Further argatroban study ‘warranted’ in acute stroke
MedWire News: Pilot trial findings suggest that combined treatment with intravenous tissue plasminogen activator (tPA) and the anticoagulant argatroban is worth pursuing.
In an editorial accompanying the study in Stroke, Philip Bath (University of Nottingham, UK) criticizes the trial for its lack of a placebo group, but also takes aim at issues and attitudes within the stroke community that made the small trial very difficult to complete.
The researchers report that 6.2% of the 65 patients in their study had symptomatic intracerebral hemorrhage or type 2 parenchymal hemorrhage. They hypothesized that a hemorrhage rate of up to 10% could be clinically acceptable if the addition of argatroban to tPA resulted in significant increases in recanalization rates.
Although tPA can be lifesaving, it results in a relatively low rate of recanalization, so co-treatment with an anticoagulant could theoretically improve recanalization and help to prevent reocclusion, leading to improved outcomes.
The patients were given standard tPA therapy, plus a 100 µg/kg bolus of argatroban followed by an infusion lasting 48 hours, which was adjusted to a target partial thromboplastin time of 1.75 times the baseline value.
Andrew Barreto (University of Texas, Houston, USA) and colleagues comment that three of the four significant hemorrhages occurred more than 18 hours into the infusion, and suggest that a shorter infusion could produce a better safety profile. However, they say that the hemorrhage rate in their study was similar to that observed in historical controls.
During the 2-hour infusion period, 55% of patients achieved sustained recanalization: 30% complete and 25% partial recanalization. At 24 hours, 78% of patients had recanalization, with 63% achieving complete recanalization.
Based on these recanalization rates, Barreto et al say that the combined treatment "may be better than tPA alone and as useful as any other intervention currently available, particularly considering the potential widespread applicability of this combined pharmacological approach." They therefore conclude that further research is "warranted."
In his editorial, Bath comments that research into anticoagulants in acute stroke patients remains active, despite numerous "neutral" trials, because of the possibility that they may augment recanalization.
Yet, he says, Barreto et al required more than 7 years to complete a study with just 65 patients, partly because "the investigators had struggled with a stroke community that was negative to the aims of the study on the grounds that combined thrombolysis and anticoagulation would inevitably be unsafe."
Bath says: "We as a stroke community must not allow our preconceived beliefs to obstruct trialists just because we think we already know the results. There are too many examples in which trial results have overturned dogma built on little or no evidence."
However, he also criticizes the study design, saying that "uncontrolled Phase II studies should be resisted by investigators, funders, sponsors, and regulators."
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By Eleanor McDermid