Department of Neurology University of Michigan Health System Ann Arbor, Michigan
The 2005 International Stroke Conference was held on February 2 to 4, 2005 in New Orleans, Louisiana. There were over 500 posters or platform presentations. Abstracts are published in Stroke 2005;36:418-524.
Anticoagulation with warfarin is widely accepted as the standard of care for stroke prevention in patients with atrial fibrillation. However, clinical trial populations represent a carefully selected group with meticulous follow-up, and the application of these findings to real-world populations is unclear. Brian Gage, MD, Washington University School of Medicine, presented a retrospective chart review of a nationwide sample of more than 23,000 Medicare patients admitted to the hospital with atrial fibrillation and examined adherence to treatment and efficacy of stroke prevention by ethnicity. The mean age of the population was 79 years, with a female predominance. Forty-nine percent of whites, 43% blacks, and 40% Hispanics were prescribed anticoagulation with warfarin at the time of hospital discharge. The proportion of patients who had no follow-up of their prothrombin time within 90 days of discharge was found to be 10% for whites, 21% for blacks, and 17% for Hispanics. Warfarin prescribed at hospital discharge was protective against recurrent stroke in whites (hazard ratio [HR]: 0.6; 95% CI: 0.52-0.70), but not in blacks (HR: 1.5; 95% CI: 0.82-2.79) and Hispanics (HR: 0.93; 95% CI: 0.44-1.95). When these results were adjusted for number of days with appropriate monitoring of coagulation profiles, warfarin was effective for all racial groups. This study highlights the importance of investigating the application of clinical trial results to real-world populations, and also provides further evidence for significant racial and ethnic disparities in health care that must be addressed.
Secondary prevention of stroke has centered on management of co-morbid risk factors such as hypertension, diabetes, and smoking. The MOSES study (MOrbidity and mortality after Stroke-Eprosartan vs nitrendipine for Secondary prevention) enrolled patients with hypertension and a history of ischemic or hemorrhagic stroke within the previous 2 years. Patients were randomized to receive treatment with the angiotensin-2 receptor antagonist eprosartan 600 mg/d or the calcium channel blocker nitrendipine 10 mg/d. In 1352 patients followed-up for a mean of 2.5 years, there was no difference in the amount of blood pressure-lowering between the groups. The primary endpoint was combined mortality along with total cardiovascular and cerebrovascular events (including recurrent events). As compared with nitrendipine, there was a 20% relative risk reduction in the primary endpoint among patients treated with eprosartan. There was also a 25% relative risk reduction for total cerebrovascular events in the eprosartan group, although that effect was not statistically significant when first events alone were considered, likely caused by inadequate statistical power. This study suggests that eprosartan is superior to nitrendipine in secondary prevention of stroke and cardiovascular events in patients with a history of ischemic or hemorrhage stroke. Whether this conclusion applies to other angiotensin receptor blockers remains unknown.
ACUTE ISCHEMIC STROKE
Because intravenous tissue plasminogen activator (t-PA) was approved for use in acute ischemic stroke in 1995, there have been no additional agents approved by the Food and Drug Administration, but some new agents have been studied in treatment trials.
The Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic t-PA (CLOTBUST) trial demonstrated that continuous 2-MHz transcranial Doppler (TCD) ultrasound enhances the efficacy of intravenous t-PA in patients with middle cerebral artery occlusion as measured by early clinical improvement and artery recanalization. This trial also demonstrated a trend toward improved 3-month clinical outcome (Alexandrov et al, N Engl J Med 2004; 351:2170-2178). Based on the results of this trial, further investigations of ultrasound-enhanced thrombolysis are ongoing. Intravenous microbubbles (MB) have been shown to further enhance ultrasound-assisted thrombolysis in experimental models. TCD and MB-enhanced thrombolysis have been hypothesized to enhance cavitation and therefore mechanical stress on the clot surface, perhaps allowing more sites for t-PA binding. Investigators presented the results of a trial of 103 patients with acute middle cerebral artery occlusion. All patients received intravenous t-PA within 3 hours, and patients were randomized to receive either placebo TCD monitoring (t-PA group), 2 hours of continuous TCD monitoring (t-PA/ultrasound [US] group), or 2 hours of continuous monitoring together with bolus intravenous injections of galactose-based microbubbles (t-PA/US/MB groups). The 2-hour rate of complete recanalization was 54.5% in the t-PA/US/MB group, 40.8% in the t-PA/US group, and 23.9% in the t-PA group. Recanalization also occurred more rapidly in the t-PA/US/MB group. There was a trend toward early clinical improvement in the t-PA/US/MB group relative to the other groups. These results are preliminary, and longer-term safety and efficacy data are required. TCD remains a highly operator-dependent technology; application of these techniques to the general population will remain a challenge.
