HRT pill: tibolone and stroke risk

“Older women have been warned that a popular HRT pill can more than double the risk of suffering a stroke,” warned the Daily Mail . It said a study of tibolone, a hormone treatment for the symptoms of menopause, raised the odds of a stroke, in women over 50, to 2.2 times that of women who did not take the drug. The study was stopped early because of the increased risk of stroke to the women in the study. The newspaper reports that although the drug did cut the risk of broken bones and breast and bowel cancer, experts advise that women over 70 years and those at risk of stroke because of high blood pressure, smoking, diabetes or irregular heartbeat should consider alternatives.

This study provides a careful analysis of the effects of tibolone, comparing the increased risk of stroke with the reduced risk of vertebral fracture. It found that for every 1,000 women who took tibolone for a year, there would be 2.3 extra strokes compared to 20.8 less vertebral fractures in women with previous fractures. Although it was reported that risk of stroke doubled, the importance to an individual depends on what the risk of a stroke is to begin with. Women with a smaller overall risk of stroke might still choose to take the drug whereas those with higher risks might avoid it.

The authors concluded that the drug should not be used in older women and those with risk factors for stroke as their risks were higher. They advise other women to talk to their doctors to decide if the higher risks are worth taking.

Where did the story come from?

Dr Steven R Cummings from the University of California in San Francisco and international colleagues from around the world, including the UK, conducted the study for a trial group known as the LIFT Trial Investigators. The study was supported by the Pharmaceutical company Organon.  The study was published in the peer-reviewed medical journal The New England Journal of Medicine .

What kind of scientific study was this?

In this randomised, double blind, placebo controlled trial, 4,538 women between the ages of 60 and 85 with osteoporosis were randomly assigned to receiving either tibolone (at a dose of 1.25 mg once daily) or an identical placebo.

The women were recruited between July 2001 and June 2003. Their osteoporosis was confirmed by T-score, a measurement of bone mineral density, which is calculated from a dual-energy X-ray absorptiometry (DEXA) scan. Osteoporosis was defined as having a T-score of −2.5 or less at the hip or lumbar spine, or a T-score of −2.0 or less with X-ray evidence of a vertebral fracture.

The researchers excluded women with very low T-scores, indicating severe osteoporosis, or a clinical diagnosis of vertebral fracture in the past year. Other women were excluded if they had had major cancers within the last five years, clotting problems, BMI of more than 34 or had used other forms of HRT or treatments for osteoporosis. All patients also received two to four tablets of calcium with vitamin D daily.

When women were first enrolled in the study, measurements of their bone density were performed. The women were followed up for an average of 34 months, during which they underwent various tests, including bone density by DEXA scan. They were also screened for breast cancer by mammogram, uterine cancer by annual transvaginal ultrasonography and cervical cancer by annual smears. Strokes were diagnosed and classified on the basis of Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scans or if the patients had shown typical neurologic findings lasting longer than 24 hours. The rates of heart disease, stroke and breast cancer were checked and verified by expert panels.

The study was initially approved at 80 sites in 22 countries. However, 10 sites in the United States discontinued the trial in January 2003 because the central review board at each site changed its rules regarding this type of trial. Before the trial began, criteria about when the trial would be stopped were established, this included how well the drug was working to reduce fractures. In October 2005, the data and safety monitoring board notified the trial sponsor, Organon – the manufacturers of tibolone, about a potential increased risk of stroke in the tibolone group. The sponsor notified the patients, and 496 women discontinued the drug.

In February 2006, it was recommended that the trial was stopped due to an increased risk of stroke and because the effect of treatment on the risk of vertebral fracture met the formal criteria for stopping the trial for efficacy. After an average 34 months of treatment, 91% of the patients had received at least 80% of the scheduled doses of a prescribed study drug.

What were the results of the study?

The researchers reported that women receiving tibolone had a decreased risk of vertebral fracture, with 70 cases per 1,000 person-years compared to 126 cases per 1,000 person-years in the placebo group. There was also a decreased risk of nonvertebral fracture in the tibolone group, with 122 cases per 1,000 person-years versus 166 cases per 1,000 person-years in the placebo group.

Additionally, the tibolone group had a decreased risk of invasive breast cancer and colon cancer. However, the confidence interval was wide for this result suggesting that more research will be required to confirm the result.

The tibolone group had an increased risk of stroke with 28 (stroke) events in the tibolone group compared to 13 events in the placebo group. Women receiving tibolone were twice as likely to have a stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P = 0.02). For this reason the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. The researchers report that there were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups.

What interpretations did the researchers draw from these results?

The researchers say that, “tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis.”

What does the NHS Knowledge Service make of this study?

This is a large study that appears to have been conducted responsibly. The trial followed accepted practice in that criteria for stopping it were established before the study began. These triggered the termination of recruiting participants and eventually the withdrawal of the drug from women in the trial and the trial stopped early.

• The trial was terminated at a stage when the results for the drugs affects on both the outcomes of vertebral fracture and stroke were statistically significant. This was important as it allows greater certainty that the effect on increasing stokes was a real effect of this drug.
• The researchers mention that the drug’s effect at reducing breast cancer found by this study, differs from the findings of observational studies that have investigated the effects of other hormone therapies around the menopause and it is not clear why this might be so.
• They also note that the incidence of colon cancer was not a pre-specified trial outcome, and the number of cases was small, suggesting that the drug might be having an effect but that this needs further investigation.

This study has provided a further warning that alerts prescribers to the risk of this drug. By providing some numbers that quantify the benefits and harms, the study will allow individual women to make a more informed decision about whether or not they want to take the drug.

Sir Muir Gray adds...

This shows the benefits of high quality research in which the data are monitored and the research stopped if it is doing more harm than good.