Impact of Cerebral Embolic Protection Devices on Disabling Stroke after Transcatheter Aortic Valve Replacement: Updated Results from the STS/ACC TVT Registry.

Background: Cerebral embolic protection devices (EPDs) were developed to mitigate the risk of stroke during transcatheter aortic valve replacement (TAVR), but their benefit remains unproven. In the PROTECTED-TAVR trial, EPD use did not reduce periprocedural stroke (primary study outcome) but led to a 62% reduction in the secondary endpoint of disabling stroke. Given these results, the impact of EPDs during TAVR remains unclear. Methods: We used STS/ACC TVT registry data to examine the association between EPD use and a proxy for disabling stroke among transfemoral TAVR patients between 1/2018-6/2023. The primary outcome was in-hospital disabling stroke-defined as stroke associated with either in-hospital death or discharge to a non-home location. We evaluated the association between EPD use and disabling stroke using instrumental variable (IV) analysis with site-level preference for EPD use as the instrument-a quasi-experimental approach that can support causal inference. In addition, we performed a propensity-score based comparison using overlap weighting as a secondary analysis. Results: The study population consisted of 414,649 patients of whom 53,389 (12.9%) received an EPD. The unadjusted rate of in-hospital disabling stroke was 0.7% among the EPD group and 0.9% in the no EPD group. EPD use was associated with a reduction in disabling stroke in both IV analysis (RR 0.87; 95% CI: 0.73-1.00) and propensity-weighted (PW) analysis (OR 0.79; 95% CI: 0.70-0.90) but was not associated with a reduction in non-disabling stroke. In subgroup analyses, the benefit of EPD was greater among those with versus without prior stroke (interaction p<0.05 for IV and PW). Conclusions: In the largest study to date, among patients undergoing TAVR, EPD use was associated with a small, borderline significant reduction in stroke associated with death or a discharge to a non-home location (a proxy for disabling stroke) that is likely to be causal in nature. Taken together with previous mechanistic and clinical studies, these findings provide credible evidence that EPDs benefit patients undergoing TAVR.

Transcatheter Edge-to-Edge Repair in COAPT-Ineligible Patients With Functional Mitral Regurgitation.

BACKGROUND: Mitral valve transcatheter edge-to-edge repair (MTEER) was approved in the United States for treatment of functional mitral regurgitation (FMR) based on results from the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial. OBJECTIVES: The authors sought to analyze outcomes of MTEER in FMR patients who would have been excluded from COAPT. METHODS: MTEER procedures performed for FMR in the TVT (Transcatheter Valve Therapy) Registry between January 1, 2013, and April 30, 2020, were categorized as "trial-ineligible" if any of the following were present: cardiogenic shock, inotropic support, left ventricular ejection fraction <20%, left ventricular end-systolic dimension >7 cm, home oxygen use, or severe tricuspid regurgitation. Trial-ineligible and trial-eligible groups were compared through 1 year using multivariable models. The primary endpoint was 1-year death or heart failure hospitalization (HFH). RESULTS: Of 6,675 patients who underwent MTEER for FMR, 3,721 (55.7%) were trial-eligible and 2,954 (44.3%) were trial-ineligible. Trial-ineligible patients had lower rates of technical procedural success (86.9% vs 92.6%; P < 0.001) and more frequent in-hospital complications (11.8% vs 5.7%; P < 0.001) compared with trial-eligible patients. A clinically meaningful improvement in health status at 30 days was observed in 78.9% and 77.0% of patients in the trial-ineligible and trial-eligible groups, respectively. There was a higher risk of 1-year death or HFH (HR: 1.73; 95% CI: 1.57-1.91; P < 0.001) in trial-ineligible patients. CONCLUSIONS: Among patients who underwent MTEER for FMR in the TVT Registry, nearly one-half would have been ineligible for the COAPT trial. Health status improvement at 30 days was similar in COAPT-ineligible and COAPT-eligible patients, but trial-ineligible patients had higher 1-year rates of death or HFH.

Modeling the Association of Volume vs Composite Outcome Thresholds With Outcomes and Access to Transcatheter Aortic Valve Implantation in the US.

