(Stroke. 2000;31:2257.)
© 2000 American Heart Association, Inc.
Comments, Opinions, and Reviews |
Tirilazad Mesylate in Acute Ischemic Stroke
A Systematic Review
Correspondence to Prof P. Bath, Division of Stroke Medicine, University of Nottingham, City Hospital Campus, Nottingham, NG5 1PB, UK. E-mail philip.bath{at}nottingham.ac.uk
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Abstract |
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Background and Purpose—Tirilazad is a nonglucocorticoid, 21-aminosteroid that inhibits lipid peroxidation. Studies in experimental models of ischemic stroke had suggested that tirilazad had neuroprotective properties. As a result, clinical studies were undertaken to assess the safety and efficacy of tirilazad in the treatment of acute ischemic stroke. We performed a systematic review of randomized, controlled trials that assessed the safety and efficacy of tirilazad in patients with acute ischemic stroke.
Methods—Trials of tirilazad were identified from searches of the Cochrane Library and communication with the Pharmacia & Upjohn company, the manufacturer of tirilazad. Data relating to early and end-of-trial case fatality, disability (Barthel Index and Glasgow Outcome Scale), phlebitis, and corrected QT interval were extracted by treatment group from published data and company reports and analyzed by using the Cochrane Collaboration meta-analysis software REVMAN.
Results—Six trials (4 published, 2 unpublished) assessing tirilazad in 1757 patients with presumed acute ischemic stroke were identified; all were double-blind and placebo controlled in design. Tirilazad did not alter early case fatality (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.79 to 1.56) or end-of-trial case fatality (OR 1.12, 95% CI 0.88 to 1.44). A just-significant increase in death and disability, assessed as either the expanded Barthel Index (OR 1.23, 95% CI 1.01 to 1.51) or Glasgow Outcome Scale (OR 1.23, 95% CI 1.01 to 1.50) was observed. Tirilazad significantly increased the rate of infusion site phlebitis (OR 2.81, 95% CI 2.14 to 3.69). Functional outcome (expanded Barthel Index) was significantly worse in prespecified subgroups of patients: females (OR 1.46, 95% CI 1.08 to 1.98) and subjects receiving low-dose tirilazad (OR 1.31, 95% CI 1.03 to 1.67); a nonsignificant worse outcome was also seen in patients with mild to moderate stroke (OR 1.40, 95% CI 0.99 to 1.98).
Conclusions—Tirilazad mesylate increases death and disability by about one fifth when given to patients with acute ischemic stroke. Although further trials of tirilazad are now unwarranted, analysis of individual patient data from the trials may help elucidate why tirilazad appears to worsen outcome in acute ischemic stroke.
Key Words: cerebral infarction • meta-analysis • neuroprotective agents • treatment outcome
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Tirilazad mesylate (U-74006F, Freedox; Pharmacia & Upjohn, Kalamazoo, Mich) is a synthetic, lipid-soluble, nonglucocorticoid, 21-aminosteroid (or lazaroid) that has been developed for the acute treatment of subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), spinal cord injury, and ischemic stroke. Its proposed mechanism of action is to inhibit iron-dependent lipid peroxidation within membranes, effects that are mediated through (1) free-radical scavenging of lipid peroxyl and hydroxyl groups, (2) reducing the formation of hydroxyl radicals, (3) decreasing membrane phospholipid fluidity, and (4) maintaining endogenous antioxidant levels (especially vitamins E and C).
Tirilazad was neuroprotective in experimental models of TBI, spinal cord injury, and SAH.1 2 3 Although human studies have shown tirilazad to be ineffective in TBI,4 it improved outcome in 2 of 4 phase III studies in SAH5 6 7 8 and is licensed for this indication in some countries. Tirilazad was also neuroprotective in animal models of ischemic stroke. It improved outcome and reduced stroke lesion size, neuronal necrosis, brain injury, and cerebral edema in gerbils and rats exposed to permanent focal ischemia.9 10 11 Tirilazad also blocked cortical hypoperfusion after spreading depression.12 Bolus doses as low as 3 mg/kg appeared to be neuroprotective, whereas doses as high as 60 mg · kg-1 · d-1 were well tolerated by monkeys. However, tirilazad had variable effects on neurological outcome in transient forebrain ischemia in the rat.13 14
Phase I results in normal, healthy, human volunteers found that single and multiple intravenous doses of up 12 mg/kg tirilazad were well tolerated15 16 17 ; local infusion-related irritation and thrombophlebitis were the main adverse events, partially explained by the presence of citrate in the vehicle solution.16 Tirilazad did not alter cerebral blood flow or its reactivity to carbon dioxide or cerebral oxygen metabolism in normal subjects.18
A number of phase II and III trials have been undertaken, of which 2 are so-far unpublished, with tirilazad in patients with ischemic stroke, and this systematic review assesses these trials in the context of safety and efficacy.
