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established in 1812 November 26, 2015 vol. 373 no. 22

The members of the writing committee ( Jackson T. Wright, Jr., M.D., Ph.D., Jeff D. Williamson, M.D., M.H.S., Paul K. Whelton, M.D., Joni K. Snyder, R.N., B.S.N., M.A., Kaycee M. Sink, M.D., M.A.S., Michael V. Rocco, M.D., M.S.C.E., David M. Reboussin, Ph.D., Mahboob Rahman, M.D., Suzanne Oparil, M.D., Cora E. Lewis, M.D., M.S.P.H., Paul L. Kimmel, M.D., Karen C. Johnson, M.D., M.P.H., David C. Goff, Jr., M.D., Ph.D., Lawrence J. Fine, M.D., Dr.P.H., Jeffrey A. Cutler, M.D., M.P.H., William C. Cush man, M.D., Alfred K. Cheung, M.D., and Walter T. Ambrosius, Ph.D.) assume re sponsibility for the overall content and integrity of the article. The affiliations of the members of the writing group are listed in the Appendix. Address reprint requests to Dr. Wright at the Division of Nephrology and Hypertension, Univer sity Hospitals Case Medical Center, Case Western Reserve University, 1100 Euclid Ave. Cleveland, OH 441066053, or at jackson . wright@ case . edu.

* A complete list of the members of the Systolic Blood Pressure Intervention Trial (SPRINT) Research Group is pro vided in the Supplementary Appendix, available at NEJM.org.

This article was published on November 9, 2015, at NEJM.org.

BACKGROUND The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain.

METHODS We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.

RESULTS At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive- treatment group and 136.2 mm Hg in the standard-treatment group. The interven- tion was stopped early after a median follow-up of 3.26 years owing to a signifi- cantly 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 intensive- treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P = 0.003). Rates of seri- ous 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, target- ing 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.)

a b s t r a c t

A Randomized Trial of Intensive versus Standard Blood-Pressure Control

The SPRINT Research Group*

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Hypertension is highly prevalent in the adult population in the United States, especially among persons older than 60 years of age, and affects approximately 1 billion adults worldwide.1,2 Among persons 50 years of age or older, isolated systolic hyperten- sion is the most common form of hypertension,3,4 and systolic blood pressure becomes more im- portant than diastolic blood pressure as an inde- pendent risk predictor for coronary events, stroke, heart failure, and end-stage renal disease (ESRD).5-13 The Global Burden of Disease Study identified elevated blood pressure as the leading risk fac- tor, among 67 studied, for death and disability- adjusted life-years lost during 2010.14

Clinical trials have shown that treatment of hypertension reduces the risk of cardiovascular disease outcomes, including incident stroke (by 35 to 40%), myocardial infarction (by 15 to 25%), and heart failure (by up to 64%).5,15,16 However, the target for systolic blood-pressure lowering is uncertain. Observational studies have shown a progressive increase in cardiovascular risk as systolic blood pressure rises above 115 mm Hg,10 but the available evidence from randomized, controlled trials in the general population of patients with hypertension only documents the benefit of treatment to achieve a systolic blood- pressure target of less than 150 mm Hg, with limited data concerning lower blood-pressure targets.11,17-21 In a trial involving patients with type 2 diabetes mellitus, the rate of major cardio- vascular events was similar with a systolic blood- pressure target of less than 120 mm Hg and the commonly recommended target of less than 140 mm Hg, though the rate of stroke was lower with the target of less than 120 mm Hg.22 A recent trial involving patients who had had a stroke compared treatment to lower systolic blood pressure to less than 130 mm Hg with treatment to lower it to less than 150 mm Hg and showed no significant benefit of the lower target with respect to the overall risk of another stroke but a significant benefit with respect to the risk of hemorrhagic stroke.23

The hypothesis that a lower systolic blood- pressure goal (e.g., <120 mm Hg) would reduce clinical events more than a standard goal was designated by a National Heart, Lung, and Blood Institute (NHLBI) expert panel in 2007 as the most important hypothesis to test regarding the prevention of hypertension-related complications

among patients without diabetes.24 The current article describes the primary results of the Sys- tolic Blood Pressure Intervention Trial (SPRINT), which compared the benefit of treatment of systolic blood pressure to a target of less than 120 mm Hg with treatment to a target of less than 140 mm Hg.

M e t h o d s

Study Design and Oversight

SPRINT was a randomized, controlled, open-la- bel trial that was conducted at 102 clinical sites (organized into 5 clinical center networks) in the United States, including Puerto Rico (see the Supplementary Appendix, available with the full text of this article at NEJM.org). A trial coordi- nating center served as a data and biostatistical core center and supervised the central laboratory, the electrocardiography reading center, the mag- netic resonance imaging reading center, and the drug-distribution center. The rationale and pro- tocol for the trial are publicly available,25,26 and the protocol is available at NEJM.org.