Importance: Professional societies and the Centers for Medicare & Medicaid Services suggest volume thresholds to ensure quality in transcatheter aortic valve implantation (TAVI). Objective: To model the association of volume thresholds vs spoke-and-hub implementation of outcome thresholds with TAVI outcomes and geographic access. Design, Setting, and Participants: This cohort study included patients who enrolled in the US Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy registry. Site volume and outcomes were determined from a baseline cohort of adults undergoing TAVI between July 1, 2017, and June 30, 2020. Exposures: Within each hospital referral region, TAVI sites were categorized by volume (<50 or ≥50 TAVIs per year) and separately by risk-adjusted outcome on the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy 30-day TAVI composite during the baseline period (July 2017 to June 2020). Outcomes of patients undergoing TAVIs from July 1, 2020, to March 31, 2022, were then modeled as though the patients had been treated at (1) the nearest higher volume (≥50 TAVIs per year) or (2) the best outcome site within the hospital referral region. Main Outcomes and Measures: The primary outcome was the absolute difference in events between the adjusted observed and modeled 30-day composite of death, stroke, major bleeding, stage III acute kidney injury, and paravalvular leak. Data are presented as the number of events reduced under the above scenarios with 95% bayesian credible intervals (CrIs) and median (IQR) driving distance. Results: The overall cohort included 166 248 patients with a mean (SD) age of 79.5 (8.6) years; 74 699 (47.3%) were female and 6657 (4.2%) were Black; 158 025 (95%) were treated in higher-volume sites (≥50 TAVIs) and 75 088 (45%) were treated in best-outcome sites. Modeling a volume threshold, there was no significant reduction in estimated adverse events (-34; 95% CrI, -75 to 8), while the median (IQR) driving time from the existing site to the alternate site was 22 (15-66) minutes. Transitioning care to the best outcome site in a hospital referral region resulted in an estimated 1261 fewer adverse outcomes (95% CrI, 1013-1500), while the median (IQR) driving time from the original site to the best site was 23 (15-41) minutes. Directionally similar findings were observed for Black individuals, Hispanic individuals, and individuals from rural areas. Conclusions and Relevance: In this study, compared with the current system of care, a modeled outcome-based spoke-and-hub paradigm of TAVI care improved national outcomes to a greater extent than a simulated volume threshold, at the cost of increased driving time. To improve quality while maintaining geographic access, efforts should focus on reducing site variation in outcomes.

Apixaban for Patients With Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial.

BACKGROUND: There are no randomized data evaluating the safety or efficacy of apixaban for stroke prevention in patients with end-stage kidney disease on hemodialysis and with atrial fibrillation (AF). METHODS: The RENAL-AF trial (Renal Hemodialysis Patients Allocated Apixaban Versus Warfarin in Atrial Fibrillation) was a prospective, randomized, open-label, blinded-outcome evaluation (PROBE) of apixaban versus warfarin in patients receiving hemodialysis with AF and a CHA2DS2-VASc score ≥2. Patients were randomly assigned 1:1 to 5 mg of apixaban twice daily (2.5 mg twice daily for patients ≥80 years of age, weight ≤60 kg, or both) or dose-adjusted warfarin. The primary outcome was time to major or clinically relevant nonmajor bleeding. Secondary outcomes included stroke, mortality, and apixaban pharmacokinetics. Pharmacokinetic sampling was day 1, day 3, and month 1. RESULTS: From January 2017 through January 2019, 154 patients were randomly assigned to apixaban (n=82) or warfarin (n=72). The trial stopped prematurely because of enrollment challenges. Time in therapeutic range (international normalized ratio, 2.0-3.0) for warfarin-treated patients was 44% (interquartile range, 23%-59%). The 1-year rates for major or clinically relevant nonmajor bleeding were 32% and 26% in apixaban and warfarin groups, respectively (hazard ratio, 1.20 [95% CI, 0.63-2.30]), whereas 1-year rates for stroke or systemic embolism were 3.0% and 3.3% in apixaban and warfarin groups, respectively. Death was the most common major event in the apixaban (21 patients [26%]) and warfarin (13 patients [18%]) arms. The pharmacokinetic substudy enrolled the target 50 patients. Median steady-state 12-hour area under the curve was 2475 ng/mL×h (10th to 90th percentiles, 1342-3285) for 5 mg of apixaban twice daily and 1269 ng/mL×h (10th to 90th percentiles, 615-1946) for 2.5 mg of apixaban twice daily. There was substantial overlap between minimum apixaban blood concentration, 12-hour area under the curve, and maximum apixaban blood concentration for patients with and without a major or clinically relevant nonmajor bleeding event. CONCLUSIONS: There was inadequate power to draw any conclusion regarding rates of major or clinically relevant nonmajor bleeding comparing apixaban and warfarin in patients with AF and end-stage kidney disease on hemodialysis. Clinically relevant bleeding events were ≈10-fold more frequent than stroke or systemic embolism among this population on anticoagulation, highlighting the need for future randomized studies evaluating the risks versus benefits of anticoagulation among patients with AF and end-stage kidney disease on hemodialysis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02942407.

Methylprednisolone for Heart Surgery in Infants - A Randomized, Controlled Trial.

