Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. METHODS: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. RESULTS: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. CONCLUSIONS: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).

Enrollment Obstacles in a Randomized Controlled Trial: A Performance Survey of Enrollment in BEST-CLI Sites.

BACKGROUND: Although randomized controlled trials (RCTs) provide the most reliable form of scientific evidence, they are challenging to complete because of a variety of enrollment obstacles. We evaluated obstacles in a large RCT by comparing survey results at high-performing sites (HPS) and low-performing sites (LPS). METHODS: The Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) trial is a prospective, pragmatic, multicenter, and multispecialty RCT that will compare clinical outcomes, quality of life, and cost in patients with CLI randomized to surgical bypass or endovascular therapy. BEST-CLI aims to enroll 2100 patients at 160 sites in North America, Europe, and New Zealand. We surveyed the 30 HPS and 30 LPS to assess perceptions of enrollment obstacles. HPS were defined by enrollment of 0.5 subjects or more per month or more than 8 total subjects enrolled. LPS were defined by enrollment of 0.1 subjects per month or only 1 subject total. Responses were compared by site performance status. RESULTS: There were 22 of 30 (73%) HPS and 14 of 30 (47%) LPS that answered the survey (P = 0.06), including 17 investigators and 31 coordinators. The mean total enrollment and rate of enrollment at HPS and LPS were 12.5 subjects at 1.5 subjects/month and 1.0 subject at 0.1 subjects/month, respectively. The most common barrier to enrollment at HPS was difficulty convincing patients and their families to participate (36%), whereas at LPS both difficulty convincing patients and difficulty motivating investigators to enroll (29% each) were most frequently cited. At HPS, the most common obstacle to consenting patients for the trial was patient/family having strong preference toward revascularization strategy (32%) and at LPS it was patient/family not wanting to have treatment chosen at random (36%). At 55% of HPS and 43% of LPS, the trial team was reported as extremely collaborative (P = 0.73), whereas 68% of HPS and 64% of LPS reported having identified a trial champion on their team (P = 1). The most restrictive perceived enrollment criterion at HPS was prior index limb stenting with significant restenosis (32%), whereas at LPS it was excessive risk for surgical bypass (43%). Materials to aid enrollment were used equally at HPS and LPS: patient brochures at 59% HPS and 64% LPS (P = 1); investigator talking points at 45% of HPS and 36% of LPS (P = 0.73). CONCLUSIONS: Patient perceptions and investigator biases are significant challenges to enrollment in large RCTs. In the BEST-CLI trial, difficulty convincing patients and families to allow treatment randomization and difficulty in motivating investigators were major enrollment obstacles.

Effects of blood storage age on immune, coagulation, and nitric oxide parameters in transfused patients undergoing cardiac surgery.

BACKGROUND: Retrospective studies suggested that storage age of RBCs is associated with inflammation and thromboembolism. The Red Cell Storage Duration Study (RECESS) trial randomized subjects undergoing complex cardiac surgery to receive RBCs stored for shorter versus longer periods, and no difference was seen in the primary outcome of change in multiple organ dysfunction score. STUDY DESIGN AND METHODS: In the current study, 90 subjects from the RECESS trial were studied intensively using a range of hemostasis, immunologic, and nitric oxide parameters. Samples were collected before transfusion and on Days 2, 6, 28, and 180 after transfusion. RESULTS: Of 71 parameters tested, only 4 showed a significant difference after transfusion between study arms: CD8+ T-cell interferon-γ secretion and the concentration of extracellular vesicles bearing the B-cell marker CD19 were higher, and plasma endothelial growth factor levels were lower in recipients of fresh versus aged RBCs. Plasma interleukin-6 was higher at Day 2 and lower at Days 6 and 28 in recipients of fresh versus aged RBCs. Multiple parameters showed significant modulation after surgery and transfusion. Most analytes that changed after surgery did not differ based on transfusion status. Several extracellular vesicle markers, including two associated with platelets (CD41a and CD62P), decreased in transfused patients more than in those who underwent surgery without transfusion. CONCLUSIONS: Transfusion of fresh versus aged RBCs does not result in substantial changes in hemostasis, immune, or nitric oxide parameters. It is possible that transfusion modulates the level of platelet-derived extracellular vesicles, which will require study of patients randomly assigned to receipt of transfusion to define.