SPRINT was sponsored by the NHLBI, with cosponsorship by the National Institute of Dia- betes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging. An independent data and safety monitoring board monitored unblinded trial results and safety events. The study was approved by the institu- tional review board at each participating study site. The steering committee designed the study, gathered the data (in collaboration with investi- gators at the clinics and other study units), made the decision to submit the manuscript for publi- cation, and vouches for the fidelity of the study to the protocol. The writing committee wrote the manuscript and vouches for the complete- ness and accuracy of the data and analysis. The coordinating center was responsible for analyz- ing the data. Scientists at the National Institutes of Health participated in the design of the study and as a group had one vote on the steering committee of the trial.

Study Population

Participants were required to meet all the follow- ing 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

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of cardiovascular events. Increased cardiovascu- lar risk was defined by one or more of the fol- lowing: clinical or subclinical cardiovascular dis- ease other than stroke; chronic kidney disease, excluding polycystic kidney disease, with an esti- mated glomerular filtration rate (eGFR) of 20 to less than 60 ml per minute per 1.73 m2 of body- surface area, calculated with the use of the four- variable Modification of Diet in Renal Disease equation; a 10-year risk of cardiovascular disease of 15% or greater on the basis of the Framing- ham 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 Appen- dix. All participants provided written informed consent.

Randomization and Interventions

Eligible participants were assigned to a sys- tolic blood-pressure target of either less than 140 mm Hg (the standard-treatment group) or less than 120 mm Hg (the intensive-treatment group). Randomization was stratified according to clinical site. Participants and study personnel were aware of the study-group assignments, but outcome adjudicators were not.

After the participants underwent randomiza- tion, their baseline antihypertensive regimens were adjusted on the basis of the study-group assignment. The treatment algorithms were sim- ilar to those used in the Action to Control Car- diovascular Risk in Diabetes (ACCORD) trial.22 These algorithms and our formulary are listed in Figures S1 and S2 and Table S1 in the Supple- mentary Appendix. All major classes of antihy- pertensive agents were included in the formulary and were provided at no cost to the participants. SPRINT investigators could also prescribe other antihypertensive medications (not provided by the study). The protocol encouraged, but did not mandate, the use of drug classes with the stron- gest evidence for reduction in cardiovascular outcomes, including thiazide-type diuretics (en- couraged as the first-line agent), loop diuretics (for participants with advanced chronic kidney disease), and beta-adrenergic blockers (for those with coronary artery disease).5,27 Chlorthalidone was encouraged as the primary thiazide-type di- uretic, and amlodipine as the preferred calcium- channel blocker.28,29 Azilsartan and azilsartan combined with chlorthalidone were donated by

Takeda Pharmaceuticals International and Arbor Pharmaceuticals; neither company had any other role in the study.

Participants were seen monthly for the first 3 months and every 3 months thereafter. Medi- cations for participants in the intensive-treat- ment group were adjusted on a monthly basis to target a systolic blood pressure of less than 120 mm Hg. For participants in the standard- treatment group, medications were adjusted to target a systolic blood pressure of 135 to 139 mm Hg, and the dose was reduced if sys- tolic blood pressure was less than 130 mm Hg on a single visit or less than 135 mm Hg on two consecutive visits. Dose adjustment was based on a mean of three blood-pressure measure- ments at an office visit while the patient was seated and after 5 minutes of quiet rest; the measurements were made with the use of an automated measurement system (Model 907, Omron Healthcare). Lifestyle modification was encouraged as part of the management strategy. Retention in the study and adherence to treat- ment were monitored prospectively and routinely throughout the trial.26

Study Measurements

Demographic data were collected at baseline. Clinical and laboratory data were obtained at baseline and every 3 months thereafter. A struc- tured interview was used in both groups every 3 months to obtain self-reported cardiovascular disease outcomes. Although the interviewers were aware of the study-group assignments, they used the same format for interviews in the two groups to minimize ascertainment bias. Medical records and electrocardiograms were obtained for documentation of events. Whenever clinical- site staff became aware of a death, a standard protocol was used to obtain information on the event.

Serious adverse events were defined as events that were fatal or life-threatening, that resulted in clinically significant or persistent disability, that required or prolonged a hospitalization, or that were judged by the investigator to represent a clinically significant hazard or harm to the participant that might require medical or surgi- cal intervention to prevent one of the other events listed above.30,31 A short list of monitored conditions were reported as adverse events if they were evaluated in an emergency department:

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hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia. We also moni- tored occurrences of acute kidney injury or acute renal failure if they were noted on admission or occurred during a hospitalization and were re- ported in the hospital discharge summary as a primary or main secondary diagnosis. The Medi- cal Dictionary for Regulatory Activities was used to classify the safety events. Coding was performed at the coordinating center, and up to three codes were assigned to each safety event. The relation- ship of serious adverse events to the intervention was assessed by the trial safety officer and re- viewed monthly by the safety committee.

