title: Safety and efficacy of ultrasound-enhanced thrombolysis: a comprehensive review and meta-analysis of randomized and nonrandomized studies.
abstract: OBJECTIVE
  Ultrasound-enhanced thrombolysis is a promising new approach to facilitate reperfusion therapies for acute ischemic stroke. So far, 3 different ultrasound technologies were used to increase the thrombolytic activity of tissue plasminogen activator (tPA), including transcranial Doppler (TCD), transcranial color-coded duplex (TCCD), and low-frequency ultrasound. We performed a meta-analysis to evaluate the safety and efficacy of ultrasound-enhanced thrombolysis compared to the current standard of care (intravenous tPA).
  
  
  METHODS
  Through Medline, Embase, and Cochrane database search, we identified and abstracted all studies of ultrasound-enhanced thrombolysis in acute cerebral ischemia. Principal investigators were contacted if data not available through peer-reviewed publication were needed. Symptomatic intracerebral hemorrhage (sICH) and recanalization rates were compared between tPA, tPA+TCD+/-microspheres (microS), tPA+TCCD+/-microS, and tPA+low-frequency ultrasound.
  
  
  RESULTS
  A total of 6 randomized (n=224) and 3 nonrandomized (n=192) studies were identified. The rates of symptomatic intracerebral hemorrhage in randomized studies were as follows: tPA+TCD, 3.8% (95% CI, 0%-11.2%); tPA+TCCD, 11.1% (95% CI, 0%-28.9%); tPA+low-frequency ultrasound, 35.7% (95% CI, 16.2%- 61.4%); and tPA alone, 2.9% (95% CI, 0%-8.4%). Complete recanalization rates were higher in patients receiving combination of TCD with tPA 37.2% (95% CI, 26.5%- 47.9%) compared with patients treated with tPA alone 17.2% (95% CI, 9.5%-24.9%). In 8 trials of high-frequency (TCD/TCCD) ultrasound-enhanced thrombolysis, tPA+TCD/TCCD+/-microS was associated with a higher likelihood of complete recanalization (pooled OR, 2.99; 95% CI, 1.70-5.25; P=0.0001) when compared to tPA alone. High-frequency ultrasound-enhanced thrombolysis was not associated with an increased risk of symptomatic intracerebral hemorrhage (pooled OR, 1.26; 95% CI, 0.44-3.60; P=0.67).
  
  
  CONCLUSIONS
  The present safety and signal-of-efficacy data of high-frequency ultrasound-enhanced thrombolysis should be taken into account in the design of future randomized controlled trials.
authors.affiliation: Comprehensive Stroke Center, Department of Neurology, University of Alabama at Birmingham Hospital, Birmingham, Ala 35294-3280, USA. tsivgoulisgiorg@yahoo.gr
authors.forename: Georgios
authors.initials: G
authors.lastname: Tsivgoulis
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eggers
authors.forename: Marc
authors.initials: M
authors.lastname: Ribo
authors.forename: Fabienne
authors.initials: F
authors.lastname: Perren
authors.forename: Maher
authors.initials: M
authors.lastname: Saqqur
authors.forename: Marta
authors.initials: M
authors.lastname: Rubiera
authors.forename: Theodoros N
authors.initials: TN
authors.lastname: Sergentanis
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Vadikolias
authors.forename: Vincent
authors.initials: V
authors.lastname: Larrue
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Molina
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Alexandrov
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000000981:diagnostic imaging* / Q000503:physiopathology / Q000628:therapy*; D003131:Combined Modality Therapy / Q000009:adverse effects / Q000379:methods / Q000706:statistics & numerical data; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D020767:Intracranial Thrombosis / Q000000981:diagnostic imaging* / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D015912:Thrombolytic Therapy / Q000009:adverse effects / Q000379:methods* / Q000706:statistics & numerical data; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D014464:Ultrasonic Therapy / Q000009:adverse effects / Q000379:methods* / Q000706:statistics & numerical data; D017585:Ultrasonography, Doppler, Transcranial / Q000009:adverse effects / Q000379:methods / Q000706:statistics & numerical data
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator