CASE STUDY

Physical Exam Height: 5 ft, 6 in Weight: 142 lb Blood pressure (BP): 135/80 mm Hg Pulse: 76 bpm Rest of exam: unremarkable Initial Laboratory Values TC: 209 mg/dL LDL-C: 142 mg/dL HDL-C: 48 mg/dL TG: 95 mg/dL Lipoprotein (a) (Lp[a]): 22 mg/dL Homocysteine: 9 μmo/L Fasting blood glucose (FBG): 90 mg/dL High-sensitivity C-reactive protein (hs-CRP): 3.5 mg/L Follow-Up Laboratory Values (6 weeks) TC: 143 mg/dL LDL-C: 78 mg/dL HDL-C: 50 mg/dL TG: 75 mg/dL hs-CRP: 1.4 mg/dL New FDA Labeling for HRT Based on an analysis of WHI data, the FDA earlier this year revised labeling for estrogen and estrogen with progestin products. The new boxed warning: highlights increased risks for heart disease, heart attacks, strokes, breast cancer emphasizes that these products are not approved for prevention of heart disease advises that these products should be prescribed at their lowest dose and for the shortest duration modifies approved indications of certain products to clarify that these drugs should be used only when benefits clearly outweigh risks http://www.fda.gov/bbs/topics /NEWS/2003/ NEW00863.html   Related information on this website: In the Current Literature section: Risk Factors and Secondary Prevention in Women with Heart Disease: The Heart and Estrogen/progestin Replacement Study In the Dynamic Slide Library section: HERS, HERS II: Relative Hazard of CHD Events Adjusted Relative Risk for First Cardiovascular Event Based on CRP, LDL-C

Hormone Replacement Therapy and Coronary Heart Disease in a Postmenopausal Woman   Robert A. Vogel, MD The following case was provided by NLEC Faculty Member Robert A. Vogel, MD, Professor of Medicine, University of Maryland School of Medicine, Baltimore, Maryland. Disclosure Information for Dr Vogel: Clinical investigator: Pfizer Inc; Novartis. A seemingly healthy 54-year-old woman presented with three episodes of brief substernal chest pain, all of which occurred while carrying groceries up a flight of stairs. The patient had a history of untreated mild hypercholesterolemia and had been a cigarette smoker until 10 years ago. For the past 6 years, she has been on hormone replacement therapy (HRT) for relief from hot flashes. The patient walked for 8 minutes on a Bruce protocol, achieving 80% of her maximal predicted heart rate (MPHR). She experienced chest pain similar to her prior episodes. Her thallium scintigram revealed a large inferior-wall reversible defect. A coronary arteriography was performed, which demonstrated a high-grade proximal right coronary artery stenosis and mild disease in the left anterior descending artery. A stent was successfully placed in the right coronary artery. The patient’s HRT was discontinued; she was then started on aspirin 81 mg/day, clopidogrel 75 mg/day, and atorvastatin 40 mg/day. Her hot flashes recurred, and paroxetine controlled-release (a selective serotonin reuptake inhibitor, or SSRI) 12.5 mg/day was begun, resulting in a reduction in the frequency of hot flashes. She did not experience further chest pain. Discussion Our understanding of the effects of hormone replacement therapy on coronary heart disease (CHD) has changed markedly over the past 5 years. Based on the lower prevalence of CHD in premenopausal women and in postmenopausal women taking HRT1 in observational studies, HRT was prescribed to 38% of postmenopausal women prior to 1998. The use of HRT was more strongly advised in postmenopausal women with CHD. The intent was to lessen the development and/or intensity of hot flashes, urogenital atrophy, osteoporosis, and heart disease.     Observational studies had suggested that HRT also increased the incidence of breast cancer, stroke, thromboembolism, and cholecystitis, but lessened incidence of colon cancer. In 1998, the surprising results of the original Heart and Estrogen/progestin Replacement Study (HERS) were published, covering the effects of 0.625 mg/day of conjugated estrogen and 2.5 mg/day of medroxyprogesterone acetate in 2,762 postmenopausal women with established CHD.2 The study demonstrated no difference in CHD events over the trial’s 4.1-year mean follow-up, but there appeared to be both an early increase and a later decrease in coronary events. The study was continued for an additional 2.7 years of follow-up.     