Alternative clinical trial designs to find a clinically important effect size of blood pressure-lowering on cognitive impairment and dementia

Background: Blood pressure (BP) lowering might reduce the risk of cognitive impairment and dementia (CID), but more information is needed to design trials optimally. Objective: To estimate trial sample sizes and durations for detecting BP-lowering effects on CID. Methods: We estimated trial sample sizes and durations for finding an effect of a Systolic Blood PRessure INtervention Trial (SPRINT)-based BP-lowering strategy versus usual care on CID and global cognition using our MIchigan ChROnic Disease SIMulation Model (MICROSIM), which simulated adults with the US population's demographics and vascular risk factors and assumed BP-lowering's effect on CID and global cognition from our pooled cardiovascular cohort study. Results: Over >139 million simulated trials across 78,000 parameters, the SPRINT-based BP-lowering strategy (versus usual care) resulted in a 2% CID relative risk reduction (RRR), much smaller than the CID RRR (15%) found in SPRINT Memory and Cognition IN Decreased Hypertension (MIND). Detecting a 2% CID RRR with >80% power would require 10-year trials with samples >50,000. Identifying the BP-lowering strategy's effect on mean global cognition would require trials of ≥10 years with >30,000 participants. However, trials of 5 years with 10,000 participants would have the power to detect the strategy's effect assuming a 15% CID RRR in SPRINT MIND. Conclusions: In this microsimulation study, we found that trials would need to be large with long follow-ups to identify the causal effects of BP-lowering on CID and cognition. However, assuming the 15% CID RRR in SPRINT MIND, trials with more feasible sizes and durations could detect those effects.