SPRINT

Published

The SPRINT Research Group. "A randomized trial of intensive versus standard blood-pressure control". The New England Journal of Medicine. 2015. 373(22):2103-2116.
PubMed • Full text • PDF

Clinical Question

In patients at high risk for CVD but who do not have a history of stroke or diabetes, does intensive BP control (target SBP <120 mm Hg) yield superior CV outcomes compared to standard treatment (target SBP 135-139 mm Hg)?

Bottom Line

In patients at high risk for CVD but who do not have a history of stroke or diabetes, intensive BP control (target SBP <120 mm Hg) improved CV outcomes and overall survival compared to standard therapy (target SBP 135-139 mm Hg), while modestly increasing the risk of some serious adverse events.

Major Points

Systolic hypertension (SBP ≥140 mm Hg) and prehypertension (SBP 120-139 mm Hg) are risk factors for myriad diseases including CAD, CKD, and stroke. Treatment conventions and guideline statements have called for the treatment of hypertension to a target SBP of <140 mm Hg, but no large trial had demonstrated this in a well-designed, randomized fashion, and it has been largely unknown whether more intensive therapy would be more efficacious. ACCORD BP (2010) demonstrated that among patients with diabetes, intensive therapy (target SBP <120 mm Hg) yielded no improvement in CV outcomes compared to standard therapy (target SBP <140 mm Hg). Similarly, SPS3-BP (2013) found no reduction in the risk of recurrent stroke in patients with recent lacunar stroke randomized to intensive (target SBP <130 mm Hg) versus conventional therapy (target SBP 130-150 mm Hg). But what of patients without known CVD or CVD risk equivalents such as diabetes? That is, it be that intensive therapy could benefit high-risk patients who haven't already had complications of CVD such as stroke?

The 2015 Systolic Blood Pressure Intervention Trial (SPRINT) studied 9,361 non-diabetic patients ≥50 years of age without a history of prior stroke who were at elevated risk for CV events. Patients were randomized to intensive BP control targeting SBP <120 mm Hg or to standard therapy targeting SBP 135-139 mm Hg. This open-label trial was powered to detect a 20% effect difference in the primary composite outcome of MI, ACS without MI, stroke, acute HF, or CV death, assuming an event rate of 2.2% per year in the standard arm, and an average follow-up of 5 years. The choice of antihypertensive was left to investigator discretion, with a preference for first-line thiazide, beta-blockers for patients with CAD, etc. Despite the planned follow-up of 5 years, the trial was stopped short after just 3 years when an interim analysis demonstrated the superiority of intensive therapy compared to the standard of care. Intensive BP control was associated with fewer primary outcome events (5.2% vs. 6.8%; P<0.001; NNT 63) and a reduction in all-cause mortality (3.3% vs. 4.5%; P=0.003; NNT 83). There was no difference in the composite endpoint of all serious adverse events, but the intensive therapy arm was associated with more non-orthostatic hypotension, syncope, electrolyte abnormalities, and AKI. Additional 1-year follow-up from SPRINT was published in 2021, without any major changes in the observed findings.

SPRINT had a major impact on the management of hypertension, with the ACC/AHA 2017 guidelines lowering hypertension's threshold from 140/90 to 130/80 mm Hg, with recommendation for BP-lowering medications at 130 mm Hg among those with additional risk factors (see Guidelines section below). In contrast the ACP/AAFP 2017 guidelines recommended initiation of antihypertensive medications among those with SBP above a 150 mm Hg SBP range (strong recommendation), with only a weak recommendation for 140 or 130 mm Hg thresholds, primarily based upon an assessment of lower quality evidence by this review group. More recently, the 2021 STEP trial randomized around 8,000 Chinese adults with or without CVD risk to intensive or standard BP targets. STEP's findings were similar to SPRINT, shoring up the evidence base to support lower BP targets in hypertension management.

Finally, there were concerns about intensive BP control and adverse effects, such as cognitive decline from theoretical hypoperfusion of the brain. Fortunately, this appears to be unfounded as the SPRINT-MIND substudy showed lower mild cognitive impairment among the intensive BP group. There were also concerns about more hypotension-related events among those with orthostatic hypotension (OH) in the intensive BP group. However, a secondary analysis of SPRINT found lower incidence of OH with intensive BP control, and hypotension-related events was not higher in the intensive BP arm.

