Publications by authors named "Vic Hasselblad"

131 Publications

Predictors of perioperative major bleeding in patients who interrupt warfarin for an elective surgery or procedure: Analysis of the BRIDGE trial.

Am Heart J 2018 Jan 21;195:108-114. Epub 2017 Sep 21.

Duke University Medical Center, Durham, NC.

Background: The use of low-molecular weight heparin bridge therapy during warfarin interruption for elective surgery/procedures increases bleeding. Other predictors of bleeding in this setting are not well described.

Methods: BRIDGE was a randomized, double-blind, placebo-controlled trial of bridge therapy with dalteparin 100 IU/kg twice daily in patients with atrial fibrillation requiring warfarin interruption. Bleeding outcomes were documented from the time of warfarin interruption until up to 37 days postprocedure. Multiple logistic regression and time-dependent hazard models were used to identify major bleeding predictors.

Results: We analyzed 1,813 patients of whom 895 received bridging and 918 received placebo. Median patient age was 72.6 years, and 73.3% were male. Forty-one major bleeding events occurred at a median time of 7.0 days (interquartile range, 4.0-18.0 days) postprocedure. Bridge therapy was a baseline predictor of major bleeding (odds ratio [OR]=2.4, 95% CI: 1.2-4.8), as were a history of renal disease (OR=2.9, 95% CI: 1.4-6.0), and high-bleeding risk procedures (vs low-bleeding risk procedures) (OR=2.9, 95% CI: 1.4-5.9). Perioperative aspirin use (OR=3.6, 95% CI: 1.1-11.9) and postprocedure international normalized ratio >3.0 (OR=2.1, 95% CI: 1.5-3.1) were time-dependent predictors of major bleeding. Major bleeding was most common in the first 10 days compared with 11-37 days postprocedure (OR=3.5, 95% CI: 1.8-6.9).

Conclusions: In addition to bridge therapy, perioperative aspirin use, postprocedure international normalized ratio >3.0, a history of renal failure, and having a high-bleeding risk procedure increase the risk of major bleeding around the time of an elective surgery/procedure requiring warfarin interruption.
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http://dx.doi.org/10.1016/j.ahj.2017.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730345PMC
January 2018

Cardiovascular adverse events in the drug-development program of bupropion for smoking cessation: A systematic retrospective adjudication effort.

Clin Cardiol 2017 Oct 12;40(10):899-906. Epub 2017 Jun 12.

Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, California.

Background: In 2011, the US Food and Drug Administration requested that GlaxoSmithKline perform retrospective adjudication of cardiovascular (CV) events reported in the bupropion drug-development trials for smoking cessation.

Hypothesis: Retrospective adjudication of clinical trial data will not increase the identification of adverse events.

Methods: We performed a comprehensive retrospective analysis of adverse events in 19 previously completed controlled US clinical trials of bupropion marketed for the treatment of smoking cessation, yielding 9479 subjects (5290 bupropion, 2927 placebo, 1018 active control [ACT], and 244 treated concurrently with bupropion and ACT). All adverse events were sent to the Duke Clinical Research Institute for adjudication by Clinical Events Classification (CEC) physician reviewers. The primary endpoint was a composite of major adverse CV events: CV death, nonfatal myocardial infarction (MI), and nonfatal stroke.

Results: Overall, 416 nonfatal CV events in 366 subjects, and 22 deaths, were identified and processed for adjudication. Of these, 7 nonfatal MIs (4 bupropion, 3 placebo, 0 ACT), 5 nonfatal strokes (1 bupropion, 3 placebo, 1 ACT), and 9 CV deaths (4 bupropion, 4 placebo, 1 ACT) were confirmed by the CEC Committee. The primary endpoint occurred in 3/4297 (0.07%) subjects in the bupropion group and in 4/2927 (0.14%) subjects in the placebo group (log-rank P value: 0.613).

Conclusions: CV events in bupropion clinical trials for smoking cessation were uncommon, with no observed increase among subjects assigned to bupropion vs placebo. However, this effort was limited by a paucity of quality data.
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http://dx.doi.org/10.1002/clc.22744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490529PMC
October 2017

Antithrombotic agents for secondary prevention after acute coronary syndromes: A systematic review and network meta-analysis.

Int J Cardiol 2017 Aug 14;241:87-96. Epub 2017 Mar 14.

Division of Cardiology, Duke University, Durham, NC, USA; Duke Clinical Research Institute, Duke University, Durham, NC, USA.

Background: Nine oral antithrombotic medications currently available in the United States and Europe have been studied in clinical trials for secondary prevention of cardiac events following acute coronary syndrome (ACS). Few combinations of these medications have been directly compared, and studies have used multiple different comparator regimens.

Methods: We performed a systematic review and network meta-analysis of randomized controlled trials evaluating one or more available oral antithrombotic therapies in patients with ACS or prior myocardial infarction (MI). Co-primary outcomes were all-cause and cardiovascular mortality compared with imputed placebo and aspirin monotherapy.

Results: Forty-seven studies (196,057 subjects) met inclusion criteria and were included in the systematic review. Almost all studies tested either aspirin monotherapy compared with placebo or a combination of antithrombotic agents that included aspirin. Nearly all regimens reduced all-cause and cardiovascular mortality compared with imputed placebo. However, compared with imputed aspirin monotherapy, only combination therapy with aspirin plus ticagrelor was associated with lower cardiovascular mortality (OR 0.80, 95% CI 0.68-0.93), and triple therapy with aspirin, clopidogrel, and very low dose rivaroxaban was associated with lower all-cause mortality (OR 0.67, 95% CI 0.49-0.90). Major bleeding was increased 45-95% with dual antithrombotic therapy, and 2-6-fold with triple therapy.

Conclusion: Few combinations of antithrombotic therapy were associated with a reduction in mortality compared with aspirin monotherapy, highlighting the difficulty in clinical interpretation of composite ischemic endpoints. Future studies may need to focus on limiting the number of antithrombotic therapies tested in combination to best balance ischemic event reduction and bleeding.
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http://dx.doi.org/10.1016/j.ijcard.2017.03.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469706PMC
August 2017

Levonorgestrel Intrauterine Device as an Endometrial Cancer Prevention Strategy in Obese Women: A Cost-Effectiveness Analysis.

Obstet Gynecol 2016 10;128(4):747-753

Divisions of Gynecologic Oncology and Clinical and Epidemiologic Research, Department of Obstetrics and Gynecology, Duke Clinical Research Institute, and the Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Objective: To estimate the cost-effectiveness of the levonorgestrel intrauterine device (IUD) as an endometrial cancer prevention strategy in obese women.

Methods: A modified Markov model was used to compare IUD placement at age 50 with usual care among women with a body mass index (BMI, kg/m) 40 or greater or BMI 30 or greater. The effects of obesity on incidence and survival were incorporated. The IUD was assumed to confer a 50% reduction in cancer incidence over 5 years. Costs of IUD and cancer care were included. Clinical outcomes were cancer diagnosis and deaths from cancer. Incremental cost-effectiveness ratios were calculated in 2015 U.S. dollars per year of life saved. One-way and two-way sensitivity analyses and Monte Carlo probabilistic analyses were performed.

