If a patient taking warfarin (Coumadin) or other anticoagulant drug suffers an intracerebral hemorrhage (ICH) and survives, the physician faces the dilemma of whether to resume the anticoagulant. On one hand, the drug was prescribed because the patient was at risk of a thromboembolic event such as stroke or pulmonary embolism. On the other hand, warfarin use may increase the risk of another ICH.
Unfortunately, we have little evidence from clinical trials on which to base the decision. Nevertheless, we believe that in selected patients the potential benefit of resuming anticoagulation outweighs the considerable risk.
In the pages that follow, we summarize when and how anticoagulation therapy should be resumed after ICH.
A DEADLY COMPLICATION OF ANTICOAGULANT THERAPY
Intracranial bleeding is the most feared and the most deadly complication of oral anticoagulant therapy.1 The substantial risks associated with oral anticoagulants likely account for these drugs being underprescribed in patients who have indications for them.2–4
While bleeding is the major risk, not all bleeding events are equally damaging. Extracranial bleeding (eg, gastrointestinal bleeding, hematuria, epistaxis) leads to death or disability in only 3% of cases, whereas intracranial bleeding such as ICH leads to death or disability 76% of cases.5
Even without anticoagulation, ICH is the deadliest form of stroke,6–9 and if the patient has been taking warfarin, the risk of disability and death is substantially higher.6,10 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.11,12 In addition, once ICH occurs, the risk of death is up to twice as high in those on warfarin.6 The bulk of this effect is likely due to a higher risk of ongoing bleeding after the event.10,13–16
Major risk factors for ICH in patients taking oral anticoagulants include a higher international normalized ratio (INR) and older age.11,17
TWO KEY QUESTIONS
Once a patient is diagnosed with warfarin-related ICH, clinicians typically take urgent measures to restore normal coagulation, hoping to limit ongoing bleeding and improve outcome.18,19
The higher the INR at presentation, the greater the risk of death.6 In addition, in retrospective studies, some authors have noted that earlier correction of the INR is associated with better outcome.14,16
While emergency reversal of warfarin is widely considered standard treatment in the acute phase,20–24 concern persists about its safety in patients at high risk of thromboembolism.
Until the results of clinical trials are available, decisions about whether to reverse and when to resume anticoagulation hinge on two questions:
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?
ACUTELY, THE RISK OF BLEEDING OUTWEIGHS THAT OF CLOTTING
High risk of hematoma expansion after ICH
Unfortunately, continued bleeding is common after ICH. In patients who present within 3 hours of symptom onset, 26% of hematomas expand more than 33% over the first hour, and another 12% expand this amount over the next 20 hours.6 In warfarin-associated ICH, up to 50% of patients develop this level of hematoma expansion, but it appears to take place over a more prolonged period of time.10,13–16 Over 70% of patients presenting acutely develop at least some amount of expansion within 24 hours.25 Therefore, the risk of hematoma expansion in the first 24 hours is likely so high that patients cannot safely receive anticoagulants during this time frame.
But not all patients are at equal risk of hematoma expansion. Several features are associated with higher risk (Table 1)10,26–40:
A large hematoma volume on presentation is a significant predictor of expansion, possibly reflecting a more severe underlying insult.26,27
Early presentation, especially within 3 hours of symptom onset, also appears to mark those at higher risk, presumably because such patients undergo computed tomography (CT) while still bleeding.26,27
Figure 1. The “spot sign” (arrow), contrast extravasation after contrast-enhanced computed tomography, is associated with a high risk of hematoma expansion.For those on warfarin, a higher INR is a significant predictor, not just of higher risk, but also of a more delayed expansion.10,28
Certain radiographic findings indicate higher risk. One is the “spot sign,” ie, contrast extravasation after contrast-enhanced CT27,29–31 (Figure 1). Apparently, the more spots present, and the denser the contrast, the greater the risk, an observation that has led to a proposed “spot-sign score” that may predict both expansion and poor outcome. 32,41
Given the high risk of hematoma expansion in the early phase, and given our inability to predict hematoma expansion, most authorities recommend immediate reversal of anticoagulation after diagnosis.42–44 Reversal of anticoagulation typically includes intravenous vitamin K, which begins to act within several hours, and repletion of coagulation factors, which act within minutes (prothrombin complex concentrates and recombinant factor VIIa [NovoSeven]) or a few hours (fresh frozen plasma).1
Dosages:
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.
Risk of thromboembolism after ICH: Ongoing and cumulative
Thromboembolism after ICH is a major concern, for two main reasons.
First, patients on oral anticoagulation typically have a preexisting risk factor and are thus at higher risk of a thromboembolic event, particularly while they are off anticoagulation. Patients with atrial fibrillation or a mechanical valve are at risk of arterial events such as ischemic stroke, whereas patients with a known venous thromboembolic condition such as deep venous thrombosis or pulmonary embolism are at risk of extension of the thrombosis or recurrence of a venous thrombotic event.
Second, ICH itself increases the risk of arterial and venous thromboembolic events. Including patients not previously on anticoagulation, this risk is as high as 7% during the initial hospitalization and 9% during the first 90 days.45,46 Worth noting is that patients who previously received anticoagulant drugs (and who are off this therapy in the acute phase) are at no higher risk of thromboembolism compared with those who never received anticoagulants.45
However, while the risk of hematoma expansion is highest at presentation and then decreases with time, the risk of thromboembolism (particularly venous thromboembolism) is ongoing and cumulative. Arterial thromboembolism is more likely to occur early, within the first week, whereas venous thromboembolism can occur later.45
Overall, studies have estimated the short-term risk of pulmonary embolism to be 1% to 2%, deep venous thrombosis 1% to 4%, myocardial ischemia about 2%, and cerebral ischemia 2% to 3%.45,46 However, when patients are actively screened, the incidence of asymptomatic deep venous thrombosis is found to be as high as 16% in the first 10 days,47 and evidence of myocardial ischemia can be detected in up to 27% of patients.48
Therefore, the risk of hematoma expansion appears to be high and the risk of thromboembolism appears to be low during the first day after ICH. Over the next days, as the risk of hematoma expansion recedes, this ratio shifts.
Studies of in-hospital anticoagulation after ICH
The data on restarting oral anticoagulation in the acute phase are sparse. In practice, clinicians typically start heparinoids in low subcutaneous doses to prevent deep venous thrombosis and, after the first few days or a week, consider increasing to a full anticoagulation dose or starting an oral anticoagulant and subsequently discontinuing the heparin when the INR is in the therapeutic range (see discussion below).
ICH patients in general may benefit from starting prophylactic-dose heparin therapy early. One randomized trial found that starting heparin in a low subcutaneous dose the day after an ICH decreased the risk of thromboembolism without increasing the risk of rebleeding.49 Another study also found no increased risk of rebleeding with early prophylactic-dose subcutaneous heparin.50
As the benefit appears to outweigh the risk, national guidelines suggest starting subcutaneous heparin early in all ICH patients, including those not previously on warfarin.42,43
Commonly used heparinoid regimens include unfractionated heparin 5,000 units subcutaneously twice a day; enoxaparin (Lovenox) 40 mg once a day; and dalteparin (Fragmin) 5,000 units once a day.51 In addition, all patients should receive optimal mechanical thromboprophylaxis, including graduated compression stockings or intermittent pneumatic compression stockings, or both.
LONG-TERM MANAGEMENT: ICH RECURRENCE VS THROMBOEMBOLISM
Risk of ICH recurrence on warfarin is not precisely known
Overall, the risk of ICH recurrence is about 1% at 3 months, and warfarin likely increases this risk.42,52 Unfortunately, the risk of ICH recurrence in patients on anticoagulation therapy after a first ICH is not clear, and no population-based study has clarified this risk. Therefore, the best we can do at present is to try to estimate the risk of recurrent warfarin-related ICH by separately examining two issues:
The risk of ICH recurrence in general
The risk of major bleeding (including ICH) in the general population of patients on warfarin.
The risk of ICH recurrence in general is about 2% to 4% per patient-year.52–54 However, this risk appears to be a function of the underlying vasculopathy. ICH location is often used as a surrogate for underlying cause. Most ICHs in deep hemispheric (basal ganglia, thalamus) or brainstem territories are likely caused by hypertensive vasculopathy, whereas lobar ICH is often associated with cerebral amyloid angiopathy.52–54 Presumably because of this distinction, ICH in a deep location recurs in about 2% of cases per year, compared with 4% for lobar ICH.53 The presence and number of microbleeds on T2-weighted gradient-echo magnetic resonance imaging appear to predict ICH recurrence; microbleeds likely are markers of more severe or widespread underlying vasculopathy.55–57
A genetic risk factor for the recurrence of lobar ICH is apolipoprotein E genotype58; future studies may highlight genetic variations that specifically modify the risk of warfarin-related ICH.59 Unfortunately, there is currently no way to modify the risk of ICH associated with cerebral amyloid angiopathy. On the other hand, in patients with hypertensive hemorrhage, antihypertensive therapy likely reduces the risk of recurrent ICH. One randomized controlled trial showed that such therapy decreased the risk of ICH by more than half.60
The risk of major bleeding in the general population of patients on warfarin may be 2% to 3% per year and is likely higher in the first month.11 The risk is higher in older patients and if the INR rises above 4.0.11,17 For some patients, it is possible to estimate the likelihood of major bleeding using validated decision-support tools that include factors such as age, sex, and medical history.11,61–64
Given the lack of data specifically addressing the risk of ICH recurrence on warfarin, the clinician is left to try to extrapolate this risk from available data using specific patient characteristics that modify the presumed risk. For example, one can combine factors such as ICH location (or better yet, the underlying cause) with decision-support tools that predict the risk of major bleeding. Close control of both blood pressure and the INR appears especially critical for patients receiving anticoagulation after ICH.11,60,65 Still, the risk does not disappear with good INR control, and most patients with anticoagulation-related ICH present with INRs within the therapeutic range.5,10,65
Long-term risk of thromboembolism depends on underlying condition
In the long term, the risk of thromboembolism depends on the reason for which the patient was originally given anticoagulation. In addition, many patients with ICH suffer decreased mobility and are therefore at higher risk of venous thromboembolism than before their event.
Nonvalvular atrial fibrillation is the most common indication for anticoagulation. For these patients, the risk of ischemic stroke is 2% to 5% per year.66,67 The system usually used to stratify this risk is CHADS2, an acronym for five key risk factors:
Congestive heart failure (1 point)
Hypertension (1 point)
Age over 75 (1 point)
Diabetes mellitus (1 point)
Prior stroke or transient ischemic attack (2 points).