BACKGROUND: Although perioperative prophylactic glucocorticoids have been used for decades, whether they improve outcomes in infants after heart surgery with cardiopulmonary bypass is unknown. METHODS: We conducted a multicenter, prospective, randomized, placebo-controlled, registry-based trial involving infants (<1 year of age) undergoing heart surgery with cardiopulmonary bypass at 24 sites participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database. Registry data were used in the evaluation of outcomes. The infants were randomly assigned to receive prophylactic methylprednisolone (30 mg per kilogram of body weight) or placebo, which was administered into the cardiopulmonary-bypass pump-priming fluid. The primary end point was a ranked composite of death, heart transplantation, or any of 13 major complications. Patients without any of these events were assigned a ranked outcome based on postoperative length of stay. In the primary analysis, the ranked outcomes were compared between the trial groups with the use of odds ratios adjusted for prespecified risk factors. Secondary analyses included an unadjusted odds ratio, a win ratio, and safety outcomes. RESULTS: A total of 1263 infants underwent randomization, of whom 1200 received either methylprednisolone (599 infants) or placebo (601 infants). The likelihood of a worse outcome did not differ significantly between the methylprednisolone group and the placebo group (adjusted odds ratio, 0.86; 95% confidence interval [CI], 0.71 to 1.05; P = 0.14). Secondary analyses (unadjusted for risk factors) showed an odds ratio for a worse outcome of 0.82 (95% CI, 0.67 to 1.00) and a win ratio of 1.15 (95% CI, 1.00 to 1.32) in the methylprednisolone group as compared with the placebo group, findings suggestive of a benefit with methylprednisolone; however, patients in the methylprednisolone group were more likely than those in the placebo group to receive postoperative insulin for hyperglycemia (19.0% vs. 6.7%, P<0.001). CONCLUSIONS: Among infants undergoing surgery with cardiopulmonary bypass, prophylactic use of methylprednisolone did not significantly reduce the likelihood of a worse outcome in an adjusted analysis and was associated with postoperative development of hyperglycemia warranting insulin in a higher percentage of infants than placebo. (Funded by the National Center for Advancing Translational Sciences and others; STRESS ClinicalTrials.gov number, NCT03229538.).

Cerebral Embolic Protection and Outcomes of Transcatheter Aortic Valve Replacement: Results From the Transcatheter Valve Therapy Registry.

BACKGROUND: Stroke remains a devastating complication of transcatheter aortic valve replacement (TAVR), which has persisted despite refinements in technique and increased operator experience. While cerebral embolic protection devices (EPDs) have been developed to mitigate this risk, data regarding their impact on stroke and other outcomes after TAVR are limited. METHODS: We performed an observational study using data from the Society for Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Patients were included if they underwent elective or urgent transfemoral TAVR between January 2018 and December 2019. The primary outcome was in-hospital stroke. To adjust for confounding, the association between EPD use and clinical outcomes was evaluated using instrumental variable analysis, a technique designed to support causal inference from observational data, with site-level preference for EPD use within the same quarter of the procedure as the instrument. We also performed a propensity score-based secondary analysis using overlap weights. RESULTS: Our analytic sample included 123 186 patients from 599 sites. The use of EPD during TAVR increased over time, reaching 28% of sites and 13% of TAVR procedures by December 2019. There was wide variation in EPD use across hospitals, with 8% of sites performing >50% of TAVR procedures with an EPD and 72% performing no procedures with an EPD in the last quarter of 2019. In our primary analysis using the instrumental variable model, there was no association between EPD use and in-hospital stroke (adjusted relative risk, 0.90 [95% CI, 0.68-1.13]; absolute risk difference, -0.15% [95% CI, -0.49 to 0.20]). However, in our secondary analysis using the propensity score-based model, EPD use was associated with 18% lower odds of in-hospital stroke (adjusted odds ratio, 0.82 [95% CI, 0.69-0.97]; absolute risk difference, -0.28% [95% CI, -0.52 to -0.03]). Results were generally consistent across the secondary end points, as well as subgroup analyses. CONCLUSIONS: In this nationally representative observational study, we did not find an association between EPD use for TAVR and in-hospital stroke in our primary instrumental variable analysis, and found only a modestly lower risk of in-hospital stroke in our secondary propensity-weighted analysis. These findings provide a strong basis for large-scale randomized, controlled trials to test whether EPDs provide meaningful clinical benefit for patients undergoing TAVR.

Hypertension Control in Adults With Diabetes Mellitus and Recurrent Cardiovascular Events: Global Results From the Trial Evaluating Cardiovascular Outcomes With Sitagliptin.

