Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke
The DIAS-4 Trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke)
Background and Purpose—The DIAS-3 trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke [phase 3]) did not demonstrate a significant clinical benefit of desmoteplase administered 3 to 9 hours after stroke in patients with major artery occlusion. We present the results of the prematurely terminated DIAS-4 trial together with a post hoc pooled analysis of the concomitant DIAS-3, DIAS-4, and DIAS-J (Japan) trials to better understand the potential risks and benefits of intravenous desmoteplase for the treatment of ischemic stroke in an extended time window.
Methods—Ischemic stroke patients with occlusion/high-grade stenosis in major cerebral arteries were randomly assigned to intravenous treatment with desmoteplase (90 μg/kg) or placebo. The primary outcome was modified Rankin Scale (mRS) score of 0 to 2 at day 90. Safety assessments included mortality, symptomatic intracranial hemorrhage, and other serious adverse events.
Results—In DIAS-4, 52 of 124 (41.9%) desmoteplase-treated and 46 of 128 (35.9%) placebo-treated patients achieved an mRS score of 0 to 2 (odds ratio, 1.45; 95% confidence interval, 0.79; 2.64; P=0.23) with equal mortality, frequency of symptomatic intracranial hemorrhage, and other serious adverse events in both the treatment arms. In the pooled analysis, mRS score of 0 to 2 was achieved by 184 of 376 (48.9%) desmoteplase-treated versus 171 of 381 (44.9%) placebo-treated patients (odds ratio, 1.33; 95% confidence interval, 0.95; 1.85; P=0.096). Treatment with desmoteplase was safe and increased the recanalization rate (107/217 [49.3%] versus 85/222 [38.3%]; odds ratio, 1.59; 95% confidence interval, 1.08–2.35; P=0.019). Recanalization was associated with favorable outcomes (mRS 0–2) at day 90 in both the treatment arms.
Conclusions—Late treatment with intravenous 90 µg/kg desmoteplase is safe, increases arterial recanalization, but does not significantly improve functional outcome at 3 months.
The efficacy of intravenous alteplase declines over time, and clinical benefits have not been established beyond 4.5 hours after stroke onset.1 It remains unclear whether intravenous thrombolytics are beneficial in carefully selected patients with ischemic stroke presenting in extended time windows.
Preliminary evidence of safety and potential efficacy in an extended time window was obtained in the DIAS (Desmoteplase in Acute Ischemic Stroke) and DEDAS (Dose Escalation of Desmoteplase in Acute Ischemic Stroke) trials.2,3 The DIAS-2 trial did not confirm efficacy, but supported an excellent safety profile with the 90 µg/kg dose.4 Pooling the data from DIAS, DEDAS, and DIAS-2 suggested that desmoteplase was beneficial for patients with proximal arterial occlusion.5 These findings provided the rationale for the concomitant DIAS-3, DIAS-4, and DIAS-J studies (Clinical Study of Desmoteplase in Japanese Patients With Acute Ischemic Stroke) of desmoteplase versus placebo in patients treated 3 to 9 hours after stroke onset.6,7 DIAS-J was a randomized phase 2 study that evaluated the safety and tolerability of desmoteplase in Japanese patients. DIAS-3 and DIAS-4 were large multinational phase 3 sister trials assessing the efficacy and safety of 90 µg/kg of desmoteplase in the 3- to 9-hour window; a majority of patients in DIAS-3 were recruited in Asia and Europe, whereas most patients in DIAS-4 were from North and Latin America and Europe.
DIAS-3 reached the preplanned sample size of 492 patients in November 2013 and showed that desmoteplase was as safe as placebo, but without clinical benefit. On receiving the results of DIAS-3, the sponsor terminated the DIAS-4 trial after the enrollment of 270 of planned 400 patients, because the goal of 2 positive trials could not be met. Here, we present the results of DIAS-4 and an exploratory analysis of the pooled DIAS-3, DIAS-4, and DIAS-J patient data using the prespecified primary and secondary end points from DIAS-3 and DIAS-4.
The goal of the pooled analysis is to investigate efficacy and safety of intravenous thrombolysis in the so far largest sample of patients with major cerebral artery occlusions being treated beyond 3 hours. In addition, we explored whether late arterial recanalization may be associated with favorable clinical outcome.
The DIAS-4 study protocol was identical to that of DIAS-3 and has been described in detail elsewhere.8 In brief, DIAS-4 was a multinational, randomized, double-blind, parallel-group placebo-controlled phase III study designed and conducted in accordance with the principles of the Declaration of Helsinki.
