Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronaryheart disease events after menopause

Context Lipoprotein(a) [Lp(a)] has been identified as an independent risk f actor for coronary heart disease (CHD) events. However, few data exist on t he clinical importance of Lp(a) lowering for CHD prevention. Hormone therap y with estrogen has been found to lower Lp(a) levels in women. Objective To determine the relationships among treatment with estrogen and progestin, serum Lp(a) levels, and subsequent CHD events in postmenopausal women. Design and Setting The Heart and Estrogen/progestin Replacement Study (HERS ), a randomized, blinded, placebo-controlled secondary prevention trial con ducted from January 1993 through July 1998 with a mean follow-up of 4.1 yea rs at 20 centers. Participants A total of 2763 postmenopausal women younger than 80 years wit h coronary artery disease and an intact uterus. Mean age was 66.7 years. Intervention Participants were randomly assigned to receive either conjugat ed equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, in 1 tablet daily (n = 1380), or identical placebo (n = 1383). Main Outcome Measures Lipoprotein(a) levels and CHD events (nonfatal myocar dial infarction and CHD death). Results Increased baseline Lp(a) levels were associated with subsequent CHD events among women in the placebo arm. After multivariate adjustment, wome n in the second, third, and fourth quartiles of baseline Lp(a) level had re lative hazards (RHs) (compared with the first quartile) of 1.01 (95% confid ence interval [CI], 0.64-1.59), 1.31 (95% CI, 0.85-2.04), and 1.54 (95% CI, 0.99-2.39), respectively, compared with women in the lowest quartile (P fo r trend =.03). Treatment with estrogen and progestin reduced mean (SD) Lp(a ) levels significantly (-5.8 [15] mg/dL) (-0.20 [0.53] mu mol/L) compared w ith placebo (0.3 [17] mg/dL) (0.01 [0.60] mu mol/L) (P<.001). In a randomiz ed subgroup comparison, women with low baseline Lp(a) levels had less benef it from estrogen and progestin than women with high Lp(a) levels; the RH fo r women assigned to estrogen and progestin compared with placebo were 1.49 (95% CI, 0.97-2.26) in the lowest quartile and 1.05 (95% CI, 0.67-1.65), 0. 78 (0.52-1.18), and 0.85 (0.58-1.25) in the second, third, and fourth quart iles, respectively (P for interaction trend =.03). Conclusions Our data suggest that Lp(a) is an independent risk factor for r ecurrent CHD in postmenopausal women and that treatment with estrogen and p rogestin lowers Lp(a) levels. Estrogen and progestin therapy appears to hav e a more favorable effect (relative to placebo) in women with high initial Lp(a) levels than in women with low levels. This apparent interaction needs confirmation in other trials.