Hypertension
Conditions
Keywords
blood pressure, antihypertensive, systolic, diastolic, heart failure, myocardial infarction, stroke, chronic kidney disease, dementia, cognitive decline
Brief summary
Elevated blood pressure (BP) is an important public health concern. It is highly prevalent, the prevalence may be increasing, and it is a risk factor for several adverse health outcomes, especially coronary heart disease, stroke, heart failure, chronic kidney disease, and decline in cognitive function. The Systolic Blood Pressure Intervention Trial (SPRINT) is a 2-arm, multicenter, randomized clinical trial designed to test whether a treatment program aimed at reducing systolic blood pressure (SBP) to a lower goal than currently recommended will reduce cardiovascular disease (CVD) risk.
Detailed description
SPRINT strived to enroll about 9250 participants aged ≥ 50 years with SBP ≥130 mm Hg and at least one additional CVD risk factor. The trial compared the effects of randomization to a treatment program of an intensive SBP goal with randomization to a treatment program of a standard goal. Target SBP goals were \<120 vs \<140 mm Hg, respectively, to create a minimum mean difference of 10 mm Hg between the two randomized groups. The primary hypothesis was that CVD event rates would be lower in the intensive arm. Participants were recruited at approximately 90 clinics within 5 clinical center networks (CCNs) over approximately a 2-year period, and were followed for 4-6 years. A total of 9361 participants were enrolled. NIH stopped the blood pressure intervention earlier than originally planned in order to quickly disseminate the significant preliminary results. Follow-up for cognitive and kidney outcomes continues during the post-intervention phase through May 2018.
Interventions
DRUGIntensive control of SBP
Participants in the Intensive arm have a goal of SBP \<120 mm Hg. Use of once-daily antihypertensive agents will be encouraged unless alternative frequency is indicated/necessary. One or more medications from the following classes of agents will be provided by the study for use in managing participants in both randomization groups to achieve study goals: Angiotension converting enzyme (ACE)-inhibitors Angiotension receptor blockers (ARBs) Direct vasodilators Thiazide-type diuretics Loop diuretics Potassium-sparing diuretics Beta-blockers Sustained-release calcium channel blockers (CCBs) Alpha1-receptor blockers Sympatholytics Combination products will be available, depending on cost, utility, or donations from pharmaceutical companies.
DRUGStandard control of SBP
Participants in the Standard BP arm have a goal of SBP \<140 mm Hg. The same medications used in the Intensive BP arm will be used for the Standard BP arm.
Sponsors
National Institute on Aging (NIA)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute of Neurological Disorders and Stroke (NINDS)
Wake Forest University Health Sciences
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* At least 50 years old Systolic blood pressure of * 130 - 180 mm Hg on 0 or 1 medication * 130 - 170 mm Hg on up to 2 medications * 130 - 160 mm Hg on up to 3 medications * 130 - 150 mm Hg on up to 4 medications Risk (one or more of the following) 1. Presence of clinical or subclinical cardiovascular disease other than stroke 2. CKD, defined as eGFR 20 - 59 ml/min/1.73m2 3. A Framingham Risk Score for 10-year CVD risk ≥ 15% 4. Age greater than 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 that causes concern regarding safety of the protocol. * One minute standing SBP \< 110 mm Hg. * Proteinuria in the following ranges (based on a measurement within the past 6 months) * 24 hour urinary protein excretion ≥1 g/day, or * 24 hour urinary albumin excretion ≥ 600 mg/day, or * spot urine protein/creatinine ratio ≥ 1 g/g creatinine, or * spot urine albumin/creatinine ratio ≥ 600 mg/g creatinine, or * urine dipstick ≥ 2+ protein * Arm circumference too large or