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SPRINT

Q: What were the key findings of the SPRINT trial?

Among patients at high cardiovascular risk without diabetes or prior stroke, targeting a systolic blood pressure of less than 120 mm Hg resulted in significantly lower rates of major adverse cardiovascular events and death from any cause compared to a target of less than 140 mm Hg. However, the intensive-treatment group experienced higher rates of certain serious adverse events, including hypotension, electrolyte abnormalities, acute kidney injury or renal failure, and syncope (when SAE + ED-visit events were combined). In combined intervention + observational follow-up, heart-failure rates no longer differed between the groups.

Final Report of a Trial of Intensive versus Standard Blood-Pressure Control

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Year of Publication: 2021

Authors: The SPRINT Research Group

Journal: The New England Journal of Medicine

Citation: N Engl J Med 2021;384:1921-1930.

Link: https://doi.org/10.1056/NEJMoa1901281

PDF: https://www.ncbi.nlm.nih.gov/pmc/articles/9907774

Clinical Question

In patients at increased cardiovascular risk without diabetes or prior stroke, does intensive systolic blood pressure control (target <120 mm Hg) result in lower rates of major adverse cardiovascular events and all-cause mortality compared to standard control (target <140 mm Hg)?

Study Overview

Objective

To assess whether targeting a systolic blood pressure <120 mm Hg (intensive treatment) provides greater cardiovascular benefit than the standard target of <140 mm Hg in high-risk adults without diabetes or prior stroke.

Study Summary

Intensive blood pressure control reduced major cardiovascular events and all-cause mortality.
Increased risk of adverse events including hypotension, AKI, and electrolyte abnormalities.
Benefits persisted during post-trial observational follow-up.

Intervention

Randomized, multicenter, open-label trial with blinded endpoint adjudication. 9361 participants aged ≥50 with increased cardiovascular risk (excluding diabetes or prior stroke) were assigned to an intensive (<120 mm Hg) or standard (<140 mm Hg) systolic BP target. Median follow-up was 3.33 years (trial period) and 3.88 years (with observational follow-up). Primary endpoint: composite of MI, acute coronary syndrome, stroke, heart failure, or CV death.

Patients per Arm

Intensive: 4678; Standard: 4683

Bottom Line

Among patients at high cardiovascular risk without diabetes or prior stroke, targeting a systolic blood pressure of less than 120 mm Hg resulted in significantly lower rates of major adverse cardiovascular events and death from any cause compared to a target of less than 140 mm Hg. However, the intensive-treatment group experienced higher rates of certain serious adverse events, including hypotension, electrolyte abnormalities, acute kidney injury or renal failure, and syncope (when SAE + ED-visit events were combined). In combined intervention + observational follow-up, heart-failure rates no longer differed between the groups.

