Quantitative Research: Article Summary

n engl j med 373;22 nejm.org November 26, 2015 2103 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 ar ticle. The aff iliations 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 44106 ­6053, 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 Supplementar y Appendix, available at NEJM.org.

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

N Engl J Med 2015;373:2103-16.

DOI: 10.1056/NEJMoa1511939 Copyright © 2015 Massachusetts Medical Society. BACKGROUND The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidit y and mortalit y 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 primar y composite outcome was myocardial infarction, other acute coronar y syndromes, stroke, heart failure, or death from cardiovascular causes.

RE SULT S 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 inter ven - tion was stopped early after a median follow-up of 3.26 years owing to a signif i - cantly lower rate of the primar y 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% conf idence inter val [CI], 0.64 to 0.89; P<0.001). All-cause mortalit y was also signif icantly 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 injur y 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 signif icantly higher rates of some adverse events were obser ved in the intensive-treatment group. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01206062.) abstr act A Randomized Trial of Intensive versus Standard Blood-Pressure Control The SPRINT Research Group* The new england journal of medicine The New England Journal of Medicine Downloaded from nejm.org on December 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. n engl j med 373;22 nejm.org November 26, 2015 2104 The new england journal of medicine H ypertension is highly pr evalent 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 coronar y events, stroke, heart failure, and end-stage renal disease (ESRD). 5 -1 3 The Global Burden of Disease Study identif ied elevated blood pressure as the leading risk fac - tor, among 67 studied, for death and disabilit y- 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. Obser vational 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 benef it of treatment to achieve a systolic blood- pressure target of less than 150 mm Hg, with limited data concerning lower blood-pressure targets. 1 1 ,17-2 1 In a trial involving patients with t ype 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 signif icant benef it of the lower target with respect to the overall risk of another stroke but a signif icant benef it 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 complicat ions among patients without diabetes. 24 The current article describes the primar y results of the Sys - tolic Blood Pressure Inter vention Trial (SPRINT), which compared the benef it 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. Methods 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 net works) in the United States, including Puerto Rico (see the Supplementar y Appendix, available with the full text of this article at NEJM.org). A trial coordi - nating center ser ved as a data and biostatistical core center and super vised the central laborator y, 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 safet y monitoring board monitored unblinded trial results and safet y 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 f idelit y 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 Supplementar y Appendix), and an increased risk A Quick Take is available at NEJM.orgThe New England Journal of Medicine Downloaded from nejm.org on December 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. n engl j med 373;22 nejm.org November 26, 2015 2105 Intensive vs. Standard Blood-Pressure Control of cardiovascular events. Increased cardiovascu - lar risk was def ined 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 f iltration rate (eGFR) of 20 to less than 60 ml per minute per 1.73 m 2 of body- surface area, calculated with the use of the four- variable Modif ication 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 Supplementar y 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 t ha n 120 mm Hg (the intensive-treatment group). Randomization was stratif ied according to clinical site. Participants and study personnel were aware of the study-group assignments, but outcome adjudicators were not. After the participants under went 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 formular y are listed in Figures S1 and S2 and Table S1 in the Supple - mentar y Appendix. All major classes of antihy - pertensive agents were included in the formular y 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-t ype diuretics (en - couraged as the f irst-line agent), loop diuretics (for participants with advanced chronic kidney disease), and beta-adrenergic blockers (for those with coronar y arter y disease). 5,27 Chlorthalidone was encouraged as the primar y thiazide-t ype 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 f irst 3 months and ever y 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 t wo consecutive visits. Dose adjustment was based on a mean of three blood-pressure measure - ments at an off ice 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). Lifest yle modif ication was encouraged as part of the management strateg y.

