DISCLOSURE Vascular Disease and Related Outcomes: Further Evidence - - PDF document

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HOWARD N HODIS, M.D. Harry J. Bauer and Dorothy Bauer Rawlins Professor of Cardiology Professor of Medicine and Preventive Medicine Director, Atherosclerosis Research Unit University of Southern California

Early and Late Intervention on Vascular Disease and Related Outcomes: Further Evidence from ELITE

October 4, 2016

DISCLOSURE

Nothing to disclose

R01AG‐024154 R01HL‐110885 ELITE is funded by the National Institute on Aging, NIH ClinicalTrials.gov number NCT00114517

The timing hypothesis was proposed to explain the apparent discordance between observational studies and RCT outcomes of postmenopausal HT. The timing hypothesis posits that there is a differential effect on atherosclerosis progression and clinical events according to when postmenopausal HT is initiated in relation to menopause and/or age. ELITE is a RCT specifically designed to directly test the timing hypothesis in relation to atherosclerosis progression and cognitive decline.

Timing Hypothesis

Hodis HN, et al. N Engl J Med 2016;374:1221‐1231. Hodis HN, et al. J Am Geriatr Soc 2013;61:1005‐1010. Hodis HN, et al. Menopause 2015;22:391‐401. Hodis HN, et al. J Am Geriatr Soc 2013;61:1011‐1018. All Ages >10 YSM, >60 y old <10 YSM, <60 y old 0.25 0.50 1.0 1.5 2.0

Relative Risk (95% CI) 0.99 (0.88‐1.11) 0.68 (0.48‐0.96) 1.03 (0.91‐1.16)

CHD Events Associated with HRT in Younger and Older Women: Meta‐analysis of 23 Randomized Controlled Trials (191,340 patient‐years)

Salpeter SR, et al. J Gen Intern Med 2006;21:363‐366. y = years YSM = years‐since‐menopause

Total Mortality Associated with HRT in Younger and Older Women: Meta‐analysis of 30 Randomized Controlled Trials (119,118 patient‐years)

All Ages >60 y old, Mean age = 66 y <60 y old, Mean age = 54 y 0.25 0.50 1.0 1.5 2.0 Relative Risk (95% CI) 0.98 (0.87‐1.18) 0.61 (0.39‐0.95) 1.03 (0.90‐1.18) Salpeter SR, et al. J Gen Intern Med 2004;19:791‐804. y = years

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>10 YSM, >60 y old <10 YSM, <60 y old 0.25 0.50 1.0 1.5 Relative Risk (95% CI) 0.52 (0.29‐0.96) 1.07 (0.96‐1.20)

Cochrane Meta‐analysis: Randomized Controlled Trials of CHD Events Associated with HRT in Younger and Older Postmenopausal Women

y = years YSM = years‐since‐menopause >10 YSM, >60 y old <10 YSM, <60 y old 0.25 0.50 1.0 1.5 2.0

Relative Risk (95% CI) 0.70 (0.52‐0.95) 1.06 (0.95‐1.18)

Cochrane Meta‐analysis: All‐Cause Mortality from Randomized Controlled Trials of HRT in Younger and Older Postmenopausal Women

y = years YSM = years‐since‐menopause Boardman HMP, et al. Cochrane Database of Systemic Reviews 2015, Issue 3:CD002229. DOI: 10.1002/14651858.CD002229.pub4.

Relative Risk of CHD: Observational Studies and Randomized Trials

Grodstein F, et al. Prog Cardiovasc Dis 1995;38:199‐210. Salpeter SR, et al. J Gen Intern Med 2006;21:363‐366. Schierbeck LL, et al. BMJ 2012; 2012;3456:e6409. Collins P, et al. Circulation 2009;119:922‐930.

Observational Studies

Age 30‐55 y Time Since Menopause <6 y

HRT Randomized Trials

Age <60 y Time Since Menopause <10 y

DOPS

Age 50 y Time Since Menopause 7 mo

RUTH

Age <60 y

Risk Estimate

0.64 0.68 0.59 0.48

0.5 1.0

0.52

Boardman HMP, et al. Cochrane Database of Systemic Reviews 2015, Issue 3:CD002229. DOI: 10.1002/14651858.CD002229.pub4.

WELL‐HART: Change in Percent Diameter Stenosis

Hodis HN, et al. N Engl J Med 2003;349:535‐545.

