Hematology

Management of warfarin-associated intracerebral hemorrhage

Management of warfarin-associated intracerebral hemorrhage
Authors
W David Freeman, MD
Maria I Aguilar, MD
Jeffrey Weitz, MD
Section Editors
Lawrence LK Leung, MD
Scott E Kasner, MD
Deputy Editor
Stephen A Landaw, MD, PhD
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Mon Aug 08 00:00:00 GMT 2011 (More)

INTRODUCTION — The use of chronic oral anticoagulation with a vitamin K antagonist can be complicated by anticoagulation-associated intracerebral hemorrhage (AAICH), especially in elderly patients. AAICH is the most devastating complication of warfarin therapy, accounting for 90 percent of warfarin-related deaths and most of the remaining permanent disability [1].

In terms of absolute risk, the rate of spontaneous intracerebral hemorrhage (ICH) among 70 year-old subjects averages 0.15 percent/year. In those anticoagulated with warfarin to an INR of 2.0 to 3.0, the rate of ICH is increased to 0.3 to 0.8 percent/year. (See “Risk of intracerebral hemorrhage in patients treated with warfarin”.)

The management of warfarin- and other vitamin K antagonist-associated ICH (AAICH, as defined above), a medical emergency, will be reviewed here [2,3].

General overviews of the complications of warfarin therapy and of the evaluation of stroke are presented separately. (See “Therapeutic use of warfarin”, section on ‘Bleeding’ and “Correcting excess anticoagulation after warfarin” and “Anticoagulation in older adults”, section on ‘Risk of bleeding’ and “Overview of the evaluation of stroke”.)

EPIDEMIOLOGY — A survey of consecutive patients admitted with supratentorial ICH to the Massachusetts General Hospital between 1994 and 2001 found that 26 percent were taking warfarin; on average, one patient per month with AAICH was admitted to this tertiary care hospital [4]. Other studies of ICH reported that about 12 percent (range 6 to 18 percent) of patients with primary ICH were receiving oral anticoagulants at the time of admission [5-9].

The incidence of AAICH has been increasing ever since the publication of important clinical trials of warfarin use for preventing ischemic stroke in elderly patients with atrial fibrillation. As an example, a study from the five-county Greater Cincinnati/Northern Kentucky area estimated the incidence of AAICH during three periods: 1988, 1993/1994, and 1999 [10]. Results of this study included:

 

  • The annual incidence of AAICH in 1999 was more than five times that noted in 1988 (4.4 versus 0.8 cases/100,000 persons per year), while the annual incidence of all ICH increased by only 50 percent between these two time periods (24.6 versus 16.5). This increase in AAICH paralleled a fourfold higher delivery of warfarin to pharmacies during this same interval.
  • For data obtained in 1999, the annual rates of AAICH increased strongly with age, being 0.3, 5.5, 24.3, and 45.9 cases/100,000 per year for those <50, 50 to 69, 70 to 79, and ≥80 years of age, respectively.

 

Significant bleeding in general is strongly associated with excessive anticoagulation (figure 1 and figure 2). However, most episodes of AAICH occur during anticoagulation intensities that are within the therapeutic ranges for most medical condition (ie, INRs between 2.0 and 3.5) [4,5,11-14]. The estimated absolute rate in such patients is 0.3 to 0.8 percent/year, depending on patient age, concomitant aspirin use, and blood pressure control.

The degree of INR prolongation at the time of AAICH correlates with initial hematoma size, progressive hematoma enlargement after admission, functional outcome, and mortality [4,9,15,16]. Over one-half of patients with AAICH die within 30 days of the onset of this complication [4,5,11,12,17-19]. In one study, for example, AAICH was fatal in two-thirds of patients with INRs >3.0 on presentation [4]. (See “Risk of intracerebral hemorrhage in patients treated with warfarin”, section on ‘ICH risk with antithrombotic therapy’.)

