This is debate on a very commonly encountered clinical scenario: Anticoagulation in cardio-embolic stroke with points for and against it

1. SHOULD ANTICOAGULATION BE
USED IN A CARDIO-EMBOLIC
STROKE? IF SO, WHEN?
Dr Tushar Patil, MD

2. CASE
A 76 years old right handed lady presented with
 Acute onset weakness of right half of body since 2 days
 Inability to speak since 2 days
No h/o
 Any other cranial nerve symptom
 Loss of conciousness
 Headache, vomitting
 Chest pain, Palpitations, Dyspnoea
Past History-
 Hypertension since 10 years, not on regular treatment
No h/o
 Ischemic heart disease,Diabetes
 Stroke,TIA
 Smoking, Tobacco chewing

3. On Examination,
 Elderly female
 BP-140/90
 Pulse-150/minute, Irregularly Irregular, good volume, all peripheral
pulsations including carotids well felt
 Resp- 20/min
 GCS-11/15
 Motor Aphasia
 Right seventh nerve supranuclear palsy
 Other cranial nerves normal
 Power- Grade 1 in right upper and lower limbs and normal on left
side
 DTR- 3+ on right side
 Plantars- Right-extensor, left – flexor
 CVS- S1 changing in intensity, no murmurs

4. INVESTIGATIONS
 Hb, TLC, DLC, Platelets, GBP- Within normal limits
 Kidney and liver function Tests – Normal
 Serum sodium-142 mEq/L
 Serum Potassium-4.1 mEq/L
 Random Blood Sugar- 68 mg/dL
 PT-INR= 1.04
 ECG- HR=150/minute, Absent P waves, Changing R-R interval
 Transthoracic 2D Echocardiography - LVEF-62%, No RWMA,
No e/o any chamber hypertrophy, No LA/LV clot, No vegetations
 CT Brain- Infarct involving left frontal, parietal and occipital
areas with foci of hemorrhage within infarct

7. DIAGNOSIS
Ischemic Stroke: Right hemiparesis with motor
aphasia – Cardioembolic stroke secondary to non-
rheumatic atrial fibrillation

8. SHOULD THIS PATIENT BE TREATED WITH
ANTICOAGULATION OR NOT?
 The effect of anticoagulation on the incidence and severity of
hemorrhagic transformation remains uncertain.
 Heparin is frequently used after an embolic stroke to prevent early
recurrence.
 The clinical dilemma rests on the balance of risk between
preventing neurologic worsening due to recurrent embolism versus
the potential for promoting symptomatic hemorrhagic
transformation.

9. YES, THE PATIENT NEEDS
ANTICOAGULATION

10. RATIONALE
 Atrial fibrillation is the most common cause of cardiac embolism
and is responsible for about 50% of all cardiogenic emboli.
 Cardioembolic stroke patients have a high risk for stroke
recurrence, and greater mortality.
 Anticoagulation with heparin/ Warfarin is therapy of choice for
stroke prevention in patients with AF who have had a stroke or
TIA, and in high-risk AF patients.
 Efficacy of antiplatelets for prevention of cardioembolic stroke is
less than anticoagulants.

11. Stroke rates in relation to age among patients in untreated control groups of
randomized trials of antithrombotic therapy.
Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from
five randomized controlled trials. Arch Intern Med 1994;154:1449–57.47

12. STROKE RISK IN PATIENTS WITH NONVALVULAR
AF NOT
TREATED WITH ANTICOAGULATION ACCORDING
TO THE CHADS2 INDEX
[1]van Walraven WC, Hart RG, Wells GA, et al. A clinical prediction rule to identify patients with atrial fibrillation and a low risk for stroke while taking aspirin.
Arch Intern Med 2003;163:936–43415;
[2] Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial
Fibrillation. JAMA 2001;285:2864 –70.

13. RISK-BASED APPROACH TO
ANTITHROMBOTIC THERAPY IN PATIENTS
WITH ATRIAL FIBRILLATION
ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation

14. Effects on all stroke (ischemic and hemorrhagic) of therapies for patients with atrial
fibrillation
Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med
1999;131:492–501.420 AFASAK indicates Copenhagen Atrial Fibrillation, Aspirin, Anticoagulation; BAATAF, Boston Area Anticoagulation Trial for
Atrial Fibrillation; CAFA, Canadian Atrial Fibrillation Anticoagulation; CI, confidence interval; EAFT, European Atrial Fibrillation Trial; SPAF, Stroke
Prevention in Atrial Fibrillation; and SPINAF, Stroke Prevention in Nonrheumatic Atrial Fibrillation.