Results: For a 50 year old with BMI 40 or greater, the IUD strategy is costlier and more effective than usual care with an incremental cost-effectiveness ratio of $74,707 per year of life saved. If the protective effect of the levonorgestrel IUD is assumed to be 10 years, the incremental cost-effectiveness ratio decreases to $37,858 per year of life saved. In sensitivity analysis, a levonorgestrel IUD that reduces cancer incidence by at least 68% in women with BMIs of 40 or greater or costs less than $500 is potentially cost-effective. For BMI 30 or greater, the incremental cost-effectiveness ratio of IUD strategy is $137,223 per year of life saved compared with usual care. In Monte Carlo analysis, IUD placement for BMI 40 or greater is cost-effective in 50% of simulations at a willingness-to-pay threshold of $100,000 per year of life saved.

Conclusion: The levonorgestrel IUD is a potentially cost-effective strategy for prevention of deaths from endometrial cancer in obese women.
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http://dx.doi.org/10.1097/AOG.0000000000001616DOI Listing
October 2016

Dichotomous Relationship Between Age and 30-Day Death or Rehospitalization in Heart Failure Patients Admitted With Acute Decompensated Heart Failure: Results From the ASCEND-HF Trial.

J Card Fail 2016 Jun 4;22(6):409-16. Epub 2016 Mar 4.

Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA.

Background: Younger age as an independent predictor of death or all-cause rehospitalization at 30 days post-randomization for hospitalized heart failure (HF) patients has not been well described.

Methods And Results: ASCEND-HF enrolled 7141 hospitalized acute HF patients (categorized by age: <45, 45 to <55, 55 to <65, 65 to <75, and ≥75 years) and followed them for 30 days to assess clinical outcomes, which included death or rehospitalization. Patients 45 to <55 years had the lowest percentages of death (1.4%) and total rehospitalizations (10.7%); percentages increased for younger (3.0% and 12.2%, respectively, for age <45 y) and older (5.8% and 12.5%, respectively, for age ≥75 y) patients. For those rehospitalized, the total HF-induced readmissions were highest in the youngest (68%) and declined with increasing age (P = .03). Although patients ≥55 years of age were more likely to die or be rehospitalized within 30 days of randomization for each additional 10 years of life, those <55 years of age had a significant reduction in death or HF rehospitalization for each 10-year increase in age (similar findings for death and HF rehospitalization).

Conclusions: There is a dichotomous relationship between age and risk of death or rehospitalization, and death or HF rehospitalization-risk decreases as age increases up to age 55 years, then increases after age 55 years.
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http://dx.doi.org/10.1016/j.cardfail.2016.02.011DOI Listing
June 2016

A Systematic Review of Race and Ethnicity in Hepatitis C Clinical Trial Enrollment.

J Natl Med Assoc 2016 Feb;108(1):24-9

Division of Gastroenterology, Duke University School of Medicine, Duke Clinical Research Institute.

The African American/Black population in the United States (US) is disproportionately affected by hepatitis C virus (HCV) and has lower response rates to current treatments. This analysis evaluates the participation of African American/Blacks in North American and European HCV clinical trials. The data source for this analysis was the PubMed database. Randomized controlled clinical trials (RCT) on HCV treatment with interferon 2a or 2b between January 2000 and December 2011 were reviewed. Inclusion criteria included English language and participants 18 years or older with chronic HCV. Exclusion criteria included non-randomized trials, case reports, cohort studies, ethnic specific studies, or studies not using interferon-alfa or PEG-interferon. Of the 588 trials identified, 314 (53.4%) fit inclusion criteria. The main outcome was the rate of African American/ Black participation in North American HCV clinical trials. A meta-analysis comparing the expected and observed rates was performed. Of the RCT's that met search criteria, 123 (39.2%) reported race. Clinical trials in North America were more likely to report racial data than European trials. Racial reporting increased over time. There was a statistically significant difference among the expected and observed participation of African Americans in HCV clinical trials in North America based on the prevalence of this disease within the population. The burden of HCV among African Americans in North America is not reflected in those clinical trials designed to treat HCV. Research on minority participation in clinical trials and how to increase minority participation in clinical trials is needed.
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http://dx.doi.org/10.1016/j.jnma.2015.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857937PMC
February 2016

Nesiritide in patients hospitalized for acute heart failure: does timing matter? Implication for future acute heart failure trials.

Eur J Heart Fail 2016 06 27;18(6):684-92. Epub 2016 Jan 27.

Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.

Aims: It remains unclear if early administration of i.v. nesiritide in patients hospitalized with acute heart failure (AHF) is associated with improved clinical outcomes.

Methods And Results: We analysed data from 7007 patients enrolled in ASCEND-HF to examine the associations between time to treatment with study medication (nesiritide or placebo) and clinical endpoints: (i) moderate to marked dyspnoea relief on a 7-point Likert scale at 6 h; (ii) 30-day all-cause mortality or re-hospitalization; and (iii) 30-day all-cause mortality. The median time to study drug administration was 16.7 h (25th, 75th percentiles = 6.5, 23.1), with significant regional variation (e.g. median of 13.0 h in Asia-Pacific vs. 18.4 h in North America). After risk adjustment, each hour delay in study medication after the first 10 h from initial hospital presentation was associated with modestly reduced odds of dyspnoea relief [(adjusted odds ratio (OR) 0.98, 95% confidence interval (CI) 0.98-0.99; P < 0.0001]. Every hour delay in study medication was associated with modestly higher all-cause mortality or re-hospitalization (unadjusted OR 1.01, 95% CI 1.01-1.02; P < 0.001) due to pre-randomization therapies and known predictors of 30-day outcomes (adjusted P = 0.12). There was no significant association between time to study drug and all-cause mortality (P > 0.08).

Conclusion: In a large international AHF trial, time to treatment with study medication varied markedly across regions. Earlier administration of study medication was associated with modestly better dyspnoea relief, but not 30-day clinical outcomes. The association between timing of treatment with study medication and study endpoints may have implications for the interpretation of AHF studies and future trial design.
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http://dx.doi.org/10.1002/ejhf.487DOI Listing
June 2016

Torsemide Versus Furosemide in Patients With Acute Heart Failure (from the ASCEND-HF Trial).

Am J Cardiol 2016 Feb 18;117(3):404-11. Epub 2015 Nov 18.

Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina; Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.