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 laborator y data were obtained at baseline and ever y 3 months thereafter. A struc - tured inter view was used in both groups ever y 3 months to obtain self-reported cardiovascular disease outcomes. Although the inter viewers were aware of the study-group assignments, they used the same format for inter views in the t wo 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 def ined as events that were fatal or life-threatening, that resulted in clinically signif icant or persistent disability, that required or prolonged a hospitalization, or that were judged by the investigator to represent a clinically signif icant hazard or harm to the participant that might require medical or surgi - cal inter vention 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: The New England Journal of Medicine Downloaded from nejm.org on December 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. n engl j med 373;22 nejm.org November 26, 2015 2106 The new england journal of medicine hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia. We also moni - tored occurrences of acute kidney injur y or acute renal failure if they were noted on admission or occurred during a hospitalization and were re - ported in the hospital discharge summar y as a primar y or main secondar y diagnosis. The Medi- cal Dictionary for Regulatory Activities was used to classif y the safet y events. Coding was performed at the coordinating center, and up to three codes were assigned to each safet y event. The relation - ship of serious adverse events to the inter vention was assessed by the trial safet y off icer and re - viewed monthly by the safet y committee.

Study Outcomes Def initions of study outcomes are outlined in the Supplementar y Appendix. A committee whose members were unaware of the study-group as - signments adjudicated the clinical outcomes specif ied in the protocol. The primar y 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 - nar y syndrome not resulting in myocardial in - farction, stroke, acute decompensated heart failure, or death from cardiovascular causes.

Secondar y outcomes included the individual components of the primar y composite outcome, death from any cause, and the composite of the primar y outcome or death from any cause. We also assessed renal outcomes, using a dif - ferent def inition for patients with chronic kidney disease (eGFR <60 ml per minute per 1.73 m 2) 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 (conf irmed by a subse - quent laborator y 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 def ined by a decrease in the eGFR of 30% or more to a value of less than 60 ml per minute per 1.73 m 2. Incident albuminuria, def ined 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 prespecif ied renal outcome. Prespecif ied subgroups of interest for all out - comes were def ined 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 primar y out - come, assuming an event rate of 2.2% per year in the standard-treatment group. Our primar y analysis compared the time to the f irst occurrence of a primar y outcome event bet ween the t wo 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 t wo- sided tests at the 5% level of signif icance, with stratif ication according to clinic. Follow-up time was censored on the date of last event ascertain - ment. Interactions bet ween treatment effect and prespecif ied 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 safet y monitoring board, with group- sequential stopping boundaries def ined with the use of the Lan–DeMets method with an O’Brien– Fleming–t ype spending function. 33 The Fine– Gray model for the competing risk of death was used as a sensitivit y analysis. 34 Results Study Participants A total of 9361 participants were enrolled be - t ween 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 The New England Journal of Medicine Downloaded from nejm.org on December 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. n engl j med 373;22 nejm.org November 26, 2015 2107 Intensive vs. Standard Blood-Pressure Control safet y monitoring board of the trial to inform the investigators and participants of the cardio - vascular-outcome results after analyses of the primar y outcome exceeded the monitoring bound - ar y at t wo consecutive time points (Fig. S3 in the Supplementar y Appendix), thus initiating the process to end the blood-pressure inter vention early. The median follow-up on August 20, 2015, was 3.26 years of the planned average of 5 years.

Blood Pressure The t wo treatment strategies resulted in a rapid and sustained bet ween-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 - mentar y 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 t wo groups, though the use of each class was greater in the intensive-treatment group (Table S2 in the Supplementary Appendix).

Clinic al Outcomes A primar y outcome event was conf irmed 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% conf idence inter - val [CI], 0.64 to 0.89; P<0.001) (Table 2). Separa - tion in the primar y outcome bet ween the groups was apparent at 1 year (Fig. 3A). The bet ween- group differences were consistent across the components of the primar y outcome and other prespecif ied secondar y 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 mortalit y bet ween the groups became apparent at ap - proximately 2 years (Fig. 3B). Causes of death are provided in Table S3 in the Supplementar y Ap -pendix. The relative risk of death from cardiovas - cular causes was 43% lower with the intensive inter vention than with the standard treatment (P = 0.005) (Table 2).