15.  OAC is highly effective for prevention of all strokes
 It has a risk reduction of 68% for both primary as well as
secondary stroke as compared to placebo.
 adjusted-dose OAC resulted in relative risk reduction of
52% as compared to aspirin.
► R. G. Hart, O. Benavente, R. McBride, and L. A. Pearce,“Antithrombotic therapy to prevent
stroke in patientswith atrial fibrillation: a meta-analysis,” Annals of Internal Medicine, vol.
131, no. 7, pp. 492–501, 1999.
►G. Y. H. Lip and S. J. Edwards, “Stroke prevention with aspirin, warfarin and ximelagatran in
patients with nonvalvular atrial fibrillation: a systematic review and metaanalysis,”
Thrombosis Research, vol. 118, no. 3, pp. 321–333, 2006
►C. Van Walraven, R. G. Hart, D. E. Singer et al., “Oral anticoagulants vs aspirin in nonvalvular
atrial fibrillation: an individual patient meta-analysis,” Journal of the American Medical
Association, vol. 288, no. 19, pp. 2441–2448, 2002.

16. ACTIVE-W
 The ACTIVE-W (Atrial Fibrillation Clopidogrel Trial
with Irbesartan for Prevention of Vascular Events)
trial compared clopidogrel plus ASA with oral
anticoagulation therapy with warfarin for prevention of
vascular events in AF patients with an average of 2 stroke
risk factors.
 Oral anticoagulation therapy with warfarin proved superior
to clopidogrel plus ASA for prevention of vascular events in
AF patients.
Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral
anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with
Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled
trial Lancet 2006;367:1903-1912.

17. ACC/AHA/ESC 2006 GUIDELINES FOR THE
MANAGEMENT OF PATIENTS WITH ATRIAL
FIBRILLATION: CLASS I RECOMMENDATIONS
 Antithrombotic therapy to prevent thromboembolism is
recommended for all patients with AF, except those with lone AF
or contraindications. (Level of Evidence: A)
 For patients without mechanical heart valves at high risk
of stroke, chronic oral anticoagulant therapy with a vitamin K
antagonist is recommended in a dose adjusted to achieve the
target intensity INR of 2.0 to 3.0, unless contraindicated. Factors
associated with highest risk for stroke in patients with AF are
prior thromboembolism (stroke, TIA, or systemic embolism)
and rheumatic mitral stenosis. (Level of Evidence: A)
 Anticoagulation with a vitamin K antagonist is recommended
for patients with more than 1 moderate risk factor. Such factors
include age 75 y or greater, hypertension, HF, impaired LV
systolic function (ejection fraction 35% or less or fractional
shortening less than 25%), and diabetes mellitus. (Level of
Evidence: A)
Circulation.2006; 114: e257-e354

18. THE INTERNATIONAL STROKE
TRIAL
 Randomized over 19,000 patients to subcutaneous heparin in doses
of 10,000 units per day, 25,000 units per day Vs placebo and aspirin
Vs placebo .
 The overall incidence of recurrent ischemic stroke within 14 days
was 3.8% in the control arm and 2.9% in heparin-treated patients.
 In patients with atrial fibrillation the incidence of recurrent stroke
within the first 14 days was 4.9% in the control arm and 2.8% in
patients treated with heparin.
The International Stroke Trial (IST): a randomised trial of aspirin,
subcutaneous heparin, both, or neither among 19 435 patients with acute
ischaemic stroke : International Stroke Trial Collaborative Group. The
Lancet, Volume 349, Issue 9065, Pages 1569 - 1581, 31 May 1997

19. TOAST
 The Trial of the Heparinoid ORG 10172 (danaparoid) in
Acute Stroke (TOAST) was a randomized, double-blind,
placebo-controlled trial in which 1281 patients were enrolled
at 36 US centers .
 In this trial, 1281 patients with ischemic stroke who presented
within 24 hours of symptom onset were randomized to this
drug or placebo intravenously for 7 days
 At 7 days, 34% of treated patients and only 28% of control
subjects had very favorable outcomes (p = 0.01).
 In a prespecified secondary analysis of TOAST data
unadjusted for multiple comparisons, a potential beneficial
effect of the heparinoid, danaparoid, was suggested in the
subgroup of patients with large artery atherosclerosis.
Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment
(TOAST) Investigators. Low molecular weight heparinoid, ORG 10172
(Dsanaparoid), and outcome after acute ischemic stroke. JAMA 1998; 279:
1265–1272.

