Clinical Trial - ALLHAT. Mortality and Morbidity During and After Antihypertensive. and Lipid-Lowering Treatment to Prevent Heart Attack Trial

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Clinical Trial - ALLHAT Mortality and Morbidity During and After Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Results by Sex Suzanne Oparil, Barry R. Davis, William C. Cushman, Charles E. Ford, Curt D. Furberg, Gabriel B. Habib, L. Julian Haywood, Karen Margolis, Jeffrey L. Probstfield, Paul K. Whelton, Jackson T. Wright Jr; for the ALLHAT Collaborative Research Group Downloaded from http://hyper.ahajournals.org/ by guest on April 22, 2018 Abstract To determine whether an angiotensin-converting enzyme inhibitor (lisinopril) or calcium channel blocker (amlodipine) is superior to a diuretic (chlorthalidone) in reducing cardiovascular disease incidence in sex subgroups, we carried out a prespecified subgroup analysis of 15638 women and 17719 men in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Total follow-up (active treatment + passive surveillance using national administrative databases to ascertain deaths and hospitalizations) was 8 to 13 years. The primary outcome was fatal coronary heart disease or nonfatal myocardial infarction. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (coronary heart disease death, nonfatal myocardial infarction, stroke, angina, coronary revascularization, heart failure [HF], or peripheral vascular disease), and end-stage renal disease. In-trial rates of HF, stroke, and combined cardiovascular disease were significantly higher for lisinopril compared with chlorthalidone, and rates of HF were significantly higher for amlodipine compared with chlorthalidone in both men and women. There were no significant treatment sex interactions. These findings did not persist through the extension period with the exception of the HF result for amlodipine versus chlorthalidone, which did not differ significantly by sex. For both women and men, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary coronary heart disease outcome or any other cardiovascular disease outcome, and chlorthalidone-based treatment resulted in the lowest risk of HF. Neither lisinopril nor amlodipine is superior to chlorthalidone for initial treatment of hypertension in either women or men. Clinical Trial Registration clinicaltrials.gov; Identifier: NCT00000542. (Hypertension. 2013;61:977-986.) Online Data Supplement Key Words: ACE inhibitor calcium channel blocker diuretic sex hypertension Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among women in developed countries, and elevated blood pressure (BP) is a leading contributor to this phenomenon. 1,2 Although the benefits of lowering increased BP in reducing CVD morbidity and mortality in the population as a whole have been well established, until recently, data documenting the specific benefits of antihypertensive treatment in reducing cardiovascular (CV) complications of hypertension in women were not available. 3 Furthermore, before the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), CVD outcome data comparing the effects of nondiuretic-based antihypertensive therapy (ie, angiotensinconverting enzyme [ACE] inhibitors or calcium channel blockers) to diuretic therapy in women were absent. This is particularly significant because hypertension is highly prevalent, difficult to control, and associated with a high incidence of CVD complications in older women, the population that was enrolled in ALLHAT. 4 6 Data from the Framingham Heart Study showed an age-related decline in BP control rates that was more pronounced in women than in men. 6 Among the oldest participants with hypertension, only 23% of women (versus 38% of men) were controlled to BP <140/90 mm Hg. A cross-sectional analysis of data from the 2005 Received September 21, 2012; first decision February 20, 2013; revision accepted February 21, 2013. From the Vascular Biology and Hypertension Program, University of Alabama at Birmingham, Birmingham, AL (S.O.); Coordinating Center for Clinical Trials, Biostatistics Division, The University of Texas School of Public Health, Houston, TX (B.R.D., C.E.F.); Preventive Medicine Section, Memphis Veterans Affairs Medical Center, Memphis, TN (W.C.C.); Department of Public Health Sciences, Wake Forest University School of Medicine, Winston- Salem, NC (C.D.F.); Veterans Affairs Medical Center Houston, Houston, TX (G.B.H); Keck School of Medicine, University of Southern California, Los Angeles, CA (L.J.H); Clinical Research, HealthPartners Institute for Education and Research, Minneapolis, MN (K.L.M); Clinical Trials Service Unit, University of Washington Medical Center Seattle, WA (J.L.P); Global Public Health, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (P.K.W); and Division of Nephrology and Hypertension, University Hospitals Case Medical Center, Cleveland, OH (J.T.W.). For the ALLHAT Trial, see JAMA 2000;61:977 986. The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/hypertensionaha. 111.00213/-/DC1. Correspondence to Barry R. Davis, Coordinating Center for Clinical Trials, The University of Texas School of Public Health, 1200 Herman Pressler St W-916, Houston, TX 77030. E-mail barry.r.davis@uth.tmc.edu 2013 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.111.00213 977

978 Hypertension May 2013 Downloaded from http://hyper.ahajournals.org/ by guest on April 22, 2018 National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey also showed that among patients with hypertension, women were less likely than men to meet BP control targets. 7 The sex disparity was particularly large in the elderly, where the odds ratio of having controlled BP in women compared with men was 0.62 (95% confidence interval [CI], 0.45 0.85). It is not clear from these studies whether the sex disparity in BP control rates in elderly patients was related to true treatment resistance among women because of biological factors or to incompletely understood characteristics of the healthcare delivery system. ALLHAT was a randomized, double-blind, National Heart, Lung, and Blood Institute-sponsored trial that recruited 42 418 participants and compared an ACE inhibitor (lisinopril), an α blocker (doxazosin), and a calcium channel blocker (amlodipine), each with a diuretic (chlorthalidone). 8,9 ALLHAT reported that chlorthalidone was not surpassed in preventing coronary heart disease (CHD) compared with doxazosin, lisinopril, or amlodipine; was more effective than these agents in preventing heart failure (HF); and was more effective than doxazosin or lisinopril in preventing stroke and a composite of CVD outcomes. 10 Results for the doxazosin arm, which was terminated early, have been reported in several articles, and are not included here. 11 17 The ALLHAT cohort included 47% women with a mean age of 67 years at enrollment and prespecified subgroups in the trial included women and men. 8,9 Thus, ALLHAT offers an excellent opportunity to compare the effects on CVD outcomes of representatives of the newer classes of antihypertensive agents versus those of the diuretic chlorthalidone in a large population of older, higher risk women. In addition, we tested whether 5 years of in-trial randomized antihypertensive treatment resulted in persistence or de novo development of mortality and morbidity differences during extended followup of 8 to 13 years. 18 21 The primary outcome for the long-term (in-trial plus post-trial) analyses was CVD mortality. This report details the results of the in-trial and post-trial analyses by sex. In particular, we now examine in detail the interactions of sex and treatment in determining CVD outcomes with emphasis on treatment effects in women. Methods The rationale and design of ALLHAT have been presented elsewhere, 7 and more extensive details are in the online-only Data Supplement. 8 Briefly, participants were women and men age 55 years with hypertension and at least 1 additional risk factor for CHD events. 8,9 All participants provided written informed consent, and all centers obtained institutional review board approval. The study adhered to the principles of the Declaration of Helsinki and Title 45, US Code of Federal Regulations, Part 46, Protection of Human Subjects. Participants (n = 33 357) were assigned by a computer-generated randomization schedule to chlorthalidone, amlodipine, or lisinopril in a ratio of 1.7:1:1, respectively. Goal BP in each randomized group was <140/90 mm Hg achieved by titrating the assigned study drug (step 1) and adding open-label agents (step 2 or 3) when necessary. Method of BP measurement is detailed elsewhere. 22 The primary outcome was a composite of fatal CHD or nonfatal myocardial infarction. 8 10 Four major prespecified secondary outcomes were (1) all-cause mortality; (2) fatal and nonfatal stroke; (3) combined CHD (the primary outcome, coronary revascularization, hospitalized angina); and (4) combined CVD (combined CHD, stroke, other treated angina, HF [fatal, hospitalized, or treated nonhospitalized], and peripheral arterial disease). Individual components of the combined outcomes also were examined. Other prespecified secondary outcomes included cancer and end-stage renal disease (ESRD; dialysis, renal transplant, or death). For the in-trial plus post-trial periods, the primary outcome was CV mortality, and secondary outcomes were mortality, stroke, CHD, HF, CVD, and ESRD. For details on the use of national databases, see online-only Data Supplement and Cushman et al. 18 For the post-trial period, data are not available on medications, serum chemistries, or BP levels. Statistical Analyses Baseline characteristics and intermediate outcomes were compared across treatments within each sex subgroup using analysis of variance for continuous covariates and contingency table analyses for categorical data. Data were analyzed according to participants randomized treatment assignments regardless of their subsequent medications (ie, intention-to-treat analysis). Six-year cumulative event rates for the in-trial data and 10-year event rates for the post-trial data were calculated using the Kaplan-Meier procedure. Cox proportional hazards models were used to obtain hazard ratios (HRs) and 95% CIs for time-to-event outcomes, and included the participant s entire trial experience for both the in-trial and the combined in-trial plus post-trial periods. Heterogeneity of treatment effects across sex subgroups was examined by testing for treatment sex interaction with the proportional hazards model using P<0.05. Given the many multivariate, subgroup, and interaction analyses performed, statistical significance at the.05 level should be interpreted with caution. Stata version 11 (Stata Corp, College Station, TX) was used for all analyses. Further details are provided in the major ALLHAT outcomes article, 10 the ALLHAT extension article, 18 and the ALLHAT extension protocol (www.allhat.org). Results A consort diagram (Figure 1) shows the number of participants who entered the trial and their status at the end of the in-trial period (March, 2002) by sex. There were 17 719 men and 15 638 women randomized into ALLHAT. Baseline Characteristics Women accounted for 47% of the ALLHAT population (Table 1). They were slightly older (by ½ year), were more likely to be black (41% versus 30%) or Hispanic (19% versus 13%), and had lower educational attainment. Although there was little difference by sex in percentages of those aged 55 to 64 years, there were fewer women than men among those aged 65 to 80 years (49% versus 53%), whereas there were more women among those aged 80 years and older (8.4% versus 4.8%). The percentage on treatment at entry was similar in men A Men Participants randomized Assigned treatment group Status at study closeout Included in analysis B Women Figure 1. Consort diagrams for men (A) and women (B).

