Women younger than 60 years who stopped using postmenopausal hormone therapy (HT) showed an increased risk for cardiac and stroke deaths during the first year after discontinuation in an observational study published November 8 in Menopause. Similar risks were not found among women older than 60 years.
“We cannot prove a definite cause-and-effect relation between the discontinuation of HT and subsequent cardiovascular death, as is often the case in epidemiological studies,” write Minttu M. Venetkoski, MD, from the University of Helsinki and Helsinki University Hospital in Finland, and colleagues. “Rapid withdrawal of estrogen at discontinuation of HT may, however, result in vasoconstriction and potentially adverse arterial changes and cardiovascular events, as the vasodilatory effects of estrogen suddenly cease,” they speculate.
The researchers identified 432,775 women in the Finland national medical registry who stopped using HT from 1994 to 2013. They compared their outcomes with those in age-matched women in the general population and in age-matched women who continued using HT. Comparisons began 3 months after women filled their last HT prescription. The study excluded 8711 women who were diagnosed with a cardiac or cerebrovascular event any time during the year before they discontinued HT and women who filled their last HT prescription after September 30, 2013.
Among the remaining 402,573 women who discontinued HT, 5204 died of cardiac causes and 3434 died of cerebrovascular causes. Average exposure to HT was 6.6 years, and average follow-up after discontinuation was 8 years.
Compared with age-matched women in the general population, women younger than 60 years and with fewer than 5 years of HT exposure had a 52% increased risk for cardiac death in the first year after they stopped HT (standardized mortality ratio [SMR], 1.52; 95% confidence interval [CI], 1.13 – 2.00). In women who took HT for more than 5 years, the risk for cardiac death in that first year approximately doubled (SMR, 2.08; 95% CI, 1.44 – 2.90) compared with women in the general population. Women older than 60 years showed no similar increased risk, and the increased risk in younger women who used HT at least 5 years disappeared after the first year following discontinuation.
Similarly, women younger than 60 years and with 5 years or fewer of HT had more than double the risk for stroke death during the first year after stopping HT (SMR, 2.62; 95% CI, 2.07 – 3.28). In women who discontinued HT after using it for more than 5 years, the risk for stroke death during that first year after discontinuation was approximately three times greater than that of women in the general population (SMR, 3.22; 95% CI, 2.29 – 4.40).
Only a slightly increased risk for stroke death was seen among women over age 60 who discontinued HT after more than 5 years of exposure (SMR, 1.22; 95% CI, 1.06 – 1.40).
Risks for both cardiac and stroke death were even greater, with statistical significance, in those discontinuing HT compared with women who continued HT. The SMRs for cardiac death were 2.27 for those under 60 who discontinued HT with 5 or fewer years of HT and 3.27 for younger women taking HT for more than 5 years.
Stroke risk in discontinuers under age 60 was 3.39 times greater during that first year after stopping 5 or fewer years of HT, and it was 4.18 times greater if the younger women had more than 5 years of exposure before stopping.
“Increased mortality risks were limited to the first post-HT year because increases in risks vanished or markedly decreased when the follow-up time was extended over more than 1 year,” the authors note.
“We could not show a significant clear-cut relation between the age at HT discontinuation and the risk of fatal cardiovascular events, yet the age of under 60 years at the discontinuation of HT was the most significant determinant for HT termination-associated death risk in our study,” the authors explain.
The findings reveal only an association between discontinuation of HT and cardiac and stroke death. Aside from their suggestion that vasoconstriction may play a role if the relationship is causal, the authors give other possible mechanisms.
“Declining estrogen may also modulate cardiac rhythm, perhaps via calcium ion channels or by preventing long QT interval, and indeed hypoestrogenic postmenopausal women with congenital long-QT syndrome have an increased risk of cardiac events,” they write. “Thus, acute withdrawal of estrogen may predispose to fatal arrhythmias, although the mechanisms are not fully understood.”
The authors also point out that estrogen positively regulates the function of cerebral arteries. Negative neurovascular effects therefore might result from stopping HT suddenly, they write.
“Moreover, cardiac events may secondarily provoke occlusive events in cerebral arteries, which could partly explain the increased risk of stroke death,” the researchers write. “This association could not, however, be elaborated in this study.”
The fact that increased risks for stroke and cardiac death tapered off among women over age 60 “suggests that vascular sensitivity to estrogen withdrawal is age-dependent,” the authors add.
The biggest limitation of the study was the lack of data on the women’s cardiovascular risk profiles, aside from excluding those with a cardiac or cerebrovascular event in the year before discontinuing HT. The researchers also did not have information on why women chose to stop HT, what dose they were taking, the route of administration, or whether the women stopped suddenly or tapered off. Some women may have chosen to discontinue HT after developing cardiovascular risk factors or symptoms. It is possible that tapering off doses could mediate or blunt the increased death risk and that different doses or administration routes carry different risks.
“Progestins can also vary in their vascular implications, and the data were not analyzed for progestin com of HT,” the authors add, and they point out a limitation in the data’s generalizability. “It is worth mentioning that estradiol and CEE [conjugated equine estrogen] may differ in cardiovascular risk profiles, and therefore our data can be applied only to populations using estradiol-based HT regimens,” they explain.
The research received funding from Päivikki and Sakari Sohlberg Foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, Finska Läkaresällskapet, the Orion Farmos Research Foundation, the Paavo Nurmi Foundation, Jane and Aatos Erkko Foundation and the Finnish government. Dr Venetkoski has disclosed no relevant financial relationships. One author has received speaking/consulting fees from Mylan and Novo Nordisk. One coauthor has been a speaker for Myland and received travel funding from Mylan, Finox Biotech, and MSD. One author has received travel funding from Johnson & Johnson and Olympus. Two authors work for EPID Research, which conducts studies for pharmaceutical companies. The remaining authors have disclosed no relevant financial relationships.
Menopause. Published online November 8, 2017. Abstract
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