The annual risk of stroke ranges from 1.9% (score of 0) to 18.2% (score of 6).68,69 In patients with nonvalvular atrial fibrillation, the excess risk of ischemic stroke without anticoagulation must be weighed against the risk of ICH recurrence.
A mechanical heart valve, another common indication, carries a risk of ischemic stroke of about 4% per year.70 A mechanical valve is traditionally considered an absolute indication for anticoagulation. However, patients with lobar ICH face a risk of recurrence that is greater than 4% per year, and so the risks of resuming anticoagulation may well outweigh the benefits.
Heart failure may be associated with a risk of ischemic stroke of 1% to 4% per year, and this is likely a function of disease severity.71
Venous thromboembolism. The risk of recurrent venous thromboembolism in patients with deep venous thrombosis or pulmonary embolism is around 4% per year.72 Given that ICH itself confers a 2% to 3% risk of these conditions, the rate of recurrence of deep venous thrombosis may well be much higher in those ICH patients who have also already had deep venous thrombosis.
Data on resuming oral anticoagulation after ICH
Several studies have examined the outcomes when oral anticoagulants were resumed after ICH (Table 2),73–76 but experts differ on when these drugs should be resumed (eg, between 1 and 10 days after onset), or even whether they should be resumed at all.19
Notably, an analysis of 52 patients found a high risk of ICH recurrence (and gastrointestinal bleeding) in patients who restarted warfarin, and a high risk of myocardial infarction and ischemic stroke in those who did not restart, with neither strategy demonstrating a clear benefit in the rate of death or disability.73 All patients with a thromboembolic event were being treated for a previous event, suggesting that secondary prevention is a stronger indication for anticoagulation than primary prevention in this population.73
IF AND WHEN TO RESTART
Two major questions to consider are whether the benefits of restarting anticoagulation outweigh the risk, and if so, when and how should anticoagulation be restarted?
Whether to restart anticoagulation
As for the risk-benefit ratio, many think that anticoagulation should be restarted only with extreme caution and possibly only in those with deep ICH or a documented history of thromboembolism.19
In one decision analysis examining whether to restart anticoagulation after ICH in patients with atrial fibrillation, the risk of thromboembolism would need to exceed 7% per year to justify restarting anticoagulation after deep ICH,67 and no risk level was high enough to justify restarting anticoagulation after lobar ICH.
For patients at sufficiently high risk of ICH recurrence, antiplatelet treatment is probably safer, as antiplatelet agents carry a substantially lower risk of bleeding.54,77–79 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. 42 They note that anticoagulation after nonlobar ICH may be considered depending on the indication.42
The decision to restart anticoagulation may also be a function of whether the underlying risk factor is a temporary one. For example, atrial fibrillation or a mechanical heart valve confers a long-term, ongoing risk of arterial thromboembolism, and such patients would not normally be considered for a short course of warfarin therapy. However, isolated deep vein thrombosis may only require anticoagulation for a limited time, such as 3 to 6 months.80 Perhaps for such patients the long-term outcome is maximized with a narrowly defined, temporary course of anticoagulation.
When to restart anticoagulation
As for when to restart, it is not certain how long after symptom onset the risk of ongoing bleeding continues. Clearly, the risk is high on the first day, but small after the first few days.
The European Stroke Initiative recommends that patients with a strong indication for anticoagulation, such as 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.43
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.42
The American College of Chest Physicians recommends starting prophylactic-dose heparin the day after an ICH, with no clear guidance on restarting warfarin.81
ALTERNATIVES TO WARFARIN
Alternatives to warfarin that show promise in reducing bleeding risk include factor Xa and direct thrombin inhibitors, which may reduce the risk of thromboembolism to an extent similar to that of warfarin, but with fewer bleeding complications.82
In patients with atrial fibrillation, the direct thrombin inhibitor dabigatran (Pradaxa) was shown to prevent ischemic stroke to a similar or greater degree than warfarin, with fewer bleeding complications.83 Further patient follow-up is under way to ensure that this drug does not cause liver problems, as did a similarly designed predecessor.84
The availability of this and other agents in various stages of development82 will probably not make warfarin extinct. Rather, they may change the “tipping point,” the threshold at which the risk of thromboembolism is high enough to justify the risks associated with restarting warfarin therapy. In addition, clinical decision tools clarifying the individual patient’s risk of thromboembolism vs the risk of ICH recurrence will help physicians tailor the therapy to the patient.
For the moment, in situations in which the decision is difficult, maximizing the use of antiplatelet agents offers the best hope.85
RECOMMENDATIONS IN LIEU OF GUIDELINES
No guideline can broadly cover every clinical scenario. Many factors go into assessing a patient’s risk of hematoma expansion or recurrent hemorrhage (Table 3) and the extent to which anticoagulation can reduce the risk of thromboembolism.
In the short term, most patients with ICH will likely benefit from acute reversal of anticoagulation, followed by gradual reinstitution of prophylactic-dose anticoagulation after the first 24 to 72 hours.
In the long term, many patients with lobar hemorrhage, cerebral amyloid angiopathy, or other risk factors may remain at higher risk of anticoagulant-related ICH recurrence than of fatal or disabling thromboembolic events and would therefore be best managed without anticoagulants. Conversely, those with deep hemispheric ICH, hypertension that can be well controlled, and a high risk of disabling thromboembolism may receive a net benefit from restarting anticoagulation.
Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med2007; 167:1414–1419.
Choudhry NK, Anderson GM, Laupacis A, Ross-Degnan D, Normand SL, Soumerai SB. Impact of adverse events on prescribing warfarin in patients with atrial fibrillation: matched pair analysis. BMJ2006; 332:141–145.
Choudhry NK, Soumerai SB, Normand SL, Ross-Degnan D, Laupacis A, Anderson GM. Warfarin prescribing in atrial fibrillation: the impact of physician, patient, and hospital characteristics. Am J Med2006; 119:607–615.
Fang MC, Go AS, Chang Y, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med2007; 120:700–705.
Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med2004; 164:880–884.
Dixon AA, Holness RO, Howes WJ, Garner JB. Spontaneous intracerebral haemorrhage: an analysis of factors affecting prognosis. Can J Neurol Sci1985; 12:267–271.
Broderick JP, Adams HP, Barsan W, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke1999; 30:905–915.
Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology2004; 63:1059–1064.
Schulman S, Beyth RJ, Kearon C, Levine MN; American College of Chest Physicians. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest2008; 133(suppl 6):257S–298S.
Flaherty ML, Kissela B, Woo D, et al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology2007; 68:116–121.
Lee SB, Manno EM, Layton KF, Wijdicks EF. Progression of warfarin-associated intracerebral hemorrhage after INR normalization with FFP. Neurology2006; 67:1272–1274.
Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke2006; 37:1465–1470.
Sjöblom L, Hårdemark HG, Lindgren A, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke2001; 32:2567–2574.
Yasaka M, Minematsu K, Naritomi H, Sakata T, Yamaguchi T. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost2003; 89:278–283.
Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation2007; 115:2689–2696.
Goldstein JN, Thomas SH, Frontiero V, et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke2006; 37:151–155.
Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc2007; 82:82–92.
Guidelines on oral anticoagulation: third edition. Br J Haematol1998; 101:374–387.
Baglin TP, Keeling DM, Watson HG; British Committee for Standards in Haematology. Guidelines on oral anticoagulation (warfarin): third edition—2005 update. Br J Haematol2006; 132:277–285.
O’Shaughnessy DF, Atterbury C, Bolton Maggs P, et al; British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol2004; 126:11–28.
Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM; Warfarin Reversal Consensus Group. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust2004; 181:492–497.
Davis SM, Broderick J, Hennerici M, et al; Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology2006; 66:1175–1181.
Broderick JP, Diringer MN, Hill MD, et al; Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Determinants of intracerebral hemorrhage growth: an exploratory analysis. Stroke2007; 38:1072–1075.
Goldstein JN, Fazen LE, Snider R, et al. Contrast extravasation on CT angiography predicts hematoma expansion in intracerebral hemorrhage. Neurology2007; 68:889–894.
Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke1996; 27:1783–1787.
Kim J, Smith A, Hemphill JC, et al. Contrast extravasation on CT predicts mortality in primary intracerebral hemorrhage. AJNR Am J Neuroradiol2008; 29:520–525.
Wada R, Aviv RI, Fox AJ, et al. CT angiography “spot sign” predicts hematoma expansion in acute intracerebral hemorrhage. Stroke2007; 38:1257–1262.
Barras CD, Tress BM, Christensen S, et al; Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Density and shape as CT predictors of intracerebral hemorrhage growth. Stroke2009; 40:1325–1331.
Delgado Almandoz JE, Yoo AJ, Stone MJ, et al. Systematic characterization of the computed tomography angiography spot sign in primary intracerebral hemorrhage identifies patients at highest risk for hematoma expansion: the spot sign score. Stroke2009; 40:2994–3000.
Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Tanaka R. Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage. Stroke1998; 29:1160–1166.
Ederies A, Demchuk A, Chia T, et al. Postcontrast CT extravasation is associated with hematoma expansion in CTA spot negative patients. Stroke2009; 40:1672–1676.
Delgado P, Alvarez-Sabín J, Abilleira S, et al. Plasma d-dimer predicts poor outcome after acute intracerebral hemorrhage. Neurology2006; 67:94–98.
Naidech AM, Jovanovic B, Liebling S, et al. Reduced platelet activity is associated with early clot growth and worse 3-month outcome after intracerebral hemorrhage. Stroke2009; 40:2398–2401.
Silva Y, Leira R, Tejada J, Lainez JM, Castillo J, Dávalos A; Stroke Project, Cerebrovascular Diseases Group of the Spanish Neurological Society. Molecular signatures of vascular injury are associated with early growth of intracerebral hemorrhage. Stroke2005; 36:86–91.
Sansing LH, Messe SR, Cucchiara BL, Cohen SN, Lyden PD, Kasner SE; CHANT Investigators. Prior antiplatelet use does not affect hemorrhage growth or outcome after ICH. Neurology2009; 72:1397–1402.
Moussouttas M, Malhotra R, Fernandez L, et al. Role of antiplatelet agents in hematoma expansion during the acute period of intracerebral hemorrhage. Neurocrit Care2010; 12:24–29.
Delgado Almandoz JE, Yoo AJ, Stone MJ, et al. The spot sign score in primary intracerebral hemorrhage identifies patients at highest risk of in-hospital mortality and poor outcome among survivors. Stroke2010; 41:54–60.
Broderick J, Connolly S, Feldmann E, et al; American Heart Association; American Stroke Association Stroke Council; High Blood Pressure Research Council; Quality of Care and Outcomes in Research Interdisciplinary Working Group. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke2007; 38:2001–2023.
