LOWER DOSAGE SAFER FOR STROKE PATIENTS
Treatment for ischaemic stroke can be made safer (especially for patients with inherently higher risk of bleeding) by reducing the dose of clot-buster tissue plasminogen activator (tPA) by a third, a new study by neurologist Vijay Sharma, associate professor at NUS Medicine and his research partners shows.
The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), which was conducted in 13 countries, enrolled a total of 3,310 predominantly Asian (63%) stroke patients who were eligible for clot-busting therapy and randomly assigned them to be treated with alteplase, a recombinant tPA (r-tPA), at either the approved standard dose of 0.9 mg per kilogram body weight or an experimental lower dose of 0.6 mg per kilogram body weight. The primary outcome measure of the trial was the rate of death or disability after 90 days.
The result of the study published in the May 10 issue of The New England Journal of Medicine (NEJM) reveals that reducing the dose of alteplase by 33% significantly decreased incidents of symptomatic intracerebral bleeding (1.0% vs. 2.1% in the standarddose group). The improvements may appear small numerically, but Assoc Prof Sharma explains how clinical impact can be substantial. “Annually, on the global scale, improving a complication rate by just one percent has the potential to save tens of thousands of people.” He and his research partner, Professor Craig Anderson of The George Institute for Global Health, in Sydney, Australia designed the research study.
Lowering the dose of alteplase also helped more patients to survive a stroke, but with a trade-off—more patients on the lower dose ended up with residual physical disability after 90 days. For every 1000 patients given the lower dose of alteplase, there were 19 fewer deaths than in the group given the standard dose of the drug. But 41 more patients were left with mild to moderately severe grades of physical disability. “A reduced dose may not provide such a good recovery of function,” notes Assoc Prof Sharma, “but for patients with an intrinsic high risk of bleeding, it is better (to receive a lower dose) than receiving nothing at all. And being alive with some recovery as a result of r-tPA is surely preferable to most patients than early death.”
In spite of the safety advantage shown, ENCHANTED failed to show non-inferiority of the lower dose of alteplase to the standard dose; 53.2% of patients given the lower dose of alteplase suffered disability or died by 90 days, while only 51.1% of patients given the standard dose suffered the same fate (odds ratio, 1.09). ENCHANTED’s finding will not change current clinical practice guidelines on tPA dose regimen, but it certainly provides clinicians a strong basis to consider a reduced dose of tPA to mitigate the risk of life-threatening intracerebral haemorrhage in individuals prone to bleeding. “Clinicians can lower the dose off-label, with the consent of the patient,” Assoc Prof Sharma assures.
He reiterates the importance of the on-going research, emphasizing what they seek is “a very high degree of precision in balancing the risks versus benefits of r-tPA”. “We are making the treatment simpler, cheaper and safer.”