Association of Weight Loss Achieved Through Metabolic Surgery With Risk and Severity of COVID-19 Infection.

IMPORTANCE: Obesity is an established risk factor for severe COVID-19 infection. However, it is not known whether losing weight is associated with reduced adverse outcomes of COVID-19 infection. OBJECTIVE: To investigate the association between a successful weight loss intervention and improved risk and severity of COVID-19 infection in patients with obesity. DESIGN, SETTING, AND PARTICIPANTS: This cohort study involved adult patients with a body mass index of 35 or higher (calculated as weight in kilograms divided by height in meters squared) who underwent weight loss surgery between January 1, 2004, and December 31, 2017, at the Cleveland Clinic Health System (CCHS). Patients in the surgical group were matched 1:3 to patients who did not have surgical intervention for their obesity (control group). The source of data was the CCHS electronic health record. Follow-up was conducted through March 1, 2021. EXPOSURES: Weight loss surgery including Roux-en-Y gastric bypass and sleeve gastrectomy. MAIN OUTCOMES AND MEASURES: Distinct outcomes were examined before and after COVID-19 outbreak on March 1, 2020. Weight loss and all-cause mortality were assessed between the enrollment date and March 1, 2020. Four COVID-19-related outcomes were analyzed in patients with COVID-19 diagnosis between March 1, 2020, and March 1, 2021: positive SARS-CoV-2 test result, hospitalization, need for supplemental oxygen, and severe COVID-19 infection (a composite of intensive care unit admission, need for mechanical ventilation, or death). RESULTS: A total of 20 212 patients (median [IQR] age, 46 [35-57] years; 77.6% female individuals [15 690]) with a median (IQR) body mass index of 45 (41-51) were enrolled. The overall median (IQR) follow-up duration was 6.1 (3.8-9.0) years. Before the COVID-19 outbreak, patients in the surgical group compared with control patients lost more weight (mean difference at 10 years from baseline: 18.6 [95% CI, 18.4-18.7] percentage points; P < .001) and had a 53% lower 10-year cumulative incidence of all-cause non-COVID-19 mortality (4.7% [95% CI, 3.7%-5.7%] vs 9.4% [95% CI, 8.7%-10.1%]; P < .001). Of the 20 212 enrolled patients, 11 809 were available on March 1, 2020, for an assessment of COVID-19-related outcomes. The rates of positive SARS-CoV-2 test results were comparable in the surgical and control groups (9.1% [95% CI, 7.9%-10.3%] vs 8.7% [95% CI, 8.0%-9.3%]; P = .71). However, undergoing weight loss surgery was associated with a lower risk of hospitalization (adjusted hazard ratio [HR], 0.51; 95% CI, 0.35-0.76; P < .001), need for supplemental oxygen (adjusted HR, 0.37; 95% CI, 0.23-0.61; P < .001), and severe COVID-19 infection (adjusted HR, 0.40; 95% CI, 0.18-0.86; P = .02). CONCLUSIONS AND RELEVANCE: This cohort study found that, among patients with obesity, substantial weight loss achieved with surgery was associated with improved outcomes of COVID-19 infection. The findings suggest that obesity can be a modifiable risk factor for the severity of COVID-19 infection.

Cardiovascular Outcomes in Patients With Type 2 Diabetes and Obesity: Comparison of Gastric Bypass, Sleeve Gastrectomy, and Usual Care.