Steiner T, Kaste M, Forsting M, et al. Recommendations for the management of intracranial haemorrhage - part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis2006; 22:294–316.
Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke2006; 37:256–262.
Goldstein JN, Fazen LE, Wendell L, et al. Risk of thromboembolism following acute intracerebral hemorrhage. Neurocrit Care2009; 10:28–34.
Christensen MC, Dawson J, Vincent C. Risk of thromboembolic complications after intracerebral hemorrhage according to ethnicity. Adv Ther2008; 25:831–841.
Lacut K, Bressollette L, Le Gal G, et al; VICTORIAh (Venous Intermittent Compression and Thrombosis Occurrence Related to Intracerebral Acute hemorrhage) Investigators. Prevention of venous thrombosis in patients with acute intracerebral hemorrhage. Neurology2005; 65:865–869.
Diringer MN, Skolnick BE, Mayer SA, et al. Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial. Stroke2010; 41:48–53.
Boeer A, Voth E, Henze T, Prange HW. Early heparin therapy in patients with spontaneous intracerebral haemorrhage. J Neurol Neurosurg Psychiatry1991; 54:466–467.
Dickmann U, Voth E, Schicha H, Henze T, Prange H, Emrich D. Heparin therapy, deep-vein thrombosis and pulmonary embolism after intracerebral hemorrhage. Klin Wochenschr1988; 66:1182–1183.
Geerts WH, Bergqvist D, Pineo GF, et al; American College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest2008; 133(suppl 6):381S–453S.
Vermeer SE, Algra A, Franke CL, Koudstaal PJ, Rinkel GJ. Long-term prognosis after recovery from primary intracerebral hemorrhage. Neurology2002; 59:205–209.
Bailey RD, Hart RG, Benavente O, Pearce LA. Recurrent brain hemorrhage is more frequent than ischemic stroke after intracranial hemorrhage. Neurology2001; 56:773–777.
Viswanathan A, Rakich SM, Engel C, et al. Antiplatelet use after intracerebral hemorrhage. Neurology2006; 66:206–209.
Greenberg SM, Eng JA, Ning M, Smith EE, Rosand J. Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage. Stroke2004; 35:1415–1420.
Lee SH, Ryu WS, Roh JK. Cerebral microbleeds are a risk factor for warfarin-related intracerebral hemorrhage. Neurology2009; 72:171–176.
Ueno H, Naka H, Ohshita T, et al. Association between cerebral microbleeds on T2*-weighted MR images and recurrent hemorrhagic stroke in patients treated with warfarin following ischemic stroke. AJNR Am J Neuroradiol2008; 29:1483–1486.
O’Donnell HC, Rosand J, Knudsen KA, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med2000; 342:240–245.
Genes for Cerebral Hemorrhage on Anticoagulation (GOCHA) Collaborative Group. Exploiting common genetic variation to make anticoagulation safer. Stroke2009; 40(suppl 3):S64–S66.
Tzourio C, Arima H, Harrap S, et al. APOE genotype, ethnicity, and the risk of cerebral hemorrhage. Neurology2008; 70:1322–1328.
Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med1998; 105:91–99.
Kuijer PM, Hutten BA, Prins MH, Büller HR. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med1999; 159:457–460.
Wess ML, Schauer DP, Johnston JA, et al. Application of a decision support tool for anticoagulation in patients with non-valvular atrial fibrillation. J Gen Intern Med2008; 23:411–417.
Singer DE, Chang Y, Fang MC, et al. Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation? The ATRIA study. Circ Cardiovasc Qual Outcomes2009; 2:297–304.
Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med2004; 141:745–752.
Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med2009; 151:297–305.
Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg SM. Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis. Stroke2003; 34:1710–1716.
Baruch L, Gage BF, Horrow J, et al. Can patients at elevated risk of stroke treated with anticoagulants be further risk stratified?Stroke2007; 38:2459–2463.
Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA2001; 285:2864–2870.
Cannegieter SC, Rosendaal FR, Briët E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation1994; 89:635–641.
Freudenberger RS, Hellkamp AS, Halperin JL, et al; SCD-HeFT Investigators. Risk of thromboembolism in heart failure: an analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Circulation2007; 115:2637–2641.
Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med1996; 125:1–7.
Claassen DO, Kazemi N, Zubkov AY, Wijdicks EF, Rabinstein AA. Restarting anticoagulation therapy after warfarin-associated intracerebral hemorrhage. Arch Neurol2008; 65:1313–1318.
De Vleeschouwer S, Van Calenbergh F, van Loon J, Nuttin B, Goffin J, Plets C. Risk analysis of thrombo-embolic and recurrent bleeding events in the management of intracranial haemorrhage due to oral anticoagulation. Acta Chir Belg2005; 105:268–274.
Butler AC, Tait RC. Restarting anticoagulation in prosthetic heart valve patients after intracranial haemorrhage: a 2-year follow-up. Br J Haematol1998; 103:1064–1066.
Bertram M, Bonsanto M, Hacke W, Schwab S. Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neurol2000; 247:209–214.
Taylor FC, Cohen H, Ebrahim S. Systematic review of long term anticoagulation or antiplatelet treatment in patients with nonrheumatic atrial fibrillation. BMJ2001; 322:321–326.
Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology2008; 71:1084–1089.
Sansing LH, Messe SR, Cucchiara BL, Cohen SN, Lyden PD, Kasner SE; CHANT Investigators. Prior antiplatelet use does not affect hemorrhage growth or outcome after ICH. Neurology2009; 72:1397–1402.
Snow V, Qaseem A, Barry P, et al; American College of Physicians; American Academy of Family Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism. Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med2007; 146:204–210.
Albers GW, Amarenco P, Easton JD, Sacco RL, Teal PA; merican College of Chest Physicians. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest2008; 133(suppl 6):630S–639S.
Hankey GJ, Eikelboom JW. Antithrombotic drugs for patients with ischaemic stroke and transient ischaemic attack to prevent recurrent major vascular events. Lancet Neurol2010; 9:273–284.
Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med2009; 361:2342–2352.
Schulman S, Wåhlander K, Lundström T, Clason SB, Eriksson H; THRIVE III Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med2003; 349:1713–1721.
Singer DE, Albers GW, Dalen JE, et al; American College of Chest Physicians. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest2008; 133(suppl 6):546S–592S.
Joshua N. Goldstein, MD, PhD Assistant Professor, Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA
Steven M. Greenberg, MD, PhD Director, Hemorrhagic Stroke Research Program, Department of Neurology, and the Vascular Center, Massachusetts General Hospital, Boston, MA
Address: Joshua N. Goldstein, MD, PhD, Department of Emergency Medicine, Massachusetts General Hospital, Zero Emerson Place, Suite 3B, Boston, MA 02114; e-mail [email protected]
Dr. Goldstein has acted as a consultant and a member of advisory committees or review panels for CSL Behring.
Joshua N. Goldstein, MD, PhD Assistant Professor, Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA
Steven M. Greenberg, MD, PhD Director, Hemorrhagic Stroke Research Program, Department of Neurology, and the Vascular Center, Massachusetts General Hospital, Boston, MA
Address: Joshua N. Goldstein, MD, PhD, Department of Emergency Medicine, Massachusetts General Hospital, Zero Emerson Place, Suite 3B, Boston, MA 02114; e-mail [email protected]
Dr. Goldstein has acted as a consultant and a member of advisory committees or review panels for CSL Behring.
Author and Disclosure Information
Joshua N. Goldstein, MD, PhD Assistant Professor, Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA
Steven M. Greenberg, MD, PhD Director, Hemorrhagic Stroke Research Program, Department of Neurology, and the Vascular Center, Massachusetts General Hospital, Boston, MA
Address: Joshua N. Goldstein, MD, PhD, Department of Emergency Medicine, Massachusetts General Hospital, Zero Emerson Place, Suite 3B, Boston, MA 02114; e-mail [email protected]
Dr. Goldstein has acted as a consultant and a member of advisory committees or review panels for CSL Behring.
If a patient taking warfarin (Coumadin) or other anticoagulant drug suffers an intracerebral hemorrhage (ICH) and survives, the physician faces the dilemma of whether to resume the anticoagulant. On one hand, the drug was prescribed because the patient was at risk of a thromboembolic event such as stroke or pulmonary embolism. On the other hand, warfarin use may increase the risk of another ICH.
Unfortunately, we have little evidence from clinical trials on which to base the decision. Nevertheless, we believe that in selected patients the potential benefit of resuming anticoagulation outweighs the considerable risk.
In the pages that follow, we summarize when and how anticoagulation therapy should be resumed after ICH.
A DEADLY COMPLICATION OF ANTICOAGULANT THERAPY
Intracranial bleeding is the most feared and the most deadly complication of oral anticoagulant therapy.1 The substantial risks associated with oral anticoagulants likely account for these drugs being underprescribed in patients who have indications for them.2–4
While bleeding is the major risk, not all bleeding events are equally damaging. Extracranial bleeding (eg, gastrointestinal bleeding, hematuria, epistaxis) leads to death or disability in only 3% of cases, whereas intracranial bleeding such as ICH leads to death or disability 76% of cases.5
Even without anticoagulation, ICH is the deadliest form of stroke,6–9 and if the patient has been taking warfarin, the risk of disability and death is substantially higher.6,10 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.11,12 In addition, once ICH occurs, the risk of death is up to twice as high in those on warfarin.6 The bulk of this effect is likely due to a higher risk of ongoing bleeding after the event.10,13–16
Major risk factors for ICH in patients taking oral anticoagulants include a higher international normalized ratio (INR) and older age.11,17
TWO KEY QUESTIONS
Once a patient is diagnosed with warfarin-related ICH, clinicians typically take urgent measures to restore normal coagulation, hoping to limit ongoing bleeding and improve outcome.18,19
The higher the INR at presentation, the greater the risk of death.6 In addition, in retrospective studies, some authors have noted that earlier correction of the INR is associated with better outcome.14,16
While emergency reversal of warfarin is widely considered standard treatment in the acute phase,20–24 concern persists about its safety in patients at high risk of thromboembolism.
Until the results of clinical trials are available, decisions about whether to reverse and when to resume anticoagulation hinge on two questions:
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?
ACUTELY, THE RISK OF BLEEDING OUTWEIGHS THAT OF CLOTTING
High risk of hematoma expansion after ICH
Unfortunately, continued bleeding is common after ICH. In patients who present within 3 hours of symptom onset, 26% of hematomas expand more than 33% over the first hour, and another 12% expand this amount over the next 20 hours.6 In warfarin-associated ICH, up to 50% of patients develop this level of hematoma expansion, but it appears to take place over a more prolonged period of time.10,13–16 Over 70% of patients presenting acutely develop at least some amount of expansion within 24 hours.25 Therefore, the risk of hematoma expansion in the first 24 hours is likely so high that patients cannot safely receive anticoagulants during this time frame.
