The document summarizes current guidelines on the use of tPA and endovascular treatment for acute ischemic stroke based on major clinical trials. It finds that early trials using intra-arterial tPA and first-generation devices showed limited benefit, but more recent trials using stent retrievers demonstrated improved recanalization rates and outcomes when endovascular treatment was initiated within 6 hours of stroke onset. The highest rates of functional independence were seen in patients who achieved near complete or complete recanalization.

1. GUIDELINES IN NEUROLOGY
Summary of current guidelines
SEPTEMBER 1, 2015
AHMED KORIESH
● ● ●
Part of
Oklahoma Residents manual of
evidence based Neurology
● ● ●

3. TPA trials
Trial Number Inclusion criteria Treatment arms Results
ECASS 1 (1995)
European Cooperative
Acute Stroke Study
620 Moderate to severe neurologic
deficit and without major early
infarct signs on initial CT.
The
Placebo versus
1.1mg/kg tPA in first
6 hours.
- Significant difference in the mRS in favor of tPA-treated
patients (P = .035)
- Shorter in-hospital stay for rt-PA treatment arm
- No statistically significant difference in mortality rate at
30 days or in the overall incidence of ICH
- Increased occurrence of large parenchymal hemorrhages
in the tPA group, therefore use was discouraged
NINDS (1995) 624 Onset in 3 hours, absence of
hemorrhage on CT and
measurable deficit on NIHSS
Placebo versus
1.1mg/kg tPA in first
3 hours.
- Clear benefit of iv tPA over placebo within 3 hours of
symptom onset; FDA approval
- 30% more likely to have no or minimal disability at 3 mo
in tPA treated group
- No significant difference in mortality
- Symptomatic ICH more common in tPA group (6% vs 0.6)
- No difference in the rate of recurrent stroke in 3 months
ECASS 2 (1999) 800 Onset in 3 hours, absence of
hemorrhage on CT and
measurable deficit on NIHSS
Placebo versus
0.9mg/kg tPA in first
6 hours
- No significant difference in mRS in both groups, however
post hoc analysis showed favorable trend with tPA
- ICH occurred in 8.8% of tPA vs 3.4% in placebo
- Conclusion: No statistical benefit of tPA but a trend
towards favorable outcome was noted
ECASS 3 (2008) 821 Onset in 3-4.5 hours
Exclusions:
>80 years old
NIHSS score >25
those on oral anticoagulants (even
if their INR was <1.7)
Combination of a previous stroke
and diabetes mellitus.
Pooled analysis from
previous 4 trials.
Placebo versus
0.9mg/kg tPA in first
3-4.5 hours
- tPA was associated with more frequent excellent 90-day
outcome on the mRS. rtPA (52.4%) than placebo (45.2%)
OR- 1.34; 95% CI, 1.02–1.76; P=0.04).
-

4. Endovascular treatment (Old trials):
Trial Number Inclusion criteria Treatment arms Results
IMS-I
(Interventional
management of
stroke)
IV (0.6mg/kg) + IA tPA
Compared with
NINDS results (IV tPA)
Better outcome at 3months at 56% compared to 30% in
NINDS
IMS-II IV + IA tPA + low
energy ultrasound
better outcome and lower mortality than NINDS
IMS-III (2013) 565 - 18-82 years age
- iv tPA within 3 hours of onset
- randomization within 40 mins,
- NIHSS>10 or >8 with CTA
evidence of LVO (ICA, M1 or
basilar)
- Procedure had to begin within 5h
and be completed within 7h after
the onset of stroke
Randomized blinded
trial to compare IV
tPA (standard dose)
vs IV tPA +
endovascular
treatment
No difference between both arms but established safety of
interventional therapy.
Limitations:
- Longer time to endovascular therapy than IMS 1 and 2
- Limited use of newer stent retrievers
- Not all subjects had documented LVO
- Smaller dose of iv tPA in the intervention arm
Synthesis (2013) 362 IV tPA candidate within 4.5h and
endovascular ttt possible in 6h.
Time window: 6h
Imaging: CT only
IV tPA versus intra-
arterial tPA (IAT) ±
embolectomy devices
Interventional therapy is NOT SUPERIOR to standard of care
MR RESCUE
(2013)
118 - large vessel, anterior circulation
patients
-A favorable penumbral pattern
was defined as a predicted infarct
core of 90 ml or less and a
proportion of predicted infarct
tissue within the at-risk region of
70% or less
randomized within 8
h to embolectomy
(using Merci or
Penumbra system) vs
standard care; using
the pretreatment
penumbral pattern
Interventional therapy is NOT SUPERIOR to standard of care in
patients with either favorable or non-favorable penumbral
pattern.
Limitations:
- Revascularization in the embolectomy group was
achieved in ONLY 67% of the patients.
- Use of first generation devices with lower
recanalization rates
- Difference of estimation of core based on CT or MRI
- Long time window

