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Background: Hypertension (HTN) is common in patients with hypertrophic cardiomyopathy (HCM), but its effect on the treatment of left ventricular outflow tract (LVOT) obstruction is undefined. Although elevated systolic blood pressure (SBP) may impact dynamic LVOT gradients, its response to cardiac myosin inhibition is unknown., Objectives: In a post hoc exploratory analysis of the EXPLORER-HCM trial (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy), the authors examined the characteristics of patients with obstructive HCM and HTN and the associations between HTN, SBP, and the response to mavacamten treatment of LVOT obstruction., Methods: Patients were stratified by baseline history of HTN and mean SBP during 30-week treatment with mavacamten or placebo. The study estimated treatment differences and evaluated HTN and SBP groups by treatment interaction. Analysis of covariance was used to model changes in continuous endpoints, and a generalized linear model was used for binary endpoints., Results: HTN was present in 119 of 251 patients (47.4%), including 60 receiving mavacamten and 59 receiving placebo. Patients with HTN vs no HTN were older (63.4 vs 54.0 years; P < 0.001), had higher SBP (134 ± 15.1 mm Hg vs 123 ± 13.8 mm Hg; P < 0.001), more comorbidities, and lower peak oxygen consumption (19 ± 3 vs 20 ± 4 mL/kg/min; P = 0.021). Patients with HTN had similar NYHA functional class (NYHA functional class II, 72% vs 73%), Valsalva LVOT gradients (72 ± 34 mm Hg vs 74 ± 30 mm Hg), Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores (70.6 ± 18.8 vs 68.9 ± 23.1), and NT pro-B-type natriuretic peptide levels (geometric mean 632 ± 129 pg/mL vs 745 ± 130 pg/mL). Mavacamten-treated patients had improvement in all primary, secondary, and exploratory endpoints regardless of HTN status or mean SBP., Conclusions: The clinical benefits of mavacamten in symptomatic, obstructive HCM were similar in patients with and without HTN, despite differences in baseline characteristics. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [EXPLORER-HCM]; NCT03470545)., Competing Interests: Funding Support and Author Disclosures MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, provided funding for statistical analyses. Dr Wang has been a consultant and/or served on advisory boards for BMS, Cytokinetics, and Biomarin; has served on the Speakers Bureau for BMS; and has received research grants from BMS and Cytokinetics. Dr Spertus has been a consultant for Alnylam, AstraZeneca, Bayer, Merck, Janssen, BMS, Edwards, Kineksia, 4DT Medical, Terumo, Cytokinetics, Imbria, and United Healthcare; has received research grants from BMS, Abbott Vascular, and Janssen; holds the copyrights to the Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire, and Peripheral Artery Questionnaire; and has served on the board of directors for Blue Cross Blue Shield of Kansas City. Dr Owens has been a consultant and/or served on advisory boards for BMS, Cytokinetics, Pfizer, Renovacor, Edgewise, Tenaya, and Lexicon. Dr Saberi has been the site principal investigator for trials for BMS, Cytokinetics, and Novartis; has served on steering committees for trials for BMS and Cytokinetics; and has received consulting/honoraria from BMS and Cytokinetics. Dr Sehnert is an employee of Bristol Myers Squibb. Dr Lakdawala has been a consultant for BMS, Pfizer, Cytokinetics, and Tenaya; and has received research support from Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Risk prediction, including early disease detection, prevention, and intervention, is essential to precision medicine. However, systematic bias in risk estimation caused by heterogeneity across different demographic groups can lead to inappropriate or misinformed treatment decisions. In addition, low incidence (class-imbalance) outcomes negatively impact the classification performance of many standard learning algorithms which further exacerbates the racial disparity issues. Therefore, it is crucial to improve the performance of statistical and machine learning models in underrepresented populations in the presence of heavy class imbalance., Method: To address demographic disparity in the presence of class imbalance, we develop a novel framework, Trans-Balance, by leveraging recent advances in imbalance learning, transfer learning, and federated learning. We consider a practical setting where data from multiple sites are stored locally under privacy constraints., Results: We show that the proposed Trans-Balance framework improves upon existing approaches by explicitly accounting for heterogeneity across demographic subgroups and cohorts. We demonstrate the feasibility and validity of our methods through numerical experiments and a real application to a multi-cohort study with data from participants of four large, NIH-funded cohorts for stroke risk prediction., Conclusion: Our findings indicate that the Trans-Balance approach significantly improves predictive performance, especially in scenarios marked by severe class imbalance and demographic disparity. Given its versatility and effectiveness, Trans-Balance offers a valuable contribution to enhancing risk prediction in biomedical research and related fields., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Few studies have directly compared different surgical procedures for uterine fibroids with respect to long-term health-related quality of life outcomes and symptom