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Figure 1. Distribution of Baseline Lipoprotein(a) Levels Among Participants in the HERS Study
Image description not available.
Levels are expressed as mg/dL (to convert mg/dL to µmol/L, multiply by 0.0357); the median value was 25.3. Final bar represents all patients with lipoprotein(a) levels >120 mg/dL.
Figure 2. Mean Change in Lipoprotein(a) at 1 Year of Follow-up Among Women Randomly Assigned to Estrogen and Progestin or Placebo
Image description not available.
Data are presented in mg/dL (to convert mg/dL to µmol/L, multiply by 0.0357), stratified by quartile of baseline level of lipoprotein(a) [Lp(a)]. Within each quartile, women assigned to estrogen and progestin had a significantly greater reduction in Lp(a) level than women assigned to placebo (P<.001). A trend of greater reduction from estrogen progestin with increasing quartile of baseline Lp(a) was observed (P<.001). Error bars indicate SD.
Figure 3. Effect of Estrogen and Progestin on Outcomes of Myocardial Infarction and Coronary Heart Disease Death
Image description not available.
Data are stratified by year of follow-up and baseline lipoprotein(a) [Lp(a)] level. Women with baseline Lp(a) levels below or equal to 25.3 mg/dL (the median) who were assigned to estrogen and progestin had an increased risk of coronary heart disease events in year 1, but no effect from estrogen and progestin in subsequent years. Women assigned to estrogen and progestin with baseline Lp(a) levels above the median had no significant difference in year 1 coronary heart disease events, but had a significant reduction in events during years 2 through 5 of follow-up. To convert mg/dL to µmol/L, multiply by 0.0357.
Table 1. Baseline Cardiovascular Risk Factors by Lipoprotein(a) Level Quartile (N = 2759)*
Image description not available.
Table 2. Risk of Recurrent Coronary Heart Disease Events by Baseline Lipoprotein(a) Level Among Women Assigned to Placebo (n = 1383)*
Image description not available.
Table 3. Coronary Heart Disease Outcomes Among Women Randomly Assigned to Estrogen and Progestin (n = 1383) or Placebo (n = 1380), Stratified by Baseline Lipoprotein(a) Level Quartile*
Image description not available.
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Original Contribution
April 12, 2000

Estrogen and Progestin, Lipoprotein(a), and the Risk of Recurrent Coronary Heart Disease Events After Menopause

Author Affiliations

Author Affiliations: Departments of Medicine (Drs Shlipak and Simon), and Epidemiology and Biostatistics (Drs Simon, Vittinghoff, and Hulley and Ms Lin), University of California, San Francisco; General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco (Drs Shlipak and Simon); Department of Family and Preventive Medicine, University of California, San Diego (Dr Barrett-Connor); Northwest Lipid Research Clinic and the University of Washington, Seattle (Dr Knopp); and American Home Products, Madison, NJ (Dr Levy).

JAMA. 2000;283(14):1845-1852. doi:10.1001/jama.283.14.1845
Context

Context Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for coronary heart disease (CHD) events. However, few data exist on the clinical importance of Lp(a) lowering for CHD prevention. Hormone therapy 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 conducted from January 1993 through July 1998 with a mean follow-up of 4.1 years at 20 centers.

Participants A total of 2763 postmenopausal women younger than 80 years with coronary artery disease and an intact uterus. Mean age was 66.7 years.

Intervention Participants were randomly assigned to receive either conjugated 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 myocardial 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, women in the second, third, and fourth quartiles of baseline Lp(a) level had relative hazards (RHs) (compared with the first quartile) of 1.01 (95% confidence 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 for trend = .03). Treatment with estrogen and progestin reduced mean (SD) Lp(a) levels significantly (–5.8 [15] mg/dL) (−0.20 [0.53] µmol/L)compared with placebo (0.3 [17] mg/dL) (0.01 [0.60] µmol/L) (P<.001). In a randomized subgroup comparison, women with low baseline Lp(a) levels had less benefit from estrogen and progestin than women with high Lp(a) levels; the RH for 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 quartiles, respectively (P for interaction trend = .03).