The longer follow-up, HERS II, was published 4 years later, covering 93% of the women in the original trial.3 During the latter follow-up period, the primary endpoint—CHD death and nonfatal myocardial infarction (MI)—hazard ratio was 1.00, ie, no benefit and no harm. Thus, the earlier suggestion that HRT would prove beneficial if continued beyond the initial period of increased prothrombotic risk proved false. Secondary endpoints—including bypass surgery, percutaneous coronary intervention, unstable angina, congestive heart failure, sudden death, stroke, and peripheral arterial disease—were not significantly different in the women receiving HRT.     The Women’s Health Initiative (WHI) tested the same HRT regimen versus placebo in 16,608 healthy postmenopausal women with an intact uterus, and estrogen alone in ~10,000 women who had previously had a hysterectomy.4 In May 2002, the Data and Safety Monitoring Board of the WHI stopped the first part of the study prematurely after 5.2 years of follow-up (planned follow-up was 8.5 years) because there was found to be a statistically significant increase in breast cancer and global disease with HRT. In the study, HRT was found to have had both beneficial and adverse effects. In WHI, hormone replacement therapy increased CHD (mortality and nonfatal MI), stroke, and thromboembolic disease. It also increased incidence of breast cancer but decreased both colon cancer incidence and fractures. Overall mortality was unaffected by HRT (hazard ratio 0.98).5     A global index was used to assess the overall HRT effect in WHI, including CHD, stroke, pulmonary embolism, breast cancer, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. HRT was found to increase the global risk (hazard ratio 1.15). The key message from WHI is that 10,000 healthy postmenopausal women on HRT will experience seven more CHD events, eight more strokes, eight more pulmonary emboli, eight more breast cancers, six fewer colorectal cancers, and five fewer hip fractures per year. The absolute 5-year increase in risk for a major disease with HRT is 1% (see Table 1). Table 1. Major Disease Effects of WHI HRT-Treated Postmenopausal Women After 1 Year Chlebowski RT et al. JAMA. 2003;289:3243-3253. Results Different From Expectations Why did the results of the primary- and secondary-prevention HRT trials turn out so differently from expectations? Hormone replacement therapy has complex effects on atherosclerosis (see Table 2). HRT has predominately good effects on lipids: It increases HDL-C and decreases LDL-C and Lp(a). In HERS, a post-hoc analysis revealed that HRT reduced the risk for heart disease in women with initially elevated Lp(a). In 25% of women, HRT also increased TG and adversely changed the mean LDL particle size to the small, dense pattern. HRT increased thrombosis and some markers of inflammation, such as hs-CRP,6 although not all cytokines were affected. Hormone replacement therapy was also found to rapidly improve endothelial function, as measured by endothelium-dependent vasodilation (although this improvement disappeared after 6 months of therapy).7 In view of these complex actions, it is not surprising that the randomized trials did not demonstrate benefit. It remains unclear whether other HRT regimens, estrogen alone, or selective estrogen receptor modulators (SERM) would be more beneficial. Table 2. Lipid and Vascular Effects of HRT Information courtesy of Robert A. Vogel, MD. Conclusion Hormone replacement therapy did not protect our patient from experiencing CHD—and may actually have contributed to it. Her hs-CRP was in the high-risk range (3–10 mg/L) while she remained on HRT. With discontinuation of the HRT and the addition of statin therapy, her hs-CRP decreased to the low intermediate-risk range (1–3 mg/L). Her LDL-C was also much lower after she had been on statin therapy than it was while she was on HRT. Finally, our patient’s hot flashes were adequately controlled on the SSRI paroxetine,8 which has proven to be more beneficial than have phytoestrogens. References* 1. Nelson HD et al. JAMA. 2002;288:872-881. 2. Hulley S et al. JAMA. 1998;280:605-613. 3. Grady D et al. JAMA. 2002;288:49-57. 4. Writing Group for the WHI Investigators. JAMA. 2002;288:321-333. 5. Chlebowski RT et al. JAMA. 2003;289:3243-3253. 6. Ridker PM et al. Circulation. 1999;100:713-716. 7. Sorensen KE et al. Circulation. 1998;97:1234-1238. 8. Stearns V et al. N Engl J Med. 2003;289:2827-2834. *For complete citations, please click here.