The numbers needed to treat to prevent a primar y 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 inter vention on the rate of the primar y outcome and on the rate of death from any cause were consistent across the prespecif ied subgroups (Fig. 4, and Fig. S5 in the Supplementar y Appendix). There were no signif icant interactions bet ween treat - ment and subgroup with respect to the primar y 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 follow ­up. 9361 Underwent ran\,domization 14,69\f Patients were\, assessed for e\bigibi\bity 5331 Were ine\bigib\b\,e or dec\binedto participate 34 Were <50 yr of ag\,e 35\f Had \bow systo\bic \,b\bood pressure at 1 min a\,fter standing \f\f84 Were taking to\,o many medications or had \,systo\bic b\bood pressure that \,was out of range 718 Were not at in\,creased cardiovascu\bar risk 703 Had misce\b\baneou\,s reasons 587 Did not give c\,onsent 653 Did not comp\bet\,e screening 4678 Were assigned \,to intensive treatment 4683 Were assigned \,to standard treatment \f\f4 Discontinued int\,ervention 111 Were \bost to fo\b\,\bow-up 154 Withdrew consen\,t \f4\f Discontinued int\,ervention 134 Were \bost to fo\b\,\bow-up 1\f1 Withdrew consen\,t 4678 Were inc\buded \,in the ana\bysis 4683 Were inc\buded \,in the ana\bysisThe New England Journal of Medicine Downloaded from nejm.org on December 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. n engl j med 373;22 nejm.org November 26, 2015 2108 The new england journal of medicine 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±9.467.9±9.5 Among those ≥75 yr of age 79.8±3.979.9±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±15.8139.7±15.4 Diastolic 78.2±11.978.0±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±0.341.08±0.34 Estimated GFR — ml/min/1.73 m 2 Among all participants 71.8±20.771.7±20.5 Among those with estimated GFR ≥60 ml/min/1.73 m 2 81.3±15.5 81.1±15.5 Among those with estimated GFR <60 ml/min/1.73 m 2 47.8±9.5 47.9±9.5 Ratio of urinary albumin (mg) to creatinine (g) 44.1±178.741.1±152.9 Fasting total cholesterol — mg/dl 190.2±41.4190.0±40.9 Fasting HDL cholesterol — mg/dl 52.9±14.352.8±14.6 Fasting total triglycerides — mg/dl 124.8±85.8127.1±95.0 Fasting plasma glucose — mg/dl 98.8±13.798.8±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±10.920.1±10.8 Table 1. Baseline Characteristics of the Study Participants.*The New England Journal of Medicine Downloaded from nejm.org on December 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. n engl j med 373;22 nejm.org November 26, 2015 2109 Intensive vs. Standard Blood-Pressure Control was treated as a competing risk in a Fine–Gray model, the results with respect to the primar y 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 signif icant bet ween-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 def ined by a decrease in the eGFR of 30% or more to a value of less than 60 ml per minute per 1.73 m 2 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 injur y 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 signif icantly 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 classif ied as possibly or def i - nitely related to the inter vention (hazard ratio, 1.88; P<0.001) (Table S5 in the Supplementar y 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 Supplementar y Appendix). Discussion 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 signif icantly 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 primar y 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 strateg y of intensive blood-pressure control to Characteristic Intensive Treatment (N = 4678) Standard Treatment (N = 4683) Body­mass index‖ 29.9±5.829.8±5.7 Antihypertensive agents — no./patient 1.8±1.01.8±1.0 Not using antihypertensive agents — no. (%) 432 (9.2)450 (9.6) * Plus–minus values are means ±SD. There were no significant differe\�nces (P<0.05) between the two groups except for statin use (P = 0.04). To convert the values for creatinine to micromoles per liter, mu\�ltiply 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 m 2 of body­surface area.

§ Race and ethnic group were self­reported.

