Management of Anticoagulant and Antiplatelet-Related ICH
Management of Anticoagulant and Antiplatelet-Related ICH
Anticoagulation medications are important treatments for numerous medical conditions including DVT, pulmonary embolism, and nonvalvular AF. Unfortunately, these medications are associated with an increased risk of ICH. Often the cause of the hemorrhage is directly related to a supratherapeutic effect of the anticoagulant. In other situations therapeutic levels can exacerbate an ICH of an alternate origin (such as trauma or cerebral aneurysm rupture).
All of the anticoagulant medications alter the coagulation cascade at various points along the extrinsic, intrinsic, or common pathways with an ultimate goal of reduced fibrin formation (Fig. 1). Because of the frequency that neurosurgeons are consulted to aid in the management of patients with anticoagulant-related ICH, neurosurgeons should at least maintain a cursory understanding of these pathways and how they relate to the various anticoagulant medications.
(Enlarge Image)
Figure 1.
The clotting cascade including common anticoagulant medications and their site of action. vit = vitamin.
Injectable anticoagulants (unfractionated heparin and enoxaparin) are most commonly used during admission to a medical facility, whereas the most commonly prescribed outpatient anticoagulant is warfarin. Warfarin's immediate predecessor was designed as a rodenticide; in the 1950s, warfarin began common usage as a medical anticoagulation therapy. Warfarin is a vitamin K antagonist and prevents the hepatic formation of the vitamin K–dependent clotting factors (II, VII, IX, and X). Numerous randomized trials and meta-analyses have confirmed warfarin is highly effective at reducing the risk of stroke from AF. However, genetic polymorphisms, several common medications, as well as changes in a patient's diet can drastically alter the anticoagulation effect, which is compounded by warfarin's relatively narrow therapeutic window. As a result, frequent drug monitoring with a prothrombin time and the INR is required. Even with frequent drug monitoring, high INR levels are frequently encountered in the outpatient setting and medication adjustments must be made. The most frequently recommended INR level for the treatment of AF is between 2 and 3. Even in the setting of strict INR monitoring during clinical trials, it can be difficult to maintain patients in this narrow therapeutic window, and subtherapeutic and supratherapeutic levels are common. International normalized ratio levels greater than 4.0 have been reported to be associated with significantly increased risk for ICH. Warfarin-related ICH patients have a significantly increased risk of hematoma expansion (OR 6.2, 95% CI 1.7–22.9) compared with ICH patients not receiving anticoagulant therapy. After decades in which warfarin was the only oral anticoagulation therapy available to patients, new oral medications have recently gained approval by the FDA (www.fda.gov) that have much similar stroke protection, more reliable dose-response relationships, and do not require blood-level monitoring. These medications include dabigatran (a direct thrombin inhibitor), and rivaroxaban and apixaban, direct inhibitors of factor Xa. Many cardiologists and neurologists have been increasingly prescribing these medications over the last few years. However, this enthusiasm has been tempered by the lack of an antidote and fear of being unable to safely manage patients taking these new medications who experience anticoagulant-related ICH. The silver lining to these uncertainties is that the incidence of major hemorrhage in Phase III clinical trials for these new oral anticoagulants is lower than that of warfarin.
A prospective randomized, open-label trial (Randomized Evaluation of Long-Term Anticoagulation Therapy, or RE-LY) compared 2 blinded doses of dabigatran (110 mg twice daily and 150 mg twice daily) with open-label adjusted dose warfarin (INR target 2.0–3.0) in 18,113 patients. Dabigatran 150 mg twice daily was found to be significantly better than warfarin at preventing stroke or systemic embolism, and dabigatran 110 mg twice daily was demonstrated as noninferior to warfarin. Both doses of dabigatran were found to produce a significant reduction in the rates of ICH and hemorrhagic stroke compared with warfarin (dabigatran 0.12%, 0.10% vs warfarin 0.38% per year; RR 0.31 and 0.26; p < 0.01 [both]). Only the 150-mg dose tested in the study is available in the US. Similar results were found in other prospective randomized, double-blind Phase III clinical trials including the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) and Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, in which rivaroxaban and apixaban were both found to demonstrate statistically significant reductions in hemorrhagic stroke compared with warfarin. Recently, the American College of Chest Physicians published their newest recommendations for antithrombotic therapy for atrial fibrillation; they are now suggesting dabigatran 150 mg twice daily rather than warfarin when oral anticoagulant therapy is recommended. As these newer oral anticoagulants are increasingly prescribed more frequently, we hope a real-world decrease in the frequency of anticoagulant-related ICH will follow. Nevertheless, there will be patients with anticoagulant-related ICH who need emergency attention and immediate reversal of the anticoagulating effects.
