Pulling Ahead After a SPRINT – Evidence for Lower Blood Pressure Goals

The debate over the intensity of blood pressure (BP) lowering for patients with hypertension has been going on for decades.  Additional fuel to the fire was recently added with the early halt and publication of the Systolic Blood Pressure Intervention Trial (SPRINT).¹  The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood (JNC 7) published in 2003 recommended a goal BP of less than 140/90 mm Hg for most patients, with a lower goal of less than 130/80 mm Hg for patients with diabetes or chronic kidney disease.² After the publication of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in 2010, which showed no benefit from a lower systolic blood pressure (SBP) goal of <120 mm Hg compared to a traditional goal of <140 mm Hg,³ most guidelines revised the goal BP for patients with diabetes to less than 140/90 mm Hg.^4-6 The evidence-based guidelines published in 2014 by the panel members appointed to the Eighth JNC (JNC 8) relaxed BP goals for patients older than 60 years without diabetes or chronic kidney disease (CKD) to <150/90 mm Hg.⁴ However, the decision to raise the BP goal in older patients was not unanimous among panel members. Some JNC 8 authors argued that some studies that support lower BP goals were not considered and worried that raising the goal BP would have a negative impact on cardiovascular (CV) events.⁷

So “how low should you go” for patients with high BP? Do lower BP goals reduce CV outcomes and death, particularly in patients at high risk?  Do they cause greater adverse effects? Or perhaps even worsen CV outcomes? These questions were examined in SPRINT.¹

The SPRINT study was a multicenter, randomized, controlled, open-label trial designed to compare the outcomes of a lower SBP goal of <120 mm Hg (intensive treatment) versus a traditional SBP goal of <140 mm Hg (standard treatment) in patients at high CVD risk.¹ Briefly, 9,361 patients greater than 50 years-of-age who were at increased CV risk but without diabetes and had a SBP between 130 and 180 mm Hg at baseline were randomized to either intensive or standard treatment. Increased CV risk was defined as one or more of the following: clinical or subclinical CVD other than stroke, chronic kidney disease (CKD) with an estimated glomerular filtration rate (eGFR) 20-59 mL/min/1.73 m², 10-year Framingham Risk score for CVD ≥15%, or age ≥75 years.  Patients with a prior stroke were excluded from the study.

After randomization, which was stratified by clinical site, participant BP regimens were adjusted following treatment algorithms similar to that used in the ACCORD trial.³ Antihypertensives with the greatest outcomes data (i.e., thiazide-type diuretics, angiotensin converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], and calcium channel blockers [CCBs]) were encouraged first-line, with additional agents used when indicated (e.g., loop diuretic for those with advanced CKD, β-blocker for those post myocardial infarction [MI]). Chlorthalidone and amlodipine were the preferred thiazide-type diuretic and CCB respectively. Azilsartan and azilsartan/chlorthalidone combination product was donated by the manufacturer.

The primary outcome of the SPRINT study was a composite of MI, acute coronary syndrome, stroke, acute decompensated heart failure, or death from CV causes. Secondary outcomes included individual components of the primary outcome, as well as all-cause mortality, and the composite of the primary outcome or death from any cause. Renal outcomes for those with and without CKD were also assessed, as well as effects of lower BP goals on incident dementia, changes in cognitive function, and cerebral small vessel ischemic disease.

Mean BP results after one year, which remained largely consistent throughout the study, was 121.4 mm Hg in the intensive treatment group and 136.2 mm Hg in the standard treatment group (P<0.001). On average, patients were on 2.8 antihypertensives in the intensive treatment group and 1.8 in the standard treatment group.

After a median follow-up of 3.26 years (planned average was 5 years) SPRINT was stopped early due to a 25% reduction in the primary composite outcome in the intensive treatment group compared to standard treatment (Hazard Ratio [HR] 0.75; 95% confidence interval [CI] 0.64-0.89; P<0.001; Number needed to treat [NNT]=61). (See Table 1) Intensive treatment was also associated with significant decreases in all-cause mortality (28%; NNT=90), heart failure (33%; NNT=123), death from CV causes (67%, NNT=172), and the primary outcome or death (22%; NNT=52).

