The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: the Systolic Blood Pressure Intervention Trial (SPRINT)

Abstract

Background: High blood pressure is an important public health concern because it is highly prevalent and a risk factor for adverse health outcomes, including coronary heart disease, stroke, decompensated heart failure, chronic kidney disease, and decline in cognitive function. Observational studies show a progressive increase in risk associated with blood pressure above 115/75 mm Hg. Prior research has shown that reducing elevated systolic blood pressure lowers the risk of subsequent clinical complications from cardiovascular disease. However, the optimal systolic blood pressure to reduce blood pressure-related adverse outcomes is unclear, and the benefit of treating to a level of systolic blood pressure well below 140 mm Hg has not been proven in a large, definitive clinical trial.

Purpose: To describe the design considerations of the Systolic Blood Pressure Intervention Trial (SPRINT) and the baseline characteristics of trial participants.

Methods: The Systolic Blood Pressure Intervention Trial is a multicenter, randomized, controlled trial that compares two strategies for treating systolic blood pressure: one targets the standard target of <140 mm Hg, and the other targets a more intensive target of <120 mm Hg. Enrollment focused on volunteers of age ≥50 years (no upper limit) with an average baseline systolic blood pressure ≥130 mm Hg and evidence of cardiovascular disease, chronic kidney disease, 10-year Framingham cardiovascular disease risk score ≥15%, or age ≥75 years. The Systolic Blood Pressure Intervention Trial recruitment also targeted three pre-specified subgroups: participants with chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m(2)), participants with a history of cardiovascular disease, and participants 75 years of age or older. The primary outcome is first the occurrence of a myocardial infarction (MI), acute coronary syndrome, stroke, heart failure, or cardiovascular disease death. Secondary outcomes include all-cause mortality, decline in kidney function or development of end-stage renal disease, incident dementia, decline in cognitive function, and small-vessel cerebral ischemic disease.

Results: Between 8 November 2010 and 15 March 2013, Systolic Blood Pressure Intervention Trial recruited and randomized 9361 people at 102 clinics, including 3331 women, 2648 with chronic kidney disease, 1877 with a history of cardiovascular disease, 3962 minorities, and 2636 ≥75 years of age.

Limitations: Although the overall recruitment target was met, the numbers recruited in the high-risk subgroups were lower than planned.

Conclusions: The Systolic Blood Pressure Intervention Trial will provide important information on the risks and benefits of intensive blood pressure treatment targets in a diverse sample of high-risk participants, including those with prior cardiovascular disease, chronic kidney disease, and those aged ≥75 years.

Keywords: Randomized clinical trial; blood pressure targets; brain structure and function; cardiovascular; cognition; geriatrics; hypertension; kidney; major adverse cardiovascular outcomes; stroke.

Figure 1

Overall cumulative recruitment in SPRINT to total of 9361.

Figure 2

CONSORT Diagram. Inclusion/exclusion criteria were applied in the order asked and are described in greater detail in Table 1 and Supplementary Table 1. BP/Meds refers to the allowable systolic blood pressure depending on the number of anti-hypertensive medications taken. High-risk factors included ≥75 years of age, history of clinical or subclinical cardiovascular disease other than stroke, chronic kidney disease, or having a ≥ 15% 10-year Framingham risk score for cardiovascular disease. Participants without at least one were excluded. Miscellaneous reasons for exclusion include a known secondary cause of hypertension that causes safety concern (N=17), significant proteinuria within the past 6 months (N=67), history of diabetes (N=116) or stroke (N=49), end-stage renal disease or polycystic kidney disease (N=7), glomerulonephritis treated with immunosuppressive therapy (N=1), symptomatic heart failure within last 6 months or left ventricular ejection fraction <35% (N=15), expected survival less than three years (N=5), cancer diagnosed within the last two years (N=33), living in the same household as another SPRINT participant (N=11), organ transplant (N=2), indication for a specific blood pressure medication that is not currently being taken without documented intolerance (N=16), cardiovascular event, procedure, or hospitalization for unstable angina within the last 3 months (N=6), factors likely to limit adherence (N=319), participation in another trial (N=30), unintentional weight loss > 10% in last 6 months (N=8), and pregnancy, trying to become pregnant, or of child-bearing potential and not practicing birth control (N=1).

Figure 3

Treatment algorithm for intensive group (target systolic blood pressure (SBP) < 120 mm Hg) ^* May begin with a single agent for participants 75 years old or older with systolic blood pressure < 140 mm Hg on 0–1 meds at study entry. A second medication should be added at the 1-Month visit if participant is asymptomatic and systolic blood pressure > 130 mm Hg. ^** May use loop diuretic for participants with advanced chronic kidney disease ^† Unless side effects warrant change in therapy ^†† Consider consulting with the Clinical Center Network before adding a fifth anti-hypertensive medication ^‡ Or until clinical decision made that therapy should not be increased further

Figure 4

Treatment algorithm for standard group (Target systolic blood pressure (SBP) < 140 mm Hg) Include β –blocker or other agents as appropriate for compelling indications ^* Unless side effects warrant change in therapy ^** Consider consulting with the Clinical Center Network before adding a fifth anti-hypertensive medication