Oparil et al ALLHAT Outcomes by Sex 979 Table 1. Baseline Characteristics of ALLHAT Participants by Sex* Downloaded from http://hyper.ahajournals.org/ by guest on April 22, 2018 Men Characteristic Chlorthalidone Amlodipine Lisinopril All Men Chlorthalidone Amlodipine Lisinopril All Women Number randomized 8084 4768 4867 17 719 7171 4280 4187 15638 Age, y, mean (SD) 66.7 (7.2) 66.7 (7.3) 66.8 (7.3) 66.7 (7.3) 67.1 (8.2) 67.1 (8.2) 67.0 (8.2) 67.1 (8.2) 55 64 3422 (42.3) 2006 (42.1) 2023 (41.6) 7451 (42.1) 3049 (42.5) 1838 (42.9) 1846 (44.1) 6733 (43.1) 65 80 4269 (52.8) 2538 (53.2) 2605 (53.5) 9412 (53.1) 3515 (49.0) 2080 (48.6) 1994 (47.6) 7589 (48.5) 80+ 393 (4.9) 224 (4.7) 239 (4.9) 856 (4.8) 607 (8.5) 362 (8.5) 347 (8.3) 1316 (8.4) Ethnicity Black 2434 (30.1) 1464 (30.7) 1464 (30.1) 5362 (30.3) 2935 (40.9) 1749 (40.9) 1746 (41.7) 6430 (41.1) Nonblack 5650 (69.9) 3304 (69.3) 3403 (69.9) 12 357 (69.7) 4236 (59.1) 2531 (59.1) 2441 (58.3) 9208 (58.9) White, non-hispanic 4413 (54.6) 2629 (55.1) 2654 (54.5) 9696 (54.7) 2789 (38.9) 1676 (39.2) 1608 (38.4) 6073 (38.8) Black, non-hispanic 2243 (27.8) 1323 (27.8) 1348 (27.7) 4914 (27.7) 2628 (36.7) 1588 (37.1) 1572 (37.5) 5788 (37.0) White Hispanic 854 (10.6) 478 (10.0) 521 (10.7) 1853 (10.5) 1058 (14.8) 630 (14.7) 615 (14.7) 2303 (14.7) Black Hispanic 191 (2.4) 141 (3.0) 116 (2.4) 448 (2.5) 307 (4.3) 161 (3.8) 174 (4.2) 642 (4.1) Other 383 (4.7) 197 (4.1) 228 (4.7) 808 (4.6) 389 (5.4) 225 (5.3) 218 (5.2) 832 (5.3) Education, y, mean (SD) 11.5 (4.1) 11.5 (4.0) 11.4 (4.1) 11.48 (4.1) 10.4 (3.9) 10.4 (3.8) 10.4 (4.0) 10.37 (3.9) Receiving antihypertensive 7249 (90.0) 4261 (89.4) 4355 (89.5) 15 865 (90.0) 6505 (90.7) 3910 (91.4) 3809 (91.0) 14 224 (91.0) treatment, n (%) Blood pressure, mm Hg, mean (SD) SBP 145.5 (16.0) 145.8 (15.7) 145.6 (15.7) 145.6 (15.8) 147.1 (15.4) 146.7 (15.6) 147.3 (15.3) 147.0 (15.4) DBP 84.3 (10.1) 84.2 (10.2) 84.4 (10.0) 84.3 (10.1) 83.8 (10.0) 83.6 (10.1) 83.8 (10.0) 83.7 (10.0) Treated at baseline SBP 144.3 (15.9) 144.7 (15.7) 144.4 (15.6) 144.5 (15.8) 146.1 (15.3) 145.6 (15.5) 146.4 (15.3) 146.0 (15.4) DBP 83.6 (10.0) 83.5 (10.1) 83.8 (10.0) 83.6 (10.0) 83.2 (9.9) 83.1 (10.0) 83.3 (9.9) 83.2 (9.9) Untreated at baseline SBP 155.5 (12.0) 155.3 (12.5) 155.8 (12.5) 155.5 (12.3) 156.7 (12.1) 158.2 (11.4) 156.9 (12.2) 157.1 (12.0) DBP 90.0 (8.9) 90.1 (9.4) 89.3 (8.9) 89.8 (9.1) 89.0 (9.3) 89.2 (9.4) 88.8 (9.7) 89.0 (9.4) Baseline lipid profile, mg/dl, mean (SD) Cholesterol Total 206.5 (40.5) 207.1 (40.2) 206.8 (39.5) 206.7 (40.1) 227.3 (44.5) 227.1 (45.7) 226.0 (43.1) 226.9 (44.5) HDL 42.4 (12.9) 42.8 (12.7) 42.2 (12.5) 42.4 (12.7) 51.9 (15.3) 52.1 (15.3) 51.8 (15.0) 51.9 (15.2) LDL 130.9 (34.9) 131.1 (34.5) 131.7 (34.3) 131.2 (34.6) 141.6 (39.1) 140.6 (39.4) 140.9 (38.4) 141.2 (39.0) Fasting triglycerides 174.4 (137.1) 172.2 (135.2) 173.0 (140.7) 173.4 (137.6) 170.7 (120.9) 173.1 (131.7) 172.5 (137.9) 171.8 (128.6) Total glucose mg/dl 123.2 (58.6) 122.4 (56.9) 122.0 (55.5) 122.6 (57.3) 127.2 (64.6) 127.1 (64.4) 126.1 (63.1) 126.9 (64.2) Fasting glucose, mg/dl 121.8 (55.8) 121.0 (53.4) 120.8 (52.2) 121.3 (54.2) 125.6 (61.2) 125.4 (60.6) 125.1 (60.0) 125.4 (60.7) Diabetes mellitus classification Diabetes mellitus 3006 (39.1) 1835 (40.6) 1797 (39.0) 6638 (39.5) 2988 (44.4) 1762 (43.6) 1713 (43.5) 6463 (43.9) Impaired fasting glucose 389 (5.1) 233 (5.2) 249 (5.4) 871 (5.2) 239 (3.6) 131 (3.2) 158 (4.0) 528 (3.6) Normoglycemic 4289 (55.8) 2447 (54.2) 2557 (55.6) 9293 (55.3) 3502 (52.0) 2147 (53.1) 2070 (52.5) 7719 (52.5) Lipid trial participants# 1931 (23.9) 1116 (23.4) 1127 (23.2) 4174 (23.6) 1824 (25.4) 1124 (26.3) 1040 (24.8) 3988 (25.5) History of CHD 2523 (31.5) 1402 (29.7) 1496 (31.0) 5421 (30.9) 1420 (19.9) 800 (18.8) 774 (18.6) 2994 (19.3) Cigarette smoker 1933 (23.9) 1153 (24.2) 1187 (24.4) 4273 (24.1) 1409 (19.7) 827 (19.3) 794 (19.0) 3030 (19.4) Atherosclerotic CVD 4407 (54.5) 2568 (53.9) 2687 (55.2) 9662 (54.5) 3493 (48.7) 2046 (47.8) 1997 (47.7) 7536 (48.2) History of MI or stroke 2258 (27.9) 1293 (27.1) 1364 (28.0) 4915 (27.7) 1323 (18.5) 805 (18.8) 694 (16.6) 2822 (18.1) History of coronary 1442 (17.8) 820 (17.2) 900 (18.5) 3162 (17.9) 544 (7.6) 286 (6.7) 318 (7.6) 1148 (7.3) revascularization Other Atherosclerotic CVD** 1841 (22.8) 1085 (22.8) 1128 (23.2) 4054 (22.9) 1763 (25.0) 1060 (25.0) 1024 (24.5) 3847 (24.6) ST-T wave 807 (10.1) 464 (9.8) 460 (9.6) 1731 (9.9) 765 (10.8) 444 (10.5) 480 (11.6) 1689 (10.9) Women (Continued )

