Implications of Early Decline in eGFR due to Intensive BP Control for Cardiovascular Outcomes in SPRINT

Significance Statement In the Systolic BP Intervention Trial (SPRINT), intensive targeting of systolic BP (goal <120 mm Hg) versus standard targeting (goal of <140 mm Hg) significantly reduced risks of cardiovascular events and all-cause mortality. However, the intensive intervention also resulted in greater early reduction of eGFR in the first 6 months, raising the question of whether reductions in eGFR resulting from intensive BP control worsen an individual’s health status. In causal mediation analyses of SPRINT data, the authors found no evidence that this early eGFR decline either mediated or modified the beneficial effects of intensive systolic BP lowering on cardiovascular events or all-cause mortality. However, longer-term follow-up studies with causal modeling are needed to better understand the downstream effects of the early reduction in eGFR that results from intensive systolic BP lowering. Background The Systolic BP Intervention Trial (SPRINT) found that intensive versus standard systolic BP control (targeting <120 or <140 mm Hg, respectively) reduced the risks of death and major cardiovascular events in persons with elevated cardiovascular disease risk. However, the intensive intervention was associated with an early decline in eGFR, and the clinical implications of this early decline are unclear. Methods In a post hoc analysis of SPRINT, we defined change in eGFR as the percentage change in eGFR at 6 months compared with baseline. We performed causal mediation analyses to separate the overall effects of the randomized systolic BP intervention on the SPRINT primary cardiovascular composite and all-cause mortality into indirect effects (mediated by percentage change in eGFR) and direct effects (mediated through pathways other than percentage change in eGFR). Results About 10.3% of the 4270 participants in the intensive group had a ≥20% eGFR decline versus 4.4% of the 4256 participants in the standard arm ( P <0.001). After the 6-month visit, there were 591 cardiovascular composite events during 27,849 person-years of follow-up. The hazard ratios for total effect, direct effect, and indirect effect of the intervention on the cardiovascular composite were 0.67 (95% confidence interval [95% CI], 0.56 to 0.78), 0.68 (95% CI, 0.57 to 0.79), and 0.99 (95% CI, 0.95 to 1.03), respectively. All-cause mortality results were similar. Conclusions Although intensive systolic BP lowering resulted in greater early decline in eGFR, there was no evidence that the reduction in eGFR owing to intensive systolic BP lowering attenuated the beneficial effects of this intervention on cardiovascular events or all-cause mortality.