Sandbox: trial template
Complete Title of Study
A randomized trial of intensive versus standard blood-pressure control
Study Acronym
SPRINT
Principal Investigator, Co-investigators, and Collaborating Institutions
Principal Investigator: The SPRINT Research Group
Overview
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.
Disease State(s) Studied
- Cardiovascular Diseases
- Hypertension
- Coronary Disease
- Heart failure
Study Phase
Study Design
Multicenter, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study.
Study Duration and Time-points
2010-2013
Interventions
- Experimental: Intensive, target SBP <120 mm Hg (n=4,678)
- Active Comparator: Standard, target SBP 135-139 mm Hg (n=4,683)
Primary Endpoint
- First occurrence of MI, ACS, stroke, HF, or CV mortality
Secondary Endpoints
- MI
- ACS without MI
- Stroke
- HF
- CV mortality
- All-cause mortality
- Composite of primary outcome or all-cause mortality
- Of those with CKD at baseline
- ≥50% reduction in GFR, long-term HD, or renal transplant
- ≥50% reduction in GFR
- Long-term HD
- New albuminuria
- Of those without CKD at baseline
- ≥30% reduction in GFR to <60 mL/min/1.73 m2
- New albuminuria
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
- Clinical CVD (non-stroke):
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
Outcome: Primary Endpoint
- 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)
Outcome: Secondary Endpoint
- 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)
Outcome: Exploratory Endpoints
- 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.
Outcome: Safety endpoints
- 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.[1]
- SAE possibly or definitely associated with the intervention 4.7% vs. 2.5% (HR 1.88; P<0.001; NNH 45)
- 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)
Statistical Analysis
- 88.7% power to detect a 20% effect with respect to the primary outcome
- Cox proportional-hazards regression with two-sided tests (HR)
- 5% level of significance
- Analysis: Intention-to-treat
Conclusions
In conclusion, lower systolic blood pressure targets of less than 120 mm Hg, as compared with < 140 mm Hg, in patients at high risk for cardiovascular events but without diabetes resulted in lower rates of major cardiovascular events and death from any cause.
Discussion and Limitations of the Trial
- Lack of generalizability to patients with diabetes, those with prior stroke, and those younger than 50 years of age.
- Recruitment limitations, lack of enrollment to older adults residing in nursing homes or assisted-living facilities.
- Safety surveillance and effects of lower blood pressure on the central nervous system and kidney cannot be reasonably interpreted until the analysis of these endpoints is completed.
Commentary
Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [1]
- Assess kidney injury related to lower systolic blood pressure. Long term adverse renal outcome.
- Meta-analysis on existing trials evaluating identical systolic-blood pressure targets.
- Can we know more characteristics on patients lost in follow-up?
- Intracranial hypoperfusion has been linked to cognitive decline in the elderly, which may be worsened by lower BP targets, although SPRINT was likely too short to detect a meaningful change in cognitive status.