SHOULD ANTICOAGULATION BE USED IN A CARDIO-EMBOLIC STROKE? IF SO, WHEN?

Dr Tushar Patil, MD

CASEA 76 years old right handed lady presented with Acute onset weakness of right half of body since 2 days Inability to speak since 2 daysNo h/o Any other cranial nerve symptom Loss of conciousness Headache, vomitting Chest pain, Palpitations, DyspnoeaPast History- Hypertension since 10 years, not on regular treatmentNo h/o Ischemic heart disease,Diabetes Stroke,TIA Smoking, Tobacco chewing

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

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

DIAGNOSIS

Ischemic Stroke: Right hemiparesis with motor aphasia – Cardioembolic stroke secondary to non-

rheumatic atrial fibrillation

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.

 

YES, THE PATIENT NEEDS ANTICOAGULATION

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.

   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

STROKE RISK IN PATIENTS WITH NONVALVULAR AF NOTTREATED 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.

RISK-BASED APPROACH TO ANTITHROMBOTIC THERAPY IN PATIENTS WITH ATRIAL FIBRILLATION

ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation

   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.

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.

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.

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

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

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. 

ACCP GUIDELINESANTITHROMBOTIC 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

NO, THE PATIENT SHOULD NOT BE ANTICOAGULATED

RATIONALE

High risk of intracranial hemorrhage Age of the patient Questionable efficacy in improving stroke

outcome Stroke with hemorrhagic conversion

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.

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

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

NEUROLOGY:ANTICOAGULANTS AND ANTIPLATELET AGENTS IN ACUTE ISCHEMIC STROKE

1. Do antithrombotic agents reduce stroke mortality and stroke-related 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)

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.

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

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

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.

COCHRANE DATABASEAnticoagulants 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.

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]

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)

ANTITHROMBOTIC AND THROMBOLYTIC THERAPY 8TH ED: ACCP GUIDELINESANTITHROMBOTIC 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;

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.

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