Statins
Data from the SPARCL trial, which was the atorvastatin study that led to the recommendation of statins for recurrent stroke prevention, showed that several patient subgroups had a higher risk of a brain hemorrhage—those who had hemorrhage at entry into the study, men, those who were older, and those with high or poorly controlled blood pressure. This question also has been analyzed in the Heart Protection Study, which was a trial of simvastatin. In that study, 1.3% of patients taking simvastatin had a hemorrhage, and 0.7% in the control group had this outcome—about a 0.6% difference. The corresponding results in the SPARCL trial were 2.3% versus 1.4%, or a 0.9% difference.
Hackam and colleagues in Ontario studied more than 17,000 statin users, compared with non–statin users, and also published a meta-analysis. The conclusion is that there is a very small, if any, increased risk of brain hemorrhage with statin therapy. “Again, there could be subsets of people who have hypertension, who are older, who are men, who take a statin agent that are at higher risk. But I think the good news is that the risk is low,” Dr. Gorelick said.
With statin therapy, total stroke incidence is decreased, all-cause mortality is decreased, and there’s a slight possible increase in hemorrhagic stroke. The FDA has maintained that the benefit of statins highly outweighs the risks.
Hormone Replacement Therapy
“HRT is making a comeback,” Dr. Gorelick said. After the Women’s Health Initiative, prescription rates for estrogen and estrogen–progestin combinations dropped precipitously. The Women’s Health Initiative found that in healthy postmenopausal women taking estrogen plus progestin, incidence of coronary artery disease was increased significantly, as were that for breast cancer, stroke, and pulmonary embolism. Colorectal cancer and hip fracture were reduced. Probable dementia and cognitive decline also were increased. For women who received conjugated equine estrogen only, there were no statistically significant benefits of taking postmenopausal hormone replacement therapy on any of these cardiovascular, cancer, or hip fracture outcomes.
In the 50-to-55 age group, conjugated equine estrogen-based therapies produced no overall sustained benefit or risk on cognitive performance in longer-tem follow-ups. Similarly, with conjugated equine estrogen and progestin, the risks of invasive breast cancer, stroke, pulmonary embolism, dementia, gall bladder disease, and urinary incontinence were increased. Decreased hip fracture, diabetes, and improvements in vasomotor symptoms were benefits. For conjugated estrogen alone, breast cancer risk was reduced.
Younger women had more favorable outcomes. “In a stratified analysis, whether women had combination therapy or single therapy, the younger women were at a lot less risk for these excess events … compared with the women who were older,” Dr. Gorelick said. “So, that now puts the focus on women who are closer to menopause and are having vasomotor symptoms.”
The North American Menopausal Society suggests that in women who are having these vasomotor symptoms, it would be reasonable around the time of menopause, for some three to five years, to use hormone replacement therapy. The American College of Obstetricians and Gynecologists similarly said that combination therapy or estrogen alone could be used in the short-term or early in menopause. The US Preventive Services Task Force recommended caution. The most recent guideline was issued in 2015 by the Endocrine Society. It said that for younger women, the short-term use of hormone replacement therapy may be acceptable. “We’re seeing consideration of more prescription of these drugs for women who are closer to menopause for short-term use,” Dr. Gorelick said.
Testosterone
Testosterone may increase the risk for polycythemia, which has been associated with venous thromboembolism and pulmonary embolism. In 2014, the FDA issued a risk statement linking testosterone therapy with venous blood clots.
Nearly 30% of people on testosterone supplementation have never had a testosterone level determination. “Men are being treated without even knowing whether they have low testosterone levels or not,” Dr. Gorelick said. “This is a very controversial area. There’s a lot of mixed data here—some suggesting an increase in cardiovascular events, others showing reduction in mortality, and one study shows no increase in myocardial infarction. I’m pointing this out because you may be looking for possible non-traditional causes of thrombosis in your stroke patients. Overall, however, it remains uncertain whether testosterone causes stroke. Further study and FDA monitoring should help to determine whether there is a cause–effect relationship.”
—Glenn S. Williams