WBC alloimmunization: effects on the laboratory and clinical endpoints of therapeutic granulocyte transfusions.

BACKGROUND: Although the subject of many previous studies, the importance of white blood cell (WBC) alloimmunization in granulocyte transfusion therapy has not been settled. In this study, we report the results of the effects of WBC antibodies in the RING (Resolving Infection in Neutropenia with Granulocytes) study, a randomized controlled trial comparing the efficacy of daily granulocyte transfusion therapy plus antimicrobials versus antimicrobials alone; the primary outcome results have been published previously. STUDY DESIGN AND METHODS: One hundred fourteen subjects were enrolled in the study. Serum samples for WBC antibody determination were obtained from each subject at baseline and at 2 and 6 weeks. One hundred subjects had at least one antibody test result. Samples were tested for human leukocyte antigen (HLA) Class I and Class II antibodies as well as for granulocyte-specific antibodies using granulocyte agglutination and immunofluorescence techniques. All testing was performed at a central laboratory. RESULTS: Baseline WBC alloimmunization was modest, depending somewhat on the assay. Seroconversion during the study was slightly higher in the granulocyte transfusion arm, but the differences were not statistically significant. There was no demonstrable effect of the presence of alloimmunization on the primary outcome (survival and microbial response at 42 days), the occurrence of transfusion reactions (either overall or pulmonary), or posttransfusion neutrophil increments. CONCLUSION: The presence or development of WBC antibodies had no demonstrable effect on any clinical aspect of granulocyte transfusion therapy. It appears that, at least in the patient population studied, there is no evidence suggesting need for concern about recipient WBC alloimmunization when prescribing granulocyte transfusions.

Laboratory predictors of bleeding and the effect of platelet and RBC transfusions on bleeding outcomes in the PLADO trial.

Bleeding remains a significant problem for many thrombocytopenic hematology/oncology patients in spite of platelet transfusions. Factors that might contribute to bleeding were analyzed for 16 320 patient-days on or after their first platelet transfusion in 1077 adult patients enrolled in the Platelet Dose (PLADO) trial. All patients had a greatly increased risk of bleeding at platelet counts of ≤5 × 109/L (odds ratio [OR], 3.1; 95% confidence interval [CI], 2.0-4.8) compared with platelet counts ≥81 × 109/L. Platelet counts between 6 × 109/L and 80 × 109/L were also associated with a somewhat elevated bleeding risk in patients receiving allogeneic stem cell transplants (SCTs) or chemotherapy but not in those undergoing autologous SCTs. Other significant laboratory predictors of bleeding were hematocrit ≤25% (OR, 1.29; 95% CI, 1.11-1.49), activated partial thromboplastin time (aPTT) 30 to ≤50 seconds (OR, 1.40; 95% CI, 1.08-1.81; P = .01), aPTT >50 seconds (OR, 2.34; 95% CI, 1.54-3.56), international normalized ratio (INR) 1.2 to 1.5 (OR, 1.46; 95% CI, 1.17-1.83), and INR >1.5 (OR, 2.05; 95% CI, 1.43-2.95). Transfusion of either platelets or red blood cells (RBCs) on days with bleeding was often not sufficient to change bleeding outcomes on the following day. Because bleeding occurred over a wide range of platelet counts among patients undergoing allogeneic SCT or chemotherapy and because platelet transfusions may not prevent bleeding, other risk factors may be involved. These may include low hematocrit and coagulation abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT00128713.

