Beyond 3 hours
In 2008, the New England Journal of Medicine published the results of the ECASS III trial, which demonstrated the safety and benefit of IV tPA up to 4.5 hours from symptom onset. The likelihood of a patient benefitting within the extended period, however, was more moderate. Nevertheless, with time limitations presenting the main barrier to potential candidates for tPA, the results from this study have opened up this therapy to many additional patients. The benefits demonstrated in the ECASS III trial have since been confirmed by an observational study (SITS-ISTR) and a meta-analysis published in 2010 from pooled data involving 3670 patients.
The time limitations imposed on IV thrombolytic therapy hinge on the fact that while the risk for intracerebral hemorrhage remains fairly constant with time (to administration of the drug after symptom onset), the benefit decreases continuously over time. Reducing the risk of hemorrhage by lowering the thrombolytic dose, and increasing the ability of the thrombolytic to cause recanalization of the artery by injecting the drug directly at the clot, addresses both of the above variables and should serve to further extend the therapeutic window. This concept was the basis of the PROACT II trial published in JAMA, 1999. One hundred eighty patients with acute middle cerebral artery occlusion were treated with either catheter directed, intraarterial (IA), recombinant prourokinase plus heparin or heparin alone within 6 hours of a stroke. Significantly more patients achieved functional independence at 90 days if they received the IA thrombolytic than if they didn’t (40% versus 24%, NNT=7). Although this study was not sufficient to achieve regulatory approval for prourokinase, the benefits seen were extrapolated for the use of IA tPA within 6 hours, and the American Heart Association recommends it as an appropriate “option” if IV tPA is contraindicated. Trials investigating the potential additional benefit of combining initial IV thrombolysis with subsequent intra-arterial clot-targeted thrombolytic therapy are currently under way.
The search to extend the IV thrombolytic therapy window has also centered on the use of advanced imaging techniques to help select for those patients with a salvageable penumbra and who are therefore more likely to benefit from thrombolysis even at a later stage. Diffusion weighted imaging (DWI) is an MRI sequence that is weighted to detect “acutely injured brain,” i.e., tissue with restricted diffusion of water molecules due to cellular swelling. This can be juxtaposed upon MRI perfusion sequences (PWI) (an illustration of relative cerebral blood flow) to demonstrate areas of “mismatch.”continued ...