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Ascertainment bias is a well-recognized source of bias in research, but few studies have systematically analyzed sources of ascertainment bias in randomized trials in which blinding is not possible and endpoint assessment is not protocolized. In the current study, we sought to evaluate differences in the clinical practice patterns of trial investigators with respect to bias in the ascertainment of pre-revascularization patient risk and the incidence of secondary endpoints post-revascularization. We conducted a cross-sectional survey of active investigators ( n = 936) from the Best Endovascular Versus Best Surgical Therapy for Patients with Critical Limb Ischemia (BEST-CLI) trial. The total survey response rate was 19.6% (183/936). Vascular surgeons were more likely than nonsurgical interventionalists to order tests for cardiac complications after both surgical bypass ( p < 0.001) and endovascular revascularization ( p = 0.038). Post-procedure, investigators were more likely to order additional testing for cardiac complications in open surgery versus endovascular cases (7% vs 16% never, 41% vs 65% rarely, 43% vs 17% sometimes, 9% vs 2% always, respectively; p < 0.0001). Significant variation in practice patterns exist in the pre- and post-procedure assessment of cardiac risk and events for patients with CLI undergoing revascularization. Variation in the ascertainment of risk and outcomes according to the type of revascularization procedure and physician specialty should be considered when interpreting the results of clinical studies, such as the BEST-CLI trial. ClinicalTrials.gov Identifier: NCT02060630

Objective The National Health Service demonstrated that regions of the United Kingdom with the highest number of patients enrolled in research studies had the lowest risk-adjusted mortality when patients were admitted to the hospital. Our goal was to investigate if this correlation was evident for patients with chronic limb threatening ischemia (CLI) treated in the United States (US). Accordingly, we examined correlations among sites participating in the Best Endovascular versus best Surgical Therapy in patients with Critical (BEST-CLI) trial, a multicenter, National Institute of Health-sponsored, international randomized controlled trial (RCT) comparing revascularization strategies in patients with CLI, and regional rates of major amputation from CLI. Methods We measured regional participation in the BEST-CLI trial by evaluating trial participation and enrollment rosters. To determine regional rates of lower limb amputation, we queried the Medicare database (2007-2016) for patients with concurrent peripheral arterial disease (PAD) and diabetes, then assessed how many had lower extremity amputations. Correlation of regional amputation rates with distribution of BEST-CLI sites in four US geographical regions was calculated using Pearson's correlation coefficients. Simple regression equations were used to calculate the significance of these correlation coefficients. Results Of 9,231,909 CLI patients, 342,406 underwent amputation in the Medicare dataset. Amputation rates per 1000 CLI patients differed by region (South 40.42, Midwest 40.12, West 34.81, Northeast 31.14). There were 116 US vascular centers, selected by volume and expertise that participated in BEST-CLI with the following distribution: South (n = 30, 26%), Midwest (n = 26, 22%), West (n = 29, 25%), and Northeast (n = 31, 27%). There was a negative correlation between the number of amputations per 1000 for Medicare CLI patients with diabetes and PAD and the number of BEST-CLI sites in the region which trended toward significance (Pearson R= -0.61, P = 0.39). Conclusions Amputation rate among Medicare CLI patients is inversely correlated with US BEST-CLI site distribution. Higher participation in clinical research, especially within large RCTs, may be a marker of optimal PAD management.

Background The FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial demonstrated that for patients with diabetes mellitus (DM) and multivessel coronary disease (MVD), coronary artery bypass grafting (CABG) is superior to percutaneous coronary intervention with drug-eluting stents (PCI-DES) in reducing the rate of major adverse cardiovascular and cerebrovascular events after a median follow-up of 3.8 years. It is not known, however, whether CABG confers a survival benefit after an extended follow-up period. Objectives The purpose of this study was to evaluate the long-term survival of DM patients with MVD undergoing coronary revascularization in the FREEDOM trial. Methods The FREEDOM trial randomized 1,900 patients with DM and MVD to undergo either PCI with sirolimus-eluting or paclitaxel-eluting stents or CABG on a background of optimal medical therapy. After completion of the trial, enrolling centers and patients were invited to participate in the FREEDOM Follow-On study. Survival was evaluated using Kaplan-Meier analysis, and Cox proportional hazards models were used for subgroup and multivariate analyses. Results A total of 25 centers (of 140 original centers) agreed to participate in the FREEDOM Follow-On study and contributed a total of 943 patients (49.6% of the original cohort) with a median follow-up of 7.5 years (range 0 to 13.2 years). Of the 1,900 patients, there were 314 deaths during the entire follow-up period (204 deaths in the original trial and 110 deaths in the FREEDOM Follow-On). The all-cause mortality rate was significantly higher in the PCI-DES group than in the CABG group (24.3% [159 deaths] vs. 18.3% [112 deaths]; hazard ratio: 1.36; 95% confidence interval: 1.07 to 1.74; p = 0.01). Of the 943 patients with extended follow-up, the all-cause mortality rate was 23.7% (99 deaths) in the PCI-DES group and 18.7% (72 deaths) in the CABG group (hazard ratio: 1.32; 95% confidence interval: 0.97 to 1.78; p = 0.076). Conclusions In patients with DM and MVD, coronary revascularization with CABG leads to lower all-cause mortality than with PCI-DES in long-term follow-up. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450)