OBJECTIVE: To determine which one of the two most common metabolic surgical procedures is associated with greater reduction in risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM) and obesity. RESEARCH DESIGN AND METHODS: A total of 13,490 patients including 1,362 Roux-en-Y gastric bypass (RYGB), 693 sleeve gastrectomy (SG), and 11,435 matched nonsurgical patients with T2DM and obesity who received their care at the Cleveland Clinic (1998-2017) were analyzed, with follow-up through December 2018. With multivariable Cox regression analysis we estimated time to incident extended MACE, defined as first occurrence of coronary artery events, cerebrovascular events, heart failure, nephropathy, atrial fibrillation, and all-cause mortality. RESULTS: The cumulative incidence of the primary end point at 5 years was 13.7% (95% CI 11.4-15.9) in the RYGB groups and 24.7% (95% CI 19.0-30.0) in the SG group, with an adjusted hazard ratio (HR) of 0.77 (95% CI 0.60-0.98, P = 0.04). Of the six individual end points, RYGB was associated with a significantly lower cumulative incidence of nephropathy at 5 years compared with SG (2.8% vs. 8.3%, respectively; HR 0.47 [95% CI 0.28-0.79], P = 0.005). Furthermore, RYGB was associated with a greater reduction in body weight, glycated hemoglobin, and use of medications to treat diabetes and cardiovascular diseases. Five years after RYGB, patients required more upper endoscopy (45.8% vs. 35.6%, P < 0.001) and abdominal surgical procedures (10.8% vs. 5.4%, P = 0.001) compared with SG. CONCLUSIONS: In patients with obesity and T2DM, RYGB may be associated with greater weight loss, better diabetes control, and lower risk of MACE and nephropathy compared with SG.

Patient-reported Outcomes After Metabolic Surgery Versus Medical Therapy for Diabetes: Insights From the STAMPEDE Randomized Trial.

OBJECTIVE: The aim of this study was to investigate the long-term effects of medical and surgical treatments of type 2 diabetes mellitus (T2DM) on patient-reported outcomes (PROs). BACKGROUND: Robust data on PROs from randomized trials comparing medical and surgical treatments for T2DM are lacking. METHODS: The Surgical Treatment And Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial showed that 5 years after randomization, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) were superior to intensive medical therapy (IMT) alone in achieving glycemic control in patients with T2DM and obesity. A subset of 104 patients participating in the STAMPEDE trial were administered two generic health-related quality of life (QoL) questionnaires (RAND-36 and EQ-5D-3L) and a diabetes-specific instrument at baseline, and then on an annual basis up to 5 years after randomization. RESULTS: On longitudinal analysis, RYGB and SG significantly improved the domains of physical functioning, general health perception, energy/fatigue, and diabetes-related QoL compared with IMT group. In the IMT group, none of the QoL components in the generic questionnaires improved significantly from baseline. No significant long-term differences were observed among the study groups in measures of psychological and social aspects of QoL. On multivariable analysis, independent factors associated with improved general health perception at long-term included baseline general health (P < 0.001), insulin independence at 5 years (P = 0.005), RYGB versus IMT (P = 0.005), and SG versus IMT (P = 0.034). Favorable changes following RYGB and SG were comparable. CONCLUSIONS: In patients with T2DM, metabolic surgery is associated with long-term favorable changes in certain PROs compared with IMT, mainly on physical health and diabetes-related domains. Psychosocial well-being warrants greater attention after metabolic surgery.

How Much Weight Loss is Required for Cardiovascular Benefits? Insights From a Metabolic Surgery Matched-cohort Study.

OBJECTIVE: The aim of this study was to determine the minimum amount of weight loss required to see a reduction in major adverse cardiovascular events (MACE). BACKGROUND: Although obesity is an established risk factor for morbidity and mortality, the minimum amount of weight loss to have a meaningful impact on cardiovascular health and survival is unknown. METHODS: Patients with obesity (body mass index ≥30 kg/m) and type 2 diabetes who underwent metabolic surgery in an academic center (1998-2017) were propensity-matched 1:5 to nonsurgical patients who received usual care. The adjusted linear and nonlinear effects of weight loss (achieved in the first 18 months after the index date) were studied to identify cut-offs for the minimum weight loss to achieve decreased risk of all-cause mortality and MACE (composite of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation). RESULTS: A total of 7201 patients (1223 surgical and 5978 nonsurgical) with a median follow-up time of 4.9 years (interquartile range, 3.5-7) were included. The positive effect of metabolic surgery was still present after adjusting for weight loss amounts, suggesting that there are weight loss-independent factors contributing to a reduction in risk of MACE and all-cause mortality in the surgical cohort. After considering the weighted estimates from a diverse set of models, the risk of MACE decreases after approximately 10% of weight is lost in the surgical group and approximately 20% in the nonsurgical group. For all-cause mortality, the threshold for benefit appeared to be approximately 5% weight loss after metabolic surgery and 20% in the nonsurgical group. CONCLUSIONS: This large matched-cohort study identified the minimum weight loss thresholds for reduction in risk of MACE and all-cause mortality in patients with obesity and diabetes. Furthermore, in our analysis, the effect of surgery was still present after accounting for weight loss, which may suggest the presence of weight-independent beneficial effects of metabolic surgery on MACE and survival.

