.6), P = .028]. When balancing baseline health profile, the between-group difference (intervention vs. control) in the change of FBS was 0.31 points (95% CI: -0.12 to 0.75; P = .154). CONCLUSIONS: The GHP-CHANGE trial showed that a peer-support lifestyle intervention program was feasible; however, it did not demonstrate a significant improvement in the FBS as compared to the control group. Further studies should assess the effects of low-cost lifestyle interventions in LMICs.

Use of prasugrel and clinical outcomes in African-American patients treated with percutaneous coronary intervention for acute coronary syndromes.

OBJECTIVE: To investigate the use of prasugrel after percutaneous coronary intervention (PCI) in African American (AA) patients presenting with acute coronary syndrome (ACS). BACKGROUND: AA patients are at higher risk for adverse cardiovascular outcomes after PCI and may derive greater benefit from the use of potent antiplatelet therapy. METHODS: Using the multicenter PROMETHEUS observational registry of ACS patients treated with PCI, we grouped patients by self-reported AA or other races. Clinical outcomes at 90-day and 1-year included non-fatal myocardial infarction (MI), major adverse cardiac events (composite of death, MI, stroke, or unplanned revascularization) and major bleeding. RESULTS: The study population included 2,125 (11%) AA and 17,707 (89%) non-AA patients. AA patients were younger, more often female (46% vs. 30%) with a higher prevalence of diabetes mellitus, chronic kidney disease, and prior coronary intervention than non-AA patients. Although AA patients more often presented with troponin (+) ACS, prasugrel use was much less common in AA vs. non-AA (11.9% vs. 21.4%, respectively, P = 0.001). In addition, the use of prasugrel increased with the severity of presentation in non-AA but not in AA patients. Multivariable logistic regression showed AA race was an independent predictor of reduced use of prasugrel (0.42 [0.37-0.49], P < 0.0001). AA race was independently associated with a significantly higher risk of MI at 90-days and 1 year after PCI. CONCLUSIONS: Despite higher risk clinical presentation and worse 1-year ischemic outcomes, AA race was an independent predictor of lower prasugrel prescription in a contemporary population of ACS patients undergoing PCI.

Long-term use of ticagrelor in patients with prior myocardial infarction.

BACKGROUND: The potential benefit of dual antiplatelet therapy beyond 1 year after a myocardial infarction has not been established. We investigated the efficacy and safety of ticagrelor, a P2Y12 receptor antagonist with established efficacy after an acute coronary syndrome, in this context. METHODS: We randomly assigned, in a double-blind 1:1:1 fashion, 21,162 patients who had had a myocardial infarction 1 to 3 years earlier to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All the patients were to receive low-dose aspirin and were followed for a median of 33 months. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. RESULTS: The two ticagrelor doses each reduced, as compared with placebo, the rate of the primary efficacy end point, with Kaplan-Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (hazard ratio for 90 mg of ticagrelor vs. placebo, 0.85; 95% confidence interval [CI], 0.75 to 0.96; P=0.008; hazard ratio for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI, 0.74 to 0.95; P=0.004). Rates of TIMI major bleeding were higher with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg) than with placebo (1.06%) (P<0.001 for each dose vs. placebo); the rates of intracranial hemorrhage or fatal bleeding in the three groups were 0.63%, 0.71%, and 0.60%, respectively. CONCLUSIONS: In patients with a myocardial infarction more than 1 year previously, treatment with ticagrelor significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke and increased the risk of major bleeding. (Funded by AstraZeneca; PEGASUS-TIMI 54 ClinicalTrials.gov number, NCT01225562.).

The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial.

