Heart and Metabolism

Coronary artery disease in women: no reason for gender-specific treatment

Professor Michael S Marber
Department of Cardiology, KCL, St Thomas’ Hospital, Lambeth Place Road,
London SE1 7EH, UK (mike.marber@kcl.ac.uk)

This issue of our quarterly is dedicated to the management of women with, or at risk of developing, coronary artery disease. The traditional view has been that the female menopause represents a watershed in cardiovascular risk. Since before the menopause overt coronary artery disease is rare. The question of whether the relationship between reduced estrogen/progestogen and increased risk is associative or causative is the theme pervading the contributions to this issue.

Within this issue Dr’s Clanachan and Fraser present numerous lines of evidence that suggest the male and female cardiovascular systems differ. These differences, as Dr’s Holdright and Hayward and Collins point out, contibute to a chronological delay of approximately 20 years in the incidence of cardiovascular complications in women compared with men. This means that the incidence of cardiovascular disease increases sharply in women after the menopause. The question has been whether this temporal association between reduction in estrogen levels and increase in manifestations of ischaemic heart disease is causal? This issue is critical since estrogen replacement therapy (ERT) is the only cardiovascular intervention that is unique to women.

The use of ERT to reduce cardiovascular risk is addressed in this issue within the article by Dr Wenger. On the basis of observational studies women who choose to take ERT, with or without progestogens, have a reduced risk of coronary heart disease but it is also possible they are better educated, more compliant and have healthier lifestyles. Observational and other data from small randomised trials supported the concept that the risk of developing ischaemic heart disease after the menopausal could be reduced by ERT. However the Heart and Estrogen/Progestin Replacement Study (HERS)[1] has radically altered this view. This study, was the first large-scale (n=2763), randomised trial of ERT (0.625mg conjugated equine estrogens with 2.5mg medroxyprogesterone acetate) versus placebo, in older (mean age 66.7yr) postmenopausal women with confirmed ischaemic heart disease adopting “hard” clinical cardiovascular endpoints of nonfatal MI or death attributable to ischaemic heart disease. After an average of 4.1 years follow up, no significant difference existed for any cardiovascular end point.

As a result of this trial most recent guidelines do not support the initiation of ERT in women with established ischemic heart disease.[2] However since, within the HERS trial, ERT was perhaps associated with an early hazard (up to year 3), but then late benefit, (years 4 and 5) therapy continuation is probably reasonable until longer term follow-up of the HERS cohort and results from other ERT trials become available.

The question of ERT therapy to reduce events in women without overt ischaemic heart disease is a complex issue. No randomised data are available to support efficacy. Moreover, there are many examples of interventions effective in a secondary setting which later prove of value in primary prevention, whereas I’m not aware of an example of an intervention failing in secondary prevention but succeeding in primary prevention. These factors, together with other possible risks of ERT such as increased incidence of thromboembolic disease, breast cancer, endometrial cancer and gallbladder disease, means their use in primary prevention of ischaemic heart disease is likely to remain contentious.
The important point made in this issue is that although ERT is of unproven benefit, other interventions, that reduce the complications of ischaemic heart disease in whole populations, are increasingly becoming proven in women as they are better represented in trial populations.[3] This is particularly the case in women with diabetes. The worrying feature however is that evidence suggests that women are being denied beneficial advice and treatment. For example in a recent ambulatory care survey in the US, women were counselled less often that men about exercise, nutrition and weight reduction2 whilst in England and Wales the prevalence of smoking is falling much more rapidly in men than in women.[4] The cause for this complacency is uncertain but may relate to guidelines that are driven by absolute risk together with a lower absolute risk of ischaemic heart disease in women. However once ischaemic heart disease is established intervention to reduce risk should no longer be gender-specific, yet in the HERS study 90% of women had LDL-cholesterol levels above 100mg/dl.[2]

These, and other issues raised in this quarterly, have opaque solutions. However one thing is clear; the reasons to treat men and women differently are becoming harder to find. Vive la difference? Perhaps not.

References

1: JAMA 1998 Aug 19;280(7):605-13

Related Articles, Books, LinkOut

Comment in:

Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.

Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E.

University of California, San Francisco 94143, USA.

CONTEXT: Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials. OBJECTIVE: To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease. DESIGN: Randomized, blinded, placebo-controlled secondary prevention trial. SETTING: Outpatient and community settings at 20 US clinical centers. PARTICIPANTS: A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years. INTERVENTION: Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1380) or a placebo of identical appearance (n = 1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years. MAIN OUTCOME MEASURES: The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered. RESULTS: Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38). CONCLUSIONS: During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue.

Publication Types:

Clinical Trial
Multicenter Study
Randomized Controlled Trial

PMID: 9718051 [PubMed - indexed for MEDLINE]

2: Circulation 1999 May 11;99(18):2480-4

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Erratum in:

2000 May 4;342(18):1376
N Engl J Med 2000 Mar 9;342(10):748

Comment in:

Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.

Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G.

Canadian Cardiovascular Collaboration Project Office, Hamilton General Hospital, McMaster University, ON. hope@ccc.mcmaster.ca

BACKGROUND: Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction, whether or not they have heart failure. We assessed the role of an angiotensin-converting-enzyme inhibitor, ramipril, in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure. METHODS: A total of 9297 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years. The primary outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper. RESULTS: A total of 651 patients who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001). Treatment with ramipril reduced the rates of death from cardiovascular causes (6.1 percent, as compared with 8.1 percent in the placebo group; relative risk, 0.74; P<0.001), myocardial infarction (9.9 percent vs. 12.3 percent; relative risk, 0.80; P<0.001), stroke (3.4 percent vs. 4.9 percent; relative risk, 0.68; P<0.001), death from any cause (10.4 percent vs. 12.2 percent; relative risk, 0.84; P=0.005), revascularization procedures (16.3 percent vs. 18.8 percent; relative risk, 0.85; P<0.001), cardiac arrest (0.8 percent vs. 1.3 percent; relative risk, 0.62; P=0.02), [corrected] heart failure (9.1 percent vs. 11.6 percent; relative risk, 0.77; P<0.001), and complications related to diabetes (6.4 percent vs. 7.6 percent; relative risk, 0.84; P=0.03). CONCLUSIONS: Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure.

Publication Types:

Clinical Trial
Multicenter Study
Randomized Controlled Trial

PMID: 10639539 [PubMed - indexed for MEDLINE]

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