Effect of CETP inhibition with evacetrapib in patients with diabetes mellitus enrolled in the ACCELERATE trial.

BACKGROUND: High-density lipoprotein (HDL) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition with evacetrapib results in a marked increase in HDL and reduction in low-density lipoprotein (LDL) levels. We evaluated the impact of treatment with evacetrapib versus placebo in the subset of 8236 patients with diabetes mellitus (DM) enrolled in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes trial. METHODS AND RESULTS: Time to first occurrence of any component of the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, revascularization, and hospitalization for unstable angina was compared among patients with DM randomized to treatment with evacetrapib (n=4127) or placebo (n=4109) over a median of 26 months of follow-up. The mean baseline LDL at initiation was 80 mg/dL with a mean baseline HDL of 44 mg/dL. In patients with DM, evacetrapib resulted in a 131% mean increase in HDL levels and a 32% mean decrease in LDL at 3 months that was sustained during the course of the trial. At 6 months, hemoglobin A1c (HbA1c) levels were lower with evacetrapib than placebo (7.08% vs 7.15%, p=0.023). Composite event rates were higher in patients with DM than without DM (Kaplan-Meier estimates: 15.2% vs 10.6%, HR 1.46, 95% CI 1.30 to 1.64, p<0.001). In the DM group, event rates for the composite endpoint (14.5% evacetrapib vs 16% placebo, HR 0.95, 95% CI 0.85 to 1.07, p=0.38) and individual components of the composite were similar for both evacetrapib and placebo groups. No significant treatment interaction between treatment assignment and diabetes status was noted. CONCLUSION: Despite a favorable increase in HDL, and decreases in LDL and HbA1c levels in patients with DM, we observed no benefits of treatment with evacetrapib on prespecified clinical outcomes in this high-risk population.

Predicting 10-Year Risk of End-Organ Complications of Type 2 Diabetes With and Without Metabolic Surgery: A Machine Learning Approach.

OBJECTIVE: To construct and internally validate prediction models to estimate the risk of long-term end-organ complications and mortality in patients with type 2 diabetes and obesity that can be used to inform treatment decisions for patients and practitioners who are considering metabolic surgery. RESEARCH DESIGN AND METHODS: A total of 2,287 patients with type 2 diabetes who underwent metabolic surgery between 1998 and 2017 in the Cleveland Clinic Health System were propensity-matched 1:5 to 11,435 nonsurgical patients with BMI ≥30 kg/m2 and type 2 diabetes who received usual care with follow-up through December 2018. Multivariable time-to-event regression and random forest machine learning models were built and internally validated using fivefold cross-validation to predict the 10-year risk for four outcomes of interest. The prediction models were programmed to construct user-friendly web-based and smartphone applications of Individualized Diabetes Complications (IDC) Risk Scores for clinical use. RESULTS: The prediction tools demonstrated the following discrimination ability based on the area under the receiver operating characteristic curve (1 = perfect discrimination and 0.5 = chance) at 10 years in the surgical and nonsurgical groups, respectively: all-cause mortality (0.79 and 0.81), coronary artery events (0.66 and 0.67), heart failure (0.73 and 0.75), and nephropathy (0.73 and 0.76). When a patient's data are entered into the IDC application, it estimates the individualized 10-year morbidity and mortality risks with and without undergoing metabolic surgery. CONCLUSIONS: The IDC Risk Scores can provide personalized evidence-based risk information for patients with type 2 diabetes and obesity about future cardiovascular outcomes and mortality with and without metabolic surgery based on their current status of obesity, diabetes, and related cardiometabolic conditions.

