Update: Hormones and Cardiovascular Disease in Women Kathryn M. Rexrode, MD, MPH Assistant Professor Division of Preventive Medicine Brigham and Women s s Hospital Harvard Medical School Overview Review the findings for hormone therapy and cardiovascular disease in the WHI. Present recent updates regarding impact of age and time since menopause effect modification by baseline risk follow-up findings after cessation of the randomized hormone therapy trials. Summarize consideration of cardiovascular risk prior to initiating hormone therapy for symptom control. 1
Heart Disease in Women Leading cause of death in women after age 40, accounting for 250, 000 deaths/year. One in 3 women will die of the disease. Heart disease begins 10-15 15 years later in women than men. Attributed to beneficial effect of estrogen on lipids, blood vessel linings and clotting factors. Age-adjusted Death Rates for CHD, Stroke, Lung and Breast Cancer in US Women Per 100,000 Population 200 150 100 50 0 114.7 148.7 Coronary Heart Disease 65.5 47.2 41.9 39.9 32.2 23.9 Stroke Lung Cancer Breast Cancer White Females Black Females (United United States: 2004). Source: : NCHS and NHLBI. 2
Annual rate of first heart attack by age, sex and race. Per 1,000 Persons 16 14 12 10 8 6 4 2 0 35-44 45-54 55-64 65-74 White Men Black Men White Women Black Women (ARIC :1987-2004) 2004). Source: NHLBI. Prevalence of CVD in Adults by Age and Sex Percent of Population 100 80 60 40 20 0 92.0 83.0 71.3 75.1 39.1 39.5 14.8 9.4 20-39 40-59 60-79 80+ Males Females (NHANES: 1999-2004). Source: NCHS and NHLBI. CVD= coronary heart disease, heart failure, stroke and hypertension. 3
Hormone Therapy and CVD In observational studies, women who used hormone therapy were at 40-50% lower risk of CHD than never users. Hormone therapy was widely promoted and prescribed as primary prevention until the results of randomized trials failed to show benefit. Many unanswered questions remain about mechanisms and practical estimates of risk. WHI Estrogen+Progestin Trial Findings, July 2002 ( N=16,608; mean age 63 yrs; mean follow-up 5.2 yrs) Risks Benefits Coronary Heart Disease 29% Stroke 41% Pulmonary Embolism 113% Breast Cancer 26% Hip Fracture 34% Colorectal Cancer 34% Threshold Level STOPPED Early, Clear Harm Stopped 3.3 years early Adapted from: Writing Group for the Women s Health Initiative. JAMA 2002;288:321-333. 4
WHI Estrogen-Alone and Health Outcomes (N=10,739; mean age 63.6 yrs; mean follow-up 6.8 yrs) Risks Stroke 39% Null CHD (0.91) Pulm Emb (1.34) Breast Cancer (0.77) Colorectal Cancer (1.08) Total Mortality (1.04) Global Index (1.01) Benefits Hip Fracture 39% STOPPED Early Threshold Level Stopped 1 year early Source: JAMA 2004; 291:1701-12. Summary of WHI hormone therapy trials: Events per 10,000 women Outcome MI Stroke VTE Breast cancer Colon cancer Fractures Dementia** E+P 7 more 8 more 18 more 6 more 6 fewer 5 fewer 23 more E alone No effect 12 more 6 more (7 fewer)* No effect 6 fewer 9 more * Borderline significance. ** For women >age 65 5
Key Differences Between the WHI and Observational Studies of Hormone Therapy (HT) WHI Cohorts Age at HT initiation (mean) 63 yrs 52 yrs Time since menopause (mean) >12 yrs 1-3 yrs Vasomotor symptoms Mostly Mostly + BMI (kg/m 2, mean) 28-30 24-25 Duration of HT use Short Long Unanswered Questions after the WHI Are the observed associations the same for younger and older women? Is there a difference in the impact of hormones on disease risk depending on length of time since menopause? Can we predict which women are at higher cardiovascular risk? Do risks persist after stopping therapy? 6
Age at Initiation: WHI Results According to Age at Randomization Relative Risk of CHD by Age Group at Baseline 50-59 60-69 70-79 Estrogen-alone 0.63 0.94 1.11 (N=418) (0.36-1.08) (0.71-1.24) (0.82-1.52) Estrogen+Progestin 1.29 1.03 1.48 (N=348) (0.79-2.12) (0.74-1.43) (1.04-2.11) Rossouw J, et al. JAMA 2007; 297:1465-1477. Age at Initiation: Relative Risk of Breast Cancer in the WHI, Stratified by Age Group Relative Risk of Breast Cancer by Age Group at Baseline 50-59 60-69 70-79 E+P 1.20 1.22 1.34 E-Alone 0.72 0.72 0.94 Chlebowski R, et al. JAMA 2003. WHI Investigators. JAMA 2004. 7
Age at Initiation: Estrogen + Progestin Therapy and Health Outcomes in the WHI by Age Group Number of Cases per 10,000 Women per Year Age 50-59 Age 60-69 Age 70-79 CHD 22 17 35 34 78 55 Stroke 14 10 32 23 61 48 VTE 19 8 35 19 27 62 Total mortality 20 31 52 47 105 101 Estrogen+progestin therapy Placebo VTE=venous thromboembolism Rossouw J, et al. JAMA 2007; 297:1465-1477. Age at Initiation: Estrogen-only Therapy and Health Outcomes in the WHI by Age Group Number of Cases per 10,000 Women per Year Age 50-59 Age 60-69 Age 70-79 CHD 14 24 54 59 88 84 Stroke 16 16 49 30 71 57 VTE 15 13 31 23 40 28 Total mortality 29 39 79 79 145 130 Estrogen only Placebo VTE=venous thromboembolism Rossouw J, et al. JAMA 2007; 297:1465-1477. 8
Estrogen-alone and Coronary Artery Calcium WHI ancillary substudy : 1064 women aged 50 to 59 years at randomization Coronary artery CT was performed after 7.4 yrs of treatment and 1.3 years after the trial was completed (8.7 yrs after randomization) Mean coronary artery calcium (CAC) score was lower among women receiving estrogen (83.1) than those receiving placebo (123.1) (P=0.02 by rank test). Multivariate ORs for CAC scores of more than 0, 10 or more, and 100 or more 0.78 (0.58-1.04), 0.74 (0.55-0.99), and 0.69 (0.48-0.98), respectively. No results for E+P. Manson JE, et al. NEJM 2007; 356: 2591-602. Years since Menopause: WHI Results According to Years Since Menopause Relative Risk of CHD by Years since menopause at baseline <10 10-19 20+ Estrogen-alone 0.48 0.96 1.12 (N=418) (0.20-1.17) (0.61-1.44) (0.86-1.46) Estrogen+Progestin 0.88 1.23 1.66 (N=348) (0.54-1.43) (0.85-1.77) (1.14-2.41) Rossouw J, et al. JAMA 2007; 297:1465-1477. 9
Years since menopause: Health Outcomes by Years Since Menopause in the WHI Trials of Hormone Therapy (E+P and E-Alone) CHD <10 y Years since menopause: 10-19 y 20+ y Total mortality <10 y 10-19 y 20+ y Global index <10 y 10-19 y 20+ y 0.76 1.10 1.28 0.76 0.98 1.14 1.05 1.12 1.09 p=0.02 p=0.51 p=0.82 1 0.2 0.7 1.2 1.7 2.2 p values for trend. The global index is a composite outcome of CHD, stroke, PE, breast cancer, colorectal cancer, endometrial cancer (estrogen+progestin trial only), hip fracture, and mortality. Rossouw JE, et al. JAMA 2007; 297:1465. Absolute Excess Risks by Years since Menopause in the WHI Hormone Trials (Cases per 10,000 person-yrs) Outcome Years since menopause <10 10-19 >20 CHD -6 +4 +16* Stroke +8 +8 +13 Total mortality -7-2 +12 Global index +6 +18 +23 * P <0.05 compared with <10 years since menopause Global index is a composite outcome of CHD, stroke, pulmonary embolism, cancer (breast, colorectal, endometrial), hip fracture and mortality. Rossouw JE, Prentice RL, Manson JE, et al. JAMA 2007. 10
Coronary Artery Calcium in Women Randomized to Estrogen alone vs. Placebo in the WHI Coronary Artery Estrogen (0.625 CEE) Calcium Score (Intention to treat) <10 (Referent) 1.00 (Referent) 10 100 0.82 (0.57-1.18) >100 300 0.72 (0.44-1.17) >300 0.58 (0.35-0.95) p-value = 0.03 Manson JE, et al. NEJM 2007; 356: 2591-602. Baseline Risk: Effect Modification by LDL Among women in the WHI randomized trials, HT increased HDL levels and the number of HDL particles. However, while HT reduced LDL levels, there was no reduction in the number of LDL particles. In a recent substudy of 369 women in the WHI who developed CHD during the trial, and 820 controls, baseline LDL interacted with HT (both types). Women with higher LDL at baseline were at higher risk of CHD with HT use (p interaction=0.03). Hsia J, et al. Arterioscl Thromb Vasc Biol 2008; 28:1582-3. Rossouw JE, et al. Arch Int Med 2008; 169: 2245-53. 11