¶ Black race includes Hispanic black and black as part of a multiracial id\�entification.

‖ The body­mass index is the weight in kilograms divided by the square of the heigh\�t in meters. Table 1. (Continued.)The New England Journal of Medicine Downloaded from nejm.org on December 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. n engl j med 373;22 nejm.org November 26, 2015 2110 The new england journal of medicine prevent one primar y outcome event was 61, and the number needed to treat to prevent one death from any cause was 90. These benef its with re - spect to both the primar y outcome and death were consistent across all prespecif ied 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 signif icantly bet ween the t wo inter ven - 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 m 2 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 injur y 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 Supplementar y 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 injur y associated with the lower systolic blood-pressure goal; however, the possibilit y of a long-term adverse renal outcome cannot be ex - cluded. These obser vations 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 benef its 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 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 blood ­ pressure medications administered at the exit of each visit. I bars represent 95% conf idence intervals. Systolic Blood Pre\gssure (mm Hg\f 150 140 130 110 120 0 1 2 3 4 5 Years No\b with Data Standard treatment\v Intensive treatment\v 1000 104\f 3115 3204 3997 4029 4222 4231 46\f3 467\f 1974 2035 3904 3920 4092 4091 4345 4375 274 2\f6 Mean No\b of Medicati\gonsStandard treatment\v Intensive treatment\v1\b9 2\b3 1\b\f 2\b7 1\b\f 2\b\f 1\b\f 2\b\f 1\b\f 2\b\f 1\b\f 2\b\f 1\b\f 2\b\f 1\b\f 2\b\f 1\b\f 2\b\f 1\b9 3\b0 Intensive treatment\v Standard treatment\v The New England Journal of Medicine Downloaded from nejm.org on December 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. n engl j med 373;22 nejm.org November 26, 2015 2111 Intensive vs. Standard Blood-Pressure Control tolic Hypertension in Europe trial, 11 and the Hypertension in the Ver y Elderly Trial18 showed the benef its 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 - powered 1 9 -2 1 or performed without specif ic 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 benef its of systolic blood-pressure targets below 150 mm Hg. 11,17-21,37 SPRINT now provides evidence of benef its for an even lower systolic blood-pressure target than that currently recom - mended in most patients with hypertension. Comparisons bet ween SPRINT and the ACCORD trial 22 are inevitable, because the trials examined identical systolic blood-pressure tar - gets (<120 mm Hg vs. <140 mm Hg). In contrast to the f indings of SPRINT, the cardiovascular and mortalit y benef its obser ved in the ACCORD trial were not statistically signif icant and were of a lesser magnitude. Several important differ - ences bet ween 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 TreatmentStandard TreatmentHazard Ratio (95% CI) P Value no. of patients (%) % per yearno. of patients (%) % per year All participants (N = 4678) (N = 4683) Primary outcome† 243 (5.2)1.65319 (6.8) 2.190.75 (0.64–0.89) <0.001 Secondary outcomes Myocardial infarction 97 (2.1)0.65116 (2.5) 0.780.83 (0.64–1.09) 0.19 Acute coronary syndrome 40 (0.9)0.2740 (0.9) 0.271.00 (0.64–1.55) 0.99 Stroke 62 (1.3)0.4170 (1.5) 0.470.89 (0.63–1.25) 0.50 Heart failure 62 (1.3)0.41100 (2.1) 0.670.62 (0.45–0.84) 0.002 Death from cardiovascular causes 37 (0.8)0.2565 (1.4) 0.430.57 (0.38–0.85) 0.005 Death from any cause 155 (3.3)1.03210 (4.5) 1.400.73 (0.60–0.90) 0.003 Primary outcome or death 332 (7.1)2.25423 (9.0) 2.900.78 (0.67–0.90) <0.001 Participants with CKD at baseline (N = 1330) (N = 1316) Composite renal outcome‡ 14 (1.1)0.3315 (1.1) 0.360.89 (0.42–1.87) 0.76 ≥50% reduction in estimated GFR§ 10 (0.8)0.2311 (0.8) 0.260.87 (0.36–2.07) 0.75 Long­term dialysis 6 (0.5)0.1410 (0.8) 0.240.57 (0.19–1.54) 0.27 Kidney transplantation 00 Incident albuminuria¶ 49/526 (9.3)3.0259/500 (11.8) 3.900.72 (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 m 2§ 127 (3.8) 1.2137 (1.1) 0.353.49 (2.44–5.10) <0.001 Incident albuminuria¶ 110/1769 (6.2)2.00135/1831 (7.4) 2.410.81 (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, a\�cute coronary syndrome, stroke, heart failure, or death from cardio­ vascular causes.