Hematoma expansion is common in the setting of anticoagulant-related ICH, leading to more deaths. Correcting the INR to 1.3 or less within 2 hours has been shown to decrease hematoma expansion. Advances and improvements have been made in methods for reversal of warfarin (a summary of common anticoagulants and their reversal methods can be found in Table 1). The first consideration for emergency management of anticoagulant-related ICH is to stop the anticoagulant agent. Blood pressure should be controlled, although there is little evidence to support a specific blood pressure goal. The authors' preference is to maintain the systolic blood pressure below 160 mm Hg. Medical management of elevated intracranial pressure should be initiated immediately. Fast-acting agents for reversal of anticoagulation by factor replacement include FFP, PCC, and rVIIa. Of these, FFP (the historical standard of care) is relatively deficient in factor IX, requires large volume infusion, and can lead to complications such as pulmonary edema and delayed reversal of INR. Recombinant factor VIIa is effective for immediate INR reversal and prevention of hematoma expansion, but is associated with increased thrombotic complications such as myocardial infarction, pulmonary embolism, and DVT. Recombinant factor VIIa has not been shown to improve survival or functional outcome and is generally not recommended for reversal in anticoagulant-related ICH. Prothrombin complex concentrate is increasing in popularity as a low-volume, rapid-reversal agent, and has been reported as superior to FFP in several studies. Individualized dosing of PCC may be the most effective method of reversal. In 1 study, individualized dosing of PCC based on the patient's body weight and initial INR was superior at reaching the target INR 15 minutes after dosing compared with the standard dosage of PCC. Similar data has led to support for PCC as the standard of care at many institutions.
Prothrombin complex concentrate formulations vary worldwide, with the US receiving FDA approval for "3-factor" PCC (II, IX, X) whereas many clinical studies conducted outside the US involve "4-factor" PCC, which includes factor VII. It is unclear whether the difference in these preparations is significant and any review of the literature on this topic needs to have this critique in mind. Even though PCC formulations have variable amounts of factor VII, PCC replaces multiple factors compared with rVIIa, and is cost effective when compared with FFP for serious bleeding. When reversing warfarin one must remember that treatment with a fast-acting agent alone is not enough for a sustained reversal effect. It is necessary to also administer vitamin K (orally or intravenously) to maintain INR reversal. In emergency situations, vitamin K should not be used alone, but should be used in conjunction with faster-acting agents because vitamin K can take up to 24 hours to achieve INR correction. Additionally, intravenous (versus oral) vitamin K is associated with a low risk of anaphylaxis, but generally remains the preferred route of administration.
New oral anticoagulants (dabigatran, rivaroxaban, apixaban) have recently been approved by the FDA for use in patients with AF for the prevention of stroke and for the treatment of acute DVT (rivaroxaban). The advantages of these medications include a more reliable anticoagulant effect, decreased risk of associated ICH, and no need for monitoring of therapeutic levels. The biggest disadvantage of these medications is the lack of an antidote. For recent dosing or recent overdose, consider oral activated charcoal to help absorb the drug and reduce the bioavailability. Strategies for reversal may include FFP, PCC, and/or rVIIa administration, but current studies show that for dabigatran these methods may be ineffective and only moderately effective with rivaroxaban. Current evidence is too weak to support a specific reversal protocol for any of these medications; thus, supportive care is essential for ICH related to these medications. As dabigatran is cleared by renal excretion, optimizing renal function is necessary. Hemodialysis has been suggested as an emergency means of removal of dabigatran, and may be the most effective means in patients with impaired creatinine clearance. With dabigatran, a normal activated partial thromboplastin time suggests no active anticoagulation effect and can be used to guide reversal therapy or timing of surgical intervention. For rivaroxaban and apixaban, emergency reversal with PCC is likely the most effective option as both are Xa inhibitors and PCC is more likely to be effective with these medications than with dabigatran (a direct thrombin inhibitor; Fig. 1). Confirmation of normal antifactor Xa assay activity is useful in showing that rivaroxaban and apixaban are no longer causing an anticoagulation effect.
In the case of anticoagulant-related ICH, warfarin remains the most commonly prescribed oral anticoagulant, but due to improved dose response, larger therapeutic windows, and reduced risk of ICH, newer oral agents such as dabigatran, rivaroxaban, and apixaban are being used with increasing frequency. Having a basic appreciation for the pharmacokinetics of these medications, including possible reversal strategies in the setting of ICH, are essential for patient safety. Although there are no specific antidotes to the newer oral anticoagulants, reversal strategies do exist and may be implemented in emergency situations. Additional research studies evaluating the best methods for reversal of these medications are ongoing and much needed.