Baseline CHD Risk Factors: CHD Outcomes in the WHI Trials (E+P and E-Alone) OR (95% CI) Biomarker CHD Risk P-Value LDL-Cholesterol (mg/dl) <130 0.66 (0.34-1.27) 0.03 >130 1.46 (1.02-2.10) Total/HDL Cholesterol Ratio <4.18 0.76 (0.44-1.29) 0.01 >4.18 1.69 (1.15-2.49) hs-crp (mg/dl) <2.0 1.01 (0.63-1.62) 0.16 >2.0 1.58 (1.05-2.39) Bray PF, et al. Am J Cardiology 2008; 101:1599-1605. Baseline CHD Risk Factors: Risk of CHD in the WHI Trials by Hormone Type OR (95% CI) Biomarker E+P E-alone P-Value LDL (mg/dl) <130 0.47 (0.19-1.13) 0.71 (0.22-2.25) 0.03 E+P >130 1.60 (0.99-2.59) 1.28 (0.72-2.26) 0.33 E alone Total/HDL <4.18 0.79 (0.40-1.54) 0.72 (0.29-1.81) 0.02 E+P >4.18 2.05 (1.22-3.46) 1.33 (0.73-2.42) 0.26 E alone hs-crp (mg/dl) <2.0 1.48 (0.81-2.70) 0.47 (0.20-1.11) 0.96 E+P >2.0 1.40 (0.80-2.44) 1.88 (0.99-3.58) 0.02 E alone Bray PF, et al. Am J Cardiology 2008; 101:1599-1605. 12
WHI Follow-up Results: Health Outcomes Three Years after Stopping E+P Relative Risks (95% CI) During Trial Post-Intervention MI 1.26 (1.00-1.59) 0.99 (0.72-1.34) Total CVD 1.13 (1.02-1.25) 1.04 (0.89-1.21) Total Cancer 1.03 (0.92-1.15) 1.24 (1.04-1.48) Breast CA 1.26 (1.02-1.56) 1.27 (0.91-1.78) Colorectal CA 0.62 (0.43-0.89) 1.08 (0.66-1.77) Total Fractures 0.76 (0.69-0.83) 0.91 (0.78-1.06) Total Mortality 0.97 (0.81-1.16) 1.15 (0.95-1.39) Heiss G, et al. JAMA 2008; 299:1036. Health Risks and Benefits after Stopping Randomized Treatment with Estrogen and Progestin 2.5 During trial 3-Yr Follow-up 2.0 1.5 1.0 0.5 CHD MI Stroke DVT/PE All CVD Breast CA All CA 0.0 Mean follow-up of 2.8 years post-intervention. Heiss G, et al. JAMA 2008; 299:1036-1045. 13
WHI: CVD Risk after Cessation of HT In contrast to the risks for cancer, which remained elevated during the 3 year follow-up, the risk of CHD, stroke, DVT and PE reverted to baseline during the follow-up period. This implies that the risks of CVD with hormone therapy might be mediated by thrombotic/ hemostatic factors, rather than direct effects on atherosclerosis. 14
Practical Considerations: In Whom Should We Consider Using Hormone Therapy? First, assess symptoms. Significant systemic symptoms of menopause Second, evaluate contraindications and stroke risk Framingham Stroke Score <10% Third, consider overall CHD risk and years since last menstrual period. <5, 6-10, 6 >10 Practical Considerations According to Framingham CHD risk score: If very low risk (<5%) consider HT if <10 years since LMP. If low risk (5-<10%) consider HT if <5 5 years since LMP. Could consider transdermal if 6-106 years since LMP. If moderate risk (10-20%) and years since LMP, could consider transdermal,, but weigh carefully. Avoid HT if more than 10 years since LMP, or if high Framingham Risk Score (>20%). 15