Guidelines

2017 ACC AHA AAPA ABC ACPM AGS APhA ASH ASPC NMA PCNA Hypertension (2017, adapted)

• New definitions for BP ranges: Normal BP is <120/<80, elevated BP is 120-129/<80, stage 1 HTN is 130-139/80-89, and stage 2 HTN is ≥140/≥90 mm Hg
• Use antihypertensive medications if prior clinical CVD or 10-year ASCVD risk score is ≥10% and BP is ≥130/≥80 mm Hg (COR I, LOE A for SBP and C-EO for DBP)
• Use antihypertensive medications if no prior clinical CVD and 10-year ASCVD risk score is <10% and BP is ≥140/≥90 mm Hg (COR I, LOE C-LD)
• First line agents include thiazide diuretics (chlorthalidone preferred), CCBs, and ACE-inhibitors or ARBs (COR I, LOE A)
  • Initial use of two first-line agents from different classes is recommended if stage 2 HTN and average BP is >20/10 mm Hg above target (COR I, LOE C-EO)
  • Initial use of one first-line agent is reasonable if stage 1 HTN and BP goal <130/80 mm Hg (COR IIa, LOE C-EO)
• Specific population recommendations:
  • Among black adults without CKD or HF, initial treatment should be with a thiazide or CCB (COR I, LOE B-R)
    • Black adults are likely to need ≥2 agents to achieve BP <130/90 mm Hg (COR I, LOE C-LD)
  • Age ≥65
    • Community-dwelling - Treat SBP to <130 mm Hg (COR I, LOE A)
    • High burden of comorbidities and limited life expectancy - Consider patient preference and use a team-based approach to decide intensity of BP lowering and choice of antihypertensives (COR IIa, LOE C-EO)
  • Stable CAD - Treat to BP goal <130/80 mm Hg (COR I, LOE B-R for SBP and C-EO for DBP)
    • Preferred medications are proven beta-blockers, ACE-inhibitors, or ARBs for compelling reasons (prior MI, stable angina), with addition of other medications including dihydropyridine-CCBs (especially for angina; COR I, LOE B-NR), thiazide diuretics, and/or mineralocorticoid receptor antagonists as needed (COR I, LE B-R for SBP and C-ED for DBP)
  • Prior stroke or TIA- Restart or initiate antihypertensives within a few days of the index event (COR I, LOE A for restarting; COR I, LOE B-R for initiation if BP >140/90); a BP goal <130/80 may be reasonable (COR IIb, LOE B-R)
    • If no history of HTN and BP <140/90, the usefulness of antihypertensives is not well-established (COR IIb, LOE C-LD)
    • If lacunar infarct, a target SBP <130 mm Hg may be reasonable (COR IIb, LOE B-R)
    • Preferred agents are thiazide diuretic, ACE-inhibitor or ARB, or combination of thiazide+ACE-inhibitor (COR I, LOE A)
  • CKD - Treat to BP goal <130/80 mm Hg (COR I, LOE B-R for SBP and C-EO for DBP)
    • If CKD stage ≥III or stage I or II with albuminuria ≥300 mg/day or ≥300 mg/g alb:creat, treating with ACE-inhibitor (COR IIa, LOE B-R) or ARB (COR IIb, LOE C-EO) is reasonable to slow kidney disease progression
    • If kidney transplantation, it's reasonable to target BP <130/80 mm Hg (COR IIa, LOE B-NR for SBP and C-EO for DBP), with calcium antagonist as choice to improve GFR and kidney survival (COR IIa, LOE B-R)
  • DM - Treat to BP goal <130/80 mm Hg (COR I, LOE B-R for SBP and C-EO for DBP)
    • Any first-line medication is effective (COR I, LOE A), but consider ACE-inhibitors and ARBs if albuminuria (COR IIb, LOE B-NR)
  • PAD - Treat similarly to patients with HTN and no PAD (COR I, LOE B-NR)
  • Increased risk for development of HF - Treat to <130/80 (COR I, LOE B-R for SBP and C-EO for DBP)
  • HFrEF - Treat with goal-directed medical therapy (e.g., proven beta-blockers, ACE-inhibitors or ARBs, etc.) targeting BP <130/80 mm Hg (COR I, LOE C-EO)
    • Do not use non-dihydropyridine CCBs (COR III, LOE B)
  • HFpEF and volume overload - Use diuretics to control HTN (COR I, LOE C-EO)
    • If persistent HTN and managed volume overload, use ACE-inhibitors or ARBs and beta-blockers to attain an SBP <130 mm Hg (COR I, LOE C-LD)

Design

• Multicenter, open-label, randomized controlled trial
• N=9,361 patients without diabetes or stroke at elevated CV risk
  • Intensive, target SBP <120 mm Hg (n=4,678)
  • Standard, target SBP 135-139 mm Hg (n=4,683)
• Setting: 102 sites in the US and Puerto Rico
• Enrollment: 2010-2013
• Median follow-up: 3.26 years (stopped prematurely; goal 5 years)
• Analysis: Intention-to-treat
• Primary outcome: First occurrence of MI, ACS, stroke, HF, or CV mortality

