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Original Article
A BS T R AC T
BACKGROUND
The most appropriate targets for systolic blood pressure to reduce cardiovascular
morbidity and mortality among persons without diabetes remain uncertain.
METHODS
At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensivetreatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment
group than in the standard-treatment group (1.65% per year vs. 2.19% per year;
hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to
0.89; P<0.001). All-cause mortality was also significantly lower in the intensivetreatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P=0.003). Rates of serious
adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney
injury or failure, but not of injurious falls, were higher in the intensive-treatment
group than in the standard-treatment group.
CONCLUSIONS
Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than
140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular
events and death from any cause, although significantly higher rates of some adverse
events were observed in the intensive-treatment group. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01206062.)
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Me thods
Study Design and Oversight
Participants were required to meet all the following criteria: an age of at least 50 years, a systolic
blood pressure of 130 to 180 mm Hg (see the
Supplementary Appendix), and an increased risk
of cardiovascular events. Increased cardiovascu-
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lar risk was defined by one or more of the following: clinical or subclinical cardiovascular disease other than stroke; chronic kidney disease,
excluding polycystic kidney disease, with an estimated glomerular filtration rate (eGFR) of 20 to
less than 60 ml per minute per 1.73 m2 of bodysurface area, calculated with the use of the fourvariable Modification of Diet in Renal Disease
equation; a 10-year risk of cardiovascular disease
of 15% or greater on the basis of the Framingham risk score; or an age of 75 years or older.
Patients with diabetes mellitus or prior stroke
were excluded. Detailed inclusion and exclusion
criteria are listed in the Supplementary Appendix. All participants provided written informed
consent.
Randomization and Interventions
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Study Outcomes
R e sult s
Study Participants
A total of 9361 participants were enrolled between November 2010 and March 2013 (Fig.1).
Descriptive baseline statistics are presented in
Table1. On August 20, 2015, the NHLBI director
accepted a recommendation from the data and
safety monitoring board of the trial to inform
the investigators and participants of the cardio-
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Blood Pressure
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The
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Standard Treatment
(N=4683)
Age 75 yr
1317 (28.2)
1319 (28.2)
1330 (28.4)
1316 (28.1)
Cardiovascular disease
940 (20.1)
937 (20.0)
Clinical
779 (16.7)
783 (16.7)
Subclinical
247 (5.3)
246 (5.3)
2870 (61.4)
2867 (61.2)
1684 (36.0)
1648 (35.2)
Overall
67.99.4
67.99.5
79.83.9
79.94.1
1379 (29.5)
1423 (30.4)
Characteristic
Criterion for increased cardiovascular risk no. (%)
503 (10.8)
481 (10.3)
2698 (57.7)
2701 (57.7)
Other
98 (2.1)
78 (1.7)
Black race
1454 (31.1)
1493 (31.9)
Systolic
139.715.8
139.715.4
Diastolic
78.211.9
78.012.0
132 mm Hg
1583 (33.8)
1553 (33.2)
>132 mm Hg to <145 mm Hg
1489 (31.8)
1549 (33.1)
145 mm Hg
1606 (34.3)
1581 (33.8)
1.070.34
1.080.34
71.820.7
71.720.5
81.315.5
81.115.5
47.89.5
47.99.5
44.1178.7
41.1152.9
190.241.4
190.040.9
52.914.3
52.814.6
124.885.8
127.195.0
98.813.7
98.813.4
1978/4645 (42.6)
2076/4640 (44.7)
2406/4661 (51.6)
2350/4666 (50.4)
Never smoked
2050 (43.8)
2072 (44.2)
Former smoker
1977 (42.3)
1996 (42.6)
Current smoker
639 (13.7)
601 (12.8)
12 (0.3)
14 (0.3)
Missing data
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Table 1. (Continued.)
Intensive Treatment
(N=4678)
Standard Treatment
(N=4683)
20.110.9
20.110.8
Body-mass index
29.95.8
29.85.7
1.81.0
1.81.0
432 (9.2)
450 (9.6)
Characteristic
* Plusminus values are means SD. There were no significant differences (P<0.05) between the two groups except for
statin use (P=0.04). To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values
for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter,
multiply by 0.01129. To convert the values for glucose to millimoles per liter, multiply by 0.05551. GFR denotes glomerular filtration rate, and HDL high-density lipoprotein.
Increased cardiovascular risk was one of the inclusion criteria.
Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m2
of body-surface area.
