The SPRINT Study was received with great fanfare when it was published on November 26th in the New England Journal of Medicine. The primary results, summarized in the publication’s abstract are these:
"Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group."
The essential word in that abstract’s conclusion - and which prevents the application of these results - is ‘targeting’. The conclusion accepted by many is that aggressive blood pressure reduction, that is the achieved blood pressure, drove the observed results. However, it may well be that the act of targeting a low blood pressure, and using cardioprotective drugs to do so, explained the results rather than the reduction of blood pressure itself. And unravelling this nuance is the key to understanding whether SPRINT’s main message is applicable to the general population. I would argue that in its current form SPRINT suffers from a major methodological short-coming that leaves us in a quagmire.
According to the study appendix, patients assigned to the intensive arm in SPRINT utilized ACE or ARBs 21.5% more than the standard arm (View Table). There is ample evidence to suggest that blockade of the renin-angiontensin (RAS) system with these medications is associated with a reduction in cardiovascular events, including mortality and that this effect is independent of blood pressure (e.g. EUROPA and HOPE Studies). And while not all studies have documented cardioprotection (e.g ALLHAT, TRANSCEND), those at high cardiovascular risk, such as the patients enrolled in SPRINT may indeed experience a blood-pressure independent benefit of RAS blockade. Interestingly, intensive blood pressure reduction had no impact on ischemic stroke and instead impacted heart failure outcomes. This lends further support to the notion that RAS blockade mediated the results rather than absolute blood pressure reduction, as the latter is predictably associated with improvements in ischemic stroke outcomes across several influential studies.
The design of SPRINT ultimately brought us to this place and could have been avoided. Study protocol could have dictated that all patients be assigned to background ACE or ARB therapy, and then randomized to BP reduction using any drugs except ACE or ARBs. This was precisely the design of ACCOMPLISH where patients on an ACE inhibitor were randomized to hydrochlorothizide or amlodipine in order to determine whether use of either of the latter two agents improved outcomes. In SPRINT, the study design introduced two interventions: intensive blood pressure reduction and intensive ACE/ARB usage in a population that stood to benefit from both interventions independently.
We can expect more analysis of the SPRINT study perhaps with a comparison of heterogeneity among users of RAS drugs to outcomes in the remaining participants, but in its current form, it is not possible to interpret the SPRINT data completely. And to be sure, one cannot conclude at this time that intensive blood pressure reduction provides superior outcomes to those achieved with standard reduction without considering the agents used to do so.