‡ The composite renal outcome for participants with CKD at baseline was th\�e 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 te\�st at least 90 days later.

¶ Incident albuminuria was defined by a doubling of the ratio of urinary a\�lbumin (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 albu\�minuria 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.*The New England Journal of Medicine Downloaded from nejm.org on December 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. n engl j med 373;22 nejm.org November 26, 2015 2112 The new england journal of medicine 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 (nonsignif icant) 12% lower risk of its primar y composite cardiovascular out - come, with a 95% conf idence inter val that in - cluded the possibilit y of a 27% lower risk, which is consistent with the cardiovascular benef it obser ved 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 - ondar y 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 benef it from combining the t wo in - tensive treatments. 38 Thus, the difference in re - sults bet ween the trials could be due to differ - ences in study design, treatment interactions, or the play of chance. An inherent difference in the cardiovascular benef its of systolic blood-pressure lowering bet ween the population with diabetes and the population without diabetes seems un - likely but cannot be ruled out. In the Secondar y 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 nonsignif icant 19% lower incidence of stroke (P = 0.08) and a signif i - cant 41% lower incidence of stroke, respectively, than the incidence with higher targets. The intensive-treatment group in SPRINT had a non - signif icant 11% lower incidence of stroke, though SPRINT also excluded persons with prevalent stroke or transient ischemic attack at baseline. In SPRINT, signif icant bet ween-group differ - ences were noted in some adverse effects that were attributed to the inter vention (Table S5 in the Supplementar y Appendix). Orthostatic hypo - tension as assessed during a clinic visit (Table 3) was obser ved 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 bet ween-group difference in injurious falls (hazard ratio, 1.00; P = 0.97). There was a higher rate of acute kidney injur y or acute renal failure in the intensive-treatment group, as noted above.