Background Diabetes mellitus (DM) is associated with complex coronary artery disease (CAD), which in turn results in increased morbidity and mortality from cardiovascular disease. Objectives This study sought to evaluate the utility of SYNTAX score (SS) for predicting future cardiovascular events in patients with DM and complex CAD undergoing either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). Methods The FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial randomized patients with DM and multivessel CAD to undergo either PCI with drug-eluting stents or CABG. The SS was calculated retrospectively by a core laboratory. The endpoint of hard cardiovascular events (HCE) was a composite of death from any cause, nonfatal myocardial infarction, and nonfatal stroke, while the endpoint of major adverse cardiac and cerebrovascular events (MACCE) was a composite of HCE and repeat revascularization. Results A total of 1,900 patients were randomized to PCI (n = 953) or CABG (n = 947). The SS was considered an independent predictor of 5-year MACCE (hazard ratio per unit of SS: 1.02; 95% confidence interval: 1.00 to 1.03; p = 0.014) and HCE (hazard ratio per unit of SS: 1.03; 95% confidence interval: 1.01 to 1.04; p = 0.002) in the PCI cohort, but not in the CABG group. There was a higher incidence of MACCE in PCI patients with low, intermediate, and high SS compared with those who underwent CABG (36.6% vs. 25.9%, p = 0.02; 43.9% vs. 26.8%, p Conclusions In DM patients with multivessel CAD, the complexity of CAD evaluated by the SS is an independent risk factor for MACCE and HCE only in patients undergoing PCI. The SS should not be utilized to guide the choice of coronary revascularization in patients with DM and multivessel CAD. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450)

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.

Background Clinical practice guidelines recommend post-operative dual antiplatelet therapy (DAPT) in patients who undergo coronary artery bypass grafting (CABG) following acute coronary syndromes (ACS). Objectives The authors have evaluated DAPT utilization rates and associated outcomes among post-CABG patients with diabetes. Methods In a post hoc, nonrandomized analysis from the FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial, we compared patients receiving DAPT (aspirin plus thienopyridine) and aspirin monotherapy at 30 days post-operatively. The primary outcome was the risk adjusted 5-year FREEDOM composite of all-cause mortality, nonfatal myocardial infarction, or stroke. Safety outcomes included major bleeding, blood transfusion, and hospitalization for bleeding. Results At 30 days post-CABG, 544 (68.4%) patients received DAPT and 251 (31.6%) patients received aspirin alone. The median (25th, 75th percentile) duration of clopidogrel therapy was 0.98 (0.23 to 1.91) years. There was no significant difference in the 5-year primary composite outcome between DAPT- and aspirin-treated patients (12.6% vs. 16.0%; adjusted hazard ratio [HR]: 0.83; 95% confidence interval [CI]: 0.54 to 1.27; p = 0.39). The 5-year primary composite outcomes were similar for patients receiving DAPT versus aspirin monotherapy respectively, in subgroups with pre-CABG ACSs (15.2% vs. 16.5%; HR: 1.06; 95% CI: 0.53 to 2.10; p = 0.88) and those with stable angina (11.6% vs. 15.8%; HR: 0.82; 95% CI: 0.50 to 1.343; p = 0.42). The composite outcomes of both treatment groups were also similar by SYNTAX score, duration of DAPT therapy, completeness of revascularization, and in off-pump CABG. No treatment-related differences in major bleeding (5.6% vs. 5.7%; HR: 1.00; 95% CI: 0.50 to 1.99; p = 0.99), blood transfusions (4.8% vs. 4.5%; HR: 1.09; 95% CI: 0.51 to 2.34; p = 0.82), or hospitalization for bleeding (2.6% vs. 3.3%; HR: 0.85; 95% CI: 0.34 to 2.17; p = 0.74) were observed between aspirin- and DAPT-treated patients, respectively. Conclusions The use of DAPT in patients with diabetes post-CABG in our cohort was high. Compared with aspirin monotherapy, no associated differences were observed in cardiovascular or bleeding outcomes, suggesting that routine use of DAPT may not be clinically warranted. (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease [FREEDOM]; NCT00086450)

