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Functional Outcomes Similar for Patients Who Took Gavestinel or Placebo
April 4, 2001 – The neuroprotectant compound gavestinel, administered up to six hours after an acute ischemic stroke, did not improve patients' functional capability at three months, according to an article in the April 4, 2001, issue of The Journal of the American Medical Association.
Ralph L. Sacco, M.D., M.S., of Columbia University and the New York-Presbyterian Hospital, New York, and colleagues investigated the efficacy of gavestinel as a neuroprotective therapy for acute ischemic stroke administered within six hours of symptom onset. The authors studied 1,367 ischemic stroke patients enrolled in the Glycine Antagonist in Neuroprotection (GAIN) Americas trial, the largest phase three acute stroke trial conducted in North America. The GAIN Americas trial was a randomized, double-blind, placebo-controlled study with enrollment from April 1998 to October 1999, conducted at 132 hospital centers across the United States and Canada.
According to background information cited in the article, recognition of the "ischemic penumbra," a region of reduced cerebral blood flow in which cell death might be prevented, has focused attention on treatments that might minimize or reverse brain damage when administered soon after stroke onset. Some research has focused on the ischemic cascade, involving energy supply failure, membrane depolarization, release of neurotransmitters, accumulation of intracellular calcium, increased production of nitric oxide and free radicals, development of cellular edema, and finally, cell death. Understanding of the ischemic cascade has helped stimulate development of neuroprotective drugs aimed at limiting brain injury in the hours following an ischemic stroke. To date, none of these drugs has shown clinical efficacy.
For the GAIN Americas trial, 701 ischemic stroke patients were randomized to receive gavestinel, and 666 received placebo. For each group, the median (middle) age was 72 years and the median time to treatment was 5.2 hours. The authors examined functional capability at three months, measured by the Barthel Index (BI), comparing the gavestinel and placebo groups.
"Patients treated with gavestinel did not show a statistically significant improvement in independence at three months compared with patients treated with placebo, after adjustment for age and baseline [National Institutes of Health Stroke Scale] score," the authors write. "The proportion who were functionally independent (BI score = 95-100) was 39 percent in the gavestinel group and 37 percent in the placebo group."
Thrombolytic therapy with intravenous recombinant tissue-type plasminogen activator (rt-PA) was administered to 333 patients. "No significant improvement in BI at three months was found for those who received rt-PA plus gavestinel compared with those who received rt-PA plus placebo," the authors report.
The three-month case fatality rate for the entire study group was similar in the gavestinel (23 percent) and placebo (20 percent) groups. There were no serious safety issues.
The authors considered several possible factors to explain their neutral results, including the possible misjudement of the therapeutic window (time during which a potentially positive effect was occurring), inadequate penetration of the drug into the central nervous system, too many mild strokes in the study population, or insensitivity of the outcome scales. "Given the concordant findings using multiple outcome measures in the GAIN trials, it is unlikely that choosing another outcome scale would have altered out conclusions," they suggest.
"The study failed to show a neuroprotective effect for gavestinel when administered within six hours of acute ischemic stroke," they conclude. "This glycine [a type of amino acid] antagonist joins the growing list of neuroprotectants that have not shown improved outcomes for patients with acute stroke, despite promising preclinical results. We still believe neuroprotection remains a viable strategy for acute stroke treatment and should continue to be studied."
Editorial: Neuroprotection in Acute Ischemic Stroke
In an accompanying editorial, Fred Plum, M.D., of Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, writes that research needs to continue to produce an effective neuroprotection therapy.
"Reducing morbidity and mortality and preserving neurologic function in patients with acute ischemic stroke requires prompt restoration of cerebral perfusion as well as effective intervention to limit or prevent progression of the ischemic cascade. The GAIN Americas study adds to the already substantial number of apparently promising neuroprotective agents that have proven ineffective when evaluated in rigorous clinical studies. Increased understanding of the dynamic physiology and molecular aspects of the penumbra, along with identification of its potential capacities for improvement by using prompt and novel diagnostic methods, may prove useful for developing new and much-needed approaches for neuroprotection therapy in acute stroke."