Change in Percent Diameter Stenosis From Baseline 2.80 2.40 2.00 1.60 1.20 0.80 0.40 0.00 Placebo Estradiol Estradiol + MPA Progression

• f Atherosclerosis

(n = 59) (n = 54) (n = 53)

P=0.66

‐0.005 0.005 0.01 0.015 0.02 Placebo Estradiol Rate of CIMT Change (mm/year)

All Subjects No Lipid Lowering Meds Lipid Lowering Meds N = 199 N = 77 N = 122

P = 0.045 P = 0.002 P = 0.92

EPAT: Rate of CIMT Change

Hodis HN, et al. Ann Intern Med 2001;135:939‐953.

Media Fatty Streak Internal Elastic Lamina Adventitia Fibrous Cap Plaque Necrotic Core Fibrous Cap Fibrous Cap MMP‐9 Mural Thrombus Plaque Plaque

Pathogenic Sequence of Vascular Aging

No HRT EPAT = HRT Early & Continued WELL‐HART = HRT Late

HRT

Age 35‐45 years Age 45‐55 years Age 55‐65 years Age >65 years

HRT

Hodis HN, et al. N Engl J Med 2003;349:535–545.

Necrotic Core

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Estrogen Inhibits Initiation but not Progression of Established Lesions in Mice

Rosenfeld ME, et al. Atherosclerosis 2002;164:251‐259.

1 2 3 4 5 6 7 8 9 10 4 10 16 22 28 34 40 Weeks Number of Mice with Lesions Iliac -E2 Iliac +E2

New Lesions Established Lesions

1 2 3 4 5 6 7 8 9 10 4 10 16 22 28 34 40 Weeks Number of Mice with Lesions Carotid -E2 Carotid +E2

Importance of Timing of Intervention on the Effect of Estrogens on Atherogenesis in Nonhuman Primates

Time

Premenopausal Years Postmenopausal Years Ovariectomy

Plaque Area (% of Placebo)

Healthy diet CEE + atherogenic diet 1. 70%1,2 Atherogenic diet CEE + atherogenic diet 2. 50%3 Healthy diet Atherogenic diet Healthy diet + CEE 3. 0%4

~ 6 Year Human Equivalent

1Clarkson et al. J Clin Endocrinol Metab 1998;83:721. 3Clarkson et al. J Clin Endocrinol Metab 2001;86:41. 2Adams et al. Arterioscler Thromb Vasc Biol 1997;17:217. 4Williams et al. Arterioscler Thromb Vasc Biol 1995;15:827.

Study design: Single‐center, randomized, double‐blinded,

placebo‐controlled trial

Trial factors:

Randomized treatment (estradiol, placebo) x time since menopause (<6 years, >10 years)

Subjects:

643 healthy postmenopausal women without preexisting CVD and diabetes mellitus

Intervention: Oral micronized 17β‐estradiol 1 mg/d

(+ vaginal micronized progesterone gel 45 mg/d x 12 days every month in women with a uterus)

Placebos Follow‐up:

Every month for the first 6 months and then every 2 months for up to 6 years

ELITE – Design

Hodis HN, et al. N Engl J Med 2016;374:1221‐1231. Hodis HN, et al. Menopause 2015;22:391‐401.

ELITE – Trial Outcomes

PrimaryOutcome – Subclinical carotid artery atherosclerosis: Rate of change in common carotid artery intima‐media thickness (measured every 6 months) Secondary Outcome – Cognition: Change in verbal memory, executive function and global cognition tested at 2.5 years and 5.0 years

Hodis HN, et al. N Engl J Med 2016;374:1221‐1231. Hodis HN, et al. Menopause 2015;22:391‐401.

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Carotid Artery Wall Imaging

Carotid Artery Intima‐Media Thickness (CIMT)

Scanner Transducer

Far wall carotid artery Jugular vein Common Carotid artery Skin surface

Hodis HN, et al. Ann Intern Med 1998;128:262‐269. Hodis HN, et al. Ann Intern Med 2001;135:939–953. Hodis HN, et al. Circulation 2002;106:1453–1459. < 0.011 mm/yr 0.011 ‐ 0.018 mm/yr 0.018 ‐ 0.034 mm/yr > 0.034 mm/yr 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

MI, Coronary Death All Cardiovascular Events p trend < 0.01 p trend < 0.01

Relative Risk

5 4.5 4 3.5 3 2.5 2 1.5 1 0.5

2166 screened by telephone 895 screened in clinic 137 allocated to Estradiol 134 allocated to Placebo 186 allocated to Estradiol 186 allocated to Placebo 125 CIMT follow‐up 123 CIMT follow‐up 172 CIMT follow‐up 176 CIMT follow‐up

<6 years since menopause N = 271 >10 years since menopause N = 372

643 randomized

Hodis HN, et al. N Engl J Med 2016;374:1221‐1231. Hodis HN, et al. Menopause 2015;22:391‐401.