980 Hypertension May 2013 Table 1. Continued Men Characteristic Chlorthalidone Amlodipine Lisinopril All Men Chlorthalidone Amlodipine Lisinopril All Women Women Downloaded from http://hyper.ahajournals.org/ by guest on April 22, 2018 LVH by ECG 1355 (16.8) 818 (17.2) 788 (16.2) 2961 (16.7) 1112 (15.5) 715 (16.7) 686 (16.4) 2513 (16.1) LVH by echocardiogram 331 (4.1) 181 (3.8) 191 (4.0) 703 (4.0) 364 (5.1) 230 (5.4) 221 (5.1) 805 (5.2) Estimated GFR (ml/min per 78.3 (19.1) 79.1 (19.4) 78.7 (19.8) 78.7 (19.4) 76.6 (20.2) 77.0 (20.0) 76.5 (19.9) 76.6 (20.1) 1.73 m 2 ), mean (SD) Body mass index, mean (SD) 29.1 (5.2) 29.1 (5.2) 29.1 (5.2) 29.1 (5.2) 30.5 (7.0) 30.7 (7.3) 30.6 (7.0) 30.6 (7.1) Atrial fibrillation/flutter, n (%) 98 (1.4) 57 (1.4) 54 (1.3) 209 (1.3) 39 (0.7) 31 (0.9) 23 (0.7) 93 (0.7) ALLHAT indicates Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; CHD, coronary heart disease; CVD, cardiovascular diseases; DBP, diastolic blood pressure; DM, diabetes mellitus; GFR, glomerular filtration rat; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVH, left ventricular hypertrophy; and SBP, systolic blood pressure. *All results are presented as percentages of the number of participants randomized to the treatment groups unless otherwise indicated. Ethnicity is by self-report Diabetes mellitus = history of diabetes mellitus at baseline or fasting glucose 126 mg/dl Impaired fasting glucose = no history and baseline fasting glucose is 110 to 125 mg/dl inclusive Normoglycemic = not classified as impaired fasting glucose, no history of diabetes mellitus and at least one fasting glucose or nonfasting glucose is <110 mg/dl. #Participants randomized to the ALLHAT Lipid Trial, an open-label substudy of pravastatin vs usual care in those participants with elevated cholesterol **Other atherosclerotic CVD is any of history of angina pectoris; history of intermittent claudication, gangrene, or ischemic ulcers; history of transient ischemic attack; coronary, peripheral vascular, or carotid stenosis 50% documented by angiography or Doppler studies; ischemic heart disease documented by reversible or fixed ischemia on stress thallium or dipyridamole thallium. ST-T wave is any major ST segment depression or T-wave inversion on any ECG in the past 2 y. ST depression 1 mm for 1 min on exercise testing or Holter monitoring; reversible wall motion abnormality on stress echocardiogram; ankle-arm index <0.9; abdominal aortic aneurysm detected by ultrasonography, computed tomography scan, or radiograph; carotid or femoral bruits. and women ( 90%). Women compared with men had slightly higher systolic BP (147.0 mm Hg versus 145.6 mm Hg), higher high-density lipoprotein and low-density lipoprotein cholesterol (52 mg/dl versus 42 mg/dl and 141 mg/dl versus 131 mg/dl, respectively), higher body mass index (30.6 versus 29.1), slightly lower estimated glomerular filtration rate (76.6 ml/min per 1.73 m 2 versus 78.7 ml/min per 1.73 m 2 ), and were more likely to be participants in the lipid-lowering trial (25.5% versus 23.6%) due to the ALLHAT-LLT eligibility criteria. Women were more likely to have diabetes mellitus (43.9% versus 39.5%), less likely to have a history of CHD (19.3% versus 30.9%), or other form of atherosclerotic CVD (48.2% versus 54.5%), including myocardial infarction, stroke, or coronary revascularization, and fewer were smokers (19.4% versus 24.1%). The prevalence of atrial fibrillation at baseline was low and about half that in men (0.7% versus 1.3%). There were no significant differences across the 3 drug treatment groups in baseline BP or other baseline characteristics within either sex subgroup, except for (1) history of myocardial infarction or stroke in women, which was lower in the lisinopril group (16.6%) than in the chlorthalidone and amlodipine groups (18.5% and 18.8%, respectively); (2) history of CHD in men, lower in the amlodipine (29.7%) than chlorthalidone group (31.5%); and (3) estimated glomerular filtration rate in men, which was lower in chlorthalidone group (78.3) than in amlodipine group (79.1). During the post-trial period, we were able to passively follow 17 411 men and 15 393 women for mortality status and 9537 men and 12 086 women for morbidity status (Figure S1 in the online-only Data Supplement). The larger differential between the sexes for morbidity status occurred because of the lack of follow-up for participants from the Department of Veterans Affairs, who were mostly male (Cushman et al 18 for details). Intermediate Outcomes BP decreased substantially during the first year of the study and showed modest further decreases during subsequent years in both sexes in all treatment groups, although the decreases in systolic BP were slightly less in women than in men across treatment groups (Figure 2 and Table 2). Together with higher baseline BPs, this resulted in significantly higher systolic BPs in women than in men during the study. Diastolic BPs showed only minor differences between sexes. In women, the mean reduction in systolic BP from baseline was 2 to 3 mm Hg greater with chlorthalidone than with lisinopril and 0.4 to 1 mm Hg greater with chlorthalidone than with amlodipine. The mean attained systolic BP in women was 2 to 3 mm Hg lower on chlorthalidone versus lisinopril, and differed by <1 mm Hg on chlorthalidone versus amlodipine. Treatment-related differences were smaller in men: follow-up systolic BPs were 1.3 to 1.5 mm Hg lower on chlorthalidone than on either amlodipine or lisinopril. Follow-up diastolic BPs in men were similar in all 3 treatment groups. Although BP control rates were lower with lisinopril compared with chlorthalidone or amlodipine, >60% of participants were controlled to <140/90 mm Hg at year 4, and mean BP was <140/90 mm Hg in both sex subgroups. The percentage of participants with controlled BP (<140/90 mm Hg) was lower in women than in men by 1% to 4% at baseline across treatment groups, and this difference increased to 6% in the chlorthalidone and lisinopril groups, but decreased to 2% in the amlodipine group after 4 years of follow-up. BP control rates at year 4 were lowest with lisinopril in both sex subgroups; control rates with chlorthalidone and amlodipine were similar in women, but greater with chlorthalidone than amlodipine in men. Prevalence of diabetes mellitus based on examining only fasting blood glucose levels at baseline (rather than glucose

Oparil et al ALLHAT Outcomes by Sex 981 Downloaded from http://hyper.ahajournals.org/ by guest on April 22, 2018 A mm Hg B mm Hg 150 140 130 Men Women 120 0 6 12 18 24 30 36 42 48 54 60 66 72 Month 90 Men Women 85 80 75 70 0 6 12 18 24 30 36 42 48 54 60 66 72 Month Figure 2. Average systolic (A) and diastolic (B) blood pressure by sex. levels or history of diabetes mellitus as in Table 1) was higher in women than men, 30.7% versus 28.0% (Table 2). 23 During follow-up, fasting blood glucose increased the least in the lisinopril arm, and the most in the chlorthalidone arm in both sex subgroups (Table 2). The percentage of participants with fasting blood glucose >126 mg/dl at 2 and 4 years of follow-up increased by 2% to 5% with chlorthalidone, increased by 1% to 2% with amlodipine, and changed by between +1% and 3% with lisinopril in both sex groups. During follow-up, changes in serum K +, serum cholesterol, and serum creatinine were similar to what has been reported previously in both sexes (data not shown). 10 For the post-trial period, data are not available on glucose, potassium, cholesterol or creatinine levels, or BP. In-Trial Primary and Secondary Outcomes Six-year event rates for the primary outcome of nonfatal myocardial infarction and fatal CHD were lower in women than in men, 9.1 versus 13.9 per 100 participants (Tables 3 and 4). Between treatments, no significant differences were noted in either sex subgroup. Rates for the secondary end points of allcause mortality, combined CHD, combined CVD, stroke, HF (treated/fatal/hospitalized), and cancer were all lower in women. Rates for components of the secondary end points, including angina, coronary revascularization, and peripheral arterial disease, were also lower in women, whereas rates for hospitalized/ fatal HF and ESRD were similar in women and men. Between treatments, no significant differences were observed for all-cause mortality or its subcomponents, CV or combined CHD mortality, in either sex (Figure 3A and 3B). In women, stroke mortality rates tended to be lower (HR=0.86; P=0.45, for amlodipine versus chlorthalidone) and higher (HR=1.38; P=0.07, for lisinopril versus chlorthalidone). In men, these differences were smaller and also not statistically significant and there were no significant sex-treatment interactions (P>0.36). Combined CVD and HF (treated/fatal/hospitalized) were significantly increased in the lisinopril versus chlorthalidone arms in both women and men, whereas both HF outcomes were significantly increased in the amlodipine versus chlorthalidone arms. Stroke was significantly increased for women only in the lisinopril versus chlorthalidone comparison. There were no significant treatment sex interactions. Individual components of the combined CVD end point did not differ by sex. Regarding other secondary outcomes, rates for cancer or ESRD were not different in the amlodipine and lisinopril arms versus the chlorthalidone arm for either women or men. Extension Results No significant differences were observed in CV mortality for amlodipine (HR, 1.01; 95% CI, 0.93 1.10) or lisinopril (HR, 0.96; CI, 0.88 1.05), each compared with chlorthalidone, overall, or for men or women (Table S1 and Figure S2). The only significant differences in secondary outcomes were for hospitalized and fatal HF, which was higher with amlodipine (HR, 1.12; CI, 1.02 1.22), and stroke mortality, which was higher with lisinopril (HR, 1.20; CI, 1.01 1.41), each compared with chlorthalidone. Although men had a significantly higher HF risk (HR=1.17; P=0.03), there were no significant interactions by sex. The only significant treatment sex interaction noted was for cancer mortality for amlodipine versus chlorthalidone. For women, the HR was 1.20, 95% CI (1.02 1.40); for men, it was 0.93, 95% CI (0.82 1.05), P for interactions =0.01. With regard to comparison of rates by sex, men had higher overall total, CVD, and CHD 10-year mortality rates than women, whereas the stroke and HF 10-year morality rates were similar, overall, and within each treatment group. For combined fatal/nonfatal outcomes, men had higher 10-year rates of CHD, CVD, stroke, cancer, and ESRD, but lower 10-year rates for HF. Discussion Subgroup analyses of ALLHAT extend the findings of this trial and those of other studies by confirming the consistency of the results in both sexes. 10,24 28 In ALLHAT, no differences in CVD outcomes by sex were detected for the in-trial or extension periods. For the in-trial period, there were significantly higher rates of HF, stroke, and combined CVD for lisinopril compared with chlorthalidone, and significantly higher rates of HF for amlodipine compared with chlorthalidone. These findings did not persist through the extension period with the exception of the HF result for amlodipine versus chlorthalidone. 18 Though men had a significant 17% increased risk for amlodipine versus chlorthalidone, this was not significantly different from the result for women. Also, the finding of significantly higher stroke mortality during the extension period overall (HR, 1.20; CI, 1.10 14.1) for lisinopril versus chlorthalidone 18 did not differ significantly by sex. These results could be consistent with many other post-trial results, wherein the medications used, including the use of diuretics, likely became more similar across the randomized groups, or could be attributable to chance.

