ANTITHROMBOTIC MANAGEMENT IN THE SETTING OF INTRACEREBRAL HEMORRHAGE

Girish Hiremath, MD, FAANS

Introduction

Spontaneous ICH (sICH) 15% of all acute strokes Deadliest stroke subtype

1 month mortality of 40% At 1 year, 75% die or are severely disabled

Initial hematoma volume remains strongest predictor of 30-day mortality and functional outcome Only modifiable predictor of outcome

Qureshi, Lancet 2009Van Asch, Lancet Neurol 2010Broderick, Stroke 1993

Hematoma Volume

Larger more likely to expand Early presentation after symptom onset Anticoagulation use Presence of APOE ε2 allele CTA spot sign

Newer marker for hematoma expansion Poor functional outcome, death Low sensitivity

Cucchiara, Stroke 2008Broderick, Stroke 2007Delgado, Stroke 2010Brouwers, Stroke 2012

Should patients be anticoagulated after a history of ICH?

Dilemma: pt with past ICH develops clear indication for A/C such as Afib Risk of thromboembolism is 4.5% with Afib Efficacy of warfarin for stroke prevention: 68%

Decision analysis models (no RCT’s)

Assumptions: Relative risk of bleeding on ASA in this cohort—SDH = 2.0 Relative risk of bleeding on A/C—ICH = 2.0; SDH = 4.0

For 1000 patients with lobar ICH, A/C would result in 31 fewer thromboembolic events, but 150 additional ICH’s

Conclusions: A/C not indicated after lobar ICH A/C resumption unclear after deep ICH (probably no unless very high risk of

ischemic stroke) ASA indicated only if RR for deep ICH is < 1.3 and for lobar ICH < 1.04

Eckman, Stroke 2003

If no anticoagulation, is antiplatelet better than no treatment at

all?

Case Example

72 year old white man presents with expressive aphasia, headache, declining mental status

Likely spontaneous—no specific hx of trauma

On ASA/PLAVIX for CAD L Acute SDH (2cm) with 1cm MLS; L

inferior frontal contusion/ICH Underwent platelet tx, emergent

craniotomy, evacuation of SDH

POD #1

POD 2—more lethargic, worse expressive aphasia (cont’d plt tx); CT shows recurrent L frontal ICH, SDH,

MLS

Redo Urgent Craniotomy…

POD 4: doing well clinically, but draining scalp incision

3 wks later—wound infection/infected bone flap—wound washout, craniectomy

ASA stopped (10 days prior), underwent Cranioplasty 5 months later with postop EDH

(developed 12h after surgery with presentation of weak RUE, expressive

aphasia)--underwent take back for evacuation

Eventually did well—sutures out… (5 surgeries later)

Story doesn’t end…

1 week later: Admitted to OSH with massive MI,

resulting in resumption of ASA/PLAVIX…

Antiplatelet use and ICH

22071 male physicians (aged 40-84) randomly assigned to 325mg ASA or placebo qOD

At 5 yrs: ASA use was associated with 2.14 X higher risk of

hemorrhagic stroke

Swedish Aspirin Low-dose Trial (SALT) 1360 pts with hx of TIA/minor stroke randomly

assigned to 75mg/d of ASA or placebo for 2.8 yrs ASA use associated with 2.78 X higher risk of

hemorrhagic stroke

Steering Committee of the Physicians’ Health Study Research Group; NEJM 1989

SALT Collaborative Group; Lancet 1991

Antiplatelet use and ICH…

Meta-analysis of 16 RCT’s on ASA use International study of 55462 participants RR reduction of MI with ASA RR reduction of ischemic stroke with ASA RR increase in hemorrhagic stroke with

ASA (84% increased RR) (all three were significant at P <.001)

He et al, JAMA 1998

What about Recurrent ICH?