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Methods |
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Study Identification
We identified studies through searches of the Cochrane Library (issue 4, 1998) and a recent study of publication quality of acute stroke randomized, controlled trials.19 The Cochrane database is the largest and most comprehensive listing of randomized, controlled trials and is based on trials present in MEDLINE and EMBASE and the results of manual journal searches. The reference lists of identified publications were also checked for additional trials. Publication language other than English was not an exclusion criterion. The pharmaceutical company that makes the drug, Pharmacia & Upjohn (formerly The Upjohn Co), was also contacted to identify trials and provide further information on each identified trial.
Study Selection
Included trials had to be truly or quasi randomized,
unconfounded, and placebo or open controlled. Tirilazad had to be
administered to adult patients within 24 hours of onset of suspected or
proven acute ischemic stroke. Trials involving patients with
definite primary intracerebral hemorrhage or
SAH were excluded.
Data Extraction
Three of us (P.B., R.I., and F.B.) independently selected trials
for inclusion and extracted information from published
data,20 21 22 23 24 25 26 internal company reports,27 28 29 30 31 32
and tabulated data provided by Pharmacia & Upjohn (B.M.,
S.A.N.-S.).
The incidence of the following binary outcomes, chosen a priori,
was determined for each treatment group in each trial: early (
10
days) case fatality; case fatality at the end of the trial; combined
death and disability at the end of the trial, assessed as the expanded
Barthel Index (EBI; cutoff <60/100, equivalent to dead or disabled)
and the Glasgow Outcome Scale (GOS; comprising groups
severely disabled, vegetative survival, and dead)33 34 ;
and phlebitis at the infusion site. Information on 1 continuous
variable, corrected QT interval at the end of treatment, was also
recorded. ·
These variables were analyzed by tirilazad dose: "low
dose" defined as 
6 mg ·
kg-1d-1 and "high
dose," >6 mg · kg-1 ·
d-1; this cutoff reflects dosing strategies in
early and later trials with tirilazad. To search for potential sources
of heterogeneity in the trials and their results,
end-of-trial case fatality and EBI were assessed for the following
subgroups of subjects: treatment delay (within 3 hours, >3 hours);
severity (mild to moderate stroke: National Institutes of Health Stroke
Scale [NIHSS] <16 or Unified Neurological Stroke Scale [UNSS]
16; severe stroke: NIHSS 16 or UNSS <16); and sex.
Data Analysis
The methodological quality of trials was assessed by using
published Cochrane Collaboration criteria.35 Data were
entered into and analyzed by using the Cochrane Collaboration
review manager package (REVMAN, version 3.1 for Macintosh).
We analyzed data for patients who received at least 1 dose of
their allotted medication, tested for heterogeneity
between trials, and calculated a weighted estimate of the treatment
effect across trials by means of the Peto odds ratio (OR) for binary
data and the weighted mean difference for continuous data.