Furosemide is the most commonly used loop diuretic in patients with heart failure (HF) despite data suggesting potential pharmacologic and antifibrotic benefits with torsemide. We investigated patients with HF in Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure who were discharged on either torsemide or furosemide. Using inverse probability weighting to account for the nonrandom selection of diuretic, we assessed the relation between choice of diuretic at discharge with 30-day mortality or HF hospitalization and 180-day mortality. Of 7,141 patients in the trial, 4,177 patients were included in this analysis, of which 87% (n = 3,620) received furosemide and 13% (n = 557) received torsemide. Torsemide-treated patients had lower ejection fraction and blood pressure and higher creatinine and natriuretic peptide level compared with furosemide. Torsemide was associated with similar outcomes on unadjusted analysis and nominally lower events on adjusted analysis (30-day mortality/HF hospitalization odds ratio 0.89, 95% CI 0.62 to 1.29, p = 0.55 and 180-day mortality hazard ratio 0.86, 95% CI 0.63 to 1.19, p = 0.37). In conclusion, these data are hypothesis-generating and randomized comparative effectiveness trials are needed to investigate the optimal diuretic choice.
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http://dx.doi.org/10.1016/j.amjcard.2015.10.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718787PMC
February 2016

Catheter ablation for ventricular tachycardia (VT) in patients with ischemic heart disease: a systematic review and a meta-analysis of randomized controlled trials.

J Interv Card Electrophysiol 2016 Mar 22;45(2):111-7. Epub 2015 Dec 22.

Department of Medicine, Duke University Medical Center, Durham, NC, USA.

Background: Patients with ischemic heart disease may have implantable cardioverter defibrillators (ICDs) implanted for primary or secondary prevention of sudden cardiac death. Although ICD shocks can be life saving, in some patients, they have been associated with increased mortality and/or morbidity. Several studies have suggested that catheter ablation may be superior to non-ablative strategies at preventing ICD shocks delivered for ventricular arrhythmias; however, this is still controversial.

Methods: We performed a meta-analysis of randomized controlled trials (RCTs) comparing catheter ablation with non-ablative strategies in treatment of ventricular tachycardia (VT) in patients with ischemic heart disease and an ICD. The primary endpoints of interest were recurrent episodes of VT and death. We used a binary random effects method to calculate the cumulative odds ratios (OR) for recurrent VT and deaths.

Results: Of a total of 643 potential citations, our search yielded three citations that met our inclusion and exclusion criteria. In the three trials, a total of 262 patients were randomized to ablation (n = 129) or non-ablative interventions (beta-blockers ± use of antiarrhythmics) (n = 133) group. The cumulative OR for recurrent VT was 0.471 (95% confidence interval (CI) = 0.176-1.257) for catheter ablation compared with non-ablative strategies, and for death, it was 0.766 (95% CI = 0.351-1.674). Excluding one study for being appreciably smaller than the other two, the OR for recurrent VT was 0.298 (95% CI = 0.164-0.543).

Conclusions: In this meta-analysis, the rate of recurrent VT was lower with VT catheter ablation compared with non-ablative strategies. There was not a significant difference in rate of death among patients receiving catheter ablation versus non-ablative strategies for management of VT. Given the lack of adequately powered RCTs comparing ablation versus medical management of VT in patients with ischemic heart disease and an ICD, larger studies with longer follow-up are needed.
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http://dx.doi.org/10.1007/s10840-015-0083-4DOI Listing
March 2016

Psyllium fiber improves glycemic control proportional to loss of glycemic control: a meta-analysis of data in euglycemic subjects, patients at risk of type 2 diabetes mellitus, and patients being treated for type 2 diabetes mellitus.

Am J Clin Nutr 2015 Dec 11;102(6):1604-14. Epub 2015 Nov 11.

Division of Endocrinology, Metabolism and Nutrition, Duke Department of Medicine, Duke University, Durham, NC.

Background: A number of health benefits are associated with intake of soluble, viscous, gel-forming fibers, including reduced serum cholesterol and the attenuation of postprandial glucose excursions.

Objective: We assess the effects of psyllium, which is a soluble, gel-forming, nonfermented fiber supplement, on glycemic control in patients who were being treated for type 2 diabetes mellitus (T2DM) and in patients who were at risk of developing T2DM.

Design: A comprehensive search was performed of available published literature (Scopus scientific database) and clinical records stored by Procter & Gamble with the use of key search terms to identify clinical studies that assessed the glycemic effects of psyllium in nondiabetic, pre-T2DM, and T2DM patients.

Results: We identified 35 randomized, controlled, clinical studies that spanned 3 decades and 3 continents. These data were assessed in 8 meta-analyses. In patients with T2DM, multiweek studies (psyllium dosed before meals) showed significant improvement in both the fasting blood glucose (FBG) concentration (-37.0 mg/dL; P < 0.001) and glycated hemoglobin (HbA1c) [-0.97% (-10.6 mmol/mol); P = 0.048]. Glycemic effects were proportional to baseline FBG; no significant glucose lowering was observed in euglycemic subjects, a modest improvement was observed in subjects with pre-T2DM, and the greatest improvement was observed in subjects who were being treated for T2DM.

Conclusions: These data indicate that psyllium would be an effective addition to a lifestyle-intervention program. The degree of psyllium's glycemic benefit was commensurate with the loss of glycemic control. Because the greatest effect was seen in patients who were being treated for T2DM, additional studies are needed to determine how best to incorporate psyllium into existing prevention and treatment algorithms with concomitant hypoglycemic medications.
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http://dx.doi.org/10.3945/ajcn.115.106989DOI Listing
December 2015

Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial.

Lancet 2016 01 5;387(10016):349-356. Epub 2015 Nov 5.

Duke Clinical Research Institute, Duke Medicine, Durham, NC, USA.

Background: REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding.

Methods: We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions.

Findings: 1616 patients were allocated REG1 and 1616 were assigned bivalirudin, of whom 1605 and 1601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1605 patients receiving REG1 versus one (<1%) of 1601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1616 patients assigned REG1 and 103 (6%) of 1616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1·05, 95% CI 0·80-1·39; p=0·72). Major bleeding was similar between treatment groups (seven [<1%] of 1605 receiving REG1 vs two [<1%] of 1601 treated with bivalirudin; OR 3·49, 95% CI 0·73-16·82; p=0·10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1·64, 1·19-2·25; p=0·002).

Interpretation: The reversible factor IXa inhibitor REG1, as currently formulated, is associated with severe allergic reactions. Although statistical power was limited because of early termination, there was no evidence that REG1 reduced ischaemic events or bleeding compared with bivalirudin.

Funding: Regado Biosciences Inc.
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http://dx.doi.org/10.1016/S0140-6736(15)00515-2DOI Listing
January 2016

Body mass index and mortality in endometrial cancer: A systematic review and meta-analysis.

Gynecol Oncol 2016 Jan 31;140(1):184-90. Epub 2015 Oct 31.

Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.

Objective: To evaluate the association between body mass index (BMI) and mortality in women with endometrial cancer.

Methods: A systematic review was performed utilizing a Medline search with Mesh keywords 'endometrial neoplasms' and ('body mass index' or 'obesity') and ('survival analysis' or 'mortality' or 'survivor' or 'survival') for studies published prior to June 2013. Inclusion criteria included studies that assessed associations between BMI and survival in endometrial cancer patients. Two investigators independently reviewed the title and abstract and full-text of articles for inclusion or exclusion decision; discordant decisions were adjudicated by a third reviewer. A random-effects model was constructed that was comparable to the standard random-effects models used in the meta-analysis of odds ratios. The model was fitted using SAS PROC NLMIXED.

