Stopping Postmenopausal HT May Increase Risk for Cardiac, Stroke Death

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When compared with age-matched HT users, even higher death risks from cardiac and cerebrovascular causes were observed in HT discontinuers.
When compared with age-matched HT users, even higher death risks from cardiac and cerebrovascular causes were observed in HT discontinuers.

Cessation of postmenopausal hormone therapy (HT) in women younger than 60 is associated with an increased risk for cardiac and stroke death in the first year after discontinuation, according to research published in Menopause.1

This study was a follow-up to a prior study2 that showed that termination of estradiol-based HT was associated with an elevated risk for cardiac and stroke death. Since the prior study was criticized3 for not excluding women with nonfatal cardiac or cerebrovascular events before HT discontinuation, this larger and updated Finnish study was conducted excluding women with a prior cardiac or stroke history.

Like the previous publication,2 researchers used data from the National Medicine Reimbursement Register of 402,573 Finnish women who discontinued HT between 1994 and 2013. Cardiac and stroke deaths in women discontinuing HT were compared with an age-matched background population and age-matched HT users. Women were classified by age at HT discontinuation as <60 or ≥60; duration of HT exposure was categorized as <5 years or >5 years. Primary outcome was cardiac or stroke death.

Of the 402,573 women, 5204 died of a cardiac event and 3434 died of a stroke. Compared with the age-matched background population, women younger than 60 who discontinued HT showed a significantly increased risk for cardiac death after ≤5 years (standard mortality ratio [SMR] 1.52; 95% CI 1.13-2.00) and after >5 years (SMR 2.08; 95% CI 1.44-2.90). In a similar fashion, the risk for stroke death increased after ≤5 years (SMR 2.62; 95% CI 2.07-3.28) and after >5 years (SMR 3.22; 95% CI 2.29-4.40).

In women age ≥60, cardiac risk was not observed in the first year after discontinuation of HT, and the risk for stroke death was elevated only in women with >5 years of HT exposure (SMR 1.22; 95% CI 1.06-1.40).

When compared with age-matched HT users, women younger than 60 at HT discontinuation had more pronounced risks for both cardiac and stroke death. Slightly elevated risks were also seen in women who discontinued HT at age 60 or older.

Some key limitations of this study included the investigators' inability to determine whether women discontinued HT abruptly or tapered it, which could be a determinant of subsequent vascular risk.  Furthermore, they were unable to compare different doses or routes of estrogen administration, which may result in different vascular effects.

The findings from this study were also seen in the women's health initiative trials (Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials; ClinicalTrials.gov identifier: NCT00000611).4 “In the women's health initiative [which investigated], the use of conjugated equine estrogen with or without a synthetic progestin, a reduction in cardiac events was found when hormone therapy was initiated in postmenopausal women under age 60 or within 10 years of menopause,” noted JoAnn V. Pinkerton, MD, executive director of the North American Menopause Society, in an interview with Endocrinology Advisor.

“It is unlikely that there will be another large prospective randomized, blinded trial of long term hormone therapy users under age 60 who discontinue hormone therapy,” said Dr Pinkerton. “The next step will be to test the biological mechanisms that may be involved in the increased cardiovascular risks after discontinuation,” concluded Dr Pinkerton.

Disclosures

Dr Mikkola has been a speaker and/or received consulting fees from Mylan and Novo Nordisk. Dr avolainen-Peltonen has been a speaker for Mylan and received funding for congress trips from Mylan, Finox Biotech, and MSD. Dr Rahkola-Soisalo has received funding for congress trips from Johnson & Johnson and Olympus. Ms Vattulainen and Mr Hoto work for EPID Research, company that performs financially supported studies to several pharmaceutical companies.

References

  1. Venetkoski M, Savolainen-Peltonen H, Rahkola-Soisalo P, et al. Increased cardiac and stroke death risk in the first year after discontinuation of postmenopausal hormone therapy [published online November 6, 2017]. Menopause. doi:10.1097/GME.0000000000001023
  2. Mikkola TS, Tuomikoski P, Lyytinen H, et al. Increased cardiovascular mortality risk in women discontinuing postmenopausal hormone therapy. J Clin Endocrinol Metab. 2015;100:4588-4594.
  3. Kaunitz AM. Does stopping menopausal hormone therapy have cardiovascular consequences? NEJM Journal Watch. Published October 27, 2015. Accessed November 11, 2017.
  4. Manson JE, Aragaki AK, Rossouw JE, et al; WHI Investigators. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the women's health initiative randomized trials. JAMA. 2017;318:927-938. 
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