1、The new england journal of medicinen engl j med 362;17 nejm.org april 29, 20101575original articleEffects of Intensive Blood-Pressure Control in Type 2 Diabetes MellitusThe ACCORD Study Group*The members of the Writing Group (Wil-liam C. Cushman, M.D., Gregory W. Evans, M.A., Robert P. Byington, Ph.
2、D., David C. Goff, Jr., M.D., Ph.D., Richard H. Grimm, Jr., M.D., Ph.D., Jeffrey A. Cutler, M.D., M.P.H., Denise G. Simons-Morton, M.D., Ph.D., Jan N. Basile, M.D., Marshall A. Corson, M.D., Jeffrey L. Probstfield, M.D., Lois Katz, M.D., Kevin A. Peterson, M.D., William T. Friedewald, M.D., John B.
3、Buse, M.D., Ph.D., J. Thomas Bigger, M.D., Hertzel C. Gerstein, M.D., and Faramarz Ismail-Beigi, M.D., Ph.D.) assume re-sponsibility for the integrity of the article. Address reprint requests to Dr. Cushman at the Preventive Medicine Section (111Q), Veterans Affairs Medical Center, 1030 Jef-ferson A
4、ve., Memphis, TN 38104, or at william.cushmanva.gov.*The members of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group are listed in Section 1 in Supplementary Appendix 1, available with the full text of this article at NEJM.org. The affiliations of the members of the Writing
5、 Group are listed in the Appendix.This article (10.1056/NEJMoa1001286) was published on March 14, 2010, at NEJM.org.N Engl J Med 2010;362:1575-85.Copyright 2010 Massachusetts Medical Society.ABSTRACTBackgroundThere is no evidence from randomized trials to support a strategy of lowering sys-tolic blo
6、od pressure below 135 to 140 mm Hg in persons with type 2 diabetes mel-litus. We investigated whether therapy targeting normal systolic pressure (i.e., 5.9 mmol/liter 73 (3.1) 72 (3.0) 0.93Elevation in serum creatinine1.5 mg/dl in men 304 (12.9) 199 (8.4) 1.3 mg/dl in women 257 (10.9) 168 (7.1) 0.00
7、1Estimated GFR 30 ml/min/1.73 m299 (4.2) 52 (2.2) 0.001Clinical measuresnullGlycated hemoglobin % 7.61.3 7.51.2 0.13Fasting plasma glucose mg/dl 147.156.6 148.157.5 0.58Plasma LDL cholesterol mg/dl 98.740.3 96.837.8 0.10Plasma HDL cholesterol mg/dl 46.714.0 47.814.9 0.02Plasma triglycerides mg/dl 0.
8、001Median 138 131Interquartile range 97210 92197Potassium mg/dl 4.30.5 4.40.5 0.17Serum creatinine mg/dl 1.10.4 1.00.5 0.001Estimated GFR ml/min/1.73 m274.825.0 80.624.8 0.001Ratio of urinary albumin (mg) to creatinine (g) 0.001Median 12.6 14.9Interquartile range 6.441.7 7.056.8Microalbuminuria no./
9、total no. (%) 656/2174 (30.2) 712/2205 (32.3) 0.13Macroalbuminuria no. /total no. (%) 143/2174 (6.6) 192/2205 (8.7) 0.009Weight kg 93.321.2 92.520.2 0.20* Plusminus values are means SD. To convert the values for glucose to millimoles per liter, multiply by 0.055551. To convert the values for cholest
10、erol 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 potassium to millimoles per liter, multiply by 0.2558. To convert the values for creatinine to micromoles per liter, multiply by 88.4. GF
11、R denotes glomerular filtration rate, HDL high-density lipoprotein, and LDL low-density lipoprotein. Serious adverse events are events that are life-threatening, cause permanent disability, or necessitate hospitalization (see Section 7 in Supplementary Appendix 1). Symptoms were assessed at 12, 36,
12、and 48 months after randomization in a random sample of 969 participants who were assessed for health-related quality of life. Data are from the last visit at which assessments were made for each participant.The New England Journal of Medicine Downloaded from nejm.org on July 16, 2011. For personal
13、use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved. The new england journal of medicinen engl j med 362;17 nejm.org april 29, 20101582the standard-therapy group (hazard ratio with in-tensive therapy, 1.07; 95% CI, 0.85 to 1.35; P = 0.55). Ra
14、tes of death from cardiovascular causes were 0.52% per year in the intensive-therapy group and 0.49% in the standard-therapy group (haz-ard ratio, 1.06; 95% CI, 0.74 to 1.52; P = 0.74).The two study groups did not differ signifi-cantly with respect to most of the other secondary outcomes. Nominally
15、significant differences were seen in the rate of total stroke (0.32% per year in the intensive-therapy group vs. 0.53% per year in the standard-therapy group; hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P = 0.01) and in the rate of nonfatal stroke (0.30% per year in the intensive-therapy group vs. 0.4
16、7% per year in the standard-therapy group; hazard ratio, 0.63; 95% CI, 0.41 to 0.96; P = 0.03). There were no significant inter-actions among prespecified subgroups (see Sec-tion 17 in Supplementary Appendix 1).DiscussionIntensive antihypertensive therapy in the ACCORD BP trial did not significantly
17、 reduce the primary cardiovascular outcome or the rate of death from any cause, despite the fact that there was a sig-nificant and sustained difference between the intensive-therapy group and the standard-therapy group in mean systolic blood pressure. There was also no significant benefit with respe
