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ESTROGEN PLUS PROGESTIN INCREASES RISK OF STROKE

PHOENIX — When the safety monitoring board at the National Heart, Lung, and Blood Institute pulled the plug on the estrogen-progestin (Prempro) arm of the Women's Health Initiative (WHI) last July, millions of women and thousands of their physicians were shocked – a treatment once touted for its ability to protect the heart and the brain was actually harmful. The investigators reported that women taking estrogen plus progestin had a 4-percent increased risk for stroke. Now, after several months of painstaking data review and analysis, the research team reports that the news on HRT is still not good, but it is not quite as bad as originally reported.

The overall increase in relative risk for stroke in postmenopausal women taking estrogen plus progestin is actually 33 percent, according to WHI principal investigator Sylvia Wasserthiel Smoller, PhD, Professor of Epidemiology and Social Medicine at Albert Einstein College of Medicine in New York. Dr. Smoller delivered the latest analysis at the American Stroke Association's International Stroke Conference.

Dr. Smoller said the “absolute risk for stroke for women taking estrogen plus progestin was 8 strokes per 10,000 women. At the time the study was halted, an estimated 6 million women were taking this hormone combination, which would account for 4,800 excess strokes.” She added that “this stroke risk appears early – within one year of initiating HRT.”

UNSAFE AT ANY AGE

The increased risk was higher among women who had a history of hypertension – at a 40-percent increase in relative risk – and lower among healthy women, who had a 28-percent increased risk for stroke. But Dr. Smoller said in an interview that the “important point is that the increased risk was consistent across all ages, regardless of risk factors.”

WHI was a randomized clinical trial that compared daily conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg versus placebo. The study was a primary prevention trial that tested the widely accepted belief that hormone replacement therapy given to postmenopausal women would reduce their risk for heart attack and stroke. The trial randomized 8,506 women to the active treatment arm and 8,102 to placebo. The study was conducted at 40 centers in the United States and women ages 50 to 79 were enrolled.

At the time the study was halted, “there were 120 strokes in the active treatment arm and 80 in the placebo group. Since that time we have accumulated a few more strokes so the current analysis is based on 133 strokes in the treatment arm and 93 in the placebo arm,” Dr. Smoller said. Eighty-three percent of the strokes were ischemic, she said.

ESTROGEN-ONLY STUDY CONTINUES

While the data from the estrogen plus progestin arm of WHI indicate no role for this HRT combination in stroke prevention, Dr. Smoller noted that WHI is an ongoing study. Currently, WHI is continuing an estrogen only primary prevention study. All the women in that study have had hysterectomies. And, while the investigators in the estrogen-progestin arm received two “Dear Doctor” warning letters before NHLBI halted the study last July, Dr. Smoller said that no warnings have been sent to investigators in the estrogen-only arm. Also, a WHI study of the effect of estrogen on brain function is continuing, she said.

“And although WHI has stopped the study medication for women in the estrogen plus progestin arm, these women will continue to be followed through 2005,” said Dr. Smoller.

Nonetheless, Dr. Smoller held out little hope for HRT true believers: “I absolutely think the stroke risk outweighs the benefits reported for hormone replacement…given a choice between stroke and sweating, I advise women to get used to sweating.”

MORE RESEARCH NEEDED

But Lawrence Brass, MD, Professor of Neurology at Yale University School of Medicine in New Haven, CT, said he is not quite ready to jump on the anti-HRT bandwagon. He said that the latest word from the WHI investigators is “not the final word on hormones and stroke.”

Dr. Brass, who was not a WHI investigator, said, “It is clear that estrogen has an effect on the system, so we were right about that. It is just not the right effect. It turned the knob the wrong way, but it may still be possible to find a way to turn the knob the right way.”

He said, for example, that estrogen may actually be beneficial if some other drug – like an antiplatelet – is given in combination with the hormone. “This is exactly what we do in Parkinson disease; levodopa makes people sick, but when carbidopa is added, it works. Or another option would be to abandon the molecule that nature gave us and go instead to a selective estrogen receptor blocker, which may give us the effect we were looking for with estrogen, but without the increased risk.”

Dr. Brass noted that a subgroup analysis of a large study suggested a decreased risk for stroke in women taking raloxifene – a selective estrogen receptor modulator (SERM) given to postmenopausal women to prevent osteoporosis – but he noted that the study was not designed as a stroke prevention study. “We need a study designed to look specifically at SERMs and stroke,” he said.

Article In Brief

  • ✓ The overall increase in relative risk for stroke in postmenopausal women taking estrogen plus progestin is actually 33 percent – a 9 percent smaller risk than previously reported – according to an analysis of data from the Women's Health Initiative study.
  • ✓ The increased risk was higher among women who had a history of hypertension and lower among healthy women, who had a 28-percent increased risk for stroke.
  • ✓ Another neurologist commented, however, that a subgroup analysis of a large study suggested a decreased risk for stroke in women taking raloxifene, a selective estrogen receptor modulator (SERM) used to treat osteoporosis. He suggested the need for a study designed to look specifically at SERMs and stroke.