5. Endovascular treatment (Recent trials):
Trial Number Inclusion criteria Treatment arms Results
MR CLEAN
(2014)
500 Large vessel, anterior circulation
patients with evidence of LVO
within 6h from onset.
Adv:
- Median time from stroke onset
to IV tPA: 85 minutes
- Median time from stroke onset
to puncture: 260 minutes
- Retrievable stents used in most
patients
Standard treatment
vs standard
treatment PLUS
endovascular
treatment for
patients with ant
circulation strokes 2ry
to LVO who could be
treated within 6h.
Endovascular treatment in patients with anterior circulation
acute ischemic stroke caused by LVO and initiated within 6 hrs
from symptoms onset is effective AND safe.
- Primary outcome: mRS 2 or less at 90 days. 32.6% for
intervention group vs. 19.1% for standard care group
(absolute difference of 13.5%; odds ratio1.67; CI 1.21.-2.3)
- No difference in mortality or symptomatic ICH
ESCAPE (2015)
Endovascular
treatment for Small
Core and Anterior
circulation Proximal
occlusion with
Emphasis on
minimizing CT to
recanalization times.
360 patients with acute ischemic
stroke with a proximal intracranial
arterial occlusion, small infarct
core, and moderate to good
collateral circulation
-No upper age limit
-Time window: 12 hours
- Imaging: CT- CTA
-Assessed infarct core volume and
collaterals
-Patients with large infarct core or
poor collaterals were excluded
-Target CT to groin puncture 60
minutes
-Target CT to first reperfusion 90
minutes
-Recommended stent retrieval
PLUS forced aspiration; balloon
guide catheter
Standard care vs.
standard care PLUS
mechanical
thrombectomy
Endovascular treatment in patients with anterior circulation
acute ischemic stroke caused by LVO and initiated within 6 hrs
from symptoms onset is effective AND safe.
- Trial stopped early, unplanned interim analysis following
publication of MR CLEAN
- Primary outcome for intervention plus standard care vs.
standard care alone 53% vs. 29.3% (p <0.001, OR2.6; CI 1.7-3.8)
- Mortality 10.4 vs. 19% (p: 0.04)
- sICH 3.6% vs. 2.7% (p: 0.75)
- Barthel Index of 95-100 at day 90: 57.7% in intervention
group vs. 33.6% in control
Differences from MR CLEAN
- Time window up to 12 hours; but again powered enough
only for up to 6 hrs
- Use of imaging to exclude participants
- More robust results in terms of good outcome (53% vs.
32.6%) and also reduced mortality
- Better recanalization rate (72% vs. 60%)
EXTEND-IA
(2015)
100 patients with acute ischemic
stroke with a proximal intracranial
arterial occlusion, small infarct
core, and moderate to good
Standard care vs.
standard care PLUS
mechanical
thrombectomy with
Endovascular treatment in patients with anterior circulation
acute ischemic stroke caused by LVO and initiated within 6 hrs
from symptoms onset is effective AND safe.

