Selection bias and subject refusal in a cluster-randomized controlled trial

Abstract Background Selection bias and non-participation bias are major methodological concerns which impact external validity. Cluster-randomized controlled trials are especially prone to selection bias as it is impractical to blind clusters to their allocation into intervention or control. This study assessed the impact of selection bias in a large cluster-randomized controlled trial. Methods The Improved Cardiovascular Risk Reduction to Enhance Rural Primary Care (ICARE) study examined the impact of a remote pharmacist-led intervention in twelve medical offices. To assess eligibility, a standardized form containing patient demographics and medical information was completed for each screened patient. Eligible patients were approached by the study coordinator for recruitment. Both the study coordinator and the patient were aware of the site’s allocation prior to consent. Patients who consented or declined to participate were compared across control and intervention arms for differing characteristics. Statistical significance was determined using a two-tailed, equal variance t-test and a chi-square test with adjusted Bonferroni p-values. Results were adjusted for random cluster variation. Results There were 2749 completed screening forms returned to research staff with 461 subjects who had either consented or declined participation. Patients with poorly controlled diabetes were found to be significantly more likely to decline participation in intervention sites compared to those in control sites. A higher mean diastolic blood pressure was seen in patients with uncontrolled hypertension who declined in the control sites compared to those who declined in the intervention sites. However, these findings were no longer significant after adjustment for random variation among the sites. After this adjustment, females were now found to be significantly more likely to consent than males (odds ratio = 1.41; 95% confidence interval = 1.03, 1.92). Conclusions Though there appeared to be a higher consent rate for females than for males, the overall impact of potential selection bias and refusal to participate was minimal. Without rigorous methodology, selection bias may be a threat to external validity in cluster-randomized trials. Trial registration NCT01983813 . Date of registration: Oct. 28, 2013

Association of Total Medication Burden With Intensive and Standard Blood Pressure Control and Clinical Outcomes: A Secondary Analysis of SPRINT

Total medication burden (antihypertensive and nonantihypertensive medications) may be associated with poor systolic blood pressure (SBP) control. We investigated the association of baseline medication burden and clinical outcomes and whether the effect of the SBP intervention varied according to baseline medication burden in SPRINT (Systolic Blood Pressure Intervention Trial). Participants were randomized to intensive or standard SBP goal (below 120 or 140 mm Hg, respectively); n=3769 participants with high baseline medication burden (≥5 medications) and n=5592 with low burden (0.5). Medication burden had minimal association with adherence or satisfaction. High baseline medication burden was associated with worse intensive SBP control and higher rates of cardiovascular disease events and serious adverse events. The relative benefits and risks of intensive SBP goals were similar regardless of medication burden. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT0120606