improvement., Objective: We examined differences in change from baseline to 1-, 2-, and 3-year follow-up in health-related quality of life and symptom severity among patients who underwent abdominal myomectomy, laparoscopic or robotic myomectomy, abdominal hysterectomy, laparoscopic or robotic hysterectomy, or uterine artery embolization., Study Design: The COMPARE-UF registry is a multiinstitutional prospective observational cohort study of women undergoing treatment for uterine fibroids. A subset of 1384 women aged 31 to 45 years who underwent either abdominal myomectomy (n=237), laparoscopic myomectomy (n=272), abdominal hysterectomy (n=177), laparoscopic hysterectomy (n=522), or uterine artery embolization (n=176) were included in this analysis. We obtained demographics, fibroid history, and symptoms by questionnaires at enrollment and at 1, 2, and 3 years posttreatment. We used the UFS-QoL (Uterine Fibroid Symptom and Quality of Life) questionnaire to ascertain symptom severity and health-related quality of life scores among participants. To account for potential baseline differences across treatment groups, a propensity score model was used to derive overlap weights and compare total health-related quality of life and symptom severity scores after enrollment with a repeated measures model. For this health-related quality of life tool, a specific minimal clinically important difference has not been determined, but on the basis of previous research, a difference of 10 points was considered as a reasonable estimate. Use of this difference was agreed upon by the Steering Committee at the time when the analysis was planned., Results: At baseline, women undergoing hysterectomy and uterine artery embolization reported the lowest health-related quality of life scores and highest symptom severity scores compared with those undergoing abdominal myomectomy or laparoscopic myomectomy (P<.001). Those undergoing hysterectomy and uterine artery embolization reported the longest duration of fibroid symptoms with a mean of 6.3 years (standard deviation, 6.7; P<.001). The most common fibroid symptoms were menorrhagia (75.3%), bulk symptoms (74.2%), and bloating (73.2%). More than half (54.9%) of participants reported anemia, and 9.4% women reported a history of blood transfusion. Across all modalities, total health-related quality of life and symptom severity score markedly improved from baseline to 1-year with the largest improvement in the laparoscopic hysterectomy group (Uterine Fibroids Symptom and Quality of Life: delta= [+] 49.2; symptom severity: delta= [-] 51.3). Those undergoing abdominal myomectomy, laparoscopic myomectomy, and uterine artery embolization also demonstrated significant improvement in health-related quality of life (delta= [+]43.9, [+]32.9, [+]40.7, respectively) and symptom severity (delta= [-]41.4, [-] 31.5, [-] 38.5, respectively) at 1 year, and the improvement persisted from baseline for uterine-sparing procedures during second (Uterine Fibroids Symptom and Quality of Life: delta= [+]40.7, [+]37.4, [+]39.3 SS: delta= [-] 38.5, [-] 32.0, [-] 37.7 and third year (Uterine Fibroids Symptom and Quality of Life: delta= [+] 40.9, [+]39.9, [+]41.1 and SS: delta= [-] 33.9, [-]36.5, [-] 33.0, respectively), posttreatment intervals, however with a trend toward decline in degree of improvement from years 1 and 2. Differences from baseline were greatest for hysterectomy; however, this may reflect the relative importance of bleeding in the Uterine Fibroids Symptom and Quality of Life, rather than clinically meaningful symptom recurrence among women undergoing uterus-sparing treatments., Conclusion: All treatment modalities were associated with significant improvements in health-related quality of life and symptom severity reduction 1-year posttreatment. However, abdominal myomectomy, laparoscopic myomectomy and uterine artery embolization indicated a gradual decline in symptom improvement and health-related quality of life by third year after the procedure., (Copyright © 2023. Published by Elsevier Inc.)

Background: Contemporary data comparing the outcomes of transradial access (TRA) vs transfemoral access (TFA) among patients presenting with acute myocardial infarction and cardiogenic shock (AMI-CS) undergoing percutaneous coronary intervention (PCI) are limited., Objectives: This study examines in-hospital outcomes and institutional variation among patients with AMI-CS undergoing TRA-PCI vs TFA-PCI., Methods: Patients admitted with AMI-CS from the NCDR CathPCI registry between April 2018 and June 2021 were included. Multivariable logistic regression and inverse probability weighting models were used to assess the association between access site and in-hospital outcomes. A falsification analysis using non-access site-related bleeding was performed., Results: Among 35,944 patients with AMI-CS undergoing PCI, 25.6% were performed with TRA. The proportion of TRA-PCI increased over the study period (22.0% in the second quarter of 2018 vs 29.1% in the second quarter of 2021; P-trend <0.001). Significant institutional-level variability in the use of TRA-PCI was also observed: 20.9% of all sites using TRA in <2% of PCIs (low utilization) vs 1.9% of all sites using TRA in >80% of PCIs (high utilization). Patients undergoing TRA-PCI had a significantly lower adjusted incidence of major bleeding (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.67-0.76), mortality (OR: 0.73; 95% CI: 0.69-0.78), vascular complications (OR: 0.67; 95% CI: 0.54-0.84), and new dialysis (OR: 0.86; 95% CI: 0.77-0.97). There was no difference in non-access site related bleeding (OR: 0.93; 95% CI: 0.84-1.03). Sensitivity analyses revealed similar benefit with TRA-PCI among patients without arterial cross-over. There were no significant interactions observed between TRA-PCI with mechanical circulatory support and in-hospital outcomes., Conclusions: In this large nationwide contemporary analysis of patients with AMI-CS, about quarter of PCIs were performed via TRA with wide variability across US institutions. TRA-PCI was associated with significantly lower incidence of in-hospital major bleeding, mortality, vascular complications, and new dialysis. This benefit was observed irrespective of mechanical circulatory support use., Competing Interests: Funding Support and Author Disclosures The American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR) supported this research. Dr Virani has received grant support from the Department of Veterans Affairs, National Institutes of Health, and Tahir and Jooma Family; and has received an honorarium from the American College of Cardiology. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

Background: Elevated triglycerides (TGs) are associated with increased risk of cardiovascular disease (CVD), but the best way to both measure TGs and assess TG-related risk remains unknown., Objective: The objective of the study was to evaluate the association between TGs and CVD and determine whether the average of a series of TG measurements is more predictive of CVD risk than a single TG measurement., Methods: We examined 15,792 study participants, aged 40-65 years, free of CVD from the Atherosclerosis Risk in Communities and Framingham Offspring studies, using fasting TG measurements across multiple examinations over time. With up to 10 years of follow-up, we assessed time-to-first CVD event, as well as a composite of myocardial infarction, stroke, or cardiovascular death., Results: Compared with a single TG measurement, average TGs over time had greater discrimination for CVD risk (C-statistic, 0.60 vs 0.57). Risk for CVD increased as average TGs rose until an inflection point of ~100 mg/dL in men and ~200 mg/dL in women, above which this risk association plateaued. The relationship between average TGs and CVD remained statistically significant in multivariable modeling adjusting for low-density lipoprotein cholesterol, and interactions were found by sex and high-density lipoprotein cholesterol level., Conclusions: The average of several TG readings provides incremental improvements for the prediction of CVD relative to a single TG measurement. Regardless of the method of measurement, higher TGs were associated with increased CVD risk, even at levels previously considered "optimal" (<150 mg/dL)., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Variation in patient characteristics and practice patterns may influence outcomes at a regional level., Methods: We assessed differences in demographics, practice patterns, outcomes, and the effect of apixaban compared with warfarin in ARISTOTLE (n = 18,201) by prespecified regions: North America, Latin America, Europe, and Asia Pacific. The primary outcomes were stroke/systemic embolism and major bleeding., Results: Compared with other regions, patients from Asia Pacific were younger, more women were enrolled in Latin America. Coronary artery disease was more prevalent in Europe and Asia Pacific had the highest rate of prior stroke and renal impairment. Over 50% of patients in North America were taking ≥9 drugs at randomization, compared with 10% in Latin America. North America had the highest rates of temporary study drug discontinuation and procedures. Time in therapeutic range (INR 2.0-3.0) on warfarin was highest in North America and lowest in Asia Pacific. After adjustment and compared with Europe, patients in Asia Pacific had 2-fold higher risk of stroke/systemic embolism and 3-fold higher risk of intracranial hemorrhage. Patients in Latin America had 2-fold increased risk of all-cause death compared with Europe. The benefits of apixaban compared with warfarin were consistent across regions; there was a pronounced reduction in major bleeding in patients from Asia Pacific compared with other regions (p-interaction = 0.03)., Conclusions: Patients with AF enrolled in prespecified regions in ARISTOTLE had differences in clinical baseline characteristics and practice patterns. After adjustment, patients in Asia Pacific and Latin America had worse outcomes than patients from other regions. The relative benefits of apixaban compared with warfarin were consistent across regions with an even greater treatment effect in the reduction of bleeding in patients from Asia Pacific., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: This study sought to determine whether age modifies the impact of key comorbidities on clinical outcomes for patients with heart failure with reduced ejection fraction (HFrEF)., Background: Comorbidities impact outcomes in HFrEF. However, the effect of age on the impact of comorbidities on prognosis is not clearly understood., Methods: Cox proportional hazards models were used assessed interactions between age and comorbidities on the primary composite endpoint (all-cause mortality or hospitalization) and secondary endpoints in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) multicenter trial of 2,331 patients with HFrEF., Results: Age did not