Systolic blood pressure (SBP) treatment targets for adults with diabetes mellitus remain unclear. SBP levels among 12 275 adults with diabetes mellitus, prior cardiovascular disease, and treated hypertension were evaluated in the TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) randomized trial of sitagliptin versus placebo. The association between baseline SBP and recurrent cardiovascular disease was evaluated using multivariable Cox proportional hazards modeling with restricted cubic splines, adjusting for clinical characteristics. Kaplan-Meier curves by baseline SBP were created to assess time to cardiovascular disease and 2 potential hypotension-related adverse events: worsening kidney function and fractures. The association between time-updated SBP and outcomes was examined using multivariable Cox proportional hazards models. Overall, 42.2% of adults with diabetes mellitus, cardiovascular disease, and hypertension had an SBP ≥140 mm Hg. The association between SBP and cardiovascular disease risk was U shaped, with a nadir ≈130 mm Hg. When the analysis was restricted to those with baseline SBP of 110 to 150 mm Hg, the adjusted association between SBP and cardiovascular disease risk was flat (hazard ratio per 10-mm Hg increase, 0.96; 95% confidence interval, 0.91-1.02). There was no association between SBP and risk of fracture. Above 150 mm Hg, higher SBP was associated with increasing risk of worsening kidney function (hazard ratio per 10-mm Hg increase, 1.10; 95% confidence interval, 1.02-1.18). Many patients with diabetes mellitus have uncontrolled hypertension. The U-shaped association between SBP and cardiovascular disease events was largely driven by those with very high or low SBP, with no difference in cardiovascular disease risk between 110 and 150 mm Hg. Lower SBP was not associated with higher risks of fractures or worsening kidney function.

Trajectory of Congestion Metrics by Ejection Fraction in Patients With Acute Heart Failure (from the Heart Failure Network).

Differences in the clinical course of congestion by underlying ejection fraction (EF) have not been well-characterized in acute heart failure (AHF). A post hoc analysis was performed using pooled data from the Diuretic Optimization Strategies Evaluation in Acute Heart Failure, Cardiorenal Rescue Study in Acute Decompensated Heart Failure, and Renal Optimization Strategies Evaluation in Acute Heart Failure trials. All patients were admitted for a primary diagnosis of AHF. Patients were grouped as reduced EF ≤40%, borderline 40% < EF < 50%, or preserved EF ≥50%. Multivariable Cox regression analysis was used to assess the association among measures of congestion and the composite of unscheduled outpatient visits, rehospitalization, or death. Mean age was 68 ± 13 years and 74% were male. Patients with a preserved EF were older, more likely to be female, less likely to have an ischemic etiology of HF, and had a higher prevalence of atrial fibrillation/flutter and chronic obstructive pulmonary disease. Compared with patients with a reduced EF, preserved EF patients had lower amino-terminal pro-b-type natriuretic peptide levels at baseline (i.e., reduced: 5,998 pg/ml [3,009 to 11,414] vs borderline: 4,420 pg/ml [1,740 to 8,057] vs preserved: 3,272 pg/ml [1,687 to 6,536]) and experienced smaller changes during hospitalization. In general, there were few differences between EF groups in the clinical course of congestion as measured by signs and symptoms of HF, body weight change, and net fluid loss. After adjusting for potential confounders, a greater improvement in global visual analog scale was associated with lower risk of unscheduled outpatient visits, rehospitalization, or death at day 60 (hazard ratio 0.94 per 10 mm increase, 95% confidence interval 0.89 to 0.995). This relation did not differ by EF (p = 0.54). In conclusion, among patients hospitalized for AHF, there were few differences in the in-hospital trajectory or prognostic value of routine markers of congestion by EF.

Implications of Alternative Hepatorenal Prognostic Scoring Systems in Acute Heart Failure (from DOSE-AHF and ROSE-AHF).

Because hepatic dysfunction is common in patients with heart failure (HF), the Model for End-Stage Liver Disease (MELD) may be attractive for risk stratification. Although alternative scores such as the MELD-XI or MELD-Na may be more appropriate in HF populations, the short-term clinical implications of these in patients with acute heart failure (AHF) are unknown. The MELD-XI and MELD-Na were calculated at baseline in 453 patients with AHF in the DOSE-AHF and ROSE-AHF trials. The correlations and associations for each score with cardiorenal biomarkers, short-term end points at 72 hours including worsening renal function and clinical events to 60 days were determined. The median MELD-XI and MELD-Na was 16 and 17, respectively. Both were correlated with baseline cystatin C, amino terminus pro-B-type natriuretic peptide, and plasma renin activity (p <0.003 for all). MELD-XI ≤16 and MELD-Na ≤17 were associated with a slight increase in cystatin C (p <0.02 for both), higher diuretic efficiency (p <0.001 for both), but not with change in global visual assessment scores (p >0.05 for both) at 72 hours. Neither score was associated with worsening renal function or worsening HF (p >0.05 for all). Similarly, both the MELD-XI and MELD-Na were not associated with 60-day death/any rehospitalization and 60-day death/HF rehospitalization in adjusted analyses when analyzes as a dichotomous or continuous variable (p >0.05 for all). In conclusion, the alternative MELD scores correlated with baseline cardiorenal biomarkers, and lower baseline MELD scoring was associated with higher diuretic efficiency and a slight increase in cystatin C through 72 hours. However, MELD-Na and MELD-XI were not predictive of 60-day clinical events.