Hormone Therapy (HT) Decision-Making Flowchart 1.Significant symptoms of menopause (moderate-tosevere hot flashes, night sweats)? No No HT Yes 2. Free of contraindications to HT and no h/o CHD, stroke, or TIA? AND No increased risk of stroke (<10% by Framingham Stroke Score)? CHD Risk Over 10 Years (Framingham CHD Risk Score) 3. Assess CHD risk and years since last menstrual period Very low (<5%) Low (5% to <10%) Moderate (10% to 20%) High (more than 20%) Yes <5 HT OK HT OK HT OK (Choose transdermal) No HT Years Since Last Menstrual Period 6 to 10 HT OK HT OK (Choose transdermal) No HT No HT >10 No HT No HT No HT No HT DECISION ABOUT DURATION OF USE: continued moderate-to-severe symptoms; patient preference; weigh baseline risks of breast cancer vs osteoporosis No No HT Adapted from: J Manson and S Bassuk. In: Harrison s Principles of Internal Medicine 2008 Conclusions No data currently suggest that hormone therapy be used for disease prevention. Definitive answers about the risks and benefits of hormones in the early menopause await the results of future trials. In women with significant systemic menopausal symptoms, evaluate baseline cardiovascular risk and years since menopause to formulate a decision about using hormone therapy. 16
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Framingham Risk Score CHD (10 year risk) Age Gender Smoking Total cholesterol HDL cholesterol SBP Taking meds for HTN http://www.framinghamheartstudy.org/risk/ Interactive calculator: http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof Stroke (10 year risk) Age Gender SBP Smoking Prior CVD Atrial fibrillation LVH Taking meds for HTN Risk of Stroke in Randomized trials of Hormone Therapy Cohort WHI WHI HERS WEST HT regimen CEE/MPA CEE CEE/MPA 17beta- estradiol RR (95%CI) 1.4 (1.1-1.9) 1.9) 1.4 (1.1-1.8) 1.8) 1.2 (0.8-1.7) 1.1 (0.8-1.4) 18
Hormone Therapy and VTE Women s s Health Initiative CEE/MPA VTE incidence 3.1/1000 vs. 1.6/1000 on placebo. HR=2.1 (1.6-2.7) Risk similar for DVT and PE CEE HR=1.4 (1.0-1.8) 1.8) DVT risk significant. Absolute Excess Risks by Age in the Combined Hormone Trials of the WHI (Cases per 10,000 pers-yrs) Outcome Age (years) 50-59 60-69 70-79 CHD -2-1 +19* Stroke +2 +14 +15 Total mortality -10-4 +16* Global index -4 +15 +43* * P <0.05 compared with age 50-59 years or <10 years since menopause Global index is a composite outcome of CHD, stroke, pulmonary embolism, cancer (breast, colorectal, endometrial), hip fracture and mortality. Rossouw JE, Prentice RL, Manson JE, et al. JAMA 2007. 19
Absolute Excess Risks by Age in the CEE+MPA Trial of the WHI (Cases per 10,000 pers-yrs) Outcome Age (years) 50-59 60-69 70-79 CHD +5 0 +24* Stroke +5 +10 +11 Total mortality -9 +4 +5 Global index +10 +21 +36 * P <0.05 compared with age 50-59 years or <10 years since menopause Global index is a composite outcome of CHD, stroke, pulmonary embolism, cancer (breast, colorectal, endometrial), hip fracture and mortality. Rossouw JE, Prentice RL, Manson JE, et al. JAMA 2007. Age at Initiation: Estrogen-Progestin Therapy and Health Outcomes in the WHI by Age Group Age 50-59 Number of Cases per 10,000 Women per Year Age 60-69 Age 70-79 CHD 22 17 35 34 55 78 Stroke 14 10 32 23 61 48 VTE 8 19 19 35 27 62 Breast Cancer 31 26 44 36 54 41 Colorectal Cancer 4 5 10 19 14 28 Hip Fracture 1 3 9 11 33 48 Total Death 20 31 52 47 105 101 Estrogen-progestin therapy Placebo VTE=venous thromboembolism 20
Age at Initiation: Estrogen-only Therapy and Health Outcomes in the WHI by Age Group Number of Cases per 10,000 Women per Year Age 50-59 Age 60-69 Age 70-79 CHD 14 24 54 59 88 84 Stroke 16 16 49 30 71 57 VTE 15 13 31 23 40 28 Breast Cancer 21 29 26 36 32 34 Colorectal Cancer 7 12 16 19 32 15 Hip fracture 4 1 4 11 32 52 Total Death 29 39 79 79 130 145 Estrogen only Placebo HT and Cerebrovascular Disease In a recent study, there was no significant increase in total ischemic volume on MRI among women on HT vs. placebo (borderline for CEE/MPA). For women older than 65, smaller brain volume and hippocampal volume were observed for women on HT than placebo. Loss particularly observed among women with cognitive deficit at baseline. Coker LH, et al. Neurology 2009; 72: 125-134. Resnick SM, et al. Neurology 2009; 72: 135-42. 21