Clinical outcomes in a cohort of patients with heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a thrombotic disorder usually prompting treatment with non-heparin anticoagulants. The benefits and risks of such treatments have not been fully assessed. METHODS: We analyzed data for 442 patients having a positive heparin-platelet factor 4 antibody test and recent heparin exposure. The primary outcome was a composite endpoint (death, limb amputation/gangrene, or new thrombosis). Secondary outcomes included bleeding and the effect of anticoagulation. FINDINGS: Seventy-one patients (16%) had HIT with thrombosis (HIT-T); 284 (64%) had HIT without thrombosis (isolated HIT); 87 (20%) did not have HIT. An intermediate or high "4T" score was found in 85%, 58%, and 8% of the three respective groups. Non-heparin anticoagulation was begun in 80%, 56%, and 45%. The composite endpoint occurred in 48%, 36%, and 17% (P = .01) of which 61%, 38%, and 40% were receiving non-heparin anticoagulation. Compared with the no HIT group, the composite endpoint was significantly more likely in HIT-T [HR 2.48 (1.35-4.55), P = .003)] and marginally more likely in isolated HIT [HR 1.66 (0.96-2.85), P = .071]. Importantly, risk increased (HR 1.77, P = .02) after platelet transfusion. Major bleeding occurred in 48%, 36%, and 16% of the three groups (P = .005). Non-heparin anticoagulation was not associated with a reduction in composite endpoint events in either HIT group. INTERPRETATION: HIT patients have high risks of death, limb amputation/gangrene, thrombosis, and bleeding. Non-heparin anticoagulant treatment may not benefit all patients and should be considered only after careful assessment of the relative risks of thrombosis and bleeding in individual patients.

Data and Safety Monitoring Board evaluation and management of a renal adverse event signal in TOPCAT.

Clinical trial Data and Safety Monitoring Boards (DSMBs) have a primary obligation of ensuring study participant safety, while maintaining trial integrity. The role of DSMBs is expanding, and ideally should include post-hoc reporting of deliberative processes related to clinically important safety issues or factors that could impact on future trial designs. We describe how the TOPCAT DSMB detected, investigated, and adjudicated an unexpectedly large renal adverse event signal midway through the trial, and offer general guidelines for dealing with similar unanticipated occurrences in future trials. The detection of a greater than expected incidence of deterioration in renal function, occurring in 6.1% of patients in the spironolactone arm compared with 3.9% in the placebo arm (P = 0.009), led to an in-depth DSMB review of associated study medication withdrawals and adverse events. The trial continued uninterrupted throughout the review, which reached the conclusions that spironolactone-associated renal dysfunction did not compromise overall patient safety or interfere with a perceived efficacy signal. Although no discrete mechanism for the spironolactone-associated renal adverse event signal was identified, likely possibilities are discussed. In clinical trials, DSMBs and co-ordinating centres should have the resources to detect, investigate, and adjudicate unexpected safety issues, with goals of ensuring patient safety and preserving the potential for detection of therapeutic effectiveness. In TOPCAT, spironolactone-associated renal dysfunction emerged as a potentially trial-threatening adverse event and, although clinically important, did not lead to compromise of patient safety, trial interruption, termination, or apparent loss of treatment effectiveness.

The impact of red blood cell storage duration on tissue oxygenation in cardiac surgery.

OBJECTIVE: Although storage alters red blood cells, several recent, randomized trials found no differences in clinical outcomes between patients transfused with red blood cells stored for shorter versus longer periods of time. The objective of this study was to see whether storage impairs the in vivo ability of erythrocytes to traverse the microcirculation and deliver oxygen at the tissue level. METHODS: A subset of subjects from a clinical trial of cardiac surgery patients randomized to receive transfusions of red blood cells stored ≤10 days or ≥21 days were assessed for thenar eminence and cerebral tissue hemoglobin oxygen saturation (StO2) via the use of near-infrared spectroscopy and sublingual microvascular blood flow via side-stream darkfield videomicroscopy. RESULTS: Among 55 subjects, there was little change in the primary endpoint (thenar eminence StO2 from before to after transfusion of one unit) and the change was similar in the 2 groups: +1.7% (95% confidence interval, -0.3, 3.8) for shorter-storage and +0.8% (95% confidence interval, -1.1, 2.9) for longer-storage; P = .61). Similarly, no significant differences were observed for cerebral StO2 or sublingual microvascular blood flow. These parameters also were not different from preoperatively to 1 day postoperatively, reflecting the absence of a cumulative effect of all red blood cell units transfused during this period. CONCLUSIONS: There were no differences in thenar eminence or cerebral StO2, or sublingual microcirculatory blood flow, in cardiac surgery patients transfused with red blood cells stored ≤10 days or ≥21 days. These results are consistent with the clinical outcomes in the parent study, which also did not differ, indicating that storage may not impair oxygen delivery by red blood cells in this setting.