Comparative Efficacy of Coronary Revascularization Procedures for Multivessel Coronary Artery Disease in Patients With Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular disease and death, yet little data exist regarding the comparative efficacy of coronary revascularization procedures in CKD patients with multivessel disease. We created a cohort of 4,687 adults who underwent cardiac catheterization, had a serum creatinine value measured within 30 days, and had more than one vessel with ≥50% stenosis. We used Cox proportional hazard regression modeling weighted by the inverse probability of treatment to examine the association between 4 treatment strategies (medical management, percutaneous coronary intervention [PCI] with bare metal stent, PCI with drug-eluting stent, and coronary artery bypass grafting [CABG]) and mortality among patients across categories of estimated glomerular filtration rate; secondary outcome was a composite of mortality, myocardial infarction, or revascularization. Compared with medical management, CABG was associated with a reduced risk of death for patients of any nondialysis CKD severity (hazard ratio [HR] range 0.43 to 0.59). There were no significant mortality differences between CABG and PCI, except a decreased death risk in CABG-treated CKD patients (HR range 0.54 to 0.55). Compared with medical management and PCI, CABG was associated with a lower risk of death, myocardial infarction, or revascularization in nondialysis CKD patients (HR range 0.41 to 0.64). There were similar associations between decreased estimated glomerular filtration rate and increased mortality across all multivessel coronary artery disease patient treatment groups. When accounting for treatment propensity, surgical revascularization was associated with improved outcomes in patients of all CKD severities. A prospective randomized trial in CKD patients is required to confirm our findings.

Implications of Using Different Definitions on Outcomes in Worsening Heart Failure.

BACKGROUND: In-hospital worsening heart failure (WHF) is an important event that has inconsistent definitions used across trials. We used data from 2 acute heart failure (HF) trials from the National Institutes of Health HF Network, DOSE (Diuretic Optimization Strategies Evaluation) and ROSE (Renal Optimization Strategies), to understand event rates associated with different WHF definitions. METHODS AND RESULTS: We pooled data from 668 patients in DOSE and ROSE and assessed the relationship between WHF and the composite end point of rehospitalization, emergency room visits for HF, and mortality through 60 days. We also assessed for a differential relationship between the timing of WHF development and outcomes. The overall incidence of WHF was 14.6% (24.1% in DOSE, 6.3% in ROSE, and 5.0% in DOSE using the ROSE definition). WHF was associated with an increase in the composite end point (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.11-2.42; P=0.01). However, the association between WHF and outcomes was significantly stronger in ROSE than in DOSE (HR, 2.67; 95% CI, 1.45-4.91; P<0.01 and HR, 1.28; 95% CI, 0.79-2.08; P=0.31, respectively). Development of WHF between baseline to 24 hours compared with 24 to 48 hours or 48 to 72 hours demonstrated a trend toward improved outcomes (HR, 0.49; 95% CI, 0.21-1.17; P=0.11 and HR, 0.45; 95% CI, 0.20-1.04; P=0.06, respectively). CONCLUSIONS: A WHF definition that excluded the intensification of diuretics resulted in a lower event rate but a stronger association with outcomes. These data support the need for continued efforts to standardize WHF definitions in clinical trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00577135 (DOSE) and NCT01132846 (ROSE).

Impaired Right Ventricular-Pulmonary Arterial Coupling and Effect of Sildenafil in Heart Failure With Preserved Ejection Fraction: An Ancillary Analysis From the Phosphodiesterase-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) Trial.

