Preventing Aneurysmal Rebleeding: Impact of a Policy of Short Term Antifibrinolytic Therapy for the Prevention of Acute Rebleeding after Aneurysm Rupture

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Preventing Aneurysmal RebleedingImpact of a
Policy of Short Term Antifibrinolytic Therapy
for the Prevention of Acute Rebleeding after
Aneurysm Rupture
E. Sander Connolly, Jr., MD Department of
Neurosurgery, New York Neurological Institute
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Incidence of Aneurysmal RebleedingCooperative
Study - 1970-80s
20 _at_ 2 weeks
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7 75 lt 3d
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Impact of Aneurysmal RebleedingIn the Modern Era

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Efforts to Reduce Aneurysmal RebleedingIn the
Delayed Surgery Era
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Antifibrinolytic Trials
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Antifibrinolytic Therapy

• e-aminocaproic acid (EACA) and transexamic acid
  (TXA) are antifibrinolytic agents
• Long-term antifibrinolytic therapy was standard
  therapy in the delayed surgery era and didnt work

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Hypothesis
Stroke (in press)

• Hyper-acute antifibrinolytic therapy may decrease
  rebleeding without causing a corresponding
  increasing in stroke.
• Brief treatment may not increase serious
  thrombotic or embolic complications

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Methods

• We instituted a policy of acute intravenous
  EACA administration (4 gram bolus followed by 1
  gram infusion over 6 hours)
• - Treatment started at the time of diagnosis,
  with cessation of the infusion 4 hours prior to
  angiography, for a maximum duration of 72 hours
  after onset of treatment.
• - Patients with ECG changes, cardiac
  troponin elevation, or symptoms of
• acute thromboembolic disease were
  excluded.
• Cohort study of the prospective outcomes of 294
  aSAH patients enrolled between 2003 and 2006
• Outcomes were compared in EACA and non-EACA
  treated patients
• Rebleeding, clinical or angiographic vasospasm,
  cerebral infarction, cerebrovascular thrombosis,
  deep venous thrombosis (DVT), pulmonary embolism
  (PE), renal failure, and myocardial ischemia

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Definitions

• Rebleed - rebleeding on CT
• - upon direct visualization (i.e.
  autopsy or sudden onset of profuse blood coming
  from EVD).
• Cerebral infarction any new infarction noted on
  CT or MRI scan
• - infarction due to vasospasm was determined by
  any new infarction in the appropriate vascular
• distribution of the without other appropriate
  etiology.
• Symptomatic vasospam
• - change in mental status of greater than 2
  points by Glasgow Coma Scale
• - new neurological deficit that could not be
  explained by another etiology.
• Angiographic vasospasm
• - patients with symptomatic vasospasm or
  elevated TCDs
• - failure to respond to induced hypertension
  and hypervolemia lead to angiography evaluate for
  vasospasm
• Cerebrovascular occlusion
• - angiographic evidence of arterial occlusion
  on diagnostic angiogram and post-operative
  angiograms

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Cohort Characteristics
294 Patients Prospectively Enrolled
245 Patients
49 Patients with non-aneurysmal SAH
172 Patients did not receive EACA
73 Patients received EACA
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Distribution of patient characteristics in EACA
and non-EACA treated patients
Aneurysmal SAH cohort characteristics no
difference between patient cohorts
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Results
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Results Rebleeding
25
20
p0.019
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Percent Rebleeding
11.4
10
2.7
5
0
Non-EACA
EACA
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Results Rebleeding
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Results Ischemia
70
Control
AF
62.2
60
57.9
50
40
Percent
27.4
30
26.7
26.0
23.8
20
10.2
10
6.2
1.6
0
0
Non-EACA
EACA
EACA
EACA
EACA
Non-EACA
Non-EACA
Non-EACA
EACA
Non-EACA
Angiographic Vasospasm
Infarction due to Vasospasm
Cerebrovascular Occlusion
Cerebral Infarction
Symptomatic Vasospasm
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Results Thrombosis
25
20
p0.003
p0.487
15
Percent
9.6
10
2.9
5
1.4
1.1
0
Non-EACA
EACA
Non-EACA
EACA
Deep Venous Thrombosis
Pulmonary Embolism
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Results Favorable Three Month Outcome
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Results Overall Outcome Favorable HH _at_ 3-months
6 absolute increase and 12 relative increase
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Meta-analysis of Long-Term Outcomes following
Acute Treatment
Study Treatment No
Treatment OR (Fixed) Weight OR
(Fixed) n/N n/N 95 CI
95 CI
67.10 1.24 (0.84 - 1.84) 32.90 1.34 (0.77 -
2.32) 100.00 1.27 (0.93-1.75)
Hillman et al. 190/254 177/251 Starke
et al. 42/73 88/175
Total (95 CI) 327
426 Test for overall significance p0.14
0.1 0.2 0.5 1 2 5 10
Favors no treatment
Favors treatment
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The Future

• Following this introductory data, we have applied
  for NIH funding to run the first randomized,
  double-blinded, placebo controlled trial to look
  at the effects of acute antifibrinolytic therapy
  transferred aSAH patients.
• Columbia University accepted as a new hub of the
  Neurological Emergency Treatment Trials (NETT)
  network
• If approved, the trial will take place through
  the 17 hub and approximately 80 spoke
  hospitals of the NETT network.

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The Neurological Emergency Treatment Trial Network
00


















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The Neurological Emergency Treatment Trial Network
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Timeline of Study
Consent First Dose Maximum 18 hours Minimum 2
hours
Initial aSAH
Admit CT Scan
Surgery
aSAH to Admit Maximum 12hours Minimum 1 hour
Admit to CT Scan and First Dose Maximum 6 hours
Minimum 1 Hour
Maximum Treatment Time 72 Hours
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Power Analysis and Sample Size

• Based on chi square analysis with the
  significance level set at 0.05 and a given power
  calculation of 80, approximately 900 subjects
  will be randomized to receive EACA (n450) or
  placebo (n450). This calculation was based on
  conservative estimates in past studies which
  demonstrated a favourable outcome in 71 of
  patients receiving antifibrinolytics acutely
  versus 62 of controls
• Based on a 10 rate of rebleeding, if 450
  patients are enrolled in each arm of this study,
  we will be able to detect a 5 difference in
  rebleeding rate.
• Based on a 27 infarction rate in the last 1000
  aSAH patients treated at CUMC, if 450 patients
  are enrolled in each arm of this study, we will
  be able to detect an 8 difference in infarction
  rate.

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Conclusions

• Acute treatment of aSAH patients with EACA is

• 1. Associated with a significant reduction in
  rebleeding (11.4 versus 2.7)
• 2. Associated with a significant increase in
  DVTs
• (1.2 versus 9.6)
• 3. Is not associated with a significant increase
  in serious side effects
• 4. A large Clinical Trial is necessary to
  evaluate long term outcomes of patients treated
  acutely with EACA

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Acknowledgements

• Robert M. Starke
• NIH Clinical Research Training Program
• Alpha Omega Alpha Research Fellowship
• Stephan A. Mayer
• Grace H. Kim
• Ricardo J. Komotar
• Markus Chwajol
• Marc Otten
• Zachary Hickman
• Andrew Ducruet

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Thanks
I keep thinking we should include something in
the Constitution in cases the people elect a
surgeon