18、ct to most of the secondary trial outcomes. At a significance level of less than 0.05, intensive blood-pressure management did reduce the rate of two closely correlated secondary outcomes total stroke and nonfatal stroke. Assuming that this finding was real, the number needed to undergo intensive bl
19、ood-pressure management to prevent one stroke over the course of 5 years was 89. These effects would be consistent with the findings of two meta-analyses of the effect of a reduction of 10 mm Hg in systolic blood pressure on the inci-dence of stroke11,12; the meta-analyses showed a relative risk wit
20、h blood-pressure reduction of 0.64 with the use of data from observational studies and of 0.59 with the use of data from drug-treat-ment trials.12The interpretation of the ACCORD BP results is complicated by the fact that the event rate observed in the standard-therapy group was al-most 50% lower th
21、an the expected rate. This re-sult may have been a consequence of the frequent use of statins and of inclusion criteria that di-Table 3. Primary and Secondary Outcomes.OutcomeIntensive Therapy(N = 2363)Standard Therapy(N = 2371)Hazard Ratio(95% CI) P Valueno. of events %/yr no. of events %/yrPrimary
22、 outcome* 208 1.87 237 2.09 0.88 (0.731.06) 0.20Prespecified secondary outcomesNonfatal myocardial infarction 126 1.13 146 1.28 0.87 (0.681.10) 0.25StrokeAny 36 0.32 62 0.53 0.59 (0.390.89) 0.01Nonfatal 34 0.30 55 0.47 0.63 (0.410.96) 0.03DeathFrom any cause 150 1.28 144 1.19 1.07 (0.851.35) 0.55Fro
23、m cardiovascular cause 60 0.52 58 0.49 1.06 (0.741.52) 0.74Primary outcome plus revasculariza-tion or nonfatal heart failure521 5.10 551 5.31 0.95 (0.841.07) 0.40Major coronary disease event 253 2.31 270 2.41 0.94 (0.791.12) 0.50Fatal or nonfatal heart failure 83 0.73 90 0.78 0.94 (0.701.26) 0.67* T
24、he primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. Major coronary disease events, as defined in the protocol, included fatal coronary events, nonfatal myocardial infarction, and unstable angina.The New England Journal of Medici
25、ne Downloaded from nejm.org on July 16, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved. Intensive Blood-Pressure Control in Type 2 Diabetesn engl j med 362;17 nejm.org april 29, 20101583rected participants with dyslipi
26、demia into the ACCORD lipid trial, leaving participants who were at lower risk in the blood-pressure trial.5The reduced power was reflected in the rela-tively wide confidence interval that does not ex-clude a 27% benefit for the primary end point.There were some signals of possible harm associated w
27、ith intensive blood-pressure control, including a rate of serious adverse events that was significantly higher in the intensive-therapy group than in the standard-therapy group. Both the estimated glomerular filtration rate and mac-roalbuminuria were reduced, but the implications of these changes on
28、 cardiovascular and renal out-comes are uncertain.The United Kingdom Prospective Diabetes Study13,14and a post hoc subgroup analysis of the Hypertension Optimal Treatment (HOT) trial15,16showed reductions in cardiovascular events with antihypertensive therapy among patients with type 2 diabetes mell
29、itus, but the participants in their intensively treated groups had much higher mean systolic blood-pressure levels (144 mm Hg in both cases) than did the participants in either group of our trial. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modi-f ied Release Controlled Ev
30、aluation trial (ADVANCE; ClinicalTrials.gov number, NCT00145925),17ac-tive treatment with an angiotensin-convertingenzyme inhibitor and a thiazide-type diuretic re-duced the rate of death but did not significantly reduce a composite macrovascular outcome. How-7 col36p6Proportion with Event1.00.80.60
31、.20.40.00 1 2 3 4 5 6 87YearsA Primary OutcomeIntensiveIntensiveIntensiveIntensiveStandardStandardStandardStandardNo. at RiskIntensiveStandard23622371227322742182219617701793211721201080112729835880108175195B Nonfatal StrokeC Nonfatal Myocardial Infarction D Death from Cardiovascular DiseaseAUTHOR:F
32、IGURE:RETAKE:SIZE4-C H/TLine ComboRevisedAUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset.Please check carefully.1st2nd3rdCushman2 of 2ARTIST:TYPE:ts04-29-10JOB: 36217 ISSUE:P=0.200.10.20.00 1 2 3 4 5 6 87Proportion with Event1.00.80.60.20.40.00 1 2 3 4 5 6 87YearsNo. at RiskInte
33、nsiveStandard23622371229122872223223518411879217421861128119631338288114186215P=0.030.10.20.00 1 2 3 4 5 6 87Proportion with Event1.00.80.60.20.40.00 1 2 3 4 5 6 87YearsNo. at RiskIntensiveStandard23622371227822782190220817871818213321411087114529936582112177201P=0.250.10.20.00 1 2 3 4 5 6 87Proport