Anticoagulant-Related ICH
Anticoagulation medications are important treatments for numerous medical conditions including DVT, pulmonary embolism, and nonvalvular AF. Unfortunately, these medications are associated with an increased risk of ICH. Often the cause of the hemorrhage is directly related to a supratherapeutic effect of the anticoagulant. In other situations therapeutic levels can exacerbate an ICH of an alternate origin (such as trauma or cerebral aneurysm rupture).
All of the anticoagulant medications alter the coagulation cascade at various points along the extrinsic, intrinsic, or common pathways with an ultimate goal of reduced fibrin formation (Fig. 1). Because of the frequency that neurosurgeons are consulted to aid in the management of patients with anticoagulant-related ICH, neurosurgeons should at least maintain a cursory understanding of these pathways and how they relate to the various anticoagulant medications.
(Enlarge Image)
Figure 1.
The clotting cascade including common anticoagulant medications and their site of action. vit = vitamin.
Injectable anticoagulants (unfractionated heparin and enoxaparin) are most commonly used during admission to a medical facility, whereas the most commonly prescribed outpatient anticoagulant is warfarin. Warfarin's immediate predecessor was designed as a rodenticide; in the 1950s, warfarin began common usage as a medical anticoagulation therapy. Warfarin is a vitamin K antagonist and prevents the hepatic formation of the vitamin K–dependent clotting factors (II, VII, IX, and X). Numerous randomized trials and meta-analyses have confirmed warfarin is highly effective at reducing the risk of stroke from AF. However, genetic polymorphisms, several common medications, as well as changes in a patient's diet can drastically alter the anticoagulation effect, which is compounded by warfarin's relatively narrow therapeutic window. As a result, frequent drug monitoring with a prothrombin time and the INR is required. Even with frequent drug monitoring, high INR levels are frequently encountered in the outpatient setting and medication adjustments must be made. The most frequently recommended INR level for the treatment of AF is between 2 and 3. Even in the setting of strict INR monitoring during clinical trials, it can be difficult to maintain patients in this narrow therapeutic window, and subtherapeutic and supratherapeutic levels are common. International normalized ratio levels greater than 4.0 have been reported to be associated with significantly increased risk for ICH. Warfarin-related ICH patients have a significantly increased risk of hematoma expansion (OR 6.2, 95% CI 1.7–22.9) compared with ICH patients not receiving anticoagulant therapy. After decades in which warfarin was the only oral anticoagulation therapy available to patients, new oral medications have recently gained approval by the FDA (www.fda.gov) that have much similar stroke protection, more reliable dose-response relationships, and do not require blood-level monitoring. These medications include dabigatran (a direct thrombin inhibitor), and rivaroxaban and apixaban, direct inhibitors of factor Xa. Many cardiologists and neurologists have been increasingly prescribing these medications over the last few years. However, this enthusiasm has been tempered by the lack of an antidote and fear of being unable to safely manage patients taking these new medications who experience anticoagulant-related ICH. The silver lining to these uncertainties is that the incidence of major hemorrhage in Phase III clinical trials for these new oral anticoagulants is lower than that of warfarin.
A prospective randomized, open-label trial (Randomized Evaluation of Long-Term Anticoagulation Therapy, or RE-LY) compared 2 blinded doses of dabigatran (110 mg twice daily and 150 mg twice daily) with open-label adjusted dose warfarin (INR target 2.0–3.0) in 18,113 patients. Dabigatran 150 mg twice daily was found to be significantly better than warfarin at preventing stroke or systemic embolism, and dabigatran 110 mg twice daily was demonstrated as noninferior to warfarin. Both doses of dabigatran were found to produce a significant reduction in the rates of ICH and hemorrhagic stroke compared with warfarin (dabigatran 0.12%, 0.10% vs warfarin 0.38% per year; RR 0.31 and 0.26; p < 0.01 [both]). Only the 150-mg dose tested in the study is available in the US. Similar results were found in other prospective randomized, double-blind Phase III clinical trials including the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) and Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, in which rivaroxaban and apixaban were both found to demonstrate statistically significant reductions in hemorrhagic stroke compared with warfarin. Recently, the American College of Chest Physicians published their newest recommendations for antithrombotic therapy for atrial fibrillation; they are now suggesting dabigatran 150 mg twice daily rather than warfarin when oral anticoagulant therapy is recommended. As these newer oral anticoagulants are increasingly prescribed more frequently, we hope a real-world decrease in the frequency of anticoagulant-related ICH will follow. Nevertheless, there will be patients with anticoagulant-related ICH who need emergency attention and immediate reversal of the anticoagulating effects.
