Endovascular thrombectomy plus standard medical care improved outcomes for patients with acute stroke compared to standard care alone when performed 6 to 24 hours after the patient was last known to be well. The DAWN trial showed that for patients with a clinical deficit disproportionate to the size of their brain infarction based on imaging, thrombectomy led to better disability and functional independence outcomes at 90 days. Benefit was seen across subgroups based on age, stroke severity, occlusion site, and time from onset. This expands the treatment window for thrombectomy beyond the typical 6 hours.

1. JOURNAL CLUB
Dr Prashant Shringi
Senior Resident
Neurology

3. DAWN TRIAL
• DWI or CTP Assessment with Clinical Mismatch in the
Triage of Wake-Up and Late Presenting Strokes
Undergoing Neurointervention with Trevo
• Published in NEJM on november 2017.

4. INRODUCTION
• Previous randomized trials that involved patients with
acute stroke showed that endovascular thrombectomy
had a clinical benefit when it was performed within 6
hours after the onset of stroke symptoms .

5. • Benefit diminished as the interval between the time that
the patient was last known to be well and thrombectomy
increased

6. • Limited information on the effect of thrombectomy that is
performed more than 6 hours after the time that the
patient was last known to be well, particularly among
patients with ischemic brain tissue that has not yet
undergone infarction and may be salvaged with
reperfusion.

7. • Patients with brain tissue that may be salvaged with
reperfusion can be identified by the presence of a clinical
deficit that is disproportionately severe relative to the
volume of infarcted tissue on imaging studies

8. • Hallmark pathophysiological feature predicting a
favourable clinical response to reperfusion therapy is the
presence of mismatch between the volume of infarct and
the total volume of critically hypoperfused brain.
• Believed that the larger the mismatch the greater the
benefit of reperfusion therapy

9. • Results of previous nonrandomized studies have
suggested that patients who have a mismatch between
the volume of brain tissue that may be salvaged and the
volume of infarcted tissue could benefit from reperfusion
of occluded proximal anterior cerebral vessels, even when
the reperfusion is performed more than 6 hours after the
patient was last known to be well.

10. PREVIOUS STUDIES
• MR CLEAN TRIAL, 2015
• O.A. Berkhemer et al

11. • CONCLUSION:
• In patients with acute ischemic stroke caused by a
proximal intracranial occlusion of the anterior circulation,
intraarterial treatment administered within 6 hours after
stroke onset was effective and safe

12. REVASCAT TRIAL
• T.G. Jovin et al, 2015
• Patients with anterior circulation stroke who could be
treated within 8 hours after symptom onset, stent retriever
thrombectomy reduced the severity of post stroke
disability and increased the rate of functional
independence.

14. • Conclusion:
• Endovascular therapy can be instituted with acceptable
safety beyond 8 hours from time last seen well when
selection is based on advanced neuroimaging. Successful
revascularization is significantly associated with higher
rates of good outcomes.

15. DAWN TRIAL
• AIMS & OBJECTIVE:
• In the DAWN (DWI or CTP Assessment with Clinical
Mismatch in the Triage of Wake-Up and Late Presenting
Strokes Undergoing Neurointervention with Trevo) trial

16. Compared endovascular thrombectomy plus standard
medical care with standard medical care alone for the
treatment of patients with acute stroke who had last been
known to be well 6 to 24 hours earlier and who had
mismatch between clinical deficit and infarct.

17. METHODS
• DAWN trial was a multicenter, prospective, randomized,
open-label trial with a Bayesian adaptive enrichment
design and with blinded assessment of end points

18. Inclusion Criteria
• Evidence of occlusion of the intracranial internal carotid
artery, the first segment of the middle cerebral artery, or
both on computed tomographic (CT) angiography or
magnetic resonance angiography.

19. • Trial protocol was approved by the institutional review
board at each participating site.
• Enrolled patients or their surrogates provided written
informed consent.

20. • Patients had to have a mismatch between the severity of
the clinical deficit and the infarct volume, which was
defined according to the following criteria:
• Group A were 80 years of age or older, had a score of 10
or higher on NIHSS and had an infarct volume of less
than 21 ml.

21. • Group B were younger than 80 years of age, had a score
of 10 or higher on the NIHSS, and had an infarct volume
of less than 31 ml.
• Group C were younger than 80 years of age, had a score
of 20 or higher on the NIHSS had an infarct volume of 31
to less than 51 ml

22. • Infarct volume was assessed with the use of DW-MRI,
and was measured with the use of automated software
(RAPID, iSchemiaView).

23. • No evidence of intracranial hemorrhage on CT or MRI .
• No evidence of an infarct involving more than one third of
the territory of the middle cerebral artery on CT or MRI at
baseline.

24. • Age of 18 years or older
• An interval between the time that the patient was last
known to be well and randomization of 6 to 24 hours
• Prestroke score of 0 or 1 on the modified Rankin scale

27. Treatment
• Patients were randomly assigned, in a 1:1 ratio
Thrombectomy plus standard medical care (the
thrombectomy group)
Standard medical care alone (the control group).

28. • Randomization was performed with the use of a central,
Web-based procedure, with block minimization processes
to balance the two treatment groups .

29. • Stratified according to-
• Mismatch criteria (Group A, Group B, or Group C),
• Interval between the time that the patient was last known
to be well and (6 to 12 hours or >12 to 24 hours)
• Occlusion site (intracranial internal carotid artery, first
segment of the middle cerebral artery).