The mortality rate associated with AAICH varies according to the neurologic status of the patient at the time of admission. A Swedish multicenter study found the following 30-day mortality rates of AAICH for the following clinical presentations [11]:

 

  • Unconscious on admission — 96 percent
  • Unconscious before start of active treatment — 80 percent
  • Treatment with warfarin antagonists while still conscious — 28 percent

 

CLINICAL PRESENTATION AND DIAGNOSIS — The onset of focal neurologic signs (eg, hemiparesis, aphasia, ataxia) in an anticoagulated patient, especially if associated with headache, nausea and vomiting, confusion, or obtundation, warrants emergent evaluation for the presence of ICH. The onset of symptoms is usually sudden (ie “stroke-like”). In about one-half of patients, the hematoma continues to enlarge during the initial 12 to 24 hours, with attendant management implications [11,16-18,20,21] (figure 3).

The mean age of patients with AAICH is in the 70s, reflecting the age distribution of anticoagulated patients, combined with a special propensity for AAICH among the elderly. (See ‘Epidemiology’ above.)

Clinical course — The slow rate of hematoma enlargement in AAICH contrasts with a more rapid course of bleeding typical of ICH in patients who are not anticoagulated. In one study that employed serial CT scanning, 7 of 13 patients (54 percent) with AAICH were noted to have ICH expansion at a median time of 21.4 hours (range: 4.6 to 61 hours) [21]. In contrast, expansion was noted in 9 of 57 (16 percent) of those hemorrhages not associated with warfarin use, although at a shorter median time of 8.4 hours (range 2.4 to 31 hours). (See “Clinical diagnosis of stroke subtypes”, section on ‘Intracerebral hemorrhage’.)

If the hematoma grows, progressive stupor and hemiplegia evolve into coma as transtentorial herniation supervenes (picture 1). Especially frequent involvement of the cerebellum in warfarin-associated ICH has been reported in most studies [9,11,12,17,22-24]. The relative distribution of lobar versus deep white matter/basal ganglia locations appears to be similar in spontaneous versus AAICH.

Diagnostic testing — ICH is visible immediately as hyperdense “white” areas on computed tomography (CT); a dark rim of uncongealed blood may also be present in actively bleeding patients with excessively prolonged INRs [17,25]. Routine MRI sequences may not detect bleeding within the first few hours, but special gradient echo (“susceptibility-weighted”) techniques are very sensitive for acute bleeding [26]. (See “Overview of the evaluation of stroke”, section on ‘Evaluation of patients with intracerebral hemorrhage’ and “Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis”, section on ‘Evaluation and diagnosis’.)

Large volume (>30 mL), intraventricular extension, and shift of midline structures are all radiologic predictors of a poor outcome [11,12,15,22,23,27].

REVERSING THE COAGULATION DEFECT — AAICH is a medical emergency requiring urgent reversal of anticoagulation. Even small hematomas in anticoagulated patients can continue to enlarge, particularly if the INR is >3.0 (picture 1) [16,28].

Therapeutic options — The therapeutic approach to clinically significant bleeding in warfarin-treated patients is discussed in detail elsewhere, but will be reviewed here in the context of AAICH [2,29]. The single randomized trial concerning the treatment of AAICH included only five patients [30]. Accordingly, treatment recommendations discussed here are based upon evidence from retrospective analysis of case series, rather than prospective, randomized trials. (See “Correcting excess anticoagulation after warfarin”, section on ‘Treatment’.)

Intravenous vitamin K — High doses (ie, 10 to 20 mg) of intravenous vitamin K can fully reverse warfarin-induced anticoagulation. However, this effect takes approximately 12 to 24 hours, during which time the ICH may continue to enlarge. Since the goal of treatment of AAICH is to return the INR to normal as soon as possible, treatment with vitamin K alone will not achieve this end, although vitamin K must be given in every case in order to achieve sustained reversal of an elevated INR. (See ‘Initial treatment’ below.)

As an example, in a retrospective study of AAICH, six patients with an initial INR on admission of 4.2 ± 2.0 were treated with vitamin K alone [31]. At approximately 12 hours after initiation of treatment their INR was still elevated at 3.0 ± 1.7.