Hematoma expansion is common in the setting of anticoagulant-related ICH, leading to more deaths. Correcting the INR to 1.3 or less within 2 hours has been shown to decrease hematoma expansion. Advances and improvements have been made in methods for reversal of warfarin (a summary of common anticoagulants and their reversal methods can be found in Table 1). The first consideration for emergency management of anticoagulant-related ICH is to stop the anticoagulant agent. Blood pressure should be controlled, although there is little evidence to support a specific blood pressure goal. The authors' preference is to maintain the systolic blood pressure below 160 mm Hg. Medical management of elevated intracranial pressure should be initiated immediately. Fast-acting agents for reversal of anticoagulation by factor replacement include FFP, PCC, and rVIIa. Of these, FFP (the historical standard of care) is relatively deficient in factor IX, requires large volume infusion, and can lead to complications such as pulmonary edema and delayed reversal of INR. Recombinant factor VIIa is effective for immediate INR reversal and prevention of hematoma expansion, but is associated with increased thrombotic complications such as myocardial infarction, pulmonary embolism, and DVT. Recombinant factor VIIa has not been shown to improve survival or functional outcome and is generally not recommended for reversal in anticoagulant-related ICH. Prothrombin complex concentrate is increasing in popularity as a low-volume, rapid-reversal agent, and has been reported as superior to FFP in several studies. Individualized dosing of PCC may be the most effective method of reversal. In 1 study, individualized dosing of PCC based on the patient's body weight and initial INR was superior at reaching the target INR 15 minutes after dosing compared with the standard dosage of PCC. Similar data has led to support for PCC as the standard of care at many institutions.
Prothrombin complex concentrate formulations vary worldwide, with the US receiving FDA approval for "3-factor" PCC (II, IX, X) whereas many clinical studies conducted outside the US involve "4-factor" PCC, which includes factor VII. It is unclear whether the difference in these preparations is significant and any review of the literature on this topic needs to have this critique in mind. Even though PCC formulations have variable amounts of factor VII, PCC replaces multiple factors compared with rVIIa, and is cost effective when compared with FFP for serious bleeding. When reversing warfarin one must remember that treatment with a fast-acting agent alone is not enough for a sustained reversal effect. It is necessary to also administer vitamin K (orally or intravenously) to maintain INR reversal. In emergency situations, vitamin K should not be used alone, but should be used in conjunction with faster-acting agents because vitamin K can take up to 24 hours to achieve INR correction. Additionally, intravenous (versus oral) vitamin K is associated with a low risk of anaphylaxis, but generally remains the preferred route of administration.
New oral anticoagulants (dabigatran, rivaroxaban, apixaban) have recently been approved by the FDA for use in patients with AF for the prevention of stroke and for the treatment of acute DVT (rivaroxaban). The advantages of these medications include a more reliable anticoagulant effect, decreased risk of associated ICH, and no need for monitoring of therapeutic levels. The biggest disadvantage of these medications is the lack of an antidote. For recent dosing or recent overdose, consider oral activated charcoal to help absorb the drug and reduce the bioavailability. Strategies for reversal may include FFP, PCC, and/or rVIIa administration, but current studies show that for dabigatran these methods may be ineffective and only moderately effective with rivaroxaban. Current evidence is too weak to support a specific reversal protocol for any of these medications; thus, supportive care is essential for ICH related to these medications. As dabigatran is cleared by renal excretion, optimizing renal function is necessary. Hemodialysis has been suggested as an emergency means of removal of dabigatran, and may be the most effective means in patients with impaired creatinine clearance. With dabigatran, a normal activated partial thromboplastin time suggests no active anticoagulation effect and can be used to guide reversal therapy or timing of surgical intervention. For rivaroxaban and apixaban, emergency reversal with PCC is likely the most effective option as both are Xa inhibitors and PCC is more likely to be effective with these medications than with dabigatran (a direct thrombin inhibitor; Fig. 1). Confirmation of normal antifactor Xa assay activity is useful in showing that rivaroxaban and apixaban are no longer causing an anticoagulation effect.
In the case of anticoagulant-related ICH, warfarin remains the most commonly prescribed oral anticoagulant, but due to improved dose response, larger therapeutic windows, and reduced risk of ICH, newer oral agents such as dabigatran, rivaroxaban, and apixaban are being used with increasing frequency. Having a basic appreciation for the pharmacokinetics of these medications, including possible reversal strategies in the setting of ICH, are essential for patient safety. Although there are no specific antidotes to the newer oral anticoagulants, reversal strategies do exist and may be implemented in emergency situations. Additional research studies evaluating the best methods for reversal of these medications are ongoing and much needed.
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