resuming anticagulation in intracerebral hemorrhage patients

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Should anticoagulation be resumed after cerebral hemorrhage?

An everyday story

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Moataz Fatthy MSc

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AGENDA…

• Rationale

• Risk factor

• Risk Stratification

• Complications

• Management

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• The most feared and the most deadly complication of oral anticoagulant therapy

• Anticoagulant therapy during and after anticoagulation-associated ICH.

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• Unfortunately, little evidence from clinical trials on which to base the decision.

• Nevertheless, the potential benefit of resuming anticoagulation outweighs the considerable risk.

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Please pick your poison (Franklin michota , MD)

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• narrow therapeutic window• vary considerably in dose-

response from patient to patient

• subject to significant interactions with other drugs and with foods.

• monitored with laboratory testing

• good patient compliance

• patient education is essential.

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• Warfarin has a striking effect on the incidence and outcomes of ICH.

• While the overall incidence of ICH in the general population is approximately 25 per 100,000 person-years

• The incidence in patients on warfarin is exponentially higher, at 2 to 3 per 100 per year, and appears to be increasing.

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• In addition, once ICH occurs, the risk of death is up to twice as high in those on warfarin

• The bulk of this effect is likely due to a higher risk of ongoing bleeding after the event.

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Risk factors for intracerebral hemorrhage during warfarin anticoagulation

Firmly established risk factors

• Advancing age (especially >75 years)

• Hypertension (especially systolic blood pressure >160 mmHg)

• History of cerebrovascular disease

• Intensity of anticoagulation

Possible risk factors • Concomitant use of aspirin

• Cerebral amyloid angiopathy

• Asian or Mexican-American ethnicity

• Tobacco smoking

• Heavy alcohol consumption

• Leukoaraiosis detected by brain CT/MRI

• Microbleeds by T2*-weighted MRI

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• A population-based study has reported a four-fold increase in the incidence of warfarin-associated ICH during the 1990s due to the increasing use of warfarin in elderly patients

• Antiplatelet therapy with aspirin increases ICH risk by about 40 percent

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• Dual antiplatelet therapy with aspirin plus clopidogrel increases the risk of ICH twofold compared with aspirin

• Combining adjusted-dose warfarin with aspirin appears to double the ICH risk compared with similar intensities of warfarin anticoagulation without aspirin.

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Suggested patient risk stratification for arterial or venous thromboembolism

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INDICATION FOR VITAMIN K ANTAGONIST

MECHANICAL HEART VALVE

ATRIAL FIBRILLATION

VENOUS THROMBOEMBOLISM

High risk

Any mitral valve prosthesisOlder prosthetic aortic valveRecent stroke or transient ischemic attack (within 6

months(

CHADS2 score ≥ 5Recent stroke or transient ischemic attack (within 3 months(Rheumatic valvular heart disease

Recent event (within 3 months(Severe thrombophilia (low protein C, protein S, or antithrombin level; antiphospholipid antibody syndrome; multiple

abnormalities(

Moderate risk

Bileaflet aortic valve prosthesis and one of the following:Atrial fibrillationPrior stroke or transient ischemic attackHypertensionDiabetesCongestive heart failureAge over 75

CHADS2 score 3 or 4Prior stroke or transient ischemic attack

Venous thromboembolic event in the past 3 to 12 monthsNonsevere thrombophilic conditions (eg, heterozygous factor II mutation(Recurrent venous thromboembolismActive cancer (treated within 6 months, or

palliative treatment(

Low risk

Bileaflet aortic valve prosthesis without atrial fibrillation, and with no other stroke risk factors

CHADS2 score ≤ 2 and no prior stroke or transient ischemic attack

Single venous thromboembolic event > 12 months ago and no other risk factors

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INDICATION FOR VITAMIN K ANTAGONIST

MECHANICAL HEART VALVE

ATRIAL FIBRILLATION

VENOUS THROMBOEMBOLISM

High risk

Any mitral valve prosthesisOlder prosthetic aortic valveRecent stroke or transient ischemic attack (within 6

months(

CHADS2 score ≥ 5Recent stroke or transient ischemic attack (within 3 months(Rheumatic valvular heart disease

Recent event (within 3 months(Severe thrombophilia (low protein C, protein S, or antithrombin level; antiphospholipid antibody syndrome; multiple

abnormalities(

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INDICATION FOR VITAMIN K ANTAGONIST

MECHANICAL HEART VALVE

ATRIAL FIBRILLATION

VENOUS THROMBOEMBOLISM

Moderate risk

Bileaflet aortic valve prosthesis and one of the following:Atrial fibrillationPrior stroke or transient ischemic attackHypertensionDiabetesCongestive heart failureAge over 75

