Systolic Blood Pressure Intervention Trial - SPRINT

Contribution To Literature:

The SPRINT trial showed that intensive BP control to SBP <120 mm Hg results in significant cardiovascular benefit in high-risk patients with hypertension compared with routine BP control to <140 mm Hg.

Description:

The goal of the trial was to compare the safety and efficacy of intensive lowering of systolic blood pressure (SBP) to <120 mm Hg versus routine management to <140 mm Hg.

Study Design

Patients were randomized to intensive SBP lowering (target <120 mm Hg) or routine SBP management (target <140 mm Hg).

  • Total number of enrollees: 9,361
  • Duration of follow-up: 5 years (median 3.26 years)

Inclusion criteria:

  • Age ≥50 years
  • Hypertension with SBP ≥130 mm Hg

At least one risk factor for heart disease:

  • Presence of clinical or subclinical cardiovascular disease other than stroke
  • Chronic kidney disease, defined as estimated glomerular filtration rate (eGFR) 20-59 ml/min/1.73 m2
  • A Framingham Risk Score for 10-year cardiovascular disease risk ≥15%
  • Age >75 years

Exclusion criteria:

  • An indication for a specific BP-lowering medication that the person is not taking and the person has not been documented to be intolerant of the medication class
  • Known secondary cause of hypertension
  • One-minute standing SBP <110 mm Hg
  • Proteinuria
  • Arm circumference too large or small to allow accurate BP measurement with available devices
  • Diabetes mellitus
  • History of stroke
  • Polycystic kidney disease
  • Glomerulonephritis treated with or likely to be treated with immunosuppressive therapy
  • eGFR <20 ml/min/1.73 m2 or end-stage renal disease
  • Cardiovascular event or procedure or hospitalization for unstable angina within last 3 months
  • Symptomatic heart failure within the past 6 months or left ventricular ejection fraction <35%
  • A medical condition likely to limit survival to <3 years or a malignancy other than nonmelanoma skin cancer within the last 2 years
  • Organ transplant

Principal Findings:

The trial was terminated early due to overwhelming evidence of benefit. The primary outcome, myocardial infarction (MI), acute coronary syndrome (ACS), stroke, congestive heart failure (CHF), or cardiovascular (CV) death, was significantly lowered in the intensive BP management arm compared with the routine management arm (5.2% vs. 6.8%, hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.64–0.89; p < 0.0001).

Individual components (event rates for intensive vs. routine management, absolute event rates):

  • MI: 2.1% vs. 2.5%, p = 0.19
  • ACS: 0.9% vs. 0.9%, p = 0.99
  • Stroke: 1.3% vs. 1.5%, p = 0.5
  • CHF: 1.3% vs. 2.1%, p = 0.002
  • CV death: 0.8% vs. 1.4%, p = 0.0005

Important secondary endpoints for intensive vs. routine BP control, absolute event rates:

  • Mortality: 3.3% vs. 4.5%, p = 0.0003
  • Among patients with chronic kidney disease: composite renal endpoint (decrease in GFR ≥50%, need for HD, renal transplant); 1.1% vs. 1.1%, p = 0.76
  • Among patients without CKD: ≥30% decline in GFR to <60 ml/min: 3.8% vs. 1.1%, p < 0.001
  • Hypotension: 2.4% vs. 1.4%, p = 0.001
  • Syncope: 2.3% vs. 1.7%, p = 0.05
  • Hyponatremia: 3.8% vs. 2.1%, p < 0.001

Generalizability to the US population: Based on National Health and Nutrition Examination Survey (NHANES) data from 2007 to 2012, it appears that 7.6% or 16.8 million US adults, and 16.7% or 8.2 million of those with treated hypertension, would meet the SPRINT eligibility criteria. Thus, 8.6 million of US adults are not currently treated for hypertension based on the SPRINT trial, highlighting the public health importance of these findings. 

Among patients aged ≥75 years (n = 2,636), primary outcomes for intensive vs. routine BP management were 7.7% vs. 11.2%, p < 0.05. All-cause mortality was 5.5% vs. 8.1%, respectively, p < 0.05.

