A SAS macro for a clustered logrank test

The clustered logrank test is a nonparametric method of significance testing for correlated survival data. Examples of its application include cluster randomized trials where groups of patients rather than individuals are randomized to either a treatment or control intervention. We describe a SAS macro that implements the 2-sample clustered logrank test for data where the entire cluster is randomized to the same treatment group. We discuss the theory and applications behind this test as well as details of the SAS code

A comparison of statistical approaches for physician-randomized trials with survival outcomes

This study compares methods for analyzing correlated survival data from physician-randomized trials of health care quality improvement interventions. Several proposed methods adjust for correlated survival data however the most suitable method is unknown. Applying the characteristics of our study example, we performed three simulation studies to compare conditional, marginal, and non-parametric methods for analyzing clustered survival data. We simulated 1,000 datasets using a shared frailty model with (1) fixed cluster size, (2) variable cluster size, and (3) non-lognormal random effects. Methods of analyses included: the nonlinear mixed model (conditional), the marginal proportional hazards model with robust standard errors, the clustered logrank test, and the clustered permutation test (non-parametric). For each method considered we estimated Type I error, power, mean squared error, and the coverage probability of the treatment effect estimator. We observed underestimated Type I error for the clustered logrank test. The marginal proportional hazards method performed well even when model assumptions were violated. Nonlinear mixed models were only advantageous when the distribution was correctly specified

Translational Data from Adeno-Associated Virus-Mediated Gene Therapy of Hemophilia B in Dogs

Preclinical testing of new therapeutic strategies in relevant animal models is an essential part of drug development. The choice of animal models of disease that are used in these studies is driven by the strength of the translational data for informing about safety, efficacy, and success or failure of human clinical trials. Hemophilia B is a monogenic, X-linked, inherited bleeding disorder that results from absent or dysfunctional coagulation factor IX (FIX). Regarding preclinical studies of adeno-associated virus (AAV)-mediated gene therapy for hemophilia B, dogs with severe hemophilia B (<1% FIX) provide well-characterized phenotypes and genotypes in which a species-specific transgene can be expressed in a mixed genetic background. Correction of the hemophilic coagulopathy by sustained expression of FIX, reduction of bleeding events, and a comprehensive assessment of the humoral and cell-mediated immune responses to the expressed transgene and recombinant AAV vector are all feasible end points in these dogs. This review compares the preclinical studies of AAV vectors used to treat dogs with hemophilia B with the results obtained in subsequent human clinical trials using muscle- and liver-based approaches

Improving Care of Patients At-Risk for Osteoporosis: A Randomized Controlled Trial

BACKGROUND: Despite accurate diagnostic tests and effective therapies, the management of osteoporosis has been observed to be suboptimal in many settings. We tested the effectiveness of an intervention to improve care in patients at-risk of osteoporosis. DESIGN: Randomized controlled trial. PARTICIPANTS: Primary care physicians and their patients at-risk of osteoporosis, including women 65 years and over, men and women 45 and over with a prior fracture, and men and women 45 and over who recently used ≥90 days of oral glucocorticoids. INTERVENTION: A multifaceted program of education and reminders delivered to primary care physicians as well as mailings and automated telephone calls to patients. Outcome: Either undergoing a bone mineral density (BMD) testing or filling a prescription for a bone-active medication during the 10 months of follow-up. RESULTS: After the intervention, 144 (14%) patients in the intervention group and 97 (10%) patients in the control group received either a BMD test or filled a prescription for an osteoporosis medication. This represents a 4% absolute increase and a 45% relative increase (95% confidence interval 9–93%, p = 0.01) in osteoporosis management between the intervention and control groups. No differences between groups were observed in the incidence of fracture. CONCLUSION: An intervention targeting primary care physicians and their at-risk patients increased the frequency of BMD testing and/or filling prescriptions for osteoporosis medications. However, the absolute percentage of at-risk patients receiving osteoporosis management remained low

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Endovascular versus Surgical Lower Extremity Revascularization among Patients with Chronic Kidney Disease

Introduction. Patients with chronic kidney disease (CKD) have a high prevalence of peripheral artery disease. How best to manage lower extremity peripheral artery disease remains unclear in this patient population. We therefore sought to compare the outcomes after endovascular versus surgical lower extremity revascularization among patients with CKD. Methods. We used data from Optum’s de-identifed Clinformatics® Data Mart Database, a nationwide database of commercially insured persons in the United States to study patients with CKD who underwent lower extremity endovascular or surgical revascularization. We used inverse probability of treatment weighting to balance covariates. We employed proportional hazard regression to study the primary outcome of major adverse limb events (MALE), defined as a repeat revascularization or amputation. We also studied each of these events separately and death from any cause. Results. In our cohort, 60,057 patients underwent endovascular revascularization and 9,338 patients underwent surgical revascularization. Endovascular revascularization compared with surgical revascularization was associated with a higher adjusted hazard of MALE (hazard ratio (HR) 1.52; 95% confidence interval (CI) 1.46–1.59). Endovascular revascularization was also associated with a higher adjusted hazard of repeat revascularization (HR 1.65; 95% CI 1.57–1.72) but a lower adjusted risk of amputation (HR 0.71; CI 0.73–0.89). Patients undergoing endovascular revascularization also had a lower adjusted hazard for death from any cause (0.85; CI 0.82–0.88). Conclusions. In this analysis of patients with CKD undergoing lower extremity revascularization, an endovascular approach was associated with a higher rate of repeated revascularization but a lower risk of subsequent amputation and death compared with surgical revascularization. Multiple factors must be considered when counseling patients with CKD, who have a high burden of comorbid conditions. Clinical trials should include more patients with kidney disease, who are often otherwise excluded from participation, to better understand the most effective treatment strategies for this vulnerable patient population