20. ACCP GUIDELINES
ANTITHROMBOTIC AND THROMBOLYTIC THERAPY
FOR ISCHEMIC STROKE
 Oral anticoagulant therapy is highly effective for both primary
and secondary prevention of stroke in patients with atrial
fibrillation .
 In the European Atrial Fibrillation Trial, patients with
recent stroke or TIA and atrial fibrillation were treated with
oral anticoagulation.
 In about half of the patients, anticoagulation was initiated
within 2 weeks after symptom onset. No increase in brain
hemorrhage was apparent in patients treated early vs later.
 In general, we recommend initiation of oral anticoagulation
therapy within 2 weeks of a cardioembolic stroke.
 Recommendation:In patients with atrial fibrillation
who have suffered a recent stroke or TIA, we
recommend long-term oral anticoagulation (target INR,
2.5; range, 2.0 to 3.0) [Grade 1A].
Chest - Volume 133, Issue 6 (June 2008)
EAFT (European Atrial Fibrillation Trial) Study Group : Secondary prevention in
non-rheumatic atrial fibrillation after transient ischaemic attack or minor
stroke. Lancet 342. 1255-1262.1993

21. NO, THE PATIENT SHOULD NOT BE
ANTICOAGULATED

22. RATIONALE
 High risk of intracranial hemorrhage
 Age of the patient
 Questionable efficacy in improving stroke
outcome
 Stroke with hemorrhagic conversion

23. INTERNATIONAL STROKE
TRIAL (IST)
 With heparin, no significant difference in 14-day mortality
(heparin, 9.0% vs no heparin, 9.3%) or 6-month outcome
(heparin, 62.9% dead or dependent vs no heparin, 62.9%).
 Even among patients treated within 6 h, no benefit for
heparin at 6 months.
 At 14 days, recurrent ischemic strokes significantly
reduced in heparin groups (from 3.8 to 2.9%) but
hemorrhagic stroke was significantly increased (from 0.4 to
1.2%), yielding no net benefit.

24. INTERNATIONAL STROKE
TRIAL (IST)
 In patients with atrial fibrillation and acute ischemic
stroke, heparin significantly reduced the risk of 14-day
ischemic stroke recurrence from 4.9 to 2.8%, but an
increased risk of hemorrhagic stroke (2.1 vs 0.4%)
neutralized the potential benefits.
 The higher-dose regimen (12,500 U bid) was associated
with more systemic bleeding, hemorrhagic strokes, and a
significantly increased risk of death or nonfatal stroke at
14 days.
The International Stroke Trial (IST): a randomised trial of aspirin,
subcutaneous heparin, both, or neither among 19 435 patients with acute
ischaemic stroke : International Stroke Trial Collaborative Group. The
Lancet, Volume 349, Issue 9065, Pages 1569 - 1581, 31 May 1997

25. ASA GUIDELINES FOR THE EARLY
MANAGEMENT OF ADULTS WITH
ISCHEMIC STROKE
Class III Recommendations
1. Urgent anticoagulation with the goal of preventing early
recurrent stroke, halting neurological worsening, or
improving outcomes after acute ischemic stroke is not
recommended for treatment of patients with acute ischemic
stroke (Class III, Level of Evidence A).
2. Urgent anticoagulation is not recommended for patients
with moderate to severe strokes because of an increased
risk of serious intracranial hemorrhagic complications
(Class III, Level of Evidence A).
3. Initiation of anticoagulant therapy within 24 hours of
treatment with intravenously administered rtPA is not
recommended (Class III, Level of Evidence B).
Guidelines for the Early Management of Adults With Ischemic Stroke :Stroke
2007, 38:1655-1711