Design and Rationale of the Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) Trial.

BACKGROUND: Critical limb ischemia (CLI) is increasing in prevalence, and remains a significant source of mortality and limb loss. The decision to recommend surgical or endovascular revascularization for patients who are candidates for both varies significantly among providers and is driven more by individual preference than scientific evidence. METHODS AND RESULTS: The Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) Trial is a prospective, randomized, multidisciplinary, controlled, superiority trial designed to compare treatment efficacy, functional outcomes, quality of life, and cost in patients undergoing best endovascular or best open surgical revascularization. Approximately 140 clinical sites in the United States and Canada will enroll 2100 patients with CLI who are candidates for both treatment options. A pragmatic trial design requires consensus on patient eligibility by at least 2 investigators, but leaves the choice of specific procedural strategy within the assigned revascularization approach to the individual treating investigator. Patients with suitable single-segment of saphenous vein available for potential bypass will be randomized within Cohort 1 (n=1620), while patients without will be randomized within Cohort 2 (n=480). The primary efficacy end point of the trial is Major Adverse Limb Event-Free Survival. Key secondary end points include Re-intervention and Amputation-Free-Survival and Amputation Free-Survival. CONCLUSIONS: The BEST-CLI trial is the first randomized controlled trial comparing endovascular therapy to open surgical bypass in patients with CLI to be carried out in North America. This landmark comparative effectiveness trial aims to provide Level I data to clarify the appropriate role for both treatment strategies and help define an evidence-based standard of care for this challenging patient population. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02060630.

Platelet Transfusion Practices Among Very-Low-Birth-Weight Infants.

IMPORTANCE: Thrombocytopenia and intraventricular hemorrhage (IVH) are common among very-low-birth-weight (VLBW) infants. Survey results suggest that US neonatologists frequently administer platelet transfusions to VLBW infants with mild to moderate thrombocytopenia. OBJECTIVES: To characterize platelet transfusion practices in US neonatal intensive care units (NICUs), to determine whether severity of illness influences platelet transfusion decisions, and to examine the association between platelet count (PCT) and the risk for IVH in the first 7 days of life. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, retrospective cohort study included 972 VLBW infants treated in 6 US NICUs, with admission dates from January 1, 2006, to December 31, 2007. Data were collected from all infants until NICU discharge or death (last day of data collected, December 4, 2008). Data were entered into the central database, cleaned, and analyzed from May 1, 2009, to February 11, 2016. INTERVENTION: Platelet transfusion. MAIN OUTCOMES AND MEASURES: Number of platelet transfusions and incidence of IVH. RESULTS: Among the 972 VLBW infants (520 [53.5%] male; mean [SD] gestational age, 28.2 [2.9] weeks), 231 received 1002 platelet transfusions (mean [SD], 4.3 [6.0] per infant; range, 1-63 per infant). The pretransfusion PCT was at least 50 000/µL for 653 of 998 transfusions (65.4%) with this information. Two hundred eighty-one transfusions (28.0%) were given during the first 7 days of life. During that period, platelet transfusions were given on 35 of 53 days (66.0%) when the patient had a PCT less than 50 000/µL and on 203 of 436 days (46.6%) when the patient had a PCT of 50 000/µL to 99 000/µL. At least 1 marker of severe illness was present on 198 of 212 patient-days (93.4%) with thrombocytopenia (PCT, <100 000/µL) when a platelet transfusion was given compared with 113 of 190 patient-days (59.5%) with thrombocytopenia when no platelet transfusion was given. Thrombocytopenia was a risk factor for intraventricular hemorrhage during the first 7 days of life (hazard ratio, 2.17; 95% CI, 1.53-3.08; P < .001). However, no correlation was found between severity of thrombocytopenia and risk for IVH. After controlling for significant clinical factors and thrombocytopenia, platelet transfusions did not have a significant effect on the incidence of IVH (hazard ratio, 0.92; 95% CI, 0.49-1.73; P = .80). CONCLUSIONS AND RELEVANCE: A large proportion of platelet transfusions were given to VLBW infants with PCT greater than 50 000/µL. Severity of illness influenced transfusion decisions. However, the severity of thrombocytopenia did not correlate with the risk for IVH, and platelet transfusions did not reduce this risk.