BACKGROUND: Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor that reduces blood glucose in patients with type 2 diabetes mellitus (T2DM) by promoting glycosuria via inhibiting urinary glucose reabsorption. In addition to improving blood glucose control, treatment with dapagliflozin results in glucose-induced osmotic diuresis, weight loss, and blood pressure lowering. Previous trials of SGLT-2 inhibitors showed reductions in cardiovascular (CV) events, including CV death and hospitalization for heart failure, and ischemic events in patients with atherosclerotic cardiovascular disease (ASCVD). RESEARCH DESIGN AND METHODS: DECLARE-TIMI 58 (NCT01730534) is a phase 3b randomized, double-blind, placebo-controlled trial designed to evaluate the CV safety and efficacy of dapagliflozin that has completed randomization of 17,160 patients with T2DM and a history of either established ASCVD (n=6,971) or multiple risk factors for ASCVD (n=10,189). Patients were randomized in a 1:1 fashion to dapagliflozin 10 mg or matching placebo. The primary safety outcome is the time to the first event of the composite of CV death, myocardial infarction, or ischemic stroke (major adverse cardiovascular events; MACEs). The co-primary efficacy outcomes are the composite of CV death, myocardial infarction, or ischemic stroke and the composite of CV death or hospitalization for heart failure. This event-driven trial will continue until at least 1,390 subjects have a MACE outcome, thereby providing >99% power to test for the primary outcome of safety of dapagliflozin measured by rejecting the hypothesis that the upper bound of the CI >1.3 for the primary outcome of MACE, as well as 85% power to detect a 15% relative risk reduction in MACE and an estimated 87% power to detect a 20% reduction in the composite of CV death or hospitalization for heart failure at a 1-sided α level of .0231. CONCLUSION: The DECLARE-TIMI 58 trial is testing the hypotheses that dapagliflozin is safe (does not increase) and may reduce the occurrence of major CV events. DECLARE-TIMI 58 is the largest study to address this question with an SGLT-2 inhibitor in patients with T2DM and with established CV disease and without CV disease but with multiple risk factors.

Safety of ticagrelor in patients with baseline conduction abnormalities: A PLATO (Study of Platelet Inhibition and Patient Outcomes) analysis.

BACKGROUND: Although bradyarrhythmias have been observed with ticagrelor and its use with advanced atrioventricular block is not recommended, questions arise regarding its use in patients with mild conduction abnormalities. The objectives were to compare rates of clinically relevant arrhythmias in relation to any mild baseline conduction abnormality in patients with acute coronary syndrome randomized to ticagrelor versus clopidogrel. METHODS: We included all subjects in the electrocardiographic (ECG) substudy of the Platelet Inhibition and Patient Outcomes trial, excluding those with missing baseline ECG or with a pacemaker at baseline (N = 15,460). Conduction abnormality was defined as sinus bradycardia, first-degree atrioventricular block, hemiblock, or bundle-branch block. The primary arrhythmic outcome was the composite of any symptomatic brady- or tachyarrhythmia, permanent pacemaker placement, or cardiac arrest through 12 months. RESULTS: Patients with baseline conduction abnormalities (n = 4,256, 27.5%) were older and more likely to experience the primary arrhythmic outcome. There were no differences by ticagrelor versus clopidogrel in the composite arrhythmic end point in those with baseline conduction disease (1-year cumulative incidence rate: 17% for both study arms; hazard ratio: 0.99 [0.86-1.15]) or without baseline conduction disease (1-year cumulative incidence rate: clopidogrel 12.8% vs ticagrelor 12.4%; hazard ratio: 0.98 (0.88-1.09). There were also no statistically significant differences between ticagrelor and clopidogrel in the rates of bradycardic (or any individual arrhythmic) events in patients with baseline conduction abnormalities. CONCLUSIONS: Ticagrelor compared to clopidogrel did not increase arrhythmic events even in subjects with acute coronary syndrome who present with mild conduction abnormalities on their baseline ECG.

Rationale and Design of Family-Based Approach in a Minority Community Integrating Systems-Biology for Promotion of Health (FAMILIA).

