Low-Dose Transdermal HRT Does Not Appear to Increase Stroke Risk

Pam Harrison

June 07, 2010

June 7, 2010 — Low-dose, transdermal hormone replacement therapy (HRT) does not appear to increase the risk for stroke compared with no HRT use, according to a study published June 3 in the BMJ.

In contrast, high-dose transdermal HRT is associated with an increased risk for stroke — a risk that is at least equal to if not higher than the risks associated with oral HRT use.

Samy Suissa, PhD, and colleagues found that the adjusted rate ratio of stroke associated with current use of transdermal HRT was 0.95 relative to no use. For the low-dose HRT patch, the risk for stroke occurred at a rate ratio of 0.81 compared with no use.

In contrast, the risk ratio of stroke in users of the high-dose patch was 1.89 compared with no use, the researchers add. Current users of oral HRT also had a 28% higher stroke risk than non-HRT users (rate ratio, 1.28) with both low and high-dose HRT.

"What we think might be happening is that there may be a threshold effect for the high-dose transdermal patch over which you start to see similar effects on cardiovascular disease markers as you might see with oral HRT, but at lower doses of the patch, there is no sign of these markers," Dr. Suissa told Medscape Neurology.

General Practice Database

For the study, the investigators used the United Kingdom's General Practice Research Database, which is a large, computerized database of longitudinal records containing medical information on a population of more than 6 million patients.

The study cohort consisted of women between the ages of 50 to 70 years between January 1, 1987, and October 31, 2006, who were without a diagnosis of stroke before study entry.

From a population of more than 870,000 women between the ages of 50 and 79 years during the study years, researchers documented 15,710 stroke diagnoses; each woman who was diagnosed with a stroke was matched with 59,958 control patients.

HRT was categorized into estrogen only, estrogen plus progestogen, progestogen only, and tibolone, and estrogen therapy was further categorized by delivery route and whether the dose of estrogen was high or low.

Oral HRT was considered low dose in products that contained .625 mg estrogen or less or 2 mg or less estradiol; high-dose oral products had more than 0.625 mg estrogen or more than 2 mg estradiol.

Transdermal patches were considered low dose if they contained 50 μg or less estrogen; patches containing more than 50 μg estrogen were considered high-dose patches.

The researchers point out the rate of stroke did not increase with the addition of a progestogen to the transdermal estrogen, at a rate ratio of 1.02 for transdermal estrogen alone compared with nonusers and 0.76 for users of transdermal estrogen plus progestogen.

Conversely, current users of oral estrogens alone increased stroke risk by 35% compared with nonusers of HRT, whereas current use of estrogen plus progestogen increased stroke risk by 24%.

When transdermal HRT was directly compared with oral HRT, stroke risk was lower, at a rate ratio of 0.74 among transdermal users, researchers add.

Furthermore, past use of transdermal HRT did not increase the risk for stroke over nonuse, whereas past use of oral HRT did, at a rate ratio of 1.36. However, as the authors note, the increased risk of past use of oral HRT of stroke risk was confined mainly to the first few months after stopping HRT, after which it dropped to rates approaching non-HRT use.

The increased risk for stroke associated with current oral HRT use was also virtually the same for both low-dose HRT (rate ratio, 1.25) and high-dose HRT (rate ratio, 1.48) compared with no HRT use.

Adjusted Rate Ratio of Stroke Associated With Current HRT Use Relative to No Use

Type of HRT Adjusted Rate Ratio
Transdermal Route
Low Dose 0.81
High Dose 1.88
Oral HRT
Low Dose 1.25
High Dose 1.31

Dr. Suissa told Medscape Neurology that the reason they undertook the current study was that the Women's Health Initiative examined only one particular type of HRT — oral HRT — but at the time, the media assumed findings extended to all forms of HRT, including transdermal HRT. In the Women’s Health Initiative, investigators in fact found that oral HRT increased stroke risk by approximately 30% — almost identical to the stroke risk seen for oral HRT in the current study.

"Our main finding is that you can have a safe threshold of the estrogen dose in these patches, and I think what they tell us is that in patients who may be at risk for stroke, you have a very safe alternative with the low-dose patch," Dr. Suissa said.

Theoretical Advantages

JoAnn Manson, MD, DrPH, from Harvard Medical School, Boston, Massachusetts, told Medscape Neurology that she did not find the findings regarding the relatively neutral stroke risk for low-dose transdermal HRT surprising, as there are theoretical advantages to the transdermal delivery route in terms of bypassing the liver.

In contrast, the finding that high-dose transdermal HRT was associated with at least as high a risk for stroke as oral HRT appears to have been corroborated by findings from the Nurses' Health Study, in which the dose of oral conjugated estrogen was related to stroke risk, where lower doses of oral HRT were not associated with increased risk, yet higher doses of oral estrogen were.

"So it is a combination of dose and route of administration because high-dose transdermal HRT does stimulate the liver synthesis of clotting proteins and inflammatory markers," she said.

Based on available evidence, Dr. Manson believes the "safest approach is low-dose HRT and the transdermal route of delivery." However, she added that she does not think the evidence is "yet conclusive, as we need randomized clinical trial evidence and additional studies to confirm this."

The research was funded by grants from the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, and Organon. Dr. Suissa received a distinguished investigator award from the Canadian Institutes of Health Research, as well as research funding from Organon, Schering, and Wyeth. Dr. Manson has disclosed no relevant financial relationships.

BMJ. Published online June 3, 2010.

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