CHADS2 score 3 or 4Prior stroke or transient ischemic attack

Venous thromboembolic event in the past 3 to 12 monthsNonsevere thrombophilic conditions (eg, heterozygous factor II mutation(Recurrent venous thromboembolismActive cancer (treated within 6 months, or

palliative treatment(

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INDICATION FOR VITAMIN K ANTAGONIST

MECHANICAL HEART VALVE

ATRIAL FIBRILLATION

VENOUS THROMBOEMBOLISM

Low risk

Bileaflet aortic valve prosthesis without atrial fibrillation, and with no other stroke risk factors

CHADS2 score ≤ 2 and no prior stroke or transient ischemic attack

Single venous thromboembolic event > 12 months ago and no other risk factors

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Extracranial bleeding leads to death or disability in only 3% of cases

Intracranial bleeding such as ICH leads to death or disability 76% of cases

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Higher risk of expansion

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• Unfortunately, continued bleeding is common after ICH.

• In patients In warfarin-associated ICH, up to 50% of patients who present within 3 hours of symptom onset, 25% of hematomas expand more than 30% over the first hour, and another 12% expand this amount over the next 24 to 48 hours or may be longer.

• Over 70% of patients presenting acutely develop at least some amount of expansion within 24 hours.

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Higher risk of expansion

• A large hematoma volume on presentation

• Early presentation, especially within 3 hours (??undergo computed tomography (CT( while still bleeding(

• Higher INR is a significant predictor, not just of higher risk, but also of a more delayed expansion.

• Certain radiographic findings indicate higher risk. One is the “spot sign,” ie, contrast extravasation after contrast-enhanced CT.

• Apparently, the more spots present, and the denser the contrast, the greater the risk “spot-sign score”

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The “spot sign” (arrow), contrast extravasation after contrast-enhanced computed tomography, is associated with a high risk of hematoma expansion.

GOLDSTEIN J N , GREENBERG S M Cleveland Clinic Journal of Medicine 2010;77:791-799

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In the acute phase..

?In the chronic phase..

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In the acute phase..

• how does the risk of further bleeding (hematoma expansion) compare with the short-term risk of thromboembolism?

In the chronic phase..

• how does the risk of recurrent hemorrhage compare with the excess risk of thromboembolism if the patient does not resume anticoagulation therapy?

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Acute phase management

• Anticoagulant reversal should be the primary consideration in the first 24 hours

Heparin or LMWH is recommended

72 hours after ICH is diagnosed

Not underweight (< 50 kg),

Normal renal function (creatinine clearance > 30 mL/minute/1.73 m2)

Normal platelet function.

Does not have coagulopathy.

warfarin-related ICH has concomitant DVTor PE (ie, < 4 weeks old), then caval interruption therapy would be indicated.

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Acute phase management

• Anticoagulant reversal should be the primary consideration in the first 24 hours

Lines of reversal

Vitamin K 5 to 10 mg intravenously

Prothrombin complex concentrates 10 to 50 U/kg

Recombinant factor VIIa 40 to 80 μg/kg

Fresh frozen plasma 10 to 50 U/kg.

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There are few relevant guidelines for the reversal of anticoagulation in patients with AAICH, and expert opinion on this subject differs

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• PCC, recombinant factor VIIa, or fresh frozen plasma given with intravenous vitamin K were advocated in the 2008 American College of Chest Physicians Guidelines for patients with life-threatening bleeding such as intracranial hemorrhage

There are few relevant guidelines for the reversal of anticoagulation in patients with AAICH, and expert opinion on this subject differs

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• Replacement of the vitamin K-dependent factors to correct the INR and the administration of intravenous vitamin K. PCCs were considered a reasonable alternative to FFP. Recombinant factor VIIa was not routinely recommended as a sole agent for reversal

• Other guidelines have suggested using various combinations of vitamin K, FFP, PCC, and recombinant factor VIIa

• PCC preparations are not readily available in emergency departments at most United States hospitals; their use is often restricted to hematology specialists, reducing their immediate availability.

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Chronic phase management

Evaluations of patients for their risk of thrombosis in light of their original indication for oral anticoagulant therapy.

The risk of ICH is related to the intensity of anticoagulation, a lower target international normalized ratio may be the best compromise, depending on the patient.

Alternatively, antiplatelet therapy alone may offer some benefit with less risk of ICH

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Whether and when to resume anticoagulation ?

• Old Dilemma

• A new trend

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Old Dilemma

• ICH in patients with atrial fibrillation, the risk of thromboembolism would need to exceed 7% per year to justify restarting anticoagulation after deep ICH,and no risk level was high enough to justify restarting anticoagulation after lobar ICH.

