My cardiologist told me that because of the results from the Women’s Health Initiative (WHI), hormone therapy in menopause may be a cardiovascular concern. Was he correct?

Your Menopause Question: My cardiologist told me that because of the results from the Women’s Health Initiative (WHI), hormone therapy in menopause may be a cardiovascular concern. Was he correct?

Our Response: Your cardiologist has raised an important issue that all too often is overlooked when the WHI results are discussed. The role of hormone replacement therapy (HRT) in breast cancer overshadows the fact that deaths from cardiovascular events are many times more frequent than deaths from breast cancer. Understandably, the emotions tied to breast cancer are much more palpable than those associated with the unknowns of cardiac disease. Perhaps this is because breast cancer is perceived as being out of one’s control, while cardiac disease offers some control through lifestyle changes.

But cardiac disease increases with age. When menopausal symptoms compromise quality of life, the value of HRT for those women with a history of cardiac disease represents a “perfect storm.” Worse, while “cardiac disease” is an all-encompassing term, past strokes or heart attacks for women suffering from menopause symptoms create an even more serious clinical dilemma. Can they be on HRT? Or must they suffer off all HRT, just because of their cardiac history?

So what do we know about the cardiac findings of the WHI? And have there been more recent studies to chart a safe passage through this conflict?

The WHI (1991 to 2002) was prompted by prior animal studies indicating that estrogen might delay or even protect against coronary artery disease. Using a 2003 subpopulation of patients from the WHI of 16,608 women ages 50 to 70 who were followed for a mean of 5.2 years, the primary objective was incidence of a nonfatal heart attack (myocardial infarction) or death due to coronary heart disease. The authors reported that PREMPRO® did not offer protection against a heart attack and may slightly increase the risk in the first year (Manson, 2003). Randomizing PREMPRO®, (an oral tablet containing Premarin® and a synthetic progestin, medroxyprogesterone acetate) versus a placebo, the study was terminated because of an increase in pulmonary artery embolism, stroke, and coronary artery disease. However, the observation that there also was an increase in breast cancer in the PREMPRO® group prompted premature stoppage of the study.

Many analyses of these results have populated the literature since those reports were made public. The average age of the women in the initial study was 64 years, roughly 13 years after the onset of menopause. And the fact that the medications were taken orally meant that following ingestion, they would enter the liver as a first pass, a process now known to increase the risk of blood clots by altering blood clotting factors 1X, T-PA, PA1 and C-reactive protein (Canonico, 2008). Does any of this matter?

As with any large study, time and reanalysis allow one to scrutinize the initial conclusions. Was it the oral preparations, or was it the age of the study population that made a difference? When a subpopulation of WHI study subjects were further subdivided in the Early versus Late Intervention Trial with Estradiol (ELITE) analysis by age (mean 55.4 versus 65.4 years) and time since menopause (3.5 versus 14.3 years), the older group of women (represented by the initial WHI conclusions) used more antihypertensive and lipid-lowering medications and had higher carotid artery intima-media thickness (CIMT) scores positively associated with blood pressure and body mass index (BMI) than the younger group. Furthermore, only the younger group demonstrated a correlation between the measure of cardiac risk (CIMT) and measures of atherosclerosis progression, including low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, sex hormone binding globulin, and serum estradiol levels. The authors concluded that HRT may be more preventative when initiated early in younger women than as a secondary prevention for older women when atherosclerosis is already established (Hodis, 2015). Earlier animal studies supported these conclusions (Clarkson, 2007).

Despite the continued controversy, the cardiac risks are real. According to the Centers for Disease Control and Prevention (2021), coronary artery disease is the most common type of heart disease. In the United States (U.S.) alone, 805,000 people die from a heart attack each year with 605,000 suffering their first-time event and 200,000 suffering a repeat heart attack (CDC, 2021).

Worse, 795,000 people in the U.S. have a stroke in one year, and in 2018, one in six deaths from cardiovascular disease were linked to a stroke. Add to that the fact that in 2009, 34% with a stroke were under 65 years, while 66% were over 65 (CDC, 2021).

With these dire statistics in which cardiac events predominate in the menopause years, does HRT need to be stopped following either a heart attack or stroke?

Stroke: In one retrospective study using data from HRT and the National Institutes of Health Stroke Score Scale (NIHSS) score, 523 women experienced ischemic strokes with half of them receiving a thrombolytic agent to dissolve the clot. Of this population, 459 were without HRT, and 64 listed HRT use. Initial NIHSS scores were better for those on HRT, and by three months, those same women continued to have improved NIHSS scores, suggesting that estradiol offers some degree of brain protection (Brown, 2019).

If age and route of HRT make a difference as it relates to cardiac risk from HRT, can one identify the select population based on these data? Perhaps.

Heart Attack: Is there a role for stopping HRT if a myocardial infarction is encountered? In a unique study from Denmark, 3,322 women aged 40 or more on HRT who survived at least one month after a myocardial infarction were followed for one year. Both those who continued HRT and those who stopped HRT in the first year post-cardiac event encountered a similar risk of reinfarction. The authors concluded that HRT in this population of patients offered no real advantage but also no real risks if HRT is stopped (Bretler, 2012). Others have suggested that stopping HRT after it has been administered actually may increase the risk of a second heart attack (Hodis, 2018).

What is the bottom line? Life is a balance of risks and benefits. Each time we get into a car we unconsciously balance risks (a drunk driver may swerve into your lane) versus benefits (getting to our desired destination). If we drink two glasses of wine at dinner each night, we balance risks of breast cancer against the pleasures of the beverage. In the end, all of our decisions are oriented toward establishing a quality of life. That effort is unique to each person. Are you a risk taker? Or are you taught caution? Most medical care also is a balance of risks and benefits as it applies to providing care and maximizing the chosen quality of life for the individual. The medical decision to offer HRT during menopause and its risks/benefits for the woman who suffers a cardiovascular event always is oriented toward allowing the patient to understand what we know of the management and how it serves her desire for a quality life.

Your cardiologist correctly expressed his or her desire to minimize risk. But now you know the rest of the story.

James Woods | 3/10/2022

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