Ultrasound Enhanced Thrombolysis for Stroke

Abstract

In the pivotal clinical trials of intravenous tissue plasminogen activator (TPA) therapy, a low rate of early arterial recanalization was suspected because only a few stroke patients may have had early dramatic clinical improvement. Tissue plasminogen activator activity can be enhanced with ultrasound, including 2 MHz transcranial Doppler (TCD). Transcranial Doppler identifies residual blood flow signals around thrombi, and, by delivering mechanical pressure waves, exposes more thrombus surface to circulating TPA. For the first time in clinical medicine, the international multicenter CLOTBUST trial showed that ultrasound enhances the thrombolytic activity of a drug in humans, thereby confirming multidisciplinary experimental research conducted worldwide for the past 30 years. In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 h after TPA bolus occurred in 25% of patients treated with TPA+TCD compared with 8% who received TPA alone ( P = 0·02). Complete clearance of a thrombus and dramatic recovery of brain functions during treatment are feasible goals for ultrasound-enhanced thrombolysis that can lead to sustained recovery. An early boost in brain perfusion seen in the target CLOTBUST group resulted in a trend of 13% more patients achieving favorable outcome at 3 months. To further enhance the ability of TPA to break up thrombi, current ongoing clinical trials include phase II studies of 2 MHz TCD with ultrasound contrast agents or (microbubbles): TCD+TPA+Levovist; TCD+TPA+MRX nano-platform (C3F8). Intra-arterial TPA delivery can be enhanced with 1·7–2·1 MHz pulsed wave ultrasound (EKOS catheter, IMS trial). Dose escalation studies of microbubbles, ultrasound exposure, and the development of an operator-independent ultrasound device are underway.