These adverse events need to be weighed against the benef its 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 primar y outcome (a composite of myocardial infarction, acute coronar y 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 conf idence interval. Cumulative Hazard 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 Years B Death \from An\b Cause A Primar\b Outcome No. at Risk Standard treatment\I Inten\five treatment 4683 46784437 44364228 4256282\b 2\b00 721 77\b Standard treatment\I 0.10 0.08 0.06 0.04 0.02 0.00 0 1 2 3 4 5 Hazard ratio with \Iinten\five treatment\I, 0.75 (\b5% CI, 0.64–0.8\b) Inten\five treatment Cumulative Hazard 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 Years No. at Risk Standard treatment\I Inten\five treatment 4683 46784528 4516 4383 43\b0 2\b\b8 3016 78\b 807 Standard treatment\I 0.10 0.08 0.06 0.04 0.02 0.00 0 1 2 3 4 5 Hazard ratio with \Iinten\five treatment\I, 0.73 (\b5% CI, 0.60–0.\b0) Inten\five treatmentThe New England Journal of Medicine Downloaded from nejm.org on December 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. n engl j med 373;22 nejm.org November 26, 2015 2113 Intensive vs. Standard Blood-Pressure Control The strengths of SPRINT include a large sample size, the diversit y 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 bet ween the t wo inter vention groups throughout the trial. The lack of generalizabilit y 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 obser vations 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\o Better Intensive Treatmen\ot Better Overall Previous C\fD No Yes \bge <75 yr 75 yr Sex Female Male Race Black Nonblack Previous cardiovas\Ccular disease No Yes Systolic blood pre\Cssure 132 mm Hg >132 to <145 mm Hg 145 mm Hg Intensive Treatmen\ot Hazard Ratio \f95% \bI)\o Standard Treatment\o Subgroup 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 wi\/th primary outcome\//tota\f 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)The New England Journal of Medicine Downloaded from nejm.org on December 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. n engl j med 373;22 nejm.org November 26, 2015 2114 The new england journal of medicine 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 signif i - cantly more frequently with the lower target. The content is solely the responsibilit y of the authors and does not necessarily represent the of f icial views of the National Institutes of Health (NIH), the Department of Veterans Af fairs, 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) 1.040.25 Conditions of interest Serious adverse event onlyHypotension 110 (2.4)66 (1.4)1.670.001 Syncope 107 (2.3)80 (1.7)1.330.05 Bradycardia 87 (1.9)73 (1.6)1.190.28 Electrolyte abnormality 144 (3.1)107 (2.3) 1.350.02 Injurious fall† 105 (2.2)110 (2.3) 0.950.71 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) 1.440.003 Bradycardia 104 (2.2)83 (1.8)1.250.13 Electrolyte abnormality 177 (3.8)129 (2.8) 1.380.006 Injurious fall† 334 (7.1)332 (7.1) 1.000.97 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)1.500.006 Serum potassium >5.5 mmol/liter 176 (3.8)171 (3.7) 1.000.97 Orthostatic hypotension¶ Alone 777 (16.6)857 (18.3) 0.880.01 With dizziness 62 (1.3)71 (1.5)0.850.35 * A serious adverse event was defined as an event that was fatal or life­threatening, that resulted in clinically significant or persistent disab\�ility, 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 preve\�nt one of the other events listed above.

† An injurious fall was defined as a fall that resulted in evaluation in a\�n emergency department or that resulted in hospitalization.

‡ Acute kidney injury or acute renal failure were coded if the diagnosis w\�as listed in the hospital discharge summary and was believed by the safety officer to be one of the top three reasons for admission or conti\�nued hospitalization. A few cases of acute kidney injury were noted in an emergency department if the participant presented for one of the othe\�r conditions of interest.

§ Adverse laboratory measures were detected on routine or unscheduled test\�s; 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 pressur\�e 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 mo\�nths, 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.The New England Journal of Medicine Downloaded from nejm.org on December 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. n engl j med 373;22 nejm.org November 26, 2015 2115 Intensive vs. Standard Blood-Pressure Control 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 Reser ve Universit y: UL1TR000439; Ohio St ate Universit y: UL1R R025755; Universit y of Pennsyl - vania: UL1R R024134 and UL1TR000003; Boston Universit y:

UL1R R025771; St anford Universit y: UL1TR000093; Tufts Univer - sit y: UL1R R025752, UL1TR000073, and UL1TR001064; Universit y of Illinois: UL1TR000050; Universit y of Pittsburgh: UL1TR000005; Universit y of Texas Southwestern: 9U54TR000017-06; Universit y of Ut ah: UL1TR000105-05; Vanderbilt Universit y: UL1TR000445; George Washington Universit y: UL1TR000075; Universit y of Cali - fornia, Davis: UL1TR000002; Universit y of Florida: UL1TR000064; Universit y of Michigan: UL1TR000433; and Tulane Universit y:

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 Af fairs. 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; St\�icht 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 Trop\�ical 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 Kidne\�y Diseases (P.L.K.), Bethesda, MD; Divisions of Cardiovascular Diseases (S.O.) and Preventive Medicine (C.E.L.), University of Alab\�ama 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.).