High doses of vitamin K also result in a variable period of refractoriness to re-institution of warfarin, a factor that needs to be kept in mind if resumption of anticoagulation is contemplated (see ‘Resumption of anticoagulation’ below).

Fresh frozen plasma — Eight units of fresh frozen plasma (FFP) are often required to immediately reverse the coagulation defect in a patient treated with a vitamin K antagonist. However, the associated volume load (approximately 2 liters) can be prohibitive, especially in patients with underlying cardiac disease. (See “Clinical use of plasma components”, section on ‘Fresh frozen plasma’.)

Guidance on the dose of FFP to be used is presented separately. (See “Correcting excess anticoagulation after warfarin”, section on ‘Significant or life-threatening bleeding’.)

Other drawbacks of FFP in this setting include the time required to check for blood compatibility (ie, ABO), thaw, and infuse this product, during which time the size of the hematoma may expand. In one report, for example, the median time interval between admission to a neuro-intensive care unit and INR normalization (ie, INR ≤1.2) was 30 hours (range: 14 to 50 hours) [32].

The cost for a course of treatment with FFP in a patient with AAICH and an INR of 3.0 has been variably estimated to be $200 to $400 US dollars [29].

Unactivated prothrombin-complex concentrates — Unactivated prothrombin-complex concentrates (PCC, also called factor IX complex), which consist of the vitamin K-dependent coagulation factors (ie, factors II, VII, IX, and X), normalize the INR more rapidly than infusion of FFP or vitamin K alone [14,33-36]. As an example, in a prospective multinational clinical trial, infusion of unactivated PCC resulted in an INR ≤1.4 within 30 minutes of infusion in all 43 patients [37].

While PCC products are easily administered and do not constitute as much of a volume load as does FFP, they are not always available at some institutions and may not be stocked in emergency departments. While PCC products available in Canada and Europe contain all four coagulation factors (ie, four-factor PCC) (see “Unactivated prothrombin complex concentrates-protein C-protein S: Drug information”), those available in the United States contain variably low concentrations of factor VII (ie, three-factor PCC) (see “Unactivated prothrombin complex concentrates (factor IX complex): Drug information”) [3,38-40]. Three-factor PCCs thus may be insufficient, by themselves, to immediately reverse the deficit in factor VII, and, we believe, should be given along with either FFP or recombinant human factor VII in order to supply the “missing” factor VII.

Thrombotic events have complicated infusion of PCC, but this risk is difficult to quantify due to varying preparations, doses, and differing patient populations in available reports [34,41,42].

If vitamin K is not also given at the time of presentation, the use of PCC alone may result in a delayed secondary rise in the INR as the coagulation factors are metabolized [14]. This is especially true of factor VII, which has an in vivo half-life of only four to six hours. (See ‘Heparin prophylaxis’ below and “Plasma derivatives and recombinant DNA-produced coagulation factors”, section on ‘Prothrombin complex concentrates’.)

The cost for a course of treatment with PCC in a patient with ICH and an INR of 3.0 has been variably estimated to be $1000 to $2000 US dollars [29].

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Recombinant factor VIIa — Recombinant factor VIIa has been used to treat major intracerebral bleeding, both spontaneous as well as following treatment with a number of different anticoagulant agents, including vitamin K antagonists [43-50], including traumatic intracerebral bleeding in patients receiving warfarin immediately prior to the trauma [51]. (See “Spontaneous intracerebral hemorrhage: Prognosis and treatment”, section on ‘Treatment’ and “Therapeutic uses of recombinant coagulation factor VIIa”.)