Impact of Baseline Glycemic Control on Residual Cardiovascular Risk in Patients With Diabetes Mellitus and High-Risk Vascular Disease Treated With Statin Therapy.

Background The contemporary impact of glycemic control on patients with diabetes mellitus at high cardiovascular risk remains unclear. We evaluated the utility of hemoglobin A1c (HbA1c) as a marker of risk on the composite end point of cardiovascular death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization in an optimally treated population with diabetes mellitus and established coronary artery disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. Methods and Results We included all patients with established diabetes mellitus and measured HbA1c (N=8145) and estimated Kaplan-Meier (KM) events rates, stratified by increasing baseline HbA1c levels censored at 30 months. We then performed a multivariable regression for the primary end point. Increasing baseline HbA1c was strongly associated with the occurrence of the primary end point (KM estimate, 12.6-18.2; P<0.001). Increasing baseline HbA1c was also associated with the triple end point of death, nonfatal myocardial infarction, and stroke (KM estimate, 7.8-11.3; P=0.003) as well as the individual end points of nonfatal myocardial infarction (KM estimate, 3.1-7.0; P<0.001), hospitalization for unstable angina (KM estimate, 1.8-5.0; P=0.003), and revascularization (KM estimate, 7.3-11.1; P=0.001), although not stroke (KM estimate, 1.4-2.4; P=0.45). The rates of cardiovascular mortality (KM estimate, 2.6-4.3; P=0.21) and all-cause mortality (KM estimate, 4.8-5.9; P=0.21) were similar regardless of baseline HbA1c levels. When adjusting for relevant baseline characteristics, baseline HbA1c was an independent predictor for the primary end point (hazard ratio, 1.06; 95% CI, 1.02-1.11; P=0.003). Conclusions Glycemic control, as measured by HbA1c, remains strongly and independently associated with cardiovascular outcomes in high-risk patients with diabetes mellitus on statin therapy. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01687998.

Plasma Aldosterone Levels Are Not Associated With Cardiovascular Events Among Patients With High-Risk Vascular Disease: Insights From the ACCELERATE Trial.

Background The failure of cholesteryl ester transfer protein inhibitor torcetrapib was associated with an off-target increase in plasma aldosterone. We sought to evaluate the impact of evacetrapib on plasma aldosterone level and determine the association between plasma aldosterone level and major adverse cardiovascular events among patients with stable high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. Methods and Results We included all patients with a plasma aldosterone level (N=1624) and determined the impact of evacetrapib exposure compared with placebo on plasma aldosterone levels after 12 months of treatment. Using baseline and postexposure aldosterone levels, hazard ratios for major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, cerebrovascular accident, hospitalization for unstable angina, and revascularization) with increasing quartile of baseline and percentage change in plasma aldosterone level at follow-up were calculated. The average age was 65.2 years, 75.7% were men, 93.7% were hypertensive, 73.3% were diabetic, and 57.6% had a prior myocardial infarction. Baseline plasma aldosterone level (85.2 [43, 150] versus 86.8 [43, 155] pmol/L; P=0.81) and follow-up percentage change (13.6% [-29, 88] versus 17.9% [-24, 87]; P=0.23) were similar between those who received evacetrapib and placebo. During median follow-up of 28 months, major adverse cardiovascular events occurred in 263 patients (16.2%). The hazard ratios for increasing quartile of baseline or percentage change in plasma aldosterone level at follow-up were not significant for major adverse cardiovascular events. These findings remained consistent when adjusting for significant characteristics. Conclusions Exposure to evacetrapib did not result in significant change in plasma aldosterone levels compared with placebo. Among patients with stable high-risk vascular disease, plasma aldosterone levels were not a predictor for future cardiovascular events. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01687998.