Race and ethnic group were self-reported.
Black race includes Hispanic black and black as part of a multiracial identification.
The body-mass index is the weight in kilograms divided by the square of the height in meters.
Serious adverse events occurred in 1793 participants in the intensive-treatment group (38.3%)
and in 1736 participants in the standard-treatment group (37.1%) (hazard ratio with intensive
treatment, 1.04; P=0.25) (Table3, and Table S4
in the Supplementary Appendix). Serious adverse
events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or acute
renal failure, but not injurious falls or bradycardia, occurred more frequently in the intensivetreatment group than in the standard-treatment
group. Orthostatic hypotension as assessed during a clinic visit was significantly less common
in the intensive-treatment group. A total of 220
participants in the intensive-treatment group
(4.7%) and 118 participants in the standardtreatment group (2.5%) had serious adverse events
that were classified as possibly or definitely related to the intervention (hazard ratio, 1.88;
P<0.001) (Table S5 in the Supplementary Appendix). The magnitude and pattern of differences
in adverse events according to treatment assignment among participants 75 years of age or
older were similar to those in the overall cohort
(Table S6 in the Supplementary Appendix).
Discussion
SPRINT showed that among adults with hypertension but without diabetes, lowering systolic
blood pressure to a target goal of less than 120
mm Hg, as compared with the standard goal of
less than 140 mm Hg, resulted in significantly
lower rates of fatal and nonfatal cardiovascular
events and death from any cause. Trial participants assigned to the lower systolic blood-pressure target (intensive-treatment group), as compared with those assigned to the higher target
(standard-treatment group), had a 25% lower
relative risk of the primary outcome; in addition,
the intensive-treatment group had lower rates of
several other important outcomes, including
heart failure (38% lower relative risk), death from
cardiovascular causes (43% lower relative risk),
and death from any cause (27% lower relative
risk). During the follow-up period of the trial
(median, 3.26 years), the number needed to treat
with a strategy of intensive blood-pressure con-
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The
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150
140
Standard treatment
130
120
Intensive treatment
110
0
Years
No. with Data
Standard treatment
Intensive treatment
4683
4678
4345
4375
4222
4231
4092
4091
3997
4029
3904
3920
3115
3204
1974
2035
1000
1048
274
286
1.9
2.3
1.8
2.7
1.8
2.8
1.8
2.8
1.8
2.8
1.8
2.8
1.8
2.8
1.8
2.8
1.8
2.8
1.9
3.0
Figure 2. Systolic Blood Pressure in the Two Treatment Groups over the Course of the Trial.
The systolic blood-pressure target in the intensive-treatment group was less than 120 mm Hg, and the target in the
standard-treatment group was less than 140 mm Hg. The mean number of medications is the number of bloodpressure medications administered at the exit of each visit. I bars represent 95% confidence intervals.
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Intensive Treatment
no. of patients
(%)
All participants
Primary outcome
% per year
Standard Treatment
no. of patients
(%)
(N=4678)
Hazard Ratio
(95% CI)
P Value
% per year
(N=4683)
243 (5.2)
1.65
319 (6.8)
2.19
0.75 (0.640.89)
<0.001
Myocardial infarction
97 (2.1)
0.65
116 (2.5)
0.78
0.83 (0.641.09)
0.19
40 (0.9)
0.27
40 (0.9)
0.27
1.00 (0.641.55)
0.99
Stroke
62 (1.3)
0.41
70 (1.5)
0.47
0.89 (0.631.25)
0.50
Heart failure
62 (1.3)
0.41
100 (2.1)
0.67
0.62 (0.450.84)
0.002
37 (0.8)
0.25
65 (1.4)
0.43
0.57 (0.380.85)
0.005
155 (3.3)
1.03
210 (4.5)
1.40
0.73 (0.600.90)
0.003
332 (7.1)
2.25
423 (9.0)
2.90
0.78 (0.670.90)
<0.001
Secondary outcomes
(N=1330)
(N=1316)
14 (1.1)
0.33
15 (1.1)
0.36
0.89 (0.421.87)
0.76
10 (0.8)
0.23
11 (0.8)
0.26
0.87 (0.362.07)
0.75
6 (0.5)
0.14
10 (0.8)
0.24
0.57 (0.191.54)
0.27
3.90
0.72 (0.481.07)
0.11
Long-term dialysis
Kidney transplantation
Incident albuminuria
49/526 (9.3)
0
3.02
(N=3332)
59/500 (11.8)
(N=3345)
127 (3.8)
1.21
37 (1.1)
0.35
3.49 (2.445.10)
<0.001
110/1769 (6.2)
2.00
135/1831 (7.4)
2.41
0.81 (0.631.04)
0.10
of benefits for an even lower systolic blood-pressure target than that currently recommended in
most patients with hypertension.