Two concerns are that use of recombinant factor VIIa corrects only the warfarin-induced reduction in factor VII activity, while PCC, FFP, and vitamin K correct the deficiency in all four of the vitamin K-dependent coagulation factors (eg, factors II, VII, IX, and X). In addition, administration of recombinant factor VIIa alone may correct the INR, since the prothrombin time is most sensitive to reductions in factor VII, giving a false sense of security that the bleeding diathesis has been corrected. There are only limited data in patients with AAICH that deal with this concern:

 

  • An initial report of a small number of patients with variable characteristics suggested that use of recombinant factor VIIa alone (initial dose: 10 to 50 microg/kg) was an effective approach to reversing AAICH [47].
  • In a report of seven consecutive patients with AAICH and a mean pre-treatment INR of 2.7 (range: 1.6 to 5.6), use of recombinant factor VIIa (mean initial dose 62 microg/kg) was associated with an immediate reduction in the INR ranging from 0.6 to 3.5, with a mean post-treatment INR of 1.08 [52]. However, full and lasting reversal of the INR was achieved only with the combined use of vitamin K, FFP, and recombinant factor VIIa. This is partially because the half-life of factor VII is short (4 to 6 hours); the half-life of activated factor VII (ie, factor VIIa) is even shorter, approximately 2.3 hours.

 

In this latter study, the mean time from AAICH onset to treatment with factor VIIa was 6.2 hours (range: 1.3 to 18 hours). Two of the seven patients died within the first week of neurologic injury; the five surviving patients were left with severe neurologic impairment.

Infusion of high-dose factor VIIa (80 microg/kg) in patients with spontaneous ICH (ie, not AAICH) was significantly associated with increased arterial thrombosis (eg, myocardial and cerebral infarctions) in a randomized trial [49]. No increase was apparent with infusion of a lower dose (20 microg/kg). In a case series of 101 patients with warfarin-associated intracranial hemorrhage (54 percent intracerebral, 30 percent subdural hematomas) who received factor VIIa (mean dose 52 mcg/kg), eight patients (8 percent) developed thromboembolic complications within two weeks of treatment [53].

The cost for a course of treatment with recombinant human factor VIIa in a patient with ICH and an INR of 3.0 is variably estimated to be $5000 to $15,000 US dollars [29].

Comparative studies — There are few studies comparing various treatments to help determine whether use of PCC results in improved clinical outcomes compared with vitamin K and/or FFP in patients with AAICH [11,31,34,36]. Additionally, there are no studies directly comparing recombinant factor VIIa infusion to PCC or FFP.

 

  • The single available randomized trial included only two patients with AAICH treated with FFP alone and three treated with FFP plus PCC, along with eight additional patients with anticoagulation-associated subdural hematomas or subarachnoid hemorrhage [30]. Although there were no significant differences in neurologic outcome between the two treatment groups, the addition of PCC was associated with a faster rate of correction of the INR.
  • A similar INR benefit with PCC was noted in a retrospective study in which the mean INR fell from 2.8 to 1.2 within 4.8 hours after PCC compared with a fall in INR from 3.0 to 1.7 within 7.3 hours after FFP [34]. PCC therapy was also associated with significantly less progression of neurologic symptoms.
  • A later retrospective study found that the 31 patients with AAICH who received PCCs alone or in combination with FFP or vitamin K had a significantly lower incidence of hematoma expansion compared with the 24 patients who did not receive PCCs [31]. As with earlier studies, most of the benefit in the PCC-treated group (ie, reduced incidence and extent of hematoma growth) appeared to be related to earlier correction of the INR. However, neither treatment was associated with an improvement in outcome.

 

TREATMENT — There are few relevant guidelines for the reversal of anticoagulation in patients with AAICH, and expert opinion on this subject differs [2,3,54-56].

 

  • PCC, recombinant factor VIIa, or fresh frozen plasma given with intravenous vitamin K were advocated in the 2008 American College of Chest Physicians Guidelines for patients with life-threatening bleeding such as intracranial hemorrhage [57].
  • American Heart Association / American Stroke Association guidelines recommend replacement of the vitamin K-dependent factors to correct the INR and the administration of intravenous vitamin K. PCCs were considered a reasonable alternative to FFP. Recombinant factor VIIa was not routinely recommended as a sole agent for reversal [54].
  • Other guidelines have suggested using various combinations of vitamin K, FFP, PCC, and recombinant factor VIIa [29,56,58,59].
  • PCC preparations are not readily available in emergency departments at most United States hospitals; their use is often restricted to hematology specialists, reducing their immediate availability. As a result, acute treatment with infusion of FFP along with vitamin K has been the most frequently used therapy for warfarin-associated ICH [55].