        Major Points
        SPRINT was the most influential blood pressure trial of the decade, fundamentally changing hypertension targets worldwide. It demonstrated that treating to SBP <120 mmHg (vs <140 mmHg) reduced cardiovascular events by ~27% and all-cause mortality by ~25% in high-risk patients without diabetes or prior stroke.
9,361 patients across 102 US centers. NIH-funded (non-industry), which enhanced credibility. Sponsor halted the intervention early after benefit was demonstrated; median intervention follow-up 3.33 years, and combined intervention + observational follow-up 3.88 years.
Primary composite (MI, ACS, stroke, HF, CV death), intervention period: 1.77%/yr intensive vs 2.40%/yr standard (HR 0.73, 95% CI 0.63–0.86, p<0.001) — 264/4678 vs 354/4683 events. The paper does not report an NNT.
All-cause mortality significantly reduced during intervention: 1.06% vs 1.41%/yr (HR 0.75, 95% CI 0.61–0.92, p=0.006) — one of the rare trials to show mortality benefit from BP lowering.
Heart failure during the intervention period: 0.45%/yr intensive vs 0.70%/yr standard (HR 0.68, 95% CI 0.50–0.92). During the postintervention period the direction reversed (HR 1.63, 95% CI 1.02–2.57; P=0.001 for interaction), and when intervention + postintervention data were combined, heart-failure rates no longer differed significantly between the groups.
Stroke itself was NOT significantly reduced: 0.45%/yr intensive vs 0.52%/yr standard (HR 0.89, 95% CI 0.64–1.23, P=0.48). Stroke made up 147 of 618 primary-outcome component events (~24%). Prior stroke patients were excluded, so this trial does not inform secondary stroke prevention.
BP was measured with an automated device (Omron HEM-907XL) by trained staff with participants seated per a prespecified protocol. The 2021 paper does NOT describe measurements as 'unattended' and does NOT provide a conversion factor to conventional clinic BP; any extrapolation to routine office BP requires caution and is not established in this report.
Serious adverse events higher with intensive treatment during the intervention period (Table 3, N=4678 intensive vs N=4683 standard): SAE hypotension 99 (2.1%) vs 58 (1.2%) (HR 1.71); combined ED-visit + SAE syncope 148 (3.2%) vs 100 (2.1%) (HR 1.48, P=0.002); SAE syncope alone was not significantly different (P=0.07). SAE electrolyte abnormalities and AKI/renal failure were also significantly more common with intensive treatment per the paper text.
SPRINT-MIND substudy showed intensive BP lowering significantly reduced mild cognitive impairment (HR 0.81, p=0.01) and a trend toward reduced probable dementia — the first large randomized evidence linking BP control to cognitive protection.
Directly influenced 2017 ACC/AHA guidelines that lowered the hypertension threshold to 130/80 mmHg (from 140/90) and set treatment targets at <130/80 for most adults.

      

Design

Study Type: Randomized clinical trial.

Randomization: 1

Blinding: Open-label for blood pressure targets, but outcome adjudication was blinded.

Enrollment Period: November 2010 through March 2013.

Follow-up Duration: Median of 3.33 years of intervention, with post-trial follow-up to 3.88 years.

Centers: 102

Countries: United States

Sample Size: 9361

Analysis: Intention-to-treat.

Inclusion Criteria

Age ≥50 years (no upper age limit — 28.2% were ≥75 years, enabling the SPRINT-SENIOR substudy).
Systolic blood pressure 130–180 mmHg (on 0–4 antihypertensive medications). Patients already on BP meds were eligible if SBP was within this range.
At least one additional indicator of increased cardiovascular risk: (a) clinical or subclinical cardiovascular disease (excluding stroke), (b) chronic kidney disease with eGFR 20–59 mL/min/1.73m² (28.3% of cohort), (c) 10-year Framingham CVD risk score ≥15%, or (d) age ≥75 years.
Willing and able to comply with intensive BP management protocol including monthly visits for dose titration.

Exclusion Criteria

Diabetes mellitus — excluded because the concurrent ACCORD-BP trial was testing similar targets in diabetics.
Previous stroke — a critical exclusion for neurologists. SPRINT cannot be used to guide secondary stroke prevention BP targets. SPS3 addressed this population.
Dementia or inability to give informed consent — though the SPRINT-MIND substudy assessed cognitive outcomes in enrolled patients.
Heart failure with reduced ejection fraction (NYHA Class III–IV) or LVEF <35%.
Expected survival <3 years from non-cardiovascular cause.
Proteinuria >1 g/day (nephrotic range).
Polycystic kidney disease.
Resident of nursing home.
eGFR <20 mL/min/1.73m² or dialysis.
Pregnancy or planned pregnancy.

Baseline Characteristics

Characteristic	Control	Active
Mean age	Not explicitly stated for standard group; overall mean 67.9 years	Not explicitly stated for intensive group; overall mean 67.9 years
Female (%)	Not explicitly stated for standard group	Not explicitly stated for intensive group
Chronic kidney disease	28.3% overall	28.3% overall
Previous cardiovascular disease	20.0% overall (supports primary-prevention cohort)	20.0% overall (supports primary-prevention cohort)

Arms

Field	Control	Intensive Treatment
Intervention	A systolic blood-pressure target of less than 140 mm Hg.	A systolic blood-pressure target of less than 120 mm Hg.
Duration	Median of 3.33 years	Median of 3.33 years