Comparisons between SPRINT and the ACCORD
trial22 are inevitable, because the trials examined
identical systolic blood-pressure targets (<120
mm Hg vs. <140 mm Hg). In contrast to the
findings of SPRINT, the cardiovascular and mortality benefits observed in the ACCORD trial were
not statistically significant and were of a lesser
magnitude. Several important differences between these trials should be noted. The ACCORD
trial enrolled participants with diabetes exclu-
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The
A Primary Outcome
1.0
0.08
0.8
Cumulative Hazard
0.10
Standard treatment
0.06
0.6
0.04
0.4
0.00
0.2
0.0
Intensive treatment
0.02
2829
2900
721
779
Years
No. at Risk
Standard treatment
Intensive treatment
4683
4678
4437
4436
4228
4256
0.10
0.08
0.8
Cumulative Hazard
0.06
0.6
0.02
0.4
0.00
0.2
0.0
Standard treatment
0.04
Intensive treatment
0
2998
3016
789
807
Years
No. at Risk
Standard treatment
Intensive treatment
4683
4678
4528
4516
4383
4390
10
of
m e dic i n e
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Subgroup
Intensive Treatment
Standard Treatment
P Value for
Interaction
243/4678 (5.2)
319/4683 (6.8)
0.75 (0.640.89)
135/3348 (4.0)
108/1330 (8.1)
193/3367 (5.7)
126/1316 (9.6)
0.70 (0.560.87)
0.82 (0.631.07)
142/3361 (4.2)
101/1317 (7.7)
175/3364 (5.2)
144/1319 (10.9)
0.80 (0.641.00)
0.67 (0.510.86)
77/1684 (4.6)
166/2994 (5.5)
89/1648 (5.4)
230/3035 (7.6)
0.84 (0.621.14)
0.72 (0.590.88)
62/1454 (4.3)
181/3224 (5.6)
85/1493 (5.7)
234/3190 (7.3)
0.77 (0.551.06)
0.74 (0.610.90)
149/3738 (4.0)
94/940 (10.0)
208/3746 (5.6)
111/937 (11.8)
0.71 (0.570.88)
0.83 (0.621.09)
71/1583 (4.5)
77/1489 (5.2)
95/1606 (5.9)
98/1553 (6.3)
106/1549 (6.8)
115/1581 (7.3)
0.70 (0.510.95)
0.77 (0.571.03)
0.83 (0.631.09)
0.36
0.32
0.45
0.83
0.39
0.77
0.50
0.75
1.00
1.20
and death that are associated with intensive control of systolic blood pressure.
The strengths of SPRINT include a large
sample size, the diversity of the population (including a large proportion of patients 75 years of
age or older), and its success in achieving the
intended separation in systolic blood pressure
between the two intervention groups throughout
the trial. The lack of generalizability to populations not included in the study such as persons with diabetes, those with prior stroke, and
those younger than 50 years of age is a limitation. It is also worth noting that we did not
enroll older adults residing in nursing homes or
assisted-living facilities. In addition, the effects
of the lower blood pressure on the central nervous system and kidney cannot be reasonably
interpreted until analysis of these end points has
been completed.
The SPRINT results raise important practical
issues. Hypertension control to a blood pressure
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Table 3. Serious Adverse Events, Conditions of Interest, and Monitored Clinical Events.