Study Outcomes

Definitions of study outcomes are outlined in the Supplementary Appendix. A committee whose members were unaware of the study-group as- signments adjudicated the clinical outcomes specified in the protocol. The primary hypothe- sis was that treatment to reach a systolic blood- pressure target of less than 120 mm Hg, as compared with a target of less than 140 mm Hg, would result in a lower rate of the composite outcome of myocardial infarction, acute coro- nary syndrome not resulting in myocardial in- farction, stroke, acute decompensated heart failure, or death from cardiovascular causes. Secondary outcomes included the individual components of the primary composite outcome, death from any cause, and the composite of the primary outcome or death from any cause.

We also assessed renal outcomes, using a dif- ferent definition for patients with chronic kidney disease (eGFR <60 ml per minute per 1.73 m2) at baseline and those without it. The renal outcome in participants with chronic kidney disease at baseline was a composite of a decrease in the eGFR of 50% or more (confirmed by a subse- quent laboratory test) or the development of ESRD requiring long-term dialysis or kidney transplantation. In participants without chronic kidney disease at baseline, the renal outcome was defined by a decrease in the eGFR of 30% or more to a value of less than 60 ml per minute per 1.73 m2. Incident albuminuria, defined for all study participants by a doubling of the ratio of urinary albumin (in milligrams) to creatinine (in grams) from less than 10 at baseline to greater than 10 during follow-up, was also a prespecified renal outcome.

Prespecified subgroups of interest for all out- comes were defined according to status with re- spect to cardiovascular disease at baseline (yes vs. no), status with respect to chronic kidney disease at baseline (yes vs. no), sex, race (black vs. non- black), age (<75 vs. ≥75 years), and baseline sys- tolic blood pressure in three levels (≤132 mm Hg, >132 to <145 mm Hg, and ≥145 mm Hg). We also planned a comparison of the effects of systolic blood-pressure targets on incident de- mentia, changes in cognitive function, and cere- bral small-vessel ischemic disease; these results are not presented here.

Statistical Analysis

We planned a 2-year recruitment period, with a maximum follow-up of 6 years, and anticipated a loss to follow-up of 2% per year. With an en- rollment target of 9250 participants, we estimated that the trial would have 88.7% power to detect a 20% effect with respect to the primary out- come, assuming an event rate of 2.2% per year in the standard-treatment group.

Our primary analysis compared the time to the first occurrence of a primary outcome event between the two study groups with the use of the intention-to-treat approach for all randomly assigned participants; for this analysis, we used Cox proportional-hazards regression with two- sided tests at the 5% level of significance, with stratification according to clinic. Follow-up time was censored on the date of last event ascertain- ment. Interactions between treatment effect and prespecified subgroups were assessed with a likelihood-ratio test for the interaction with the use of Hommel-adjusted P values.32 Interim analyses were performed for each meeting of the data and safety monitoring board, with group- sequential stopping boundaries defined with the use of the Lan–DeMets method with an O’Brien– Fleming–type spending function.33 The Fine– Gray model for the competing risk of death was used as a sensitivity analysis.34

R e s u l t s

Study Participants

A total of 9361 participants were enrolled be- tween November 2010 and March 2013 (Fig. 1). Descriptive baseline statistics are presented in Table 1. On August 20, 2015, the NHLBI director accepted a recommendation from the data and

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safety monitoring board of the trial to inform the investigators and participants of the cardio- vascular-outcome results after analyses of the primary outcome exceeded the monitoring bound- ary at two consecutive time points (Fig. S3 in the Supplementary Appendix), thus initiating the process to end the blood-pressure intervention early. The median follow-up on August 20, 2015, was 3.26 years of the planned average of 5 years.

Blood Pressure

The two treatment strategies resulted in a rapid and sustained between-group difference in sys- tolic blood pressure (Fig. 2). At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard-treatment group, for an average difference of 14.8 mm Hg. The mean diastolic blood pressure at 1 year was 68.7 mm Hg in the intensive-treatment group and 76.3 mm Hg in the standard-treatment group (Fig. S4 in the Supple- mentary Appendix). Throughout the 3.26 years of follow-up, the mean systolic blood pressure was 121.5 mm Hg in the intensive-treatment group and 134.6 mm Hg in the standard-treat- ment group, and the mean number of blood- pressure medications was 2.8 and 1.8, respec- tively. The relative distribution of antihypertensive medication classes used was similar in the two groups, though the use of each class was greater in the intensive-treatment group (Table S2 in the Supplementary Appendix).

Clinical Outcomes

A primary outcome event was confirmed in 562 participants — 243 (1.65% per year) in the inten- sive-treatment group and 319 (2.19% per year) in the standard-treatment group (hazard ratio with intensive treatment, 0.75; 95% confidence inter- val [CI], 0.64 to 0.89; P<0.001) (Table 2). Separa- tion in the primary outcome between the groups was apparent at 1 year (Fig. 3A). The between- group differences were consistent across the components of the primary outcome and other prespecified secondary outcomes (Table 2).

