Response to Comment on Buckley et al. Intensive Versus Standard Blood Pressure Control in SPRINT-Eligible Participants of ACCORD-BP. Diabetes Care 2017;40:1733–1738

Drs. Mi and Mukamal (1) have recently proposed an additional interpretation of the discrepant results of the Systolic Blood Pressure Intervention Trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) trial. Although we continue to support our conclusions that SPRINT-eligible ACCORD-BP participants benefited from intensive blood pressure lowering, we recognize that our results do not exclude the important contributions from other factors as explanations for the discrepant results of ACCORD-BP and SPRINT (2). Indeed, several alternative hypotheses have been proposed in an attempt to explain the discordant results of SPRINT and ACCORD-BP (3,4). We therefore welcome the contributions by Mi and Mukamal to this important conversation.

One of the principal differences between our approach and the analysis by Mi and Mukamal (1) is the inclusion of ACCORD patients randomized to intensive glucose lowering. We considered this group of patients to be less reflective of clinical practice—and therefore excluded them from our analysis—because no guidelines or professional organizations recommend treating to hemoglobin A_1c levels below 6.0%. Although Mi and Mukamal considered this group to be more reflective of “real-life practice, which includes patients with good control,” there may be significant differences between achieving a hemoglobin A_1c <6.0% in a subpopulation of ideal responders and aggressively treating all patients to a hemoglobin A_1c <6.0%. Moreover, as noted in Supplementary Figs. 2 and 3 from our original analysis (2), the benefits of intensive blood pressure lowering were only evident in SPRINT-eligible ACCORD-BP patients, and these benefits disappear completely in SPRINT-eligible ACCORD-BP patients randomized to intensive glucose lowering. Similarly, an analysis of the entire ACCORD program by the ACCORD investigators also found evidence that the effects of intensive glucose lowering may have interfered with the effects of the other two interventions (5).

A second significant difference between our analyses is the focus on total mortality by Mi and Mukamal (1). Although we agree that total mortality is less susceptible to classification bias than the other prespecified end points, we note that not all interventions translate immediately into mortality reductions and overreliance on any one outcome may limit sensitivity to detect clinically important findings. As total mortality was neutral in ACCORD-BP, analysis of total mortality in any subgroup is likely to also result in neutral results.

Confidence in our analysis is further strengthened by a separate, but similar, analysis conducted by Bress et al. (6), which reported 31% and 23% reductions in major adverse cardiovascular events and all-cause mortality, respectively, in SPRINT participants with prediabetes who were randomized to intensive blood pressure control. Similar to our analysis, which did not find an interaction between the effect of intensive blood pressure control and diabetes status, Bress et al. did not detect a significant interaction between the effect of intensive blood pressure control and prediabetes status.