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Results |
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Study Identification and Characteristics
Six randomized, controlled trials of tirilazad involving a total of 1757 patients with presumed or confirmed ischemic stroke were identified and have been included in the analyses (Table 1
); no studies were excluded. The
first trial was a phase II sequential dose-escalation study involving
111 patients and tested tirilazad at doses ranging between 0.6 and 6
mg · kg-1 ·
d-1.20 21 27 The highest dose was
well tolerated and was used in 2 phase III efficacy studies, 1 in North
America22 23 29 and the other in Europe, Israel, and New
Zealand.25 30 Both of these trials were stopped
prematurely after recruiting a total of 1110 patients to allow higher
doses of tirilazad to be tested as a result of information from studies
in patients with SAH, animal dose-response data, and interim
analyses.29 30 A second phase II trial assessed
the safety and feasibility of administering tirilazad at 10 mg ·
kg-1 · d-1 and
involved 55 patients.28 Two additional phase III trials
were then started, 1 in North America26 31 and the other
in Europe and Australasia.32 These studies differed from
the previous trials because women were given a higher dose (12 mg
· kg-1 · d-1)
than men (10 mg · kg-1 ·
d-1) to compensate for differential
pharmacokinetics. After an alert from the safety monitoring committee
of the European/Australasian study, both trials were stopped early
after having recruited a total of 481 patients. Subsequently, further
development of tirilazad for ischemic stroke was ceased.
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Trial Designs
All of the trials were placebo controlled and truly randomized by
using prenumbered treatment and placebo vials, thereby ensuring
concealment of allocation. Patients were randomized in blocks of
2,32 4,29 30 31 or 528 . The trials
were triple-blind (patient, drug administrator, and outcome assessor),
although the presence of injection site phlebitis may have reduced
blinding in some instances.
Data Quality
Data on patients receiving at least 1 dose of tirilazad were
analyzed for all 6 studies; because all randomized patients
received their allocated treatment in the 2 phase II safety
trials,21 27 28 their data are the same as "intention to
treat." In total, 1544 of 1591 (97.0%) of randomized patients in the
4 phase III studies received their medication, so the exclusion of data
from untreated patients is not likely to have materially affected the
results.
Case Fatality and Disability
Data on case fatality were available for all 6 trials. Tirilazad
had no effect on either early or end-of-trial case fatality (Figures 1a and 1b and Table 2); there was no evidence of
heterogeneity between the trials (Table 2) nor
of any dose relationship (6 mg ·
kg-1 · d-1 versus
>6 mg · kg-1 ·
d-1) with mortality. Analysis of
end-of-trial case fatality by sex revealed that males had a
nonsignificant increase in mortality (OR 1.23, 95% confidence interval
[CI] 0.89 to 1.71), whereas females had a nonsignificant decrease (OR
0.89, 95% CI 0.60 to 1.31).
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Three-month end-of-trial death and disability were assessed in trials
by using the EBI (cutoff <60/100). Patients who received tirilazad had
a significantly worse outcome than those who received placebo (Figure 1c
and Table 2). Possible explanations for this finding
were sought through analysis of functional outcome in
prespecified subgroups of patients (Table 3). Significant increases in combined
death and disability were observed in females and those receiving
low-dose tirilazad; patients presenting with milder stroke also
appeared to have a worse outcome (Table 3). Functional outcome
was not related to the time delay between stroke onset and drug
administration. Alternative use of the GOS as a measure of functional
outcome revealed an OR virtually identical to that of the EBI (Table 2).
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Safety
All 6 trials reported the incidence of phlebitis at the infusion
site (Figures 1d and 2); tirilazad
caused a 2-fold increase in phlebitis (OR 2.68, 95% CI 2.05 to 3.50),
raising the control rate from 10.2% to 22.4% (Figure 1).
Tirilazad nonsignificantly increased the corrected QT interval by 7.5
ms (95% CI -0.8 to +15.9 ms) when measured at the end of treatment on
day 4 in 4 studies (n=572).
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Discussion |
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This systematic review is the first to assess, in their entirety, data resulting from the commercial development of a potential neuroprotective agent in acute stroke. It also reports for the first time data from 2 European-based phase III trials of tirilazad, TESS (Tirilazad Efficacy Stroke Study) and TESS II. Our results confirm those of individual studies showing that tirilazad is ineffective in ischemic stroke. However, the aggregated data suggest that tirilazad may have worsened functional outcome after stroke, as assessed with the EBI and GOS. This end point is most relevant to patients and has been used as the primary outcome in many recent efficacy trials in acute stroke. Furthermore, analysis of functional data by subgroup found significantly worse outcomes with tirilazad in female patients and those given a low dose and a trend to a worse outcome in those subjects with mild to moderate stroke. It is difficult to rationalize these findings: treated women had a trend to a lower death rate yet greater disability. Similarly, the relationship of a poor outcome with a low rather than a high dose of the drug is counterintuitive. The finding of a trend to a worse outcome in mild to moderate stroke could reflect that it is easier to detect worsening outcomes in patients with mild rather than severe stroke. However, each of these findings could simply represent the play of chance.