Results: 1451 studies were identified and reviewed in duplicate, 18 met inclusion criteria. A random-effects meta-analysis demonstrated significantly higher odds of mortality with increasing BMI in endometrial cancer patients. Specifically the odds ratios were 1.01, 1.17, 1.26, and 1.66 for BMI categories of 25-29.9, 30-34.9, 35-39.9, and 40+, respectively. The odds ratio for all-cause mortality in endometrial cancer patients with a BMI≥40 compared to those with a BMI<25 was 1.66 (CI: 1.10-2.51, p=0.02). A single dose-response model indicated that a 10% increase in BMI resulted in a 9.2% increase in the odds of all-cause mortality (p=0.007).

Conclusion: Increased BMI is significantly associated with increased all-cause mortality in women with endometrial cancer, with the highest risk for those with a BMI≥40.
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http://dx.doi.org/10.1016/j.ygyno.2015.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065832PMC
January 2016

Individual Proton Pump Inhibitors and Outcomes in Patients With Coronary Artery Disease on Dual Antiplatelet Therapy: A Systematic Review.

J Am Heart Assoc 2015 Oct 29;4(11). Epub 2015 Oct 29.

Division of General Internal Medicine, Duke University Medical Center, Durham, NC (R.J.D.).

Background: Observational studies evaluating the possible interaction between proton pump inhibitors (PPIs) and clopidogrel have shown mixed results. We conducted a systematic review comparing the safety of individual PPIs in patients with coronary artery disease taking clopidogrel.

Methods And Results: Studies performed from January 1995 to December 2013 were screened for inclusion. Data were extracted, and study quality was graded for 34 potential studies. For those studies in which follow-up period, outcomes, and multivariable adjustment were comparable, meta-analysis was performed.The adjusted odds or hazard ratios for the composite of cardiovascular or all-cause death, myocardial infarction, and stroke at 1 year were reported in 6 observational studies with data on individual PPIs. Random-effects meta-analyses of the 6 studies revealed an increased risk for adverse cardiovascular events for those taking pantoprazole (hazard ratio 1.38; 95% CI 1.12-1.70), lansoprazole (hazard ratio 1.29; 95% CI 1.09-1.52), or esomeprazole (hazard ratio 1.27; 95% CI 1.02-1.58) compared with patients on no PPI. This association was not significant for omeprazole (hazard ratio 1.16; 95% CI 0.93-1.44). Sensitivity analyses for the coronary artery disease population (acute coronary syndrome versus mixed) and exclusion of a single study due to heterogeneity of reported results did not have significant influence on the effect estimates for any PPIs.

Conclusions: Several frequently used PPIs previously thought to be safe for concomitant use with clopidogrel were associated with greater risk of adverse cardiovascular events. Although the data are observational, they highlight the need for randomized controlled trials to evaluate the safety of concomitant PPI and clopidogrel use in patients with coronary artery disease.
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http://dx.doi.org/10.1161/JAHA.115.002245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845227PMC
October 2015

Worsening heart failure during hospitalization for acute heart failure: Insights from the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF).

Am Heart J 2015 Aug 15;170(2):298-305. Epub 2015 Apr 15.

Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.

Background: Despite initial in-hospital treatment of acute heart failure (HF), some patients experience worsening HF (WHF). There are limited data about the outcomes and characteristics of patients who experience in-hospital WHF.

Methods And Results: We assessed the characteristics and outcomes of patients with and without WHF in the ASCEND-HF trial. Worsening HF was defined as at least 1 symptom or sign of new, persistent, or WHF requiring additional intravenous inotropic/vasodilator or mechanical therapy during index hospitalization. We assessed the relationship between WHF and 30-day mortality, 30-day mortality or HF hospitalization, and 180-day mortality. We also assessed whether there was a differential association between early (days 1-3) vs late (day ≥4) WHF and outcomes. Of 7,141 patients with acute HF, 354 (5%) experienced WHF. Patients with WHF were more often male and had a history of atrial fibrillation or diabetes, lower blood pressure, and higher creatinine. After risk adjustment, WHF was associated with increased 30-day mortality (odds ratio 13.37, 95% CI 9.85-18.14), 30-day mortality or HF rehospitalization (odds ratio 6.78, 95% CI 5.25-8.76), and 180-day mortality (hazard ratio 3.90, 95% CI 3.14-4.86) (all P values < .0001). There was no evidence of a difference in outcomes between early and late WHF (all P values for comparison ≥ .2).

Conclusions: Worsening HF during index hospitalization was associated with worse 30- and 180-day outcomes. Worsening HF may represent an important patient-centered outcome in acute HF and a focus of future treatments.
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http://dx.doi.org/10.1016/j.ahj.2015.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581586PMC
August 2015

Predictors of clinical outcomes in acute decompensated heart failure: Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure outcome models.

Am Heart J 2015 Aug 11;170(2):290-7. Epub 2015 Apr 11.

Cleveland Clinic Foundation, Cleveland, OH.

Background: Patients hospitalized for acute decompensated heart failure (ADHF) are at high risk for early mortality and rehospitalization. Risk stratification of ADHF using clinically available data on admission is increasingly important to integrate with clinical pathways. Our goal was to create a simple method of screening patients upon admission to identify those with increased risk of future adverse events.

Methods: Using ASCEND-HF, a pragmatic clinical trial conducted in 398 sites globally, we developed and validated logistic regression risk models for (a) 30-day mortality/HF rehospitalization, (b) 30-day mortality/all-cause rehospitalization, (c) 30-day all-cause mortality, and (d) 180-day all-cause mortality. Fifty-one candidate variables were evaluated based on prior publications and clinical review. Final models were selected based on stepwise selection with entry and a staying criterion of P < .01. The 30-day mortality model was externally validated, and coefficients were converted to an additive risk score.

Results: Among 7,141 patients, the median age was 67 years, 34% were female, and 80% had a left ventricular ejection fraction <40%. The models had between 5 and 12 risk factors with c-indices ranging from 0.68 to 0.75. A simplified score, including age, systolic blood pressure, sodium, blood urea nitrogen, and dyspnea at rest, discriminated 30-day mortality risk from 0.5% (score 0) to 53% (score 10).

Conclusions: Commonly available clinical variables provide simple risk stratification for clinical outcomes among patients with ADHF, and these models may be considered for integration into routine clinical care.
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http://dx.doi.org/10.1016/j.ahj.2015.04.006DOI Listing
August 2015

Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation.

N Engl J Med 2015 Aug 22;373(9):823-33. Epub 2015 Jun 22.

From St. Joseph's Healthcare Hamilton (J.D.D.) and the Department of Medicine (J.D.D.) and Hamilton Health Science Center (S.S., A.G.G.T.), McMaster University, Hamilton, ON, Canada; Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset (A.C.S.), and Mount Sinai Medical Center, New York (A.S.D.) - both in New York; Hurley Medical Center, Flint, MI (S.K.); University of Cincinnati College of Medicine, Cincinnati (R.C.B.); NorthShore University HealthSystem, Evanston (J.A.C.), and Rush University Medical Center, Chicago (A.K.J.) - both in Illinois; University of Washington Medical Center, Seattle (D.A.G.); Veterans Affairs Loma Linda Healthcare System, Loma Linda, CA (A.J.); and Duke Clinical Research Institute (D.F.K., V.H.) and Department of Medicine (T.L.O.), Duke University Medical Center, Durham, NC.

