The Systolic Blood Pressure Intervention Trial (SPRINT), a landmark study demonstrated that intensive systolic blood pressure (SBP) lowering (SBP target <120 versus <140 mmHg) reduced the risk of death and major cardiovascular disease (CVD) events in persons without diabetes but at high cardiovascular risk. Despite the success of SPRINT, lowering of diastolic blood pressure (DBP) as a consequence of the SPRINT intensive therapy intervention has been cited as a cause for concern in adopting SPRINT findings in routine clinical practice. Based on a number of observational reports of J-shaped curves indicating associations of both low and high DBPs with worse CVD outcomes, strong causal inferences on lowering DBP have been drawn. The central question is whether the J-curve phenomenon observed in the observational studies reflects a causal effect of low DBP on cardiovascular outcomes. The most direct and valid method of testing the J-curve hypothesis is to actively intervene to lower DBP, particularly in those with DBP < 70 mm Hg; if lowering DBP is deleterious below a certain DBP level, one would expect that the effects of lowering SBP on CVD outcomes and death would be modified by baseline level of DBP. In a recent SPRINT publication, we identified U-shaped relationships between baseline DBP and the primary CVD composite outcome and all-cause mortality. In randomized comparisons, however, intensive SBP lowering that also lowered DBP was beneficial rather than hazardous. Indeed, intensive SBP lowering seemed to result in similarly beneficial effects across each of the quintiles of DBP at baseline. In the current proposal, we seek to leverage five, large, multi-center NIH funded clinical trials that randomized participants across a spectrum of baseline characteristics to different BP goals. We will conduct a participant level meta-analysis to examine the interactions of baseline DBP with the respective BP interventions on CVD and kidney endpoints and all-cause mortality. The primary hypothesis is that while baseline DBP has a non-causal U-shaped relationship with CVD endpoints, baseline DBP does not modify the effect of BP lowering on CVD endpoints. The secondary hypotheses are that despite similar non-causal U- shaped relationships of baseline DBP with kidney outcomes and all-cause death, baseline DBP does not modify the effects of BP intervention on these outcomes. The proposed study is of public health importance. If the results show that lower baseline DBP does not moderate the effect of BP lowering interventions on outcomes, this will be reassuring for clinicians and provide credence to widespread adoption of SPRINT findings. On the other hand, if there are interactions, this study will provide a basis for caution in application of the SPRINT findings in specific subgroups with a low DBP.
There are concerns about whether lowering diastolic blood pressure with intensive systolic blood pressure lowering is harmful. This proposal will examine this question using data from five large NIH funded clinical trials.