6. 1
collateral circulation
Time window: 6h
Imaging: CT – CTA – CTP
Ischemic core of less than 70 ml
and salvageable brain tissue on
CTP
Primary outcomes:
- Reperfusion at 24 hours
- Early neurological
improvement at day 3 (equal
to or greater than 8 point
reduction on NIHSS or score
of 0 or 1)
Secondary outcome: mRS at 90 d
Solitaire retriever
- Trial stopped early after MR CLEAN
- Interim analysis performed with total 70 patients only (35
each group)
- Median stroke onset to groin puncture: 210 minutes
- Median hospital arrival to groin puncture: 113 minutes
- Median hospital arrival to reperfusion: 156 minutes
- Reperfusion at 24 hrs: 89% vs. 34%
- Early neurological improvement: 80% vs. 37%
- No difference in rate of mortality or sICH
- mRS 2 or less at 90 days: 70% vs. 40%
SWIFT-PRIME
(2015)
196 patients with acute ischemic
stroke with a proximal intracranial
arterial occlusion, small infarct
core, and moderate to good
collateral circulation
Time window: 6h
Imaging: CT – CTA – CTP
Ischemic core of less than 70 ml
and salvageable brain tissue on
CTP
Primary outcome: mRS at 90 d
Standard care vs.
standard care PLUS
mechanical
thrombectomy with
stent retriever
In patients receiving IV tPA for acute ischemic stroke due to
occlusions in the proximal anterior intracranial circulation,
thrombectomy with a stent retriever within six hours from
symptoms onset improved functional outcome at 90 days
- mRS 2 or less at day 90: 60% vs. 35%
o absolute difference of 25%
- No significant difference in terms of mortality or sICH
rates
REVASCAT 206 Acute ischemic stroke and NIHSS
score of ≥6
Intracranial ICA or M1 occlusion by
CTA, MRA, or DSA.
No significant improvement at 30
minutes postinitiation of tPA
Groin puncture possible within 8h
ASPECT < 7 in CT or < 6 in DWI
were EXCLUDED
Maximum age 85
Best medical therapy
versus IV tPA plus
endovascular
treatment with
Solitaire FR device
- mRS 2 or less at day90: 43.7% vs. 28.2% (adjusted OR,
2.1; 95% CI, 1.1–4.0).
- No difference in mortality or sICH
- Recanalization TICI 2b/3: 66%

7. 2
 The old trials (MS, Synthesis & MR RESCUE) used almost exclusively intra-arterial r-tPA and first-generation endovascular devices alone
or in combination, achieved recanalization rates of 25% to 41%.
 The new trials (MR CLEAN, EXCAPE, EXTEND, SWIFT & REVCAST) using almost exclusively stent retrievers demonstrated improved
results for both recanalization rates and outcome.
 Clinical outcome improved with increasing effectiveness of recanalization. Those with partial recanalization (TICI 2a) did not do as well as
those with near complete/complete recanalization.
 TICI 2b/3 reflected as differences in discharge disposition (41.0% of TICI 2b/3 group discharged home vs 17.4% of TICI 2a) and functional
outcome (34% with a TICI grade of 2a had an mRS score of 0 to 2 at 90 days vs in 49% a TICI grade of 2b/3).

