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

Abstract

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.

Keywords: cardiovascular disease; hypertension; mortality; renal hemodynamics.

Graphical abstract

Figure 1.

Distinction between the observed change in eGFR and the acute effect of the treatment. Shown are percent changes in eGFR from baseline to 6 months under the standard SBP intervention (open squares) and under the intensive SBP intervention (solid squares) for four hypothetical participants. The difference in these changes between the intensive and standard SBP interventions (represented by the vertical arrows) define the acute effects of the treatment for these four patients. We actually observe the change in eGFR for only one of the two interventions, depending on each patient’s randomly assigned treatment (depicted by the large open circles). We cannot observe the acute effect in any individual participant, but instead can observe the percent change in eGFR only under the participants’ assigned interventions. The direction and magnitude of the acute effects may deviate from the direction and magnitude of the observed percent changes in eGFR. The indirect effect of the treatment which is mediated by change in eGFR is the difference in the outcome that results if the acute change in eGFR is modified by the amounts indicated by the vertical arrows.

Figure 2.

Mediation of effect of the SBP interventions on the CVD composite or mortality by early eGFR decline (∆eGFR). The overall (or total) effect of the SBP intervention on the CVD composite or all-cause mortality may be decomposed into the indirect effect (A and B) mediated by ∆eGFR and the direct effect (C), which represents the effect of the intervention through pathways unrelated to ∆eGFR. The effect of ∆eGFR on the CVD composite or all-cause mortality (B) reflects the consequences of variation in ∆eGFR resulting from the SBP intervention as well as other factors, including natural variation in eGFR, measurement error, and disease progression that would have occurred in the absence of the intervention. The indirect effect (A×B) represents the consequences of the acute effect of the SBP intervention on ∆eGFR for the CVD composite or all-cause mortality. Although the total effect of the SBP intervention can be estimated using intent-to-treat analysis under the randomized design, estimation of the indirect and direct effects requires control of confounding factors that jointly influence ∆eGFR and the CVD composite or all-cause mortality.

Figure 3.

Box plots for ∆eGFR% and for ∆eGFR in the standard and intensive SBP arms. Shown are the first percentile, 25th percentile, median, 75th percentile, and 99th percentile.

Figure 4.

Association of ∆eGFR% with the CVD composite and all-cause mortality by randomized treatment arm. There was no evidence of nonlinear relationships on the log scale between the hazards between ∆GFR% and the CVD and all-cause mortality endpoints (P values for nonlinearity in the standard and intensive SBP arms were P=0.40 and P=0.47 for the CVD composite and P=0.33 and P=0.19 for all-cause mortality, respectively).

Figure 5.

Controlled direct effects of SBP intervention at different levels of ΔeGFR%. The figure displays the estimated controlled direct effects of the intensive SBP intervention on the CVD composite (left) and all-cause mortality (right) when ΔeGFR% is held fixed at the values indicated on the horizontal axis. The interaction P values between ΔeGFR% and the randomized SBP group are 0.12 for the CVD composite and 0.20 for all-cause mortality, indicating that controlled direct effects do not differ significantly between different levels of early change in ΔeGFR%.