To the Editor:
The dramatic clinical recovery during tissue plasminogen activator (tPA) infusion with continuous transcranial Doppler (TCD) monitoring seen in 8 of 40 patients reported by Alexandrov et al1 is both exciting and unprecedented. The fact that their patients had more severe strokes than those in the NINDS study, with average NIHSS scores of 33% higher, is particularly impressive. Cardiologists are used to seeing marked clinical improvement in at least half their myocardial infarction patients when thrombolysis is performed within 3 hours of onset. The lack of an immediate clinical response to thrombolysis was noted in the first round of letters discussing the NINDS study2 and is consistent with my own clinical experience (in 10 or so cases) and that of other clinical neurologists.
The authors advance the hypothesis that the sound energy of TCD exposes more of the clot surface to tPA, presumably permitting more effective clot lysis. They argue for a controlled trial of thrombolysis with and without prolonged TCD. However, no study at any time with concomitant controls has replicated the NINDS results. Although ECASS-II3 demonstrated a 40.3% favorable outcome in the alteplase group, the placebo group did nearly as well (36.6%), even when the smaller subset of patients treated within 3 hours is considered. A recent community report (without controls) is less sanguine—reporting a 9% symptomatic intracerebral hemorrhage rate and a 30% any hemorrhage rate in 138 patients4 (note the authors). Combine the 2 studies, and any therapeutic advantage of tPA for ischemic stroke vanishes (because the symptomatic intracerebral hemorrhage rate in the NINDS study was 6%).
Nonetheless, the results reported by Alexandrov et al are exciting and should be followed up. However, a proper study of prolonged TCD in the management of acute ischemic stroke should include a control group not receiving thrombolytics at all, since the therapeutic efficacy of tPA in ischemic stroke is still under serious question. The initial group studied should be the large number of patients arriving in the emergency room between 3 and 6 hours after onset, those in whom thrombolytic therapy has not proven to be of any benefit. Ultimately, TCD should be studied by itself in the first 3 hours; but the academic and medical-legal establishments in the United States have made such a study impossible to carry out in this country. However, tPA is not yet approved for stroke treatment in Europe, and perhaps a study such as ECASS-III could properly investigate the dramatic clinical response to tPA and prolonged TCD by comparing the combination of tPA and TCD and tPA and TCD separately to placebo. Concurrent placebo controls are crucial, because the rate of good outcome in the placebo group has varied so widely in different studies. Historical controls just won’t do.
This would not be the first time in diseases affecting the brain that an effective therapy was found while investigating something else. Cade found lithium because he wanted to make urate salts more soluble. Valproic acid was discovered because it was used as the oily vehicle to dissolve a lipophilic drug being tested as an anticonvulsant.
Blood contains huge amounts of clotting factors and fibrinolytic factors. It is well known that most intracranial arterial occlusions resolve in time without any thrombolytic therapy, although too late to do the stroke patient any good. It is possible that prolonged TCD, by itself, allows the natural fibrinolytic factors already present in blood and endothelium to penetrate and dissolve the clot in time to benefit the patient.
Against this idea are the experimental results that ultrasound given to artificial clots in glass capillaries does not dissolve them unless tPA is present.5 However, glass capillaries do not contain endothelium and the cellular elements of blood. It is also well recognized that mechanical stress alters endothelial gene expression and platelet function. However, this is just theoretical quibbling. A significant clinical effect has likely been shown by Alexandrov, and it should be properly investigated further. A therapeutic effect of prolonged TCD by itself, if demonstrated, will likely have far wider application to human disease than just stroke.
- Copyright © 2000 by American Heart Association
Alexanrov AV, Demchuk AM, Felberg RA, Christou I, Barber PA, Burgin WS, Malkoff M, Wojner AW, Grotta JC. High rate of complete recanalization and dramatic clinical recovery during tPA infusion when continuously monitored with 2-MHz transcranial Doppler monitoring. Stroke.. 2000;31:610–614.
Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P. Randomized double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS-II). Lancet.. 1998;352:1245–1251.
Demchuk AM, Morgenstern MD, Kreiger DW, Chi TL, Hu W, Wein TH, Hardy RJ, Grotta JC, Buchan AM. Serum glucose level and diabetes predict tissue plasminogen activator–related intracerebral hemorrhage in acute ischemic stroke. Stroke.. 1999;30:34–39.
Suchkova V, Siddiqi FN, Carstensen EL, Dalecki D, Child S, Francis CW. Enhancement of fibrinolysis with 40-kHz ultrasound. Circulation.. 1998;98:1030–1035.
We appreciate the thoughtful comments by Dr Robinson regarding potential enhancement of thrombolysis with transcranial Doppler ultrasound. However, we disagree with his interpretation of data on tPA efficacy.