But not all patients are at equal risk of hematoma expansion. Several features are associated with higher risk (Table 1)10,26–40:
A large hematoma volume on presentation is a significant predictor of expansion, possibly reflecting a more severe underlying insult.26,27
Early presentation, especially within 3 hours of symptom onset, also appears to mark those at higher risk, presumably because such patients undergo computed tomography (CT) while still bleeding.26,27
Figure 1. The “spot sign” (arrow), contrast extravasation after contrast-enhanced computed tomography, is associated with a high risk of hematoma expansion.For those on warfarin, a higher INR is a significant predictor, not just of higher risk, but also of a more delayed expansion.10,28
Certain radiographic findings indicate higher risk. One is the “spot sign,” ie, contrast extravasation after contrast-enhanced CT27,29–31 (Figure 1). Apparently, the more spots present, and the denser the contrast, the greater the risk, an observation that has led to a proposed “spot-sign score” that may predict both expansion and poor outcome. 32,41
Given the high risk of hematoma expansion in the early phase, and given our inability to predict hematoma expansion, most authorities recommend immediate reversal of anticoagulation after diagnosis.42–44 Reversal of anticoagulation typically includes intravenous vitamin K, which begins to act within several hours, and repletion of coagulation factors, which act within minutes (prothrombin complex concentrates and recombinant factor VIIa [NovoSeven]) or a few hours (fresh frozen plasma).1
Dosages:
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.
Risk of thromboembolism after ICH: Ongoing and cumulative
Thromboembolism after ICH is a major concern, for two main reasons.
First, patients on oral anticoagulation typically have a preexisting risk factor and are thus at higher risk of a thromboembolic event, particularly while they are off anticoagulation. Patients with atrial fibrillation or a mechanical valve are at risk of arterial events such as ischemic stroke, whereas patients with a known venous thromboembolic condition such as deep venous thrombosis or pulmonary embolism are at risk of extension of the thrombosis or recurrence of a venous thrombotic event.
Second, ICH itself increases the risk of arterial and venous thromboembolic events. Including patients not previously on anticoagulation, this risk is as high as 7% during the initial hospitalization and 9% during the first 90 days.45,46 Worth noting is that patients who previously received anticoagulant drugs (and who are off this therapy in the acute phase) are at no higher risk of thromboembolism compared with those who never received anticoagulants.45
However, while the risk of hematoma expansion is highest at presentation and then decreases with time, the risk of thromboembolism (particularly venous thromboembolism) is ongoing and cumulative. Arterial thromboembolism is more likely to occur early, within the first week, whereas venous thromboembolism can occur later.45
Overall, studies have estimated the short-term risk of pulmonary embolism to be 1% to 2%, deep venous thrombosis 1% to 4%, myocardial ischemia about 2%, and cerebral ischemia 2% to 3%.45,46 However, when patients are actively screened, the incidence of asymptomatic deep venous thrombosis is found to be as high as 16% in the first 10 days,47 and evidence of myocardial ischemia can be detected in up to 27% of patients.48
Therefore, the risk of hematoma expansion appears to be high and the risk of thromboembolism appears to be low during the first day after ICH. Over the next days, as the risk of hematoma expansion recedes, this ratio shifts.
Studies of in-hospital anticoagulation after ICH
The data on restarting oral anticoagulation in the acute phase are sparse. In practice, clinicians typically start heparinoids in low subcutaneous doses to prevent deep venous thrombosis and, after the first few days or a week, consider increasing to a full anticoagulation dose or starting an oral anticoagulant and subsequently discontinuing the heparin when the INR is in the therapeutic range (see discussion below).
ICH patients in general may benefit from starting prophylactic-dose heparin therapy early. One randomized trial found that starting heparin in a low subcutaneous dose the day after an ICH decreased the risk of thromboembolism without increasing the risk of rebleeding.49 Another study also found no increased risk of rebleeding with early prophylactic-dose subcutaneous heparin.50
As the benefit appears to outweigh the risk, national guidelines suggest starting subcutaneous heparin early in all ICH patients, including those not previously on warfarin.42,43
Commonly used heparinoid regimens include unfractionated heparin 5,000 units subcutaneously twice a day; enoxaparin (Lovenox) 40 mg once a day; and dalteparin (Fragmin) 5,000 units once a day.51 In addition, all patients should receive optimal mechanical thromboprophylaxis, including graduated compression stockings or intermittent pneumatic compression stockings, or both.
LONG-TERM MANAGEMENT: ICH RECURRENCE VS THROMBOEMBOLISM
Risk of ICH recurrence on warfarin is not precisely known
Overall, the risk of ICH recurrence is about 1% at 3 months, and warfarin likely increases this risk.42,52 Unfortunately, the risk of ICH recurrence in patients on anticoagulation therapy after a first ICH is not clear, and no population-based study has clarified this risk. Therefore, the best we can do at present is to try to estimate the risk of recurrent warfarin-related ICH by separately examining two issues:
The risk of ICH recurrence in general
The risk of major bleeding (including ICH) in the general population of patients on warfarin.
The risk of ICH recurrence in general is about 2% to 4% per patient-year.52–54 However, this risk appears to be a function of the underlying vasculopathy. ICH location is often used as a surrogate for underlying cause. Most ICHs in deep hemispheric (basal ganglia, thalamus) or brainstem territories are likely caused by hypertensive vasculopathy, whereas lobar ICH is often associated with cerebral amyloid angiopathy.52–54 Presumably because of this distinction, ICH in a deep location recurs in about 2% of cases per year, compared with 4% for lobar ICH.53 The presence and number of microbleeds on T2-weighted gradient-echo magnetic resonance imaging appear to predict ICH recurrence; microbleeds likely are markers of more severe or widespread underlying vasculopathy.55–57
A genetic risk factor for the recurrence of lobar ICH is apolipoprotein E genotype58; future studies may highlight genetic variations that specifically modify the risk of warfarin-related ICH.59 Unfortunately, there is currently no way to modify the risk of ICH associated with cerebral amyloid angiopathy. On the other hand, in patients with hypertensive hemorrhage, antihypertensive therapy likely reduces the risk of recurrent ICH. One randomized controlled trial showed that such therapy decreased the risk of ICH by more than half.60
The risk of major bleeding in the general population of patients on warfarin may be 2% to 3% per year and is likely higher in the first month.11 The risk is higher in older patients and if the INR rises above 4.0.11,17 For some patients, it is possible to estimate the likelihood of major bleeding using validated decision-support tools that include factors such as age, sex, and medical history.11,61–64
Given the lack of data specifically addressing the risk of ICH recurrence on warfarin, the clinician is left to try to extrapolate this risk from available data using specific patient characteristics that modify the presumed risk. For example, one can combine factors such as ICH location (or better yet, the underlying cause) with decision-support tools that predict the risk of major bleeding. Close control of both blood pressure and the INR appears especially critical for patients receiving anticoagulation after ICH.11,60,65 Still, the risk does not disappear with good INR control, and most patients with anticoagulation-related ICH present with INRs within the therapeutic range.5,10,65
Long-term risk of thromboembolism depends on underlying condition
In the long term, the risk of thromboembolism depends on the reason for which the patient was originally given anticoagulation. In addition, many patients with ICH suffer decreased mobility and are therefore at higher risk of venous thromboembolism than before their event.
Nonvalvular atrial fibrillation is the most common indication for anticoagulation. For these patients, the risk of ischemic stroke is 2% to 5% per year.66,67 The system usually used to stratify this risk is CHADS2, an acronym for five key risk factors:
Congestive heart failure (1 point)
Hypertension (1 point)
Age over 75 (1 point)
Diabetes mellitus (1 point)
Prior stroke or transient ischemic attack (2 points).
The annual risk of stroke ranges from 1.9% (score of 0) to 18.2% (score of 6).68,69 In patients with nonvalvular atrial fibrillation, the excess risk of ischemic stroke without anticoagulation must be weighed against the risk of ICH recurrence.
A mechanical heart valve, another common indication, carries a risk of ischemic stroke of about 4% per year.70 A mechanical valve is traditionally considered an absolute indication for anticoagulation. However, patients with lobar ICH face a risk of recurrence that is greater than 4% per year, and so the risks of resuming anticoagulation may well outweigh the benefits.
Heart failure may be associated with a risk of ischemic stroke of 1% to 4% per year, and this is likely a function of disease severity.71
Venous thromboembolism. The risk of recurrent venous thromboembolism in patients with deep venous thrombosis or pulmonary embolism is around 4% per year.72 Given that ICH itself confers a 2% to 3% risk of these conditions, the rate of recurrence of deep venous thrombosis may well be much higher in those ICH patients who have also already had deep venous thrombosis.
Data on resuming oral anticoagulation after ICH
Several studies have examined the outcomes when oral anticoagulants were resumed after ICH (Table 2),73–76 but experts differ on when these drugs should be resumed (eg, between 1 and 10 days after onset), or even whether they should be resumed at all.19
Notably, an analysis of 52 patients found a high risk of ICH recurrence (and gastrointestinal bleeding) in patients who restarted warfarin, and a high risk of myocardial infarction and ischemic stroke in those who did not restart, with neither strategy demonstrating a clear benefit in the rate of death or disability.73 All patients with a thromboembolic event were being treated for a previous event, suggesting that secondary prevention is a stronger indication for anticoagulation than primary prevention in this population.73
IF AND WHEN TO RESTART
Two major questions to consider are whether the benefits of restarting anticoagulation outweigh the risk, and if so, when and how should anticoagulation be restarted?
Whether to restart anticoagulation
As for the risk-benefit ratio, many think that anticoagulation should be restarted only with extreme caution and possibly only in those with deep ICH or a documented history of thromboembolism.19
In one decision analysis examining whether to restart anticoagulation after ICH in patients with atrial fibrillation, the risk of thromboembolism would need to exceed 7% per year to justify restarting anticoagulation after deep ICH,67 and no risk level was high enough to justify restarting anticoagulation after lobar ICH.
For patients at sufficiently high risk of ICH recurrence, antiplatelet treatment is probably safer, as antiplatelet agents carry a substantially lower risk of bleeding.54,77–79 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. 42 They note that anticoagulation after nonlobar ICH may be considered depending on the indication.42
The decision to restart anticoagulation may also be a function of whether the underlying risk factor is a temporary one. For example, atrial fibrillation or a mechanical heart valve confers a long-term, ongoing risk of arterial thromboembolism, and such patients would not normally be considered for a short course of warfarin therapy. However, isolated deep vein thrombosis may only require anticoagulation for a limited time, such as 3 to 6 months.80 Perhaps for such patients the long-term outcome is maximized with a narrowly defined, temporary course of anticoagulation.