Conclusions Our data suggest that Lp(a) is an independent risk factor for recurrent CHD in postmenopausal women and that treatment with estrogen and progestin lowers Lp(a) levels. Estrogen and progestin therapy appears to have 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.

Lipoprotein(a) [Lp(a)] has been found to be an independent risk factor for coronary heart disease (CHD) events in most17 but not all810 prospective studies of men without known coronary artery disease. Few prospective studies have evaluated the importance of Lp(a) as a risk factor among women or among persons with CHD.11 Furthermore, it is unknown whether interventions directed at lowering Lp(a) levels will affect subsequent risk of CHD. Lipoprotein(a) levels are not lowered by most lipid-lowering medications, diet, or exercise.12,13 Among standard lipid-lowering therapies, only nicotinic acid has been shown to reduce Lp(a) levels.1418

Recently, estrogen and the combination of estrogen and progestin have been found to lower Lp(a) levels in postmenopausal women.1824 Because these studies have been conducted in women without CHD and without assessment of CHD outcomes, the clinical importance of lowering Lp(a) levels among women is unknown.

The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized, blinded, placebo-controlled trial of the effect of daily conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, on the rate of new coronary events over a mean follow-up of 4.1 years in 2763 postmenopausal women with known CHD. We evaluated the clinical importance of Lp(a) as a predictor of CHD events among women with coronary artery disease; the efficacy of estrogen and progestin in lowering Lp(a) levels in this population; and the relationship among estrogen and progestin treatment, Lp(a) levels, and subsequent CHD events.

METHODS
Subjects

The design, methods, and primary results of the HERS study have been published previously.25,26 Briefly, HERS participants were postmenopausal women younger than 80 years who had been previously diagnosed as having coronary artery disease and had not had a hysterectomy. Coronary heart disease inclusion criteria required evidence of 1 or more of the following: history of myocardial infarction (MI), coronary artery bypass graft surgery, percutaneous coronary revascularization, or angiographic evidence of at least a 50% occlusion of 1 or more major coronary arteries. Exclusion criteria included a recent CHD event, New York Heart Association class IV or severe class III congestive heart failure, serum triglyceride levels greater than 3.39 mmol/L (300 mg/dL), recent use of any hormone therapy, uncontrolled hypertension or diabetes mellitus, a disease (other than CHD) judged likely to be fatal within 4 years, or intolerance to hormone replacement therapy. At enrollment, participants were randomly assigned to receive a single identical tablet containing either conjugated equine estrogen, 0.625 mg, and medroxyprogesterone acetate, 2.5 mg, or placebo.

Measurements

Demographic characteristics, health history, CHD risk factors, medication use, and quality of life were assessed at baseline. Baseline levels of fasting total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and Lp(a) were determined by the Lipoprotein Analytical Laboratory at Johns Hopkins University Hospital in compliance with standards set by the Centers for Disease Control and Prevention. Subsequent lipid level measurements were performed at 1 year of follow-up.

Lipoprotein(a) levels were measured immunochemically with a sandwich enzyme-linked immunosorbent assay that uses a monoclonal antibody to apolipoprotein(a) [apo(a)] (antibody 1D1) as the capture antibody (Strategic Diagnostics, Newark, Del). Capable of detecting all 11 Lp(a) isoforms, the antibody recognizes an epitope in the kringle 4 domains of the apo(a) component of Lp(a), but does not cross-react with plasminogen. The assay was calibrated by the manufacturer with a reference pool supplied by the Northwest Lipid Research Clinic (Seattle, Wash) that used purified Lp(a) as the standard. Lipoprotein(a) concentrations are reported as milligrams per deciliter (micromoles per liter).27

Follow-up and Outcome Ascertainment

Follow-up visits to the clinical centers occurred at 4-month intervals over a mean of 4.1 years. All suspected outcome events were reported to the HERS coordinating center and documentation was obtained for adjudication. All events were classified independently by 2 coordinating center reviewers, and discordant classifications were resolved in discussions between the reviewers.