A total of 365 deaths occurred — 155 in the intensive-treatment group and 210 in the stan- dard-treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P = 0.003). Separation in mortality between the groups became apparent at ap- proximately 2 years (Fig. 3B). Causes of death are provided in Table S3 in the Supplementary Ap-

pendix. The relative risk of death from cardiovas- cular causes was 43% lower with the intensive intervention than with the standard treatment (P = 0.005) (Table 2).

The numbers needed to treat to prevent a primary outcome event, death from any cause, and death from cardiovascular causes during the median 3.26 years of the trial were 61, 90, and 172, respectively. The effects of the intervention on the rate of the primary outcome and on the rate of death from any cause were consistent across the prespecified subgroups (Fig. 4, and Fig. S5 in the Supplementary Appendix). There were no significant interactions between treat- ment and subgroup with respect to the primary outcome or death from any cause. When death

Figure 1. Eligibility, Randomization, and Follow-up.

Discontinued intervention refers to participants who discontinued the study treatment but did not withdraw consent or become lost to followup.

9361 Underwent randomization

14,692 Patients were assessed for eligibility

5331 Were ineligible or declined to participate 34 Were <50 yr of age

352 Had low systolic blood pressure at 1 min after standing

2284 Were taking too many medications or had systolic blood pressure that was out of range

718 Were not at increased cardiovascular risk

703 Had miscellaneous reasons 587 Did not give consent 653 Did not complete screening

4678 Were assigned to intensive treatment

4683 Were assigned to standard treatment

224 Discontinued intervention 111 Were lost to follow-up 154 Withdrew consent

242 Discontinued intervention 134 Were lost to follow-up 121 Withdrew consent

4678 Were included in the analysis 4683 Were included in the analysis

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Characteristic Intensive Treatment

(N = 4678) Standard Treatment

(N = 4683)

Criterion for increased cardiovascular risk — no. (%)†

Age ≥75 yr 1317 (28.2) 1319 (28.2)

Chronic kidney disease‡ 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)

Framingham 10yr cardiovascular disease risk score ≥15% 2870 (61.4) 2867 (61.2)

Female sex — no. (%) 1684 (36.0) 1648 (35.2)

Age — yr

Overall 67.9±9.4 67.9±9.5

Among those ≥75 yr of age 79.8±3.9 79.9±4.1

Race or ethnic group — no. (%)§

NonHispanic black 1379 (29.5) 1423 (30.4)

Hispanic 503 (10.8) 481 (10.3)

NonHispanic white 2698 (57.7) 2701 (57.7)

Other 98 (2.1) 78 (1.7)

Black race§¶ 1454 (31.1) 1493 (31.9)

Baseline blood pressure — mm Hg

Systolic 139.7±15.8 139.7±15.4

Diastolic 78.2±11.9 78.0±12.0

Distribution of systolic blood pressure — no. (%)

≤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)

Serum creatinine — mg/dl 1.07±0.34 1.08±0.34

Estimated GFR — ml/min/1.73 m2

Among all participants 71.8±20.7 71.7±20.5

Among those with estimated GFR ≥60 ml/min/1.73 m2 81.3±15.5 81.1±15.5

Among those with estimated GFR <60 ml/min/1.73 m2 47.8±9.5 47.9±9.5

Ratio of urinary albumin (mg) to creatinine (g) 44.1±178.7 41.1±152.9

Fasting total cholesterol — mg/dl 190.2±41.4 190.0±40.9

Fasting HDL cholesterol — mg/dl 52.9±14.3 52.8±14.6

Fasting total triglycerides — mg/dl 124.8±85.8 127.1±95.0

Fasting plasma glucose — mg/dl 98.8±13.7 98.8±13.4

Statin use — no./total no. (%) 1978/4645 (42.6) 2076/4640 (44.7)

Aspirin use — no./total no. (%) 2406/4661 (51.6) 2350/4666 (50.4)

Smoking status — no. (%)

Never smoked 2050 (43.8) 2072 (44.2)

Former smoker 1977 (42.3) 1996 (42.6)

Current smoker 639 (13.7) 601 (12.8)

Missing data 12 (0.3) 14 (0.3)

Framingham 10yr cardiovascular disease risk score — % 20.1±10.9 20.1±10.8

Table 1. Baseline Characteristics of the Study Participants.*

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was treated as a competing risk in a Fine–Gray model, the results with respect to the primary outcome were virtually unchanged (hazard ratio, 0.76; 95% CI, 0.64 to 0.89).