When to restart anticoagulation
As for when to restart, it is not certain how long after symptom onset the risk of ongoing bleeding continues. Clearly, the risk is high on the first day, but small after the first few days.
The European Stroke Initiative recommends that patients with a strong indication for anticoagulation, such as 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.43
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.42
The American College of Chest Physicians recommends starting prophylactic-dose heparin the day after an ICH, with no clear guidance on restarting warfarin.81
ALTERNATIVES TO WARFARIN
Alternatives to warfarin that show promise in reducing bleeding risk include factor Xa and direct thrombin inhibitors, which may reduce the risk of thromboembolism to an extent similar to that of warfarin, but with fewer bleeding complications.82
In patients with atrial fibrillation, the direct thrombin inhibitor dabigatran (Pradaxa) was shown to prevent ischemic stroke to a similar or greater degree than warfarin, with fewer bleeding complications.83 Further patient follow-up is under way to ensure that this drug does not cause liver problems, as did a similarly designed predecessor.84
The availability of this and other agents in various stages of development82 will probably not make warfarin extinct. Rather, they may change the “tipping point,” the threshold at which the risk of thromboembolism is high enough to justify the risks associated with restarting warfarin therapy. In addition, clinical decision tools clarifying the individual patient’s risk of thromboembolism vs the risk of ICH recurrence will help physicians tailor the therapy to the patient.
For the moment, in situations in which the decision is difficult, maximizing the use of antiplatelet agents offers the best hope.85
RECOMMENDATIONS IN LIEU OF GUIDELINES
No guideline can broadly cover every clinical scenario. Many factors go into assessing a patient’s risk of hematoma expansion or recurrent hemorrhage (Table 3) and the extent to which anticoagulation can reduce the risk of thromboembolism.
In the short term, most patients with ICH will likely benefit from acute reversal of anticoagulation, followed by gradual reinstitution of prophylactic-dose anticoagulation after the first 24 to 72 hours.
In the long term, many patients with lobar hemorrhage, cerebral amyloid angiopathy, or other risk factors may remain at higher risk of anticoagulant-related ICH recurrence than of fatal or disabling thromboembolic events and would therefore be best managed without anticoagulants. Conversely, those with deep hemispheric ICH, hypertension that can be well controlled, and a high risk of disabling thromboembolism may receive a net benefit from restarting anticoagulation.
If a patient taking warfarin (Coumadin) or other anticoagulant drug suffers an intracerebral hemorrhage (ICH) and survives, the physician faces the dilemma of whether to resume the anticoagulant. On one hand, the drug was prescribed because the patient was at risk of a thromboembolic event such as stroke or pulmonary embolism. On the other hand, warfarin use may increase the risk of another ICH.
Unfortunately, we have little evidence from clinical trials on which to base the decision. Nevertheless, we believe that in selected patients the potential benefit of resuming anticoagulation outweighs the considerable risk.
In the pages that follow, we summarize when and how anticoagulation therapy should be resumed after ICH.
A DEADLY COMPLICATION OF ANTICOAGULANT THERAPY
Intracranial bleeding is the most feared and the most deadly complication of oral anticoagulant therapy.1 The substantial risks associated with oral anticoagulants likely account for these drugs being underprescribed in patients who have indications for them.2–4
While bleeding is the major risk, not all bleeding events are equally damaging. Extracranial bleeding (eg, gastrointestinal bleeding, hematuria, epistaxis) leads to death or disability in only 3% of cases, whereas intracranial bleeding such as ICH leads to death or disability 76% of cases.5
Even without anticoagulation, ICH is the deadliest form of stroke,6–9 and if the patient has been taking warfarin, the risk of disability and death is substantially higher.6,10 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.11,12 In addition, once ICH occurs, the risk of death is up to twice as high in those on warfarin.6 The bulk of this effect is likely due to a higher risk of ongoing bleeding after the event.10,13–16
Major risk factors for ICH in patients taking oral anticoagulants include a higher international normalized ratio (INR) and older age.11,17
TWO KEY QUESTIONS
Once a patient is diagnosed with warfarin-related ICH, clinicians typically take urgent measures to restore normal coagulation, hoping to limit ongoing bleeding and improve outcome.18,19
The higher the INR at presentation, the greater the risk of death.6 In addition, in retrospective studies, some authors have noted that earlier correction of the INR is associated with better outcome.14,16
While emergency reversal of warfarin is widely considered standard treatment in the acute phase,20–24 concern persists about its safety in patients at high risk of thromboembolism.
Until the results of clinical trials are available, decisions about whether to reverse and when to resume anticoagulation hinge on two questions:
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?
ACUTELY, THE RISK OF BLEEDING OUTWEIGHS THAT OF CLOTTING
High risk of hematoma expansion after ICH
Unfortunately, continued bleeding is common after ICH. In patients who present within 3 hours of symptom onset, 26% of hematomas expand more than 33% over the first hour, and another 12% expand this amount over the next 20 hours.6 In warfarin-associated ICH, up to 50% of patients develop this level of hematoma expansion, but it appears to take place over a more prolonged period of time.10,13–16 Over 70% of patients presenting acutely develop at least some amount of expansion within 24 hours.25 Therefore, the risk of hematoma expansion in the first 24 hours is likely so high that patients cannot safely receive anticoagulants during this time frame.
But not all patients are at equal risk of hematoma expansion. Several features are associated with higher risk (Table 1)10,26–40:
A large hematoma volume on presentation is a significant predictor of expansion, possibly reflecting a more severe underlying insult.26,27
Early presentation, especially within 3 hours of symptom onset, also appears to mark those at higher risk, presumably because such patients undergo computed tomography (CT) while still bleeding.26,27
Figure 1. The “spot sign” (arrow), contrast extravasation after contrast-enhanced computed tomography, is associated with a high risk of hematoma expansion.For those on warfarin, a higher INR is a significant predictor, not just of higher risk, but also of a more delayed expansion.10,28
Certain radiographic findings indicate higher risk. One is the “spot sign,” ie, contrast extravasation after contrast-enhanced CT27,29–31 (Figure 1). Apparently, the more spots present, and the denser the contrast, the greater the risk, an observation that has led to a proposed “spot-sign score” that may predict both expansion and poor outcome. 32,41
Given the high risk of hematoma expansion in the early phase, and given our inability to predict hematoma expansion, most authorities recommend immediate reversal of anticoagulation after diagnosis.42–44 Reversal of anticoagulation typically includes intravenous vitamin K, which begins to act within several hours, and repletion of coagulation factors, which act within minutes (prothrombin complex concentrates and recombinant factor VIIa [NovoSeven]) or a few hours (fresh frozen plasma).1
Dosages:
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.
Risk of thromboembolism after ICH: Ongoing and cumulative
Thromboembolism after ICH is a major concern, for two main reasons.
First, patients on oral anticoagulation typically have a preexisting risk factor and are thus at higher risk of a thromboembolic event, particularly while they are off anticoagulation. Patients with atrial fibrillation or a mechanical valve are at risk of arterial events such as ischemic stroke, whereas patients with a known venous thromboembolic condition such as deep venous thrombosis or pulmonary embolism are at risk of extension of the thrombosis or recurrence of a venous thrombotic event.
Second, ICH itself increases the risk of arterial and venous thromboembolic events. Including patients not previously on anticoagulation, this risk is as high as 7% during the initial hospitalization and 9% during the first 90 days.45,46 Worth noting is that patients who previously received anticoagulant drugs (and who are off this therapy in the acute phase) are at no higher risk of thromboembolism compared with those who never received anticoagulants.45
However, while the risk of hematoma expansion is highest at presentation and then decreases with time, the risk of thromboembolism (particularly venous thromboembolism) is ongoing and cumulative. Arterial thromboembolism is more likely to occur early, within the first week, whereas venous thromboembolism can occur later.45
Overall, studies have estimated the short-term risk of pulmonary embolism to be 1% to 2%, deep venous thrombosis 1% to 4%, myocardial ischemia about 2%, and cerebral ischemia 2% to 3%.45,46 However, when patients are actively screened, the incidence of asymptomatic deep venous thrombosis is found to be as high as 16% in the first 10 days,47 and evidence of myocardial ischemia can be detected in up to 27% of patients.48
Therefore, the risk of hematoma expansion appears to be high and the risk of thromboembolism appears to be low during the first day after ICH. Over the next days, as the risk of hematoma expansion recedes, this ratio shifts.
Studies of in-hospital anticoagulation after ICH
The data on restarting oral anticoagulation in the acute phase are sparse. In practice, clinicians typically start heparinoids in low subcutaneous doses to prevent deep venous thrombosis and, after the first few days or a week, consider increasing to a full anticoagulation dose or starting an oral anticoagulant and subsequently discontinuing the heparin when the INR is in the therapeutic range (see discussion below).
ICH patients in general may benefit from starting prophylactic-dose heparin therapy early. One randomized trial found that starting heparin in a low subcutaneous dose the day after an ICH decreased the risk of thromboembolism without increasing the risk of rebleeding.49 Another study also found no increased risk of rebleeding with early prophylactic-dose subcutaneous heparin.50
As the benefit appears to outweigh the risk, national guidelines suggest starting subcutaneous heparin early in all ICH patients, including those not previously on warfarin.42,43
Commonly used heparinoid regimens include unfractionated heparin 5,000 units subcutaneously twice a day; enoxaparin (Lovenox) 40 mg once a day; and dalteparin (Fragmin) 5,000 units once a day.51 In addition, all patients should receive optimal mechanical thromboprophylaxis, including graduated compression stockings or intermittent pneumatic compression stockings, or both.
LONG-TERM MANAGEMENT: ICH RECURRENCE VS THROMBOEMBOLISM
Risk of ICH recurrence on warfarin is not precisely known
Overall, the risk of ICH recurrence is about 1% at 3 months, and warfarin likely increases this risk.42,52 Unfortunately, the risk of ICH recurrence in patients on anticoagulation therapy after a first ICH is not clear, and no population-based study has clarified this risk. Therefore, the best we can do at present is to try to estimate the risk of recurrent warfarin-related ICH by separately examining two issues:
The risk of ICH recurrence in general
The risk of major bleeding (including ICH) in the general population of patients on warfarin.