Primary outcomes included nonfatal MI and CHD death, which included sudden death within 1 hour of symptoms, unobserved death that occurred out of the hospital in the absence of other known cause, or death due to coronary revascularization procedure or congestive heart failure. Diagnosis of MI was based on an algorithm that incorporated clinical symptoms, electrocardiographic abnormalities, and cardiac enzyme levels.25 Secondary CHD outcomes included coronary artery bypass graft surgery, percutaneous coronary revascularization, and hospitalization for unstable angina.

Statistical Analysis

To evaluate the association of baseline Lp(a) levels with other known predictors of CHD events, we divided the HERS cohort of women into quartiles based on Lp(a) level at enrollment. Using analysis of variance and χ2 statistics, we compared demographic characteristics, CHD risk factors, previous cardiovascular disease history, other lipid and lipoprotein levels, and medical treatments among women in the 4 quartiles.

The association of baseline Lp(a) values with subsequent CHD events was evaluated independently of estrogen and progestin treatment among HERS participants randomized to the placebo arm of the study. We developed Cox proportional hazards models using a forward stepwise procedure to include variables that were associated with Lp(a) at P<.10. Multivariable-adjusted relative hazards (RHs) for each quartile of baseline Lp(a) level were calculated and compared with the lowest quartile. A χ2 test of trend was used to determine the relationship among quartiles. When we repeated the analysis with a model that included all the variables in Table 1, the point estimates were virtually identical.

We determined the effect of hormone therapy on Lp(a) levels by calculating the difference between measurements at baseline and at 1 year of follow-up. Using a 2-tailed t test, we compared the difference between participants in the 2 treatment arms. We repeated these comparisons within each baseline Lp(a) level quartile and tested for linear trend in Lp(a) level reduction across quartiles.

We evaluated the effect of changes in Lp(a) levels on CHD events after year 1 for the women assigned to estrogen and progestin. For each woman in the study, the difference in Lp(a) from enrollment to 1-year follow-up was calculated and defined as Lp(a) level reduction; subjects were then divided into quartiles of Lp(a) level reduction. Using Cox proportional hazard models that included covariables from Table 1 significant at P<.10, baseline Lp(a) values, variables representing the 1-year differences in lipid and lipoprotein levels, and compliance with treatment assignment, we determined the association between the reduction in Lp(a) level and CHD events.

To explore the presence of an interaction between hormonal therapy and baseline Lp(a) values, we performed a stratified analysis by quartile of the baseline Lp(a) value. Within each quartile, we compared outcomes among participants assigned to estrogen and progestin or placebo using an unadjusted proportional hazards model. We evaluated the effect of hormonal therapy on CHD events by baseline Lp(a) quartile using a χ2 test for trend. We repeated this analysis comparing women above and below the median value of Lp(a). Because the effect of hormonal therapy on primary CHD events appeared to change over time,26 we also stratified outcomes occurring before and after the 1-year visits.

Because the 8% of our cohort that was African American had much higher Lp(a) levels at baseline, we examined whether excluding this group from all analyses would alter the conclusions and found that it did not. All analyses were conducted using SAS, version 6.12.28 Two-tailed tests with P<.05 were considered statistically significant.

RESULTS
Baseline Characteristics

Among the 2763 participants in the HERS study, baseline Lp(a) measurements were available for 2759 women. Levels of Lp(a) were skewed to the right (Figure 1); the median level was 25.3 mg/dL (0.90 µmol/L), whereas the mean (SD) was 33.7 (32.6) mg/dL (1.20 [1.16] µmol/L).

We compared baseline characteristics of the women by quartile of Lp(a) level (Table 1). No associations between Lp(a) quartile and age or education level were observed. African American women had higher mean Lp(a) levels than other women (58 mg/dL vs 32 mg/dL [2.1 µmol/L vs 1.1 µmol/L]; P<.001); more than half of the African American women were in the highest quartile for the overall cohort. Women in the highest Lp(a) quartile were less likely to be current smokers (P<.05).