Population

Inclusion Criteria

• Age ≥50 years
• SBP (mmHg) in a range:
  • 130-180 on ≤1 medication
  • 130-170 on ≤2 medications
  • 130-160 on ≤3 medications
  • 130-150 on ≤4 medications
• ≥1 of the following CVD risk criteria:
  • Clinical CVD (non-stroke):
    • Prior MI, PCI, CABG, CEA, or carotid stenting
    • Revascularized PAD
    • ACS ± EKG changes, EKG changes on a stress test, or ischemic findings on other cardiac imaging
    • ≥50% stenosis of coronary, carotid, or LE artery, or
    • AAA ≥5 cm
  • Subclinical CVD:
    • Carotid artery calcium score ≥400 in prior 2 years
    • ABI ≤0.90 in prior 2 years, or
    • LVH on EKG, echocardiogram, or other imaging in prior 2 years
  • CKD: eGFR 20-59 mL/min/1.73 m² on MDRD in prior 6 months
  • Framingham estimated 10-year CVD risk ≥15% in prior 12 months
  • Age ≥75 years

Exclusion Criteria

• DM
• Stroke
• Not on disease-appropriate antihypertensives (eg, beta blocker and recent MI)
• Secondary cause of hypertension
• If able to stand, 1 min standing SBP <110
• Proteinuria in any of the following ranges:
  • ≥1g/day urine protein
  • ≥600 mg/day urine albumin
  • Spot protein:creatinine ≥1g protein/g creatinine
  • Spot albumin:creatinine ≥600 mg/g creatinine
  • Urine dipstick ≥2+ protein if none of the above are available
• Polycystic kidney disease
• Glomerulonephritis
• eGFR < 20 mL/min/1.73 m²
• CV event, procedure, or UA hospitalization in prior 3 months
• Symptomatic HF in prior 6 mo
• LVEF <35%
• Life-limiting illness
• Poor adherence
• Organ transplant
• Unintentional weight loss >10% in prior 6 months
• Pregnancy

Baseline Characteristics

From the intensive group

• Demographics: Age 68 years, female 36%
  • Race/ethnicity: Black 31%, non-Hispanic black 29%, Hispanic 11%, Non-Hispanic white 58%, other 2%
• Criterion for increased CV risk:
  • CVD: 20%
    • Clinical: 17%
    • Subclinical CV disease: 5%
  • CKD: 28%
  • Framingham 10-year risk >15%: 61% (avg risk 20%)
  • Age ≥75 years: 28%
• Body measurements: BP 140/78 mmHg, BMI 30 kg/m²
  • SBP: ≤132 mmHg 34%, 132-145 mmHg 32%, ≥145 mmHg 34%
• Laboratory: Serum creatinine 1.07 mg/dl (eGFR 72 mL/min/1.73 m²), urine albumin:creatinine 44 mg/g, Tchol 190 mg/dL, HDL 53 mg/dL, TG 125 mg/dL, fasting glucose 99 mg/dL
• Medications: Statin 43%, ASA 52%, antihypertensives 1.8/patient (none 9%)
• Smoking status: Never 44%, former 42%, current 14%

Interventions

• Patients randomized in an open label fashion to a group:
  • Intensive - Target SBP <120 mm Hg
  • Standard - Target SBP 135-139 mm Hg
• Antihypertensives were encouraged per standard practice:
  • Thiazide diuretics (primarily chlorthalidone) were encouraged as first-line agents
  • Loop diuretics were encouraged for those with CKD
  • Beta-blockers were encouraged for those with CAD
• Lifestyle modifications were encouraged
• Study medications were provided free of cost to participants

Outcomes

Comparisons are intensive vs. standard therapy groups.