8. 3
Important Clinical Trials in Stroke:
Trial Year Bottom Line
Stroke Secondary prophylaxis:
RAF 2015 Early stroke recurrence and cerebral bleeding in patients with
AF and acute ischemic stroke treated with anticoagulants for
secondary prevention (warfarin, LMWH, none).
Initiating anticoagulants within 4-14days of onset resulted in
lower risk of (stroke, TIA, bleeding) compared to starting it
before or after this time frame.
Warfarin was associated with lowest risk (7% vs 16.8% with
LMWH, 12.3% LMWH followed by warfarin)
Risk was proportional to CHADS2:
2 had no events – 3 (1.7%) – 4 (9.8%) – 5 (10.2%) – 6 (12%) – 7 (17%)
BRIDGE 2015 Perioperative bridging anticoagulation in patients with AF.
(Warfarin held 5 days before surgery, LMWH started 3 days
and stopped 1 day before surgery, Warfarin and LMWH (till
INR reached 2) were restarted 12h after surgery)
Bridging with LMWH was associated with significant increase in
major bleeding with no significant decrease in
thromboembolism.
Don’t bridge with LMWH before surgery in patients with AF
ARCH 2014 ASA + clopidogrel vs Warfarin in aortic arch plaque > 4mm Study not completed due to lack of funds
CHANCE 2013 ASA and Clopidogrel in acute ischemic stroke and TIA DAPS for the first 21 days after stroke was superior to ASA alone
for reducing risk of stroke in first 90 days with no increase in
significant bleeding
2013 Antiplatelet treatment for prevention of CVA in patients with
vascular disease.
DAPS (dual antiplatelet ASA + Clopidogrel) was superior (RR
reduction 20%) compared with ASA alone in stroke prevention
with no increase in ICH.
CADISS-NR 2012 Antiplatelet Vs Anticoagulation for dissection No significant difference between antiplatlets and
anticoagulation for stroke prevention in patients with dissection.
Underpowered – nonrandamized study
WARCEF 2012 Warfarin and Aspirin in patients with heart failure and sinus
rhythm
Comparing ASA Vs Warfarin for stroke prophylaxis in patients
with low EF and sinus rhythm.
ARISTOTLE 2011 Apixaban Vs Warfarin in patients with Afib Apixaban 5mg bid is superior to warfarin for stroke prevention
and causes less ICH and major bleeding.
AVERROS 2011 Apixaban Vs Aspirin in patients with afib who are unsuitable
for warfarin
Apixaban 5mg bid is superior to ASA for stroke prevention
ROCKET-AF 2011 Rivaroxaban VS Warfarin in Nonvalcular Afib Rivaroxaban is non-inferior to warfarin for stroke prevention
Rivaroxaban is associated with less ICH but more GI bleeding risk.
CLAIR 2011 Clopidogrel + ASA Vs ASA alone for reducing embolization in
patients with acute symptomatic cerebral or carotid stenosis
ASA 160:750 + Plavix load 300 then maintenance is superior to
ASA alone reduction of micro-emboli (RR 54.4%) in patients with

9. 4
intra or extracranial athero (>50% in US or MR)
DAP also was associated with 6% reduction in recurrent stroke
SPS-3 2011 Secondary Prevention of Small subcortical strokes DAP was not superior than ASA 325 alone for stroke prevention
SBP < 130 associated with less incidence of stroke.
EARLY 2010 ASA + extended release dipyridamole for secondary stroke
prevention within 24h of onset
Dipyridamole 200mg bid + ASA 25 bid is not superior to ASA
monotherapy in preventing disability at 90 days.
Stroke Acute management:
PASS 2015 Preventive Antibiotic in Stroke study Ceftriaxone for 4 days after acute ischemic stroke reduced rate of
infection BUT didn’t affect 3 months outcome.
CATIS 2014 BP control Vs permissive HTN in acute ischemic stroke.
Lowering BP 10:25% within 24h to reach goal of < 140/90
within 7 days
No significant difference in primary outcome (death and MRS)
but better BP control in the active group after 3 months.
ReCCLAIM I 2014 Intravascular cooling in acute ischemic stroke patients with
projected poor outcomes was protective against reperfusion
hemorrhage after endovascular therapy
Hypothermia was protective against ICH after intravascular
thrombectomy (OR 0.09 compared to 0.56)
DESTINY II 2014 Hemicraniectomy in patients >60 years with malignant MCA
infarction
Hemicraniectomy within 48h is associated with more survival
(57% vs 28%), less severe disability (38% vs 18%), less herniation
but more risk of infection.
CLEAR ER 2013 Combined Eptifibatide and IV tPA in acute ischemic stroke No significant difference in outcome between the two groups (IV
tPA + Eptifibatide VS IV tPA + Placebo)
ALIAS 2013 High dose Albumin for ttt of acute ischemic stroke Albumin 2mg/kg within 5 hours of onset didn’t improve
outcomes
DEFUSE 2 2012 MRI profile and response to endovascular reperfusion after
stroke
Comparing acute ischemic stroke patients with and without
MR DWI & PWI mismatch for outcomes after endovascular
treatment
OR for favorable outcome in DWI-PWI mismatch group was 8.8
Vs 0.2 in DWI-PWI match group
FLAME 2012 Fluoxetine for motor recovery after acute ischemic stroke Fluoxetine 20mg started 5-10 days after moderate to severe
stroke is effective in improving motor performance using FMM
(Fugl-Meyer motor scale). Treatment group achieved mean 12.4
point improvement in UE Vs 2.1 in control
EAGLE 2010 CRAO: IA tPA Vs conservative treatment IA tPA didn’t show significant difference in visual acuity after 1
month in patients with CRAO
Modifying Risk Factors:
Intracranial stenosis:
VISSIT 2015 Balloon expandable stent for symptomatic intracranial Balloon stenting + medical therapy was harmful compared with