significantly modify the effect of any comorbidity on the primary endpoint. However, age significantly modified the effect of body mass index (BMI) on all-cause mortality (interaction p = 0.02). Among patients ≥70 years of age, there was a U-shaped relationship between BMI and 1-year mortality, where BMI of 20 kg/m 2 corresponded to 17.6%; a BMI of 30 kg/m 2 corresponded to 7.0%; and a BMI of 40 kg/m 2 corresponded to 11%. For patients <60 years of age, mortality increased nonsignificantly from 3.2% to 3.7% with increasing BMI. Age also modified the effect of depressive symptoms on all-cause mortality (interaction p = 0.03). Among patients ≥70 years of age, a 1-year mortality rate significantly increased from 7.8% for a Beck Depression Inventory (BDI) score of 5% to 15.6% for BDI of 20. For patients <60 years of age, mortality was nonsignificantly related to BDI. Cumulative comorbidity scores were stronger predictors than age for mortality/hospitalization., Conclusions: In chronic HFrEF, age markedly altered the impact of BMI and depressive symptoms on all-cause mortality, with much higher risk in older patients, but was not as strong a predictor of mortality/hospitalizations as cumulative comorbidity score. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to compare the appropriate use and outcomes of percutaneous coronary intervention (PCI) between top-ranked and nonranked hospitals., Background: The U.S. News & World Report "Best Hospitals" rankings are an influential consumer-directed publication of hospital quality, and are commonly used in promotional campaigns by hospital systems., Methods: Hospitals in the National Cardiovascular Data Registry CathPCI registry between July 1, 2014, and June 30, 2015, were classified as top-ranked if they were included in the 2015 U.S. News & World Report 50 best "Cardiology and Heart Surgery" hospitals. The remaining were classified as nonranked. We compared in-hospital mortality, post-procedural bleeding, post-procedural acute kidney injury, and the proportion of appropriate PCI procedures between top-ranked and nonranked hospitals., Results: A total of 509,153 PCIs at 654 hospitals were included, of which 55,550 (10.9%) were performed at 44 top-ranked hospitals. After adjusting for patient case mix, PCIs performed at top-ranked hospitals had similar odds of in-hospital mortality (adjusted odds ratio [aOR]: 0.96; 95% confidence interval [CI]: 0.83 to 1.12; p = 0.64), acute kidney injury (aOR: 1.10; 95% CI: 0.98 to 1.22; p = 0.099), and bleeding (aOR: 1.15; 95% CI: 0.99 to 1.31; p = 0.052). Top-ranked hospitals had a slightly lower proportion of appropriate PCI compared with nonranked hospitals (89.2% vs. 92.8%; OR: 0.56; 95% CI: 0.45 to 0.69; p < 0.001)., Conclusions: PCI performed at top-ranked hospitals was not associated with superior outcomes compared with PCI at nonranked hospitals. The inclusion of metrics based on clinical data may be important for hospital quality rankings., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Critical limb ischaemia (CLI) implies an increased risk of cardiovascular morbidity and mortality, and the optimal antithrombotic treatment is not established., Design, Materials, Methods: The EUCLID trial investigated the effect of monotherapy with ticagrelor versus clopidogrel in 13,885 patients with peripheral artery disease (PAD); the primary endpoint was cardiovascular death, myocardial infarction, or ischaemic stroke. Patients planned for revascularisation or amputation within 3 months, were excluded. This analysis focuses on the subgroup with CLI, defined by rest pain (58.8%), major (9.0%) or minor (32.2%) tissue loss., Results: In EUCLID, 643 patients (4.6%) had CLI at baseline. Diabetes mellitus was more common in the CLI group, while coronary disease, carotid disease, and hypertension were more common in the non-CLI group. A majority of CLI patients (62.1%) had only lower extremity PAD. In patients enrolled on the ankle brachial index (ABI) criteria, ABI was 0.55 ± 0.21 (mean ± SD) for those with CLI versus 0.63 ± 0.15 for those without CLI. The primary efficacy endpoint significantly increased among patients with CLI compared with those without CLI with a rate of 8.85 versus 4.28/100 patient years (adjusted for baseline characteristics hazard ratio [HR] 1.43 [95% CI 1.16-1.76]; p = 0.0009). When acute limb ischaemia requiring hospitalisation was added to the model, significant differences remained (adjusted HR 1.38, [95% CI 1.13-1.69]; p = 0.0016). The 1 year mortality was 8.9%. A trend towards increased lower limb revascularisation among those with CLI was observed. Bleeding (TIMI major, fatal, intracranial) did not differ between those with and without CLI., Conclusions: Nearly 5% of patients enrolled in EUCLID had CLI at baseline. Milder forms of CLI dominated, a result of the trial design. Patients with CLI had a significantly higher rate of cardiovascular mortality and morbidity versus those without CLI. Further efforts are required to reduce the risk of cardiovascular events in PAD, especially in patients with CLI. CLINICALTRIALS.GOV: NCT01732822., (Copyright © 2017 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Background: Balancing risks and benefits of revascularization in elderly patients with multivessel coronary artery disease (CAD) is challenging. The appropriate revascularization strategy for elderly patients with multivessel CAD is unclear., Methods: We used the Duke Databank for Cardiovascular Disease