Several neuroprotective agents for acute ischemic stroke have shown promise in laboratory models, but the search for an effective neuroprotective medication in humans remains unsuccessful. Myron Ginsberg, MD, University of Miami School of Medicine, presented the results of a dose escalation and safety trial of 25% human albumin. A total of 65 patients with acute ischemic stroke were given human albumin within 16 hours of stroke onset in five escalating dose tiers (mean time of administration was 8.0 ± 3.7 hours of stroke onset). A total of six patients died (all with severe stroke), but none of the deaths was likely albumin-related. Three patients had pulmonary edema requiring diuretics and one patient had congestive heart failure leading to prolonged hospitalization. The study was not powered to determine efficacy and there was no placebo control, but there was a trend toward a dose effect on clinical outcome at 3 months. The National Institutes of Health stroke scale score improved from a mean initial 14.1 to 7.8 at 3 months in the lower-dose tier compared with a change from 16.1 to 3.4 in the higher-dose tier. A phase 3 trial is planned in which albumin will be given within 4.5 hours of stroke onset; recruitment for additional study sites is ongoing.
The application of intravenous t-PA to acute ischemic stroke has been limited by the fact that it must be administered within 3 hours time to be effective. This time limit excludes most ischemic stroke patients because they arrive too late. Are there alternative thrombolytic agents or imaging techniques to identify potential candidates for treatment beyond the 3-hour window? This question was the basis for the Dose Escalation study of Desmoteplase in Acute ischemic Stroke (DEDAS) trial, a multicenter, randomized, double-blind, placebo-controlled, dose escalation and safety trial of a novel thrombolytic agent called desmoteplase. Anthony Furlan, MD, Cleveland Clinic Foundation, presented the results of this study. Patients who presented between 3 and 9 hours from the onset of symptoms underwent perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI). If the PWI area was 20% greater than the DWI area (“PWI-DWI mismatch”) and the PWI area was at least 2 cm in diameter (two indicators of a large ischemic penumbra), 38 patients were randomized to a low or high single-dose injection of desmoteplase or placebo. No symptomatic intracerebral hemorrhages occurred in any group despite the 9-hour treatment window. The study was not powered to detect efficacy, but a larger randomized placebo-controlled trial is being planned. The lack of hemorrhages supports the notion that advanced imaging may have a potential role in patient selection for thrombolysis beyond the 3-hour time window.
Intracerebral hemorrhage is a devastating condition with no effective antidote. The volume of the intracerebral hemorrhage is a consistent predictor of mortality. Early growth of intracerebral hemorrhage with expansion of hematoma has been demonstrated to occur in up to 40% of patients. Activated recombinant factor VII (rFVIIa) is currently approved to treat bleeding in hemophiliacs who have inhibitors to factor VIII or IX and is undergoing investigation as a potential agent to stop early hematoma expansion in intracerebral hemorrhage. A small pilot trial (38 patients) of rFVIIa in non-hemophiliac patients with intracerebral hemorrhage did not produce any adverse events (Mayer et al, Stroke 2005;36:74-9). A larger study involved 400 patients randomized to receive placebo or a single bolus injection of rFVIIa in three dose tiers (Mayer et al, N Engl J Med 2005;352:777-85). All patients had to have had a computed tomography scan within 3 hours of hemorrhage onset and had to receive the study drug within 60 minutes of the scan. The primary outcome was the mean change in hemorrhage volume at 24 hours, with a secondary outcome of 90-day clinical status. Mean hemorrhage volume increased by 29% in the placebo group compared with 11% in the highest dose tier rFVIIa group (p = 0.015). At 90 days, 69% of patients in the placebo group were dependent on others for daily care or were dead (modified Rankin scale of 4-6), as compared with 52% in the pooled treatment group (P < 0.05). There was a trend toward increased risk of venous thrombosis, myocardial infarction, or ischemic stroke in the treatment group (7% versus 2%). However, there was no increased risk of fatal or disabling adverse events. This is first published report of an effective treatment of intracerebral hemorrhage. Additional studies are required to further demonstrate safety and efficacy in a larger group of patients.
Darin B. Zahuranec, MD
Department of Neurology University of Michigan Health System Ann Arbor, Michigan
© 2005 Lippincott Williams & Wilkins, Inc.