BACKGROUND: Right ventricular (RV) dysfunction (RVD) is a poor prognostic factor in heart failure with preserved ejection fraction (HFpEF). The physiological perturbations associated with RVD or RV function indexed to load (RV-pulmonary arterial [PA] coupling) in HFpEF have not been defined. HFpEF patients with marked impairment in RV-PA coupling may be uniquely sensitive to sildenafil. METHODS AND RESULTS: In a subset of HFpEF patients enrolled in the Phosphodiesteas-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial, physiological variables and therapeutic effect of sildenafil were examined relative to the severity of RVD (tricuspid annular plane systolic excursion [TAPSE]) and according to impairment in RV-PA coupling (TAPSE/pulmonary artery systolic pressure) ratio. The prevalence of atrial fibrillation and diuretic use, n-terminal probrain natriuretic peptide levels, renal dysfunction, neurohumoral activation, myocardial necrosis and fibrosis biomarkers, and the severity of diastolic dysfunction all increased with severity of RVD. Peak oxygen consumption decreased and ventilatory inefficiency (VE/VCO2 slope) increased with increasing severity of RVD. Many but not all physiological derangements were more closely associated with the TAPSE/pulmonary artery systolic pressure ratio. Compared with placebo, at 24 weeks, TAPSE decreased, and peak oxygen consumption and VE/CO2 slope were unchanged with sildenafil. There was no interaction between RV-PA coupling and treatment effect, and sildenafil did not improve TAPSE, peak oxygen consumption, or VE/VCO2 in patients with pulmonary hypertension and RVD. CONCLUSIONS: HFpEF patients with RVD and impaired RV-PA coupling have more advanced heart failure. In RELAX patients with RVD and impaired RV-PA coupling, sildenafil did not improve RV function, exercise capacity, or ventilatory efficiency. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867.

Serum Bicarbonate in Acute Heart Failure: Relationship to Treatment Strategies and Clinical Outcomes.

BACKGROUND: Though commonly noted in clinical practice, it is unknown if decongestion in acute heart failure (AHF) results in increased serum bicarbonate. METHODS AND RESULTS: For 678 AHF patients in the DOSE-AHF, CARRESS-HF, and ROSE-AHF trials, we assessed change in bicarbonate (baseline to 72-96 hours) according to decongestion strategy, and the relationship between bicarbonate change and protocol-defined decongestion. Median baseline bicarbonate was 28 mEq/L. Patients with baseline bicarbonate ≥28 mEq/L had lower ejection fraction, worse renal function and higher N-terminal pro-B-type natriuretic peptide than those with baseline bicarbonate <28 mEq/L. There were no differences in bicarbonate change between treatment groups in DOSE-AHF or ROSE-AHF (all P > .1). In CARRESS-HF, bicarbonate increased with pharmacologic care but decreased with ultrafiltration (median +3.3 vs -0.9 mEq/L, respectively; P < .001). Bicarbonate change was not associated with successful decongestion (P > .2 for all trials). CONCLUSIONS: In AHF, serum bicarbonate is most commonly elevated in patients with more severe heart failure. Despite being used in clinical practice as an indicator for decongestion, change in serum bicarbonate was not associated with significant decongestion.

Clinical impact of stress dose steroids in patients with septic shock: insights from the PROWESS-Shock trial.

INTRODUCTION: The aim of our study was to evaluate the clinical impact of the administration of intravenous steroids, alone or in conjunction with drotrecogin-alfa (activated) (DrotAA), on the outcomes in septic shock patients. METHODS: We performed a sub-study of the PROWESS-Shock trial (septic shock patients who received fluids and vasopressors above a predefined threshold for at least 4 hours were randomized to receive either DrotAA or placebo for 96 hours). A propensity score for the administration of intravenous steroids for septic shock at baseline was constructed using multivariable logistic regression. Cox proportional hazards model using inverse probability of treatment weighting of the propensity score was used to estimate the effect of intravenous steroids, alone or in conjunction with DrotAA, on 28-day and 90-day all-cause mortality. RESULTS: A total of 1695 patients were enrolled of which 49.5% received intravenous steroids for treatment of septic shock at baseline (DrotAA + steroids N = 436; DrotAA + no steroids N = 414; placebo + steroids N = 403; placebo + no steroids N = 442). The propensity weighted risk of 28-day as well as 90-day mortality in those treated vs. those not treated with steroids did not differ among those randomized to DrotAA vs. placebo (interaction p-value = 0.38 and p = 0.27, respectively) nor was a difference detected within each randomized treatment. Similarly, the course of vasopressor use and cardiovascular SOFA did not appear to be influenced by steroid therapy. In patients with lung infection (N = 744), abdominal infection (N = 510), Gram-positive sepsis (N = 420) and Gram-negative sepsis (N = 461), the propensity weighted risk of 28-day as well as 90-day mortality in those treated vs. those not treated with steroids did not differ among those randomized to DrotAA vs. placebo nor was a difference detected within each randomized treatment. CONCLUSIONS: In the present study of septic shock patients, after adjustment for treatment selection bias, we were unable to find noticeable positive impact from intravenous steroids for treatment of septic shock at baseline either in patients randomized for DrotAA or placebo. TRIAL REGISTRATION: Clinicaltrials.gov NCT00604214 . Registered 24 January 2008.

