New WHI Analysis Links HRT to Atrial Fibrillation

November 26, 2012

STANFORD, California — A new analysis of the Women's Health Initiative (WHI) trials shows that the risk of atrial fibrillation (AF) was modestly elevated in women taking postmenopausal hormone replacement therapy (HRT) [1]. The lead author said that this arrhythmia "should certainly be added to the list of potentially harmful outcomes," when women are weighing the risks and benefits of hormone therapy.

Dr Marco V Perez (Stanford University Medical Center, CA) and colleagues report their findings--which Perez says is the first research to be published based on a new and recent linkage of WHI results to Medicare data--in an article published online November 20, 2012 in Circulation Arrhythmia and Electrophysiology.

"Women [with a hysterectomy] taking estrogen alone in WHI had a higher rate of AF. This was not seen in women with an intact uterus taking estrogen plus medroxyprogesterone, but when we combined the two groups, we did see a significant effect," Perez told heartwire .

Anecdotal Evidence Suggests Role of Hormones in AF

Perez explained that in their cardiac electrophysiology and arrhythmia clinic at Stanford they have noticed that rates of AF are much higher in men than women, and that rates appear to "vary dramatically" among the latter. Anecdotal evidence "suggests that endogenous hormones may play a role in AF in women," he said, "because patients have reported that at certain times--during a period, pregnancy, or menopause--their arrhythmias can flare-up."

Patients have reported that at certain times--during a period, pregnancy, or menopause--their arrhythmias can flare-up.

"This highlights the idea that there may be an effect of the hormones themselves on arrhythmias, and the recent linkage of WHI with Medicare allowed us to examine this comprehensive database of claim codes to identify cases of AF," he noted.

Incident AF was identified using EKG and diagnosis codes from Medicare, or hospitalization records, and hazard ratios (HRs) were estimated using Cox proportional-hazards regression.

After excluding participants with baseline AF, there were 611 incident cases over a mean 5.6 years among 16 128 WHI participants taking estrogen plus progesterone, and 683 cases over a mean 7.1 years among 10 251 taking estrogen alone.

Incident AF was more frequent in the active, as compared with the placebo, groups of both trials, reaching significance in the trial of estrogen alone in women with prior hysterectomy (HR 1.12; p=0.05) and in the pooled analysis (HR 1.12; p=0.05), but not in the estrogen plus progestin trial (HR 1.07; p=0.44).

These results were only minimally affected by adjustment for incident stroke, coronary artery disease, and heart failure, "suggesting that the HRT effect on incident AF may be, at least in part, mediated through an increase in incident cardiovascular disease caused by HRT use," wrote Perez and colleagues.

Perez said he still feels it is "reasonable" that women use HRT during menopause for the management of symptoms, as is recommended--which is for the shortest duration possible and at the lowest dose.

"Women need to balance the risks and benefits," he said, but noted that he would now add AF to the list of risks associated with HRT.

Asked about recent trials that have shown no increase in cardiovascular disease risk with HRT, including one from Denmark and the Kronos Early Estrogen Prevention Study (KEEPS) study, Perez said these studies "had limitations" and he still stands by the warning regarding AF, although he stressed that further studies are needed to elucidate the relationship between estrogen use and arrhythmias.

The authors report no conflicts of interest.