 

Regardless of the preparations used, it is extremely important to minimize delays in their administration, in hopes of reducing the high mortality and morbidity of AAICH [29,60].

Initial treatment — For patients with AAICH we recommend emergent initial fourfold treatment in an attempt to reverse the anticoagulation as rapidly as possible and minimize or prevent enlargement of the hematoma [61]. The following recommendations are in general agreement with the 2011 British Committee for Standards in Hematology [62], the 2008 ACCP Guidelines [57] and the 2007 American Heart Association/ American Stroke Association Stroke Council Guidelines (table 1) [54]:

 

  • Immediate cessation of all anticoagulant and antiplatelet therapy
  • Vitamin K 10 mg by slow intravenous infusion (eg, no faster than 1 mg/min to minimize anaphylactic/anaphylactoid risk) [14,34]. Vitamin K can be repeated every 12 hours for persistent INR elevation [57].
  • Infusion of four-factor PCC alone or three-factor PCC in combination with FFP or recombinant human factor VIIa
  • If PCC is not rapidly available, the use of FFP, with or without recombinant factor VIIa, is indicated, with the caveats as noted above. (See ‘Fresh frozen plasma’ above.)

 

Calculation of the dose of PCC (in International Units) or FFP (in mL) required to reverse the effects of warfarin can be estimated based upon the patient’s initial INR and body weight [63]. Guidance on the suggested dose of PCC to be employed is presented separately. (See “Correcting excess anticoagulation after warfarin”, section on ‘Significant or life-threatening bleeding’.)

The dose of PCC is based on the factor IX content of the preparation; after initial infusion of 500 to 1000 international units at a rate of 100 international units/min, subsequent infusion of PCC should be at a rate of ≤25 international units/min.

Treatment goals and efficacy — The goal of therapy should be an INR in the normal range (ie, <1.4 in most laboratories) [14,41]. The INR should be checked 30 minutes following the initial infusion to be certain that it has returned to normal; if not, infusion of additional PCC or factor VIIa should be considered [37,38]. Serial INR determinations should be performed over the next 24 hours (eg, INR checked every 4 to 6 hours for the first 24 hours), and then checked daily for a few days to assure that the initial INR correction is maintained. (See ‘Unactivated prothrombin-complex concentrates’ above.)

There are limited data on the efficacy of PCC in patients with AAICH. Successful treatment of nine such patients using relatively low doses of PCC has been reported [14]. Patients were given 500 or 1000 international units depending upon prolongation of the INR to <4.5 or >4.5, respectively, with additional administration of 500 international units based upon a repeat INR obtained after the initial infusion. The INR was corrected within 10 minutes of completion of the infusion at a median dosage of 12.5 international units/kg. Hematoma enlargement occurred in only two of the nine patients; there were no thromboembolic episodes in this group, which included four patients with prosthetic heart valves.

In this and two other series of patients treated with PCC, there was only one of 10 patients who suffered subsequent ICH enlargement when the INR was corrected to normal [14,16,64]. Worsening occurred 12 to 72 hours later in four patients with an incompletely corrected INR (eg, INRs of 1.5, 1.9, 2.7, and 3.2), combined with the use of heparin in 3. Based upon this anecdotal evidence, it seems prudent to monitor the patient carefully in order to keep the INR in the normal range (ie, INR <1.2) for the first 72 hours after ICH.

Available data suggest that the use of PCC in AAICH is relatively safe (table 2). However, in one study, large ischemic strokes occurred on days 2, 4, and 5 in three of seven patients treated with PCC (including two of seven with prosthetic heart valves) despite concomitant treatment with heparin in low doses that did not prolong the activated partial thromboplastin time [64]. The dosages and content of the PCC preparation were not reported.