Periodontal disease in patients with chronic coronary heart disease: Prevalence and association with cardiovascular risk factors.

AIM: There are reported links between periodontal disease (PD) and cardiovascular (CV) risk but data are lacking, especially from populations with established coronary heart disease (CHD). This study describes self-reported indicators of PD and associations with CV risk factors in a global stable CHD population. METHODS AND RESULTS: A total of 15,828 participants in the global STABILITY trial underwent a physical examination, blood sampling, and completed a lifestyle questionnaire. They reported remaining number of teeth (none, 1-14, 15-20, 21-25 or 26-32 (all)) and frequency of gum bleeding (never/rarely, sometimes, often or always). Adjusted linear and logistic regression models assessed associations between tooth loss, gum bleeding, and socioeconomic and CV risk factors. A total of 40.9% of participants had <15 remaining teeth; 16.4% had no teeth; and 25.6% reported gum bleeding with large differences in prevalence among countries, regions and ethnic groups. Less tooth loss was associated with lower levels of glucose, low-density lipoprotein (LDL) cholesterol, systolic blood pressure, waist circumference and hs-CRP; higher estimated glomerular filtration rate; decreased odds for diabetes and smoking, and increased odds for higher education, alcohol consumption and work stress. Gum bleeding was associated with higher LDL cholesterol and systolic blood pressure; decreased odds for smoking, but increased odds for higher education, alcohol consumption and stress. CONCLUSION: Self-reported indicators of PD were common in this chronic CHD population and were associated with an increasing socioeconomic and CV risk factor burden. However, causality between self-reported PD and CV risk and outcome needs further investigation.

Effect of platelet inhibition with cangrelor during PCI on ischemic events.

BACKGROUND: The intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)-receptor antagonist that acts rapidly and has quickly reversible effects. METHODS: In a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guideline-recommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours. RESULTS: The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P=0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups. CONCLUSIONS: Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.).

Rationale and design of the Cangrelor versus standard therapy to acHieve optimal Management of Platelet InhibitiON PHOENIX trial.

BACKGROUND: Despite robust efficacy in the reduction of ischemic events in patients who require percutaneous coronary intervention (PCI), current P2Y(12) inhibitors have limitations. In particular, they require hours to be effective, and they can only be administered orally. Cangrelor is an intravenous, potent, and reversible P2Y(12) inhibitor with fast onset and offset of action. We designed CHAMPION PHOENIX to evaluate the efficacy and safety of cangrelor in patients with atherosclerosis undergoing PCI. TRIAL DESIGN: The CHAMPION PHOENIX is a randomized, double-blind, double-dummy, superiority trial comparing cangrelor with clopidogrel standard of care in approximately 10,900 patients who have not previously received a P2Y(12) inhibitor and who require PCI, including patients with stable angina and with acute coronary syndromes (with or without ST-segment elevation). The primary objective of the study is to demonstrate that cangrelor will reduce the incidence of the composite of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis in the 48 hours after randomization compared with clopidogrel without excessive periprocedural bleeding. The key secondary objective is to demonstrate that cangrelor will reduce the incidence of stent thrombosis. Myocardial infarction will be defined according to the universal MI definition, adapting the definition of PCI-related (type 4a) MI. Bleeding will be assessed according to the thrombolysis in myocardial infarction, GUSTO, and Bleeding Academic Research Consortium (BARC) scales. CONCLUSION: The CHAMPION PHOENIX may establish the role of cangrelor in the care of patients who require PCI across the spectrum of stable and unstable coronary diseases in the setting of current treatment strategies.

Aerobic and resistance training effects on energy intake: the STRRIDE-AT/RT study.