Meta-analysis of 1880 ICH survivors between 1982 and 2000

Mean age 65 Mean f/u: 3.4 yrs from index ICH Stroke recurrence:

59% hemorrhagic 26% ischemic

Recurrent ICH occurs at 2X the rate of ischemic stroke in survivors of primary ICH

2.4% per year rate of recurrent ICH Higher risk with lobar hemorrhage

Bailey et al; Neurology 2001

Resumption of AP following ICH?Viswanathan et al

207 patients with index ICH Lobar Deep

AP prescribed in 22% of survivors Avg of 5.4 months after index ICH Most commonly for ischemic cardiovascular dz ICH recurred in 22% of survivors

No increase in risk of recurrent ICH with ASA resumption (p = 0.73) ICH location not factor (lobar vs. deep)

Limitations: Selection bias (pts felt to be high risk for repeated ICH likely did not have

AP resumption) Resumption of ASA did NOT significantly improve cardiovasc morbidity (p

=.75) Small sample size (only 46 pts had recurrent ICH)Viswanathan et al; Neurology

2006Donnan and Ly; Neurology 2006

Resumption of AP following ICHFlynn et al

Observational, Community-based study in Scotland 417 pts with ICH

120 prescribed Antiplatelet medications (28.8%) Median time from d/c to AP use was 14.8 months 40 ischemic strokes/MI 14 recurrent ICH Study found no association between AP use and recurrent

ICH

Limitations: Small sample size Selection bias ? Delay in resuming of AP to 14.8 months after index ICH

Flynn et al; Stroke 2010

In summary: When to resume ASA after ICH?

There is no good answer! No good literature to guide the

neurosurgeon (or neurologist) There is not likely to be a RCT In general, it is prudent to wait at least

one month Must be made on a case-by-case basis NOT by a “protocol-driven” approach

DVT Prophylaxis in the setting of ICH

VTE is frequent in pts with ischemic and hemorrhagic stroke

5% of early deaths following stroke attributed to PE

VTE in elective NS patients

Incidence of DVT in untreated NS pts: 18-50% Multiple studies have shown the safety of pharmacological

DVT prophylaxis in the setting of elective NS In 555 pts undergoing elective NS procedures, LDSQUFH:

Reduced DVT by 43% (measured by U/S) Risk reduction NOT assoc with incr hemorrhage Did not alter the rate of PE No correlation between DVT and PE

(In general, 30% of pts with acute PE have no LE DVT) PE directly related only to length of procedure (? Lack of statistical power)

Khaldi et al; J Neurosurg 2011;Agnelli et al; NEJM 1998;Geerts; Chest 2001Cage et al; J Neurooncology 2009Chibbaro Surg Neurol 2008

Mechanical Prophylaxis in sICH works!

133/151 evaluated at day 10 after ICH Endpoints: a/symptomatic DVT/PE 14 asymptomatic DVT’s identified

3 in ES only group 11 in ES + IPC group

IPC combined with graded ES reduced the risk of asymptomatic DVT at day 10 following ICH by 71% compared with ES alone.

Lacut et al; Neurology 2005 (VICTORIAh study)

Anticoagulants in prevention of VTE in sICH

Meta-analysis of RCT’s of prophylactic use (within 6 days) of SQ UFH LMWH Heparinoids

Endpoints: A/symptomatic DVT A/symptomatic PE Death A/symptomatic hematoma enlargement

Paciaroni et al; J Thrombosis and Haemostasis 2011

Anticoagulants in prevention of VTE in sICH

4 studies included 2 used UFH 2 used LMWH

Results: A/C resulted in sig reduction in:

PE A/C resulted in NON-sig

Reduction in mortality Reduction in DVT Hematoma enlargement

Paciaroni et al; J Thrombosis and Haemostasis 2011

Other Studies…

97 patients with sICH were all given LMWH in the form of Enoxaparin or Dalteparin

2 patients developed moderate enlargement of hematoma

No fatal PE’s

Limitations:Non-randomized; no control group; limited sample size

Kiphuth et al; Cerebrovasc Dis 2009

Anticoagulants in prevention of VTE in traumatic ICH

2 cohorts of 107, 129 pts each with tICH (1 served as a historic control)

Both groups tx with SCD’s Following stable Head CT, 1 group underwent tx with

either LMWH (Lovenox 30mg BID or SQUFH 5000 TID) Group A (no tx): DVT rate was 5.6% Group B (tx): DVT rate was 0% No progression of ICH NO sig difference in rate of PE (P = 0.179) with trend

towards lower rate of PE in pts undergoing pharmacological prophylaxis

Farooqui et al; J Neurosurg 2013

Summary: Pharmacological DVT prophylaxis in the setting of ICH In general, rates of DVT and PE are reduced with the

use of pharmacological prophylaxis in the setting of sICH and tICH

There is probably no significant hematoma enlargement with the use of such prophylaxis

However, many studies show no significant correlation between DVT and PE; some show no significant reduction in rate of PE with pharm prophylaxis

The idea that mortality is reduced with the use of pharmacological DVT prophylaxis is yet to be proven

Thank You