Mean values of LDL and HDL cholesterol were greater in the higher Lp(a) quartiles, whereas triglyceride levels were lower (P<0.01 for each comparison). Women in the highest Lp(a) quartile were more likely to be receiving lipid-lowering agents. The significant associations between Lp(a) quartile and the other lipid levels persisted after adjustment for differences in the use of lipid lowering medications. Women in the highest Lp(a) quartile more frequently used aspirin and calcium channel blockers (P<.05).

Association Between Baseline Lp(a) Level and Recurrent CHD Events

We examined the association of baseline Lp(a) quartile with subsequent CHD events in women assigned to placebo. After adjustment for differences in other baseline characteristics, the initial Lp(a) measurement was associated with CHD risk (Table 2). Women in the highest Lp(a) quartile had a 54% (95% confidence interval [CI], 0%-140%) increased risk of primary CHD events compared with women in the lowest Lp(a) quartile. Compared with the lowest Lp(a) quartile, the relative risk for revascularization events was also significantly greater in the highest Lp(a) quartile (61%; 95% CI 10%-130%). We observed a similar increase in risk (although nonsignificant) for unstable angina admissions and for the 2 components of primary CHD events (CHD death and nonfatal MI).

Effect of Estrogen and Progestin on Lp(a) Level

Participants randomized to receive estrogen and progestin had significant reductions in serum Lp(a) levels after 1 year of treatment compared with women who were randomized to placebo (Figure 2). The mean (SD) change in Lp(a) level was −5.8 (15) mg/dL (−0.2 [0.5] µmol/L) for women assigned to hormonal therapy, and 0.34 (17) mg/dL (0.01 [0.6] µmol/L) for women assigned to placebo (P<.001). Although we observed a highly significant reduction associated with estrogen and progestin in each quartile of baseline Lp(a) level, the magnitude of this difference was greatest in the higher quartiles (P for trend, <.001).

Impact of Lp(a) Level Reduction on CHD Events

We examined whether the reduction of Lp(a) levels after 1 year of estrogen and progestin treatment was associated with a reduced risk of subsequent CHD events. Cox regression analysis revealed no significant association, but inspection of the data suggested a possible threshold effect. Among women assigned to estrogen and progestin, those who were in the quartile of greatest Lp(a) level reduction (>−8.8 mg/dL [>−0.31 µmol/L]) had a significantly lower risk of CHD events compared with women who had smaller reductions in Lp(a) level (RH, 0.62; 95% CI, 0.38-1.00 after adjusting for all risk covariates significant at P<.10; compliance; and changes in LDL cholesterol, HDL cholesterol, and triglycerides). When primary events were analyzed separately, reduction in Lp(a) level appeared to be associated with decreased risk for MI (RH, 0.46; 95% CI, 0.25-0.85), but not for CHD death (RH, 0.99; 95% CI, 0.47-2.05). Changes in LDL cholesterol, HDL cholesterol, and triglyceride levels at 1 year were not associated with decreased CHD risk, either as continuous or quartile predictors.

Effect of Estrogen and Progestin Therapy on CHD Risk After Stratification by Baseline Lp(a) Level

There was no overall effect of estrogen and progestin on primary CHD events (Table 3). However, we did find evidence of a possible subgroup interaction. Baseline Lp(a) level appeared to modify the effect of estrogen and progestin treatment on risk of CHD events (P for interaction = .03). When divided into quartiles of baseline Lp(a) levels, there was a 15% to 22% decreased risk of CHD events (nonfatal MI and CHD death) among women with the highest baseline levels of Lp(a) who were randomized to estrogen and progestin (compared with those assigned to placebo) and a 49% increased risk among women with the lowest baseline Lp(a) levels who were randomized to estrogen and progestin (Table 3). Another way to look at the same interaction is to compare women above and below the median baseline Lp(a) value. Estrogen and progestin therapy was associated with an RH for CHD events of 1.26 (95% CI, 0.93-1.71) for women with a baseline Lp(a) level below the median value of 25.3 mg/dL (0.90 µmol/L), in contrast to an RH of 0.82 (95% CI, 0.62-1.08) for women with baseline Lp(a) level above the median (P for interaction = .04). Lipoprotein(a) levels did not modify the association between hormone treatment and revascularization or hospitalization for unstable angina.