Among participants who had chronic kidney disease at baseline, no significant between-group difference in the composite outcome of a de- crease in the eGFR of 50% or more or the devel- opment of ESRD was noted, though the number of events was small (Table 2). Among partici- pants who did not have chronic kidney disease at baseline, the incidence of the outcome defined by a decrease in the eGFR of 30% or more to a value of less than 60 ml per minute per 1.73 m2 was higher in the intensive-treatment group than in the standard-treatment group (1.21% per year vs. 0.35% per year; hazard ratio, 3.49; 95% CI, 2.44 to 5.10; P<0.001).

Serious Adverse Events

Serious adverse events occurred in 1793 partici- pants in the intensive-treatment group (38.3%) and in 1736 participants in the standard-treat- ment group (37.1%) (hazard ratio with intensive treatment, 1.04; P = 0.25) (Table 3, and Table S4 in the Supplementary Appendix). Serious adverse events of hypotension, syncope, electrolyte ab- normalities, and acute kidney injury or acute renal failure, but not injurious falls or bradycar- dia, occurred more frequently in the intensive- treatment group than in the standard-treatment group. Orthostatic hypotension as assessed dur- ing 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 standard- treatment group (2.5%) had serious adverse events that were classified as possibly or defi- nitely related to the intervention (hazard ratio, 1.88; P<0.001) (Table S5 in the Supplementary Appendix). The magnitude and pattern of differ- ences in adverse events according to treatment assignment among participants 75 years of age or older were similar to those in the overall co- hort (Table S6 in the Supplementary Appendix).

D i s c u s s i o n

SPRINT showed that among adults with hyperten- sion 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 as- signed 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 inten- sive-treatment group had lower rates of several other important outcomes, including heart fail- ure (38% lower relative risk), death from cardio- vascular 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 control to

Characteristic Intensive Treatment

(N = 4678) Standard Treatment

(N = 4683)

Bodymass index‖ 29.9±5.8 29.8±5.7

Antihypertensive agents — no./patient 1.8±1.0 1.8±1.0

Not using antihypertensive agents — no. (%) 432 (9.2) 450 (9.6)

* Plus–minus 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 glomer ular filtration rate, and HDL highdensity 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 bodysurface area. § Race and ethnic group were selfreported. ¶ Black race includes Hispanic black and black as part of a multiracial identification. ‖ The bodymass index is the weight in kilograms divided by the square of the height in meters.

Table 1. (Continued.)

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prevent one primary outcome event was 61, and the number needed to treat to prevent one death from any cause was 90. These benefits with re- spect to both the primary outcome and death were consistent across all prespecified subgroups, including participants 75 years of age or older.

Owing in part to a lower-than-expected de- cline in the eGFR and to the early termination of the trial, the number of renal events was small. Among participants who had chronic kidney disease at baseline, the number of participants with a decrease in the eGFR of 50% or more or reaching ESRD over the course of the trial did not differ significantly between the two interven- tion groups. Among participants who did not have chronic kidney disease at baseline, a decrease in the eGFR of 30% or more to a value of less than 60 ml per minute per 1.73 m2 occurred more frequently in the intensive-treatment group than in the standard-treatment group (1.21% per year vs. 0.35% per year). Among all participants, acute kidney injury or acute renal failure occurred

more frequently in the intensive-treatment group than in the standard-treatment group (Table 3, and Table S5 in the Supplementary Appendix). The differences in adverse renal outcomes may be related to a reversible intrarenal hemody- namic effect of the greater reduction in blood pressure and greater use of diuretics, angioten- sin-converting–enzyme inhibitors, and angio- tensin-receptor blockers in the intensive-treat- ment group.35,36 With the currently available data, there is no evidence of substantial permanent kidney injury associated with the lower systolic blood-pressure goal; however, the possibility of a long-term adverse renal outcome cannot be ex- cluded. These observations and hypotheses need to be explored further in analyses that incorpo- rate more clinical outcomes and longer follow-up.

The results of SPRINT add substantially to the evidence of benefits of lowering systolic blood pressure, especially in older patients with hypertension. Trials such as the Systolic Hyper- tension in the Elderly Program trial,17 the Sys-

Figure 2. Systolic Blood Pressure in the Two Treatment Groups over the Course of the Trial.

The systolic bloodpressure target in the intensivetreatment group was less than 120 mm Hg, and the target in the standardtreatment group was less than 140 mm Hg. The mean number of medications is the number of blood pressure medications administered at the exit of each visit. I bars represent 95% confidence intervals.