982 Hypertension May 2013 Table 2. Blood Pressure and Fasting Glucose Results at Baseline and Follow-Up Downloaded from http://hyper.ahajournals.org/ by guest on April 22, 2018 Men BP and Fasting Glucose Results Chlorthalidone Amlodipine Lisinopril All Men Chlorthalidone Amlodipine Lisinopril All Women Participants, n Baseline 8084 4768 4867 17 719 7171 4280 4187 15 638 Year 1 6945 4101 4148 15 194 5919 3508 3372 12 799 Year 2 6377 3727 3744 13 848 5362 3155 2956 11 473 Year 4 5256 3113 3051 11 420 4124 2524 2274 8922 Systolic blood pressure mm Hg, mean (SD) Baseline 145.5 (15.9) 145.8 (15.7) 145.6 (15.7) 145.6 (15.8) 147.1 (15.4) 146.7 (15.6) 147.3 (15.3) 147.0 (15.4) Year 1 136.1 (15.5) 137.8 (14.6) 138.7 (18.0) 137.3 (16.0) 137.7 (16.2) 139.3 (15.2) 141.6 (19.0) 139.2 (16.8) Year 2 135.1 (15.3) 136.7 (14.4) 137.3 (17.6) 136.1 (15.8) 136.9 (16.5) 137.6 (15.7) 139.9 (18.1) 137.9 (16.8) Year 4 132.9 (15.5) 134.2 (14.5) 134.4 (17.0) 133.7 (15.7) 135.3 (16.0) 135.6 (15.5) 137.0 (17.5) 135.8 (16.2) Mean change in SBP from baseline, mm Hg, mean (SD) Year 1 9.1 (18.4) 7.8 (18.8) 6.7 (20.4) 8.1 (19.1) 9.0 (19.1) 7.2 (18.8) 5.6 (21.2) 7.6 (19.7) Year 2 10.1 (19.0) 8.9 (18.4) 7.8 (20.3) 9.2 (19.2) 9.8 (19.8) 8.8 (19.8) 7.0 (21.2) 8.8 (20.2) Year 4 12.0 (19.6) 11.3 (19.3) 10.8 (20.6) 11.5 (19.8) 11.2 (19.9) 10.8 (20.0) 9.6 (21.4) 10.7 (20.3) Diastolic blood pressure mm Hg, mean (SD) Baseline 84.3 (10.1) 84.2 (10.2) 84.4 (10.0) 84.3 (10.1) 83.8 (10.0) 83.6 (10.1) 83.8 (10.0) 83.7 (10.0) Year 1 79.7 (9.6) 79.0 (9.5) 79.9 (10.5) 79.6 (9.8) 78.9 (9.6) 78.3 (9.6) 80.0 (10.5) 79.0 (9.9) Year 2 78.5 (9.6) 78.0 (9.4) 78.6 (10.5) 78.4 (9.8) 78.2 (9.5) 77.4 (9.8) 78.7 (10.1) 78.0 (9.7) Year 4 76.4 (9.8) 75.7 (9.5) 76.5 (10.4) 76.2 (9.9) 76.5 (9.4) 75.8 (9.6) 76.8 (10.3) 76.4 (9.7) Mean change in DBP from baseline, mg/dl, mean (SD) Year 1 4.3 (10.6) 5.0 (10.9) 4.4 (11.2) 4.5 (10.9) 4.7 (11.2) 5.2 (10.8) 3.6 (11.5) 4.5 (11.2) Year 2 5.6 (11.1) 6.1 (11.1) 5.5 (11.3) 5.7 (11.1) 5.4 (11.3) 6.1 (11.4) 4.8 (11.7) 5.5 (11.4) Year 4 7.5 (11.6) 8.3 (11.5) 7.7 (11.9) 7.8 (11.6) 6.9 (11.5) 7.6 (11.4) 6.5 (12.1) 7.0 (11.6) Blood pressure <140/90 mm Hg, n (%) Baseline 2344 (29.0) 1339 (28.1) 1352 (27.8) 5035 (28.4) 1810 (25.2) 1156 (27.0) 1031 (24.6) 3997 (25.6) Year 1 4123 (59.4) 2318 (56.5) 2213 (53.4) 8654 (57.0) 3309 (55.9) 1880 (53.6) 1588 (47.1) 6777 (53.0) Year 2 4047 (63.5) 2162 (58.0) 2114 (56.5) 8323 (60.1) 3109 (58.0) 1785 (56.6) 1513 (51.2) 6407 (55.8) Year 4 3658 (69.6) 2077 (66.7) 2001 (66.0) 7736 (67.8) 2630 (63.8) 1630 (64.6) 1359 (60.0) 5619 (63.0) Fasting glucose, mg/dl* Participants at 6003 3523 3657 13 183 5093 3015 3000 11 108 baseline, n Year 2 3320 1917 1892 7129 2517 1501 1353 5371 Year 4 2828 1612 1566 6006 2021 1260 1093 4374 Mean (SD) baseline 121.8 (55.9) 121.1 (53.5) 121.1 (52.5) 121.4 (54.3) 125.7 (61.4) 125.7 (60.9) 125.3 (60.1) 125.6 (60.9) Baseline if have 118.0 (48.8) 118.0 (47.9) 119.3 (48.7) 118.3 (48.5) 122.5 (57.4) 122.7 (58.4) 120.4 (54.8) 122.0 (57.0) 2 yr follow-up Year 2 125.9 (55.5) 121.2 (51.8) 121.5 (53.8) 123.4 (54.1) 129.9 (63.9) 124.0 (57.6) 120.6 (55.3) 125.9 (60.2) Year 4 125.0 (53.1) 122.3 (48.8) 122.3 (51.0) 123.5 (51.4) 128.3 (59.6) 126.1 (56.6) 120.3 (51.5) 125.7 (56.9) Change from baseline, mg/dl, mean (SD) Year 2 7.2 (48.4) 2.4 (45.7) 2.4 (47.4) 4.6 (47.5) 8.1 (53.3) 2.0 (52.9) 0.23 (49.5) 4.4 (52.4) Year 4 5.1 (54.5) 4.4 (48.7) 2.6 (48.5) 4.2 (51.4) 7.1 (59.1) 4.2 (56.8) 1.5 (49.0) 4.8 (56.1) Fasting glucose 126 mg/dl, n (%) Baseline 1650 (27.5) 997 (28.3) 1043 (28.5) 3690 (28.0) 1573 (31.0) 926 (30.7) 916 (30.5) 3415 (30.7) Year 2 1083 (32.6) 559 (29.2) 560 (29.6) 2202 (30.9) 844 (33.5) 461 (30.7) 369 (27.3) 1674 (31.2) Year 4 911 (32.2) 488 (30.3) 464 (29.6) 1863 (31.0) 670 (33.2) 395 (31.4) 300 (27.5) 1365 (31.2) *The number of participants with fasting glucose values is smaller than the numbers for the other measurements because the participants frequently arrived nonfasting, were asked to return fasting, and did not. The mean at baseline was also calculated for fasting glucose for only those participants who had a fasting glucose at year-2 follow-up. This is to make it easier for the reader to understand the mean changes, which are calculated only for participants with measurements at both time points. The mean changes are calculated using only those participants who have both a value at baseline and a value at the indicated year of follow-up. All other means are calculated for all participants at the designated time point. Women