10. 5
stenosis medical therapy alone.
COSS 2011 Extracrania-Intracranial bypass surgery for stroke prevention
in patient with hemodynamic cerebral ischemia
EC-IC didn’t reduce risk of stroke in symptomatic patients with
atherosclerotic ICA occlusion
SAMMPRIS 2011 Stenting + medical therapy Vs medical therapy alone for
intracranial arterial stenosis
Medical management is superior to stenting in patients with
intracranial stenosis >70% for prevention of stroke.
Aggressive medical management consisted of ASA 325 indefinite
+ Plavix for 3 months + SBP < 140, LDL < 70
Stroke rate was 20% in stenting arm Vs 12.2% in non-stenting
arm after 1 year.
75% of strokes in stenting arm occurred in 1st
day after stenting
Atrial finrillation:
PROTECT AF 2013 Comparing Watchman percutaneous Lt atrial appendage
closure device to Warfarin in patients with AF over 2 years.
(Watchman device placed followed by 45 days of warfarin
then 4.5 months of dual antiplatelet then ASA lifelong)
Watchman device is not inferior to warfarin in stroke prevention
Limitations: Non blinded – manufacturer sponsored trail
PFO
RESPECT 2013 Closure of PFO Vs medical therapy after cryptogenic stroke No significant difference in stroke prevention between PFO
closure with STARFLex device vs medical therapy.
4.2% serious adverse outcomes related to the procedure.
CLOSURE I 2012 Closure Vs medical therapy in patients with cryptogenic
stroke with patent foramen ovale
Closure of PFO with STARFLex was not superior to medical
treatment with aspirin or warfarin in stroke prevention.
Closure group associated with increased postprocedural Afib
ICA stenosis
CREST 2010 CAS Vs CAE for treatment of carotid artery stenosis CAS associated with more periprocedural risk of stroke
CEA associated with more periprocedural MI
Patients > 70 years had better outcome with CEA
Patients < 70 years had better outcome with CAS
Cryptogenic stroke
EMBRACE 2014 Noninvasive 30 day cardiac monitoring vs 24h monitoring in
detecting afib in patients with cryptogenic stroke > 55 years.
Afib detected in 16.1% of active group vs 3.7% in controls
75% of patients who were found to have afib were captured
during first 2 weeks.
Crystal AF 2014 Insertable cardiac monitoring vs conventional follow up in
detecting afib in patients with cryptogenic stroke
Afib detected in 8.9% of active group vs 1.4% in controls at 6
months
Afib detected in 12.4% of active group vs 2% in controls at 12
months