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
A composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes.	Primary	2.40% per year (354/4683 events)	1.77% per year (264/4678 events)	0.73	<0.001
All-cause mortality (intervention period)	Secondary	1.41% per year	1.06% per year	HR 0.75 (95% CI, 0.61 to 0.92)	0.006
Heart failure (intervention period)	Secondary	0.70% per year (105 events)	0.45% per year (68 events)	HR 0.68 (95% CI, 0.50 to 0.92)	0.01
Death from cardiovascular causes (intervention period)	Secondary	0.47% per year (71 events)	0.27% per year (41 events)	HR 0.58 (95% CI, 0.39 to 0.84)	0.004
Myocardial infarction (combined intervention + postintervention follow-up)	Secondary	Not reported here as rate/yr	Not reported here as rate/yr	HR 0.71 (95% CI, 0.56 to 0.90)	0.005
Stroke (intervention period)	Secondary	0.52% per year (78 events)	0.45% per year (69 events)	HR 0.89 (95% CI, 0.64 to 1.23)	0.48
Notes	Adverse	From Table 3 (intervention period). Denominators: N=4678 intensive vs N=4683 standard. 'SAE' = serious adverse event; 'ED/SAE' = emergency-department visit or serious adverse event.
Hypotension (SAE)	Adverse	58 (1.2%)	99 (2.1%)	HR 1.71	<0.001
Syncope (SAE alone)	Adverse	—	—	Not significant for SAE alone	0.07
Syncope (SAE or ED visit combined)	Adverse	100 (2.1%)	148 (3.2%)	HR 1.48	0.002
Electrolyte abnormalities (SAE)	Adverse	—	—	Significantly higher in intensive group per paper text and Table 3	Significant per paper text (see Table 3 for exact values)
Acute kidney injury or renal failure (SAE)	Adverse	—	—	Significantly higher in intensive group per paper text and Table 3	Significant per paper text (see Table 3 for exact values)

Criticisms

Stopped early — early stopping can overestimate treatment effects; however, post-trial follow-up to 3.88 years confirmed persistent benefit for the primary outcome and mortality (though the heart-failure difference did not persist).
BP was measured with an automated device (Omron HEM-907XL) by trained staff with participants seated per protocol. The 2021 paper does not describe the measurements as 'unattended' and does not provide a conversion factor to conventional clinic BP; extrapolation of SPRINT targets to routine office measurement is debated but is not addressed in this report.
Excluded BOTH diabetes and prior stroke — the two largest populations needing BP guidance. ACCORD-BP (diabetes) and SPS3 (stroke) addressed these populations separately; SPRINT's results cannot be directly extrapolated to them.
Higher SAE AKI/renal failure with intensive treatment — while most acute kidney events were mild and largely reversible, long-term renal consequences of aggressive BP lowering remain uncertain.
US-only trial — limits generalizability to other healthcare systems where monthly medication titration visits may not be feasible.
Open-label BP targets — physicians and patients knew the target, potentially influencing non-BP management (Hawthorne effect).
Stroke was NOT significantly reduced (HR 0.89, 95% CI 0.64–1.23, P=0.48) — despite being a component of the primary endpoint. SPRINT does not support intensive BP for stroke prevention specifically.
Mean SBP achieved was 120.0 mmHg (intensive) vs 133.9 mmHg (standard) at the last intervention-period visit — actual difference was ~14 mmHg, not the 20 mmHg target difference.
Polypharmacy: intensive group required more antihypertensive medications — additional medication burden, cost, side effects, and adherence challenges are clinically significant, especially in elderly patients.
In combined intervention + postintervention follow-up, heart-failure rates no longer differed between groups, suggesting the HF benefit may depend on sustained intensive treatment.

Funding

National Institutes of Health contracts (HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C) and an interagency agreement (A-HL-13-002-001) — NHLBI, NIDDK, NIA, and NINDS. Several trial sites were supported by Clinical and Translational Science Awards funded by the NIH National Center for Advancing Translational Sciences (NCATS). 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; neither company had any other role in the trial.

Based on: SPRINT (The New England Journal of Medicine, 2021)