In the HERS trial, there was an increased CHD risk associated with estrogen and progestin in year 1 and a subsequent decreased CHD risk in years 3 through 5.26 We examined this time-dependent effect stratified by baseline Lp(a) levels (above and below the median of 25.3 mg/dL [0.90 µmol/L]) (Figure 3). Among women with baseline Lp(a) levels below the median, we observed an increased risk of CHD events during the first year among those assigned to estrogen and progestin (RH, 2.10; 95% CI, 1.05-4.19), compared with those assigned to placebo. During subsequent years, there was no decreased risk of CHD events in women assigned to estrogen and progestin (RH, 1.10; 95% CI, 0.78-1.56). Among women with baseline Lp(a) levels above the median, the RH associated with hormonal therapy was 1.26 (95% CI, 0.75-2.10) during the first year, decreasing to 0.68 (95% CI, 0.48-0.95) during subsequent years of follow-up.

COMMENT

Lipoprotein(a) is a unique molecule comprising a lipoprotein particle resembling LDL cholesterol that is covalently bonded to apo(a), a large plasma glycoprotein.29 The individual characteristics of these 2 components are thought to be responsible for the apparent pathogenic role of Lp(a), which has no known physiologic function. The LDL cholesterol component likely contributes to atherogenesis, whereas apo(a), similar in structure to plasminogen, may promote thrombosis. Thus Lp(a), which has been isolated in the arterial wall at sites of atherosclerosis,30,31 may serve as a link between the pathogenic processes of atherosclerosis and thrombosis.12,13,29

Investigators independently identified Lp(a) using both immunoelectrophoretic techniques32 [called Lp(a) lipoprotein] and lipoprotein electrophoresis (called pre-β-1-lipoprotein33 or sinking pre-β-lipoprotein).34 After further analysis found the 2 entities to be related,3436 epidemiological studies identified the association of the molecule with atherosclerosis and CHD.35,37 Since then, multiple prospective cohort studies have evaluated the relationship between Lp(a) and CHD risk in persons without known heart disease. Although the majority of studies have found an independent risk associated with Lp(a),17 others, most notably the Physicians' Health Study, have found no association.810

In HERS, 4 major findings pertaining to this lipoprotein were observed among postmenopausal women with known coronary artery disease: (1) Lp(a) was an independent risk factor for CHD events; (2) estrogen and progestin lowered Lp(a) levels; (3) large reductions in Lp(a) levels were associated with decreased risk for recurrent CHD events; and (4) baseline Lp(a) appeared to modify the effect of estrogen and progestin treatment. The last finding is an interaction: women with high initial Lp(a) levels had lower rates of CHD events in the hormone therapy group compared with the placebo group, and those with low initial Lp(a) levels had higher CHD rates in the hormone therapy group compared with the placebo group.

Lp(a) as a CHD Risk Factor

Although multiple studies have evaluated the association of Lp(a) with CHD in patients without known coronary artery disease, only 1 prior study examined Lp(a) as a risk factor for recurrent CHD events.11 HERS demonstrates that Lp(a) is associated with recurrent CHD events in a population of women with known coronary artery disease. This association was independent of other significant predictors.26

Effect of Hormone Therapy on Lp(a) Levels

Previous trials have demonstrated that estrogen (with or without progestins) lowers Lp(a) levels in healthy postmenopausal women.1923 HERS confirmed the effect of estrogen and progestin on Lp(a) and demonstrated that this effect also occurs among women with known CHD.

