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James C. Grotta
Best Stroke Advances in Prevention, Treatment, and Neuroprotection

Investigators are attacking stroke on several fronts, encompassing prevention, treatment, and neuroprotection, according to stroke expert James C. Grotta, MD, chairman of the department of neurology at the University of Texas in Houston, discussing the most important 2006 papers in stroke research, drugs, and devices. In an interview, Dr. Grotta discussed the impact that each development has had on treatment and future stroke research.

PREVENTIVE STRATEGIES

Not all results were positive. The Clopidogrel for High Atherothrombotic Risk and Ischemia Stabilization, Management, and Avoidance trial showed no benefit and possibly even some harm (N Engl J Med 2006;354:1706–1717).

The investigators randomized more than 15,000 subjects with symptomatic atherothrombotic disease or multiple risk factors to receive clopidogrel in a dose of 75 mg/day plus low-dose aspirin (75–162 mg/day), or aspirin and placebo, following the patients for a median of 28 months. Among those with clinically evident disease, there was a 6.9 percent rate of primary endpoints — a composite of stroke, myocardial infarction, or death from cardiovascular causes — compared to 7.9 percent among patients in the placebo group (p=0.046). The rate of primary endpoints was 6.6 percent for clopidogrel and 5.5 percent for placebo in patients with multiple risk factors (p=0.20). The authors concluded that, overall, clopidogrel had no effect on the incidence of primary endpoints compared to aspirin alone.

Similarly, the Endarterectomy Versus Angioplasty in Patients with Severe Symptomatic Carotid Stenosis trial seriously questioned the notion that stents might provide high-risk patients with an equally effective but less invasive alternative to endarterectomy (N Engl J Med 2006; 355:1660–1671). About half the participants, 262, were randomized to endarterectomy, while 265 had stents. All patients had had a transient ischemic attack (TIA) or a nondisabling stroke within 120 days before enrollment, and all had stenosis of 60- to 99-percent in the symptomatic carotid.

The rate of primary endpoints — a composite of stroke or death within 30 days of treatment — was 9.6 percent among patients in the stenting group, significantly more than the 3.9 percent in the endarterectomy group. The trial was designed to determine the superiority of stenting, but instead, “we observed that stenting carried a greater risk than did endarterectomy,” the authors wrote. They terminated the trial early.

Two other studies yielded more encouraging findings. The European-Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) compared the efficacy of dipyridamole plus aspirin to aspirin and placebo at preventing death from vascular causes, nonfatal stroke or heart attack, or major bleeding complications in patients who had a minor stroke or TIA within the prior six months.

More than 1,300 patients were randomized to each group. Within a mean follow-up period of 3.5 years, 13 percent in the dipyridamole group and 16 percent in the placebo group had a primary outcome event — nonfatal stroke, heart attacks or hemorrhage, or death from cardiovascular causes — leading the authors to conclude that patients with a history of cerebral arterial ischemia should receive therapy with aspirin and dipyridamole rather than aspirin alone (Lancet 2006;367:1665–1673). The difference between the two groups may seem modest, but they translate into a consistently lower relative risk of first-outcome events, ranging from 0.67 to 0.88, associated with dipyridamole.

Dipyridamole is “the only antiplatelet drug ever clearly shown, now in two large trials, to be better than aspirin, and it also does not produce any increase in bleeding risk,” Dr. Grotta observed.

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) lived up to its name, demonstrating that a daily dose of 80 mg atorvastatin resulted in significantly lower LDL cholesterol and a lower risk of stroke, compared to placebo (N Engl J Med 2006;355:549–559).

Figure

Dr. James Grotta noted that not all the reports were positive, but each development will have an impact on treatment and future stroke research.

The 4,731 patients had had a stroke or TIA one to six months before enrollment, and were randomly assigned to either group. The mean LDL levels among those in the atorvastatin and placebo groups were 73 mg/dL and 129 mg/dL, respectively. During a median follow-up period of 4.9 years, 11.2 percent of the patients taking atorvastatin had a second stroke, compared to 13.1 percent of the patients receiving placebo (p=0.03). “This study confirmed for the first time that cholesterol lowering prevents stroke,” Dr. Grotta said. “A 2 percent absolute reduction in yearly risk is actually quite large” and comparable to that of aspirin, he pointed out.