small to allow accurate blood pressure measurement with available devices * Diabetes mellitus, * History of stroke (not CE or stenting) * Diagnosis of polycystic kidney disease * Glomerulonephritis treated with or likely to be treated with immunosuppressive therapy * eGFR \< 20 ml/min /1.73m2 or end-stage renal disease (ESRD) * Cardiovascular event or procedure (as defined above as clinical CVD for study entry) or hospitalization for unstable angina within last 3 months * Symptomatic heart failure within the past 6 months or left ventricular ejection fraction (by any method) \< 35% * A medical condition likely to limit survival to less than 3 years or a malignancy other than non-melanoma skin cancer within the last 2 years * Any factors judged by the clinic team to be likely to limit adherence to interventions. * Failure to obtain informed consent from participant * Currently participating in another clinical trial (intervention study). Note: Patient must wait until the completion of his/her activities or the completion of the other trial before being screened for SPRINT. * Living in the same household as an already randomized SPRINT participant * Any organ transplant * Unintentional weight loss \> 10% in last 6 months * Pregnancy, currently trying to become pregnant, or of child-bearing potential and not using birth control.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With First Occurrence of a Myocardial Infarction (MI), Acute Coronary Syndrome (ACS), Stroke, Heart Failure (HF), or CVD Death | 6 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With All-cause Mortality | 6 years | — |
| Number of CKD Participants Who Experienced a 50% Decline From Baseline eGFR | 6 years | — |
| Participants Who Developed End Stage Renal Disease | 6 years | — |
| Number of Patients With All-cause Dementia | 6 years | A 3-step process was used ascertain incident cases of all-cause dementia. First, to identify possible cases of dementia a brief Cognition Screening Battery was administered to all participants. Participants who score below the pre-designated screening cut-point for possible cognitive impairment during follow-up were administered a more comprehensive and detailed neurocognitive test battery (the Extended Cognitive Assessment Battery) plus the Functional Assessment Questionnaire (FAQ) which assesses impairments in daily living skills as a result of cognitive impairments. Last, all the above available tests and questionnaire data were submitted to a centralized, web-based system for adjudication by a panel of dementia experts who assigned final study classifications of probable dementia (PD), mild cognitive impairment (MCI) or no impairment (NI). |
| Small Vessel Cerebral Ischemic Disease | 4 years | Change over 4 years in total white matter lesion volume from baseline Change over 4 years in total brain volume from baseline Because of the skewed distribution for WML volume, we first applied an inverse hyperbolic sine transformation (asinh), which is similar to a log transformation but can accommodate values of zero. Linear mixed models, including random effects for participant and MRI facility, were used to estimate the change in WML volume and TBV between the treatment groups, including time since randomization (in days) and intracranial volume as covariates. Because the inverse hyperbolic sine transformation is nonlinear, and given the context of a mixed-effects model, back-transformation to the original scale of cm3 is difficult |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intensive Control of SBP Participants randomized into the Intensive BP arm had a goal of SBP \<120 mm Hg. 2-drug therapy initiated in most participants; age ≥75 years and SBP 130-139 mm Hg on 0-1 drug; may begin with 1 drug, but add second at 1 month if SBP ≥130 mm Hg; drugs added and/or titrated at each visit (monthly) to achieve SBP \<120 mm Hg; at periodic visits: addition of another drug required if not at goal.