Association of Metabolic Surgery With Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes and Obesity.

IMPORTANCE: Although metabolic surgery (defined as procedures that influence metabolism by inducing weight loss and altering gastrointestinal physiology) significantly improves cardiometabolic risk factors, the effect on cardiovascular outcomes has been less well characterized. OBJECTIVE: To investigate the relationship between metabolic surgery and incident major adverse cardiovascular events (MACE) in patients with type 2 diabetes and obesity. DESIGN, SETTING, AND PARTICIPANTS: Of 287 438 adult patients with diabetes in the Cleveland Clinic Health System in the United States between 1998 and 2017, 2287 patients underwent metabolic surgery. In this retrospective cohort study, these patients were matched 1:5 to nonsurgical patients with diabetes and obesity (body mass index [BMI] ≥30), resulting in 11 435 control patients, with follow-up through December 2018. EXPOSURES: Metabolic gastrointestinal surgical procedures vs usual care for type 2 diabetes and obesity. MAIN OUTCOMES AND MEASURES: The primary outcome was the incidence of extended MACE (composite of 6 outcomes), defined as first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation. Secondary end points included 3-component MACE (myocardial infarction, ischemic stroke, and mortality) and the 6 individual components of the primary end point. RESULTS: Among the 13 722 study participants, the distribution of baseline covariates was balanced between the surgical group and the nonsurgical group, including female sex (65.5% vs 64.2%), median age (52.5 vs 54.8 years), BMI (45.1 vs 42.6), and glycated hemoglobin level (7.1% vs 7.1%). The overall median follow-up duration was 3.9 years (interquartile range, 1.9-6.1 years). At the end of the study period, 385 patients in the surgical group and 3243 patients in the nonsurgical group experienced a primary end point (cumulative incidence at 8-years, 30.8% [95% CI, 27.6%-34.0%] in the surgical group and 47.7% [95% CI, 46.1%-49.2%] in the nonsurgical group [P < .001]; absolute 8-year risk difference [ARD], 16.9% [95% CI, 13.1%-20.4%]; adjusted hazard ratio [HR], 0.61 [95% CI, 0.55-0.69]). All 7 prespecified secondary outcomes showed statistically significant differences in favor of metabolic surgery, including mortality. All-cause mortality occurred in 112 patients in the metabolic surgery group and 1111 patients in the nonsurgical group (cumulative incidence at 8 years, 10.0% [95% CI, 7.8%-12.2%] and 17.8% [95% CI, 16.6%-19.0%]; ARD, 7.8% [95% CI, 5.1%-10.2%]; adjusted HR, 0.59 [95% CI, 0.48-0.72]). CONCLUSIONS AND RELEVANCE: Among patients with type 2 diabetes and obesity, metabolic surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident MACE. The findings from this observational study must be confirmed in randomized clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03955952.

Baseline fasting plasma insulin levels predict risk for major adverse cardiovascular events among patients with diabetes and high-risk vascular disease: Insights from the ACCELERATE trial.