Intensive Treatment
(N=4678)
Variable
Standard Treatment
(N=4683)
Hazard Ratio
P Value
1.04
0.25
1793 (38.3)
1736 (37.1)
Conditions of interest
Serious adverse event only
Hypotension
110 (2.4)
66 (1.4)
1.67
0.001
Syncope
107 (2.3)
80 (1.7)
1.33
0.05
87 (1.9)
73 (1.6)
1.19
0.28
Electrolyte abnormality
Bradycardia
144 (3.1)
107 (2.3)
1.35
0.02
Injurious fall
105 (2.2)
110 (2.3)
0.95
0.71
193 (4.1)
117 (2.5)
1.66
<0.001
158 (3.4)
93 (2.0)
1.70
<0.001
Syncope
163 (3.5)
113 (2.4)
1.44
0.003
Bradycardia
104 (2.2)
83 (1.8)
1.25
0.13
Electrolyte abnormality
177 (3.8)
129 (2.8)
1.38
0.006
Injurious fall
334 (7.1)
332 (7.1)
1.00
0.97
204 (4.4)
120 (2.6)
1.71
<0.001
180 (3.8)
100 (2.1)
1.76
<0.001
6 (0.1)
0.02
114 (2.4)
74 (1.6)
1.50
0.006
176 (3.8)
171 (3.7)
1.00
0.97
777 (16.6)
857 (18.3)
0.88
0.01
62 (1.3)
71 (1.5)
0.85
0.35
Orthostatic hypotension
Alone
With dizziness
* A serious adverse event was defined as an event that was fatal or life-threatening, that resulted in clinically significant or persistent disability, that required or prolonged a hospitalization, or that was judged by the investigator to represent a clinically significant hazard or harm to
the participant that might require medical or surgical intervention to prevent one of the other events listed above.
An injurious fall was defined as a fall that resulted in evaluation in an emergency department or that resulted in hospitalization.
Acute kidney injury or acute renal failure were coded if the diagnosis was listed in the hospital discharge summary and was believed by the
safety officer to be one of the top three reasons for admission or continued hospitalization. A few cases of acute kidney injury were noted in
an emergency department if the participant presented for one of the other conditions of interest.
Adverse laboratory measures were detected on routine or unscheduled tests; routine laboratory tests were performed at 1 month, then quarterly during the first year, then every 6 months.
Orthostatic hypertension was defined as a drop in systolic blood pressure of at least 20 mm Hg or in diastolic blood pressure of at least
10 mm Hg at 1 minute after the participant stood up, as compared with the value obtained when the participant was seated. Standing
blood pressures were measured at screening, baseline, 1 month, 6 months, 12 months, and yearly thereafter. Participants were asked if they
felt dizzy at the time the orthostatic measure was taken.
less than 140 mm Hg, in patients at high risk curred significantly more frequently with the
for cardiovascular events but without diabetes lower target.
The content is solely the responsibility of the authors and
resulted in lower rates of fatal and nonfatal
does not necessarily represent the official views of the National
major cardiovascular events and death from Institutes of Health (NIH), the Department of Veterans Affairs,
any cause. However, some adverse events oc- or the U.S. Government.
12
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Supported
by
contracts
(HHSN268200900040C,
HHSN268200900046C,
HHSN268200900047C,
HHSN268200900048C, and HHSN268200900049C) and an interagency agreement (A-HL-13-002-001) from the NIH, including the National Heart, Lung, and Blood Institute (NHLBI), the
National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke. Several study sites
were supported by Clinical and Translational Science Awards
funded by the National Center for Advancing Translational Sciences of the NIH (Case Western Reserve University:
UL1TR000439; Ohio State University: UL1RR025755; University of Pennsylvania: UL1RR024134 and UL1TR000003; Boston
University: UL1RR025771; Stanford University: UL1TR000093;
Tufts University: UL1RR025752, UL1TR000073, and
Appendix
The affiliations of the members of the writing group are as follows: the Division of Nephrology and Hypertension, University Hospitals
Case Medical Center, Case Western Reserve University (J.T.W., M.R.), and Division of Nephrology and Hypertension, Louis Stokes
Cleveland Veterans Affairs (VA) Medical Center (M.R.), Cleveland; Sticht Center on Aging (J.D.W., K.M.S.), Section on Nephrology
(M.V.R.), and Department of Biostatistical Sciences (D.M.R., W.T.A.), Wake Forest School of Medicine, Winston-Salem, NC; Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans (P.K.W.); Clinical Applications
and Prevention Branch, National Heart, Lung, and Blood Institute (J.K.S., L.J.F., J.A.C.), and Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases (P.L.K.), Bethesda, MD; Divisions of Cardiovascular
Diseases (S.O.) and Preventive Medicine (C.E.L.), University of Alabama at Birmingham, Birmingham; Department of Preventive Medicine, University of Tennessee Health Science Center (K.C.J.), and the Preventive Medicine Section, VA Medical Center (W.C.C.), Memphis; School of Public Health, University of Colorado, Aurora (D.C.G.); and Division of Nephrology and Hypertension, University of
Utah, Salt Lake City (A.K.C.).
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