Intensive control of SBP: Use of once-daily antihypertensive agents was encouraged unless alternative frequency was necessary. One or more medications from the following classes of agents were provided by the study for use in managing participants in both groups to achieve study goals:
Angiotension converting enzyme (ACE)-inhibitors Angiotension receptor blockers (ARBs) Direct vasodilators Thiazide-type diuretics Loop diuretics Potassium-sparing diuretics Beta-blockers Sustained-release calcium channel blockers (CCBs) Alpha1-receptor blockers Sympatholytics | 4,678 |
| Standard Control of SBP Participants randomized into the Standard arm had a goal of SBP \<140 mm Hg. Intensify therapy if SBP ≥160 mm Hg @ 1 visit; ≥140 mm Hg @ 2 consecutive visits; Down-titration if SBP \<130 mm Hg @ 1 visit; \<135 mm Hg @ 2 consecutive visits
Standard control of SBP: The same medications used in the Intensive BP arm will be used for the Standard BP arm. | 4,683 |
| Total | 9,361 |
Baseline characteristics
| Characteristic | Intensive Control of SBP | Standard Control of SBP | Total |
|---|---|---|---|
| Age, Continuous Age overall | 67.9 year STANDARD_DEVIATION 9.4 | 67.9 year STANDARD_DEVIATION 9.5 | 67.9 year STANDARD_DEVIATION 9.4 |
| Antihypertensive agents - no./patient | 1.8 agents per patient STANDARD_DEVIATION 1 | 1.8 agents per patient STANDARD_DEVIATION 1 | 1.8 agents per patient STANDARD_DEVIATION 1 |
| Aspirin use Aspirin Use | 2406 Participants | 2350 Participants | 4756 Participants |
| Aspirin use No Aspirin Use | 2255 Participants | 2316 Participants | 4571 Participants |
| Aspirin use Unknown Aspirin Use | 17 Participants | 17 Participants | 34 Participants |
| Baseline BP mm Hg Diastolic | 78.2 mm Hg STANDARD_DEVIATION 11.9 | 78.0 mm Hg STANDARD_DEVIATION 12 | 78.1 mm Hg STANDARD_DEVIATION 11.9 |
| Baseline BP mm Hg Systolic | 139.7 mm Hg STANDARD_DEVIATION 15.8 | 139.7 mm Hg STANDARD_DEVIATION 15.4 | 139.7 mm Hg STANDARD_DEVIATION 15.6 |
| Black race | 1454 Participants | 1493 Participants | 2947 Participants |
| Body-mass index | 29.9 kg/m^2 STANDARD_DEVIATION 5.8 | 29.8 kg/m^2 STANDARD_DEVIATION 5.7 | 29.9 kg/m^2 STANDARD_DEVIATION 5.8 |
| Criterion for increased cardiovascular risk Age > 75 years | 1317 Participants | 1319 Participants | 2636 Participants |
| Criterion for increased cardiovascular risk Cardiovascular disease | 940 Participants | 937 Participants | 1877 Participants |
| Criterion for increased cardiovascular risk Cardiovascular disease clinical | 779 Participants | 783 Participants | 1562 Participants |
| Criterion for increased cardiovascular risk Cardiovascular disease subclinical | 247 Participants | 246 Participants | 493 Participants |
| Criterion for increased cardiovascular risk Chronic kidney disease | 1330 Participants | 1316 Participants | 2646 Participants |
| Criterion for increased cardiovascular risk Framingham CVD risk score >= 15% | 2870 Participants | 2867 Participants | 5737 Participants |
| Distribution of systolic blood pressure < 132 mm Hg | 1583 Participants | 1553 Participants | 3136 Participants |
| Distribution of systolic blood pressure > 132 mm Hg to < 145 mm Hg | 1489 Participants | 1549 Participants | 3038 Participants |
| Distribution of systolic blood pressure > 145 mm Hg | 1606 Participants | 1581 Participants | 3187 Participants |
| Estimated GFR Among all participants | 71.8 ml/min/1.73 m2 STANDARD_DEVIATION 20.7 | 71.7 ml/min/1.73 m2 STANDARD_DEVIATION 20.5 | 71.7 ml/min/1.73 m2 STANDARD_DEVIATION 20.6 |
| Estimated GFR Among those with estimated GFR < 60 ml/min/1.73 m | 47.8 ml/min/1.73 m2 STANDARD_DEVIATION 9.5 | 47.9 ml/min/1.73 m2 STANDARD_DEVIATION 9.5 | 47.8 ml/min/1.73 m2 STANDARD_DEVIATION 9.5 |