Primary Outcome

First ACS, stroke, HF, or CV death

5.2% vs. 6.8% (HR 0.75; 95% CI 0.64-0.89; P<0.001; NNT 63)

Secondary Outcomes

MI

2.1% vs. 2.5% (HR 0.83; 95% CI 0.64-1.09; P=0.19)

ACS without MI

0.9% vs. 0.9% (HR 1.00; 95% CI 0.64-1.55; P=0.99)

Stroke

1.3% vs. 1.5% (HR 0.89; 95% CI 0.62-1.25; P=0.50)

HF

1.3% vs. 2.1% (HR 0.62; 95% CI 0.45-0.84; P=0.002; NNT 125)

CV mortality

0.8% vs. 1.4% (HR 0.57; 95% CI 0.38-0.85; P=0.005; NNT 167)

All-cause mortality

3.3% vs. 4.5% (HR 0.73; 95% CI 0.60-0.90; P=0.003; NNT 83)

Composite of primary outcome or all-cause mortality

7.1% vs. 9.0% (HR 0.78; 95% CI 0.67-0.90; P<0.001; NNT 53)

Of those with CKD at baseline

≥50% reduction in GFR, long-term HD, or renal transplant: 1.1% vs. 1.1% (HR 0.89; 95% CI 0.42-1.87; P=0.76)

≥50% reduction in GFR: 0.8% vs. 0.8% (HR 0.87; 95% CI 0.36-2.07; P=0.75)

Long-term HD: 0.5% vs. 0.8% (HR 0.57; 95% CI 0.19-2.54; P=0.27)

Renal transplant: none

New albuminuria: 9.3% vs. 11.8% (HR 0.72; 95% CI 0.48-1.07; P=0.11)

Above defined as doubling of albumin:creatinine ratio from <10 to >10 mg albumin/g creatinine.

Of those without CKD at baseline

≥30% reduction in GFR to <60 mL/min/1.73 m²: 3.8% vs. 1.1% (HR 3.49; 95% CI 2.44-5.10; P<0.001; NNH 37)

New albuminuria: 6.2% vs. 7.4% (HR 0.81; 95% CI 0.63-1.04; P=0.10)

Additional Outcomes

BP at year 1

SBP: 121.4 vs. 136.2 mmHg

DBP: 68.7 vs. 76.3 mmHg

Number of antihypertensives

2.8 vs. 1.8

None: 2.7% vs. 11.3%

1: 10.5% vs. 31.1%

2: 30.5% vs. 33.3%

3: 31.8% vs. 17.2%

≥4: 24.3% vs. 6.9%

Breakdown of medication utilization is presented on page 30 of the supplementary appendix.

Subgroup Analysis

There was no significant interaction for the primary outcome by CKD at baseline, age, sex, race, prior CVD, or SBP.

Adverse Events

Serious adverse event (SAE)

38.3% vs. 37.1% (HR 1.04; P=0.25)

Hypotension: 2.4% vs. 1.4% (HR 1.67; P=0.001; NNH 100)

Syncope: 2.3% vs. 1.7% (HR 1.33; P=0.05; NNH 167)

Bradycardia: 1.9% vs. 1.6% (HR 1.19; P=0.28)

Electrolyte abnormality: 3.1% vs. 2.3% (HR 1.35; P=0.02; NNH 125)

Fall with injury: 2.2% vs. 2.3% (HR 0.95; P=0.71)

AKI/ARF: 4.1% vs. 2.5% (HR 1.66; P<0.001; NNH 63)

SAE possibly or definitely associated with the intervention 4.7% vs. 2.5% (HR 1.88; P<0.001; NNH 45)

Above is from page 33 of supplemental appendix.

SAE or ED visit

Hypotension: 3.4% vs. 2.0% (HR 1.70; P<0.001; NNH 71)

Syncope: 3.5% vs. 2.4% (HR 1.44; P=0.003; NNH 91)

Bradycardia: 2.2% vs. 1.8% (HR 1.25; P=0.13)

Electrolyte abnormality: 3.8% vs. 2.8% (HR 1.38; P=0.006; NNH 100)

Fall with injury: 7.1% vs. 7.1% (HR 1.00; P=0.97)

AKI/ARF: 4.4% vs. 2.6% (HR 1.71; P<0.001; NNH 56)

Laboratory abnormality

Na <130 mmol/L: 3.8% vs. 2.1% (HR 1.76; P<0.001; NNH 59)

Na >150 mmol/L: 0.1% vs. 0% (HR not given; P=0.02; NNH 1,000)

K <3 mmol/L: 2.4% vs. 1.6% (HR 1.50; P=0.006; NNH 125)

K >5.5 mmol/L: 3.8% vs. 3.7% (HR 1.00; P=0.97)

Orthostatic hypotension

16.6% vs. 18.3% (HR 0.88; P=0.01; NNT 59)

With dizziness: 1.3% vs. 1.5% (HR 0.85; P=0.35)

Criticisms

• Early cessation of trials is associated with introduction of bias, including overestimation of effect sizes
• No enrollment of those in nursing homes or assisted living facilities
• Low rate of ASA and statin use
• Cognitive outcomes not presented here

Funding

• NIH (NHLBI, NIDDK, NINDS, NIA)