BACKGROUND: Despite optimal treatment, type II diabetes mellitus remains associated with an increased risk for future cardiovascular events. We sought to determine the association between baseline fasting plasma insulin levels and major adverse cardiovascular outcomes in patients with type II diabetes mellitus and high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. METHODS: We included all patients with type II diabetes mellitus who had a central laboratory measured fasting plasma insulin level drawn at baseline as part of the study protocol. Hazard ratios were generated for the risk of major adverse cardiovascular outcomes (composite of cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina and coronary revascularization) with increasing quartile of baseline fasting plasma insulin level. We then performed a multivariable regression adjusting for significant baseline characteristics. RESULTS: Among 12,092 patients in ACCELERATE, 2042 patients with type II diabetes mellitus had a baseline fasting plasma insulin level drawn. Median follow-up was 28 months. The study population had a mean age of 66.6 years, 79.2% male and 96.2% had established coronary artery disease. During follow-up, major adverse cardiovascular outcomes occurred in 238 patients (11.6%); of these events, 177 were coronary revascularization (8.7%). We observed a statistically significant relationship between rates of revascularization and rising quartile of baseline fasting plasma insulin level which was not noted for the other individual components of major adverse cardiovascular outcomes. Patients with type II diabetes mellitus who underwent revascularization were noted to have significantly higher baseline fasting plasma insulin levels (27.7 vs 21.4 mU/L, p-value = 0.009) although baseline haemoglobin A1c (6.63% vs 6.55%), body mass index (31.5 vs 31.1 kg/m2) and medical therapy were otherwise similar to the group not undergoing revascularization. Following multivariable regression adjusting for significant characteristics including exposure to evacetrapib, the log of baseline fasting plasma insulin level was found to be an independent predictor for major adverse cardiovascular outcomes (hazard ratio = 1.36, 95% confidence interval = 1.09-1.69, p-value = 0.007); this was driven by need for future revascularization (hazard ratio = 1.56, 95% confidence interval = 1.21-2.00, p-value = 0.001). CONCLUSION: In a contemporary population of patients with type II diabetes mellitus and high-risk vascular disease on optimum medical therapy, baseline hyperinsulinaemia was an independent predictor for major adverse cardiovascular outcomes and need of future coronary revascularization. These results suggest a pathophysiological link between hyperinsulinaemia and progression of atherosclerotic vascular disease among diabetics.

The potential benefits of aspirin for primary cardiovascular prevention in rheumatoid arthritis: a secondary analysis of the PRECISION Trial.

Objective: Guidelines exist for the use of low-dose aspirin in the general population for primary cardiovascular (CV) prevention, but the risk-benefit considerations may differ in RA. While RA confers an increased CV risk, such patients more likely use NSAIDs and corticosteroids. Methods: We conducted a cohort study to assess potential risks and benefits of low-dose aspirin. We estimated incidence rates and hazard ratios (HRs) using Cox regression among subjects with RA but no known CV disease in the Prospective Randomized Evaluation of Celecoxib Integrated Safety Vs Ibuprofen Or Naproxen trial. The primary exposure of interest was low-dose aspirin, and all enrolled patients were provided open-label esomeprazole. The primary composite outcome was major NSAID toxicity, including major adverse CV event (MACE), clinically significant gastrointestinal events, renal events and all-cause mortality. Results: We found 1852 subjects with RA in Prospective Randomized Evaluation of Celecoxib Integrated Safety Vs Ibuprofen Or Naproxen without known CV disease; 540 reported using low-dose aspirin for CV prevention and 1312 did not. Any major NSAID toxicity was observed in 79 (6.0%) non-aspirin users and 37 (6.9%) aspirin users (P = 0.50). Aspirin users experienced all components of the primary outcome at a similar rate to non-users. In fully adjusted models, the risk for major NSAID toxicity was similar between aspirin exposure groups (HR = 1.08, 95% CI: 0.69, 1.69). The risk for MACE was also similar between exposure groups in age- and gender-adjusted models (HR = 1.23, 95% CI: 0.72, 2.10). Conclusion: RA patients using low-dose aspirin with chronic NSAIDs and esomeprazole had a similar risk of major NSAID toxicity and MACE as patients who did not.

Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial.