S ys

to lic

B lo

o d

P re

ss u

re (

m m

H g)

150

140

130

110

120

0 1 2 3 4 5

Years

No. with Data Standard treatment Intensive treatment

1000 1048

3115 3204

3997 4029

4222 4231

4683 4678

1974 2035

3904 3920

4092 4091

4345 4375

274 286

Mean No. of Medications Standard treatment Intensive treatment

1.9 2.3

1.8 2.7

1.8 2.8

1.9 3.0

Intensive treatment

Standard treatment�

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tolic Hypertension in Europe trial,11 and the Hypertension in the Very Elderly Trial18 showed the benefits of lowering systolic blood pressure below 150 mm Hg. However, trials evaluating systolic blood-pressure levels lower than those studied in these trials have been either under- powered19-21 or performed without specific sys- tolic blood-pressure targets.37 A major component of the controversy regarding the selection of the systolic blood-pressure goal in this population has resulted from inadequate data on the risks versus benefits of systolic blood-pressure targets below 150 mm Hg.11,17-21,37 SPRINT now provides evidence of benefits for an even lower systolic

blood-pressure target than that currently recom- mended in most patients with hypertension.

Comparisons between SPRINT and the ACCORD trial22 are inevitable, because the trials examined identical systolic blood-pressure tar- gets (<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 differ- ences between these trials should be noted. The ACCORD trial enrolled participants with diabe- tes exclusively, whereas SPRINT excluded par- ticipants with diabetes; in addition, the sample

Outcome Intensive Treatment Standard Treatment Hazard Ratio

(95% CI) P Value

no. of patients (%) % per year no. of patients (%) % per year

All participants (N = 4678) (N = 4683)

Primary outcome† 243 (5.2) 1.65 319 (6.8) 2.19 0.75 (0.64–0.89) <0.001

Secondary outcomes

Myocardial infarction 97 (2.1) 0.65 116 (2.5) 0.78 0.83 (0.64–1.09) 0.19

Acute coronary syndrome 40 (0.9) 0.27 40 (0.9) 0.27 1.00 (0.64–1.55) 0.99

Stroke 62 (1.3) 0.41 70 (1.5) 0.47 0.89 (0.63–1.25) 0.50

Heart failure 62 (1.3) 0.41 100 (2.1) 0.67 0.62 (0.45–0.84) 0.002

Death from cardiovascular causes 37 (0.8) 0.25 65 (1.4) 0.43 0.57 (0.38–0.85) 0.005

Death from any cause 155 (3.3) 1.03 210 (4.5) 1.40 0.73 (0.60–0.90) 0.003

Primary outcome or death 332 (7.1) 2.25 423 (9.0) 2.90 0.78 (0.67–0.90) <0.001

Participants with CKD at baseline (N = 1330) (N = 1316)

Composite renal outcome‡ 14 (1.1) 0.33 15 (1.1) 0.36 0.89 (0.42–1.87) 0.76

≥50% reduction in estimated GFR§ 10 (0.8) 0.23 11 (0.8) 0.26 0.87 (0.36–2.07) 0.75

Longterm dialysis 6 (0.5) 0.14 10 (0.8) 0.24 0.57 (0.19–1.54) 0.27

Kidney transplantation 0 0

Incident albuminuria¶ 49/526 (9.3) 3.02 59/500 (11.8) 3.90 0.72 (0.48–1.07) 0.11

Participants without CKD at baseline‖ (N = 3332) (N = 3345)

≥30% reduction in estimated GFR to <60 ml/ min/1.73 m2§

127 (3.8) 1.21 37 (1.1) 0.35 3.49 (2.44–5.10) <0.001

Incident albuminuria¶ 110/1769 (6.2) 2.00 135/1831 (7.4) 2.41 0.81 (0.63–1.04) 0.10

* CI denotes confidence interval, and CKD chronic kidney disease. † The primary outcome was the first occurrence of myocardial infarction, acute coronary syndrome, stroke, heart failure, or death from cardio

vascular causes. ‡ The composite renal outcome for participants with CKD at baseline was the first occurrence of a reduction in the estimated GFR of 50% or

more, longterm dialysis, or kidney transplantation. § Reductions in the estimated GFR were confirmed by a second laboratory test at least 90 days later. ¶ Incident albuminuria was defined by a doubling of the ratio of urinary albumin (in milligrams) to creatinine (in grams) from less than 10 at

baseline to greater than 10 during followup. The denominators for number of patients represent those without albuminuria at baseline. ‖ No longterm dialysis or kidney transplantation was reported among participants without CKD at baseline.

Table 2. Primary and Secondary Outcomes and Renal Outcomes.*

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size of the ACCORD trial was only half that of SPRINT (4733 vs. 9361). SPRINT enrolled an older cohort (mean age, 68 years, vs. 62 years in the ACCORD trial), with 28% of participants 75 years of age or older, and also included partici- pants with chronic kidney disease. The ACCORD trial showed a (nonsignificant) 12% lower risk of its primary composite cardiovascular out- come, with a 95% confidence interval that in- cluded the possibility of a 27% lower risk, which is consistent with the cardiovascular benefit

observed in SPRINT. The ACCORD trial also used a factorial design that included compari- sons of standard and intensive glycemic and lipid treatment targets in the same trial. A sec- ondary analysis of the ACCORD results showed that, as compared with the combined standard glycemia and blood-pressure treatments, inten- sive blood-pressure treatment alone reduced ma- jor cardiovascular outcomes by 26% without additional benefit from combining the two in- tensive treatments.38 Thus, the difference in re- sults between the trials could be due to differ- ences in study design, treatment interactions, or the play of chance. An inherent difference in the cardiovascular benefits of systolic blood-pressure lowering between the population with diabetes and the population without diabetes seems un- likely but cannot be ruled out.