Background: It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecular-weight heparin for the prevention of perioperative arterial thromboembolism and would be superior to bridging with respect to major bleeding.

Methods: We performed a randomized, double-blind, placebo-controlled trial in which, after perioperative interruption of warfarin therapy, patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin per kilogram of body weight) or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was resumed within 24 hours after the procedure. Follow-up of patients continued for 30 days after the procedure. The primary outcomes were arterial thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding.

Results: In total, 1884 patients were enrolled, with 950 assigned to receive no bridging therapy and 934 assigned to receive bridging therapy. The incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (risk difference, 0.1 percentage points; 95% confidence interval [CI], -0.6 to 0.8; P=0.01 for noninferiority). The incidence of major bleeding was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, 0.20 to 0.78; P=0.005 for superiority).

Conclusions: In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.).
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http://dx.doi.org/10.1056/NEJMoa1501035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931686PMC
August 2015

Supervised vs unsupervised exercise for intermittent claudication: A systematic review and meta-analysis.

Am Heart J 2015 Jun 26;169(6):924-937.e3. Epub 2015 Mar 26.

Division of Cardiology, Duke University Medical Center, Durham, NC; Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.

Background: Supervised exercise (SE) is widely accepted as an effective therapy for intermittent claudication (IC), but its use is limited by cost. Unsupervised exercise (UE) represents a less costly alternative. We assessed the comparative effectiveness of SE vs UE in patients with IC.

Methods And Results: We searched PubMed, EMBASE, and the Cochrane Database of Systematic Reviews and identified 27 unique studies (24 randomized controlled trials, 4 observational studies) that evaluated the comparative effectiveness of SE vs UE in 2074 patients with IC. Compared with UE, SE was associated with a moderate improvement in maximal walking distance at 6 months (effect size 0.77, 95% CI 0.36-1.17, P < .001) and 12 months (effect size 0.56, 95% CI 0.34-0.77, P < .001). Supervised exercise also improved claudication distance to a moderate extent compared with UE at 6 months (effect size 0.63, 95% CI 0.40-0.85, P < .001) and 12 months (effect size 0.41, 95% CI 0.18-0.65, P = .001). There was no difference in the Short Form-36 quality of life at 6 months (effect size -0.05, 95% CI -0.50 to 0.41, P = .84) or walking impairment questionnaire distance (effect size 0.24, 95% CI -0.03 to 0.50, P = .08) or speed (effect size 0.26, 95% CI -0.06 to 0.59, P = .11).

Conclusions: In claudication patients, SE is more effective than UE at improving maximal walking and claudication distances, yet there is no difference in general quality of life or patient-reported community-based walking. Further studies are needed to investigate the relationship between functional gain and disease-specific quality of life.
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http://dx.doi.org/10.1016/j.ahj.2015.03.009DOI Listing
June 2015

Comparative Effectiveness of Medical Therapy, Supervised Exercise, and Revascularization for Patients With Intermittent Claudication: A Network Meta-analysis.

Clin Cardiol 2015 Jun 12;38(6):378-86. Epub 2015 May 12.

Division of Cardiology, Duke University Medical Center, Durham, North Carolina.

Background: There are limited data on the comparative effectiveness of medical therapy, supervised exercise, and revascularization to improve walking and quality of life in patients with intermittent claudication (IC).

Hypothesis: Supervised exercise and revascularization was superior to medical therapy in IC.

Methods: We studied the comparative effectiveness of exercise training, medications, endovascular intervention, and surgical revascularization on outcomes including functional capacity (walking distance and timing), quality of life, and mortality. We searched PubMed, EMBASE, and the Cochrane Database of Systematic Reviews from January 1995 to August 2012 for relevant English-language studies. Two investigators independently collected data. Meta-analyses with random-effects models of direct comparisons were supplemented by mixed-treatment analyses to incorporate data from placebo comparisons, head-to-head comparisons, and multiple treatment arms.

Results: Thirty-five unique studies evaluated treatment modalities in 7475 patients with IC. Compared with usual care, only exercise training improved both maximal walking distance (150 meters; 95% confidence interval: 35-266 meters, P = 0.01) and initial claudication distance (39 meters; 95% confidence interval: 9-65 meters, P = 0.003). All modalities were associated with improved quality of life (Short Form-36 physical functioning score) compared with usual care, but there were no differences between treatments. There were insufficient safety data to assess treatment-related complications. All-cause mortality was not significantly different between modalities.

Conclusions: Evidence is insufficient to determine treatment superiority for improving quality of life and walking parameters in IC patients. Further studies with attention to study design, standardized efficacy and safety endpoints, and appropriate subgroup reporting are necessary to determine comparative effectiveness.
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http://dx.doi.org/10.1002/clc.22406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711096PMC
June 2015

Complications from prophylactic replacement of cardiac implantable electronic device generators in response to United States Food and Drug Administration recall: A systematic review and meta-analysis.

Heart Rhythm 2015 Jul 3;12(7):1558-64. Epub 2015 Apr 3.

Duke Clinical Research Institute, Durham, North Carolina; Duke University Medical System, Durham, North Carolina. Electronic address:

Background: The number of cardiac implantable electronic device (CIED) recalls and advisories has increased over the past 3 decades, yet no consensus exists on how to best manage patients with these CIEDs, partially because rates of complications from prophylactic replacement are unknown.

Objective: The purpose of this study was to establish rates of complications when recalled CIED generators are replaced prophylactically.

Methods: We searched MEDLINE and the Cochrane Controlled Trials Register for reports of prophylactic replacement of recalled CIED generators. Studies with <20 subjects were excluded. We then conducted a meta-analysis of qualifying studies to determine the rates of combined major complications, mortality, and reoperation.

Results: We identified 7 citations that met our inclusion criteria and reported ≥1 end-points of interest. Four were single center, and 3 were multicenter. Six studies collected data retrospectively (n = 1213) and 1 prospectively (n = 222). Using a random effects model to combine data from all included studies, the rate of major complications was 2.5% (95% confidence interval [CI] 1.0%-4.5%). Combining data from 6 studies reporting mortality and reoperation, the rates were 0.5% (95% CI 0.1%-0.9%) and 2.5% (95% CI 0.8%-4.5%), respectively.

Conclusion: Prophylactic replacement of recalled CIED generators is associated with a low mortality rate but nontrivial rates of other major complications similar to those reported when CIED generators are replaced for other reasons. Thus, when considering replacing a recalled CIED generator, known risks of elective generator replacement likely apply and can be weighed against risks associated with device failure.
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http://dx.doi.org/10.1016/j.hrthm.2015.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517571PMC
July 2015

Loop diuretic dose adjustments after a hospitalization for heart failure: insights from ASCEND-HF.

Eur J Heart Fail 2015 Mar 23;17(3):340-6. Epub 2015 Jan 23.

