Risk of Thrombolysis-Associated Intracerebral Hemorrhage: The Need to Compare Apples With Apples
To the Editor:
We read with interest the dose-escalation safety study of tenecteplase (TNK) within 3 hours of stroke.1 Both this study and the pilot study of desmoteplase within 3 to 9 hours2 clearly demonstrate that higher doses of thrombolytic agents have increased rates of symptomatic intracerebral hemorrhage (sICH). Moreover, both studies revisit a hypothesis considered, but never tested with recombinant tissue plasminogen activator (rtPA), that lower thrombolytic doses may provide comparable efficacy with less sICH risk.
Lower rtPA doses (<0.9 mg/kg) were never adequately tested for their risk/benefit profiles in stroke patients. The initial rtPA pilot trial, in 1987, used 0.35 (n=6), 0.60 (n=12), 0.85 (n=30), 0.95 (n=25), and 1.08 mg/kg (n=1) within 90 minutes after stroke.3 Notably similar to the desmoteplase and TNK pilot studies, no sICHs were seen until the 0.95 mg/kg tier. A second pilot study at 90 to 180 minutes after stroke, using 0.6 (n=8), 0.85(n=6), and 0.95 mg/kg (n=6) rtPA,4 had 1 sICH in the 2 highest tiers. Subsequently, a small placebo-controlled trial of 0.85 mg/kg had no sICHs in the treated group (n=14).5 To maximize the potential benefit of rtPA, while accounting for a likely increased sICH risk, 0.9 mg/kg was chosen for the NINDS trial. There was no evidence of different efficacy at lower doses in these pilot trials. A proposed trial to compare 0.6 mg/kg with 0.9 mg/kg of rtPA in the mid 1990s was not approved for funding by the NINDS.
Cardiac studies clearly indicate that TNK is unlikely to be safer than rtPA, regarding sICH, when equipotent doses in humans are used. Specifically, the ASSENT-2 trial found 0.5 mg/kg TNK had almost identical clinical efficacy and sICH rates in acute myocardial infarction, compared with ≈1.1 mg/kg rtPA.6 Thus, 0.9 mg/kg rtPA may be bio-equivalent to 0.4 mg/kg TNK. Lower TNK doses would need to be compared against lower rtPA doses. Also, the baseline National Institutes of Health Stroke Scale score, a critical predictor of sICH,7 was lower in the TNK pilot stroke trial than the NINDS rtPA stroke trial.
Moreover, the cardiac literature has not found any third-generation thrombolytic more effective than rtPA, suggesting that third-generation thrombolytics at bio-equivalent doses may have similar safety and efficacy profiles.
The TNK investigators assert the bio-equivalence of 0.1 mg/kg TNK to 0.9 mg/kg rtPA based on a rabbit model.8 However, models of young animals using human proteins are likely to give very different estimates of dosing safety and efficacy. This is illustrated by the fact that 0.1 mg/kg TNK showed no clinical efficacy in an ischemic stroke rabbit model.9
We do not know if the current rtPA dose is the ideal balance of risk and benefit. The upcoming well-designed TNK trial is an excellent opportunity to examine whether a lower thrombolytic dose can offer similar efficacy with less risk of sICH.
Haley EC, Jr, Lyden PD, Johnston KC, Hemmen TM. A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke. Stroke. 2005; 36: 607.
Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, Fischer M, Furlan A, Kaste M, Lees KR, Soehngen M, Warach S. The Desmoteplase In Acute Ischemic Stroke trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005; 36: 66–73.
Brott TG, Haley EC, Jr, Levy DE, Barsan W, Broderick J, Sheppard GL, Spilker J, Kongable GL, Massey S, Reed R, et al. Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke. 1992; 23: 632–640.
Haley EC, Jr., Levy DE, Brott TG, Sheppard GL, Wong MC, Kongable GL, Torner JC, Marler JR. Urgent therapy for stroke. Part II. Pilot study of tissue plasminogen activator administered 91–180 minutes from onset. Stroke. 1992; 23: 641–645.
Haley E, Brott T, Sheppard G, Barsan W, Broderick J, Marler J, Kongable G, Spilker J, Massedy S, Hansen C, Torner J. Pilot randomized trial of tissue plasminogen activator in acute ischemic stroke. Stroke. 1993; 24: 1000–10004.
Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke. 1997; 28: 2109–2118.
Thomas GR, Thibodeaux H, Errett CJ, Badillo JM, Keyt BA, Refino CJ, Zivin JA, Bennett WF. A long-half-life and fibrin-specific form of tissue plasminogen activator in rabbit models of embolic stroke and peripheral bleeding. Stroke. 1994; 25: 2072–2079.
We thank Khatri et al for their interest in our article. We re-emphasize the preliminary nature of our observations with tenecteplase in acute ischemic stroke. With such preliminary data, there are many potential interpretations, and the one posed by Khatri et al is certainly one of them. However, whereas the cardiac experience has taught us much about thrombolytics, in general, and tenecteplase and alteplase, in particular, we would urge circumspection in directly extrapolating the cardiac experience to the ischemic stroke arena. The streptokinase experience is a cautionary tale in that regard. We also agree with Khatri et al that it is possibly hazardous to extrapolate dosing information directly from animal models to humans.
We continue to regard our preliminary tenecteplase experience in human stroke as encouraging. Future planned studies of tenecteplase in stroke will test a range of doses of tenecteplase compared with a concurrent control group treated with standard dose alteplase. These studies are carefully designed to guard against a reduction in efficacy in an effort to achieve an improvement in safety. Unfortunately, these studies will not answer the question of whether lower doses of alteplase might accomplish the same goals.