Oparil et al ALLHAT Outcomes by Sex 983 Table 3. Clinical Outcomes by Antihypertensive Treatment Group (Women) Downloaded from http://hyper.ahajournals.org/ by guest on April 22, 2018 In a previous summary of the ALLHAT findings, 29 it was noted that BP differences may account for some but not all of the advantages seen with chlorthalidone. ALLHAT has reported analyses using achieved BP levels as time-dependent covariates in a Cox proportional hazard regression model showing that after adjustment for BP, the differences in risk of stroke and HF between treatment arms remain statistically significant, with only slight reduction in the HRs. 10,14,17,30 Also, in this previous summary, 29 it was noted that at doses equivalent to that used in ALLHAT (chlorthalidone, average of 20 mg/d), it is likely that attributes of chlorthalidone extend to the class of thiazide and thiazide-type diuretics. There was 1 significant treatment by sex interaction for the extended follow-up for cancer mortality (P=0.01 for interaction) for amlodipine versus chlorthalidone; women had an HR=1.20 (95%CI, 1.02 1.40; P=0.02), whereas men had an HR=0.93 (95% CI, 0.82 1.05; P=0.26). For the in-trial period, the results were similar significant treatment sex interaction (P=0.03 for interaction) for amlodipine versus chlorthalidone women had an HR=1.19 (95% CI, 0.93 1.51; P=0.16), whereas men had an HR=0.82 (0.68 0.97; P=0.02). Given the many analyses performed, this may just be the play of chance. These findings are consistent with results of a prospectively designed overview by the Blood Pressure Lowering Treatment Trialists Collaboration of 31 randomized controlled trials of antihypertensive treatment with CVD outcomes that included 87 349 women and 103 268 men. 3 The collaboration, which included ALLHAT, tested whether there were 6-y Rate per 100 Persons (SE), n Hazard Ratio and 95% Confidence Interval Outcomes Chlorthalidone Amlodipine Lisinopril Total A/C L/C Total randomized, n 7171 4280 4187 15 638 Primary end point CHD (nonfatal MI + fatal CHD) 9.2 (0.5), 477 8.9 (0.6), 282 9.2 (0.6), 287 9.1 (0.3), 1046 0.99 (0.86 1.14) 1.05 (0.91 1.21) Secondary end points Mortality outcomes All-cause mortality 15.7 (0.6), 867 15.1 (0.7), 491 15.3 (0.7), 499 15.4 (0.4), 1857 0.96 (0.86 1.07) 1.00 (0.90 1.11) CV mortality 7.9 (0.4), 416 7.9 (0.5), 244 7.8 (0.5), 246 7.9 (0.3), 906 0.97 (0.83 1.13) 1.00 (0.86 1.17) CHD 4.0 (0.3), 206 3.8 (0.4), 116 3.7 (0.4), 116 3.9 (0.2), 438 0.94 (0.76 1.18) 0.97 (0.78 1.21) Stroke 1.2 (0.2), 69 1.3 (0.2), 35 1.7 (0.3), 54 1.4 (0.1), 158 0.86 (0.58 1.28) 1.38 (0.98 1.96) Heart Failure 1.4 (0.2), 63 1.4 (0.2), 45 1.4 (0.3), 37 1.4 (0.1), 145 1.12 (0.77 1.62) 0.92 (0.62 1.37) Cancer 2.8 (0.3), 155 3.1 (0.3), 107 2.6 (0.3), 86 2.8 (0.2), 348 1.19 (0.93 1.51)* 1.03 (0.80 1.32) Combined fatal/nonfatal outcomes Combined CVD 26.8 (0.7), 1526 27.3 (0.9), 944 28.4 (0.9), 963 27.3 (0.5), 3433 1.03 (0.95 1.12) 1.11 (1.02 1.20) Stroke 5.3 (0.3), 281 4.5 (0.4), 139 6.3 (0.5), 196 5.3 (0.2), 616 0.84 (0.69 1.02) 1.21 (1.01 1.45) Renal disease 1.8 (0.2), 83 1.9 (0.3), 55 2.2 (0.3), 62 2.0 (0.2), 200 1.08 (0.77 1.51) 1.27 (0.91 1.76) Cancer 6.8 (0.4), 366 6.7 (0.5), 229 7.3 (0.5), 226 6.9 (0.3), 821 1.06 (0.90 1.25) 1.09 (0.93 1.29) Heart failure (treated /hospitalized/fatal) 7.9 (0.5), 379 9.6 (0.6), 302 8.3 (0.5), 268 8.5 (0.3), 949 1.32 (1.13 1.53) 1.22 (1.04 1.42) Hospitalized/fatal heart failure 6.8 (0.4), 325 8.0 (0.5), 251 6.7 (0.5), 206 7.1 (0.3), 782 1.28 (1.08 1.50) 1.09 (0.91 1.29) Hospitalized angina 6.3 (0.3), 369 6.6 (0.5), 221 7.3 (0.5), 243 6.6 (0.2), 833 0.98 (0.83 1.16) 1.14 (0.97 1.34) Coronary revascularization 6.4 (0.4), 349 6.8 (0.5), 227 6.5 (0.5), 208 6.5 (0.3), 784 1.08 (0.92 1.28) 1.03 (0.87 1.22) Peripheral arterial disease 3.1 (0.3), 175 2.5 (0.3), 90 3.7 (0.4), 117 3.1 (0.2), 382 0.85 (0.66 1.10) 1.15 (0.91 1.45) CV indicates cardiovascular; CVD, cardiovascular disease; HR, hazard ratio; and MI, myocardial infarction. *Cancer mortality: significant treatment sex interaction (P=0.03 for interaction) for A vs C. Female: HR 1.19 (0.93 1.51, P=0.16). Male: HR 0.82 (0.68 0.97, P=0.02). important differences between sexes in the effects of different BP-lowering regimens. 3 Separate overviews were carried out for trials comparing active agents with placebo, more intensive with less intensive BP-lowering regimens, and 1 active agent with another. For all treatment comparisons, mean baseline BPs were slightly higher for women compared with men, but achieved BP reductions were comparable in both sexes. There was no evidence of a difference in the effects of BP-lowering treatment regimens between women and men for any CVD outcome except stroke. For stroke, there was some evidence that women, but not men, derive greater benefit from calcium channel blocker-based regimens than ACE inhibitor-based regimens. Evidence for this interaction was of borderline (P=0.05) statistical significance and, in view of the large number (42) of subgroup analyses made in the study, was attributed by the authors to chance. Overall, there was no evidence that women and men derived different levels of outcome benefit from BP reduction or that regimens based on different drug classes were more effective in one sex than the other. On the basis of these observations, the authors concluded that a patient s sex should not influence decisions about the need for BP-lowering therapy, the magnitude of BP reduction to be sought, or the selection of drug class. These findings reinforce the conclusions of earlier overviews of aggregated data from randomized trials that compared active treatment with placebo or less systematically treated controls and reported results by sex. 31 33 The earlier analyses concluded that treatment effects (as assessed

984 Hypertension May 2013 Table 4. Clinical Outcomes by Antihypertensive Treatment Group (Men) Downloaded from http://hyper.ahajournals.org/ by guest on April 22, 2018 by HRs) on morbidity and mortality did not differ between women and men. Although absolute benefit of treatment did differ between sexes for some outcomes (eg, greater for CHD and mortality in men) but not others (eg, stroke), the sex differences in absolute benefit were entirely attributable to differences in underlying risk. With regard to choice of first-step drugs, early trial evidence suggested no significant differences in major outcomes between diuretic-based and β-blocker based treatment in either sex. Other outcome trials of BP treatment that reported results by sex confirm the ALLHAT findings. With regard to calcium channel blocker-based treatment, the placebo-controlled Systolic Hypertension in Europe trial reported no interaction by sex for either stroke or cardiac outcomes, 34 and 1 direct comparator trial, the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial 25 reported no sex difference in relative risks for the primary composite CV outcome in the study as a whole, which were near unity, or between treatment arms (verapamil versus β-blocker or diuretic). A prespecified subgroup analysis from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial found a relative excess of the primary composite CV end point with valsartan-based compared with amlodipine-based treatment in women but not in men. 35,36 Much of this outcome benefit was attributed to greater BP reduction with amlodipine in women. However, the authors questioned whether there is a genuine sex difference in the cardiac protection afforded 6-y Rate per 100 Persons (SE), n Hazard Ratio and 95% Confidence Interval Outcomes Chlorthalidone Amlodipine Lisinopril Total A/C L/C Total randomized 8084 4768 4867 17 719 Primary end point CHD (nonfatal MI + fatal CHD) 14.1 (0.5), 878 14.0 (0.6), 508 13.5 (0.6), 493 13.9 (0.3), 1879 0.98 (0.88 1.10) 0.94 (0.84 1.05) Secondary end points Mortality outcomes All-cause mortality 20.4 (0.5), 1345 19.7 (0.7), 763 19.8 (0.7), 797 20.0 (0.4), 2905 0.95 (0.88 1.04) 0.98 (0.90 1.06) CV mortality 9.1 (0.4), 581 9.9 (0.5), 370 9.6 (0.5), 362 9.5 (0.3), 1313 1.05 (0.93 1.20) 1.03 (0.90 1.17) CHD 5.4 (0.3), 338 5.5 (0.4), 202 5.5 (0.4), 205 5.4 (0.2), 745 0.99 (0.84 1.18) 1.00 (0.84 1.18) Stroke 1.6 (0.2), 91 1.6 (0.2), 58 1.6 (0.2), 61 1.6 (0.1), 210 1.05 (0.76 1.44) 1.11 (0.81 1.52) Heart failure 0.8 (0.1), 51 1.2 (0.2), 38 1.0 (0.2), 33 1.0 (0.1), 122 1.27 (0.84 1.91) 1.06 (0.69 1.63) Cancer* 6.1 (0.3), 369 4.6 (0.4), 175 5.5 (0.4), 208 5.5 (0.2), 752 0.82 (0.68 0.97)* 0.94 (0.80 1.11) Combined fatal/nonfatal outcomes Combined CVD 35.4 (0.7), 2376 36.8 (0.9), 1454 37.8 (0.9), 1515 36.4 (0.4), 5345 1.04 (0.98 1.11) 1.07 (1.00 1.15) Stroke 6.3 (0.3), 380 6.4 (0.4), 231 6.5 (0.4), 250 6.4 (0.2), 861 1.00 (0.86 1.18) 1.09 (0.93 1.28) Renal disease 1.9 (0.2), 105 2.3 (0.3), 73 1.9 (0.3), 64 2.0 (0.1), 242 1.13 (0.85 1.52) 1.00 (0.74 1.35) Cancer 12.9 (0.5), 799 13.0 (0.6), 463 12.4 (0.6), 461 12.8 (0.3), 1723 0.98 (0.88 1.10) 0.96 (0.86 1.08) Heart failure (treated/hospitalized/fatal) 7.9 (0.4), 466 11.0 (0.6), 385 9.2 (0.5), 333 9.1 (0.3), 1184 1.41 (1.24 1.61) 1.18 (1.03 1.36) Hospitalized/fatal heart failure 6.5 (0.4), 375 8.9 (0.5), 307 7.2 (0.5), 253 7.3 (0.3), 935 1.40 (1.20 1.62) 1.12 (0.96 1.31) Hospitalized angina 10.7 (0.4), 681 10.2 (0.5), 400 11.5 (0.6), 438 10.8 (0.3), 1519 0.98 (0.87 1.11) 1.06 (0.94 1.20) Coronary revascularization 11.9 (0.5), 737 12.9 (0.6), 472 13.5 (0.6), 495 12.6 (0.3), 1704 1.10 (0.98 1.23) 1.12 (1.00 1.25) Peripheral arterial disease 4.9 (0.3), 328 4.7 (0.4), 169 5.0 (0.4), 193 4.9 (0.2), 690 0.88 (0.73 1.05) 0.97 (0.81 1.16) CV indicates cardiovascular; CVD, cardiovascular disease; HR, hazard ratio; and MI, myocardial infarction. *Cancer mortality: significant treatment sex interaction (P=0.03 for interaction) for A vs C. Female: HR 1.19 (0.93 1.51, P=0.16). Male: HR 0.82 (0.68 0.97, P=0.02). by the amlodipine-based versus valsartan-based treatment because the trend toward less HF in valsartan-treated patients was significant only in men. The results of ALLHAT differ from those of a smaller trial carried out in a less diverse population in which fewer events were reported. The Australian National Blood Pressure-2 (ANBP-2) trial showed a lack of benefit of ACE inhibitor (enalapril)-based treatment compared with diuretic-based treatment in women, but not in men. 37 There was a nonsignificant interaction by sex in the context of an overall marginally significant difference (P=0.05) favoring the ACE inhibitor for all CV events/total mortality. Only 524 events were observed in women in ANBP-2, suggesting that the apparent lack of benefit of ACE inhibitor treatment reflected inadequate power to detect a beneficial effect of renin-angiotensin-aldosterone system blockade in hypertensive women, in whom event rates are lower than in men. The different results may also reflect differences in baseline characteristics of the populations included in ANBP-2 compared with ALLHAT. ANBP-2 included an older population with higher baseline systolic and diastolic BPs and lower prevalence of CHD, cerebrovascular disease, diabetes mellitus, and smoking. Perspectives The similarity of the treatment effects in ALLHAT by sex is robust because of the large sample size equally distributed between men and women. The ALLHAT conclusion reported