Duke Clinical Research Institute, Durham, NC, USA; Department of Medicine, Duke University School of Medicine, Durham, NC, USA.

Aims: Loop diuretics are a cornerstone of heart failure (HF) treatment, but data regarding diuretic dose adjustments after a HF hospitalization and the association with subsequent outcomes are limited. This study was therefore conducted to determine these factors.

Methods And Results: We analysed data from 6119 patients enrolled in ASCEND-HF, examining the association between loop diuretic use at the time of discharge, compared with admission, and the composite outcome of 30-day HF re-hospitalization or all-cause mortality. The majority of patients, 3921 (64%), were taking a loop diuretic on admission. At discharge, 3411 (56%) patients were prescribed higher doses compared with admission, including 1867 (31%) initiating daily outpatient diuretics; 1912 (31%) had no dose change and 795 (13%) were prescribed lower doses compared with admission. Initiation of an oral loop diuretic at discharge was independently associated with better 30-day outcomes compared with no dose change [adjusted odds ratio (OR) 0.51, 95% confidence interval (CI) 0.37-0.68]. However, for patients that were already established on a loop diuretic prior to admission, change in the dose at discharge was not associated with improved outcomes compared with no dose change (adjusted OR 0.92, 95% CI 0.79-1.07).

Conclusions: In a large multinational clinical trial, 56% of patients hospitalized with HF were either initiated on a daily loop diuretic at discharge or discharged on higher doses compared with admission. In patients established on diuretics prior to hospitalization, we found no association between changes to chronic doses at discharge and improved outcomes, whereas initiation of loop diuretic therapy was associated with better outcomes compared with no dose change.
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http://dx.doi.org/10.1002/ejhf.235DOI Listing
March 2015

Hypotension during hospitalization for acute heart failure is independently associated with 30-day mortality: findings from ASCEND-HF.

Circ Heart Fail 2014 Nov 3;7(6):918-25. Epub 2014 Oct 3.

From the Duke Clinical Research Institute, Durham, NC (P.A.P., G.H., C.M.O., P.J.S., V.H., R.M.C., A.F.H.); Duke University Medical Center, Durham, NC (C.M.O., R.M.C., A.F.H.); Central Hospital Cardiology Division, Stavanger, Norway (K.D.); Division of Cardiology, Department of Medicine, University of Alberta and Mazankowski Alberta Heart Institute, Edmonton, Canada (J.A.E., P.W.A.); Janssen Research & Development, LLC, Raritan, NJ (R.M.M.); Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.); Cleveland Clinic Foundation, OH (R.C.S., W.H.W.T.).

Background: Outcomes associated with episodes of hypotension while hospitalized with acute decompensated heart failure are not well understood.

Methods And Results: Using data from Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), we assessed factors associated with in-hospital hypotension and subsequent 30-day outcomes. Patients were classified as having symptomatic or asymptomatic hypotension. Multivariable logistic regression was used to determine factors associated with in-hospital hypotension, and Cox proportional hazards models were used to assess the association between hypotension and 30-day outcomes. We also tested for treatment interaction with nesiritide on 30-day outcomes and the association between in-hospital hypotension and renal function at hospital discharge. Overall, 1555 of 7141 (21.8%) patients had an episode of hypotension, of which 73.1% were asymptomatic and 26.9% were symptomatic. Factors strongly associated with in-hospital hypotension included randomization to nesiritide (odds ratio, 1.98; 95% confidence interval [CI], 1.76-2.23; P<0.001), chronic metolazone therapy (odds ratio, 1.74; 95% CI, 1.17-2.60; P<0.001), and baseline orthopnea (odds ratio, 1.31; 95% CI, 1.13-1.52; P=0.001) or S3 gallop (odds ratio, 1.21; 95% CI, 1.06-1.40; P=0.006). In-hospital hypotension was associated with increased hazard of 30-day mortality (hazard ratio, 2.03; 95% CI, 1.57-2.61; P<0.001), 30-day heart failure hospitalization or mortality (hazard ratio, 1.58; 95% CI, 1.34-1.86; P<0.001), and 30-day all-cause hospitalization or mortality (hazard ratio, 1.40; 95% CI, 1.22-1.61; P<0.001). Nesiritide had no interaction on the relationship between hypotension and 30-day outcomes (interaction P=0.874 for death, P=0.908 for death/heart failure hospitalization, P=0.238 death/all-cause hospitalization).

Conclusions: Hypotension while hospitalized for acute decompensated heart failure is an independent risk factor for adverse 30-day outcomes, and its occurrence highlights the need for modified treatment strategies.

Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00475852.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.113.000872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456178PMC
November 2014

Nesiritide, renal function, and associated outcomes during hospitalization for acute decompensated heart failure: results from the Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure (ASCEND-HF).

Circulation 2014 Sep 29;130(12):958-65. Epub 2014 Jul 29.

From the Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (V.M.v.D., A.A.V.); Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (A.F.H., A.S., V.H., C.M.O., R.C.S.); Mazankowski Alberta Heart Institute, Edmonton, Canada (J.A.E.); Duke Translational Medicine Institute, Durham, NC (R.M.C.); University of Maryland Hospital, Division of Cardiology, Baltimore, MD (S.S.G.); Cleveland Clinic Foundation, Cleveland, OH (W.H.W.T.); British Heart Foundation Cardiovascular Research Centre, Glasgow, Scotland, UK (J.J.M.); and Central Hospital Cardiology Division, Stavanger, Norway (K.D.).

Background: Contradictory results have been reported on the effects of nesiritide on renal function in patients with acute decompensated heart failure. We studied the effects of nesiritide on renal function during hospitalization for acute decompensated heart failure and associated outcomes.

Methods And Results: A total of 7141 patients were randomized to receive either nesiritide or placebo and creatinine was recorded in 5702 patients at baseline, after infusion, discharge, peak/nadir levels until day 30. Worsening renal function was defined as an increase of serum creatinine >0.3 mg/dL and a change of ≥25%. Median (25(th)-75(th) percentile) baseline creatinine was 1.2 (1.0-1.6) mg/dL and median baseline blood urea nitrogen was 25 (18-39) mmol/L. Changes in both serum creatinine and blood urea nitrogen were similar in nesiritide-treated and placebo-treated patients (P=0.20 and P=0.41) from baseline to discharge. In a multivariable model, independent predictors of change from randomization to hospital discharge in serum creatinine were a lower baseline blood urea nitrogen, higher systolic blood pressure, lower diastolic blood pressure, previous weight gain, and lower baseline potassium (all P<0.0001). The frequency of worsening renal function during hospitalization was similar in the nesiritide and placebo group (14.1% and 12.8%, respectively; odds ratio with nesiritide 1.12; confidence interval, 0.95-1.32; P=0.19) and was not associated with death alone and death or rehospitalization at 30 days. However, baseline, discharge, and change in creatinine were associated with death alone and death or rehospitalization for heart failure (all tests, P<0.0001).