BACKGROUND: The 2020 American Heart Association Impact Goal aims to improve cardiovascular health of all Americans by 20% while reducing deaths from cardiovascular disease and stroke by 20%. A large step toward this goal would be to better understand and take advantage of the significant intersection between behavior and biology across the entire life-span. In the proposed FAMILIA studies, we aim to directly address this major knowledge and clinical health gap by implementing an integrated family-centric health promotion intervention and focusing on the intersection of environment and behavior, while understanding the genetic and biologic basis of cardiovascular disease. METHODS: We plan to recruit 600 preschool children and their 600 parents or caregivers from 12-15 Head Start schools in Harlem, NY, and perform a 2:1 (2 intervention/1 control) cluster randomization of the schools. The preschool children will receive our intensive 37-hour educational program as the intervention for 4 months. For the adults, those in the "intervention" group will be randomly assigned to 1 of 2 intervention programs: an "individual-focused" or "peer-to-peer based." The primary outcome in children will be a composite score of knowledge (K), attitudes (A), habits (H), related to body mass index Z score (B), exercise (E), and alimentation (A) (KAH-BEA), using questionnaires and anthropometric measurements. For adults, the primary outcome will be a composite score for behaviors/outcomes related to blood pressure, exercise, weight, alimentation (diet) and tobacco (smoking; Fuster-BEWAT score). Saliva will be collected from the children for SNP genotyping, and blood will be collected from adults for RNA sequencing to identify network models and predictors of primary prevention outcomes. CONCLUSION: The FAMILIA studies seek to demonstrate that targeting a younger age group (3-5 years) and using a family-based approach may be a critical strategy in promoting cardiovascular health across the life-span.

A 30-month worksite-based lifestyle program to promote cardiovascular health in middle-aged bank employees: Design of the TANSNIP-PESA randomized controlled trial.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide. With atherosclerosis as the underlying cause for many CVD events, prevention or reduction of subclinical atherosclerotic plaque burden (SAPB) through a healthier lifestyle may have substantial public health benefits. OBJECTIVE: The objective was to describe the protocol of a randomized controlled trial investigating the effectiveness of a 30-month worksite-based lifestyle program aimed to promote cardiovascular health in participants having a high or a low degree of SAPB compared with standard care. METHODS: We will conduct a randomized controlled trial including middle-aged bank employees from the Progression of Early Subclinical Atherosclerosis cohort, stratified by SAPB (high SAPB n=260, low SAPB n=590). Within each stratum, participants will be randomized 1:1 to receive a lifestyle program or standard care. The program consists of 3 elements: (a) 12 personalized lifestyle counseling sessions using Motivational Interviewing over a 30-month period, (b) a wrist-worn physical activity tracker, and (c) a sit-stand workstation. Primary outcome measure is a composite score of blood pressure, physical activity, sedentary time, body weight, diet, and smoking (ie, adapted Fuster-BEWAT score) measured at baseline and at 1-, 2-, and 3-year follow-up. CONCLUSIONS: The study will provide insights into the effectiveness of a 30-month worksite-based lifestyle program to promote cardiovascular health compared with standard care in participants with a high or low degree of SAPB.

Use of prasugrel vs clopidogrel and outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention in contemporary clinical practice: Results from the PROMETHEUS study.

BACKGROUND AND OBJECTIVES: We sought to determine the frequency of use and association between prasugrel and outcomes in acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI) in clinical practice. METHODS: PROMETHEUS was a multicenter observational registry of acute coronary syndrome patients undergoing PCI from 8 centers in the United States that maintained a prospective PCI registry for patient outcomes. The primary end points were major adverse cardiovascular events at 90days, a composite of all-cause death, nonfatal myocardial infarction, stroke, or unplanned revascularization. Major bleeding was defined as any bleeding requiring hospitalization or blood transfusion. Hazard ratios (HRs) were generated using multivariable Cox regression and stratified by the propensity to treat with prasugrel. RESULTS: Of 19,914 patients (mean age 64.4years, 32% female), 4,058 received prasugrel (20%) and 15,856 received clopidogrel (80%). Prasugrel-treated patients were younger with fewer comorbid risk factors compared with their counterparts receiving clopidogrel. At 90days, there was a significant association between prasugrel use and lower major adverse cardiovascular event (5.7% vs 9.6%, HR 0.58, 95% CI 0.50-0.67, P<.0001) and bleeding (1.9% vs 2.9%, HR 0.65, 95% CI 0.51-0.83, P<.001). After propensity stratification, associations were attenuated and no longer significant for either outcome. Results remained consistent using different approaches to adjusting for potential confounders. CONCLUSIONS: In contemporary clinical practice, patients receiving prasugrel tend to have a lower-risk profile compared with those receiving clopidogrel. The lower ischemic and bleeding events associated with prasugrel use were no longer evident after accounting for these baseline differences.