Patients presenting with large hematomas who are comatose along with signs of transtentorial herniation have a negligible chance of recovery [11,23]. No therapy has been proven beneficial in this setting and the expense of PCC or factor VIIa may not be warranted.

Heparin prophylaxis — As noted above, thrombosis has been reported following the use of PCC, and the risk may vary with the specific preparation [34,41,42,64]. Because of this concern, it has been recommended that low doses of heparin or LMW heparin be given following infusion of PCC to minimize this risk. However, there are no strongly supportive data for this course of action.

If the INR is corrected to normal using PCC, it may be reasonable to begin low-dose subcutaneous unfractionated heparin or low-dose LMW heparin 48 hours after ICH onset in patients with prosthetic heart valves and to restart warfarin at five to seven days. The timing of heparin prophylaxis and reinitiation of warfarin therapy in these and other patients are discussed in detail below (see ‘Resumption of anticoagulation’ below).

Surgical evacuation — The role of surgical evacuation in cerebellar and lobar ICH during anticoagulation has not been well defined, and most neurosurgeons are reluctant to operate in the setting of impaired hemostasis. However, given the high mortality accompanying AAICH, surgical treatment after reversing anticoagulation can be considered in selected patients [23,52,64,65].

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Favorable outcomes have been reported in some patients with significant shifts of midline structures, uncal herniation, large hemorrhage volume, and/or preoperative coma [66]. (See “Spontaneous intracerebral hemorrhage: Prognosis and treatment”, section on ‘Surgery’.)

Management of hypertension — The systemic blood pressure is often markedly elevated following AAICH, but hypertension has not been shown to be an independent predictor of outcome [11]. Although there are no good data regarding optimal management, keeping the systolic blood pressure <180 mmHg during the acute phase appears reasonable [2,14,16]. (See “Treatment of hypertension in patients who have had a stroke” and “Spontaneous intracerebral hemorrhage: Prognosis and treatment”, section on ‘Blood pressure control’.)

Resumption of anticoagulation — The indications for chronic oral anticoagulation should be carefully reassessed in the wake of an episode of AAICH. Available data do not allow accurate estimation of the long-term risk of recurrent ICH for survivors of AAICH who are subsequently restarted on oral anticoagulation (table 3) [19,67].

The few available case series suffer from potential selection and publication biases. Survivors selected for resumption of anticoagulation tend to be younger patients with prosthetic heart valves; their absolute risk of recurrent ICH following resumption of anticoagulation is likely to be much lower than that for elderly patients with atrial fibrillation [5,68,69].

MRI gradient-echo techniques to detect clinically silent microbleeds may stratify the risk of recurrent ICH. However, the sensitivity and specificity of these techniques have not been adequately defined to apply to individual patients at the present time.

For primary prevention of ischemic stroke in most elderly patients with atrial fibrillation (AF), the long-term high risk of recurrent AAICH usually does not warrant reinitiation of anticoagulation. For patients with prosthetic heart valves or for secondary prevention of ischemic stroke in patients with AF, the risks of thromboembolism in the absence of anticoagulation are much higher, and the risk/benefit assessment appears to favor use of anticoagulation [19,70]. (See “Anticoagulant and antiplatelet therapy in patients with an acute or prior intracerebral hemorrhage”.)

Optimal timing — Available data are inadequate to determine the optimal timing for restarting anticoagulation following an episode of AAICH (table 4) [2]. The acute treatment used to reverse anticoagulation may be a factor in this decision, since, as noted above, high doses of vitamin K may make the patient refractory to reinstitution of warfarin for a variable period of time.