Lp(a) Level Reductions and CHD Risk

Because Lp(a) levels are not altered by most lipid-lowering drugs, lipid trials have not examined whether lowering Lp(a) levels reduces risk of CHD. The 1 drug that does lower Lp(a), nicotinic acid,14,16,17 reduced CHD and mortality rates when compared with placebo in the Coronary Drug Project38; however, the relative contribution of favorable changes in LDL and HDL cholesterol and Lp(a) levels to the mortality reduction is unknown because neither HDL cholesterol nor Lp(a) level was measured in that study.38 Thus, our study is the first to have examined the association between Lp(a) level reduction and future CHD events.

Inspection of our data suggested the possibility of an association between Lp(a) level reduction and decreased CHD events within the active treatment group that was independent of both baseline levels and changes in LDL and HDL cholesterol and triglyceride levels; in fact, change in Lp(a) level was the only 1 of the 4 lipid change variables that had any statistically significant association with CHD risk. However, the association between Lp(a) level reduction and CHD risk was not present over the whole range of values for Lp(a) level change (as examined by Cox regression analysis). Only women with substantial reductions in Lp(a) (>−8.8 mg/dL [>−0.31 µmol/L]) had a significant decrease in risk for CHD events, and the risk reduction was observed for MI but not for the CHD death outcome. Interpretation of this nonrandomized association awaits future studies to address the possibility that it is due to chance or unmeasured confounders.

An Interaction Between Lp(a) Levels and Hormone Therapy

Independent of the effects of baseline Lp(a) level and Lp(a) level reduction on CHD events, we examined whether Lp(a) levels might modify the effect of estrogen and progestin on CHD events. Such an interaction did appear to be present—the effect of estrogen and progestin compared with placebo on recurrent CHD events was significantly different among subgroups with low or high Lp(a) levels. However, true interactions are rare,39 and the finding that estrogen and progestin decreased CHD risk among women with elevated Lp(a) levels could be due to chance. In fact, among the many possible subgroups evaluated by the HERS investigators, the number of significant interactions (including the Lp(a) interaction) was roughly the proportion expected from chance. On the other hand, the risk relationship between Lp(a) level and CHD outcomes suggests a possible threshold at the median for this group of women (25.3 mg/dL [0.90 µmol/L]); this finding, together with the skewed distribution of Lp(a) levels in the population,40 is compatible with a true biological interaction.

The possible benefit of estrogen and progestin therapy to women with elevated Lp(a) levels should be evaluated within the context of the primary results of the HERS study.26 Overall, HERS demonstrated that estrogen and progestin had neither a beneficial nor a harmful effect on CHD events. There was a suggestion of an increased risk of CHD events in the hormone treatment group during year 1 and a trend toward decreased risk during years 3 through 5 of the trial. After stratifying HERS participants by baseline Lp(a) levels above and below the median value, we found that the increased CHD risk associated with hormone therapy in year 1 was primarily observed in women with low Lp(a) levels. Furthermore, women with high initial Lp(a) levels had a decreased CHD risk in years 2 through 5 that achieved nominal criteria for statistical significance.

If confirmed by other studies, our findings could have implications regarding screening and treatment for elevated levels of Lp(a). Although screening for elevated Lp(a) levels has been considered to help identify individuals at risk for CHD, the practice has not been recommended, in part because options for lowering Lp(a) levels are limited.29 Estrogen and progestin treatment clearly lowers Lp(a) levels, as do high doses of nicotinic acid.14 However, policies on screening strategy will require further studies of the potential benefits and harm of these treatments in the context of the clinical situation and alternative treatments such as statins for preventing CHD. In particular, any decision to begin estrogen and progestin treatment in a woman with known coronary artery disease must be made in the context of the overall null effect of the HERS trial and the significantly increased risk of venous thromboembolic disease in women taking estrogen and progestin.26,41

In conclusion, we found Lp(a) to be an independent and modifiable risk factor for CHD events in postmenopausal women with known coronary artery disease. Further studies, such as the ongoing HERS II follow-up study and the Women's Health Initiative, will be helpful in clarifying the possible interaction among hormone therapy, Lp(a) levels, and CHD risk.

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