Conclusions: Nesiritide did not affect renal function in patients with acute decompensated heart failure. Baseline, discharge, and change in renal function were associated with 30-day mortality or rehospitalization for heart failure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.113.003046DOI Listing
September 2014

Pharmacologic and behavioral interventions to improve cardiovascular risk factors in adults with serious mental illness: a systematic review and meta-analysis.

J Clin Psychiatry 2014 May;75(5):e424-40

Center for Health Services Research in Primary Care, Durham Veteran Affairs Medical Center (152), 508 Fulton St, Durham, NC 27705

Objective: Individuals with serious mental illness have high rates of cardiovascular disease (CVD) risk factors and mortality. This systematic review was conducted to evaluate pharmacologic and behavioral interventions to reduce CVD risk in adults with serious mental illness.

Data Sources: MEDLINE, EMBASE, PsycINFO, ClinicalTrials.gov, and Cochrane Database of Systematic Reviews were searched from January 1980 to July 2012 for English language studies. Examples of search terms used include schizophrenia, bipolar disorder, antipsychotics, weight, glucose, lipid, and cardiovascular disease.

Study Selection: Two reviewers independently screened citations and identified 33 randomized controlled trials of at least 2 months' duration that enrolled adults with serious mental illness and evaluated pharmacologic or behavioral interventions targeting weight, glucose, or lipid control.

Data Extraction: Reviewers extracted data, assessed applicability, and evaluated study quality; the team jointly graded overall strength of evidence.

Results: We included 33 studies. Most studies targeted weight control (28 studies). Compared with control groups, weight control was improved with behavioral interventions (mean difference = -3.13 kg; 95% CI, -4.21 to -2.05), metformin (mean difference = -4.13 kg; 95% CI, -6.58 to -1.68), anticonvulsive medications topiramate and zonisamide (mean difference = -5.11 kg; 95% CI, -9.48 to -0.74), and adjunctive or antipsychotic switching to aripiprazole (meta-analysis not possible). Evidence was insufficient for all other interventions and for effects on glucose and lipid control. The small number of studies precluded analyses of variability in treatment effects by patient characteristics.

Conclusions: Few studies have evaluated interventions addressing 1 or more CVD risk factors in people with serious mental illness. Glucose- and lipid-related results were mainly reported as secondary outcome assessments in studies of weight-management interventions. Comparative effectiveness studies are needed to test multimodal strategies, agents known to be effective in nonserious mental illness populations, and antipsychotic-management strategies.
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http://dx.doi.org/10.4088/JCP.13r08558DOI Listing
May 2014

Comparative effectiveness of endovascular and surgical revascularization for patients with peripheral artery disease and critical limb ischemia: systematic review of revascularization in critical limb ischemia.

Am Heart J 2014 Apr 4;167(4):489-498.e7. Epub 2014 Jan 4.

Duke Clinical Research Institute, Duke University Medical Center, Durham, NC; Division of Cardiology, Duke University Medical Center, Durham, NC.

Background: For patients with critical limb ischemia (CLI), the optimal treatment to enhance limb preservation, prevent death, and improve functional status is unknown. We performed a systematic review and meta-analysis to assess the comparative effectiveness of endovascular revascularization and surgical revascularization in patients with CLI.

Methods: We systematically searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for relevant English-language studies published from January 1995 to August 2012. Two investigators screened each abstract and full-text article for inclusion, abstracted the data, and performed quality ratings and evidence grading. Random-effects models were used to compute summary estimates of effects, with endovascular treatment as the control group.

Results: We identified a total of 23 studies, including 1 randomized controlled trial, which reported no difference in amputation-free survival at 3 years (odds ratio [OR] 1.22, 95% CI 0.84-1.77) and all-cause mortality (OR 1.07, 0.73-1.56) between the 2 treatments. Meta-analysis of the observational studies showed a statistically nonsignificant reduction in all-cause mortality at 6 months (11 studies, OR 0.85, 0.57-1.27) and amputation-free survival at 1 year (2 studies, OR 0.76, 0.48-1.21) in patients treated with endovascular revascularization. There was no difference in overall death, amputation, or amputation-free survival at ≥2 years.

Conclusions: The currently available literature suggests that there is no difference in clinical outcomes for patients with CLI treated with endovascular or surgical revascularization. There is a paucity of high-quality data available to guide clinical decision making, especially as it pertains to patient subgroups or anatomical considerations.
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http://dx.doi.org/10.1016/j.ahj.2013.12.012DOI Listing
April 2014

Oral contraceptive use for the primary prevention of ovarian cancer.

Evid Rep Technol Assess (Full Rep) 2013 Jun(212):1-514

Objective: To estimate the overall balance of harms and benefits from the potential use of oral contraceptives (OCs) for the primary prevention of ovarian cancer

Data Sources: We searched PubMed®, Embase®, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for English-language studies published from January 1990 to June 2012 that evaluated the potential benefits (reduction in ovarian, colorectal, and endometrial cancers) and harms (increase in breast and cervical cancer, and vascular complications) of OC use.

Review Methods: Two investigators screened each abstract and full-text article for inclusion; the investigators abstracted data, and they performed quality ratings, applicability ratings, and evidence grading. Random-effects models were used to compute summary estimates of effects. A simulation model was used to estimate the effects of OC use on the overall balance of benefits and harms.

Results: We reviewed 55 studies relevant to ovarian cancer outcomes, 66 relevant to other cancers, and 50 relevant to vascular events. Ovarian cancer incidence was significantly reduced in OC users (OR [odds ratio], 0.73; 95% CI [confidence interval], 0.66 to 0.81), with greater reductions seen with longer duration of use. Breast cancer incidence was slightly but significantly increased in OC users (OR, 1.08; 95% CI, 1.00 to 1.17), with a significant reduction in risk as time since last use increased. The risk of cervical cancer was significantly increased in women with persistent human papillomavirus infection who used OCs, but heterogeneity prevented a formal meta-analysis. Incidences of both colorectal cancer (OR, 0.86; 95% CI, 0.79 to 0.95) and endometrial cancer (OR, 0.57; 95% CI, 0.43 to 0.76) were significantly reduced by OC use. The risk of vascular events was increased in current OC users compared with nonusers, although the increase in myocardial infarction was not statistically significant. The overall strength of evidence for ovarian cancer prevention was moderate to low, primarily because of the lack of randomized trials and inconsistent reporting of important characteristics of use, such as duration. The simulation model predicted that the combined increase in risk of breast and cervical cancers and vascular events was likely to be equivalent to or greater than the decreased risk in ovarian cancer, although the harm/benefit ratio was much more favorable when protection against endometrial and colorectal cancers was added, resulting in net gains in life expectancy of approximately 1 month.

Conclusions: There is insufficient evidence to recommend for or against the use of OCs solely for the primary prevention of ovarian cancer. Although the net effects of the current patterns of OC use likely result in increased life expectancy when other noncontraceptive benefits are included, the harm/benefit ratio for ovarian cancer prevention alone is uncertain, particularly when the potential quality-of-life impact of breast cancer and vascular events are considered.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4781074PMC
June 2013

Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis.

J Clin Oncol 2013 Nov 21;31(33):4188-98. Epub 2013 Oct 21.

