Shadi Yaghi, MD, was still a resident at Columbia University when he saw a patient with a stroke who was given tissue plasminogen activator to bust the stroke-causing clot.
“We treated the patient with the standard of care suggested by the American Heart Association — cryoprecipitate and platelets,” said Dr. Yaghi, now an assistant professor of neurology at Brown University. “The patient kept bleeding. Then we had to start investigational treatments.”
The patient responded well to Factor VII and surgical treatments, but that led Dr. Yaghi to look for a better way to support these patients. That search proved mostly fruitless, which led to the conclusion that patients were not being monitored for bleeding in the critical period and that they often received treatment late or not at all.
Bleeding after tissue plasminogen activator treatment for stroke has long been a stumbling block to using the clot-busting treatment, yet few have looked critically at how often it happens or how to treat it. Dr. Yaghi and his colleagues pooled results from many centers in a retrospective study aimed at determining the extent of the problem and which treatments were being used. They examined records from patients with symptomatic intracerebral hemorrhage from 10 primary and comprehensive stroke centers across the United States. (JAMA Neurol 2015;72:1451.)
A total of 128 (3.3%) of the 3,894 patients treated who received tissue plasminogen activator (tPA) within four and a half hours of symptoms of an ischemic stroke had symptomatic intracerebral hemorrhage. The median time from giving tPA and diagnosis of an intracerebral hemorrhage was 470 minutes, and the median time from diagnosis of the hemorrhage to treatment was 112 minutes. Sixty-seven of the 128 patients (52.3%) died in the hospital, and eight of 22 (26.8%) saw a significant increase in the size of their blood clot. Low levels of fibrinogen were associated with increased size of the clot.
The factor most commonly associated with death in these patients was a switch in code status to comfort measures after the bleeding was diagnosed, the authors noted, which occurred in 28.9 percent of patients 24 hours after bleeding was diagnosed. Only 49 (38.2%) patients received any treatment at all for the intracerebral hemorrhage.
The researchers noted that treating symptomatic intracerebral hemorrhage did not appear to reduce the likelihood of dying in the hospital or the size of the blood clot.
“I expected that the treatments we were using were not efficacious,” said Dr. Yaghi. “There is a wide variability in the treatments and no solid evidence to support the treatments we do use.”
Risks and Benefits
Just doing this study was difficult, he said. Doing one to test therapies would be even more so. “I don't think we can do a randomized trial. The study we did showed a significant delay in diagnosing and treating this condition. When we are treating this condition, we are not giving enough treatment,” he said.
Dr. Yaghi said he knows many emergency physicians are hesitant to use tPA and other lytics for stroke because of the hemorrhage potential. “Any treatment has a risk, and we are always weighing the risks and benefits,” he said, adding that trials, however, show the effectiveness of thrombolysis in ischemic stroke. “Treatment with tPA has more benefit than the small risk of hemorrhage. Patients come in, asking for the treatment.”
Two factors showed up in his study. “More symptomatic hemorrhages happen after two hours, yet the checks we do in the first two hours are more frequent. We are doing less frequent checks when the bleeding is more likely to happen,” Dr. Yaghi said.
Not treating can have a real downside, however. “Patients who have big strokes have a higher risk of bleeding because they have a big stroke. They don't get worse until there is a lot of bleeding, and then it is too late to give any treatment. Mortality is high, even with treatment,” he said.
“This is an eye-opener for the stroke community,” he said. “We have to shorten the time to diagnosis and treatment. In this study, the time to treatment took too long, probably because it takes a long time to get cryoprecipitate from the blood bank. In our institution, we are trying to get to treatment right away. We want to administer the cryoprecipitate in less than 30 minutes.”
Dr. Yaghi said he thinks the perception is that a patient will not do well once he bleeds so it likely does not matter whether the patient receives treatment immediately or in 30 minutes. “We could do a study to look at the outcomes of patients diagnosed and treated before and after the core measures are established. Then we could see if it makes a difference in outcomes,” he said.
Tiffany Cossey, MD, a clinical fellow, and Nicole R. Gonzales, MD, an associate professor of neurology at the University of Texas McGovern Medical School at Houston, wrote in an accompanying editorial that “we must also consider the possibility that treatment of sICH [symptomatic intracerebral hemorrhage] may not ultimately affect outcome; once sICH has occurred, the damage might be too extensive. (JAMA Neurol 2015;72:1416.)
“Our treatment is all over the place. Some degree of consistency is needed. The study authors proposed figuring out the risk factors for developing hemorrhage, targeting patients who get tPA, and using those prognostic variables. We may want to measure blood pressure more often, and if that is a risk factor, change the protocol for the high-risk group,” said Dr. Gonzales.
“There is a group that does not believe the tPA data. Another group feels that the risk is not worth the benefit in some patients, e.g., those with mild stroke. The stroke has to be severe enough to expose patients to the risk to tPA.”
Making this last group more comfortable with using the drug could have benefit, she said.
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