Final SPRINT Results Endorse Intensive BP Control
Some adverse events remained higher in the intensive group, but “the ‘lower is better’ message is still there,” Cora Lewis says.
With all events adjudicated, intensive blood pressure-lowering remains superior to standard control when it comes to reducing adverse clinical outcomes in nondiabetic patients at high cardiovascular risk, with that benefit accompanied by higher risks of some serious adverse events, including hypotension, electrolyte abnormalities, acute kidney injury/failure, and syncope, final results of the SPRINT trial show.
When the initial trial results were released in November 2015, investigators had not yet been able to adjudicate all potential outcome events that occurred during the intervention period because the study was stopped early. In addition, they had not yet collected or analyzed data after the intervention period ended.
Those tasks have now been completed and the final results, published in the May 20, 2021, issue of the New England Journal of Medicine, continue to show significant reductions in the primary composite outcome (MI, other ACS, stroke, acute decompensated heart failure, or cardiovascular death) and all-cause death with treatment to a systolic goal of less than 120 mm Hg versus a goal of less than 140 mm Hg.
These findings don’t change the message that should be taken away from SPRINT, lead author Cora Lewis, MD (University of Alabama at Birmingham), told TCTMD. “Where we end up is still that the intensive group had a greater benefit. A few of the safety outcomes we’re particularly interested in were still a bit more common in the intensive group—things like hypotension. But in general, the ‘lower is better message’ is still there.”
Vivek Bhalla, MD (Stanford University School of Medicine, CA), a member of the American Heart Association’s Council on Hypertension, agreed.
“The SPRINT trial highly suggests that intensive blood pressure control reduces cardiovascular events and reduces mortality in a high-risk population,” he commented to TCTMD. “These findings further buttress the original study and further support what the 2017 AHA and ACC guidelines recommend for a blood pressure target goal.”
A Fuller Picture
The initial SPRINT results reported about 5-and-a-half years ago were based on data collected through August 20, 2015, when the trial was prematurely stopped due to benefits in the intensive arm. But some events that occurred up to that date had not yet been adjudicated at the time of publication. This new NEJM paper contains the full results encompassing all adjudicated outcomes during the intervention period, as well as events occurring in the postintervention period stretching from August 20, 2015, to July 29, 2016, which includes the trial closeout visits. During that span, BP control was returned to participants’ usual physicians.
In an analysis incorporating all adjudicated events, intensive treatment remained superior to standard control in terms of the primary composite outcome (1.77% vs 2.40% per year; HR 0.73; 95% CI 0.63-0.86) and all-cause mortality (1.06% vs 1.41% per year; HR 0.75; 95% CI 0.61-0.92); those numbers are similar to what was initially reported.
Lewis noted that the trial received some criticism based on its inclusion of nonfatal heart failure in the composite outcome, so the investigators did a post hoc analysis that excluded that endpoint; there was still a significant benefit associated with intensive BP control (HR 0.75; 95% CI 0.63-0.89).
Rates of MI, heart failure, and CV deaths all were significantly reduced with treatment to a lower systolic goal during the intervention period, adding MI to the outcomes that significantly favored intensive treatment in the initial report.
Among patients with chronic kidney disease (CKD) at baseline, there was no difference between treatment arms for a composite renal outcome. However, among those without CKD, a 30% reduction in estimated glomerular filtration rate (eGFR) to less than 60 mL/min/1.73 m2 was more common in the intensive group (HR 3.67; 95% CI 2.62-5.26), similar to the initial trial report.
Heart Failure Difference Reverses
During the observational postintervention period, the difference in systolic BP between the treatment arms narrowed due to a greater average increase in the intensive arm (6.9 vs 2.6 mm Hg). Comparisons of outcomes between intensive and standard control in this window were largely consistent with what was demonstrated during the intervention period, although risk of acute decompensated heart failure went in the opposite direction. Instead of the lower risk with intensive treatment seen during the main trial phase (HR 0.68; 95% CI 0.50-0.92), it was higher (HR 1.63; 95% CI 1.02-2.57).
The researchers checked to see whether changes in antihypertensive medications could explain the discrepancy, and they found that diuretics, ACE inhibitors, and hydralazine were more frequently stopped in participants who had been randomized to intensive versus standard treatment. Most patients with heart failure events during this period, however, did not have changes to their regimens.
It’s also possible that the finding could be due to “random variation due to few cases having occurred during the postintervention period,” the researchers write in their paper. Lewis told TCTMD that “we think that it’s probably due to a small number of events and so it’s just sort of an imprecise estimate. It could be that heart failure is just really sensitive to blood pressure and so the rise in the systolic that you saw in the intensive treatment group, maybe that came into play. Hard to know on that.”
There are multiple possible explanations for that finding, Bhalla said. One “could be that when you take patients who are at risk for heart failure events and who were in the intensive arm and you let their blood pressure come back up, which is effectively what happened when they released the restrictions on the two different arms, then those patients may be at higher risk of heart failure events compared to patients in the standard arm whose blood pressure was likely more stable before and after the end of the trial,” he said.
More detail on the types of heart failure events that occurred during the postintervention period would be needed to fully understand what’s going on there, Bhalla added, noting that diastolic heart failure events would be consistent with a mechanism related to rising systolic BP.
Lewis said the pattern of safety events in this updated analysis is consistent with what was seen in the initial trial report.
Overall, serious adverse events occurred at similar rates in the two trial arms, although those related to hypotension, electrolyte abnormalities, acute kidney injury/failure, and syncope (when emergency department visits were added in) were more frequent in the intensive group. The results were consistent in an analysis combining events in the intervention and postintervention periods.
Differences between phases was seen in the composite renal outcome among patients without CKD, with a higher risk associated with intensive treatment during the intervention phase and no difference between groups during the postintervention period (P = 0.004 for interaction).
“As reported previously, most of the acute adverse events affecting the kidney were solitary, were mild (as determined on the basis of the modified Kidney Disease: Improving Global Outcomes [KDIGO] criteria), and were followed by nearly complete recovery of kidney function within 1 year,” the authors note. “The decrease in eGFR occurred early among the patients without chronic kidney disease in the intensive-treatment group, and after 18 months the difference between treatment groups stabilized, a finding consistent with a hemodynamic reduction in glomerular pressure.”
The SPRINT Research Group. Final report of a trial of intensive versus standard blood-pressure control. N Engl J Med. 2021;384:1921-1930.
- SPRINT was supported by contracts and an interagency agreement from the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke. Several trial sites were supported by Clinical and Translational Science Awards funded by the National Center for Advancing Translational Sciences of the NIH. The trial was also supported in part with resources and use of facilities through the Department of Veterans Affairs. Azilsartan and azilsartan combined with chlorthalidone were donated by Takeda Pharmaceuticals International and Arbor Pharmaceuticals.
- Lewis reports receiving grants from the NHLBI/NIH during the conduct of the study.