Impact of proton pump inhibitors and dual antiplatelet therapy cessation on outcomes following percutaneous coronary intervention: Results From the PARIS Registry.

BACKGROUND: Proton pump inhibitors (PPI) may decrease the availability of clopidogrel by competitive antagonism, leading to a potential increase in ischemic events. METHODS: We evaluated patients from the all-comer PARIS registry treated with dual antiplatelet therapy (DAPT) with aspirin and clopidogrel following coronary stenting for outcomes stratified by PPI use. Two-year major adverse cardiovascular events (MACE), composite of cardiac death, myocardial infarction, definite or probable stent thrombosis or target lesion revascularization (TLR), and net adverse cardiac events (NACE), composite of MACE or Bleeding Academic Research consortium (BARC) type 3 or 5 bleeding were assessed. We also explored associations between PPI use and patterns of 2-year DAPT cessation. RESULTS: The cohort comprised 4635 patients (23% PPI users) with mean age 64.4 ±11.4 years. Two year adjusted risk of MACE (HR: 1.27, 95% CI: 1.04-1.55), NACE (HR: 1.21, 95% CI: 1.01-1.44) and TLR (HR: 1.33, 95% CI: 1.04-1.71) were significantly higher in PPI users vs. non-users, without a difference in bleeding. Although the incidence of 2-year DAPT discontinuation and interruption was similar, DAPT disruption was significantly lower among PPI users vs. non-users (10.0% vs. 14.7%, P <0.0001). Compared to non-PPI users on continued DAPT, disruption was associated with higher MACE in both PPI users (HR: 2.34, 95% CI: 1.38-3.97) and non-users (HR: 1.41, 95% CI: 1.02-1.94) but greater BARC 3,5 bleeding only in non-PPI users (HR: 2.06, 95% CI: 1.21-3.51). CONCLUSIONS: In clopidogrel treated PCI patients, the 2-year adjusted risk of MACE and NACE was significantly higher in PPI users driven by higher TLR compared to non-PPI users, without a difference in bleeding. PPI use was associated with lower incidence of DAPT disruption without an increase in disruption related bleeding compared to non-PPI users on DAPT. © 2016 Wiley Periodicals, Inc.

The role of reduced heart rate volatility in predicting disposition from the emergency department.

OBJECTIVE: Heart rate volatility (HRVO) is a physiological parameter that is believed to reflect the sympathetic activity of the autonomic nervous system. We explored the utility of HRVO as a predictive tool for declining physiological states, hypothesising that patients admitted from the resuscitation area of the ED to a high-dependency unit (HDU) experience low HRVO compared with patients who did not. METHODS: We retrospectively reviewed HR data recordings, medical charts and disposition decisions from the ED of patients who were admitted to the five resuscitation beds in our adult ED between 29 April 2014 and 30 May 2015. HRVO was calculated for each 5 min interval; it was measured as the SD of all HRs within that interval. Logistic regression was used to model the odds of admission to a HDU given low HRVO during ED stay. RESULTS: HR data from 2051 patients was collected and approximately 7 million HR data points were analysed. 402 patients experienced low HRVO. Patients who experienced low HRVO during their ED stay were twice as likely to be admitted to a HDU from the ED (OR=2.07, 95% CI 1.64 to 2.60; p<0.001). CONCLUSIONS: Our result provides additional evidence supporting previously published data indicating that autonomic nervous system measures such as HRVO could serve as important and useful clinical tools in the early triage of critically ill patients in the ED.

