RIVIERA BEACH, FL—Drugs that are commonly used in clinical practice may confer a slight increase in stroke risk, said Philip B. Gorelick, MD, MPH, Professor of Translational Science and Molecular Medicine at Michigan State University College of Human Medicine and Medical Director at Mercy Health Hauenstein Neurosciences in Grand Rapids, Michigan. At the 42nd Annual Meeting of the Southern Clinical Neurological Society, Dr. Gorelick discussed the stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, vitamin E, statins, hormone replacement therapy (HRT), and testosterone replacement therapy. “These drugs have a small risk of stroke, but there is a risk of stroke,” said Dr. Gorelick. “There might be a one-in-a-thousand or one-in-ten-thousand risk, but you need to consider these because medication administration is very complex in our patients.”
NSAIDs
The medical community has general concerns regarding NSAIDs and elevation of vascular and gastrointestinal (GI) bleeding. Data from the Coxib and Traditional NSAID Trialists’ Collaboration showed that for major vascular events such as nonfatal heart attack, stroke, or a vascular death, the cyclo-oxygenase-2 inhibitors (coxibs) increased the risk by 37%, diclofenac increased the risk by 41%, and ibuprofen increased the risk by about 44%. Naproxen did not increase the risk. “I’m not saying that naproxen is what you should be using,” Dr. Gorelick said. “All I’m saying is that it didn’t increase the risk.” For vascular death alone, the coxibs and diclofenac increased the risk to a statistically significant degree; naproxen did not. All of these drugs doubled heart failure risk. “Any of them in your heart failure patients could be dangerous,” Dr. Gorelick said. All of these drugs increased the risk of GI bleeding by about two to four times.
Dr. Gorelick added a note of caution regarding ibuprofen and aspirin. “Ibuprofen will block the aspirin effect.” If a patient has to be on ibuprofen and aspirin, Dr. Gorelick recommends giving the aspirin first and following it an hour later with ibuprofen. “That way, the aspirin has a chance to work and inhibit the platelet.”
In 2015, the FDA strengthened an existing warning about NSAIDs and the increased risk of heart attack or stroke. It said that the risk with NSAIDs can occur as early as the first two weeks of treatment. Higher doses entail greater risk. These adverse events can occur in people with or without cardiovascular disease, but risk is greater in persons who have cardiovascular risk. There is an increased risk of heart failure and there is an increased risk of death in the first year for patients who have already had a heart attack.
Antidepressants
About 30% to 40% of patients with stroke have depression after their stroke. Many patients with stroke are on antidepressants, and research has suggested that selective serotonin reuptake inhibitors (SSRIs) might help promote recovery after stroke. “Any time you use one of these SSRIs as an antidepressant, similar to the anticonvulsant drugs, you have to inform your patient that there is a higher risk of suicide or having suicidal thoughts,” Dr. Gorelick cautioned.
SSRIs may enhance motor and cognitive recovery, but they may have antiplatelet properties. Just as caution has been recommended when combining aspirin and NSAIDs, an additive effect may be at play with SSRIs. Combination of SSRIs with aspirin or NSAIDs may further increase the risk of bleeding, as may a history of brain hemorrhage or anticoagulant use. “You may be potentiating the increase for brain hemorrhage,” Dr. Gorelick said.
Meta-analysis data from Hackam and colleagues showed that for SSRIs, incidence of intracranial hemorrhage is increased by about 1.5 times, intracerebral hemorrhage by 1.4 times, and a combination of these drugs with oral anticoagulants by more than 1.5 times. “Whether you look at cohort studies, case–control studies, or crossover studies, there is a substantial relative increase. But the absolute risk is small—one per 10,000,” Dr. Gorelick said. Rates may be higher, though, among patients with a past history of intracranial hemorrhage, especially lobar hemorrhage.
A study in Korea looked at intracranial hemorrhage in patients taking antidepressants and NSAIDs. The combined use of NSAIDs with antidepressants was associated with a 60% increased risk of intracranial hemorrhage within 30 days of initial therapy use, but there was no statistically significant meaningful difference by antidepressant drug class. “These agents individually have small risks, but when you start combining them with drugs with antithrombotic properties, you may be increasing the risk,” Dr. Gorelick said.
Vitamin E
Meta-analysis data show that with 300 to 900 IU of vitamin E, total incidence of stroke was slightly reduced, but not to a statistically significant degree. Hemorrhagic stroke was increased by about 22%. Ischemic stroke in the stratified analysis was reduced by about 10%. “You reduce ischemic stroke, you increase hemorrhagic stroke, but the absolute effects are very small—0.8 more hemorrhagic strokes, 2.1 fewer ischemic strokes per 1,000 treated. It is a trade-off.”