to identify patients aged 75 years or more who had multivessel disease and treatment with percutaneous coronary intervention or coronary artery bypass graft surgery (CABG) within 30 days of the index catheterization between October 1, 2003, and June 30, 2013. The primary outcome was a composite of all-cause death, myocardial infarction, and coronary revascularization through latest follow-up. Associations between bare-metal stents (BMS), drug-eluting stents (DES), CABG, and outcomes were determined using multivariable Cox proportional hazards modeling, adjusting for potential confounders with CABG as the reference. Comparisons between BMS and DES were done using BMS as the reference., Results: We identified 763 patients who met the criteria (BMS, n = 202; DES, n = 411; CABG, n = 150). The median age was 79 years (interquartile range, 76 to 82), and the median follow-up was 6.28 years. After adjustment, both BMS and DES were associated with a higher risk of the primary outcome. The BMS versus CABG hazard ratio was 1.58 (95% confidence interval: 1.15 to 2.19, p = 0.01). The DES versus CABG hazard ratio was 1.45 (95% confidence interval: 1.08 to 1.95, p = 0.01). The adjusted hazard ratio for DES versus BMS (0.92, 95% confidence interval: 0.71 to 1.19, p = 0.51) was not statistically significant., Conclusions: In this single-center analysis of 763 elderly patients with multivessel disease, CABG was associated with the best overall clinical outcomes, but was selected for a minority of patients. An adequately powered, randomized trial should be considered to define the best treatment strategy for this population., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We investigated the frequency and characteristics of intracranial hemorrhage (ICH), the factors associated with the risk of ICH, and outcomes post-ICH overall and by randomized treatment. We identified patients with ICH from the overall trial population enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial who received ≥1 dose of the study drug (n = 18 140). ICH was adjudicated by a central committee. Cox regression models were used to identify factors associated with ICH. ICH occurred in 174 patients; most ICH events were spontaneous (71.7%) versus traumatic (28.3%). Apixaban resulted in significantly less ICH (0.33% per year), regardless of type and location, than warfarin (0.80% per year). Independent factors associated with increased risk of ICH were enrollment in Asia or Latin America, older age, prior stroke/transient ischemic attack, and aspirin use at baseline. Among warfarin-treated patients, the median (25th, 75th percentiles) time from most recent international normalized ratio (INR) to ICH was 13 days (6, 21 days). Median INR prior to ICH was 2.6 (2.1, 3.0); 78.5% of patients had a pre-ICH INR <3.0. After ICH, the modified Rankin scale score at discharge was ≥4 in 55.7% of patients, and the overall mortality rate at 30 days was 43.3% with no difference between apixaban- and warfarin-treated patients. ICH occurred at a rate of 0.80% per year with warfarin regardless of INR control and at a rate of 0.33% per year with apixaban and was associated with high short-term morbidity and mortality. This highlights the clinical relevance of reducing ICH by using apixaban rather than warfarin and avoiding concomitant aspirin, especially in patients of older age. This trial was registered at www.clinicaltrials.gov as #NCT00412984., (© 2017 by The American Society of Hematology.)

Background: Evidence supporting use of antithrombotic therapy in atrial fibrillation (AF) is based mainly on data from patients with permanent, persistent, or paroxysmal AF. Less is known about the risk following a new diagnosis of AF and the efficacy and safety of apixaban in these patients., Methods: Using data from ARISTOTLE, we assessed the relationship between timing of AF diagnosis and clinical outcomes and the efficacy and safety of apixaban versus warfarin in these patients. Recently diagnosed AF was defined as a new diagnosis of AF within 30days prior to enrollment. Cox proportional hazards models were used to determine the association between recently diagnosed AF and clinical outcomes. We also assessed the efficacy and safety of apixaban versus warfarin according to time since AF diagnosis., Results: In ARISTOTLE, 1899 (10.5%) patients had recently diagnosed AF. After adjustment, patients with recently versus remotely diagnosed AF had a similar risk of stroke/systemic embolism (HR=1.07, 95% CI=0.80-1.42; p=0.67), but higher mortality was seen in patients with recently diagnosed AF (adjusted HR=1.21, 95% CI=1.02-1.43; p=0.03). The beneficial effects of apixaban, compared with warfarin, on clinical outcomes were consistent, irrespective of timing of AF diagnosis (all interaction p-values >0.12)., Conclusion: Patients with recently diagnosed AF had a similar risk of stroke but higher mortality than patients with remotely diagnosed AF, suggesting that they are not at "low risk" and warrant stroke prevention strategies. The benefits of apixaban over warfarin were preserved, irrespective of timing of AF diagnosis., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study aimed to compare whether reduced heart rate (HR) or higher beta-blocker (BB) dose affected outcomes to a greater extent in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial population., Background: Recent data have shown that HR is an important modifiable factor in reducing mortality in heart failure (HF) patients. It has also been shown that titration of doses of BBs improves outcomes of morbidity and mortality in chronic HF patients with reduced ejection fraction. We aimed to compare whether reduced HR or higher BB dose affected outcomes to a greater extent in the HF-ACTION trial population., Methods: HF-ACTION was a randomized, multicenter trial enrolling 2,331 ambulatory HF patients with systolic dysfunction (New York Heart Association functional class II to IV, left ventricular ejection fraction <0.35) randomized to exercise training versus usual care, with median follow-up of 2.5 years. BB dose at baseline was standardized by use of carvedilol equivalents. BB dose and HR were analyzed by discrete groups (higher/lower dose; higher/lower HR). The relationship of BB dose, HR, and the primary endpoint of all-cause mortality or all-cause hospitalization and other cardiovascular secondary endpoints were determined before and after adjustment for variables found to be significantly associated with outcome in the HF-ACTION cohort., Results: There was a significant inverse relationship between either BB dose (higher was better) or HR (lower was better) and all-cause death or hospitalization in unadjusted analysis; however, only BB dose was significant for improved mortality outcomes. After adjustment for other predictors of outcome, only BB dose remained significant for improving all-cause death or hospitalization. BB dose, but not HR, was associated with improved outcomes of other cardiovascular endpoints in unadjusted analysis but did not remain significant when adjusted for other predictors of outcome in this cohort., Conclusions: There were more associated improvements in outcomes with higher BB dose than with reduced HR in this well-treated HF cohort with systolic dysfunction, which suggests that titration of BB doses may confer a greater benefit than reduction of HR in such patients. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Using data from ARISTOTLE, we describe the periprocedural management of anticoagulation and rates of subsequent clinical outcomes among patients chronically anticoagulated with warfarin or apixaban. We recorded whether (and for how long) anticoagulant therapy was interrupted preprocedure, whether bridging therapy was used, and the proportion of patients who experienced important clinical outcomes during the 30 days postprocedure. Of 10 674 procedures performed during follow-up in 5924 patients, 9260 were included in this analysis. Anticoagulant treatment was not interrupted preprocedure 37.5% of the time. During the 30 days postprocedure, stroke or systemic embolism occurred after 16/4624 (0.35%) procedures among apixaban-treated patients and 26/4530 (0.57%) procedures among warfarin-treated patients (odds ratio [OR] 0.601; 95% confidence interval [CI] 0.322-1.120). Major bleeding occurred in 74/4560 (1.62%) procedures in the apixaban arm and 86/4454 (1.93%) in the warfarin arm (OR 0.846; 95% CI 0.614-1.166). The risk of death was similar with apixaban (54/4624 [1.17%]) and warfarin (49/4530 [1.08%]) (OR 1.082; 95% CI 0.733-1.598). Among patients in ARISTOTLE, the 30-day postprocedure stroke, death, and major bleeding rates were low and similar in apixaban- and warfarin-treated patients, regardless of whether anticoagulation was stopped beforehand. Our findings suggest that many patients on chronic anticoagulation can safely undergo procedures; some will not require a preprocedure interruption of anticoagulation. ARISTOTLE was registered at www.clinicaltrials.gov as #NCT00412984., (© 2014 by The American Society of Hematology.)

Background: A substantial portion of patients with atrial fibrillation (AF) also have coronary artery disease (CAD) and are at risk for coronary events. Warfarin is known to reduce these events, but increase the risk of bleeding. We assessed the effects of apixaban compared with warfarin in AF patients with and without prior CAD., Methods and Results: In ARISTOTLE, 18,201 patients with AF were randomized to apixaban or warfarin. History of CAD was defined as documented CAD, prior myocardial infarction, and/or history of coronary revascularization. We analyzed baseline characteristics and clinical outcomes of patients with and without prior CAD and compared outcomes by randomized treatment using Cox models. A total of 6639 (36.5%) patients had prior CAD. These patients were more often male, more likely to have prior stroke, diabetes, and hypertension, and more often received aspirin at baseline (42.2% vs. 24.5%). The effects of apixaban were similar among patients with and without prior CAD on reducing stroke or systemic embolism and death from any cause (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.71-1.27, P for interaction=0.12; HR 0.96, 95% CI 0.81-1.13, P for interaction=0.28). Rates of myocardial infarction were numerically lower with apixaban than warfarin among patients with and without prior CAD. The effect of apixaban on reducing major bleeding and intracranial hemorrhage was consistent in patients with and without CAD., Conclusions: In patients with AF, apixaban more often prevented stroke or systemic embolism and death and caused less bleeding than warfarin, regardless of the presence of prior CAD. Given the common occurrence of AF and CAD and the higher rates of cardiovascular events and death, our results indicate that apixaban may be a better treatment option than warfarin for these high-risk patients., (© 2013.)