Left ventricular hypertrophy (LVH) progression (n = 8,164): Among participants without baseline LVH, intensive BP lowering reduced LVH on electrocardiogram (HR 0.54, 95% CI 0.43-0.68). Similarly, among participants with baseline LVH (n = 605, 7.4%), intensive BP lowering was more likely to show LVH regression (HR 1.66, 95% CI 1.31-2.11). Adjusting for LVH did not attenuate the risk of CV disease (CVD) with intensive lowering, suggesting that LVH improvement was not a significant driver of CVD reduction with intensive BP lowering.

Effect on patient-reported outcomes: Patient-reported outcome measures included the scores on the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the Veterans RAND 12-Item Health Survey, the Patient Health Questionnaire 9-item depression scale (PHQ-9), among others. Participants who received intensive treatment received an average of one additional antihypertensive medication, and the systolic blood pressure was 14.8 mm Hg (95% confidence interval, 14.3-15.4) lower in the group that received intensive treatment than in the group that received standard treatment. Mean PCS, MCS, and PHQ-9 scores were relatively stable over a median of 3 years of follow-up, with no significant differences between the two treatment groups. Satisfaction with BP medications was high.

Cost-effectiveness: A microsimulation model was created to assess costs, clinical outcomes, and quality-adjusted life-years (QALYs) among SPIRIT-eligible adults. The mean number of QALYs was estimated to be 0.27 higher among patients who received intensive control than among those who received standard control and would cost approximately $47,000 more per QALY gained if there were a reduction in adherence and treatment effects after 5 years; the cost would be approximately $28,000 more per QALY gained if the treatment effects persisted for the remaining lifetime of the patient. Most simulation results indicated that intensive treatment would be cost-effective (51-79% below the willingness-to-pay threshold of $50,000 per QALY and 76-93% below the threshold of $100,000 per QALY), regardless of whether treatment effects were reduced after 5 years or persisted for the remaining lifetime.

BP measurement differences: A post hoc survey was conducted at SPRINT closeout sites as to whether BP measurements were usually attended or unattended by staff. Patients were divided into four groups: always alone, never alone, alone for rest, and alone for BP measurement. Improvements in primary endpoint and total mortality with intensive BP lowering were similar between these four groups (p for interaction for primary endpoint = 0.88), suggesting that the results were insensitive to whether or not patient BP measurements were made in an attended fashion.

Role of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) in risk stratification: Median (25th and 75th percentiles) concentration of hs-cTnT was 9.4 (6.4, 14.1) ng/L with 25.6% having values ≥14 ng/L. Median NT-proBNP was 86 (37, 197) pg/ml with 38.2% having concentrations ≥125 pg/ml. Higher baseline values of hs-cTnT and NT-proBNP were each associated with a greater risk of death, the composite of death and heart failure, and the SPRINT primary composite outcome, with highest risk among those with abnormal levels of both biomarkers.

Outcomes based on predicted risk: Predictive models were created for long-term CVD composite endpoint (c-index 0.71), all-cause mortality (c-index 0.75), and treatment-related side effects (c-index 0.69). The baseline factors that were most strongly associated with a higher risk for the CVD composite outcome were older age, history of CVD, and impaired kidney function. The predicted magnitude of benefit of intensive versus standard treatment in terms of absolute risk reduction grew linearly as baseline risk increased. For instance, the risk of long-term composite CVD events was 2.4% at the 10th percentile and 14% at the 90th percentile. The predicted risks of composite CVD events and treatment-related adverse events (AEs) demonstrated close correlation. Few participants were predicted as high benefit with low AE risk (1.8%) or low benefit with high AE risk (1.5%).

Interpretation:

The results of this landmark trial indicate that intensive BP lowering to a target <120 mm Hg is superior to routine management with a target of <140 mm Hg in high-risk nondiabetic patients with hypertension, including in elderly patients. There were also reductions noted in CV and all-cause mortality, accompanied by a reduction in CHF. An intensive strategy also reduced the risk of developing LVH among patients without baseline LVH and resulted in greater LVH regression among those with evidence of baseline LVH. An intensive strategy carried a higher risk of hypotension, syncope, and accelerated reductions in GFR (only in patients without CKD at baseline). There also appeared to be effect modification by baseline CV risk. For instance, patients with low 10-year Framingham risk scores had higher non-CV mortality with more aggressive BP lowering. High-sensitivity troponin and NT-proBNP may be helpful biomarkers for risk stratification. This is a landmark trial and is likely to result in a paradigm shift in the management of patients with hypertension.