IMPORTANCE: Few cardiovascular outcomes trials have been conducted for obesity treatments. Withdrawal of 2 marketed drugs has resulted in controversy about the cardiovascular safety of obesity agents. OBJECTIVE: To determine whether the combination of naltrexone and bupropion increases major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction) compared with placebo in overweight and obese patients. DESIGN, SETTING, AND PARTICIPANTS: Randomized, multicenter, placebo-controlled, double-blind noninferiority trial enrolling 8910 overweight or obese patients at increased cardiovascular risk from June 13, 2012, to January 21, 2013, at 266 US centers. After public release of confidential interim data by the sponsor, the academic leadership of the study recommended termination of the trial and the sponsor agreed. INTERVENTIONS: An Internet-based weight management program was provided to all participants. Participants were randomized to receive placebo (n=4454) or naltrexone, 32 mg/d, and bupropion, 360 mg/d (n=4456). MAIN OUTCOMES AND MEASURES: Time from randomization to first confirmed occurrence of a MACE. The primary analysis planned to assess a noninferiority hazard ratio (HR) of 1.4 after 378 expected events, with a confidential interim analysis after approximately 87 events (25% interim analysis) to assess a noninferiority HR of 2.0 for consideration of regulatory approval. RESULTS: Among the 8910 participants randomized, mean age was 61.0 years (SD, 7.3 years), 54.5% were female, 32.1% had a history of cardiovascular disease, and 85.2% had diabetes, with a median body mass index of 36.6 (interquartile range, 33.1-40.9). For the 25% interim analysis, MACE occurred in 59 placebo-treated patients (1.3%) and 35 naltrexone-bupropion-treated patients (0.8%; HR, 0.59; 95% CI, 0.39-0.90). After 50% of planned events, MACE occurred in 102 patients (2.3%) in the placebo group and 90 patients (2.0%) in the naltrexone-bupropion group (HR, 0.88; adjusted 99.7% CI, 0.57-1.34). Adverse effects were more common in the naltrexone-bupropion group, including gastrointestinal events in 14.2% vs 1.9% (P < .001) and central nervous system symptoms in 5.1% vs 1.2% (P < .001). CONCLUSIONS AND RELEVANCE: Among overweight or obese patients at increased cardiovascular risk, based on the interim analyses performed after 25% and 50% of planned events, the upper limit of the 95% CI of the HR for MACE for naltrexone-bupropion treatment, compared with placebo, did not exceed 2.0. However, because of the unanticipated early termination of the trial, it is not possible to assess noninferiority for the prespecified upper limit of 1.4. Accordingly, the cardiovascular safety of this treatment remains uncertain and will require evaluation in a new adequately powered outcome trial. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01601704.

Relationship between activated clotting time and ischemic or hemorrhagic complications: analysis of 4 recent randomized clinical trials of percutaneous coronary intervention.

BACKGROUND: Unfractionated heparin (UFH) is the most widely used antithrombin during percutaneous coronary intervention (PCI). Despite significant pharmacological and mechanical advancements in PCI, uncertainty remains about the optimal activated clotting time (ACT) for prevention of ischemic or hemorrhagic complications. METHODS AND RESULTS: We analyzed the outcome of all UFH-treated patients enrolled in 4 large, contemporary PCI trials with independent adjudication of ischemic and bleeding events. Of 9974 eligible patients, maximum ACT was available in 8369 (84%). The median ACT was 297 seconds (interquartile range 256 to 348 seconds). The incidence of death, myocardial infarction, or revascularization at 48 hours, by ACT quartile, was 6.2%, 6.8%, 6.0%, and 5.7%, respectively (P=0.40 for trend). Covariate-adjusted rate of ischemic complications was not correlated with maximal procedural ACT (continuous value, P=0.29). Higher doses of UFH (>5000 U, or up to 90 U/kg) were independently associated with higher rates of events. The incidence of major or minor bleeding at 48 hours, by ACT quartile, was 2.9%, 3.5%, 3.8%, and 4.0%, respectively (P=0.04 for trend). In a multivariable logistic model with a spline transformation for ACT, there was a linear increase in risk of bleeding as the ACT approached 365 seconds (P=0.01), which leveled off beyond that value. Increasing UFH weight-indexed dose was independently associated with higher bleeding rates (OR 1.04 [1.02 to 1.07] for each 10 U/kg, P=0.001). CONCLUSIONS: In patients undergoing PCI with frequent stent and potent platelet inhibition use, ACT does not correlate with ischemic complications and has a modest association with bleeding complications, driven mainly by minor bleeding. Lower values do not appear to compromise efficacy while increasing safety.