Objectives: The PLATO (Platelet Inhibition and Patient Outcomes) angiographic substudy sought to compare the efficacy of ticagrelor versus clopidogrel with respect to angiographic outcomes before and after PCI in the setting of acute coronary syndrome., Background: Greater platelet inhibition has been associated with improved angiographic outcomes before and after percutaneous coronary intervention (PCI). Therefore, it was hypothesized that treatment with ticagrelor, which achieves more rapid, higher, and more consistent platelet inhibition, would be associated with improved angiographic outcomes when compared with those of clopidogrel treatment., Methods: The angiographic cohort consists of 2,616 patients drawn from the 18,624-patient PLATO trial. Clopidogrel naïve or pre-treated patients were randomized to 180 mg of ticagrelor or 300 mg of clopidogrel (75 mg for clopidogrel pre-treated patients). PCI patients were administered, as per treatment group: 1) an additional 90 mg of ticagrelor if >24 h following the initial loading dose; or 2) an optional further 300 mg of clopidogrel or placebo (total 600 mg) prior to PCI. The substudy primary endpoint was the incidence of post-PCI TIMI (Thrombolysis In Myocardial Infarction) myocardial perfusion grade 3 (TMPG 3) among patients who received a study drug prior to PCI., Results: In total, 21.3% of patients were pretreated with clopidogrel prior to randomization. There was a short time interval between randomization and PCI (median: 0.68 [interquartile range (IQR): 0.30 to 2.21] h) among all patients. Post-PCI TMPG 3 was similar between the ticagrelor and clopidogrel groups (47.1% vs. 46.9%; p = 0.96). Likewise, the following pre-PCI outcomes were similar in the ticagrelor and clopidogrel groups, respectively: TMPG 3 (30.5% vs. 31.2%), TIMI flow grade 3 (37.1% vs. 39.3%), corrected TIMI frame count (median: 100 vs. 71 frames), TIMI thrombus grade 0 (24.1% vs. 27.6%), minimum lumen diameter (median: 0.3 [IQR: 0.0 to 0.6] vs. 0.3 [IQR: 0.0 to 0.6] mm) and percentage of diameter stenosis (median: 89 [IQR: 78 to 100] vs. 89 [IQR: 77 to 100])., Conclusions: Neither coronary flow nor myocardial perfusion, evaluated on coronary angiograms performed before or following PCI procedures within a few hours after the start of oral antiplatelet treatment in the setting of acute coronary syndromes, demonstrated a difference with ticagrelor versus clopidogrel. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Post-partum haemorrhage is a leading cause of global maternal morbidity and mortality. Misoprostol, a prostaglandin analogue with uterotonic activity, is an attractive option for treatment because it is stable, active orally, and inexpensive. We aimed to assess the effectiveness of misoprostol as an adjunct to standard uterotonics compared with standard uterotonics alone for treatment of post-partum haemorrhage., Methods: Women delivering vaginally who had clinically diagnosed post-partum haemorrhage due to uterine atony were enrolled from participating hospitals in Argentina, Egypt, South Africa, Thailand, and Vietnam between July, 2005, and August, 2008. Computer-generated randomisation was used to assign women to receive 600 microg misoprostol or matching placebo sublingually; both groups were also given routine injectable uterotonics. Allocation was concealed by distribution of sealed and sequentially numbered treatment packs in the order that women were enrolled. Providers and women were masked to treatment assignment. The primary outcome was blood loss of 500 mL or more within 60 min after randomisation. Analysis was by intention to treat. This study is registered, number ISRCTN34455240., Findings: 1422 women were assigned to receive misoprostol (n=705) or placebo (n=717). The proportion of women with blood loss of 500 mL or more within 60 min was similar between the misoprostol group (100 [14%]) and the placebo group (100 [14%]; relative risk 1.02, 95% CI 0.79-1.32). In the first 60 min, an increased proportion of women on misoprostol versus placebo, had shivering (455/704 [65%] vs 230/717 [32%]; 2.01, 1.79-2.27) and body temperature of 38 degrees C or higher (303/704 [43%] vs 107/717 [15%]; 2.88, 2.37-2.50)., Interpretation: Findings from this study do not support clinical use of 600 microg sublingual misoprostol in addition to standard injectable uterotonics for treatment of post-partum haemorrhage., Funding: Bill & Melinda Gates Foundation, and UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Variation in and irreversibility of platelet inhibition with clopidogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopidogrel in such patients., Methods: At randomisation, an invasive strategy was planned for 13 408 (72.0%) of 18 624 patients hospitalised for acute coronary syndromes (with or without ST elevation). In a double-blind, double-dummy study, patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300-600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6-12 months. All patients were given aspirin. The primary composite endpoint was cardiovascular death, myocardial infarction, or stroke. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00391872., Findings: 6732 patients were assigned to ticagrelor and 6676 to clopidogrel. The primary composite endpoint occurred in fewer patients in the ticagrelor group than in the clopidogrel group (569 [event rate at 360 days 9.0%] vs 668 [10.7%], hazard ratio 0.84, 95% CI 0.75-0.94; p=0.0025). There was no difference between clopidogrel and ticagrelor groups in the rates of total major bleeding (691 [11.6%] vs 689 [11.5%], 0.99 [0.89-1.10]; p=0.8803) or severe bleeding, as defined according to the Global Use of Strategies To Open occluded coronary arteries, (198 [3.2%] vs 185 [2.9%], 0.91 [0.74-1.12]; p=0.3785)., Interpretation: Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objective: We postulated that calcium supplementation of calcium-deficient pregnant women would lower vascular resistance in uteroplacental and fetoplacental circulations., Study Design: Pulsatility index (PI) and resistance index (RI) (uterine and umbilical arteries) and presence of bilateral uterine artery diastolic notching were assessed by Doppler ultrasound between 20-36 weeks' gestation in 510 healthy, nulliparous Argentinean women with deficient calcium intake in a randomized, placebo-controlled, double-blinded trial., Results: Average umbilical and uterine artery RI and PI tended to be lower in the supplemented group at each study week. Differences became statistically significant for umbilical artery RI and PI from 32 and 36 weeks, respectively. Estimated probabilities of bilateral uterine artery diastolic notching trended toward lower values in calcium-supplemented women., Conclusion: Calcium supplementation of pregnant women with deficient calcium intake may affect uteroplacental and fetoplacental blood flow by preserving the vasodilation of normal gestation., (2010 Mosby, Inc.)