The incidence and prognostic significance of acute kidney injury (AKI) in patients with diabetes mellitus and multivessel coronary artery disease undergoing coronary revascularization is not well known. The current analysis included patients randomized to PCI vs. CABG as part of the FREEDOM trial. We sought to examine the impact of AKI and its predictors in diabetic patients with multivessel coronary artery disease undergoing PCI vs. CABG.We conducted a pre-specified subgroup analysis of the FREEDOM trial to examine the incidence, correlates and impact of AKI according to revascularization strategy. AKI predictors were identified using multivariable logistic regression and associations between AKI and outcomes were examined using Cox regression. The primary endpoint was the composite occurrence of all-cause death, stroke or myocardial infarction at 5 years of follow-up.KI occurred more frequently in patients following CABG (15.6%) compared with PCI (9.1%) (p 0.001). AKI was associated with a higher risk for major cardiovascular events (MACE) at 5 years (34.6% vs. 20.5%, p 0.001), an effect that remained large and significant irrespective of CABG (HR = 2.18 95% CI 1.44-3.31, p ≤0.001) or PCI (HR = 2.08 95% CI 1.35-3.21, p 0.0001). There was a non-significant interaction (p-value = 0.89) between the revascularization method and AKI, supporting that AKI is a significant risk factor in both revascularization methods.Although risk for AKI was higher in patients undergoing CABG, the impact of AKI on MACE was substantial irrespective of revascularization strategy. Preventive strategies to identify patients at risk for AKI are warranted to mitigate the long-term effects of this complication.

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 count500/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.

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.

Background The optimal method of coronary revascularization among patients with diabetes mellitus (DM) and multivessel coronary artery disease (CAD) complicated by chronic kidney disease (CKD) remains unknown. Purpose To examine the impact of coronary artery bypass surgery (CABG) vs. percutaneous coronary intervention (PCI) on cardiovascular outcomes in patients with diabetes with and without CKD. Methods We conducted an ‘as-treated’ subgroup analysis of the FREEDOM trial to examine the therapeutic efficacy of CABG vs. PCI among patients with DM stratified by the presence ( n = 451) or absence ( n = 1392) of CKD. We defined CKD as an estimated glomerular filtration rate (eGFR)

Popat et al. [1] recently reported evidence for interaction between Cytochrome P450 1A2 (CYP1A2) genotype and coffee on the risk of developing Parkinson’s disease (PD). This finding is particularly intriguing because caffeine consumption is inversely associated with risk of developing PD, and CYP1A2 is involved in metabolism of caffeine. Popat et al also suggested that the coffee–PD association was strongest among homozygous carriers of the slow-metabolizer CYP1A2_ rs762551_CC genotype. In an accompanying editorial [2] Mellick and Ross point out that caffeine-metabolism genes have not been found to associate with PD in genome-wide studies. Were the genes missed because coffee and interaction were not in the analytical model? Considering the high potential significance of this observation, we attempted to replicate it using 1458 persons with PD and 931 controls from the NeuroGenetics Research Consortium (NGRC), all Caucasian of European Origin, with detailed life-time coffee consumption data [3] and genotyped using Illumina HumanOmni1-Quad_v1-0_B genotyping array [4]. rs2472304 was genotyped, rs762551 and rs2470890 were imputed with high accuracy (imputation-information-score>0.98) [5]. The study was approved by Institutional Review Boards. We first tested interaction under the same model as Popat et al. adjusting for age and sex while stratifying coffee-consumption as ever/never (Table 1). In addition, we reanalyzed the data with coffee stratified as high/low (defined at median), which is a more sensitive measure for NGRC due to high coffee-consumption and few non-coffee-drinkers in NGRC. We also tried models where principal components and smoking were added as covariates. As noted by Mellick and Ross [3] both population structure (genetic mixtures) and smoking could confound these results. Inclusion of principal components corrects for population structure in European-Americans due to Jewish/non-Jewish ancestry and European country-of-origin [4]. Inclusion of smoking as a covariate helps assess if results are affected by the correlation between smoking and coffee-drinking, and the inverse association of smoking with PD [3]. Unfortunately, we did not replicate the reported interactions under any of the models, nor did we find a stronger PD-coffee association among slow-metabolizers (Table 1). Table 1 Test results for SNPxCoffee interaction and genotype-specific PD-coffee association