Beyond the null hypothesis--do the HERS results disprove the estrogen/coronary heart disease hypothesis?

T purpose of the recently published Heart and Estrogen/Progestin Replacement Study (HERS) was to determine if hormone replacement therapy (HRT) decreases the risk for subsequent cardiovascular events in postmenopausal women with established coronary heart disease (CHD).1 HRT has many potential cardioprotective biologic effects.2 Most observational studies such as the Nurses’ Health Study indicated that women who “self-select” to take HRT have approximately a 50% lower risk of CHD.3 However, a few studies did not find HRT to be cardioprotective.4 HERS was the first prospective randomized, double-blind, placebo-controlled trial of the effects of HRT (with conjugated estrogen and medoxyprogesterone acetate) on CHD risk. It enrolled 2,763 postmenopausal women (average age 67 years). Surprisingly, after 4 years of follow-up, there were 179 CHD events in the HRT group and 182 in the placebo group with 57 events in the HRT group and 38 in the placebo group in year 1 (relative hazard [RH] 1.5).5 In the first 4 months of the trial there was an RH of 2.3. However, in years 4 and 5 there were 40 events in the HRT group and 53 in the placebo group (RH 0.75).5 Because of this late trend for benefit, the HERS investigators are following 2,297 participants for at least 3 more years, while they continue with their assigned treatment groups. This study extension is known as HERS II. The failure of HERS to achieve a positive result does not disprove the estrogen/heart disease hypothesis, since the trial was significantly underpowered. The average duration of follow-up was nearly 7 months less than originally planned. This resulted from enrollment of a large percentage of the participants within the final 6 months of the 18-month recruitment period. There was a higher than expected crossover rate between the groups. There was a 1.7%/ year crossover rate from placebo to HRT (1%/year was expected), and an 18% crossover from HRT to placebo in the first year (5% rate was expected). The event rate in HERS was lower than expected, 3.3%/ year, rather than the 5% that was predicted. It was predicted that the event rate in the placebo group would be 24%, but the actual rate was 13%. The incremental benefit of HRT may not be as great as had been predicted, because many more women are now treated with proven preventive therapies. More women than ever before are being treated with statins, aspirin, b blockers, and angiotensin-converting enzyme inhibitors, all of which decrease events in patients with CHD.6 Another potential explanation for the neutral outcome of HERS is that progestin may attenuate the cardioprotective effect of estrogen. Medroxyprogesterone acetate has been shown to decrease the beneficial effects of estrogen on coronary vasoreactivity and inhibition of atherosclerosis in cynomolgus monkeys.7 Perhaps another type of progestin that is less androgenic may have led to better results.8 However, recent data indicate that the HRT regimen used in HERS does indeed improve brachial artery vasoreactivity to a greater degree than does statin therapy.9 The early increase in CHD events observed in HERS may possibly be due to a thrombogenic effect of HRT in a small percentage of “susceptible” women. A possible thrombogenic risk may have been increased by HRT in smaller, thinner women because the dose was not adjusted for body mass. The HERS investigators will need to determine if the women who sustained CHD events during the first year of the trial had a more “thrombogenic profile” or if they had more extensive coronary disease at baseline. Potential thrombogenic risk factors include Factor V Leiden10 and platelet genetic polymorphisms such as platelet antigen-2 (PlA2).11 The interaction between these risk factors and hormones will need to be investigated further. Prospective identification of women who are susceptible to the potential thrombogenic effects of HRT could allow clinicians to limit prescription of the therapy to appropriate women.5 The HERS investigators also need to report if there were subgroups of women who derived clinical benefit from HRT, such as those with low high-density lipoprotein cholesterol or high lipoprotein(a), because HRT significantly improves these lipid fractions. Most women receiving HRT in observational studFrom The Departments of Medicine/Cardiology and Obstetrics & Gynecology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and The Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Manuscript received August 31, 1999; revised manuscript received and accepted November 3, 1999. Address for reprints: Roger S. Blumenthal, MD, The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Carnegie 538, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, Maryland 21287. E-mail: rblument@jhmi.edu.