• The American Heart Association comments that for nonvalvular atrial fibrillation, long-term anticoagulation should be avoided after spontaneous lobar ICH, but that antiplatelet agents may be considered.

• The decision to restart anticoagulation may also be a function of whether the underlying risk factor is a temporary or long term one .

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Old Dilemma

Clearly, the risk is high on the first day, but small after the first few days.

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• A history of embolic stroke with atrial fibrillation, should be restarted on warfarin after 10 to 14 days, depending on the risk of thromboembolism and ICH recurrence.

Old Dilemma

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• The American College of Chest Physicians recommends starting prophylactic-dose heparin the day after an ICH, with no clear guidance on restarting warfarin.

Old Dilemma

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• The American Heart Association suggests that, in patients with a very high risk of thromboembolism for whom restarting warfarin is considered, warfarin may be restarted 7 to 10 days after ICH onset.

A new trend

• The decision to resume anticoagulation after anticoagulant-associated intracranial hemorrhage should be based on the risk of rebleeding vs the risk of thrombosis.

• Patients determined to be at high risk of thrombosis and low risk of rebleeding are the best candidates for resuming anticoagulation.

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INDICATION FOR VITAMIN K ANTAGONIST

MECHANICAL HEART VALVE

ATRIAL FIBRILLATION

VENOUS THROMBOEMBOLISM

High risk

Any mitral valve prosthesisOlder prosthetic aortic valveRecent stroke or transient ischemic attack (within 6

months(

CHADS2 score ≥ 5Recent stroke or transient ischemic attack (within 3 months(Rheumatic valvular heart disease

Recent event (within 3 months(Severe thrombophilia (low protein C, protein S, or antithrombin level; antiphospholipid antibody syndrome; multiple

abnormalities(

Moderate risk

Bileaflet aortic valve prosthesis and one of the following:Atrial fibrillationPrior stroke or transient ischemic attackHypertensionDiabetesCongestive heart failureAge over 75

CHADS2 score 3 or 4Prior stroke or transient ischemic attack

Venous thromboembolic event in the past 3 to 12 monthsNonsevere thrombophilic conditions (eg, heterozygous factor II mutation(Recurrent venous thromboembolismActive cancer (treated within 6 months, or

palliative treatment(

Low risk

Bileaflet aortic valve prosthesis without atrial fibrillation, and with no other stroke risk factors

CHADS2 score ≤ 2 and no prior stroke or transient ischemic attack

Single venous thromboembolic event > 12 months ago and no other risk factors

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Suggested risk stratification for recurrent intracranial hemorrhage

High risk

Cerebral amyloid angiopathy or lobar intracranial hemorrhage

Microbleeds on magnetic resonance imaging

Moderate risk

Hypertensive vasculopathy or deep intracranial hemorrhage with any of the

following: Normal international normalized ratio at the time the hemorrhage is diagnosed

Patient not compliant with the dosing and monitoring of vitamin K antagonist therapy Patient not compliant with antihypertensive therapy

Low riskHypertensive vasculopathy or deep intracranial hemorrhage in a compliant patient

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Suggested risk stratification for recurrent intracranial hemorrhage

High risk

Cerebral amyloid angiopathy or lobar intracranial hemorrhage Microbleeds on magnetic resonance

imaging

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Suggested risk stratification for recurrent intracranial hemorrhage

Moderate risk

Hypertensive vasculopathy or deep intracranial hemorrhage with any of the

following: Normal international normalized ratio at the time the hemorrhage is diagnosed

Patient not compliant with the dosing and monitoring of vitamin K antagonist therapy Patient not compliant with antihypertensive therapy

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Suggested risk stratification for recurrent intracranial hemorrhage

Low riskHypertensive vasculopathy or deep intracranial hemorrhage in a compliant patient

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RISK OF ICH RISK OF THROMBOEMBOLISM

High Moderate Low

High Do not resume Do not resume Do not resume

Moderate Individualized approach

Individualized approach

Do not resume

Low Resume Resume Do not resume

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How to avoid …

• Good control of warfarin intensity and limiting the use of aspirin, will reduce the risk of ICH.

• Blood pressure control is especially important for avoiding ICH. The use of warfarin in elderly patients should go hand in hand with aggressive blood pressure management.

• If patients on long-term warfarin have a history of falls, risk factor screening/intervention program for reducing the risk of falls may be of value.

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Take home message

• Pick up your poison• ICH is the nightmare• Acute management includes anticoagulant reversal and

should be the primary consideration in the first 24 hours

• Patients determined to be at high risk of thrombosis and low risk of rebleeding are the best candidates for resuming anticoagulation.

• Consider INR control ,BP control, patients with recurrent falls and other anticoagulation methods with higher compliance

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