Impact of glycoprotein IIb/IIIa inhibitors on the efficacy and safety of ticagrelor compared with clopidogrel in patients with acute coronary syndromes: Analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial.

BACKGROUND: Ticagrelor reduced cardiovascular events compared with clopidogrel in PLATO without increasing overall major bleeding. We evaluated whether the use of glycoprotein IIb/IIIa inhibitor (GPI) impacts the relative efficacy and safety of ticagrelor compared with clopidogrel. METHODS: PLATO randomized 18,624 subjects with acute coronary syndrome to ticagrelor versus clopidogrel. The primary efficacy end point was cardiovascular death/myocardial infarction/stroke, and the primary safety end point was major bleeding. The use of GPI was at the physician's discretion and open-label. We evaluated outcomes at 30 days stratified by GPI use in the subgroup of 9,983 patients who underwent percutaneous coronary intervention (PCI) within 72 hours. RESULTS: A total of 4,020 (40%) received a GPI. Those receiving a GPI were more likely to be younger, be male, and undergo multivessel PCI. There was no interaction between treatment and GPI use for the primary efficacy and safety end points. Patients treated without GPI had a lower rate of definite stent thrombosis and higher rate of minor/major bleeding with ticagrelor compared with clopidogrel (P < .05), whereas there was no such difference with GPI (P interaction < .05). CONCLUSIONS: In patients with acute coronary syndrome undergoing early PCI, the efficacy and safety of ticagrelor as compared with clopidogrel were not modified by GPI use according to the primary efficacy and safety end point of the trial, although there were indications of greater benefit on definite stent thrombosis and more major or minor bleeding with ticagrelor in patients without (vs with) GPI treatment.

Resistant in-stent restenosis in the drug eluting stent era.

BACKGROUND: In the drug eluting stent (DES) era, repeat in-stent restenosis (ISR) of the same coronary lesion, despite percutaneous coronary intervention (PCI), is a rare but challenging problem that has not been reported. We aim to describe what we propose as the occurrence of "resistant"-ISR (R-ISR) in the DES era, including angiographic patterns and outcomes. METHODS: We defined R-ISR as the recurrence of an ISR episode after successful treatment of the same lesion. We identified 276 consecutive patients with 291 lesions who had R-ISR between May 2003 and June 2012. Quantitative coronary angiography (QCA) was performed for the first and second ISR episodes. Outcomes at one year, including death, myocardial infarction (MI), and target lesion failure (TLF), were analyzed. RESULTS: Patients with R-ISR had a high frequency of diabetes (62%), chronic kidney disease (39%), bifurcation lesions (51%), and moderate to severe calcified lesions (52%). The most common pattern of R-ISR was focal (77%). R-ISR lesions were treated with DES implantation (55%) or balloon-only strategy (45%). The mortality rate and TLF at 2-years were 9.3% and 51% respectively. The overall 2-year TLF rate did not vary with the originally implanted stent, angiographic pattern (focal versus diffuse), or revascularization strategy. CONCLUSIONS: R-ISR appears to consist predominantly of focal lesions and occurs in patients at high clinical and angiographic risk, conceivably owing to their unique diabetic and coronary calcification profile. Clinical outcomes are suboptimal irrespective of angiographic pattern or treatment strategy, indicating the recalcitrant nature of the disease, and need for aggressive treatment of cardiovascular risk factors and novel interventional approaches. © 2016 Wiley Periodicals, Inc.

Low intraoperative heart rate volatility is associated with early postoperative mortality in general surgical patients: a retrospective case-control study.