11. Unruptured Intracranial Aneurysm: (AHA/ASA June-2015)
Risk factors modification:
1. Given that smoking appears to increase the risk of UIA formation, patients with UIA should
be counseled regarding the importance of smoking cessation
2. Patients with UIA should monitor blood pressure and undergo treatment for hypertension.
Management:
3. Patients with an aSAH should undergo careful assessment for a coexistent UIA.
4. DSA is reasonable as the most sensitive imaging for follow-up of treated aneurysms.
5. CTA and MRA are useful for detection and followup of UIA.
6. It is reasonable to perform MRA as an alternative for follow-up for treated aneurysms, with
DSA used as necessary when deciding on therapy.
7. Coiled aneurysms, especially those with wider neck or dome diameters or those that have
residual filling, should have follow-up evaluation. The timing and duration of follow-up is
uncertain, and additional investigation is necessary.
8. Patients with aneurysms with documented enlargement during follow-up should be offered
treatment in the absence of prohibitive comorbidities
9. Treatment of UIAs in patients with a family history of IA is reasonable even in aneurysms at
smaller sizes than spontaneously occurring IAs
Endovascular treatment:
 Use of coated coils is not beneficial compared with bare-metal coil
 Endovascular treatment of UIAs is recommended to be performed at high-volume centers.
Clipping versus coiling:
 Endovascular coiling is associated with a reduction in procedural morbidity and mortality
over surgical clipping in selected cases but has an overall higher risk of recurrence
Aneurysm Follow-Up (Patients Treated Without Surgery or Endovascular Coiling):
 Radiographic follow-up with MRA or CTA at regular intervals is indicated.
 First follow-up study at 6 to 12 months after initial discovery, followed by subsequent yearly
or every other year follow-up, may be reasonable.
 It may be reasonable to consider TOF MRA rather than CTA for repeated long-term follow-up
Screening:
 Screening for aneurysms by MRA or CTA is indicated in:
 Patients with ≥2 family members with IA or SAH
 Patients with a history of autosomal dominant polycystic kidney disease,
 Patients with coarctation of the aorta
 Patients with microcephalic osteodysplastic primordial dwarfism

12. Management of ICH: (AHA/ASA May-2015)
Emergency Diagnosis and Assessment:
 CTA and contrast-enhanced CT may be considered to help identify patients at risk for hematoma
expansion
Hemostasis and Coagulopathy, Antiplatelet Agents, and DVT Prophylaxis:
 Patients with a severe coagulation factor deficiency or severe thrombocytopenia should receive
appropriate factor replacement therapy or platelets, respectively.
 Patients with ICH whose INR is elevated because of VKA should have their VKA withheld, receive
therapy to replace vitamin K–dependent factors and correct the INR, and receive intravenous
vitamin K. PCCs may have fewer complications and correct the INR more rapidly than FFP and
might be considered over FFP (Class IIb; Level of Evidence B). rFVIIa does not replace all clotting
factors, and although the INR may be lowered, clotting may not be restored in vivo; therefore,
rFVIIa is not recommended for VKA reversal in ICH.
 For patients with ICH who are taking dabigatran, rivaroxaban, or apixaban, treatment with
FEIBA, other PCCs, or rFVIIa might be considered on an individual basis. Activated charcoal might
be used if the most recent dose of dabigatran, apixaban, or rivaroxaban
 The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain.
 Although rFVIIa can limit the extent of hematoma expansion in noncoagulopathic ICH patients,
there is an increase in thromboembolic risk with rFVIIa and no clear clinical benefit in unselected
patients. Thus, rFVIIa is not recommended.
 Pneumatic compression should be used for prevention of venous thromboembolism. Graduated
compression stockings are not beneficial to reduce DVT or improve outcome.
 After documentation of cessation of bleeding, low dose subcutaneous low-molecular-weight
heparin or unfractionated heparin may be considered for prevention of venous thromboembolism in
patients with lack of mobility after 1 to 4 days from onset.
BP Recommendations:
 SBP should be lowered to 140 mmHg in patients with ICH (Class I; Level of Evidence A)
Seizures and Antiseizure Drugs:
 Continuous EEG monitoring is probably indicated in ICH patients with depressed mental status
that is out of proportion to the degree of brain injury.
 Prophylactic antiseizure medication is not recommended.
Management of Medical Complications:
 Systematic screening for myocardial ischemia or infarction with electrocardiogram and cardiac
enzyme testing after ICH is reasonable.
ICP Monitoring and Treatment:

13. 1
 If CPP monitoring is indicated, CPP of 50 to 70 mmHg may be reasonable to maintain depending
on the status of cerebral auto regulation.
 Corticosteroids should not be administered for treatment of elevated ICP in ICH (Class III; Level
of Evidence B).
IVH:
 Although intraventricular administration of rtPA in IVH appears to have a fairly low complication
rate, the efficacy and safety of this treatment are uncertain.
 The efficacy of endoscopic treatment of IVH is uncertain
Surgical Treatment of ICH:
 Patients with cerebellar hemorrhage who are deteriorating neurologically or who have
brainstem compression and/or hydrocephalus from ventricular obstruction should undergo
surgical removal of the hemorrhage as soon as possible. Initial treatment of these patients with
ventricular drainage rather than surgical evacuation is not recommended.
 A policy of early hematoma evacuation is not clearly beneficial compared with hematoma
evacuation when patients deteriorate.
 Supratentorial hematoma evacuation in deteriorating patients might be considered as a life-
saving measure.
 The effectiveness of minimally invasive clot evacuation with stereotactic or endoscopic
aspiration with or without thrombolytic usage is uncertain.
Prevention of Recurrent ICH:
 Risk factors for ICH recurrence: (1) lobar location of the initial ICH; (2) older age; (3) presence
and number of microbleeds on gradient echo MRI; (4) ongoing anticoagulation; and (5) presence
of apolipoprotein E ε2 or ε4 alleles.
 Measures to control BP should begin immediately after ICH onset. A long-term goal of BP < 130
mmHg systolic and 80 mmHg diastolic is reasonable.
 Lifestyle modifications, including avoidance of alcohol use greater than 2 drinks per day, tobacco
use, and illicit drug use, as well as treatment of obstructive sleep apnea, are probably beneficial.
 Avoidance of long-term anticoagulation with warfarin as a treatment for nonvalvular atrial
fibrillation is probably recommended after warfarin-associated spontaneous lobar ICH because
of the relatively high risk of recurrence.
 Anticoagulation after nonlobar ICH and antiplatelet monotherapy after any ICH might be
considered, particularly when there are strong indications for these agents.
 The optimal timing to resume oral anticoagulation after anticoagulant-related ICH is uncertain.
Avoidance of oral anticoagulation for at least 4 weeks, in patients without mechanical heart
valves, might decrease the risk of ICH recurrence. If indicated, aspirin monotherapy can
probably be restarted in the days after ICH, although the optimal timing is uncertain.
 The usefulness of dabigatran, rivaroxaban, or apixaban in patients with atrial fibrillation and past
ICH to decrease the risk of recurrence is uncertain.
 There are insufficient data to recommend restrictions on the use of statins in ICH patients

14. Stroke prevention in Non-Valvular A-fib:
Source: http://www.neurology.org/content/82/8/716.full
 In clinical trials the new oral anticoagulants are non-inferior or superior to warfarin for
reducing stroke (EVID).
 Clinicians should choose one of the following options:
 Warfarin, target international normalized ratio (INR) 2.0–3.0
 Dabigatran (Pradaxa) 150 mg twice daily (if creatinine clearance [CrCl] > 30 mL/min)
 Rivaroxaban (Xarelto) 15 mg/day (if CrCl 30–49 mL/min) or 20 mg/day
 Apixaban (Eliquis) 5 mg twice daily (if serum creatinine < 1.5 mg/dL) or 2.5 mg twice
daily if any two of the following criteria are present:
- serum creatinine > 1.5 mg/dL and < 2.5 mg/dL
- body weight ≤ 60 kg
- age ≥ 80 years
 In patients with high risk of intracranial hemorrhage: Avoid Warfarin
 Clinicians should administer Dabigatran, Rivaroxaban, or Apixaban to patients who have
NVAF requiring anticoagulant medication and are at higher risk of intracranial bleeding.
 Risk of ICH is: Warfarin (0.7%/year) – Dabigatran (0.3) – Apixaban (0.33) - Rivaroxaban (0.5)
 In patients with high risk of GI bleeding: Use Apixiban
 Clinicians might offer Apixaban to patients with NVAF and GI bleeding risk who require
anticoagulant medication.
 Risk of GI bleeding is higher with Dabigatran>Rivaroxaban>Warfarin>Apixaban
Numbers
ASA less effective than warfarin: RRR 22% Vs 68% (RELA trail)
ASA + Plavix more effective than ASA: RR 0.72 compared to ASA
ASA + Plavix associated with more risk of bleeding: RR 1.5 compared to ASA