| Estimated GFR Among those with estimated GFR >= 60 ml/min/1.73 m | 81.3 ml/min/1.73 m2 STANDARD_DEVIATION 15.5 | 81.1 ml/min/1.73 m2 STANDARD_DEVIATION 15.5 | 81.2 ml/min/1.73 m2 STANDARD_DEVIATION 15.5 |
| Fasting HDL cholesterol - mg/dl | 52.9 mg/dl STANDARD_DEVIATION 14.3 | 52.8 mg/dl STANDARD_DEVIATION 14.6 | 52.9 mg/dl STANDARD_DEVIATION 14.5 |
| Fasting plasma glucose - mg/dl | 98.8 mg/dl STANDARD_DEVIATION 13.7 | 98.8 mg/dl STANDARD_DEVIATION 13.4 | 98.8 mg/dl STANDARD_DEVIATION 13.5 |
| Fasting total cholesterol - mg/dl | 190.2 mg/dl STANDARD_DEVIATION 41.4 | 190.0 mg/dl STANDARD_DEVIATION 40.9 | 190.1 mg/dl STANDARD_DEVIATION 41.2 |
| Fasting total triglycerides - mg/dl | 124.8 mg/dl STANDARD_DEVIATION 85.8 | 127.1 mg/dl STANDARD_DEVIATION 95 | 125.9 mg/dl STANDARD_DEVIATION 90.5 |
| Framingham 10-yr cardiovascular disease risk score | 24.8 probability STANDARD_DEVIATION 12.6 | 24.8 probability STANDARD_DEVIATION 12.5 | 24.8 probability STANDARD_DEVIATION 12.5 |
| Not using antihypertensive agents - no. (%) | 432 Participants | 450 Participants | 882 Participants |
| Race/Ethnicity, Customized Hispanic | 503 Participants | 481 Participants | 984 Participants |
| Race/Ethnicity, Customized Non-Hispanic black | 1379 Participants | 1423 Participants | 2802 Participants |
| Race/Ethnicity, Customized Non-Hispanic white | 2698 Participants | 2701 Participants | 5399 Participants |
| Race/Ethnicity, Customized Other | 98 Participants | 78 Participants | 176 Participants |
| Ratio of urinary albumin (mg) to creatinine (g) | 44.1 ratio STANDARD_DEVIATION 178.7 | 41.1 ratio STANDARD_DEVIATION 152.9 | 42.6 ratio STANDARD_DEVIATION 166.3 |
| Serum creatinine | 1.07 mg/dl STANDARD_DEVIATION 0.34 | 1.08 mg/dl STANDARD_DEVIATION 0.34 | 1.07 mg/dl STANDARD_DEVIATION 0.34 |
| Sex: Female, Male Female | 1684 Participants | 1648 Participants | 3332 Participants |
| Sex: Female, Male Male | 2994 Participants | 3035 Participants | 6029 Participants |
| Smoking status - no. (%) Current smoker | 639 Participants | 601 Participants | 1240 Participants |
| Smoking status - no. (%) Former smoker | 1977 Participants | 1996 Participants | 3973 Participants |
| Smoking status - no. (%) Missing data | 12 Participants | 14 Participants | 26 Participants |
| Smoking status - no. (%) Never smoked | 2050 Participants | 2072 Participants | 4122 Participants |
| Statin use No Statin Use | 2667 Participants | 2564 Participants | 5231 Participants |
| Statin use Statin Use | 1978 Participants | 2076 Participants | 4054 Participants |
| Statin use Unknown Statin Use | 33 Participants | 43 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 155 / 4,678 | 210 / 4,683 |
| other Total, other adverse events | 1,399 / 4,678 | 1,342 / 4,683 |
| serious Total, serious adverse events | 1,793 / 4,678 | 1,736 / 4,683 |
Outcome results
Primary
Number of Participants With First Occurrence of a Myocardial Infarction (MI), Acute Coronary Syndrome (ACS), Stroke, Heart Failure (HF), or CVD Death
Time frame: 6 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intensive Control of SBP | Number of Participants With First Occurrence of a Myocardial Infarction (MI), Acute Coronary Syndrome (ACS), Stroke, Heart Failure (HF), or CVD Death | 243 Participants |
| Standard Control of SBP | Number of Participants With First Occurrence of a Myocardial Infarction (MI), Acute Coronary Syndrome (ACS), Stroke, Heart Failure (HF), or CVD Death | 319 Participants |
p-value: <0.00195% CI: [0.64, 0.89]Regression, Cox
Secondary
Number of CKD Participants Who Experienced a 50% Decline From Baseline eGFR
Time frame: 6 years
Population: Participants with CKD at baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intensive Control of SBP | Number of CKD Participants Who Experienced a 50% Decline From Baseline eGFR | 10 Participants |