First, clinical assessment of dramatic recovery during and shortly after TPA infusion was not a goal of the NINDS rt-PA study protocol that targeted the early improvement end point at 24 hours. In a post hoc analysis, 27% of tPA-treated patients recovered completely or had an improvement of ≥10 NIHSS points at 24 hours compared with 12% of placebo-treated patients (P=0.002).R1 These data indicate that early dramatic recovery could have occurred during the NINDS rt-PA Stroke Study in some patients treated with TPA but without externally applied ultrasound.
Second, a 9% hemorrhage rate reported by Demchuk et alR2 includes patients treated at 2 centers, Houston and Calgary, and this hemorrhage rate is more representative of the first steps in implementation of tPA therapy. Our own experience that replicates the NINDS rt-PA Stroke Study was published separately (7% symptomatic hemorrhage rate),R3 and our ongoing assessment of tPA therapy in Houston (>300 patients treated from 1996 through 2000) indicates even lower rates of hemorrhage (unpublished data). A recent multicenter phase-IV assessment of tPA by the STARS collaboratorsR4 showed a 3.3% symptomatic hemorrhage rate despite protocol violations in 32.6% of patients. Outcome after tPA therapy relates to appropriateness,R5 and hemorrhagic complication rates may be higher in community hospitals.R6 However, the results of the NINDS rt-PA Stroke Study have now been successfully replicated in several postapproval studies. The benefit from tPA therapy was seen even after the impact of hemorrhagic complications had been accounted for in the NINDS rt-PA Stroke Study: patients with advanced age and severe stroke had higher rate of intracerebral hemorrhage, but more of these patients recovered when treated with tPA compared with placebo.R1 R7
Third, existing data indicate that withholding thrombolytic therapy and administering placebo in a patient otherwise eligible for intravenous TPA during the first 3 hours after stroke onset is unethical, at least in this country.R8 However, we agree that a potential independent effect of external ultrasound on clot recanalization needs to be proved against placebo.
Perhaps this could be accomplished in patients presenting outside the conventional window for thrombolytic therapy. Laboratory research indicates that such an independent effect is most likely present with kilohertz range of frequency,R9 and a 2-MHz transcranial Doppler may not be able to achieve this because of tremendous attenuation of sound energy through temporal bone. However, possible interactions of 2-MHz TCD with natural fibrinolytic factors, fibrin structure, and vessel wall factors may deserve further study.
Finally, dismissing the NINDS rt-PA Stroke Study data in view of the overall negative ECASS results and historic reports of hemorrhagic complications is incorrect. Our cohort study does not provide as strong evidence of clinical effect as does a well-conducted randomized trial such as the NINDS rt-PA Stroke Study. Although our data are intriguing and point to a possible synergistic effect of TCD and TPA,R10 this question should be subjected to scientific scrutiny in a proper trial to demonstrate ultrasound-enhanced thrombolysis with TPA for stroke.
We are pleased that Dr Robinson shares our excitement in seeing dramatic clinical recovery during TPA infusion, and his letter raises several important points that need to be addressed in a prospective trial. Indeed, if a noninvasive diagnostic modality has a therapeutic effect on thrombolysis, this may open a new frontier in clinical applications of ultrasound.
Demchuk AM, Morgenstern MD, Krieger DW, Chi TL, Hu W, Wein TH, Hardy RJ, Grotta JC, Buchan AM. Serum glucose level and diabetes predict tissue plasimogen activator–related intracerebral hemorrhage in acute ischemic stroke. Stroke.. 1999;30:34–39.
Chiu D, Krieger D, Villar-Cordova C, Kasner SE, Morgenstern LB, Bratina PL, Yatsu FM, Grotta JC. Intravenous tissue plasminogen activator for acute stroke: feasibility, safety, and efficacy in the first year of clinical practice. Stroke.. 1998;29:18–22.
Buchan AM, Barber PA, Newcommon N, Karbalai HG, Demchuk AM, Hoyte KM, Klein GM, Feasby TE. Effectiveness of t-PA in acute ischemic stroke: outcome relates to appropriateness. Neurology.. 2000;54:679–684.
Alexandrov AV, Grotta JC, Reiser S. Bioethical principles in stroke management. In: Cohen SN, ed. Management of Ischemic Stroke: A Clinical Approach. New York, NY: McGraw-Hill;2000:523–533.
Alexandrov AV, Demchuk AM, Felberg RA, Christou Z, Barber PA, Burgin WS, Malkoff M, Wojner AW, Grotta JC. High rate of complete recanalization and dramatic clinical recovery during TPA infusion when continuously monitored by 2-MHz transcranial Doppler. Stroke.. 2000;31:610–614.