Impact of Spironolactone on Longitudinal Changes in Health-Related Quality of Life in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial.

BACKGROUND: Heart failure (HF) with preserved ejection fraction patients have equally impaired health-related quality of life (HRQL) compared with those with HF with reduced ejection fraction, but limited studies have evaluated the impact of therapies on changes in HRQL. METHODS AND RESULTS: Patients ≥50 years of age, with symptomatic HF and left ventricular ejection fraction ≥45%, were enrolled in Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) and randomized to spironolactone or placebo. Patients completed the Kansas City Cardiomyopathy Questionnaire (KCCQ), which was the primary HRQL instrument, and EQ5D visual analog scale at baseline, 4 months, 12 months, and annually thereafter. McMaster Overall Treatment Evaluation was assessed at 4 and 12 months to assess global change scores. Change scores (+SD) were calculated to determine between-group differences, and multivariable repeated-measures models were created to identify other factors associated with change scores. Paired KCCQ data were available for 91.7% of 3445 TOPCAT patients. By 4 months, the mean change in KCCQ was 7.7±16 and mean change in EQ5D visual analog scale was 4.7±16. Adjusted mean changes in KCCQ for the spironolactone group were significantly better than those for the placebo group at 4-month (1.54 better; P=0.002), 12-month (1.35 better; P=0.02), and 36-month (1.86 better; P=0.02) visits. No between-group differences in EQ5D visual analog scale change scores or McMaster Overall Treatment Evaluation were noted. Older age, obesity, current smoking, New York Heart Association class III/IV, and comorbid illnesses were associated with declines in KCCQ scores. Use of spironolactone was an independent predictor of improved KCCQ scores. CONCLUSIONS: In symptomatic HF with preserved ejection fraction patients, use of spironolactone was associated with an improvement in HF-specific HRQL. Several modifiable risk factors were associated with HRQL deterioration. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection.

High-dose granulocyte transfusion therapy has been available for 20 years, yet its clinical efficacy has never been conclusively demonstrated. We report here the results of RING (Resolving Infection in Neutropenia with Granulocytes), a multicenter randomized controlled trial designed to address this question. Eligible subjects were those with neutropenia (absolute neutrophil count <500/µL) and proven/probable/presumed infection. Subjects were randomized to receive either (1) standard antimicrobial therapy or (2) standard antimicrobial therapy plus daily granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. The primary end point was a composite of survival plus microbial response, at 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Fifty-six subjects were randomized to the granulocyte arm and 58 to the control arm. Transfused subjects received a median of 5 transfusions. Mean transfusion dose was 54.9 × 10(9) granulocytes. Overall success rates were 42% and 43% for the granulocyte and control groups, respectively (P > .99), and 49% and 41%, respectively, for subjects who received their assigned treatments (P = .64). Success rates for granulocyte and control arms did not differ within any infection type. In a post hoc analysis, subjects who received an average dose per transfusion of ≥0.6 × 10(9) granulocytes per kilogram tended to have better outcomes than those receiving a lower dose. In conclusion, there was no overall effect of granulocyte transfusion on the primary outcome, but because enrollment was half that planned, power to detect a true beneficial effect was low. RING was registered at www.clinicaltrials.gov as #NCT00627393.

Effects of red-cell storage duration on patients undergoing cardiac surgery.

BACKGROUND: Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoing cardiac surgery may be especially vulnerable to the adverse effects of transfusion. METHODS: We conducted a randomized trial at multiple sites from 2010 to 2014. Participants 12 years of age or older who were undergoing complex cardiac surgery and were likely to undergo transfusion of red cells were randomly assigned to receive leukocyte-reduced red cells stored for 10 days or less (shorter-term storage group) or for 21 days or more (longer-term storage group) for all intraoperative and postoperative transfusions. The primary outcome was the change in Multiple Organ Dysfunction Score (MODS; range, 0 to 24, with higher scores indicating more severe organ dysfunction) from the preoperative score to the highest composite score through day 7 or the time of death or discharge. RESULTS: The median storage time of red-cell units provided to the 1098 participants who received red-cell transfusion was 7 days in the shorter-term storage group and 28 days in the longer-term storage group. The mean change in MODS was an increase of 8.5 and 8.7 points, respectively (95% confidence interval for the difference, -0.6 to 0.3; P=0.44). The 7-day mortality was 2.8% in the shorter-term storage group and 2.0% in the longer-term storage group (P=0.43); 28-day mortality was 4.4% and 5.3%, respectively (P=0.57). Adverse events did not differ significantly between groups except that hyperbilirubinemia was more common in the longer-term storage group. CONCLUSIONS: The duration of red-cell storage was not associated with significant differences in the change in MODS. We did not find that the transfusion of red cells stored for 10 days or less was superior to the transfusion of red cells stored for 21 days or more among patients 12 years of age or older who were undergoing complex cardiac surgery. (Funded by the National Heart, Lung, and Blood Institute; RECESS ClinicalTrials.gov number, NCT00991341.).

Baseline distribution of participants with depression and impaired quality of life in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial.

BACKGROUND: Previous studies have demonstrated the psychosocial effect of heart failure in patients with reduced ejection fraction. However, the effects on patients with preserved ejection fraction have not yet been elucidated. This study aimed to determine the baseline characteristics of participants with heart failure with preserved ejection fraction as it relates to impaired quality of life (QOL) and depression, identify predictors of poor QOL and depression, and determine the correlation between QOL and depression. METHODS AND RESULTS: Among patients enrolled in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT), 3400 patients completed the Kansas City Cardiomyopathy Questionnaire, 3395 patients completed European QOL 5D Visual Analog Scale, and 1431 patients in United States and Canada completed the Patient Health Questionnaire-9. The mean summary score on the Kansas City Cardiomyopathy Questionnaire was 54.8, and on European QOL 5D Visual Analog Scale, it was 60.3; 27% of patients had moderate to severe depression. Factors associated with better Kansas City Cardiomyopathy Questionnaire and European QOL 5D Visual Analog Scale via multiple logistic regression analysis were American region, older age, no history of angina pectoris or asthma, no use of hypoglycemic agent, more activity level, and lower New York Heart Association class. Factors associated with depression via multiple logistic regression analysis included younger age, female sex, comorbid angina, chronic obstructive pulmonary disease, use of a hypoglycemic agent, lower activity level, higher New York Heart Association class, and selective serotonin reuptake inhibitor use. There were significant correlations between each of the QOL scores and depression. CONCLUSIONS: Patients with heart failure with preserved ejection fraction, who were younger had higher New York Heart Association class or comorbid angina pectoris, had lower activity levels, lived in Eastern Europe or were taking hypoglycemic agents, were more likely to have impaired QOL and depression. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Transfusion-related adverse events in the Platelet Dose study.