Patricia G. Moorman, Laura J. Havrilesky, Jennifer M. Gierisch, Remy R. Coeytaux, William J. Lowery, Vic Hasselblad, and Evan R. Myers, Duke University School of Medicine; Laura J. Havrilesky, Duke Cancer Institute, Duke University Health System; Jennifer M. Gierisch, Center for Health Services Research in Primary Care, Durham Veterans Affairs Medical Center; Jennifer M. Gierisch, Remy R. Coeytaux, Michaela Dinan, Amanda J. McBroom, and Gillian D. Sanders, Duke Clinical Research Institute, Durham; and Rachel Peragallo Urrutia, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC.

Purpose: To estimate the risks of ovarian cancer and breast cancer associated with oral contraceptive (OC) use among women at elevated risk owing to mutations in BRCA1/2 or a strong family history.

Methods: We searched PubMed, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published 2000 to 2012 that evaluated associations between OC use and breast or ovarian cancer among women who are carriers of a BRCA1/2 mutation or have a family history of breast or ovarian cancer.

Results: From 6,476 unique citations, we identified six studies examining ovarian cancer risk in BRCA1/2 mutation carriers and eight studies examining breast cancer risk in BRCA1/2 mutation carriers. For BRCA1/2 mutation carriers combined, meta-analysis showed an inverse association between OC use and ovarian cancer (odds ratio [OR], 0.58; 95% CI, 0.46 to 0.73) and a nonstatistically significant association with breast cancer (OR, 1.21; 95% CI, 0.93 to 1.58). Findings were similar when examining BRCA1 and BRCA2 mutation carriers separately. Data were inadequate to perform meta-analyses examining duration or timing of use. For women with a family history of ovarian or breast cancer, we identified four studies examining risk for ovarian cancer and three for breast cancer, but differences between studies precluded combining the data for meta-analyses, and no overall pattern could be discerned.

Conclusion: Our analyses suggest that associations between ever use of OCs and ovarian and breast cancer among women who are BRCA1 or BRCA2 mutation carriers are similar to those reported for the general population.
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http://dx.doi.org/10.1200/JCO.2013.48.9021DOI Listing
November 2013

Transtibial versus independent drilling techniques for anterior cruciate ligament reconstruction: a systematic review, meta-analysis, and meta-regression.

Am J Sports Med 2013 Nov 15;41(11):2693-702. Epub 2013 Oct 15.

Jonathan C. Riboh, Division of Sports Medicine and Shoulder Surgery, Department of Orthopaedic Surgery, Duke University, 6002 Tahoe Drive, Durham, NC 27713.

Background: While numerous cadaveric, in vivo, and clinical studies have compared transtibial and independent drilling of femoral tunnels during anterior cruciate ligament reconstruction, there is no evidence-based consensus on which technique affords the best outcome.

Hypothesis: There is no difference in clinical outcome between transtibial and independent drilling of femoral tunnels.

Study Design: Systematic review with meta-analysis and meta-regression.

Methods: Cadaveric, in vivo, and clinical studies comparing transtibial and independent drilling techniques were systematically identified. A qualitative synthesis of nonrandomized studies and meta-analysis of randomized controlled trials (RCTs) were performed. In addition, a meta-regression analysis of RCTs that did not directly compare drilling techniques was performed.

Results: A total of 49 studies were included in the qualitative review, and 15 were included in the meta-analysis; 22 studies were included in the meta-regression. In biomechanical studies, independent drilling placed the center of the femoral tunnel closer to the center of the femoral footprint (mean difference, 2.69 mm; 95% CI, 0.46-4.92; P < .00001). Independent drilling reduced anterior tibial translation with the Lachman examination (mean difference, 2.2 mm; 95% CI, 0.34-4.07; P = .02), 134 N of anterior load (mean difference, 1 mm; 95% CI, 0.29-1.71; P = .006), and simulated pivot shift (mean difference, 3.36 mm; 95% CI, 1.88-4.85; P < .00001). The meta-analysis showed improved Lysholm scores with independent drilling (mean difference, -0.62 points; 95% CI, -1.09 to -0.55; P = .009), although the clinical relevance of this small difference is questionable. There were no significant differences in International Knee Documentation Committee (IKDC) objective scores or Tegner scores between groups. With the meta-regression, there were no significant differences in failure rates or IKDC objective scores.

Conclusion: While there are biomechanical data suggesting improved knee stability and more anatomic graft placement with independent drilling, no significant clinical differences were found between the 2 techniques.

Clinical Relevance: The current evidence shows that transtibial and independent drilling techniques have equivalent clinical outcomes at short-term to midterm follow-up. The long-term effects of subtle differences in tunnel position and postoperative knee kinematics should be further studied in dedicated, prospective cohort and randomized studies.
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http://dx.doi.org/10.1177/0363546513506979DOI Listing
November 2013

Effect of levosimendan on survival and adverse events after cardiac surgery: a meta-analysis.

J Cardiothorac Vasc Anesth 2013 Dec 16;27(6):1224-32. Epub 2013 Sep 16.

Duke Clinical Research Institute, 2400 Pratt Street, Durham, NC. Electronic address:

Objective: Left ventricular systolic dysfunction is associated with increased morbidity and mortality in patients undergoing cardiac surgery. The authors performed a meta-analysis investigating the effects of levosimendan in cardiac surgery patients with and without preoperative systolic dysfunction.

Design: Meta-analysis of randomized controlled trials.

Setting: Hospital.

Participants: The 1,155 patients who participated in 14 randomized controlled trials of perioperative levosimendan were included.

Interventions: None.

Measurements And Main Results: PubMed, EMBASE, the Cochrane database of clinical trials, and conference proceedings were searched for clinical trials of perioperative levosimendan in patients undergoing cardiac surgery through May 1, 2012. Studies were grouped by mean ejection fraction (EF). Those with a mean EF <40% were designated as low-EF. Pooled results demonstrated a reduction in mortality with levosimendan (risk difference [RD]-4.2%; 95% CI -7.2%, -1.1%; p = 0.008). Subgroup analysis showed that this benefit was confined to the low-EF studies (RD -7.0%; 95% CI -11.0%, -3.1%; p < 0.001). No benefit was observed in the preserved-EF subgroup (RD +1.1%; 95% CI -3.8%, +5.9%; p = 0.66). Significant reductions also were seen in the need for dialysis (RD -4.9%; 95% CI -8.2%, -1.6%; p = 0.003), myocardial injury (RD -5.0%; 95% CI -8.3%, -1.7%; p = 0.003), and postoperative atrial fibrillation (RD -8.1%; 95% CI -13.3%, -3.0%; p = 0.002).

Conclusions: Levosimendan was associated with reduced mortality and other adverse outcomes in patients undergoing cardiac surgery, and these benefits were greatest in patients with reduced EF. These data support the need for adequately powered randomized clinical trials to confirm the benefits of levosimendan in patients with reduced EF undergoing cardiac surgery.
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http://dx.doi.org/10.1053/j.jvca.2013.03.027DOI Listing
December 2013