Baseline Demographic Characteristics

Characteristic

<6 Years‐Since‐Menopause (n=248) Placebo (123) Active (125) >10 Years‐Since‐Menopause (n=348) Placebo (176) Active (172) Time since menopause, years (median, IQR) 3.5 (1.8,4.9) 3.5 (2.0,5.3) 14.1 (11.4,18.1) 14.5 (11.4,18.8) Age, years (median, IQR) 55.4 (52.5,57.8) 55.4 (53.2,57.9) 63.0 (59.9,67.0) 64.3 (60.5,68.6) Race or ethnicity, no. (%) White, non‐Hispanic 73 (59.3%) 88 (70.4%) 127 (72.2%) 127 (73.8%) Black, non‐Hispanic 14 (11.4%) 7 (5.6%) 14 (8.0%) 17 (9.9%) Hispanic 20 (16.3%) 16 (12.8%) 23 (13.1%) 20 (12.4%) Asian 16 (13.0%) 14 (11.2%) 12 (6.8%) 8 (4.7%) Education, no. (%) Less than high school 1 (0.8%) 2 (1.1%) High school or some college 38 (30.9%) 27 (21.6%) 71 (40.3%) 56 (32.6%) College graduate 85 (69.1%) 97 (77.6%) 103 (58.5%) 116 (67.4%) Type of menopause, no. (%) Natural 120 (97.6%) 119 (95.2%) 144 (81.8%) 146 (84.9%) Surgical 3 (2.4%) 6 (4.8%) 32 (18.2%) 26 (15.1%)

IQR = interquartile range Hodis HN, et al. N Engl J Med 2016;374:1221‐1231.

Variable

<6 Years‐Since‐Menopause (n=248) Placebo (123) Active (125) >10 Years‐Since‐Menopause (n=348) Placebo (176) Active (172) Carotid artery intima‐media thickness, mm 0.75 (0.73,0.76)1 0.75 (0.73,0.76) 0.79 (0.77,0.80) 0.78 (0.77,0.80) Body mass index, kg/m2 (median, IQR) 26.0 (23.2,29.7) 26.2 (23.3,30.6) 26.4 (23.1,29.6) 27.2 (23.2,31.2) Systolic blood pressure, mmHg (median, IQR) 115 (106,125) 117 (108,123) 116 (110,126) 120 (112,127) Diastolic blood pressure, mmHg (median, IQR) 77 (70,81) 75 (71,80) 73 (69,78) 74 (70,79) Serum lipids (median, IQR) LDL cholesterol, mg/dl 134 (115,160) 139 (119,161) 133 (115,155) 131 (112,151) HDL cholesterol, mg/dl 63 (51,75) 63 (54,77) 66 (55,80) 63 (53,78) Total cholesterol, mg/dl 222 (198,247) 225 (207,245) 223 (206,243) 218 (198,242) Triglycerides, mg/dl 90 (74,129) 95 (65,119) 93 (72,129) 92 (68,133)

Baseline Clinical, Laboratory and Ultrasound Characteristics

Hodis HN, et al. N Engl J Med 2016;374:1221‐1231. IQR = interquartile range

1 Mean (95% CI)

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Study Medication Compliance

Menopause Stratum

Median (interquartile range) Estradiol Placebo < 6 years 98% (96% ‐ 100%) 98% (93% ‐ 100%) > 10 years 98% (93% ‐ 100%) 98% (94% ‐ 100%)

Hodis HN, et al. N Engl J Med 2016;374:1221‐1231.

P=0.29 P‐value for interaction = 0.007

Estradiol >10 yrs Placebo >10 yrs Placebo <6 yrs Estradiol <6 yrs

P=0.008 Years Carotid Artery Intima‐media Thickness (mm)

Hodis HN, et al. N Engl J Med 2016;374:1221‐1231.

