Response to Letter Regarding Article “Influence of baseline diastolic blood pressure on effects of intensive compared to standard blood pressure control”

We very much appreciate the thoughtful comments by Imprialos et al. on our manuscript on baseline diastolic blood pressure (DBP) and cardiovascular outcomes in SPRINT¹. They wondered whether participants with baseline DBP more than 70 mm Hg with reductions to less than 70mm Hg did worse. In the second quintile (Table 1) the mean baseline DBP was above 70 mm Hg (71 ± 2 mm) Hg¹. As shown in Figure 1, the achieved DBP in the intensive systolic blood pressure (SBP) group was lower than that of the standard SBP group (65.2 ± 6.6 versus 71.6 ± 6.8 mm Hg) and as shown in Figures 2 and 3, there was no evidence that the intensive SBP group had worse cardiovascular outcomes, irrespective of the baseline DBP¹.

Achieved DBP is a reflection of a multitude of factors including the underlying arterial stiffness (patients with stiffer arteries generally experience lower DBP). Analyses based on achieved DBP, where DBP was not the object of the randomized intervention, are likely to be confounded due to underlying vascular stiffness and perhaps other factors. A recent non-randomized, observational analysis of achieved DBP in SPRINT suggested a J curve phenomenon². As it was an observational analysis, causal inferences should not be drawn. Indeed, another recent publication on achieved blood pressures in SPRINT³ showed that in both study arms, low on-treatment SBP or DBP was associated with worse outcomes, but with different dose response patterns that reflect the different SPB targets in two groups; therefore, it appears that it is not the attained blood pressure but is rather the underlying patient characteristics that result in lower DBP that explain worse outcomes.

We also appreciate the thoughtful comments by Rahman et al. We agree that observational studies have suggested that low DBP is associated with coronary heart disease events. The central question is whether this observation reflects a causal relation. While coronary perfusion depends upon diastolic flow, other factors contribute to the balance of myocardial O₂ supply and demand. As shown by Hoffman and Buckberg⁴, myocardial O₂ supply-to-demand index is given by the equation:

$$\text{Myocardial }{\mathrm{O}}_2\text{ supply to demand index}=\frac{(\text{DPTI X Arterial oxygen content})}{(\text{SPTI X Relative LV mass X Relative LV wall tension})}$$

where, DTPI = diastolic pressure-time index and SPTI = systolic pressure-time index.

As is evident from the above equation, lowering SBP might preserve or improve myocardial O₂ balance by decreasing myocardial O₂ demand by decreasing SPTI and decreasing afterload with consequent regression of left ventricular hypertrophy and LV mass. Moreover, lowering SBP might decrease endothelial damage, slow progression of atherosclerosis and thereby, preserve myocardial blood flow and O₂ supply over time. Therefore, contrary to the common belief that lowering SBP in patients with low DBP and baseline coronary artery disease (CAD) worsens myocardial O₂ balance resulting in poorer CV outcomes, it is conceivable that in some populations, lowering SBP preserves or improves myocardial O₂ balance, resulting in cardio-protective effects that are either preserved or even accentuated.

We would caution against deconstructing the primary CVD composite into its components and then comparing each outcome within each quintile of DBP by the two randomized groups given statistical power limitations. Nonetheless, the analyses of supplemental Figure S2¹ on non-stroke CVD events (which comprise non-fatal myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, acute decompensated heart failure, or death from CVD) show that, while low baseline DBP was observationally associated with these outcomes, there was no evidence that low baseline DBP modified the beneficial effects of intensive SBP lowering.

While our analyses are post-hoc, they are nonetheless randomized comparisons. Figure 1D presents post-randomization pulse pressure. As pulse pressure is mathematically related to SBP and the intervention is on SBP, adjustment for post-randomization pulse pressure as suggested by Rahman et al is in effect adjusting for post-randomization SBP. Hence, post-randomization pulse pressure is not a confounder rather an intermediate variable through which intensive SBP lowering might improve outcomes.

In aggregate, the data presented in our original article¹ suggest that the U-shaped association of DBP with cardiovascular events is unlikely to represent a causal relation.