| Standard Control of SBP | Number of CKD Participants Who Experienced a 50% Decline From Baseline eGFR | 12 Participants |
p-value: 0.5895% CI: [0.34, 1.83]Regression, Cox
Secondary
Number of Participants With All-cause Mortality
Time frame: 6 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intensive Control of SBP | Number of Participants With All-cause Mortality | 155 Participants |
| Standard Control of SBP | Number of Participants With All-cause Mortality | 210 Participants |
p-value: 0.00395% CI: [0.6, 0.9]Regression, Cox
Secondary
Number of Patients With All-cause Dementia
A 3-step process was used ascertain incident cases of all-cause dementia. First, to identify possible cases of dementia a brief Cognition Screening Battery was administered to all participants. Participants who score below the pre-designated screening cut-point for possible cognitive impairment during follow-up were administered a more comprehensive and detailed neurocognitive test battery (the Extended Cognitive Assessment Battery) plus the Functional Assessment Questionnaire (FAQ) which assesses impairments in daily living skills as a result of cognitive impairments. Last, all the above available tests and questionnaire data were submitted to a centralized, web-based system for adjudication by a panel of dementia experts who assigned final study classifications of probable dementia (PD), mild cognitive impairment (MCI) or no impairment (NI).
Time frame: 6 years
Population: Participants who completed at least 1 cognitive assessment during follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intensive Control of SBP | Number of Patients With All-cause Dementia | 149 Participants |
| Standard Control of SBP | Number of Patients With All-cause Dementia | 176 Participants |
p-value: 0.195% CI: [0.67, 1.04]Regression, Cox
Secondary
Participants Who Developed End Stage Renal Disease
Time frame: 6 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intensive Control of SBP | Participants Who Developed End Stage Renal Disease | 12 Participants |
| Standard Control of SBP | Participants Who Developed End Stage Renal Disease | 8 Participants |
Secondary
Small Vessel Cerebral Ischemic Disease
Change over 4 years in total white matter lesion volume from baseline Change over 4 years in total brain volume from baseline Because of the skewed distribution for WML volume, we first applied an inverse hyperbolic sine transformation (asinh), which is similar to a log transformation but can accommodate values of zero. Linear mixed models, including random effects for participant and MRI facility, were used to estimate the change in WML volume and TBV between the treatment groups, including time since randomization (in days) and intracranial volume as covariates. Because the inverse hyperbolic sine transformation is nonlinear, and given the context of a mixed-effects model, back-transformation to the original scale of cm3 is difficult
Time frame: 4 years
Population: Of the 670 participants with WML volume measurement at baseline, 462 completed the follow-up MRI. Image quality control requirements were not met for 13 participants with a follow-up MRI scan, resulting in a sample of 449 adults.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Intensive Control of SBP | Small Vessel Cerebral Ischemic Disease | Change in total white matter lesion volume from ba | 0.23 asinh(cm3) |
| Intensive Control of SBP | Small Vessel Cerebral Ischemic Disease | Change in total brain volume from baseline | -7.7 asinh(cm3) |
| Standard Control of SBP | Small Vessel Cerebral Ischemic Disease | Change in total white matter lesion volume from ba | 0.37 asinh(cm3) |
| Standard Control of SBP | Small Vessel Cerebral Ischemic Disease | Change in total brain volume from baseline | -6.8 asinh(cm3) |