SPRINT Research Group; Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff DC Jr, Fine LJ, Cutler JA, Cushman WC, Cheung AK, Ambrosius WT. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015 Nov 26;373(22):2103-16. doi: 10.1056/NEJMoa1511939. Epub 2015 Nov 9. Erratum in: N Engl J Med. 2017 Dec 21;377(25):2506. doi: 10.1056/NEJMx170008. PMID: 26551272; PMCID: PMC4689591.

https://www.nejm.org/doi/10.1056/NEJMoa1511939

The SPRINT Trial, published in 2015, randomized patients (>9000) at increased cardiovascular risk to intensive (SBP <120 mmHg) or standard (SBP <140 mmHg) blood pressure targets. The study was stopped early, after a median of 3.26 years of follow-up due to substantially lower rates of the primary endpoint of cardiovascular events and mortality (1.65% per year vs. 2.19% per year; HR 0.75; 95% CI, 0.64 to 0.89; P<0.001) and mortality (HR 0.73; 95% CI, 0.60 to 0.90; P=0.003) in the intensive treatment group. This was despite higher incidence of many adverse outcomes, including hypotension, syncope, electrolyte abnormalities, acute kidney injury, and incident chronic kidney disease in the intensive treatment group.

The problem, like in many blood pressure studies, is that patients were assigned a blood pressure target, not a drug, with their prior regimens “adjusted on the basis of the study-group assignment.” With so many different drugs in play, we do not know how much of the benefit is attributed to a specific systolic blood pressure versus various external cardiovascular and renal benefits of the drugs. In fact, the investigators intentionally looked for that extra squeeze. As they explain, “The protocol encouraged, but did not mandate, the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes, including thiazide-type diuretics (encouraged as the first-line agent), loop diuretics (for participants with advanced chronic kidney disease), and beta-adrenergic blockers (for those with coronary artery disease).^5,27 Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.”

With more room to reduce blood pressure in the intensive group, these patients had more opportunity to absorb these other benefits. Perhaps they just prevented a lot of heart failure exacerbations with higher doses of diuretics. While admirable, does it have anything to do with systolic blood pressure, and will the next patient benefit, especially if the wrong drug (which could be the most potent blood pressure reducer) is chosen? Unclear.

It is well known that many aspects of medical practice are driven by limited data, anecdotal experience, or tradition. In other areas, however, there is extensive data, but it is systematically confounded. This is especially true in our management of hypertension, where we fail to separate the impact of reducing blood pressure from the ancillary effects of the drugs themselves. As a result, we are prone to making inappropriate conclusions about how much blood pressure reduction (if any) is beneficial and the potential harm of these actions.

To address this confounding, we will review these studies one-by-one and point out the underappreciated confounding factors that need to be considered.

Thanks for reading, and please come back often for more.