ESC meeting, Stockholm, August 30, 16.30-18.00, 2010 Potential dangers of hormone replacement therapy in women at high risk Karin Schenck-Gustafsson MD, PhD, FESC Professor, Chief consultant Department of Cardiology Karolinska University Hospital, Stockholm, Sweden Head and founder Centre of Gender Medicine Karolinska Institute, Stockholm, Sweden
Recent case CCU Karolinska : 50-y old woman with a minor MI and normal coronaries Hormone therapy since age 40 because of premature menopause Discharged without hormones Outpatient clinic 6 weeks later: Sleep disturbancies, anxiety, heavy climacteric symptoms sleeping pills in increasing doses After 3 months: Low BP, vertigo, bad Q of L, suicide thoughts hormones reinstituted, sleeping pills reduced and then discontinued After 6 months: habital status Karin Schenck-Gustafsson 2
Which are the negative effects of hormone therapy in the menopause? Healthy women Increased risk of DVT and pulmonary embolism Increased risk of breast cancer Increased risk of stroke Slight increased risk of CHD at least during the first year CHD women The same but with only estrogen without gestagen not so obvious negative effects for CHD Karin Schenck-Gustafsson 3
USA Hormone Replacement Therapy and Cardiovascular Disease. A Statement for Healthcare Professionals from the AHA Mosca L, Collins P, Herrington D, et al Circulation, 2001;104:499-503. EUROPE Management of the cardiovascular risk in the peri- menopausal woman: a consensus statement of European cardiologists and gynecologists Collins P, Rosano G, Casy C et al Eur Heart J 2007, 28, 2028-2040
ESTROGEN EFFECTS Endotelial function Lipids Atheromatosis Mendelsohn et al, NEJM 1999; 340:1801-11 Karin Schenck-Gustafsson 5
Proposed hormone related cardiovascular riskfactors Polycystic ovarian syndrome Premature menopause Preclampsia Complications at birth Gestational diabetes Gestational hypertension Karin Schenck-Gustafsson 6
Coronary spasm Estrogen i.c Karin Schenck-Gustafsson 7
Post-menopausal (Post) Post Post Post 10 m Endothelial morphology 10 m 10 m Pre 10 m Pre 10 m Pre Karin Schenck-Gustafsson 8 Pre-menopausal (Pre) Kublickiene K et al, J Clin End Met 2008
Studies of hormone therapy and cardiovascular disease Primary prevention Observational Trials Nurses Health Study Danish study Experimental Trials exercise tests intra coronary estrogen injections carotid intima media animal studies alfa and beta estrogen receptors Secondary prevention HERS I and II (European WISP) Phase West Esprit Several studies with surrogate end points Randomized Clinical Trials (RCT) WHI WISDOM Onogoing studies-therapuetic window Karin Schenck-Gustafsson 9
Randomized controlled trials of HRT secondary prevention for coronary heart disease CEE=conjugated equine estrogens. MPA=medroxyprogesterone acetate. Study HRT Route Relative risk, mi (95% conf interval) N HERS (Hulley, 1998) PHASE (Clarke, 2002) WEST (Viscoli, 2001) ESPRIT (Cherry, 2002) CEE/MPA Oral 0.99 (0.8 to 1.22) 2769 17β-oestradiol Patch 1.29 (0.84 to 1.95) 255 17β-oestradiol Oral 1.1 (0.6 to 1.9) 664 Oestradiol valerate Oral 0.99 (0.7 to 1.41) 1017 Karin Schenck-Gustafsson 10
EHJ Oct 2008,Lökkegaard E etal About 700.000 women About 5000 MI Karin Schenck-Gustafsson 11
WHI studies (Designed 1991-2) Postmenopausal women, 50 to 79 years, 68,132 women ( mean age 63 years) in the randomised clinical study 93,676 women in the observational study The WHI Extension Study is following up 115,400 participants from each of the original WHI study components until 2010. The randomised CT evaluated three distinct interventions: 1] a low-fat eating pattern (n=48,835) 2] hormone replacement therapy (HRT) CEE 0.625mg for hysterectomised women (n=10,739), CEE 0.625mg and MPA 2.5mg for women with a uterus (n=16,608), 3] calcium and vitamin D supplementation (n=36,282). If eligible, women could choose to enroll in one, two, or all three of the randomized trial components. Karin Schenck-Gustafsson 12
