Earlier Treatment Needed for ICH After tPA in Stroke

October 27, 2015

The first multicenter study to look at treatments for post-thrombolysis symptomatic intracerebral hemorrhage (ICH) has not shown any significant benefit of using any therapy (mainly cryoprecipitate) in these patients.

But the authors point out that both diagnosis and treatment occurred too late for meaningful benefit, and they make several recommendations on how treatment options may be improved.

The study, published online in JAMA Neurology on October 26, was conducted by a team led by Shadi Yaghi, MD, Brown University, Providence, Rhode Island.

"We found that there was a large variability in treatment but the majority of patients were not given any treatment at all," he commented to Medscape Medical News. "This is probably because of the perception among physicians that any treatment is futile."

"While this study did not show a significant reduction in mortality or in hematoma expansion in patients who received treatment, this may be explained by long delays in diagnosis of ICH and start of treatment. I personally don't think treatment is futile. Mortality is very high in these patients, and we believe that if diagnosis and treatment started earlier then there may be a benefit," he added.

In an accompanying editorial, Tiffany Cossey, MD, and Nicole R. Gonzales, MD, University of Texas Medical School at Houston, agree that more studies need to be done to improve treatment for these patients.

They write: "Although sICH [symptomatic ICH] may be an uncommon occurrence, the known risk weighs heavily on the decision of clinicians to administer tPA [tissue plasminogen activator], as well as on the decisions of patients and families regarding treatment. It is worthwhile to dedicate efforts to minimizing the risk of this complication for both the direct and indirect benefits."

For the study, the researchers analyzed data from 10 primary and comprehensive stroke centers across the United States on patients with symptomatic ICH after having been given thrombolysis for stroke.

Of 3894 patients treated with tPA within 4.5 hours after symptom onset of ischemic stroke, 128 (3.3%) had a symptomatic ICH. The median time of ICH diagnosis was 470 minutes after tPA (range, 30 to 2572 minutes), and the median time from diagnosis to treatment was 112 minutes (range, 12 to 628 minutes).

The in-hospital mortality rate was 52.3%, and 26.8% of patients had hematoma expansion, defined as a 33% increase in the hematoma volume on follow-up imaging.

Results suggested a trend toward lower in-hospital mortality in patients receiving any treatment for ICH vs no treatment (29.9% vs 47.55%), but this did not reach significance (P = .06).

The receipt of any medical treatment vs no treatment was not associated with hematoma expansion (50.0% vs 59.0%; P = .20).

The researchers note that patients with hematoma expansion were more likely (36.3% vs 25.0%; P = .01) to have severe hypofibrinogenemia (fibrinogen level, <150 mg/dL), which they say highlights a role for cryoprecipitate in reversing tPA coagulopathy.

Too Little, Too Late

Dr Yaghi commented: "Based on the mechanism of action of thrombolysis, it makes sense to give cryoprecipitate containing fibrinogen. tPA only has a short life but reduced fibrinogen levels continue for more than 24 hours."

He said that at present a standard dose tends to be used, which is probably not enough, and it is also given too late. "Hematoma growth starts very early. It is very important to treat early."

In the paper, the researchers note that a decrease in fibrinogen level by more than 200 mg/dL from baseline at 6 hours after tPA is associated with ICH. "Given that 10 U of cryoprecipitate increases fibrinogen levels by 50 to 80 mg/dL, administration of this standard dose may have resulted in underdosing," they write.

Dr Yaghi pointed out that other studies of hemorrhage caused by warfarin have shown a mortality benefit from giving cryoprecipitate early on. "We need to identify the patients with symptomatic ICH as soon as possible and give the cryoprecipitate straight away. Then we need to monitor fibrinogen levels and top the cryoprecipitate up accordingly," he added.

He said patients with symptomatic ICH were easily identified if they had had a mild stroke as they would have a sudden worsening of symptoms. "But this is more difficult to detect in patients who have had a major stroke who are at a higher risk for ICH."

He suggested that stroke patients who have received tPA should have continued frequent neurologic monitoring, as tools to predict ICH should also be used to allow for earlier detection. This could include an earlier computed tomography (CT) scan. "At present they do tend to have a CT scan but not until about 24 hours after tPA treatment. That is too late. Two scans may be necessary: one early on and one later on. We need to study this."

Dr Yaghi also suggested that other treatment approaches should be investigated, such as targeting the disruption of the blood-brain barrier, which occurs during ICH. "This is a risk factor for bleeding," he noted. "There are no treatments for this at present." Also, efforts should be directed to trying to prevent reperfusion injury, which can contribute to ICH. This could include better control of blood pressure, he said.

In their editorial, Dr Cossey and Dr Gonzales write, "Perhaps it would be reasonable to consider a lower blood pressure goal in the setting of recanalization after administration of tPA instead of the guideline-recommended goal of less than 180/105."

They add that that all the issues raised by Yaghi et al are best addressed prospectively using data from large-scale stroke registries already in existence.

Dr Yaghi reports receiving funding from the Stroke Trials Network (StrokeNet) of the National Institute of Neurological Disorders and Stroke. Other coauthors were consultants for Stryker, Covidien, and HeartWare Inc. Dr Cossey and Dr Gonzales have disclosed no relevant financial relationships.

JAMA Neurology. Published online October 26, 2015. Full text Editorial


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