It is not clear why tirilazad was not only ineffective but also potentially worsened outcome after stroke. The drug was neuroprotective in experimental stroke,9 10 11 13 although the relevance of such preclinical models to clinical efficacy has been questioned,36 37 particularly because efficacy is usually judged differently in experimental (reduced infarct size) and human (reduced death and dependency/disability) stroke. Tirilazad was not only safe and well tolerated in 4 trials studying patients with SAH5 6 7 8 but also improved outcome in 2 of these studies. SAH is now a licensed indication for the drug in some countries. However, other studies provide indirect information on why tirilazad was not beneficial in acute ischemic stroke. First, tirilazad was not always effective in experimental models of stroke.14 Second, it was ineffective in closed TBI,4 a condition known to involve cerebral ischemia. Third, tirilazad had no effect on infarct volume (a weak surrogate marker of outcome38 ) in 2 of the 4 phase III trials in ischemic stroke.39 Fourth, more than three quarters of patients received tirilazad after 3 hours, a time when neuroprotection is less likely to be effective. Fifth, tirilazad caused thrombophlebitis and might then have induced fever and a systemic inflammatory state, clinical scenarios known to be associated with a poor outcome.40 Last, tirilazad can prolong the corrected QT interval, which could increase the risk of fatal ventricular dysrhythmias. Analysis of 4 trials in which ECGs were performed revealed that tirilazad increased the corrected QT interval by 7.5 ms, although this prolongation is unlikely to have caused any significant clinical effects. No satisfactory biochemical explanation for toxicity exists. In particular, although tirilazad is a steroid, it has not been found to exhibit glucocorticoid activity in humans15 16 or to affect the pituitary adrenocortical axis in rats.41 Hence, it is unlikely that tirilazad worsened outcome through glucocorticoid effects, although it remains unclear what effects corticosteroids have in acute ischemic stroke.42 We plan to perform a systematic review of the individual patient data from the 6 randomized, controlled trials of tirilazad in ischemic stroke to further explore why subgroups of patients receiving the drug fared worse. This approach will allow multivariate analyses to be performed with assessment of interactions between prognostic variables (including age, sex, stroke severity, and time to treatment) and the associations between the corrected QT interval and phlebitis with outcome.
Tirilazad is not the only putative neuroprotectant to have failed development in the treatment of stroke. Three other drugs have also been associated with a worse outcome: selfotel (CGS 19755, a glutamate receptor antagonist),43 44 enlimomab (an anti–intercellular adhesion molecule antibody),45 and diaspirin–cross-linked hemoglobin (a human hemoglobin solution).46 Development of other potential neuroprotectants has also ceased, including aptiganel (an N-methyl-D-aspartate ion channel blocker), calcium channel blockers (flunarizine, isradipine, lifarizine, and nimodipine47 ), eliprodil (an N-methyl-D-aspartate polyamine receptor antagonist), lubeluzole (a modulator of nitric oxide activity), and GV150526 (a glycine receptor antagonist). Unfortunately, there is no common explanation for the failure of all of these latter drugs, but small sample sizes, unrealistic expectations for the magnitude of efficacy, administration too late after the onset of stroke (in contrast to SAH, for which drugs are generally administered before the development of ischemia), inadequate phase II testing, and the failure of the drug to reach the ischemic area because of arterial occlusion have all contributed to varying degrees. In some cases, unintended collateral effects may have contributed to study failures, eg, on blood pressure or infection.45 46 48 Unfortunately, many trial results have not been published in full, making a detailed analysis of study design and of drug safety and efficacy impossible, eg, trials relating to aptiganel, eliprodil, enlimomab, and lubeluzole. Other compounds have been incompletely tested, eg, prostacyclin, pentoxifylline, and theophylline,49 50 51 and their safety and efficacy remain unclear. Only agents that alter hemostasis have shown promise. Aspirin was found to have small but useful effects on death and disability and early recurrent stroke in 2 megatrials.52 53 Thrombolysis with intravenous tissue plasminogen activator appears to improve outcome when given hyperacutely after stroke,54 although only 1 of the 5 phase III trials was positive on its primary outcome.55 56 57 58 Finally, intra-arterial urokinase and ancrod each improved outcome in their first phase III studies,59 60 although the results of larger, second efficacy trials are awaited.