Study sites recruited patients with ischemic stroke within 3 to 9 hours of witnessed symptom onset, between 18 and 85 years of age, with a National Institute of Health Stroke Scale (NIHSS) score of 4 to 24 and occlusion or high-grade stenosis in proximal segments of the middle, anterior, or posterior cerebral arteries (MCA-M1 and MCA-M2, ACA, and PCA) as assessed with computed tomography angiography (CTA) or magnetic resonance angiography (MRA) and corresponding to the acute neurological deficit. Patients were excluded if they had acute ischemic injury exceeding 1 of 3 of the MCA territory, half of the ACA or PCA territory, or intracranial hemorrhage (ICH). We defined acute ischemic injury (ischemic core volume) as x-ray hypoattenuation (hypodensity) within the affected arterial territory on computed tomography (CT) or restricted diffusion (increased signal) on diffusion-weighted imaging (DWI). Patients with a prestroke modified Rankin Scale (mRS) score of >1 were excluded. Details of the informed consent procedure and the inclusion/exclusion criteria are presented in the online-only Data Supplement.
Like in DIAS-3, study sites randomized eligible patients 1:1 to desmoteplase 90 µg/kg or placebo, given as a single intravenous bolus injection. Computer-generated randomization lists with stratification for baseline NIHSS (4–14 or 15–24) and for age (18–65, 66–75, and 76–85 years) were used (online-only Data Supplement).
At baseline and between 12 and 24 hours after study medication administration, patients were imaged with CT or magnetic resonance imaging depending on the preference of the study site. Magnetic resonance imaging included DWI, MRA, T2-fluid attenuation inversion recovery, and gradient echo (T2*) sequences. CT included a nonenhanced CT and CTA, the latter being obligatory at baseline and optional at follow-up. An imaging committee consisting of 4 experienced neuroradiologists (online-only Data Supplement) retrospectively assessed brain and vessel imaging for eligibility (occlusion/high-grade stenosis) independently from the study sites and blinded to all clinical information except the hemisphere affected. In addition, the committee assessed the MRAs and CTAs using the TIMI scale (Thrombolysis in Myocardial Infarction) with the scores: 0=complete occlusion, 1=near complete occlusion, 2=mild-to-moderate stenosis, and 3=normal open vascular segment. TIMI 0 and 1 was categorized as arterial occlusion and TIMI 2 and 3 as arterial patency or recanalization. The committee also measured the volume (mL) of ischemic injury at baseline and follow-up on CT or DWI using computerized planimetry (Io software, Synarc, or Alice, Parexel).
Safety assessments included mortality at day 90, any ICH, symptomatic ICH (SICH) defined as ICH on imaging resulting in a worsening of ≥4 points on NIHSS, major bleeding other than SICH, symptomatic ischemic edema (defined as brain edema with mass effect on imaging resulting in a worsening of ≥4 points on NIHSS), and other adverse events. An adjudication committee blinded to treatment, evaluated all deaths and neurological worsening by ≥4 NIHSS points and categorized their causes.
The primary efficacy end point for DIAS-4 was favorable outcome (mRS, 0–2). Only certified raters assessed mRS ratings by direct examination blinded to treatment allocation.
Key secondary efficacy end points (ordered hierarchically) were decreased in NIHSS by ≥8 points from baseline or an NIHSS score of ≤1 at day 90, and the combination of the dichotomized mRS and the NIHSS response.
The mRS response at day 90 was also analyzed using the ordinal scale (with scores 5 [severe disability] and 6 [death] merged into 1 category).
We also analyzed the primary efficacy end point in the following key subgroups (prespecified for DIAS-4 and assessed by the imaging committee):
Patients with core-lesion volume of <25 mL on DWI and <25 mL on CT.
Patients with time from stroke onset to treatment ≤7 hours and >7 hours.
Patients with TIMI score of 0 to 1 at baseline according imaging committee judgment.
In addition, the recanalization rate was assessed at 12 to 24 hours using CTA or MRA in the subgroup of patients with a baseline vessel TIMI score of 0 or 1.
The DIAS-4 protocol prespecified the following data sets: all patients-treated set—comprising all randomized patients who received study medication (all safety analyses); full-analysis set—all treated patients with at least 1 postbaseline measurement of mRS, and the per-protocol set—all full-analysis set patients fulfilling predefined inclusion/exclusion criteria in retrospect (Table I in the online-only Data Supplement).
Like in DIAS-3, we calculated the required sample size using a power of 80% and a 2-sided significance level of 5%. The original sample size was 302 patients (151 in each group), assuming an effect size of 15 percentage points (40% responders with desmoteplase versus 25% with placebo) based on post hoc analyses of the DEDAS, DIAS, and DIAS-2 trials.2–5 The protocol-specified analysis of the primary efficacy end point was performed using a logistic regression model with treatment and geographical region as covariates, and baseline NIHSS score, age, and time from stroke onset to treatment as covariates. In case of missing data on outcome at day 90, the last observation was carried forward when analyzing the full-analysis set and per-protocol set. For the primary efficacy end point in prespecified key subgroups of patients with core-lesion volume of <25 mL on DWI or <25 mL on CT and patients with time from stroke onset to treatment ≤7 hours and >7 hours, we used a logistic regression model similar to the primary analysis, including a treatment by imaging modality and treatment by time from stroke interaction factor, respectively.