Karin Schenck-Gustafsson 13
Karin Schenck-Gustafsson 14
Estrogen Therapy and Coronary-Artery Calcification JoAnn E. Manson, M.D., Dr.P.H. et al for the WHI and WHI-CACS Investigators N Engl J Med 2007, 356:2591-2602 June 21, 2007 Number 25 Karin Schenck-Gustafsson 15
Years since menopause and starting HRT Karin Schenck-Gustafsson 16
Coronary heart disease per 10,000 women per year Combined HRT The excess absolute risk at 50-59 + 5 60-69 +1 70-79 + 23 Oestrogen alone The reduced absolute risk at 50-59 - 10 60-69 years -5 with an excess risk at 70-79 + 4 Rossouw, J. E. et al. JAMA 2007;297:1465-1477. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause Karin Schenck-Gustafsson 17
Coronary heart disease per 10,000 women per year WHI combining both arms Absolute risk at 50-59 -2 60-69 -1 70-79 + 19 Rossouw, J. E. et al. JAMA 2007;297:1465-1477. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause Karin Schenck-Gustafsson 18
Stroke cases per 10,000 women per year. Combined HRT Excess absolute risk at 50-59 + 4 60-69 + 9 70-79 + 13 Oestrogen alone HRT Excess absolute risk at 50-59 0 60-69 +19 70-79 +14 Rossouw, J. E. et al. JAMA 2007;297:1465-1477. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause Karin Schenck-Gustafsson 19
Stroke cases per 10,000 women per year WHI combined trials. Hormone therapy increased the risk of stroke (HR, 1.32; 95% CI, 1.12-1.56). Risk did not vary significantly by age or time since menopause. Rossouw, J. E. et al. JAMA 2007;297:1465-1477. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause Karin Schenck-Gustafsson 20
Rossouw, J. E. et al. JAMA 2007;297:1465-1477. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause Hormone therapy increased the risk of stroke (HR, 1.32; 95% CI, 1.12-1.56). Risk did not vary significantly by age or time since menopause. Tendency for the effects of HT on total mortality to be more favorable in younger than older women (HR of 0.70 for 50-59 years; 1.05 for 60-69 years, and 1.14 for 70-79 years; P for trend =.06). Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause. These data should be considered in regard to the short-term treatment of menopausal symptoms. Copyright Karin restrictions Schenck-Gustafsson may apply.
In-depth proteomic discovery analysis: B2M and IGFBP4 risk markers for CHD and stroke candidate markers of disease risk candidate mediators of HT effects on CHD and stroke Novel proteins associated with risk for coronary heart disease or stroke among postmenopausal women identified by in-depth plasma proteome profiling. Prentice RL, et al Genome Med. 2010 Jul 28;2(7):48.
Treatment for bothersome menopausal symptoms Life style changes healthy weight, smoking cessation, relaxation response techniques, acupuncture, increased physical activity Nonprescription medications isoflavone supplements, soy products, black cohosh, vitamin E Nonhormonal prescription medication clonidine, paroxetine,venlafaxine, gabapentin, SSRIs, SNRIs, vaginal lubricants and moisturisers. Hormone therapy estrogen, tibolone
We have no clincical placebo-controlled randomized studies with morbidity and mortality outcomes than for estrogens (mostly conjugated equine) and different kinds of gestagens. So, no evidence based facts for all other treatments of menopausal symptoms as it comes to the CHD risks! Karin Schenck-Gustafsson 24
Conclusions Bothersome menopausal symptoms the only indication for HT Women with CHD and bothersome menopausal symptoms: Important to do a risk-benefit analysis in every case also for cardiologists If HT is started, it should be as low dose as possible and as short duration as possible Karin Schenck-Gustafsson 25
Thank you! Karin Schenck-Gustafsson 26