The conflicting messages from available case series are illustrated by the following reports and a literature review:

In one series, 141 patients with warfarin-associated intracranial hemorrhage (including 87 with ICH and 43 with subdural hemorrhage) and a high thromboembolic risk had anticoagulation interrupted for a mean of 10 days [71]. Only 3 patients (2 percent) experienced thromboembolic events (including one of 57 with prosthetic heart valves). The authors concluded that the risk of thromboembolism is low if warfarin is discontinued for only one to two weeks. In this report, no information was given about reversal of anticoagulation and whether INRs were corrected to normal in most patients. However, a previous report describing part of this patient cohort mentioned routine use of FFP and vitamin K [72].

The thrombotic risk may be greater in patients treated with PCC. As noted above, large ischemic strokes were reported in three of seven patients with AAICH and prosthetic cardiac valves treated with PCC, despite concomitant treatment with heparin in low doses insufficient to increase the activated partial thromboplastin time [64]. As a result, the authors advocated the use of full-dose intravenous heparin on the day following treatment with PCC.

A literature review of 20 hemorrhagic and 28 thromboembolic (TE) events that occurred subsequent to an anticoagulant-related ICH made the following observations [73]:

 

  • Hemorrhagic complications were more common within the first 24 to 72 hours following presentation. Risk factors for hemorrhage included younger age, traumatic cause for the index ICH, subdural hematomas, and failure to reverse anticoagulation (table 5).
  • TE complications mostly took place after 72 hours following presentation and were more common in younger patients and those with spinal hemorrhage, multiple hemorrhages, and non-traumatic cause for the index ICH. Reinitiation of anticoagulation at a lower intensity significantly increased the risk of TE complications (table 5).
  • Although even less data were available concerning the timing of reinitiation of anticoagulation and subsequent hemorrhagic or TE events, when anticoagulation was reinitiated within 24 hours, six of the seven complications were hemorrhagic. When anticoagulation was reinitiated more than 72 hours after the index ICH, 10 of the 12 complications were TE (table 5).

 

In short, available data are sparse, mostly retrospective, and are generally inadequate to assess the risks and benefits of heparin for VTE prevention in patients with acute ICH. However, most of the hemorrhagic events that have been reported occurred when anticoagulation was started within the first 24 hours, and most of the TE events when anticoagulation was started more than 72 hours following the index event.

There are alternative ways to interpret these anecdotal data. The range of recommendations include withholding warfarin anticoagulation for four to six weeks [74], withholding warfarin for one to two weeks [5,28,71,72], and the administration of full-dose intravenous heparin immediately after the INR has been corrected to normal [64,75]. One hypothesis to explain the dramatic difference in observed rates of thromboembolism following reversal of anticoagulation is a prothrombotic state caused by infusion of high-dose PCC [64].

In the absence of consensus on this issue, if the INR is corrected to normal using PCC, it seems reasonable to begin low-dose subcutaneous heparin or LMW heparin 48 hours after ICH onset for routine VTE prophylaxis. For patients who will resume anticoagulation, warfarin can be restarted at 7 to 14 days [2,54,76]. (See “Anticoagulant and antiplatelet therapy in patients with an acute or prior intracerebral hemorrhage”, section on ‘Prevention of VTE’.)

Pneumatic compression stockings and early ambulation should be considered if leg paresis is present and control of hypertension, if present, is strongly recommended. (See ‘Management of hypertension’ above.)

Use of antiplatelet agents — Use of antiplatelet agents (eg, aspirin) is known to increase the risk of bleeding at any site in warfarin-treated patients, and is therefore likely to increase the risk of recurrent ICH. As an example, in a meta-analysis of six trials, the relative risk for ICH was 2.4 with warfarin plus aspirin compared to warfarin alone [77]. (See “Therapeutic use of warfarin”, section on ‘Use of NSAIDs and antiplatelet agents’.)

As a result, antiplatelet agents, including low-dose aspirin, should be avoided if possible in patients restarted on warfarin after an episode of AAICH. When aspirin must be used, the lowest effective INR (eg, 1.8 to 2.5 for patients with AF) should be achieved before aspirin is started, coupled with especially vigilant INR monitoring to avoid excessive anticoagulation. Control of blood pressure is also critical for minimizing the risk of recurrent ICH. Lowering the systolic blood pressure by 10 mmHg is likely to reduce this risk by one-half [20]. (See “Spontaneous intracerebral hemorrhage: Prognosis and treatment”, section on ‘Blood pressure control’.)