DIAS-J was a phase II dose-escalation study designed to test the safety and tolerability of 2 doses (70 and 90 µg/kg) of desmoteplase in Japanese patients.7 Only data from patients treated with 90 µg/kg of desmoteplase or placebo are included in the pooled analyses. The DIAS-J study protocol was identical to those of DIAS-3 and DIAS-4 except that only magnetic resonance imaging at baseline was used and only patients with occlusion/severe stenosis in the proximal MCA (M1 and M2 of MCA) were included in DIAS-J.
The analysis of pooled data from DIAS-3, DIAS-4, and DIAS-J was not prespecified, but followed the statistical analysis plan of DIAS-3 and DIAS-4. We performed all pooled analyses on the intent-to-treat (ITT) analysis set. The worst case was used in case of missing data on outcome at day 90. Tests for heterogeneity between studies were performed in separate models with interaction between study and treatment (and interaction variable if relevant, see below).
Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke-4
The study was conducted between February 7, 2009 and October 7, 2014. A total of 270 patients were randomized from 81 hospitals in 17 countries from Europe, North America, Latin and South America, South Africa, and Asia (listed in the online-only Data Supplement). Patients were randomly assigned to desmoteplase (n=135) or placebo (n=135). Figure (A) shows the CONSORT (Consolidated Standards of Reporting Trials) diagram, and Table 1 presents the baseline characteristics. Thirteen patients were randomized, but not treated, five patients were treated, but had no valid functional assessment done, leaving 252 for the efficacy analysis. In each of the treatment arms, 67 patients were retrospectively found not to fulfill all inclusion/exclusion criteria leaving 57 patients in the desmoteplase group and 61 patients in the placebo group for the per protocol data set (Table I in the online-only Data Supplement).
Table 2 presents the outcomes on the primary and secondary efficacy end points.
Desmoteplase did not significantly increase the proportion of patients with mRS score of 0 to 2 at day 90 by (absolute difference: 6%, P=0.2290) but increased the recanalization rate at 12 to 24 hours by and absolute difference of 22.8% (P=0.0198).
Desmoteplase tended to increase the proportion of patients with mRS score of 0 to 2 at day 90 by an absolute difference of 3.6% (P=0.0786; Table 3). There was no statistically significant heterogeneity between the 3 studies for the primary end point (P=0.10 for study×treatment interaction). The treatment effect was similar in patients with ischemic injury volume of <25 mL at baseline and for patients with treatment initiation before and after 7 hours. Treatment with desmoteplase was associated with a higher recanalization rate at 12 to 24 hours (11.1% absolute increase, P=0.0168). The ordinal analysis of the primary end point did not show a treatment response.
Recanalization was associated with favorable outcomes at day 90 (mRS, 0–2) in both the desmoteplase-treated (P<0.0001) and placebo-treated patients (P=0.0004). Recanalization was associated with better outcomes for patients in the desmoteplase group, regardless of whether the patients were treated before or after 7 hours. There was no difference in treatment effect by region or by affected vessel.
Table 4 presents the safety analysis showing no significant differences between the treatment groups of all 3 trials and the pooled analysis. In DIAS-4, 15 of 126 (11.9%) of the desmoteplase patients died compared with 18 of 131 (13.7%) placebo patients (hazard ratio, 0.82; 95% confidence interval, 0.41: 1.63; P=0.57). Of these 33 patients, 2 of 126 (1.6%) patients died within the first 7 days in the desmoteplase group and 6 of 131 (4.6%) in the placebo group. The SICH rates in DIAS-4 were 3 of 131 (2.3%) in the placebo group and 6 of 126 (4.8%) in the desmoteplase group. In the pooled population, these rates were 10 of 385 (2.6%) and 12 of 382 (3.1%), respectively.
Because of early termination, DIAS-4 was underpowered with only 270 patients randomized and did not meet its primary efficacy end point; outcomes in the desmoteplase group were similar to the anticipated outcomes based on the study design projections. Favorable clinical outcomes in the placebo group were, however, more frequent than anticipated (36% versus 25%). In contrast to DIAS-3, patients with small ischemic injury volume on CT, but not on DWI, tended to benefit from desmoteplase. DIAS-4 confirmed that treatment with intravenous 90 µg/kg desmoteplase is safe, despite a median time to the treatment of 7.3 hours. Desmoteplase increased the recanalization rate in the subgroup of patients with confirmed arterial occlusions at baseline and vessel imaging at 24 to 48 hours after randomization.