Heart rate volatility (HRVO) is hypothesized to be a physiological measure of sympathetic activity and is defined by the standard deviation (SD) of the heart rate (HR) in beats per minutes (BPM) over fixed time intervals. To investigate the relationship between low HRVO (SD < 0.5 BPM) during surgical procedures and mortality within 48 h post-procedure. We retrospectively reviewed all adult general surgical procedures performed at our center from January 1, 2003 through July 1, 2013 to identify patients who died within 48 h post-procedure. Demographic, heart rate, and mortality data were extracted from the electronic anesthesia record. Propensity score analysis was used to find matching controls based on age, gender, ASA score, anesthesia type, Charlson index, procedure type, emergency status, year, use of preoperative beta blocker, hypertension, diabetes, atrial fibrillation and heart failure. HRVO was calculated for each 5 min interval as the SD of all HR's within that interval. Negative binomial regression was then used to model the count of intervals with HRVO < 0.5 BPM for the duration of the surgery. During the 10 year study period, 283 patients died within 48 h of procedure finish. These patients were matched to 566 patients who did not die within 48 h after procedure. Patients who died had a 39 % increase in frequency of low HRVO episodes compared to patients who survived (RR 1.39, 95 % CI 1.13-1.72; p = 0.003). Low HRVO during surgical procedure is associated with increased mortality risk within 48 h after procedure. Strategies to identify HRVO early and modify it may lead to improvement in outcomes.

Strategies for multivessel revascularization in patients with diabetes.

BACKGROUND: In some randomized trials comparing revascularization strategies for patients with diabetes, coronary-artery bypass grafting (CABG) has had a better outcome than percutaneous coronary intervention (PCI). We sought to discover whether aggressive medical therapy and the use of drug-eluting stents could alter the revascularization approach for patients with diabetes and multivessel coronary artery disease. METHODS: In this randomized trial, we assigned patients with diabetes and multivessel coronary artery disease to undergo either PCI with drug-eluting stents or CABG. The patients were followed for a minimum of 2 years (median among survivors, 3.8 years). All patients were prescribed currently recommended medical therapies for the control of low-density lipoprotein cholesterol, systolic blood pressure, and glycated hemoglobin. The primary outcome measure was a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: From 2005 through 2010, we enrolled 1900 patients at 140 international centers. The patients' mean age was 63.1±9.1 years, 29% were women, and 83% had three-vessel disease. The primary outcome occurred more frequently in the PCI group (P=0.005), with 5-year rates of 26.6% in the PCI group and 18.7% in the CABG group. The benefit of CABG was driven by differences in rates of both myocardial infarction (P<0.001) and death from any cause (P=0.049). Stroke was more frequent in the CABG group, with 5-year rates of 2.4% in the PCI group and 5.2% in the CABG group (P=0.03). CONCLUSIONS: For patients with diabetes and advanced coronary artery disease, CABG was superior to PCI in that it significantly reduced rates of death and myocardial infarction, with a higher rate of stroke. (Funded by the National Heart, Lung, and Blood Institute and others; FREEDOM ClinicalTrials.gov number, NCT00086450.).

Antithrombotic strategy variability in ATrial fibrillation and obstructive coronary disease revascularized with PCI-rationale and study design of the prospective observational multicenter AVIATOR 2 registry.