Finally, the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution study showed that a perfusion/diffusion mismatch profile can identify patients most likely to benefit from early reperfusion with tPA. Seventy-four patients had an MRI immediately before receiving intravenous tPA within three to six hours of symptom onset, and a second MRI three to six hours after tPA administration. The mismatch profile was defined as an MRI-generated perfusion-weighted image (PWI) lesion volume at least 10 ml greater than, and 120 percent of, the diffusion-weighted image. A reduction in PWI volume of at least 10 ml and 30 percent on the second scan qualified as early reperfusion.

Of the 33 (45 percent) patients meeting the target mismatch profile, 31 achieved early reperfusion, and of those patients, 67 percnet had a favorable clinical outcome, defined as a score of 0–1 on the National Institutes of Health Stroke Scale (NIHSS), or at least an 8-point improvement in NIHSS score at 30 days. Clinical outcomes were favorable in only 19 percent of the target mismatch patients who did not achieve early reperfusion (p=0.011). Patients with a “no mismatch” profile did not benefit from early reperfusion, and in a subset with a profile defined as malignant, early reperfusion was associated with an increased risk of fatal intracranial hemorrhage (Ann Neurol 2006; 60:508–517).

CLOTBUSTERS

Several papers examined novel ways of lysing or weakening cerebral clots to enhance the action of tissue plasminogen activator (tPA). In an exploratory study with 111 patients, galactose-based microbubbles added to ultrasound and tPA produced faster and more extensive recanalization than tPA plus ultrasound or tPA alone (p=0.038).

There was a corresponding trend toward better short- and long-term outcomes among the patients who underwent the tiny bubble treatment (Stroke 2006;37:425–429).

Meanwhile, preliminary findings from an open-label study of 15 people who received a bolus of the thrombin inhibitor argatroban following tPA infusion were promising with regard to safety and recanalization, although these results await confirmation in a larger group of subjects (Arch Neurol 2006;63:1057–1062).

NEUROPROTECTION

Attempts at post-stroke neuroprotection often prove frustrating because animal studies frequently yield promising results that do not pan out in humans. So the Stroke-Acute Ischemic NXY Treatment (SAINT I) study attracted much interest last year when its authors reported that the anti-free radical agent NXY-059 might be neuroprotective. SAINT I was a placebo-controlled, randomized, double-blind examination of intravenous NXY-059 infusion within six hours of symptom onset. In the post-protocol analysis, which included 764 patients who received the drug and 761 who got the placebo, NXY-059 was associated with significantly less disability at 90 days, as measured on the modified Rankin scale (N Engl J Med 2006;354:588–600).

This study was the first to show a positive effect of a neuroprotective treatment against stroke, Dr. Grotta told Neurology Today, and the authors noted that a larger study with 3,200 subjects was in the works. Unfortunately, “the follow-up study did not confirm these results, and [NXY-059] will be abandoned,” Dr. Grotta said.

Human albumin may have greater neuroprotective potential. In preliminary findings from the Albumin in Acute Stroke study, an open-label, dose-escalation pilot study designed to evaluate the safety of moderate to high doses of 25 percent albumin in stroke patients, the probability of a good outcome associated with high doses (1.37–2.05 g/kg) was 81 percent higher than with the lower doses used (0.34–1.03 g/kg). Of the 82 patients participating in the trial, 42 also received tPA. Patients who received high-dose albumin as well as tPA were three times more likely to have a good outcome than patients in the lower-dose group (Stroke 2006;37:2107–2114).

This study provided the safety and feasibility data necessary to move a phase 3 study forward, Dr. Grotta explained. That study is now ongoing. Despite the disappointing findings with other agents, “this treatment has gone through rigorous preclinical testing, and the human studies are funded by the NIH, so there is some optimism that the results of the phase 3 study may be positive.”

References

• Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706–1717.
• Mas J-L, Chatellier G, Beyssen B, et al. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med 2006;355:1660–1671.
• Algra A, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367:1665–1673.
• Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549–559.
• Molina CA, Ribo M, Rubiera M, et al. Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke 2006;37:425–429.
• Sugg RM, Pary JK, Uchino K, et al. Argatroban tPA stroke study. Arch Neurol 2006;63:1057–1062.
• Lees KR, Zivin JA, Ashwood T, et al. NXY-059 for acute ischemic stroke. N Engl J Med 2006;354:588–600.
• Palesch YY, Hill MD, Ryckborst KJ, et al. The ALIAS pilot trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke—II: Neurologic outcome and efficacy analysis. Stroke 2006;37:2107–2114.
• Albers GW, Thijs VN, Wechsler L et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: The diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) Study. Ann Neurol 2006;60:508–517.