The risk of ICH recurrence in general is about 2% to 4% per patient-year.52–54 However, this risk appears to be a function of the underlying vasculopathy. ICH location is often used as a surrogate for underlying cause. Most ICHs in deep hemispheric (basal ganglia, thalamus) or brainstem territories are likely caused by hypertensive vasculopathy, whereas lobar ICH is often associated with cerebral amyloid angiopathy.52–54 Presumably because of this distinction, ICH in a deep location recurs in about 2% of cases per year, compared with 4% for lobar ICH.53 The presence and number of microbleeds on T2-weighted gradient-echo magnetic resonance imaging appear to predict ICH recurrence; microbleeds likely are markers of more severe or widespread underlying vasculopathy.55–57
A genetic risk factor for the recurrence of lobar ICH is apolipoprotein E genotype58; future studies may highlight genetic variations that specifically modify the risk of warfarin-related ICH.59 Unfortunately, there is currently no way to modify the risk of ICH associated with cerebral amyloid angiopathy. On the other hand, in patients with hypertensive hemorrhage, antihypertensive therapy likely reduces the risk of recurrent ICH. One randomized controlled trial showed that such therapy decreased the risk of ICH by more than half.60
The risk of major bleeding in the general population of patients on warfarin may be 2% to 3% per year and is likely higher in the first month.11 The risk is higher in older patients and if the INR rises above 4.0.11,17 For some patients, it is possible to estimate the likelihood of major bleeding using validated decision-support tools that include factors such as age, sex, and medical history.11,61–64
Given the lack of data specifically addressing the risk of ICH recurrence on warfarin, the clinician is left to try to extrapolate this risk from available data using specific patient characteristics that modify the presumed risk. For example, one can combine factors such as ICH location (or better yet, the underlying cause) with decision-support tools that predict the risk of major bleeding. Close control of both blood pressure and the INR appears especially critical for patients receiving anticoagulation after ICH.11,60,65 Still, the risk does not disappear with good INR control, and most patients with anticoagulation-related ICH present with INRs within the therapeutic range.5,10,65
Long-term risk of thromboembolism depends on underlying condition
In the long term, the risk of thromboembolism depends on the reason for which the patient was originally given anticoagulation. In addition, many patients with ICH suffer decreased mobility and are therefore at higher risk of venous thromboembolism than before their event.
Nonvalvular atrial fibrillation is the most common indication for anticoagulation. For these patients, the risk of ischemic stroke is 2% to 5% per year.66,67 The system usually used to stratify this risk is CHADS2, an acronym for five key risk factors:
Congestive heart failure (1 point)
Hypertension (1 point)
Age over 75 (1 point)
Diabetes mellitus (1 point)
Prior stroke or transient ischemic attack (2 points).
The annual risk of stroke ranges from 1.9% (score of 0) to 18.2% (score of 6).68,69 In patients with nonvalvular atrial fibrillation, the excess risk of ischemic stroke without anticoagulation must be weighed against the risk of ICH recurrence.
A mechanical heart valve, another common indication, carries a risk of ischemic stroke of about 4% per year.70 A mechanical valve is traditionally considered an absolute indication for anticoagulation. However, patients with lobar ICH face a risk of recurrence that is greater than 4% per year, and so the risks of resuming anticoagulation may well outweigh the benefits.
Heart failure may be associated with a risk of ischemic stroke of 1% to 4% per year, and this is likely a function of disease severity.71
Venous thromboembolism. The risk of recurrent venous thromboembolism in patients with deep venous thrombosis or pulmonary embolism is around 4% per year.72 Given that ICH itself confers a 2% to 3% risk of these conditions, the rate of recurrence of deep venous thrombosis may well be much higher in those ICH patients who have also already had deep venous thrombosis.
Data on resuming oral anticoagulation after ICH
Several studies have examined the outcomes when oral anticoagulants were resumed after ICH (Table 2),73–76 but experts differ on when these drugs should be resumed (eg, between 1 and 10 days after onset), or even whether they should be resumed at all.19
Notably, an analysis of 52 patients found a high risk of ICH recurrence (and gastrointestinal bleeding) in patients who restarted warfarin, and a high risk of myocardial infarction and ischemic stroke in those who did not restart, with neither strategy demonstrating a clear benefit in the rate of death or disability.73 All patients with a thromboembolic event were being treated for a previous event, suggesting that secondary prevention is a stronger indication for anticoagulation than primary prevention in this population.73
IF AND WHEN TO RESTART
Two major questions to consider are whether the benefits of restarting anticoagulation outweigh the risk, and if so, when and how should anticoagulation be restarted?
Whether to restart anticoagulation
As for the risk-benefit ratio, many think that anticoagulation should be restarted only with extreme caution and possibly only in those with deep ICH or a documented history of thromboembolism.19
In one decision analysis examining whether to restart anticoagulation after ICH in patients with atrial fibrillation, the risk of thromboembolism would need to exceed 7% per year to justify restarting anticoagulation after deep ICH,67 and no risk level was high enough to justify restarting anticoagulation after lobar ICH.
For patients at sufficiently high risk of ICH recurrence, antiplatelet treatment is probably safer, as antiplatelet agents carry a substantially lower risk of bleeding.54,77–79 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. 42 They note that anticoagulation after nonlobar ICH may be considered depending on the indication.42
The decision to restart anticoagulation may also be a function of whether the underlying risk factor is a temporary one. For example, atrial fibrillation or a mechanical heart valve confers a long-term, ongoing risk of arterial thromboembolism, and such patients would not normally be considered for a short course of warfarin therapy. However, isolated deep vein thrombosis may only require anticoagulation for a limited time, such as 3 to 6 months.80 Perhaps for such patients the long-term outcome is maximized with a narrowly defined, temporary course of anticoagulation.
When to restart anticoagulation
As for when to restart, it is not certain how long after symptom onset the risk of ongoing bleeding continues. Clearly, the risk is high on the first day, but small after the first few days.
The European Stroke Initiative recommends that patients with a strong indication for anticoagulation, such as 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.43
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.42
The American College of Chest Physicians recommends starting prophylactic-dose heparin the day after an ICH, with no clear guidance on restarting warfarin.81
ALTERNATIVES TO WARFARIN
Alternatives to warfarin that show promise in reducing bleeding risk include factor Xa and direct thrombin inhibitors, which may reduce the risk of thromboembolism to an extent similar to that of warfarin, but with fewer bleeding complications.82
In patients with atrial fibrillation, the direct thrombin inhibitor dabigatran (Pradaxa) was shown to prevent ischemic stroke to a similar or greater degree than warfarin, with fewer bleeding complications.83 Further patient follow-up is under way to ensure that this drug does not cause liver problems, as did a similarly designed predecessor.84
The availability of this and other agents in various stages of development82 will probably not make warfarin extinct. Rather, they may change the “tipping point,” the threshold at which the risk of thromboembolism is high enough to justify the risks associated with restarting warfarin therapy. In addition, clinical decision tools clarifying the individual patient’s risk of thromboembolism vs the risk of ICH recurrence will help physicians tailor the therapy to the patient.
For the moment, in situations in which the decision is difficult, maximizing the use of antiplatelet agents offers the best hope.85
RECOMMENDATIONS IN LIEU OF GUIDELINES
No guideline can broadly cover every clinical scenario. Many factors go into assessing a patient’s risk of hematoma expansion or recurrent hemorrhage (Table 3) and the extent to which anticoagulation can reduce the risk of thromboembolism.
In the short term, most patients with ICH will likely benefit from acute reversal of anticoagulation, followed by gradual reinstitution of prophylactic-dose anticoagulation after the first 24 to 72 hours.
In the long term, many patients with lobar hemorrhage, cerebral amyloid angiopathy, or other risk factors may remain at higher risk of anticoagulant-related ICH recurrence than of fatal or disabling thromboembolic events and would therefore be best managed without anticoagulants. Conversely, those with deep hemispheric ICH, hypertension that can be well controlled, and a high risk of disabling thromboembolism may receive a net benefit from restarting anticoagulation.
Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med2007; 167:1414–1419.
Choudhry NK, Anderson GM, Laupacis A, Ross-Degnan D, Normand SL, Soumerai SB. Impact of adverse events on prescribing warfarin in patients with atrial fibrillation: matched pair analysis. BMJ2006; 332:141–145.
Choudhry NK, Soumerai SB, Normand SL, Ross-Degnan D, Laupacis A, Anderson GM. Warfarin prescribing in atrial fibrillation: the impact of physician, patient, and hospital characteristics. Am J Med2006; 119:607–615.
Fang MC, Go AS, Chang Y, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med2007; 120:700–705.
Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med2004; 164:880–884.
Dixon AA, Holness RO, Howes WJ, Garner JB. Spontaneous intracerebral haemorrhage: an analysis of factors affecting prognosis. Can J Neurol Sci1985; 12:267–271.
Broderick JP, Adams HP, Barsan W, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke1999; 30:905–915.
Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology2004; 63:1059–1064.
Schulman S, Beyth RJ, Kearon C, Levine MN; American College of Chest Physicians. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest2008; 133(suppl 6):257S–298S.
Flaherty ML, Kissela B, Woo D, et al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology2007; 68:116–121.
Lee SB, Manno EM, Layton KF, Wijdicks EF. Progression of warfarin-associated intracerebral hemorrhage after INR normalization with FFP. Neurology2006; 67:1272–1274.
Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke2006; 37:1465–1470.
Sjöblom L, Hårdemark HG, Lindgren A, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke2001; 32:2567–2574.
Yasaka M, Minematsu K, Naritomi H, Sakata T, Yamaguchi T. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost2003; 89:278–283.
Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation2007; 115:2689–2696.
Goldstein JN, Thomas SH, Frontiero V, et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke2006; 37:151–155.
Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc2007; 82:82–92.
Guidelines on oral anticoagulation: third edition. Br J Haematol1998; 101:374–387.
Baglin TP, Keeling DM, Watson HG; British Committee for Standards in Haematology. Guidelines on oral anticoagulation (warfarin): third edition—2005 update. Br J Haematol2006; 132:277–285.
O’Shaughnessy DF, Atterbury C, Bolton Maggs P, et al; British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol2004; 126:11–28.
Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM; Warfarin Reversal Consensus Group. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust2004; 181:492–497.
Davis SM, Broderick J, Hennerici M, et al; Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology2006; 66:1175–1181.
Broderick JP, Diringer MN, Hill MD, et al; Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Determinants of intracerebral hemorrhage growth: an exploratory analysis. Stroke2007; 38:1072–1075.
Goldstein JN, Fazen LE, Snider R, et al. Contrast extravasation on CT angiography predicts hematoma expansion in intracerebral hemorrhage. Neurology2007; 68:889–894.
Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke1996; 27:1783–1787.