BACKGROUND: In the era of novel antithrombotic therapy, the optimal treatment for patients with nonvalvular atrial fibrillation (AF) or flutter undergoing percutaneous coronary intervention (PCI) is undetermined. STUDY DESIGN: The AVIATOR 2 study is a multicenter prospective observational registry that will enroll approximately 2,500 patients with nonvalvular AF or flutter undergoing PCI starting March 2015 over an 18-month enrollment period. Antithrombotic therapy selection will be at the discretion of the treating physician. An integral feature of this study is the use of a smartphone-based survey to capture physician and patient perspectives regarding antithrombotic therapies after PCI. Survey-derived patient treatment concerns, perceived need, and affordability will be used to calculate the risk of non-adherence. Subjective risk for ischemic or bleeding events will be correlated with previously validated risk scores as well as observed event rates at 1, 6, or 12 months post-PCI. ENDPOINTS: The primary efficacy end point will be major adverse cardiac and cerebrovascular events, a composite occurrence of death, nonfatal myocardial infarction, stroke, stent thrombosis, and clinically driven target lesion revascularization at 1 year. The primary safety end point will be major bleeding as per Bleeding Academic Research Consortium criteria types 2, 3, or 5. The secondary end points will include (i) net adverse clinical events, a composite occurrence of all major adverse cardiac and cerebrovascular events, and major bleeding at 1 year; (ii) correlation between estimated subjective and objective (CHADS2, CHA2DS2-VASc, stent thrombosis score, HAS-BLED, and ATRIA scores) ischemic and bleeding risks; (iii) modes of antithrombotic therapy cessation and their impact on outcomes; and (iv) correlation between observed and expected non-adherence to treatment. SUMMARY: AVIATOR 2 is a real-world registry designed to evaluate ischemic and bleeding outcomes according to conventional and novel antithrombotic regimens in patients with nonvalvular AF or flutter undergoing PCI. The study will also provide insights in to physician- and patient-centered factors affecting treatment selection and adherence and their overall impact on clinical outcomes. The study is registered on clinicaltrials.gov NCT02362659.

Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial).

BACKGROUND: The prevalence of both atrial fibrillation (AF) and diabetes mellitus (DM) are rising, and these conditions often occur together. Also, DM is an independent risk factor for stroke in patients with AF. We aimed to examine the safety and efficacy of rivaroxaban vs warfarin in patients with nonvalvular AF and DM in a prespecified secondary analysis of the ROCKET AF trial. METHODS: We stratified the ROCKET AF population by DM status, assessed associations with risk of outcomes by DM status and randomized treatment using Cox proportional hazards models, and tested for interactions between randomized treatments. For efficacy, primary outcomes were stroke (ischemic or hemorrhagic) or non-central nervous system embolism. For safety, the primary outcome was major or nonmajor clinically relevant bleeding. RESULTS: The 5,695 patients with DM (40%) in ROCKET AF were younger, were more obese, and had more persistent AF, but fewer had previous stroke (the CHADS2 score includes DM and stroke). The relative efficacy of rivaroxaban and warfarin for prevention of stroke and systemic embolism was similar in patients with (1.74 vs 2.14/100 patient-years, hazard ratio [HR] 0.82) and without (2.12 vs 2.32/100 patient-years, HR 0.92) DM (interaction P = .53). The safety of rivaroxaban vs warfarin regarding major bleeding (HRs 1.00 and 1.12 for patients with and without DM, respectively; interaction P = .43), major or nonmajor clinically relevant bleeding (HRs 0.98 and 1.09; interaction P = .17), and intracerebral hemorrhage (HRs 0.62 and 0.72; interaction P = .67) was independent of DM status. Adjusted exploratory analyses suggested 1.3-, 1.5-, and 1.9-fold higher 2-year rates of stroke, vascular mortality, and myocardial infarction in DM patients. CONCLUSIONS AND RELEVANCE: The relative efficacy and safety of rivaroxaban vs warfarin was similar in patients with and without DM, supporting use of rivaroxaban as an alternative to warfarin in diabetic patients with AF.

Modifiability of Composite Cardiovascular Risk Associated With Chronic Kidney Disease in Type 2 Diabetes With Finerenone.

