Beyond 3 hours, both IV and IA approaches are being evaluated, based on pooled data from all patients treated with IV TPA, showing that there may be some benefit at least to 5 hours after symptom onset.

Furthermore, physiologic brain imaging purports to demonstrate reversibly damaged penumbral tissue for up to 12–24 hours in some cases. However, such therapy is not approved by the FDA in the USA, or by other regulatory agencies in other countries.

This is because the clinical efficacy of treatment beyond 3 hours has never been proven in a prospective randomized trial. At some time point after symptom onset in most stroke patients, it may be worse to open an artery than to leave it occluded, if the tissue is already dead and non-salvageable, since such tissue is at increased risk of bleeding during reperfusion.

Several studies of either IV or IA treatment up to 9 hours after symptom onset are ongoing based on the assumption that there is a subset of patients who can still safely respond to treatment in the 3–9-hour interval.

Most of these studies are using CT and MRI to identify those patients who have persisting occlusion, who still harbor salvageable tissue, and in whom the existing damage is not so severe that recanalization would be excessively risky.

This rapidly moving area of stroke research should be clarified by the completion of these trials in the next year or so. Unfortunately, none of these studies are directly comparing IV to IA treatment, and existing case series do not demonstrate a clear superiority in terms of either safety or clinical outcome of either approach beyond 3 hours.

IA therapy refers to IA thrombolytics given directly into the clot, mechanical clot disruption, or both. In general, the trend is toward more mechanical methods, particularly in those patients who have already received IV TPA, or who have contraindications (for instance, elevated INR) to thrombolytics.

The MERCI retrieval catheter and device has been approved by the FDA to open cerebral arterial occlusions, but has not yet been shown to improve outcome compared to standard treatment.