References 1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global bur - den of hypertension: analysis of world - wide dat a. Lancet 2005; 365:

217-23.2. Go AS, Mozaf farian D, Roger VL, et al.

Heart disease and stroke st atistics — 2014 update: a report from the American Heart Association. Circulation 2014; 129(3):

e 2 8 -2 9 2 .

3. Franklin SS. Cardiovascular risks re - lated to increased diastolic, systolic and pulse pressure: an epidemiologist’s point of view. Pathol Biol (Paris) 1999; 47:

594- 603.

4. Franklin SS, Jacobs MJ, Wong ND, L’It alien GJ, Lapuert a P. Predominance of isolated systolic hypertension among middle-aged and elderly US hyperten - sives: analysis based on National Health and Nutrition Examination Sur vey (NHANES) III. Hypertension 2001; 37:

869- 74 .

5. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint Na - tional Committee on Prevention, Detec - tion, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA 2003; 289: 2560-72.

6. Collins R, Peto R, MacMahon S, et al.

Blood pressure, stroke, and coronar y heart disease. 2. Short-term reductions in blood pressure: over view of randomised drug trials in their epidemiological con - text. Lancet 1990; 335: 827-38.7. Hsu CY, McCulloch CE, Darbinian J, Go AS, Iribarren C. Elevated blood pres - sure and risk of end-st age renal disease in subjects without baseline kidney disease.

Arch Intern Med 2005; 165:

923-8. 8. Lev y D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hyper - tension to congestive heart failure. JAMA 1996; 275: 1557-62.

9. MacMahon S, Peto R, Cut ler J, et al.

Blood pressure, stroke, and coronar y heart disease. Part 1: prolonged dif fer - ences in blood pressure: prospective ob - ser vational studies corrected for the re - gression dilution bias. Lancet 1990; 335:

765 -74 .

10. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specif ic relevance of usual blood pressure to vascular mor - t alit y: a met a-analysis of individual dat a for one million adults in 61 prospective studies. Lancet 2002; 360: 1903-13.

11. St aessen JA, Fagard R, Thijs L, et al.

Randomised double-blind comparison of placebo and active treatment for older pa - tients with isolated systolic hypertension.

Lancet 1997; 350: 757-64.

12. Vasan RS, Larson MG, Leip EP, et al.

Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001; 345: 1291-7.

13. Sundström J, Arima H, Jackson R, et al. Ef fects of blood pressure reduction in mild hypertension: a systematic review and met a-analysis. Ann Intern Med 2015; 162: 184-91.

14. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injur y attribut able to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224-60.

15. Neal B, MacMahon S, Chapman N. Ef - fects of ACE inhibitors, calcium ant ago - nists, and other blood-pressure-lowering drugs: results of prospectively designed over views of randomised trials. Lancet 2000; 356: 1955-64.

16. Psat y BM, Smith NL, Siscovick DS, et al. Health outcomes associated with anti - hypertensive therapies used as f irst-line agents: asystematic review and met a- analysis. JA MA 1997; 277: 739-45.

17. SHEP Cooperative Research Group.

Prevention of stroke by antihypertensive drug treatment in older persons with iso - lated systolic hypertension: f inal results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265:

3255- 64.

18. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358: 1887-98.

19. JATOS Study Group. Principal results of the Japanese trial to assess optimal sys - tolic blood pressure in elderly hyperten - sive patients ( JATOS). Hypertens Res 2008; 3 1 : 2 1 1 5 -2 7.

20. Ogihara T, Sarut a T, Rakugi H, et al.

Target blood pressure for treatment of isolated systolic hypertension in the elder - ly: Valsart an in Elderly Isolated Systolic Hypertension study. Hypertension 2010; 56: 196-202.

21. Verdecchia P, St aessen JA, Angeli F, et al. Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open- label randomised trial. Lancet 2009; 374:

525-33.