SUMMARY AND RECOMMENDATIONS

Diagnosis — The onset of focal neurologic signs (eg, hemiparesis, aphasia, ataxia) in a patient receiving anticoagulation with a vitamin K antagonist, especially if associated with headache, nausea and vomiting, confusion, or obtundation, warrants emergent evaluation for the presence of intracerebral hemorrhage (ICH).

ICH is visible immediately as hyperdense “white” areas on computed tomography (CT); a dark rim of uncongealed blood may also be present in actively bleeding patients with an excessively prolonged INR. Special gradient echo (“susceptibility-weighted”) MRI techniques are also very sensitive for acute bleeding. (See ‘Diagnostic testing’ above.)

Treatment goals — Anticoagulant-associated ICH (AAICH) is a medical emergency with an extremely high morbidity and mortality. Even small hemorrhagic areas in anticoagulated patients can continue to enlarge, particularly if the INR is >3.0. Accordingly, treatment must be provided to reverse the effects of anticoagulation in as timely a manner as possible and to maintain such correction for a minimum of 72 hours. (See ‘Treatment’ above.)

Initial treatment plan — In order to attain the above-noted goals, we recommend that the following plan be initiated (table 1) (Grade 1A):

 

  • Immediate cessation of all anticoagulant and antiplatelet therapy
  • For immediate and short-term reversal of anticoagulation (eg, minutes to hours) we recommend infusion of an agent (ie, prothrombin complex concentrates (PCC), recombinant human factor VIIa, fresh frozen plasma (FFP)) to reverse the anticoagulant effect as rapidly as possible. (See ‘Choice of agent’ below.)
  • For longer-term reversal of anticoagulation (ie, hours to days) we recommend administration of vitamin K by slow intravenous infusion, rather than by the oral or subcutaneous route. The usual dose is 10 mg, which can be repeated every 12 hours for persistent INR elevation.

 

Choice of agent — There are no randomized trials which have determined the relative efficacy and safety of PCC, FFP, and factor VIIa in AAICH. The choice of agent primarily depends upon its timely availability in an urgent care setting (table 1). (See ‘Therapeutic options’ above.)

 

  • In institutions where four-factor PCC is available (eg, Canada and Europe), we suggest PCC over factor VIIa or FFP because it rapidly provides all of the vitamin-K dependent coagulation factors in a small infused volume (Grade 2C). The distinction between 3-factor and 4-factor PCC preparations can be found above. (See ‘Unactivated prothrombin-complex concentrates’ above.)
  • In institutions where four-factor PCC is not available (eg, the United States), we suggest the use of three-factor PCC along with small volumes of FFP (eg, 2 units) to supply the missing factor VII (Grade 2C). If volume overload from FFP is a concern, three-factor PCC plus low-dose recombinant factor VIIa (eg, 20 mcg/kg) is a reasonable option. Fresh frozen plasma is indicated when neither PCC nor recombinant human factor VIIa is available.

 

Additional management issues — Although there are few controlled trials available for guidance, the following additional management issues need to be addressed:

 

  • Keeping the systolic blood pressure <180 mmHg during the acute phase is advisable. (See ‘Management of hypertension’ above.)
  • Given the high mortality accompanying AAICH, surgical evacuation of the hematoma after reversing anticoagulation can be considered in selected patients. (See ‘Surgical evacuation’ above.)
  • If the INR has been corrected to normal using PCCs, it is reasonable to begin low-dose prophylactic subcutaneous heparin or LMW heparin 48 hours after ICH onset. For patients who will resume anticoagulation, warfarin can be restarted at 7 to 14 days. Pneumatic compression stockings and early ambulation should be considered if leg paresis is present.

 

REFERENCES

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