Oparil et al ALLHAT Outcomes by Sex 985 Downloaded from http://hyper.ahajournals.org/ by guest on April 22, 2018 Hosp/Fatal Stroke Cumulative Event Rate Trt/Hosp/Fatal CHF CHD Hosp/Fatal Cancer ESRD 0.20 0.10 Total Mortality0.30 A Chlorthalidone Amlodipine Lisinopril 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 for the whole cohort that neither lisinopril nor amlodipine is superior to chlorthalidone for initial therapy of hypertension also applies to the prespecified subgroups defined by sex. These drugs did not surpass the diuretic chlorthalidone in lowering BP, tolerability, or in preventing major clinical complications of hypertension. Sources of Funding This study was supported by contracts NO1-HC-35130 and HHSN268201100036C with the National Heart, Lung, and Blood Institute. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial investigators acknowledge study medications contributed by Pfizer, Inc., (amlodipine and doxazosin), 0.30 0.20 0.10 0.50 0.40 0.40 0.30 0.30 0.20 0.20 0.10 0.10 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Combined CVD0.50 0.09 0.06 0.03 C E 0.09 0.06 0.03 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 0.15 0.10 0.05 G 0.15 0.10 0.05 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 0.18 0.12 0.06 I 0.18 0.12 0.06 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 K 0.15 0.15 0.12 0.12 0.09 0.09 0.06 0.06 0.03 0.03 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 0.03 0.02 0.01 M Men 0.03 0.02 0.01 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Years to Event B D F H J L N Women Figure 3. Kaplan-Meier curves for morbidity and mortality rates by sex and treatment group. AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin) and financial support provided by Pfizer, Inc. Disclosures Dr Cushman has received honoraria from Amgen, Daiichi Sankyo, Novartis, Noven, Sanofi, Takeda, Theravance; and has received research support from GlaxcoSmithKline and Novartis. Dr Davis has received honoria from Amgen and Takeda. Dr Habib has received research support from AstraZeneca, GlaxcoSmithKline, and Sanofi Aventis. Dr Margolis has received research support from Bristol- Myers Squibb. Dr Oparil has received honoraria from Eli Lilly, Schering Plough, Novartis, Daiichi Sankyo, Boehringer Ingelheim, Forest Pharmaceuticals, NicOx, Forest Laboratories, Pfizer, Omron Healthcare; and has received research support from Bristol-Myers Squibb, Takeda, Daiichi Sankyo, Gilead, Merck, Amgen, Boehringer Ingelheim, Sanofi Aventis, Abott Laboratories, and GlaxoSmithKline. Dr Wright has received honoraria from Sanofi Aventis, CVRx, Daiichi Sankyo, and Novartis. The other authors have no conflicts to report. References 1. 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986 Hypertension May 2013 Downloaded from http://hyper.ahajournals.org/ by guest on April 22, 2018 14. Davis BR, Cutler JA, Furberg CD, Wright JT, Farber MA, Felicetta JV, Stokes JD; ALLHAT Collaborative Research Group. Relationship of antihypertensive treatment regimens and change in blood pressure to risk for heart failure in hypertensive patients randomly assigned to doxazosin or chlorthalidone: further analyses from the Antihypertensive and Lipid-Lowering treatment to Prevent Heart Attack Trial. Ann Intern Med. 2002;137(5 part 1):313 320. 15. Piller LB, Davis BR, Cutler JA, Cushman WC, Wright JT Jr, Williamson JD, Leenen FH, Einhorn PT, Randall OS, Golden JS, Haywood LJ; The ALLHAT Collaborative Research Group. Validation of heart failure events in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants assigned to doxazosin and chlorthalidone. Curr Control Trials Cardiovasc Med. 2002;3:10. 16. 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Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA. 2003;289:2073 2082. 26. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145 153. 27. Hansson L, Lindholm LH, Ekbom T, Dahlöf B, Lanke J, Scherstén B, Wester PO, Hedner T, de Faire U. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999;354:1751 1756. 28. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992; 327: 685 691. 29. Wright JT Jr, Probstfield JL, Cushman WC, Pressel SL, Cutler JA, Davis BR, Einhorn PT, Rahman M, Whelton PK, Ford CE, Haywood LJ, Margolis KL, Oparil S, Black HR, Alderman MH; ALLHAT Collaborative Research Group. ALLHAT findings revisited in the context of subsequent analyses, other trials, and meta-analyses. Arch Intern Med. 2009;169:832 842. 30. Davis BR, Piller LB, Cutler JA, Furberg C, Dunn K, Franklin S, Goff D, Leenen F, Mohiuddin S, Papademetriou V, Proschan M, Ellsworth A, Golden J, Colon P, Crow R; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Role of diuretics in the prevention of heart failure: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation. 2006;113:2201 2210. 31. MacMahon SW, Cutler JA, Furberg CD, Payne GH. The effects of drug treatment for hypertension on morbidity and mortality from cardiovascular disease: a review of randomized controlled trials. Prog Cardiovasc Dis. 1986;29(3 suppl 1):99 118. 32. Simons-Morton DG, Cutler JA, Allender PS. Hypertension treatment trials and stroke occurrence revisited. A quantitative overview. Ann Epidemiol. 1993;3:555 562. 33. Gueyffier F, Boutitie F, Boissel JP, Pocock S, Coope J, Cutler J, Ekbom T, Fagard R, Friedman L, Perry M, Prineas R, Schron E. Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men. A meta-analysis of individual patient data from randomized, controlled trials. The INDANA Investigators. Ann Intern Med. 1997;126:761 767. 34. Staessen JA, Thijs L, Celis H, Gasowski J, Wang JG, Fagard RH; Systolic Hypertension in Europe Trial Investigators (the Syst-Eur Trial). Dihydropyridine calcium-channel blockers for antihypertensive treatment in older patients evidence from the Systolic Hypertension in Europe Trial. S Afr Med J. 2001;91:1060 1068. 35. Zanchetti A, Julius S, Kjeldsen S, et al. Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan and amlodipine: An analysis of findings from the VALUE trial. J Hypertens. 2006;24:2163 2168. 36. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A; VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363:2022 2031. 37. Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ; Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin-converting enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003;348:583 592. Novelty and Significance What Is New? This analysis includes >15 000 women, the largest female cohort in a trial to examine the comparative efficacy of antihypertensive medications. Participants were actively followed for an average of 4.9 years and passively followed for an additional average of 4 years, making this one of the longest follow-up times for this type of trial. What Is Relevant? Hypertension is highly prevalent, difficult to control, and associated with a high incidence of cardiovascular disease complications in older women, the population that was enrolled in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Epidemiological evidence shows that women are less likely than men to meet blood pressure control targets. Summary The ALLHAT conclusion reported for the whole cohort that neither lisinopril nor amlodipine is superior to chlorthalidone for initial therapy of hypertension also applies to the prespecified subgroups defined by sex.

Downloaded from http://hyper.ahajournals.org/ by guest on April 22, 2018 Mortality and Morbidity During and After Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: Results by Sex Suzanne Oparil, Barry R. Davis, William C. Cushman, Charles E. Ford, Curt D. Furberg, Gabriel B. Habib, L. Julian Haywood, Karen Margolis, Jeffrey L. Probstfield, Paul K. Whelton and Jackson T. Wright, Jr for the ALLHAT Collaborative Research Group Hypertension. 2013;61:977-986; originally published online March 25, 2013; doi: 10.1161/HYPERTENSIONAHA.111.00213 Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://hyper.ahajournals.org/content/61/5/977 Data Supplement (unedited) at: http://hyper.ahajournals.org/content/suppl/2013/03/25/hypertensionaha.111.00213.dc1 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Hypertension is online at: http://hyper.ahajournals.org//subscriptions/

1 Online Supplement Mortality and morbidity during and after ALLHAT: Results by gender Suzanne Oparil, MD; Barry R. Davis, MD, PhD; William C. Cushman, MD; Charles E. Ford, PhD; Curt D. Furberg, MD, PhD; Gabriel B. Habib, MD; L. Julian Haywood, MD; Karen Margolis, MD, MPH; Jeffrey L. Probstfield, MD; Paul K. Whelton, MB, MD, MSc; Jackson T. Wright, Jr, MD, PhD; for the ALLHAT Collaborative Research Group (see JAMA 2000;283:1973 1975). From the Vascular Biology & Hypertension Program, University of Alabama at Birmingham, Birmingham, AL (S.O.); Coordinating Center for Clinical Trials, Biostatics Division, The University of Texas School of Public Health, Houston, TX (B.R.D., C.E.F.); Preventive Medicine Section, Memphis Veterans Affairs Medical Center, Memphis, TN (W.C.C.); Department of Public Health Sciences, Wake Forest University School of Medicine, Winston Salem, NC (C.D.F.); Veterans Affairs Medical Center Houston, Houston, TX (G.B.H); Keck School of Medicine, University of Southern California, Los Angeles, CA (L.J.H); Clinical Research, HealthPartners Institute for Education and Research, Minneapolis, MN (K.L.M); Clinical Trials Service Unit, University of Washington Medical Center Seattle, WA (J.L.P); Global Public Health, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (P.K.W); Division of Nephrology and Hypertension, University Hospitals Case Medical Center, Cleveland, OH (J.T.W.). Clinical trial registration: www.clinicaltrials.gov, NCT00000542