DIAS-4 failed to show a significant effect on clinical outcome, we suspect the primary reasons for this were (1) DIAS-4 was terminated early and, therefore, was underpowered to detect the projected effect of desmoteplase on the primary outcome, (2) the dose of 90 µg/kg was too low to achieve sufficient brain tissue reperfusion in enough subjects to allow significantly better functional recovery, and (3) tissue reperfusion did not result in functional recovery in some patients because of irreversible injury (disappearance of penumbra).
The pooled sample of DIAS-3, DIAS-4, and DIAS-J patients represents the largest pool of ischemic stroke patients with proven major cerebral artery occlusions treated with intravenous thrombolytics between 3 and 9 hours after stroke onset. We did not include the 86 patients treated with 90 µg/kg of desmoteplase in the earlier DIAS, DEDAS, and DIAS-2 because they had been selected with inclusion/exclusion criteria that differed from the more recent larger studies.
With almost 800 patients, an ITT analysis of the pooled data showed a nonsignificant trend toward a small beneficial effect of desmoteplase on functional outcome. Desmoteplase increased significantly the recanalization rate by absolute difference of 11% in the subgroup described above for DIAS-4, suggesting that 90 µg/kg of desmoteplase had a biological effect on obstructing thrombi leading to reperfusion and potentially improved functional recovery. Interestingly, we observed excellent functional outcomes (mRS, 0–1) in 29% after placebo treatment similar to the 30.6% (357/1166) excellent outcome rate in placebo-treated patients who were randomized after 4.5 hours in the alteplase randomized trials.1 This confirms that ≈1 of 3 of ischemic stroke patients with small ischemic cores and presumably good collaterals presenting late after stroke onset have excellent long-term outcomes without thrombolysis even if vessel imaging shows a major intracranial artery occlusion. The challenge will remain to identify the 2 of 3 patients who likely will have persistent neurological deficits without treatment. Moreover, our data suggest that late recanalization even beyond 7 hours after stroke onset is closely associated with favorable functional outcome and not with an increased rate of SICH. These results are in line with the recent 5 successful trials of endovascular therapy, where thrombectomy was initiated beyond 3 hours after stroke onset.9–13
The statistically significant increase in recanalization rates from an unexpected 38.4% after placebo to 49.5% (desmoteplase) was apparently too small to achieve statistically significant clinical benefits in the late time window. One can speculate that thrombolytic therapy in this type of patient—treatment beyond 3 hours, major artery occlusion, but small–moderate ischemic lesion—might be beneficial if higher rates of arterial recanalization are achieved compared with the considerable placebo effect, for example, in combination with thrombectomy or by a more potent thrombolytic agent.
In summary, treatment with intravenous 90 µg/kg desmoteplase administered 3 to 9 hours after stroke onset in patients with proven cerebral artery occlusions did not significantly increase favorable clinical outcomes, although it modestly increased arterial recanalization with no increased rate of SICH. Identification of patients with major cerebral artery occlusions and a small ischemic core seems to be a relevant target for more effective means for arterial recanalization beyond 3 hours.
Sources of Funding
This study was supported by H. Lundbeck A/S.
R. von Kummer reports personal fees from H. Lundbeck A/S, Boehringer Ingelheim, Covidien, and Brainsgate, Penumbra, Inc; Drs Mori, Truelsen, J.-K.S. Jensen, Dr Grønning, K.-O. Lovblad, Drs Romero, Chabriat, Dávalos, and Shuaib report personal fees from H. Lundbeck A/S; J.B. Fiebach reports personal fees from H. Lundbeck A/S, Boehringer Ingelheim, Cerevast, BioClinica, Synarc, and Perceptive; Dr Pedraza reports personal fees from H. Lundbeck A/S and Synarc; Dr Chang reports compensation from H. Lundbeck A/S and grants from Ministry of Science and Technology, Taiwan; G.A. Ford reports personal fees from AstraZeneca, Cerevast, Medtronic and Pfizer, and grants from Boehringer Ingelheim; Dr Grotta reports grants and personal fees from H. Lundbeck A/S, personal fees from Genentech, Frazer, and Stryker; Dr Kaste reports personal fees from H. Lundbeck A/S and Siemens AG; Dr Schwamm reports personal fees from Mass Department of Public Health, H. Lundbeck A/S, Penumbra, and grants from NINDS-NIH and Genentech; Dr Albers reports grants and personal fees from H. Lundbeck A/S, iSchemaView, and Covidien.
Guest Editor for this article was Seemant Chaturvedi, MD.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.013715/-/DC1.
- Received April 9, 2016.
- Revision received July 30, 2016.
- Accepted August 5, 2016.
- © 2016 American Heart Association, Inc.
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