PURPOSE: Our study characterizes food and energy intake responses to long-term aerobic training (AT) and resistance training (RT) during a controlled 8-month trial. METHODS: In the STRRIDE-AT/RT trial, overweight/obese sedentary dyslipidemic men and women were randomized to AT (n = 39), RT (n = 38), or a combined treatment (AT/RT, n = 40) without any advice to change their food intakes. Quantitative food intake assessments and food frequency questionnaires were collected at baseline (before training) and after 8 months of training (end of training); body mass (BM) and fat-free mass (FFM) were also assessed. RESULTS: In AT and AT/RT, respectively, meaningful decreases in reported energy intake (REI) (-217 and -202 kcal, P < 0.001) and in intakes of fat (-14.9 and -14.9 g, P < 0.001, P = 0.004), protein (-8.3 and -10.7 g, P = 0.002, P < 0.001), and carbohydrate (-28.1 and -14.7 g, P = 0.001, P = 0.030) were found by food frequency questionnaires. REI relative to FFM decreased (P < 0.001 and P = 0.002), as did intakes of fat (-0.2 and -0.3 g, P = 0.003 and P = 0.014) and protein (-0.1 and -0.2 g, P = 0.005 and P < 0.001) in AT and AT/RT and carbohydrate (-0.5 g, P < 0.003) in AT only. For RT, REI by quantitative daily dietary intake decreased (-3.0 kcal.kg(-1) FFM, P = 0.046), as did fat intake (-0.2 g, P = 0.033). BM decreased in AT (-1.3 kg, P = 0.006) and AT/RT (-1.5 kg, P = 0.001) but was unchanged (0.6 kg, P = 0.176) in RT. CONCLUSIONS: Previously sedentary subjects completing 8 months of AT or AT/RT reduced their intakes of calories and macronutrients and BM. In RT, fat intakes and REI (when expressed per FFM) decreased, BM was unchanged, and FFM increased.

Implementing rapid HIV testing with or without risk-reduction counseling in drug treatment centers: results of a randomized trial.

OBJECTIVES: We examined the effectiveness of risk reduction counseling and the role of on-site HIV testing in drug treatment. METHODS: Between January and May 2009, we randomized 1281 HIV-negative (or status unknown) adults who reported no past-year HIV testing to (1) referral for off-site HIV testing, (2) HIV risk-reduction counseling with on-site rapid HIV testing, or (3) verbal information about testing only with on-site rapid HIV testing. RESULTS: We defined 2 primary self-reported outcomes a priori: receipt of HIV test results and unprotected anal or vaginal intercourse episodes at 6-month follow-up. The combined on-site rapid testing participants received more HIV test results than off-site testing referral participants (P<.001; Mantel-Haenszel risk ratio=4.52; 97.5% confidence interval [CI]=3.57, 5.72). At 6 months, there were no significant differences in unprotected intercourse episodes between the combined on-site testing arms and the referral arm (P=.39; incidence rate ratio [IRR]=1.04; 97.5% CI=0.95, 1.14) or the 2 on-site testing arms (P=.81; IRR=1.03; 97.5% CI=0.84, 1.26). CONCLUSIONS: This study demonstrated on-site rapid HIV testing's value in drug treatment centers and found no additional benefit from HIV sexual risk-reduction counseling.

Extended valganciclovir prophylaxis to prevent cytomegalovirus after lung transplantation: a randomized, controlled trial.

BACKGROUND: Cytomegalovirus (CMV) is the most prevalent opportunistic infection after lung transplantation. Current strategies do not prevent CMV in most at-risk patients. OBJECTIVE: To determine whether extending prophylaxis with oral valganciclovir from the standard 3 months to 12 months after lung transplantation is efficacious. DESIGN: Randomized, clinical trial. Patients were randomly assigned by a central automated system to treatment or placebo. Patients and investigators were blinded to treatment status. (ClinicalTrials.gov registration number: NCT00227370) SETTING: Multicenter trial involving 11 U.S. lung transplant centers. PATIENTS: 136 lung transplant recipients who completed 3 months of valganciclovir prophylaxis. INTERVENTION: 9 additional months of oral valganciclovir (n = 70) or placebo (n = 66). MEASUREMENTS: The primary end point was freedom from CMV disease (syndrome or tissue-invasive) on an intention-to-treat basis 300 days after randomization. Secondary end points were CMV disease severity, CMV infection, acute rejection, opportunistic infections, ganciclovir resistance, and safety. RESULTS: CMV disease occurred in 32% of the short-course group versus 4% of the extended-course group (P < 0.001). Significant reductions were observed with CMV infection (64% vs. 10%; P < 0.001) and disease severity (110 000 vs. 3200 copies/mL, P = 0.009) with extended treatment. Rates of acute rejection, opportunistic infections, adverse events, CMV UL97 ganciclovir-resistance mutations, and laboratory abnormalities were similar between groups. During the 6 months after study completion, a low incidence of CMV disease was observed in both groups. LIMITATION: Longer-term effects of extended prophylaxis were not assessed. CONCLUSION: In adult lung transplant recipients who have received 3 months of valganciclovir, extending prophylaxis by an additional 9 months significantly reduces CMV infection, disease, and disease severity without increased ganciclovir resistance or toxicity. A beneficial effect with regard to prevention of CMV disease seems to extend at least through 18 months after transplantation.