30. • Trial was conducted at 26 centers in the United States,
Canada, Europe, and Australia,
• At least 40 mechanical thrombectomy procedures had
been performed at each center annually.

31. • Enrolled patients were admitted to stroke units or
intensive care units.
• Patients who had not received intravenous alteplase
could receive therapy with antiplatelet agents, which could
be started within 24 hours after randomization.

32. • Standard medical care was provided in accordance with
local guidelines.
• Thrombectomy was performed with the use of the Trevo
device (Stryker Neurovascular),a retrievable self-
expanding stent that is used to remove occlusive thrombi
and restore blood flow.

34. End Points
End points, scores on the modified Rankin scale were
obtained through in person, formal, structured interviews
with patients and caregivers that were performed by local
certified assessors.

35. • Patients for whom in-person assessment was not
possible, telephone interviews with patients, caregivers,
or both were performed.

36. Primary outcome
• Primary endpoint for this trial is the 90-day mRS score.
• DAWN analyzes this standard endpoint by converting the
mRS scores into weights that directly reflect patient and
society valuation of outcome health states

37. • Primary endpoint analysis is a comparison of the
difference between the average weighted mRS score at
90 days post randomization between the active and
control groups

40. Secondary outcomes
• Efficacy
• Both arms:
• 1).Comparison of the proportion of subjects with a good
functional outcome at 90 days,
• defined as mRS 0–2, between the active and control
groups analyzed as a traditional Fisher test adjusted for
stratification variables.

41. • 2).Comparison of the proportion of subjects with‘‘early
response’’ at day 5–7/discharge (whichever is earlier)
• -defined as a NIHSS drop of 10 from baseline or NIHSS
score 0 or 1, between the active and control groups

42. • 3).Difference in all cause mortality rates at 90 days
between the two group.
• 4).Comparison of the median 24 h infarct size at 24 (6/24)
h from randomization, by MRI T2/Flair or CT (if MR is
contraindicated), between the treatment and control
groups

43. • Treatment arm only:
• Analysis of vessel reperfusion rates (percentages) post
device and post procedure, by angiography core lab
measurement of mTICI2b.

44. Primary safety outcome
• Both Arms:
• Incidence of stroke-related mortality at 90 days.

45. Secondary safety outcomes
• Both arms:
• 1. Incidence of SICH, by ECASS III definition within 24
(6/24) h post randomization .

46. • 2. Incidence of neurological deterioration from baseline
NIHSS score through day 5–7/discharge (whichever is
earlier) post randomization .
• -Neurological deterioration is defined as 4 point increase
in the NIHSS score from the baseline score

47. Secondary safety outcomes
• Treatment arm only:
• Incidence of procedure related and device related serious
adverse events-
 vascular perforation
 intramural arterial dissection
 embolization to new territory
 access site complication requiring surgical repair or
blood transfusion
 intra-procedural mortality
 device failure (in vivo breakage)

49. Statistical Analysis
• Adaptive trial design allowed for a sample size ranging
from 150 to 500 patients
• Bayesian posterior probability of heterogeneity
• Fischer Test
• Forest plot

50. • During interim analyses, the decision to stop or continue
enrollment was based on a prespecified calculation of the
probability that thrombectomy plus standard care would
be superior to standard care alone with respect to the first
primary end point

51. Results
• Patient Characteristics:
• From September 2014 through February 2017, a total of
206 patients were enrolled in the trial
• 107 were randomly assigned to the thrombectomy group
and 99 to the control group.

52. • Thrombectomy was performed in 105 of the 107 patients
in the thrombectomy group.
• Ipsilateral carotid angioplasty was performed in 3 of the
107 patients

53. Discussion
• DAWN trial showed that, patients with stroke due to
occlusion of the intracranial internal carotid artery or
proximal middle cerebral artery who had last been known
to be well 6 to 24 hours earlier and who had a mismatch
between the severity of the clinical deficit and the infarct
volume-

54. • Outcomes for disability and functional independence at 90
days were better with thrombectomy plus standard
medical care than with standard medical care alone.

55. • Benefit of thrombectomy was consistent across
prespecified subgroups that were defined according to
age, stroke severity, occlusion site, time to treatment, and
type of stroke onset

58. • Endovascular thrombectomy in patients with stroke is
usually performed within 6 hours after the onset of stroke.

59. • Rate of functional independence in the thrombectomy
group in this trial,( in which patients received treatment 6
to 24 hours after stroke onset)
• Similar to the rate reported in a pooled analysis of five
trials of thrombectomy, In which patients predominantly
received treatment within 6 hours after stroke onset
• 49% and 46%, respectively

60. • Rate of functional independence in the control group in
this trial was lower than the rate in the control group in the
pooled analysis (13% vs. 26%).
• Worse outcomes in control group were related to the
lower rate of treatment with intravenous alteplase (14% in
DAWN trial vs. 88% in the pooled analysis)

61. • Patients were enrolled in DAWN trial after the accepted
window of time in which intravenous thrombolytic therapy
is typically administered

62. LIMITATIONS
• Randomization was stratified according to prognostic
variables that the investigators determined to be most
pertinent in the patient population
• These variables were balanced between the two
treatment groups

65. Conclusion
• Outcomes for disability were better with thrombectomy
plus standard medical care than with standard medical
care alone
• Among patients with acute stroke who received treatment
6 to 24 hours after they had last been known to be well

66. • Trial restricted enrollment to patients with infarcts of a
small or medium volume.

67. THANK YOU
•