ELITE – CIMT Progression by Treatment and Postmenopausal Strata

Coronary Artery Outcome Placebo Estradiol P Value P Value for Postmenopause Stratum Interaction Least‐squares mean CAC score (95% CI) Early postmenopause Late postmenopause 1.03 (0.48‐1.58) 2.26 (1.84‐2.67) 1.21 (0.70‐1.73) 2.04 (1.61‐2.47) 0.57 0.46 0.36 CAC present (%) Early postmenopause Late postmenopause 30.4 57.5 39.1 56.4 0.16 0.88 0.29 Least‐squares mean CCTA total stenosis score (95% CI) Early postmenopause Late postmenopause 1.63 (0.77‐2.49) 2.90 (2.26‐3.55) 1.68 (0.88‐2.68) 2.81 (2.12‐3.49) 0.92 0.84 0.83 Least‐squares mean CCTA total plaque score (95% CI) Early postmenopause Late postmenopause 1.59 (0.70‐2.49) 3.05 (2.38‐3.72) 1.84 (1.01‐2.68) 2.64 (1.93‐3.35) 0.53 0.47 0.35

Measures of Coronary Artery Atherosclerosis – Established Lesions

Hodis HN, et al. N Engl J Med 2016;374:1221‐1231.

ELITE – Major Adverse Events

Menopause <6 years

• No. Subjects

Placebo Active (n=134) (n=137) Menopause 10 years

• No. Subjects

Placebo Active (n=186) (n=186) CORONARY DISEASE 1 2 3 Myocardial infarction 1 ‐ 1 1 Silent myocardial infarction ‐ ‐ 1 ‐ Unstable angina ‐ ‐ ‐ 2 Coronary artery stent insertion ‐ ‐ ‐ 1 CANCER 6 5 10 12 Breast cancer 3 3 5 7 Endometrial cancer ‐ 1 2 1 Colorectal cancer ‐ 1 2 2 Ovarian epithelial cancer ‐ ‐ 1 ‐ Malignant peritoneal neoplasm 1 ‐ ‐ ‐ Gastric cancer 1 ‐ ‐ ‐ Pancreatic cancer 1 ‐ ‐ ‐ Glioma ‐ ‐ ‐ 1 B‐cell lymphoma ‐ ‐ 1 ‐ Mycosis fungoides ‐ ‐ ‐ 1 CEREBROVASCULAR DISEASE Transient ischemic attack 1 ‐ 1 1 VENOUS THROMBOSIS Deep vein thrombosis ‐ ‐ 2 1 Pulmonary embolism ‐ ‐ ‐ 2 DEATH (pancreatic cancer and glioma) 1 ‐ ‐ 1 Hodis HN, et al. Circulation 2014;130:A13283.

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ELITE supports the timing hypothesis whereby women who start HT within 6 years of menopause show a significant slowing of subclinical carotid artery atherosclerosis whereas women who are >10 years postmenopausal when starting HT show no difference from placebo. ELITE supports the concept that HT reduces early atherosclerosis but not established lesions. ELITE results are consistent with the majority of the literature that shows that women who are young and/or in close proximity to menopause when starting HT have reduced coronary heart disease and overall mortality. ELITE adverse events show no difference between treatment groups.

Conclusions Acknowledgements

Clinical Center Staff: Liny Zurbrugg RN (Clinic Coordinator), Esther Bhimani MA, Martha Charlson RD, Irma Flores MA, Martha Huerta, Thelma LaBree MA, Sonia Lavender MA, Violetta McElreath RN, Janie Teran, Philip Zurbrugg Ultrasound Image Acquisition and Processing Laboratory: Robert H. Selzer MS* (Director), Yanjie Li MD (Technical Director), Mei Feng MD, Lora Whitfield‐Maxwell RN, Ming Yan MD, PhD Data Coordinating Center: Wendy J. Mack PhD* (Director), Stanley P. Azen PhD*, Farzana Choudhury MS, Carlos Carballo, Laurie Dustin MS, Adrian Herbert, Naoko Kono MPH, George Martinez, Olga Morales Atherosclerosis Research Unit Core Lipid/Lipoprotein Laboratory: Juliana Hwang‐Levine PharmD* (Director), Gail Izumi CLS, Arletta Ramirez CLS, Luci Rodriguez Gynecology and Mammography: Donna Shoupe MD*, Juan C. Felix MD, Pulin Sheth, Mary Yamashita USC Endocrinology Laboratory: Carole Spencer Neurocognition: Victor W. Henderson MD*, Carol A. McCleary, PhD, Jan A. St. John MPH Kaiser Permanente Medical Center Recruitment Site: Malcolm G. Munro, MD Cardiac Computed Tomography Core Center: Matthew J. Budoff MD (Director), Lily Honoris MD, Chris Dailing, Sivi Carson Data Safety Monitoring Board: Leon Speroff MD (Chairman), Robert Knopp MD (deceased), Richard Karas MD, Joan Hilton PhD