22. Cushman WC, Evans GW, Byington The New England Journal of Medicine Downloaded from nejm.org on December 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. n engl j med 373;22 nejm.org November 26, 2015 2116 Intensive vs. Standard Blood-Pressure Control RP, et al. Ef fects of intensive blood-pres - sure control in t ype 2 diabetes mellitus. N Engl J Med 2010; 362:

1575-85.23. Benavente OR, Cof fey CS, Conwit R, et al. Blood-pressure t argets in patients with recent lacunar stroke: the SPS3 ran - domised trial. Lancet 2013; 382:

507-15.24. Working group report: Expert Panel on a Hypertension Treatment Trial Initia - tive meeting summar y, 2007. Bethesda, MD, National Heart Lung and Blood Insti - tute (http://www .nhlbi .nih .gov/ sites/ www .nhlbi .nih .gov/ f iles/ hypertsnsion-full .pdf ).

25. Systolic Blood Pressure Inter vention Trial (SPRINT) protocol. November 1, 2012 (https:/ / w w w .sprinttrial .org/ public/ Protocol_Current .pdf ).

26. Ambrosius WT, Sink KM, Foy CG, et al. The design and rationale of a multi - center clinical trial comparing two strate - gies for control of systolic blood pressure:

the Systolic Blood Pressure Inter vention Trial (SPRINT). Clin Trials 2014; 11:

532- 46.

2 7. Lindholm LH, Carlberg B, Samuels - son O. Should bet a blockers remain f irst choice in the treatment of primar y hyper - tension? A met a-analysis. Lancet 2005; 366: 1545-53.

28. ALLHAT Of f icers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hyper - tensive patients randomized to angioten - sin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihy - pertensive and Lipid-Lowering Treatment to Prevent Heart Att ack Trial (ALLHAT).

JAMA 2002; 288: 2981-97.

29.

Ernst ME, Carter BL, Goerdt CJ, et al.

Comparative antihypertensive ef fects of hydrochlorothiazide and chlorthalidone on ambulator y and off ice blood pressure.

Hypertension 2006; 47: 352-8.

30. Of f ice for Human Research Protec - tions. OHRP guidance on unanticipated problems and adverse events. 2007 (http:// w w w .hhs .gov/ ohrp/ policy/ advevntguid .ht m l).

31. Food and Drug Administration. Code of Federal Regulations. Tit le 21CFR312.32a, 2013 (http://www .accessdata .fda .gov/ scripts/ cdrh/ cfdocs/ cfcfr/ cfrsearch .cfm?fr =312 .32).32. Hommel G. A st agewise rejective multiple test procedure based on a modi - f ied Bonferroni test. Biometrika 1988; 75:

383-86.

33. Proschan MA, Lan KKG, Wittes JT.

Statistical monitoring of clinical trials: a unif ied approach. New York: Springer, 2006.

34. Fine JP, Gray R J. A proportional haz - ards model for the subdistribution of a competing risk. J Am St at Assoc 1999; 94:

496-509.

35. Bakris GL, Weir MR. Angiotensin- converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med 2000; 160: 685-93.

36. Apperloo AJ, de Zeeuw D, de Jong PE.

A short-term antihypertensive treatment- induced fall in glomerular f iltration rate predicts long-term st abilit y of renal func - t ion. Kidney Int 1997; 51: 793-7.37. Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A. The Felodipine Event Reduc - tion (FEVER) Study: a randomized long- term placebo-controlled trial in Chinese hypertensive patients. J Hypertens 2005; 2 3: 2 1 5 7-7 2 .

38. Margolis KL, O’Connor PJ, Morgan TM, et al. Outcomes of combined cardio - vascular risk factor management strate - gies in t ype 2 diabetes: the ACCORD ran - domized trial. Diabetes Care 2014; 37:

1721-8 .

39. Nwank wo T, Yoon SS, Burt V, Gu Q.

Hypertension among adults in the United St ates: National Health and Nutrition Ex - amination Sur vey, 2011–2012. NCHS Dat a Brief 2013; 133: 1-8.

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