BACKGROUND: How platelet (PLT) product characteristics such as dose, source (whole blood derived [WBD] vs. apheresis), storage duration, and ABO matching status affect the risks of transfusion-related adverse events (TRAEs) is unclear. Similarly, more information is needed to define how recipient characteristics affect the frequency of TRAEs after PLT transfusion. STUDY DESIGN AND METHODS: In the multicenter Platelet Dose ("PLADO") study, pediatric and adult hematology-oncology patients with hypoproliferative thrombocytopenia were randomized to receive low-dose (LD), medium-dose (MD), or high-dose (HD) PLT prophylaxis for a pretransfusion PLT count of not more than 10 × 10(9) /L. All PLT units (apheresis or WBD) were leukoreduced. Post hoc analyses of PLADO data were performed using multipredictor models. RESULTS: A total of 5034 PLT transfusions to 1102 patients were analyzed. A TRAE occurred with 501 PLT transfusions (10.0%). The most common TRAEs were fever (6.6% of transfusions), allergic or hypersensitivity reactions (1.9%), and sinus tachycardia (1.8%). Patients assigned HD PLTs were more likely than LD or MD patients to experience any TRAE (odds ratio for HD vs. MD, 1.50; 95% confidence interval, 1.10-2.05; three-group comparison p = 0.02). PLT source and ABO matching status were not significantly related to overall TRAE risk. Compared to a patient's first PLT transfusion, subsequent PLT transfusions were less likely to have a TRAE reported, primarily due to a lower risk of allergic or hypersensitivity reactions. CONCLUSION: The most important PLT unit characteristic associated with TRAEs was PLT dose per transfusion. HD PLTs may increase the risk of TRAEs, and LD PLTs may reduce the risk.

Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial.

BACKGROUND: Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) patients with heart failure and preserved left ventricular ejection fraction assigned to spironolactone did not achieve a significant reduction in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalization for management of heart failure) compared with patients receiving placebo. In a post hoc analysis, an ≈4-fold difference was identified in this composite event rate between the 1678 patients randomized from Russia and Georgia compared with the 1767 enrolled from the United States, Canada, Brazil, and Argentina (the Americas). METHODS AND RESULTS: To better understand this regional difference in clinical outcomes, demographic characteristics of these populations and their responses to spironolactone were explored. Patients from Russia/Georgia were younger, had less atrial fibrillation and diabetes mellitus, but were more likely to have had prior myocardial infarction or a hospitalization for heart failure. Russia/Georgia patients also had lower left ventricular ejection fraction and creatinine but higher diastolic blood pressure (all P<0.001). Hyperkalemia and doubling of creatinine were more likely and hypokalemia was less likely in patients receiving spironolactone in the Americas with no significant treatment effects in Russia/Georgia. All clinical event rates were markedly lower in Russia/Georgia, and there was no detectable impact of spironolactone on any outcomes. In contrast, in the Americas, the rates of the primary outcome, cardiovascular death, and hospitalization for heart failure were significantly reduced by spironolactone. CONCLUSIONS: This post hoc analysis demonstrated greater potassium and creatinine changes and possible clinical benefits with spironolactone in patients with heart failure and preserved ejection fraction from the Americas. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Cardiac structure and function and prognosis in heart failure with preserved ejection fraction: findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) Trial.

BACKGROUND: Abnormalities in cardiac structure and function in heart failure with preserved ejection fraction may help identify patients at particularly high risk for cardiovascular morbidity and mortality. METHODS AND RESULTS: Cardiac structure and function were assessed by echocardiography in a blinded core laboratory at baseline in 935 patients with heart failure with preserved ejection fraction (left ventricular ejection fraction ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial and related to the primary composite outcome of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest, and its components. At a median follow-up of 2.9 years, 244 patients experienced the primary outcome. Left ventricular hypertrophy (adjusted hazard ratio, 1.52; 95% confidence interval, 1.16-2.00), elevated left ventricular filling pressure (E/E'; adjusted hazard ratio 1.05 per 1 integer increase; 95% confidence interval, 1.02-1.07), and higher pulmonary artery pressure assessed by the tricuspid regurgitation velocity (hazard ratio, 1.23 per 0.5 m/s increase; 95% confidence interval, 1.02-1.49) were associated with the composite outcome and heart failure hospitalization alone after adjusting for clinical and laboratory variables. The risk of adverse outcome associated with left ventricular hypertrophy was additive to the risk associated with elevated E/E'. CONCLUSIONS: Among heart failure with preserved ejection fraction patients enrolled in TOPCAT, left ventricular hypertrophy, higher left ventricular filling pressure, and higher pulmonary artery pressure were predictive of heart failure hospitalization, cardiovascular death, or aborted cardiac arrest independent of clinical and laboratory predictors. These features, both alone and in combination, identify heart failure with preserved ejection fraction patients at particularly high risk for cardiovascular morbidity and mortality. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.