26. NEUROLOGY:ANTICOAGULANTS AND
ANTIPLATELET AGENTS IN ACUTE ISCHEMIC
STROKE
Do antithrombotic agents reduce stroke mortality and stroke-related
1.
morbidity?
Abciximab, unfractionated heparin, LMW heparins, and heparinoids have
not been shown to reduce mortality or stroke-related morbidity when used
within 48 hours of onset in patients with acute ischemic stroke.
2. Do antithrombotic agents reduce early stroke recurrence?
unfractionated heparin and LMW heparin/heparinoids, when used within
48 hours of onset in patients with acute ischemic stroke, have not been
shown to reduce the rate of stroke recurrence.
3. What are the risks of hemorrhage associated with antithrombotic agents?
There is an increase in both systemic and CNS hemorrhage in patients
treated with aspirin, subcutaneous unfractionated heparin, or LMW
heparin/heparinoids
Anticoagulants and antiplatelet agents in acute ischemic stroke :Report of the Joint Stroke
Guideline Development Committee of the American Academy of Neurology and the American
Stroke Association. Neurology - Volume 59, Issue 1 (July 2002)

27.  A summary of stroke “megatrials” demonstrated recurrent ischemic
stroke rates to range between 0.63 and 2.20/100 patients per week,
and most experts now agree that the older estimates for recurrent
stroke rates were high (Swanson 1999).
 The large numbers of evaluated patients in the International Stroke
Trial and TOAST trial support the conclusions that the overall risk
of early recurrent stroke is low and the absolute benefit of routine
heparin is marginal.
 The risks and benefits in carefully assessed and closely monitored
patient subgroups remain uncertain.
Swanson RA. Intravenous heparin for acute stroke: what can we
learn from the megatrials? Neurology.1999 Jun 10;52(9):1746-50.

28.  A large metaanalysis of 22 trials among 23,547 patients
showed that immediate anticoagulation of patients with acute
ischemic stroke was not associated with a significant reduction
in death or dependency. [1]
 Although anticoagulants were associated with about 9 fewer
recurrent ischemic strokes per 1,000 treated, this was offset by
a similar increase of 9 symptomatic intracranial hemorrhages
per 1,000 treated.
 Only a single randomized trial has evaluated this regimen
compared with placebo for patients with acute stable stroke
since 1980.
 No significant difference in stroke progression or neurologic
outcome was detected in this relatively small study (n = 225).
[2]
[1]Gubitz G, Sandercock P, Counsell C: Anticoagulants for acute ischaemic
stroke. Cochrane Database Syst Rev . CD000024.2004
[2]Duke RJ, Bloch RF, Turpie AG, et al: Intravenous heparin for the
prevention of stroke progression in acute partial stable stroke. Ann Intern
Med 105. 825-828.1986

29.  Rothrock et al evaluated 121 consecutive patients with
acute cardioembolic stroke. Forty-nine were
therapeutically anticoagulated within 96 hours of stroke
onset, and 41 received no anticoagulants within the first 2
weeks after stroke.
 The incidences of clinically significant brain hemorrhage
(2%) and early recurrent embolization (2%) were equally
low in both groups.
 acute anticoagulation may be employed safely in most
patients with cardioembolic stroke but that such treatment
does not clearly benefit this population as a whole.
JF Rothrock, HC Dittrich, S McAllen, BJ Taft and PD Lyden. Acute
anticoagulation following cardioembolic stroke .Stroke 1989;20:730-734

30.  The Cerebral Embolism Study Group reported that 22 of
24 patients with symptomatic hemorrhagic transformation
were associated with anticoagulation therapy[1] .
 Some reports suggest that although anticoagulation does
not precipitate hemorrhagic transformation,
anticoagulation may worsen the severity of spontaneous
bleeding (Cerebral Embolism Study Group
1983[1]; 1987[2]).
[1]Immediate anticoagulation of embolic stroke: a randomized trial.
Cerebral Embolism Study Group. Stroke 1983, 14:668-676
[2]Cardioembolic stroke, early anticoagulation, and brain
hemorrhage. Cerebral Embolism Study Group.Arch Intern Med.
1987 Apr;147(4):636-40.

31. COCHRANE DATABASE
Anticoagulants offered no net advantages over antiplatelet agents in
acute ischaemic stroke. The combination of low-dose UFH and
aspirin appeared in a subgroup analysis to be associated with net
benefits compared with aspirin alone.
Berge E, Sandercock PAG. Anticoagulants versus antiplatelet agents for acute ischaemic stroke.
Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD003242. DOI:
10.1002/14651858.CD003242 .