The trial design is also interesting because it suggests that hypertension treatment should be individualized based on underlying risk of CV outcomes rather than based on absolute values alone. This change has occurred in lipid management as well, based on the most recent Eighth Joint National Committee (JNC 8) guidelines. The public health importance of this trial will be large. These findings are contrary to the smaller ACCORD trial in patients with diabetes mellitus, where aggressive BP lowering was not associated with superior CV outcomes.

References:

Bress AP, Greene T, Derington CG, et al. Patient Selection for Intensive Blood Pressure Management Based on Benefit and Adverse Events. J Am Coll Cardiol 2021;77:1977-90.

Editorial Comment: Diamond JA, Schussheim AE, Phillips RA. Another Nudge to Overcome the Treatment-Risk Paradox in Blood Pressure Management. J Am Coll Cardiol 2021;77:1991-3.

Presented by Dr. Jarett D. Berry at the American Heart Association Virtual Scientific Sessions, November 15, 2020.

Presented by Dr. Karen C. Johnson at the American Heart Association Annual Scientific Sessions (AHA 2017), Anaheim, CA, November 13, 2017.

Berlowitz DR, Foy CG, Kazis LE, et al., on behalf of the SPRINT Research Group. Effect of Intensive Blood-Pressure Treatment on Patient-Reported Outcomes. N Engl J Med 2017;377:733-44.

Bress AP, Bellows BK, King JB, et al., on behalf of the SPRINT Research Group. Cost-Effectiveness of Intensive versus Standard Blood-Pressure Control. N Engl J Med 2017;377:745-55.

Soliman EZ, Ambrosius WT, Cushman WC, et al., on behalf of the SPRINT Research Study Group. Effect of Intensive Blood Pressure Lowering on Left Ventricular Hypertrophy in Patients with Hypertension: The Systolic Blood Pressure Intervention (SPRINT) Trial. Circulation 2017;136:440-50.

Williamson JD, Supiano MA, Applegate WB, et al., on behalf of the SPRINT Research Group. Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years: A Randomized Clinical Trial. JAMA 2016;315:2673-82.

The SPRINT Research Group. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med 2015;373:2103-16.

Bress AP, Tanner RM, Hess R, Colantonio LD, Shimbo D, Muntner P. Generalizability of results from the Systolic Blood Pressure Intervention Trial (SPRINT) to the US adult population. J Am Coll Cardiol 2016;67:463-72.

Presented by Dr. Paul K. Whelton at the American Heart Association Scientific Sessions, Orlando, FL, November 9, 2015.

Editorial: Drazen JM, Morrissey S, Campion EW, Jarcho JA. A SPRINT to the Finish. N Engl J Med 2015;373:2174-5.

Editorial: Perkovic V. Redefining Blood-Pressure Targets — SPRINT Starts the Marathon. N Engl J Med 2015;373:2175-8.

Perspective: Chobanian AV. Time to Reassess Blood-Pressure Goals. N Engl J Med 2015;373:2093-5.

Clinical Decisions: Yeh J. Blood Pressure Control. N Engl J Med 2015;373:2180-2.

Study Design: Ambrosius WT, Sink KM, Foy CG, et al., on behalf of the SPRINT Study Research Group. 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). Clin Trials 2014;11:532-46.

Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, ACS and Cardiac Biomarkers, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Hypertension

Keywords: Acute Coronary Syndrome, Blood Pressure, Blood Pressure Determination, Geriatrics, Hypertension, Hypertrophy, Left Ventricular, Heart Failure, Metabolic Syndrome X, Myocardial Infarction, Natriuretic Peptide, Brain, Primary Prevention, Renal Insufficiency, Chronic, Risk Factors, Stroke, Troponin T, AHA Annual Scientific Sessions, AHA20, AHA17


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