Kim J, Smith A, Hemphill JC, et al. Contrast extravasation on CT predicts mortality in primary intracerebral hemorrhage. AJNR Am J Neuroradiol2008; 29:520–525.
Wada R, Aviv RI, Fox AJ, et al. CT angiography “spot sign” predicts hematoma expansion in acute intracerebral hemorrhage. Stroke2007; 38:1257–1262.
Barras CD, Tress BM, Christensen S, et al; Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Density and shape as CT predictors of intracerebral hemorrhage growth. Stroke2009; 40:1325–1331.
Delgado Almandoz JE, Yoo AJ, Stone MJ, et al. Systematic characterization of the computed tomography angiography spot sign in primary intracerebral hemorrhage identifies patients at highest risk for hematoma expansion: the spot sign score. Stroke2009; 40:2994–3000.
Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Tanaka R. Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage. Stroke1998; 29:1160–1166.
Ederies A, Demchuk A, Chia T, et al. Postcontrast CT extravasation is associated with hematoma expansion in CTA spot negative patients. Stroke2009; 40:1672–1676.
Delgado P, Alvarez-Sabín J, Abilleira S, et al. Plasma d-dimer predicts poor outcome after acute intracerebral hemorrhage. Neurology2006; 67:94–98.
Naidech AM, Jovanovic B, Liebling S, et al. Reduced platelet activity is associated with early clot growth and worse 3-month outcome after intracerebral hemorrhage. Stroke2009; 40:2398–2401.
Silva Y, Leira R, Tejada J, Lainez JM, Castillo J, Dávalos A; Stroke Project, Cerebrovascular Diseases Group of the Spanish Neurological Society. Molecular signatures of vascular injury are associated with early growth of intracerebral hemorrhage. Stroke2005; 36:86–91.
Sansing LH, Messe SR, Cucchiara BL, Cohen SN, Lyden PD, Kasner SE; CHANT Investigators. Prior antiplatelet use does not affect hemorrhage growth or outcome after ICH. Neurology2009; 72:1397–1402.
Moussouttas M, Malhotra R, Fernandez L, et al. Role of antiplatelet agents in hematoma expansion during the acute period of intracerebral hemorrhage. Neurocrit Care2010; 12:24–29.
Delgado Almandoz JE, Yoo AJ, Stone MJ, et al. The spot sign score in primary intracerebral hemorrhage identifies patients at highest risk of in-hospital mortality and poor outcome among survivors. Stroke2010; 41:54–60.
Broderick J, Connolly S, Feldmann E, et al; American Heart Association; American Stroke Association Stroke Council; High Blood Pressure Research Council; Quality of Care and Outcomes in Research Interdisciplinary Working Group. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke2007; 38:2001–2023.
Steiner T, Kaste M, Forsting M, et al. Recommendations for the management of intracranial haemorrhage - part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis2006; 22:294–316.
Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke2006; 37:256–262.
Goldstein JN, Fazen LE, Wendell L, et al. Risk of thromboembolism following acute intracerebral hemorrhage. Neurocrit Care2009; 10:28–34.
Christensen MC, Dawson J, Vincent C. Risk of thromboembolic complications after intracerebral hemorrhage according to ethnicity. Adv Ther2008; 25:831–841.
Lacut K, Bressollette L, Le Gal G, et al; VICTORIAh (Venous Intermittent Compression and Thrombosis Occurrence Related to Intracerebral Acute hemorrhage) Investigators. Prevention of venous thrombosis in patients with acute intracerebral hemorrhage. Neurology2005; 65:865–869.
Diringer MN, Skolnick BE, Mayer SA, et al. Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial. Stroke2010; 41:48–53.
Boeer A, Voth E, Henze T, Prange HW. Early heparin therapy in patients with spontaneous intracerebral haemorrhage. J Neurol Neurosurg Psychiatry1991; 54:466–467.
Dickmann U, Voth E, Schicha H, Henze T, Prange H, Emrich D. Heparin therapy, deep-vein thrombosis and pulmonary embolism after intracerebral hemorrhage. Klin Wochenschr1988; 66:1182–1183.
Geerts WH, Bergqvist D, Pineo GF, et al; American College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest2008; 133(suppl 6):381S–453S.
Vermeer SE, Algra A, Franke CL, Koudstaal PJ, Rinkel GJ. Long-term prognosis after recovery from primary intracerebral hemorrhage. Neurology2002; 59:205–209.
Bailey RD, Hart RG, Benavente O, Pearce LA. Recurrent brain hemorrhage is more frequent than ischemic stroke after intracranial hemorrhage. Neurology2001; 56:773–777.
Viswanathan A, Rakich SM, Engel C, et al. Antiplatelet use after intracerebral hemorrhage. Neurology2006; 66:206–209.
Greenberg SM, Eng JA, Ning M, Smith EE, Rosand J. Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage. Stroke2004; 35:1415–1420.
Lee SH, Ryu WS, Roh JK. Cerebral microbleeds are a risk factor for warfarin-related intracerebral hemorrhage. Neurology2009; 72:171–176.
Ueno H, Naka H, Ohshita T, et al. Association between cerebral microbleeds on T2*-weighted MR images and recurrent hemorrhagic stroke in patients treated with warfarin following ischemic stroke. AJNR Am J Neuroradiol2008; 29:1483–1486.
O’Donnell HC, Rosand J, Knudsen KA, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med2000; 342:240–245.
Genes for Cerebral Hemorrhage on Anticoagulation (GOCHA) Collaborative Group. Exploiting common genetic variation to make anticoagulation safer. Stroke2009; 40(suppl 3):S64–S66.
Tzourio C, Arima H, Harrap S, et al. APOE genotype, ethnicity, and the risk of cerebral hemorrhage. Neurology2008; 70:1322–1328.
Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med1998; 105:91–99.
Kuijer PM, Hutten BA, Prins MH, Büller HR. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med1999; 159:457–460.
Wess ML, Schauer DP, Johnston JA, et al. Application of a decision support tool for anticoagulation in patients with non-valvular atrial fibrillation. J Gen Intern Med2008; 23:411–417.
Singer DE, Chang Y, Fang MC, et al. Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation? The ATRIA study. Circ Cardiovasc Qual Outcomes2009; 2:297–304.
Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med2004; 141:745–752.
Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med2009; 151:297–305.
Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg SM. Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis. Stroke2003; 34:1710–1716.
Baruch L, Gage BF, Horrow J, et al. Can patients at elevated risk of stroke treated with anticoagulants be further risk stratified?Stroke2007; 38:2459–2463.
Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA2001; 285:2864–2870.
Cannegieter SC, Rosendaal FR, Briët E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation1994; 89:635–641.
Freudenberger RS, Hellkamp AS, Halperin JL, et al; SCD-HeFT Investigators. Risk of thromboembolism in heart failure: an analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Circulation2007; 115:2637–2641.
Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med1996; 125:1–7.
Claassen DO, Kazemi N, Zubkov AY, Wijdicks EF, Rabinstein AA. Restarting anticoagulation therapy after warfarin-associated intracerebral hemorrhage. Arch Neurol2008; 65:1313–1318.
De Vleeschouwer S, Van Calenbergh F, van Loon J, Nuttin B, Goffin J, Plets C. Risk analysis of thrombo-embolic and recurrent bleeding events in the management of intracranial haemorrhage due to oral anticoagulation. Acta Chir Belg2005; 105:268–274.
Butler AC, Tait RC. Restarting anticoagulation in prosthetic heart valve patients after intracranial haemorrhage: a 2-year follow-up. Br J Haematol1998; 103:1064–1066.
Bertram M, Bonsanto M, Hacke W, Schwab S. Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neurol2000; 247:209–214.
Taylor FC, Cohen H, Ebrahim S. Systematic review of long term anticoagulation or antiplatelet treatment in patients with nonrheumatic atrial fibrillation. BMJ2001; 322:321–326.
Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology2008; 71:1084–1089.
Sansing LH, Messe SR, Cucchiara BL, Cohen SN, Lyden PD, Kasner SE; CHANT Investigators. Prior antiplatelet use does not affect hemorrhage growth or outcome after ICH. Neurology2009; 72:1397–1402.
Snow V, Qaseem A, Barry P, et al; American College of Physicians; American Academy of Family Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism. Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med2007; 146:204–210.
Albers GW, Amarenco P, Easton JD, Sacco RL, Teal PA; merican College of Chest Physicians. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest2008; 133(suppl 6):630S–639S.
Hankey GJ, Eikelboom JW. Antithrombotic drugs for patients with ischaemic stroke and transient ischaemic attack to prevent recurrent major vascular events. Lancet Neurol2010; 9:273–284.
Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med2009; 361:2342–2352.
Schulman S, Wåhlander K, Lundström T, Clason SB, Eriksson H; THRIVE III Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med2003; 349:1713–1721.
Singer DE, Albers GW, Dalen JE, et al; American College of Chest Physicians. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest2008; 133(suppl 6):546S–592S.
Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med2007; 167:1414–1419.
Choudhry NK, Anderson GM, Laupacis A, Ross-Degnan D, Normand SL, Soumerai SB. Impact of adverse events on prescribing warfarin in patients with atrial fibrillation: matched pair analysis. BMJ2006; 332:141–145.
Choudhry NK, Soumerai SB, Normand SL, Ross-Degnan D, Laupacis A, Anderson GM. Warfarin prescribing in atrial fibrillation: the impact of physician, patient, and hospital characteristics. Am J Med2006; 119:607–615.
Fang MC, Go AS, Chang Y, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med2007; 120:700–705.
Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med2004; 164:880–884.
Dixon AA, Holness RO, Howes WJ, Garner JB. Spontaneous intracerebral haemorrhage: an analysis of factors affecting prognosis. Can J Neurol Sci1985; 12:267–271.
Broderick JP, Adams HP, Barsan W, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke1999; 30:905–915.
Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology2004; 63:1059–1064.
Schulman S, Beyth RJ, Kearon C, Levine MN; American College of Chest Physicians. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest2008; 133(suppl 6):257S–298S.
Flaherty ML, Kissela B, Woo D, et al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology2007; 68:116–121.
Lee SB, Manno EM, Layton KF, Wijdicks EF. Progression of warfarin-associated intracerebral hemorrhage after INR normalization with FFP. Neurology2006; 67:1272–1274.
Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke2006; 37:1465–1470.
Sjöblom L, Hårdemark HG, Lindgren A, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke2001; 32:2567–2574.
Yasaka M, Minematsu K, Naritomi H, Sakata T, Yamaguchi T. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost2003; 89:278–283.
Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation2007; 115:2689–2696.
Goldstein JN, Thomas SH, Frontiero V, et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke2006; 37:151–155.
Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc2007; 82:82–92.
Guidelines on oral anticoagulation: third edition. Br J Haematol1998; 101:374–387.
Baglin TP, Keeling DM, Watson HG; British Committee for Standards in Haematology. Guidelines on oral anticoagulation (warfarin): third edition—2005 update. Br J Haematol2006; 132:277–285.
O’Shaughnessy DF, Atterbury C, Bolton Maggs P, et al; British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol2004; 126:11–28.
Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM; Warfarin Reversal Consensus Group. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust2004; 181:492–497.
Davis SM, Broderick J, Hennerici M, et al; Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology2006; 66:1175–1181.
Broderick JP, Diringer MN, Hill MD, et al; Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Determinants of intracerebral hemorrhage growth: an exploratory analysis. Stroke2007; 38:1072–1075.
Goldstein JN, Fazen LE, Snider R, et al. Contrast extravasation on CT angiography predicts hematoma expansion in intracerebral hemorrhage. Neurology2007; 68:889–894.
Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke1996; 27:1783–1787.
Kim J, Smith A, Hemphill JC, et al. Contrast extravasation on CT predicts mortality in primary intracerebral hemorrhage. AJNR Am J Neuroradiol2008; 29:520–525.
Wada R, Aviv RI, Fox AJ, et al. CT angiography “spot sign” predicts hematoma expansion in acute intracerebral hemorrhage. Stroke2007; 38:1257–1262.
Barras CD, Tress BM, Christensen S, et al; Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Density and shape as CT predictors of intracerebral hemorrhage growth. Stroke2009; 40:1325–1331.
Delgado Almandoz JE, Yoo AJ, Stone MJ, et al. Systematic characterization of the computed tomography angiography spot sign in primary intracerebral hemorrhage identifies patients at highest risk for hematoma expansion: the spot sign score. Stroke2009; 40:2994–3000.
Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Tanaka R. Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage. Stroke1998; 29:1160–1166.
Ederies A, Demchuk A, Chia T, et al. Postcontrast CT extravasation is associated with hematoma expansion in CTA spot negative patients. Stroke2009; 40:1672–1676.
Delgado P, Alvarez-Sabín J, Abilleira S, et al. Plasma d-dimer predicts poor outcome after acute intracerebral hemorrhage. Neurology2006; 67:94–98.
Naidech AM, Jovanovic B, Liebling S, et al. Reduced platelet activity is associated with early clot growth and worse 3-month outcome after intracerebral hemorrhage. Stroke2009; 40:2398–2401.
Silva Y, Leira R, Tejada J, Lainez JM, Castillo J, Dávalos A; Stroke Project, Cerebrovascular Diseases Group of the Spanish Neurological Society. Molecular signatures of vascular injury are associated with early growth of intracerebral hemorrhage. Stroke2005; 36:86–91.
Sansing LH, Messe SR, Cucchiara BL, Cohen SN, Lyden PD, Kasner SE; CHANT Investigators. Prior antiplatelet use does not affect hemorrhage growth or outcome after ICH. Neurology2009; 72:1397–1402.
Moussouttas M, Malhotra R, Fernandez L, et al. Role of antiplatelet agents in hematoma expansion during the acute period of intracerebral hemorrhage. Neurocrit Care2010; 12:24–29.
Delgado Almandoz JE, Yoo AJ, Stone MJ, et al. The spot sign score in primary intracerebral hemorrhage identifies patients at highest risk of in-hospital mortality and poor outcome among survivors. Stroke2010; 41:54–60.
Broderick J, Connolly S, Feldmann E, et al; American Heart Association; American Stroke Association Stroke Council; High Blood Pressure Research Council; Quality of Care and Outcomes in Research Interdisciplinary Working Group. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke2007; 38:2001–2023.
Steiner T, Kaste M, Forsting M, et al. Recommendations for the management of intracranial haemorrhage - part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis2006; 22:294–316.
Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke2006; 37:256–262.
Goldstein JN, Fazen LE, Wendell L, et al. Risk of thromboembolism following acute intracerebral hemorrhage. Neurocrit Care2009; 10:28–34.
Christensen MC, Dawson J, Vincent C. Risk of thromboembolic complications after intracerebral hemorrhage according to ethnicity. Adv Ther2008; 25:831–841.
Lacut K, Bressollette L, Le Gal G, et al; VICTORIAh (Venous Intermittent Compression and Thrombosis Occurrence Related to Intracerebral Acute hemorrhage) Investigators. Prevention of venous thrombosis in patients with acute intracerebral hemorrhage. Neurology2005; 65:865–869.
Diringer MN, Skolnick BE, Mayer SA, et al. Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial. Stroke2010; 41:48–53.
Boeer A, Voth E, Henze T, Prange HW. Early heparin therapy in patients with spontaneous intracerebral haemorrhage. J Neurol Neurosurg Psychiatry1991; 54:466–467.
Dickmann U, Voth E, Schicha H, Henze T, Prange H, Emrich D. Heparin therapy, deep-vein thrombosis and pulmonary embolism after intracerebral hemorrhage. Klin Wochenschr1988; 66:1182–1183.
Geerts WH, Bergqvist D, Pineo GF, et al; American College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest2008; 133(suppl 6):381S–453S.
Vermeer SE, Algra A, Franke CL, Koudstaal PJ, Rinkel GJ. Long-term prognosis after recovery from primary intracerebral hemorrhage. Neurology2002; 59:205–209.
Bailey RD, Hart RG, Benavente O, Pearce LA. Recurrent brain hemorrhage is more frequent than ischemic stroke after intracranial hemorrhage. Neurology2001; 56:773–777.
Viswanathan A, Rakich SM, Engel C, et al. Antiplatelet use after intracerebral hemorrhage. Neurology2006; 66:206–209.
Greenberg SM, Eng JA, Ning M, Smith EE, Rosand J. Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage. Stroke2004; 35:1415–1420.
Lee SH, Ryu WS, Roh JK. Cerebral microbleeds are a risk factor for warfarin-related intracerebral hemorrhage. Neurology2009; 72:171–176.
Ueno H, Naka H, Ohshita T, et al. Association between cerebral microbleeds on T2*-weighted MR images and recurrent hemorrhagic stroke in patients treated with warfarin following ischemic stroke. AJNR Am J Neuroradiol2008; 29:1483–1486.
O’Donnell HC, Rosand J, Knudsen KA, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med2000; 342:240–245.
Genes for Cerebral Hemorrhage on Anticoagulation (GOCHA) Collaborative Group. Exploiting common genetic variation to make anticoagulation safer. Stroke2009; 40(suppl 3):S64–S66.
Tzourio C, Arima H, Harrap S, et al. APOE genotype, ethnicity, and the risk of cerebral hemorrhage. Neurology2008; 70:1322–1328.
Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med1998; 105:91–99.
Kuijer PM, Hutten BA, Prins MH, Büller HR. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med1999; 159:457–460.
Wess ML, Schauer DP, Johnston JA, et al. Application of a decision support tool for anticoagulation in patients with non-valvular atrial fibrillation. J Gen Intern Med2008; 23:411–417.
Singer DE, Chang Y, Fang MC, et al. Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation? The ATRIA study. Circ Cardiovasc Qual Outcomes2009; 2:297–304.
Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med2004; 141:745–752.
Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med2009; 151:297–305.
Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg SM. Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis. Stroke2003; 34:1710–1716.
Baruch L, Gage BF, Horrow J, et al. Can patients at elevated risk of stroke treated with anticoagulants be further risk stratified?Stroke2007; 38:2459–2463.
Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA2001; 285:2864–2870.
Cannegieter SC, Rosendaal FR, Briët E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation1994; 89:635–641.
Freudenberger RS, Hellkamp AS, Halperin JL, et al; SCD-HeFT Investigators. Risk of thromboembolism in heart failure: an analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Circulation2007; 115:2637–2641.
Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med1996; 125:1–7.
Claassen DO, Kazemi N, Zubkov AY, Wijdicks EF, Rabinstein AA. Restarting anticoagulation therapy after warfarin-associated intracerebral hemorrhage. Arch Neurol2008; 65:1313–1318.
De Vleeschouwer S, Van Calenbergh F, van Loon J, Nuttin B, Goffin J, Plets C. Risk analysis of thrombo-embolic and recurrent bleeding events in the management of intracranial haemorrhage due to oral anticoagulation. Acta Chir Belg2005; 105:268–274.
Butler AC, Tait RC. Restarting anticoagulation in prosthetic heart valve patients after intracranial haemorrhage: a 2-year follow-up. Br J Haematol1998; 103:1064–1066.
Bertram M, Bonsanto M, Hacke W, Schwab S. Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neurol2000; 247:209–214.
Taylor FC, Cohen H, Ebrahim S. Systematic review of long term anticoagulation or antiplatelet treatment in patients with nonrheumatic atrial fibrillation. BMJ2001; 322:321–326.
Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology2008; 71:1084–1089.
Sansing LH, Messe SR, Cucchiara BL, Cohen SN, Lyden PD, Kasner SE; CHANT Investigators. Prior antiplatelet use does not affect hemorrhage growth or outcome after ICH. Neurology2009; 72:1397–1402.
Snow V, Qaseem A, Barry P, et al; American College of Physicians; American Academy of Family Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism. Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med2007; 146:204–210.
Albers GW, Amarenco P, Easton JD, Sacco RL, Teal PA; merican College of Chest Physicians. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest2008; 133(suppl 6):630S–639S.
Hankey GJ, Eikelboom JW. Antithrombotic drugs for patients with ischaemic stroke and transient ischaemic attack to prevent recurrent major vascular events. Lancet Neurol2010; 9:273–284.
Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med2009; 361:2342–2352.
Schulman S, Wåhlander K, Lundström T, Clason SB, Eriksson H; THRIVE III Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med2003; 349:1713–1721.
Singer DE, Albers GW, Dalen JE, et al; American College of Chest Physicians. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest2008; 133(suppl 6):546S–592S.
Given the high risk of hematoma expansion in the early phase of acute ICH, most experts recommend reversing anticoagulation immediately.
Many clinicians start subcutaneous heparinoids in low doses 24 to 72 hours after ICH to prevent deep vein thrombosis, and after the first few days or a week, consider either increasing the dose to a full anticoagulation dose or making a transition to oral anticoagulants.
Many patients with lobar hemorrhage or cerebral amyloid angiopathy may remain at higher risk of anticoagulant-related ICH recurrence than thromboembolic events and would therefore be best managed without anticoagulants.
Those with deep hemispheric ICH, hypertension that can be well controlled, and a high risk of disabling thromboembolism may receive net benefit from restarting anticoagulation.