Importance: It is currently unclear whether chronic kidney disease (CKD)-associated cardiovascular risk in type 2 diabetes (T2D) is modifiable. Objective: To examine whether cardiovascular risk can be modified with finerenone in patients with T2D and CKD. Design, Setting, and Participants: Incidence rates from Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Programme Analysis (FIDELITY), a pooled analysis of 2 phase 3 trials (including patients with CKD and T2D randomly assigned to receive finerenone or placebo) were combined with National Health and Nutrition Examination Survey data to simulate the number of composite cardiovascular events that may be prevented per year with finerenone at a population level. Data were analyzed over 4 years of consecutive National Health and Nutrition Examination Survey data cycles (2015-2016 and 2017-2018). Main Outcomes and Measures: Incidence rates of cardiovascular events (composite of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, or hospitalization for heart failure) were estimated over a median of 3.0 years by estimated glomerular filtration rate (eGFR) and albuminuria categories. The outcome was analyzed using Cox proportional hazards models stratified by study, region, eGFR and albuminuria categories at screening, and cardiovascular disease history. Results: This subanalysis included a total of 13 026 participants (mean [SD] age, 64.8 [9.5] years; 9088 male [69.8%]). Lower eGFR and higher albuminuria were associated with higher incidences of cardiovascular events. For recipients in the placebo group with an eGFR of 90 or greater, incidence rates per 100 patient-years were 2.38 (95% CI, 1.03-4.29) in those with a urine albumin to creatinine ratio (UACR) less than 300 mg/g and 3.78 (95% CI, 2.91-4.75) in those with UACR of 300 mg/g or greater. In those with eGFR less than 30, incidence rates increased to 6.54 (95% CI, 4.19-9.40) vs 8.74 (95% CI, 6.78-10.93), respectively. In both continuous and categorical models, finerenone was associated with a reduction in composite cardiovascular risk (hazard ratio, 0.86; 95% CI, 0.78-0.95; P = .002) irrespective of eGFR and UACR (P value for interaction = .66). In 6.4 million treatment-eligible individuals (95% CI, 5.4-7.4 million), 1 year of finerenone treatment was simulated to prevent 38 359 cardiovascular events (95% CI, 31 741-44 852), including approximately 14 000 hospitalizations for heart failure, with 66% (25 357 of 38 360) prevented in patients with eGFR of 60 or greater. Conclusions and Relevance: Results of this subanalysis of the FIDELITY analysis suggest that CKD-associated composite cardiovascular risk may be modifiable with finerenone treatment in patients with T2D, those with eGFR of 25 or higher, and those with UACR of 30 mg/g or greater. UACR screening to identify patients with T2D and albuminuria with eGFR of 60 or greater may provide significant opportunities for population benefits.

The Future REvascularization Evaluation in patients with Diabetes mellitus: optimal management of Multivessel disease (FREEDOM) trial: clinical and angiographic profile at study entry.

BACKGROUND: The optimal revascularization strategy for diabetic patients with multivessel coronary artery disease (MVD) remains uncertain for lack of an adequately powered, randomized trial. The FREEDOM trial was designed to compare contemporary coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI) with drug-eluting stents in diabetic patients with MVD against a background of optimal medical therapy. METHODS: A total of 1,900 diabetic participants with MVD were randomized to PCI or CABG worldwide from April 2005 to March 2010. FREEDOM is a superiority trial with a mean follow-up of 4.37 years (minimum 2 years) and 80% power to detect a 27.0% relative reduction. We present the baseline characteristics of patients screened and randomized, and provide a comparison with other MVD trials involving diabetic patients. RESULTS: The randomized cohort was 63.1 ± 9.1 years old and 29% female, with a median diabetes duration of 10.2 ± 8.9 years. Most (83%) had 3-vessel disease and on average took 5.5 ± 1.7 vascular medications, with 32% on insulin therapy. Nearly all had hypertension and/or dyslipidemia, and 26% had a prior myocardial infarction. Mean hemoglobin A1c was 7.8 ± 1.7 mg/dL, 29% had low-density lipoprotein <70 mg/dL, and mean systolic blood pressure was 134 ± 20 mm Hg. The mean SYNTAX score was 26.2 with a symmetric distribution. FREEDOM trial participants have baseline characteristics similar to those of contemporary multivessel and diabetes trial cohorts. CONCLUSIONS: The FREEDOM trial has successfully recruited a high-risk diabetic MVD cohort. Follow-up efforts include aggressive monitoring to optimize background risk factor control. FREEDOM will contribute significantly to the PCI versus CABG debate in diabetic patients with MVD.