2 Extended Follow up Outcomes: Definitions and Determination Mortality Only Endpoints Mortality data were available during both in-trial and post-trial periods for the entire cohort except for Canadian participants (n= 553, due to lack of availability of necessary identifying information) (Figure 1). In-trial deaths were ascertained by investigators and confirmed by death certificates, and posttrial deaths, from NDI and SSA. In-trial causes of death were determined by investigators. When the cause of death was reported as unknown, we used the NDI Plus database, which also provided causespecific mortality for the post-trial period. Data from NDI and SSA used Social Security number, name, date of birth, and sex (NDI only) as matching criteria. CVD mortality (death due to CHD, stroke, HF, or other CVD) was designated a priori as the primary endpoint. Total mortality and categories of death were prespecified and assessed as important secondary outcomes (see research protocol at www.allhat.org). A death identified through NDI or SSA was verified at the ALLHAT Clinical Trials Center (CTC) after receipt and review of a death certificate from the state or other jurisdiction. Of 6492 death certificates requested for the groups compared herein, 6488 (99.9%) were received, and 6367 (98.1% of those received) were determined to be for an ALLHAT participant. Death certificates were not obtainable for 4 deaths; these deaths and their reported causes were included in the main analyses, as the matching algorithm had been demonstrated to be highly reliable. Causes of death (ICD-10 coding) from NDI Plus were collapsed into 11 categories (see research protocol at www.allhat.org). These were initally provided under the International Classification of Diseases (ICD) 9 th revision; for deaths occurring in 1999 forward, the ICD-10 th revision. The World Health Organization (WHO) s Two-way Translator for the Ninth and Tenth Revisions (1997) was used to convert ICD-10 codes to ICD-9. Fatal and Nonfatal Endpoints Hospitalization data were available for both in-trial and post-trial periods for the majority of participants. During the in-trial period, events were ascertained and classified by investigators and confirmed by the ALLHAT CTC based on discharge summaries. Unlike previous reports from ALLHAT, in-trial ESRD events (chronic dialysis or kidney transplant) were ascertained from the United States Renal Data System (USRDS). During the post-trial period, nonfatal events were ascertained from the Centers for Medicare and Medicaid Services (CMS [formerly HCFA]) and the USRDS. Events identified through CMS data were classified using the provided ICD-9 codes from those sources. During the post-trial period, nonfatal outcome data, except for ESRD, are only available for participants from non-va U.S. clinical centers who have valid Medicare or Social Security numbers (65% of all participants), due to lack of access for administrative reasons. The following fatal/non-fatal composites were prespecified as secondary endpoints: CVD (CVD death or hospitalized non-fatal MI, stroke, or HF), CHD (CHD death or hospitalized non-fatal MI), stroke (fatal or non-fatal hospitalized), HF (fatal or non-fatal hospitalized), and ESRD. Details on how the databases were used to identify events are noted in our online protocol (see www.allhat.org). For the post-trial period, data are not available on medications, BP levels, outpatient morbidity, or laboratory values.

3 Table S1A: Outcomes through the extension period by antihypertensive treatment group (men) Chlorthalidone Amlodipine Lisinopril All men Outcomes 10 y rate(se) per 100 persons HR*(95% CI) P 10 y rate(se) Per 100 persons HR * (95% CI) P 10 y rate(se) per100 persons 10 y rate(se) Mortality outcomes per100 persons All Cause mortality 37.0(0.6) 36.6(0.7) 0.97(0.92 1.03) 0.40 36.5(0.7) 0.97(0.92 1.03) 0.35 37.8(0.4) CV mortality 18.1(0.5) 18.2(0.6) 1.01(0.93 1.10) 0.21 17.7(0.6) 0.96(0.88 1.05) 0.43 18.1(0.3) CHD 10.3(0.4) 9.8(0.5) 0.96(0.85 1.08) 0.48 10.0(0.5) 0.96(0.85 1.08) 0.53 10.1(0.3) Stroke 2.7(0.2) 2.8(0.3) 1.04(0.82 1.32) 0.74 3.1(0.3) 1.14(0.91 1.43) 0.26 2.8(0.1) Heart failure 1.7(0.2) 1.7(0.2) 0.94(0.70 1.27) 0.70 1.5(0.2) 0.81(0.60 1.11) 0.20 1.7(0.1) Cancer 10.1(0.4) 9.7(0.5) 0.93(0.82 1.05) 0.26 10.4(0.5) 1.00(0.89 1.13) 0.95 10.1(0.3) Combined fatal/ nonfatal outcomes CHD 21.3(0.7) 21.3(0.9) 0.98(0.87 1.10) 0.73 20.8(0.9) 0.97(0.87 1.09) 0.62 21.2(0.5) CVD 40.2(0.8) 42.1(1.1) 1.06(0.98 1.15) 0.13 40.1(1.1) 1.00(0.92 1.08) 0.94 40.7(0.6) Heart failure 14.8(0.7) 16.1(0.9) 1.17(1.02 1.34) 0.03 14.7(0.8) 0.99(0.86 1.14) 0.91 15.1(0.4) Stroke 13.0(0.6) 14.6(0.8) 1.06(0.92 1.23) 0.41 14.3(0.8) 1.06(0.92 1.23) 0.42 13.8(0.4) Cancer 17.4(0.7) 18.4(0.9) 1.04(0.92 1.18) 0.51 17.1(0.8) 0.98(0.87 1.11) 0.80 17.6(0.5) ESRD 3.3(0.2) 3.3(0.3) 1.01(0.82 1.26) 0.89 2.8(0.3) 0.85(0.68 1.07) 0.18 3.2(0.2) Abbreviations: CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; ESRD, end stage renal disease *Comparisons are amlodipine to chlorthalidone and lisinopril to chlorthalidone

Table S1B: Outcomes through the extension period by antihypertensive treatment group (women) Chlorthalidone Amlodipine Lisinopril All women Outcomes 10 y rate(se) per 100 persons 10 y rate(se) per 100 persons HR*(95% CI) P 10 y rate(se) per 100 persons HR*(95% CI) P 10 y rate(se) per100 persons All Cause mortality 29.7(0.6) 29.3(0.7) 0.99(0.93 1.06) 0.87 28.3(0.7) 0.96(0.90 1.03) 0.28 29.2(0.4) CV mortality 14.6(0.5) 14.1(0.6) 0.98(0.88 1.08) 0.67 13.8(0.6) 0.96(0.87 1.07) 0.48 14.3(0.3) CHD 6.9(0.3) 7.2(0.4) 1.04(0.90 1.21) 0.61 6.2(0.4) 0.91(0.78 1.06) 0.24 6.8(0.2) Stroke 2.5(0.2) 2.3(0.3) 0.96(0.75 1.25) 0.79 3.0(0.3) 1.26(0.99 1.60) 0.06 2.6(0.1) Heart failure 2.0(0.2) 1.8(0.2) 0.94(0.70 1.27) 0.71 1.7(0.2) 0.96(0.71 1.29) 0.77 1.9(0.1) Cancer 6.0(0.3) 6.9(0.4) 1.20(1.02 1.40) 0.02 6.2(0.4) 1.01(0.86 1.19) 0.91 6.3(0.2) Combined fatal or nonfatal hospitalized events CHD 16.7(0.6) 16.9(0.8) 1.02(0.91 1.14) 0.71 16.1(0.7) 0.98(0.87 1.10) 0.77 16.6(0.4) CVD 37.4(0.7) 35.7(0.9) 1.00(0.92 1.07) 0.94 35.5(0.9) 0.98(0.91 1.06) 0.61 36.5(0.5) Heart failure 15.9(0.6) 16.1(0.7) 1.08(0.96 1.22) 0.18 15.4(0.8) 1.00(0.88 1.13) 0.98 15.8(0.4) Stroke 13.3(0.6) 12.1(0.7) 0.93(0.81 1.06) 0.30 13.2(0.7) 1.02(0.90 1.17) 0.72 12.9(0.4) Cancer 11.9(0.5) 13.4(0.7) 1.13(0.99 1.29) 0.06 12.6(0.7) 1.04(0.91 1.19) 0.54 12.5(0.4) ESRD 2.8(0.2) 2.9(0.3) 1.03(0.82 1.31) 0.78 3.1(0.3) 1.13(0.89 1.42) 0.31 2.9(0.2) Abbreviations: CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; ESRD, end stage renal disease *Comparisons are amlodipine to chlorthalidone and lisinopril to chlorthalidone Cancer mortality significant treatment x gender interaction (P=.01 for interaction) for A vs C. Women: HR 1.20 (1.02 1.40, P=.02). Men: HR 0.93 (0.82 1.05, P=.26). 4