In the Secondary Prevention of Small Sub- cortical Strokes trial (intensive systolic blood- pressure goal <130 mm Hg)23 and in the ACCORD trial (intensive systolic blood-pressure goal <120 mm Hg), the lower blood-pressure target was associated with a nonsignificant 19% lower incidence of stroke (P = 0.08) and a signifi- cant 41% lower incidence of stroke, respectively, than the incidence with higher targets. The intensive-treatment group in SPRINT had a non- significant 11% lower incidence of stroke, though SPRINT also excluded persons with prevalent stroke or transient ischemic attack at baseline.

In SPRINT, significant between-group differ- ences were noted in some adverse effects that were attributed to the intervention (Table S5 in the Supplementary Appendix). Orthostatic hypo- tension as assessed during a clinic visit (Table 3) was observed less frequently in the intensive- treatment group than in the standard-treatment group (P = 0.01), but syncope was more common among participants in the intensive-treatment group than among those in the standard-treat- ment group (3.5% vs. 2.4%, P = 0.003), as was hypotension (3.4% vs. 2.0%, P<0.001). There was no between-group difference in injurious falls (hazard ratio, 1.00; P = 0.97). There was a higher rate of acute kidney injury or acute renal failure in the intensive-treatment group, as noted above. These adverse events need to be weighed against the benefits with respect to cardiovascular events and death that are associated with intensive con- trol of systolic blood pressure.

Figure 3. Primary Outcome and Death from Any Cause.

Shown are the cumulative hazards for the primary outcome (a composite of myocardial infarction, acute coronary syndrome, stroke, heart failure, or death from cardiovascular causes) (Panel A) and for death from any cause (Panel B). The inset in each panel shows the same data on an enlarged y axis. CI denotes confidence interval.

C u

m u

la ti

ve H

az ar

d 1.0

0.8

0.6

0.4

0.2

0.0 0 1 2 3 4 5

Years

B Death from Any Cause

A Primary Outcome

No. at Risk Standard treatment Intensive treatment

4683 4678

4437 4436

4228 4256

2829 2900

721 779

Standard treatment

0.10

0.08

0.06

0.04

0.02

0.00 0 1 2 3 4 5

Hazard ratio with intensive treatment, 0.75 (95% CI, 0.64–0.89)

Intensive treatment

C u

m u

la ti

ve H

az ar

1.0

0.8

0.6

0.4

0.2

0.0 0 1 2 3 4 5

Years

No. at Risk Standard treatment Intensive treatment

4683 4678

4528 4516

4383 4390

2998 3016

789 807

Standard treatment

0.10

0.08

0.06

0.04

0.02

0.00 0 1 2 3 4 5

Hazard ratio with intensive treatment, 0.73 (95% CI, 0.60–0.90)

Intensive treatment

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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 popula- tions not included in the study — such as per- sons with diabetes, those with prior stroke, and those younger than 50 years of age — is a limi- tation. 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 ner- vous 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 of less than 140/90 mm Hg is achieved in only about 50% of the general population in the

United States, which suggests that control to even that level is challenging.39 We excluded patients with more severe hypertension, and control of systolic blood pressure to less than 120 mm Hg required, on average, one additional antihyper- tensive drug. In addition, the median systolic blood pressure in the intensive-treatment group was just above 120 mm Hg, which indicates that more than half the participants had a systolic blood pressure above the 120 mm Hg target. These observations suggest that achieving a sys- tolic blood-pressure goal of less than 120 mm Hg in the overall population of patients with hypertension would be more demanding and time-consuming for both providers and patients than achieving a goal of 140 mm Hg, and would necessitate increased medication costs and clin- ic visits.

In conclusion, targeting a systolic blood pres- sure of less than 120 mm Hg, as compared with less than 140 mm Hg, in patients at high risk for

Figure 4. Forest Plot of Primary Outcome According to Subgroups.

The dashed vertical line represents the hazard ratio for the overall study population. The box sizes are proportional to the precision of the estimates (with larger boxes indicating a greater degree of precision). The subgroup of no previous chronic kidney disease (CKD) includes some participants with unknown CKD status at baseline. Black race includes Hispanic black and black as part of a multiracial identification.