34、ion with Event1.00.80.60.20.40.00 1 2 3 4 5 6 87YearsNo. at RiskIntensiveStandard23622371230423132252226818701922220122181143122031739391118188221P=0.740.10.20.00 1 2 3 4 5 6 87Figure 2. KaplannullMeier Analyses of Selected Outcomes.Shown are the proportions of patients with events for the primary c
35、omposite outcome (Panel A) and for the individual components of the primary outcome (Panels B, C, and D). The insets show close-up versions of the graphs in each panel.The New England Journal of Medicine Downloaded from nejm.org on July 16, 2011. For personal use only. No other uses without permissi
36、on. Copyright 2010 Massachusetts Medical Society. All rights reserved. The new england journal of medicinen engl j med 362;17 nejm.org april 29, 20101584ever, the ADVANCE trial had no specified blood-pressure goals, and the mean systolic blood pres-sure in the intensive group (135 mm Hg) was not as
37、low as the mean systolic blood pressure even in the ACCORD standard-therapy group. It is pos-sible that lowering systolic blood pressure from the mid-130s to approximately 120 mm Hg does not further reduce most cardiovascular events or the rate of death, and most of the benefit from lowering blood p
38、ressure is achieved by targeting a goal of less than 140 mm Hg. Alternatively, it is possible that 5 years is not long enough to see significant cardiac benefits from the normaliza-tion of systolic blood pressure among persons with diabetes who have good control of glycemia, especially when other ef
39、fective treatments, such as statins and aspirin, are used frequently.There are several limitations of the ACCORD BP trial. First, the trial had an open-label design, a design that was not likely to have affected blood-pressure goals or measurement or the blinded ascertainment of the outcomes but may
40、 have af-fected the reporting of adverse events; second, the rate of cardiovascular events was lower than the expected rate in the standard-therapy group; and third, patients younger than 40 years of age were not included in the study and patients older than 79 years of age were not included after t
41、he vanguard phase. In addition, although it was not the intent of this trial to test the blood-pressure goal of 130 mm Hg that was recommended in the JNC 7 (a recommendation that was made after the ACCORD trial was initiated), it would be difficult to argue that such a target would be better than a
42、target of 140 mm Hg, since even a blood-pressure goal of 120 mm Hg did not confer benefit.In conclusion, the ACCORD BP trial evaluated the effect of targeting a systolic blood pressure of 120 mm Hg, as compared with a goal of 140 mm Hg, among patients with type 2 diabetes at high risk for cardiovasc
43、ular events. The results provide no evidence that the strategy of intensive blood-pressure control reduces the rate of a com-posite of major cardiovascular events in such patients.Supported by contracts from the National Heart, Lung, and Blood Institute (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01
44、-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, and IAA#Y1-HC-9035 and IAA#Y1-HC-1010). Other components of the National Institutes of Health, including the National In-stitute of Diabetes and Digestive and Kidney Diseases, the Na-tional Institute on Aging, and the National Eye Institute, con-t
45、 ributed f unding. The Centers for Disease Cont rol and Prevent ion funded substudies within ACCORD on cost-effectiveness and health-related quality of life. General Clinical Research Centers provide support at many sites. The following companies pro-vided study medications, equipment, or supplies:
46、Abbott Labo-ratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline Pharma-ceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuti-cals, Novo Nordisk, Omron Healthcare, Sanofi-Aventis U.S., and Takeda. Disclosure forms provided by the a
47、uthors are available with the full text of this article at NEJM.org.APPENDIXThe affiliations of the ACCORD Blood Pressure writing group are as follows: Preventive Medicine Section, Memphis Veterans Af-fairs (VA) Medical Center, Memphis (W.C.C.); Division of Public Health Sciences, Wake Forest Univer
48、sity School of Medicine, Winston-Salem, NC (G.W.E., R.P.B., D.C.G.); Berman Center for Outcomes and Clinical Research (R.H.G.), and Department of Fam-ily Practice and Community Health, University of Minnesota (K.A.P.) both in Minneapolis; National Heart, Lung, and Blood Institute, Bethesda, MD (J.A.
49、C., D.G.S.-M.); Primary Care, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC (J.N.B.); Department of Medicine, University of Washington, Seattle (M.A.C., J.L.P.); VA New York Harbor Healthcare System (L.K.), Departments of Biostatistics and Epidemiology, Columbia University Mailman School of Public Health (W.T.F.), and Division of Cardiology, Columbia University College of Physicians and Surgeons (J.T.B.) all in New York; Division of Endocrinology, Univer-sity of North Carolina School of Medicine, Chape