15. 1
Dabigatran & Warfarin:
 In patients with NVAF, Dabigatran administration is probably more effective for reducing the
risk of stroke or systemic embolism (150 mg twice daily, RRR 34%) than is warfarin administration.
 Hemorrhage risks were similar overall between Dabigatran 150 mg administration twice daily and
warfarin administration (INR 2.0–3.0), but intracranial hemorrhage was less frequent with
administration of Dabigatran 150 mg twice daily (Dabigatran vs warfarin, RR 0.40 [95% CI 0.27%–
0.60%]) (1 Class I study).
 Dabigatran 150 mg bid was associated with a higher rate of GI bleeding (1.51%/y vs 1.02%/y).
Rivaroxaban & Warfarin:
 In patients with NVAF at high risk of cerebral or systemic embolism, Rivaroxaban is probably as
effective as warfarin for the prevention of cerebral and systemic embolism, without difference in
the risks of major bleeding episodes overall except GI bleeding. However, Rivaroxaban is
associated with a lesser frequency of intracranial hemorrhage and fatal bleeding as
compared with warfarin (RRR 22% [95% CI 5.5%–35.3%]) (single Class I study).
Apixaban & Warfarin:
 Apixaban 5 mg twice daily is likely more effective than warfarin in patients with NVAF at moderate
risk of embolism (RRR 20.3% [95% CI 4.8%–33.3%]). The superiority of Apixaban is related to
decreased risk of bleeding (including intracranial bleeding) and reduced mortality (1 Class
I study), whereas its effect on reduction of risk of cerebral and systemic embolism is not superior
to that of warfarin.
ASA-Plavix & Warfarin:
 Oral anticoagulation therapy is likely more effective than clopidogrel plus aspirin for stroke
prevention (RR stroke 1.72). Intracranial bleeding is more common with oral anticoagulation
therapy than with clopidogrel plus aspirin (single Class I study).

16. Periprocedural Management of Antithrombotic
Medications: doi: http://dx.doi.org/10.1212/WNL.0b013e318294b32d
Question 1: What is the TE risk of temporarily discontinuing an antithrombotic medication (APs and ACs)?
 Antiplatelet agents: Estimated stroke risk varies with the duration of aspirin discontinuation:
relative risk (RR) was 1.97 for 2 weeks and 1.40 for 5 months (one Class II study each).
 Anticoagulant: No available studies to assess stroke risk with anticoagulant discontinuation
Question 2: What are the perioperative bleeding risks of continuing AP agents?
 Aspirin doesn’t increase bleeding risk in patients undergoing:
o Dental surgery
o Colonoscopic polypectomy
o (TRUS)-guided prostate biopsy
o CTS surgery
o Spinal/epidural anesthesia/pain procedures
 Aspirin does increase bleeding risk in patients undergoing: Orthopedic procedures
Question 3: What are the perioperative bleeding risks of continuing anticoagulation?
 It is highly probable that warfarin does not increase clinically important bleeding risks with
dental extractions (four Class I studies).
 Warfarin might not increase clinically important bleeding with EMG (one Class II study).
 AC might increase bleeding with colonoscopic polypectomy, some of which is clinically
important (one Class III study)
 Warfarin might not increase clinically important bleeding when different urologic procedures
are considered together (two Class III studies)