0.75 1.00 1.20

Standard Treatment BetterIntensive Treatment Better

Overall

Previous CKD

Yes

Age

<75 yr

≥75 yr

Sex

Female

Male

Race

Black

Nonblack

Previous cardiovascular disease

Yes

Systolic blood pressure

≤132 mm Hg

>132 to <145 mm Hg

≥145 mm Hg

Intensive Treatment Hazard Ratio (95% CI)Standard TreatmentSubgroup

0.77 (0.57–1.03) 0.83 (0.63–1.09)

0.70 (0.51–0.95)

0.71 (0.57–0.88) 0.83 (0.62–1.09)

0.77 (0.55–1.06)

0.74 (0.61–0.90)

0.72 (0.59–0.88)

0.84 (0.62–1.14)

0.80 (0.64–1.00) 0.67 (0.51–0.86)

0.82 (0.63–1.07)

0.75 (0.64–0.89)

0.50

0.70 (0.56–0.87)

P Value for Interaction

0.36

0.32

0.45

0.83

0.39

0.77

no. of patients with primary outcome/total no. (%)

243/4678 (5.2)

135/3348 (4.0)

108/1330 (8.1)

142/3361 (4.2)

101/1317 (7.7)

77/1684 (4.6)

166/2994 (5.5)

62/1454 (4.3)

181/3224 (5.6)

149/3738 (4.0)

94/940 (10.0)

71/1583 (4.5)

77/1489 (5.2)

95/1606 (5.9)

319/4683 (6.8)

193/3367 (5.7)

126/1316 (9.6)

175/3364 (5.2)

144/1319 (10.9)

89/1648 (5.4)

230/3035 (7.6)

85/1493 (5.7)

234/3190 (7.3)

208/3746 (5.6)

111/937 (11.8)

98/1553 (6.3)

106/1549 (6.8)

115/1581 (7.3)

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cardiovascular events but without diabetes re- sulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause. However, some adverse events occurred signifi- cantly more frequently with the lower target.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH), the Department of Veterans Affairs, or the U.S. Government.

Supported by contracts (HHSN268200900040C, HHSN268200900046C, HHSN268200900047C,

Variable Intensive Treatment

(N = 4678) Standard Treatment

(N = 4683) Hazard Ratio P Value

no. of patients (%)

Serious adverse event* 1793 (38.3) 1736 (37.1) 1.04 0.25

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

Bradycardia 87 (1.9) 73 (1.6) 1.19 0.28

Electrolyte abnormality 144 (3.1) 107 (2.3) 1.35 0.02

Injurious fall† 105 (2.2) 110 (2.3) 0.95 0.71

Acute kidney injury or acute renal failure‡ 193 (4.1) 117 (2.5) 1.66 <0.001

Emergency department visit or serious adverse event

Hypotension 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

Acute kidney injury or acute renal failure‡ 204 (4.4) 120 (2.6) 1.71 <0.001

Monitored clinical events

Adverse laboratory measure§

Serum sodium <130 mmol/liter 180 (3.8) 100 (2.1) 1.76 <0.001

Serum sodium >150 mmol/liter 6 (0.1) 0 0.02

Serum potassium <3.0 mmol/liter 114 (2.4) 74 (1.6) 1.50 0.006

Serum potassium >5.5 mmol/liter 176 (3.8) 171 (3.7) 1.00 0.97

Orthostatic hypotension¶

Alone 777 (16.6) 857 (18.3) 0.88 0.01

With dizziness 62 (1.3) 71 (1.5) 0.85 0.35

* A serious adverse event was defined as an event that was fatal or lifethreatening, 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 quar terly 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.

Table 3. Serious Adverse Events, Conditions of Interest, and Monitored Clinical Events.

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HHSN268200900048C, and HHSN268200900049C) and an inter- agency agreement (A-HL-13-002-001) from the NIH, including the National Heart, Lung, and Blood Institute (NHLBI), the Na- tional 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 fund- ed by the National Center for Advancing Translational Sciences of the NIH (Case Western Reserve University: UL1TR000439; Ohio State University: UL1RR025755; University of Pennsyl- vania: UL1RR024134 and UL1TR000003; Boston University: UL1RR025771; Stanford University: UL1TR000093; Tufts Univer- sity: UL1RR025752, UL1TR000073, and UL1TR001064; University

of Illinois: UL1TR000050; University of Pittsburgh: UL1TR000005; University of Texas Southwestern: 9U54TR000017-06; University of Utah: UL1TR000105-05; Vanderbilt University: UL1TR000445; George Washington University: UL1TR000075; University of Cali- fornia, Davis: UL1TR000002; University of Florida: UL1TR000064; University of Michigan: UL1TR000433; and Tulane University: P30GM103337 COBRE Award NIGMS). The trial was also sup- ported in part with respect to resources and the use of facilities by the Department of Veterans Affairs.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the study participants, without whom this trial would not have been possible.

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; Depart- ment 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 Hema- tologic 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 Medi- cine, University of Tennessee Health Science Center (K.C.J.), and the Preventive Medicine Section, VA Medical Center (W.C.C.), Mem- phis; 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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