Table 1. Selected Outcomes of SPRINT¹

* Hazard ratio

† Number needed to treat/number needed to harm. NNT for primary outcome, death from any cause, and death from CV causes reported from the text

‡ First occurrence of MI, acute coronary syndrome, stroke, heart failure, or death from CV causes

§ Event that was fatal or life-threatening, resulted in clinically significant or persistent disability, required or prolonged a hospitalization, or was judged to represent a clinically significant hazard or harm to the participant that might require medical or surgical intervention

In patients with CKD at baseline, lower BP goals did not decreased risk of the composite renal outcome (first occurrence of a reduction in eGFR more than 50%, long-term dialysis, or kidney transplantation), individual components of the composite renal outcome, or incident albuminuria.

It is important to note that a significant proportion of patients in this trial (28%) were ≥75 years of age. Subgroup analyses demonstrated that independently living older adults benefited from more intensive BP goals (HR=0.67, 95% CI 0.51-0.86; NNT=31), perhaps more so than patients <75 years (HR=0.80; 95% CI 0.64-1.00).

Overall, intensive treatment did not result in more serious adverse events when compared to standard treatment (HR 1.04: P=0.25).  However, lower BP goals did increase the likelihood of hypotension, syncope, and electrolyte abnormalities (See Table 2). Paradoxically, intensive treatment was associated with a 22% lower risk of orthostatic hypotension (NNT=59) and the risk of injurious falls was similar in the treatment arms.  In patients without CKD at baseline, a greater than 30% reduction in eGFR to <60 mL/min/1.73m² was observed more frequently with intensive treatment (HR 3.49, 95% CI 2.44-5.10, P<0.001; Number needed to harm [NNH]=37).

SPRINT was well designed and executed.  The study provides strong evidence in support of lower BP goals in patients with, or at high risk for, adverse CV outcomes. While previous meta-analyses have suggested no benefit for lower BP goals in a high-risk population,⁸ a more recent meta-analysis support lower SBP goals, consistent with SPRINT findings.⁹

SPRINT was stopped early by the Data Safety Monitoring Board because of a significant benefit on the primary outcome and overall mortality. Although these results are impressive, care should be taken when applying the results to individual patients. First, it is important to note the population studied. Only patients who were older than 50 years and had either established CVD or were at high risk for CVD were included. Patients with diabetes and a prior history of stroke were excluded. In addition, while there were significant differences in the primary outcome and several secondary outcomes, intensive BP lowering was not benign. None-the-less, the benefits of lower goals in terms of hard CV outcomes and mortality outweigh the harms for most patients. In addition, no J-curve (i.e., increased risk of adverse CV outcomes with lower BP) was not seen in the trial.

Important questions remain unanswered. SPRINT did not include patients with diabetes. In the ACCORD trial, intensive BP lowering did not reduce the composite outcome of MI, stroke, of CV death.³ ACCORD however used a different study design, had far fewer subjects (n=4733), and a lower-than-expected event rate. Thus, ACCORD was likely under powered. Second, it remains to be seen what effects lower BP goals have on dementia, cognition, and cerebral small-vessel disease. These results from the SPRINT study have yet to be published. Moreover, further analyses of renal outcomes are needed. In the primary analysis, lower BP goals did not appear to improve renal outcomes in patients with CKD at baseline and caused adverse renal effects in those without CKD at baseline. Additional data regarding the rate of eGFR decline and the cause(s) of acute kidney injury events are needed.

More than one-quarter of the participants in SPRINT were older than 75 years of age and older adults appeared to have benefitted most. These findings call into question recommendations by guidelines with relaxed BP goals (<150/90 mm Hg) in the elderly.^4,5

Another important consideration is the additional time and resources that will be required to achieve lower BP goals. Patients required on average one additional antihypertensive medication. This will result in higher costs for medication and laboratory monitoring, as well as increase the potential for side effects. Despite these limitations, the findings from SPRINT are generalizable to many patients. A recent analysis estimated that approximately 16.8 million US adults — including 8.2 million with treated hypertension — met SPRINT eligibility criteria.¹⁰

The SPRINT study is an extremely important trial that will likely influence clinical practice guideline recommendations — similar to the effect ALLHAT had on the JNC-7. SPRINT lends strong support to lower BP goals in patients >50 years who are at high risk of CV events. SPRINT refutes recent recommendations for relaxed BP goals in the elderly. Will SPRINT bring consensus to BP goals or add confusion? What are your thoughts?