Desmoteplase Fails to Improve Outcome After Ischemic Stroke
NEW YORK, December 23, 2008 (Reuters Health)—After encouraging early trials of desmoteplase for stroke thrombolysis three to nine hours after symptom onset, the lack of benefit in the phase III trial came as a major disappointment.
However, the study investigators and the author of an editorial believe that the failure to replicate the original positive findings may be due to the mild strokes in the current study, reported in the February issue of the Lancet Neurology, published online on December 17, 2008.
In the phase III trial, 193 patients with acute ischemic stroke were randomized and 186 were treated between three and nine hours after symptom onset: 57 with a low dose of desmoteplase 90 µg/kg, 66 with a high dose of 125 µg/kg, and 63 with placebo.
Lead author Dr. Werner Hacke, at the University of Heidelberg, Germany, and colleagues reported that at 90 days, clinical response rates were 47% in the low-dose group, 36% in the high-dose group, and 46% in the placebo group.
Also, they reported, “There was no significant effect of treatment on core lesion volume.”
Rates of symptomatic intracranial hemorrhage were similar to those in the earlier studies (3.5% with the low dose, 4.5% with the high dose, and 0% with placebo). Overall mortality rates, however, were 11% with low-dose desmoteplase, 21% with the high dose, and only 6% with placebo.
The authors pointed out that “despite having similar selection criteria,” the phase II trials and the current trial differed in several respects. For example, they said, “baseline strokes were less severe” in this trial, with a median NIH Stroke Scale score at admission of 9 in this group versus 12 in the earlier studies, a difference that “might explain most of the positive placebo response.”
Other factors too may have “masked or increased the difficulty of showing a potential benefit of desmoteplase,” the researchers wrote, including small core lesions and an “inadequate sample size owing to an overly optimistic predicted size effect.”
In his editorial, Dr. Michael D. Hill, of the University of Calgary, Alberta, Canada, wrote, “The inclusion of patients without vascular occlusions ... might account for the failure to show any efficacy of desmoteplase over placebo.”
Dr. Hill pointed out that the investigators used multimodal CT or MRI to define “tissue at risk,” and he went on to highlight the limits of available multimodal imaging techniques for identifying patients “who ought to be ... most suited to fast perfusion.
“Although desmoteplase might yet prove to be the thrombolytic of choice, the ... trial design forged too far ahead of the imaging science,” he said. In the next trial, he added, “vascular status will be measured noninvasively before treatment as an inclusion criterion and used as an outcome, and the ... study will test a single hypothesis: Does the drug work?”
Lancet Neurol. 2008 Dec 17; [Epub ahead of print].
Large, Prospective Study Supports Statin’s Antidementia Properties
NEW YORK, January 8 (Reuters Health)—In the largest cohort study to date, statin treatment was found to reduce the incidence of Alzheimer’s disease, regardless of the drug’s lipophilicity or the individual’s apolipoprotein E (APOE) genotype.
Numerous studies have looked at the relationship between statin use and the development of Alzheimer’s disease, with conflicting results. One explanation for the inconsistencies is that “only the lipophilic statins, which could cross the blood-brain barrier more easily, would affect brain cholesterol metabolism.”
In the January issue of the Journal of Neurology, Neurosurgery, and Psychiatry, Dr. M. M. B. Breteler and colleagues, at the Erasmus Medical Center in Rotterdam, the Netherlands, explored these issues using data from the prospective, population-based Rotterdam Study. The analysis included 6,992 subjects, 55 or older, who were free of dementia when examined between 1990 and 1993.
During follow-up until 2005 (mean, 9.2 years), 582 subjects were diagnosed with Alzheimer’s disease. After controlling for sociodemographic and clinical factors, statin users had a significantly reduced risk of Alzheimer’s disease, compared with those who never used statins (adjusted hazard ratio, 0.57).
The protective effect was similar for lipophilic and hydrophilic statins and for persons with and without an APOE ε4 allele.
On the other hand, the use of other cholesterol-lowering drugs (fibrates, bile-acid binding resins, or nicotinic acid and derivatives) failed to exhibit similar benefit.
“All in all,” Dr. Larry Sparks, of the Sun Health Research Institute in Sun City, Arizona, wrote in an accompanying editorial, “it is clear that somewhere between normal cognitive performance and profound dementia of Alzheimer’s disease, statin therapy exerts a beneficial effect.”