Response to Letter by Hefzy and Mitsias
We are grateful to Drs Hefzy and Mitsias for their letter. Although we concur that hemorrhagic transformation after successful reperfusion is a potential contributor to the disjunction between recanalization rates and rates of better outcomes on binary measures in trials of intra-arterial fibrinolysis, we think it unlikely to be a major factor. As the 2 National Institute of Neurological Disorders and Stroke tissue plasminogen activator trials and the Diffusion and Perfusion Imaging Evaluation For Understanding Stroke Evolution (DEFUSE) trial showed, major hemorrhagic transformations typically occur in patients who, at the time of treatment, already harbor large ischemic tissue volumes with advanced bioenergetic failure and a poor prognosis.1,2 As a result, reperfusion hemorrhages generally make little independent contribution to rates of poor outcomes once the presence or absence of a favorable target lesion (small core, large penumbra) is taken into account.
Analysis of the available study-level data from our meta-analysis shows a relationship opposite to that which Drs Hefzy and Mitzias hypothesize. Across the 3 trials (Prolyse in Acute Cerebral Thromboembolism [PROACT 1], PROACT 2, Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial [MELT]) with analyzable data, in the treatment arms in which all patients were exposed to lytic therapy, higher recanalization rates were associated with lower rates of symptomatic intracerebral hemorrhage (r=−0.9). However, a study-level meta-analysis does not permit detailed dissection of this issue and we acknowledge that further investigation in detailed, patient-level data sets is merited.
J.L.S. has received honoraria from universities as a visiting professor; is an employee of the University of California, which holds a patent on retriever devices for stroke; is a scientific consultant regarding trial design and conduct to Concentric Medical, Talecris, and Ev3; is a site investigator in multicenter trials sponsored by Lundbeck for which the University of California Regents receive payments based on the clinical trial contracts for the number of subjects enrolled; is a site investigator in the National Institutes of Health IMS 3 and CLEAR-ER multicenter clinical trials, for which the University of California Regents receive payments based on the clinical trial contracts for the number of subjects enrolled; has declined consulting/honoraria monies from Genentech since 2002; and is funded by National Institutes of Health–National Institute of Neurological Disorders and Stroke Awards P50 NS044378 and U01 NS 44364.
Saver JL. Hemorrhage after thrombolytic therapy for stroke: the clinically relevant number needed to harm. Stroke. 2007; 38: 2279–2283.
Lansberg MG, Thijs VN, Bammer R, Kemp S, Wijman CA, Marks MP, Albers GW. Risk factors of symptomatic intracerebral hemorrhage after tPA therapy for acute stroke. Stroke. 2007; 38: 2275–2278.