Table S2A. In trial and post trial hazard ratios (men) 5 Hazard Ratio (95 % Confidence Interval) Amlodipine vs Chlorthalidone Lisinopril vs Chlorthalidone Outcomes In Trial Post Trial P In Trial Post Trial P All cause mortality 0.96(0.88 1.04) 0.99(0.92 1.07) 0.56 0.98(0.90 1.07) 0.97(0.89 1.05) 0.83 CV mortality 1.05(0.93 1.19) 0.97(0.86 1.10) 0.39 1.03(0.91 1.17) 0.91(0.81 1.03) 0.18 CHD 0.98(0.83 1.17) 0.93(0.79 1.10) 0.66 1.00(0.85 1.19) 0.92(0.78 1.09) 0.50 Stroke 1.07(0.77 1.47) 1.01(0.71 1.43) 0.81 1.15(0.84 1.57) 1.12(0.80 1.57) 0.92 Heart Failure 1.24(0.83 1.87) 0.70(0.45 1.09) 0.06 1.01(0.65 1.55) 0.66(0.42 1.03) 0.18 Other CVD 1.16(0.86 1.55) 1.13(0.91 1.40) 0.89 1.02(0.75 1.38) 0.88(0.70 1.12) 0.48 Non CV mortality 0.85(0.75 0.97) 1.01(0.91 1.12) 0.05 0.92(0.82 1.04) 1.01(0.91 1.12) 0.25 Cancer 0.80(0.67 0.96) 1.08(0.91 1.28) 0.02 0.93(0.79 1.10) 1.08(0.91 1.28) 0.22 Kidney disease 1.77(0.91 3.44) 0.96(0.60 1.52) 0.14 1.55(0.78 3.06) 1.00(0.63 1.58) 0.30 Accident/suicide/homicide 0.48(0.27 0.84) 1.13(0.69 1.48) 0.02 0.68(0.42 1.13) 1.02(0.62 1.69) 0.26 Other non CVD 0.94(0.77 1.14) 0.95(0.82 1.10) 0.92 0.91(0.75 1.11) 0.96(0.83 1.11) 0.66 Unknown cause 1.20(0.84 1.71) 0.91(0.47 1.73) 0.45 1.14(0.80 1.62) 0.95(0.50 1.79) 0.62 Combined fatal or nonfatal hospitalized events CHD 0.98(0.84 1.13) 0.98(0.82 1.18) 0.95 0.95(0.82 1.10) 1.00(0.84 1.20) 0.66 CVD 1.11(0.99 1.24) 1.01(0.90 1.14) 0.28 1.05(0.94 1.17) 0.94(0.84 1.06) 0.21 Heart failure 1.51(1.24 1.84) 0.91(0.75 1.11) 1.18(0.96 1.45) 0.86(0.70 1.04) 0.03 Stroke 1.06(0.85 1.31) 1.07(0.87 1.32) 0.92 1.14(0.93 1.40) 1.00(0.81 1.23) 0.37 Cancer 0.98(0.84 1.15) 1.17(0.95 1.44) 0.19 0.94(0.80 1.10) 1.07(0.86 1.32) 0.34 ESRD 1.24(0.88 1.74) 0.89(0.67 1.18) 0.14 0.88(0.60 1.27) 0.84(0.63 1.12) 0.87 Abbreviations: CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; ESRD, end stage renal disease

Table S2B. In trial and post trial hazard ratios (women) 6 Hazard Ratio (95 % Confidence Interval) Amlodipine vs Chlorthalidone Lisinopril vs Chlorthalidone Outcomes In Trial Post Trial P In Trial Post Trial P All cause mortality 0.97(0.87 1.08) 1.01(0.92 1.10) 0.60 1.00(0.90 1.11) 0.93(0.85 1.02) 0.33 CV mortality 0.98(0.84 1.14) 0.98(0.85 1.12) 0.99 1.01(0.86 1.17) 0.93(0.80 1.07) 0.42 CHD 0.95(0.76 1.19) 1.12(0.92 1.37) 0.29 0.97(0.78 1.21) 0.86(0.69 1.07) 0.45 Stroke 0.88(0.60 1.31) 1.03(0.74 1.45) 0.56 1.38(0.98 1.95) 1.16(0.83 1.61) 0.47 Heart Failure 1.12(0.77 1.62) 0.72(0.43 1.18) 0.16 0.92(0.62 1.37) 1.00(0.64 1.58) 0.77 Other CVD 1.01(0.71 1.43) 0.83(0.64 1.08) 0.39 0.87(0.60 1.26) 0.87(0.67 1.13) 0.97 Non CV mortality 0.96(0.82 1.13) 1.02(0.90 1.15) 0.59 1.00(0.85 1.18) 0.93(0.82 1.05) 0.46 Cancer 1.20(0.94 1.53) 1.19(0.97 1.46) 0.97 1.01(0.79 1.31) 1.01(0.81 1.25) 0.98 Kidney disease 0.58(0.26 1.30) 1.01(0.62 1.66) 0.25 1.11(0.58 2.14) 0.83(0.49 1.42) 0.49 Accident/suicide/homicide 0.63(0.25 1.60) 1.08(0.54 2.17) 0.36 0.86(0.37 2.00) 1.20(0.61 2.37) 0.55 Other non CVD 0.85(0.67 1.08) 0.92(0.79 1.08) 0.57 0.99(0.79 1.25) 0.88(0.75 1.04) 0.41 Unknown cause 0.99(0.68 1.45) 1.45(0.81 2.61) 0.28 0.94(0.64 1.39) 1.21(0.65 2.26) 0.50 Combined fatal or nonfatal hospitalized events CHD 0.97(0.84 1.13) 1.08(0.91 1.28) 0.38 1.02(0.88 1.19) 0.93(0.78 1.12) 0.46 CVD 1.00(0.90 1.11) 0.99(0.89 1.10) 0.87 1.06(0.95 1.17) 0.90(0.81 1.01) 0.04 Heart failure 1.27(1.07 1.50) 0.94(0.80 1.11) 0.01 1.06(0.88 1.27) 0.96(0.81 1.13) 0.44 Stroke 0.83(0.68 1.03) 1.00(0.84 1.19) 0.19 1.20(0.99 1.45) 0.89(0.74 1.07) 0.03 Cancer 1.09(0.92 1.30) 1.18(0.97 1.43) 0.56 1.11(0.93 1.32) 0.96(0.78 1.18) 0.31 ESRD 1.08(0.75 1.54) 1.00(0.73 1.37) 0.76 1.35(0.96 1.90) 0.96(0.70 1.33) 0.15 Abbreviations: CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; ESRD, end stage renal disease

7 Figure S1A. CONSORT diagram for extension period for all cause mortality (men) 17,411 participants randomized 7,935 Assigned to receive chlorthalidone 4,684 Assigned to receive amlodipine 4,792 Assigned to receive lisinopril Status at Study Closeout 4,549 Known alive 3,095 Confirmed dead 9 Lost to follow up 4 Refused follow up 278 Other unknown Status at Study Closeout 2,713 Known alive 1,798 Confirmed dead 6 Lost to follow up 4 Refused follow up 163 Other unknown Status at Study Closeout 2,781 Known alive 1,830 Confirmed dead 6 Lost to follow up 5 Refused follow up 170 Other unknown 7,935 Included in analysis 4,684 Included in analysis 4,792 Included in analysis

8 Figure S1B. CONSORT diagram for extension period for all cause mortality (women) 15,393 participants randomized 7,067 Assigned to receive chlorthalidone 4,214 Assigned to receive amlodipine 4,112 Assigned to receive lisinopril Status at Study Closeout 4,374 Known alive 2,177 Confirmed dead 18 Lost to follow up 9 Refused follow up 489 Other unknown Status at Study Closeout 2,614 Known alive 1,299 Confirmed dead 11 Lost to follow up 3 Refused follow up 287 Other unknown Status at Study Closeout 2,552 Known alive 1,224 Confirmed dead 18 Lost to follow up 7 Refused follow up 311 Other unknown 7,067 Included in analysis 4,214 Included in analysis 4,112 Included in analysis

9 Figure S2A. CONSORT diagram for extension period for cardiovascular disease (men) 9,537 Participants randomized 4,369 Assigned to receive chlorthalidone 2,524 Assigned to receive amlodipine 2,644 Assigned to receive lisinopril Status at Study Closeout 2,419 Known alive 1,804 Confirmed dead 6 Lost to follow up 2 Refused follow up 138 Other unknown Status at Study Closeout 1,403 Known alive 1,047 Confirmed dead 2 Lost to follow up 2 Refused follow up 70 Other unknown Status at Study Closeout 1,452 Known alive 1,097 Confirmed dead 3 Lost to follow up 3 Refused follow up 89 Other unknown 4,369 Included in analysis 2,524 Included in analysis 2,644 Included in analysis

10 Figure S2B. CONSORT diagram for extension period for cardiovascular disease (women) 12,086 participants aandomized 5,545 Assigned to receive chlorthalidone 3,340 Assigned to receive amlodipine 3,201 Assigned to receive lisinopril Status at Study Closeout 3,223 Known alive 1,961 Confirmed dead 11 Lost to follow up 7 Refused follow up 343 Other unknown Status at Study Closeout 1,967 Known alive 1,172 Confirmed dead 5 Lost to follow up 1 Refused follow up 195 Other unknown Status at Study Closeout 1,891 Known alive 1,085 Confirmed dead 12 Lost to follow up 4 Refused follow up 209 Other unknown 5,545 Included in analysis 3,340 Included in analysis 3,201 Included in analysis

11 Figure S3. Kaplan Meier plots of mortality and morbidity rates by gender and treatment group for extension period Cumulative mortality/event rate Men Women Total mortality Cardiovascular mortality Years to death/event

12 Figure S3. (continued) Cumulative mortality/event rate Men Women CHD mortality Stroke mortality Years to death/event

13 Figure S3. (continued) Cumulative mortality/event rate Men Women Heart failure mortality Coronary heart diseasee nonfatal/fatal event Years to death/event

14 Figure S3. (continued) Cumulative mortality/event rate Men Women Cardiovascular diseasee nonfatal/fatal event Heart failure nonfatal/fatal event Years to death/event

15 Figure S3. (continued) Cumulative mortality/event rate Men Women Stroke nonfatal/fatal event Cancer mortality Years to death/event

16 Figure S3. (continued) Cumulative mortality/event rate Men Women Renal disease nonfatal event Years to death/event

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