Background: Caesarean delivery rates continue to increase worldwide. Our aim was to assess the association between caesarean delivery and pregnancy outcome at the institutional level, adjusting for the pregnant population and institutional characteristics., Methods: For the 2005 WHO global survey on maternal and perinatal health, we assessed a multistage stratified sample, comprising 24 geographic regions in eight countries in Latin America. We obtained individual data for all women admitted for delivery over 3 months to 120 institutions randomly selected from of 410 identified institutions. We also obtained institutional-level data., Findings: We obtained data for 97,095 of 106,546 deliveries (91% coverage). The median rate of caesarean delivery was 33% (quartile range 24-43), with the highest rates of caesarean delivery noted in private hospitals (51%, 43-57). Institution-specific rates of caesarean delivery were affected by primiparity, previous caesarean delivery, and institutional complexity. Rate of caesarean delivery was positively associated with postpartum antibiotic treatment and severe maternal morbidity and mortality, even after adjustment for risk factors. Increase in the rate of caesarean delivery was associated with an increase in fetal mortality rates and higher numbers of babies admitted to intensive care for 7 days or longer even after adjustment for preterm delivery. Rates of preterm delivery and neonatal mortality both rose at rates of caesarean delivery of between 10% and 20%., Interpretation: High rates of caesarean delivery do not necessarily indicate better perinatal care and can be associated with harm.

Background: The reduction of maternal deaths is a key international development goal. Evidence-based health policies and programmes aiming to reduce maternal deaths need reliable and valid information. We undertook a systematic review to determine the distribution of causes of maternal deaths., Methods: We selected datasets using prespecified criteria, and recorded dataset characteristics, methodological features, and causes of maternal deaths. All analyses were restricted to datasets representative of populations. We analysed joint causes of maternal deaths from datasets reporting at least four major causes (haemorrhage, hypertensive disorders, sepsis, abortion, obstructed labour, ectopic pregnancy, embolism). We examined datasets reporting individual causes of death to investigate the heterogeneity due to methodological features and geographical region and the contribution of haemorrhage, hypertensive disorders, abortion, and sepsis as causes of maternal death at the country level., Findings: 34 datasets (35,197 maternal deaths) were included in the primary analysis. We recorded wide regional variation in the causes of maternal deaths. Haemorrhage was the leading cause of death in Africa (point estimate 33.9%, range 13.3-43.6; eight datasets, 4508 deaths) and in Asia (30.8%, 5.9-48.5; 11,16 089). In Latin America and the Caribbean, hypertensive disorders were responsible for the most deaths (25.7%, 7.9-52.4; ten, 11,777). Abortion deaths were the highest in Latin America and the Caribbean (12%), which can be as high as 30% of all deaths in some countries in this region. Deaths due to sepsis were higher in Africa (odds ratio 2.71), Asia (1.91), and Latin America and the Caribbean (2.06) than in developed countries., Interpretation: Haemorrhage and hypertensive disorders are major contributors to maternal deaths in developing countries. These data should inform evidence-based reproductive health-care policies and programmes at regional and national levels. Capacity-strengthening efforts to improve the quality of burden-of-disease studies will further validate future estimates.

Objective: Preeclampsia, gestational hypertension, and unexplained intrauterine growth restriction may have similar determinants and consequences. In this study, we compared determinants and perinatal outcomes associated with these obstetric conditions., Study Design: We analyzed 39,615 pregnancies (data from the WHO Antenatal Care Trial), of which 2.2% were complicated by preeclampsia, 7.0% by gestational hypertension, and 8.1% by unexplained intrauterine growth restriction (ie, not associated with maternal smoking, maternal undernutrition, preeclampsia, gestational hypertension, or congenital malformations). We compared the risk factors associated with these groups. Fetal death, preterm delivery, and severe neonatal morbidity and mortality were the primary outcomes. Logistic regression analyses were adjusted for study site, socioeconomic status, and (if appropriate) birth weight and gestational age., Results: Diabetes, renal or cardiac disease, previous preeclampsia, urinary tract infection, high maternal age, twin pregnancy, and obesity increased the risk of both hypertensive conditions. Previous large-for-age birth, reproductive tract surgery, antepartum hemorrhage and reproductive tract infection increased the risk for gestational hypertension only. Independent of maternal age, primiparity was a risk factor only for preeclampsia. Both preeclampsia and gestational hypertension were associated with increased risk for fetal death and severe neonatal morbidity and mortality. Mothers with preeclampsia compared with those with unexplained intrauterine growth restriction were more likely to have a history of diabetes, renal or cardiac disease, chronic hypertension, previous preeclampsia, body mass index more than 30 kg/cm2, urinary tract infection and extremes of maternal age. Conversely, unexplained intrauterine growth restriction was associated with higher risk of low birth weight in previous pregnancies, but not with previous preeclampsia. Both conditions increased the risk for perinatal outcomes independently but preeclampsia was associated with considerable higher risk., Conclusion: Preeclampsia and gestational hypertension shared many risk factors, although there are differences that need further evaluation. Both conditions significantly increased morbidity and mortality. Conversely, preeclampsia and unexplained intrauterine growth restriction, often assumed to be related to placental insufficiency, seem to be independent biologic entities.