Postmenopausal Hormone Replacement Therapy and Cardiovascular Disease: The WHI Trial

29 Jun

Postmenopausal Hormone ReplacementThe Women’s Health Initiative (WHI) is a long-term, prospective, experimental study that addresses the use of HRT for the primary prevention of CHD among healthy, postmenopausal women. Data collection was recently suspended in the continuous combined HRT group (CEEs 0.625 mg/day with MPA 2.5 mg each day) after 5.2 years, and the results of this arm were published early; however, the estrogen monotherapy arm is still ongoing. Data were released early from the combined HRT arm because of evidence that the risks were outweighing the benefit for these subjects. This arm of the study included 16,608 postmenopausal women with an intact uterus who were between ages 50 and 79 (mean = 63.3 years). Subjects were randomly assigned to receive either continuous, combined HRT (CEEs 0.625 mg/day with MPA 2.5 mg/day) or placebo.

The primary outcomes were the same as those in the HERS trial, with a CHD event being defined as nonfatal AMI or death from CHD. Breast cancer was the primary adverse effect that was monitored. Secondary outcomes included stroke, pulmonary embolism, endometrial cancer, hip fracture, and death attributable to other causes.

Evaluation of HRT risks indicated that the incidence of CHD was higher among subjects receiving HRT (hazard ratio [HR] = 1.29, 95% CI, 1.02-1.63). The increased prevalence of CHD events was primarily caused by nonfatal AMI (HR = 1.32, 95% CI, 1.02-1.72). However, the number of nonfatal strokes was significantly higher in the HRT group (HR = 1.50, 95% CI, 1.08-2.08). Venous thromboembolism was twice as prevalent among HRT users (HR = 2.11, 95% CI, 1.58-2.82); this was slightly lower than that observed in the HERS trial. In addition to the lack of CHD benefit, the incidence of invasive breast cancer was higher among HRT users (HR = 1.26, 95% CI, 1.00-1.59) but did not reach statistical significance.

Several benefits of HRT were observed. The risk of colorec-tal cancer was significantly decreased (HR = 0.63, 95% CI, 0.43-0.92), and the incidence of hip, vertebral, and other osteo-porotic fractures was significantly lower among HRT users (HR = 0.76, 95% CI, 0.69-0.85).

This study demonstrated that the use of continuous combined HRT containing CEEs 0.625 mg and MPA 2.5 mg daily did not provide a benefit for the primary prevention of CHD among healthy postmenopausal patients. The risks of CHD, throm-boembolism, and possibly breast cancer with combined HRT outweighed the benefits observed in this study.

The MORE Trial

The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a prospective, five-year experimental study that evaluated the effect of raloxifene on a number of outcomes. Cardiovascular events were a secondary outcome of this study. The sample included 7,705 postmenopausal women with osteoporosis. Subjects were randomly assigned to one of three groups: raloxifene 60 mg/day, 120 mg/day, or placebo. The CHD outcome measures included coronary events (i.e., AMI, unstable angina, or coronary ischemia) and cerebrovascular events (i.e., stroke or TIA).

Results indicated no difference in CHD risks between groups for the women receiving raloxifene 60 mg/day (RR = .86, 95% CI, 0.64-1.15) or 120 mg/day (relative risk [RR] = .98, 95% CI, 0.74-1.30). However, a subset analysis indicated that among subjects with an increased risk of CHD at baseline level, CHD risk was significantly decreased with both doses of raloxifene when compared to placebo (RR = .60, 95% CI, 0.38-0.95). No increase in cardiovascular risk was detected among treatment groups at any point in time during the study.

These results suggest that treatment with raloxifene 60 to 120 mg/day had no effect on primary prevention of CHD among postmenopausal women with osteoporosis but did show benefit in decreasing CHD among women with increased CHD risks. Because these endpoints were secondary outcomes, these results should be confirmed with an experimental study designed and powered to evaluate CHD risk as a primary outcome. buy antibiotics canada


Prospective, experimental trials do not support the benefit of continuous combined HRT therapy for the primary or secondary prevention of CHD that had been suggested with earlier observational studies.

In the HERS, HERS II, and WHI trials, only one regimen of HRT was evaluated, medroxyprogesterone acetate (Prempro®, Wyeth-Ayerst), which included the progestin MPA. It is known that although it is necessary to add a progestin to a regimen in patients with an intact uterus to decrease the risk of endometrial cancer, progestins attenuate the benefits of estrogen. In the PEPI trial, MPA was shown to offset the beneficial effects of estrogen more than the other progestin (MP) that was studied in this trial. It is not clear whether the results observed in these studies can be applied to all combined HRT therapies, including low-dose HRT regimens that include other progestins and other HRT dosage forms.

It has yet to be resolved whether estrogen monotherapy will be beneficial for the prevention of CHD among women who have had a hysterectomy and do not require progestin. This estrogen monotherapy arm of the WHI trial is still ongoing, and results should be available in three years. These data should provide more information on the benefit of estrogen monotherapy for the primary prevention of CHD. The usefulness of this regimen for the secondary prevention still needs to be evaluated. generic cialis soft tabs

Finally, the results of the MORE trial look promising for the CHD benefit of raloxifene among women with an established risk for CHD development, but these results require verification in future studies.

In the meantime, it is advisable not to recommend the use of continuous CEE and MPA combination therapy solely for primary or secondary prevention of CHD. Individualized patient recommendations must be made on the basis of the known benefits and the risks of HRT. The established benefits of HRT include effective control of menopausal symptoms, a decreased risk of osteoporotic fractures, and a decreased risk of colon cancer. The potential risks of HRT include a significant increase of thromboembolic disease and a possible increased risk of breast cancer. Clinicians must make individualized recommendations based on these data and patient-specific characteristics, including medical and family history.


Patient-specific characteristics and evidence-based medicine will determine who will benefit from HRT. Although there are theoretical reasons to expect decreased CHD risk with HRT, based on current evidence, HRT should not be recommended for primary and secondary CHD prevention. For women with cardiovascular risks, clinicians should focus on interventions that have proved effective to decrease CHD risks. These include smoking cessation, weight management, and exercise. Clinicians should also carefully screen for, monitor, and treat concomitant disease states known to increase CHD risks such as dyslipidemia, diabetes mellitus, and hypertension.