32. DVT & PE
 DVT and PE are frequent complications of stroke, with about 5%
of early deaths attributed to PE. [1]
 In an overview analysis among acute stroke patients,
anticoagulants were associated with 4 fewer pulmonary emboli
per 1,000 (OR, 0.60; 95% CI, 0.44–0.81). [2]
 In the IST, there was a significant reduction in the frequency of
fatal or nonfatal PE, from 0.8 to 0.5%, among those treated with
SC UFH (p < 0.05). [3]
 In a metaanalysis among 740 acute ischemic stroke subjects from
four trials, there was a significant reduction in the odds of DVT
(OR, 0.52; 95% CI, 0.56–0.79) among those allocated to low-
molecular-weight heparins or heparinoids vs standard UFH. [4]
 Two trials of direct comparisons between a low-molecular-weight
heparin and UFH have shown similar safety and efficacy for
enoxaparin and noninferiority for certoparin. [5] , [6]

33. PREVAIL
PREVENTION OF VENOUS
THROMBOEMBOLISM AFTER ACUTE
ISCHEMIC STROKE
 Open-label, randomized comparison of enoxaparin 40 mg
SC qd or UFH 5,000 U SC q12h in patients with ischemic
stroke [7]
 1,762 patients randomized within 48 h of symptom onset
and stratified on stroke severity (NIHSS < or ≥14).
 10% patients in the enoxaparin group had a primary end
point compared to 18% in patients randomized to UFH,
yielding a 43% RRR (0.57; 95% CI, 0.44–0.76; p = 0.0001).
 The results for proximal DVT were 5% in the enoxaparin
group and 10% in the UFH group (p = 0.0003).
 The risk of both symptomatic intracranial bleeding and
major extracranial hemorrhage was also similar in both
groups (1% each)

34. ANTITHROMBOTIC AND THROMBOLYTIC
THERAPY 8TH ED: ACCP GUIDELINES
ANTITHROMBOTIC AND THROMBOLYTIC
THERAPY FOR ISCHEMIC STROKE
For acute stroke patients with restricted mobility,
we recommend prophylactic low-dose SC heparin
or low-molecular-weight heparins (Grade 1A).
[1] Antiplatelet Trialists' Collaboration : Collaborative overview of randomised trials of antiplatelet therapy: III. Reduction
in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients.
BMJ 308. 235-246.1994
[2] Gubitz G, Sandercock P, Counsell C: Anticoagulants for acute ischaemic stroke. Cochrane Database Syst
Rev . CD000024.2004
[3] International Stroke Trial (IST) : A randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435
patients with acute ischaemic stroke: International Stroke Trial Collaborative Group. Lancet 349. 1569-1581.1997;
[4] Sandercock P, Counsell C, Stobbs SL: Low-molecular-weight heparins or heparinoids versus standard unfractionated
heparin for acute ischaemic stroke. Cochrane Database Syst Rev . CD000119.2005;
[5] Diener HC, Ringelstein EB, von Kummer R, et al: Prophylaxis of thrombotic and embolic events in acute ischemic
stroke with the low-molecular-weight heparin certoparin: results of the PROTECT Trial. Stroke 37. 139-144.2006
[6 ]Hillbom M, Erila T, Sotaniemi K, et al: Enoxaparin vs heparin for prevention of deep-vein thrombosis in acute
ischaemic stroke: a randomized, double-blind study. Acta Neurol Scand 106. 84-92.2002;
[7] Sherman DG, Albers GW, Bladin C, et al: The efficacy and safety of enoxaparin versus unfractionated heparin for the
prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised
comparison. Lancet 369. 1347-1355.2007;

35. COCHRANE DATABASE
• Since the last version of the review, neither of the two new
relevant studies have provided additional information to
change the conclusions.
• In patients with acute ischaemic stroke, immediate
anticoagulant therapy is not associated with net short or long-
term benefit.
• Treatment with anticoagulants reduced recurrent stroke, deep
vein thrombosis and pulmonary embolism, but increased
bleeding risk.
• The data do not support the routine use of any the currently
available anticoagulants in acute ischaemic stroke.
Sandercock PAG, Counsell C, Kamal AK. Anticoagulants for acute ischaemic
stroke. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.:
CD000024. DOI: 10.1002/14651858.CD000024.pub3.

36. THANK YOU