Development of drugs that aim to improve outcome after acute stroke is in a critical state. Some drugs have been frankly toxic, while more have simply been ineffective. Conventional phase III efficacy studies have been unreliable for at least 2 drugs (alteplase and lubeluzole), with studies reporting varying efficacy. It is clear that future studies of neuroprotectants will need to use improved trial designs and especially, larger sample sizes. The addition of neuroprotection to thrombolysis may also improve the latter’s efficacy,61 as already demonstrated in experimental stroke.11 Phase II studies also need to be improved, in particular with the use of neuroimaging to demonstrate that a drug is reducing stroke lesion size, a surrogate measure of efficacy. Furthermore, labeling studies of putative neuroprotective drugs should be performed to ensure that they are actually reaching the ischemic brain lesion.
However, it is also apparent that continuous and cumulative real-time tracking of drug efficacy and safety needs to take place during phase II and phase III development by using sequential meta-analytical techniques so that unnecessary and potentially unsafe trials can be prevented from starting. In this respect, it is possible that interpretation of sequential reviews of data from trials of calcium channel blockers, lubeluzole, selfotel, and tirilazad would have led to earlier cessation of their development. Systematic reviews of individual patient data from trials of these drugs may contribute further information on the failure of these drugs and how to improve the design of future studies. Such systematic reviews may also guard against bias62 by reporting previously unpublished data from individual trials, as has been done in the current article.
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Acknowledgments |
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P.M.W.B. is Stroke Association Professor of Stroke Medicine. F.J.B. is funded by NHS Executive (Trent) (grant SPGS 236). The members of the Tirilazad International Steering Committee were all members of 1 or more Tirilazad Trial Advisory Committees and, as such, received expenses and honoraria from Pharmacia & Upjohn (previously The Upjohn Co) for attending meetings. Data extraction and analyses were performed independently of the company, and no member of the committee received direct or indirect support for involvement in this review.
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Footnotes |
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1 Participating investigators are listed in the Appendix.
Part of this work was presented at the Seventh European Stroke Conference, Edinburgh, Scotland, May 27–30, 1998, and published in abstract form (Cerebrovasc Dis. 1998;8[suppl 4]:34).
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Tirilazad International Steering Committee (in alphabetical order): P.M.W. Bath (University of Nottingham, Nottingham, UK); S. Blecic (Erasme Hospital, Brussels, Belgium); J. Bogousslavsky (CHUV, Lausanne, Switzerland); G. Boysen (Hvidovre Hospital, Hvidovre, Denmark); S. Davis (Royal Melbourne Hospital, Melbourne, Australia); E. Diez-Tejedor (Hospital La Paz, Madrid, Spain); J.M. Ferro (Hospital St. Maria, Lisbon, Portugal); J. Gommans (Hawkes Bay Hospital, Hastings, New Zealand); W. Hacke (Universitätsklinikum Heidelberg, Heidelberg, Germany); B. Indredavik (Trondheims Sykehus, Trondheim, Norway); B. Norrving (Universitetssjukhuset, Lund, Sweden); J.M. Orgogozo (Chairman, Hopital Pellegrin, Bordeaux, France); E.B. Ringelstein (Universitat Münster, Münster, Germany); and M.L. Sacchetti (Università La Sapienza, Rome, Italy).
Analysis and Writing: P.M.W. Bath, R. Iddenden, F.J. Bath, and J.M. Orgogozo.
Pharmacia & Upjohn (Kalamazoo, Mich): B.C. Musch, D.M. Brosse, and S.A. Naberhuis-Stehouwer.
This review will be published in The Cochrane Library.63
Received April 4, 2000; revision received May 23, 2000; accepted May 25, 2000.
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References |
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