Warfarin and intracranial haemorrhage

Blood Reviews (2009) 23, 1–9

www.elsevier.com/locate/blre

REVIEW

Warfarin and intracranial haemorrhage Rebecca Appelboam

a,1

, Elfyn O. Thomas

b,*

a

Anaesthesia and Intensive Care Medicine, Royal Devon and Exeter Hospital, Barrack Road, Exeter, Devon EX2 5DW, UK b Department of Intensive Care Medicine, Derriford Hospital, Plymouth, Devon PL6 8DH, UK

KEYWORDS

Summary Spontaneous intracerebral haemorrhage is one of the most feared complications of long-term anticoagulation. Warfarin therapy not only increases the likelihood of suffering an intracranial haemorrhage, but also increases the mortality associated with it. This review aims to examine the incidence, pathogenesis, and outcome following a warfarin associated intracranial haemorrhage. It also evaluates the available evidence regarding optimal management of these patients, including timing and strategies for reversal of the coagulopathy, the role of neurocritical care and surgery, and indications for re-anticoagulation once the acute phase has past. The specific management of patients with prosthetic heart valves is also discussed. A summary of current societal guidelines is also included, as are some key practice points. c 2008 Elsevier Ltd. All rights reserved.

Anticoagulation; Warfarin; Intracerebral haemorrhage; Prothrombin complex concentrate; Recombinant activated factor VIIl; Neurosurgery; Critical care; Outcome



Introduction Major haemorrhage secondary to long-term oral anticoagulation (OAC) is said to occur in between 1% and 5% of patients per annum with an incidence that increases with increasing patient age, duration of therapy, and intensity of anticoagulation.1,2 The most feared haemorrhagic complication is spontaneous intracerebral haemorrhage (ICH). This occurs 8–10 times more frequently than in non-anticoagu* Corresponding author. Tel.: +44 1752 792555; fax: +44 1752 792548. E-mail addresses: [email protected] (R. Appelboam), [email protected] (E.O. Thomas). 1 Tel.: +44 1392 402474.



lated patients,3 and more than doubles ICH related mortality with reported incidences as high as 67%.4–8 (Table 1) There is an association between haematoma size and International Normalised Ratio (INR) at the time of bleeding.9 Furthermore, warfarin increases the risk of in-hospital haematoma expansion, not only in the first 24 h, but also beyond this, and this expansion has been correlated with mortality.10,11 Other clinical and radiological factors determining mortality include Glasgow Coma Score at presentation, age P80 years, infratentorial origin of ICH and presence of intraventricular haemorrhage.12 The most common indication for long-term anticoagulation is the prevention of ischaemic stroke in patients with atrial fibrillation. Other indications

0268-960X/$ - see front matter c 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.blre.2008.05.001

2

R. Appelboam, E.O. Thomas Table 1

Outcome of warfarin associated intracranial haemorrhage.

Reference

Subject

n

Findings

Effect of AC on outcome after ICH

102

Sjo ¨blom et al.5

Management and prognosis after AC-related ICH

151

Yasaka et al.6

Predisposing factors for enlargement of ICH in patients on AC Death and disability from warfarin associated intracranial and extracranial haemorrhage

47

Warfarin-associated intraventricular haemorrhage

88

Patients on warfarin had double the rate of ICH mortality (52% versus 25.8%) Mortality related to level of consciousness on admission, ICH volume, and intraventricular blood. Higher rate of deterioration in 1st 24–48 h in anticoagulated versus nonanticoagulated patients Enlargement of ICH associated with initial INR >2, and inadequate correction of INR 76% patients with ICH had major disability/died by 30 days, compared with 3% patients with extracranial haemorrhage Overall mortality of warfarin ICH 45%. Ventricular extension of ICH associated with 75% 30day mortality. Predictors of mortality = ICH volume, intraventricular spread, and age

Rosand et al.

4

Fang et al.7

Zubkov et al.8

72 ICH, 98 ECH

n = number of patients, AC = anticoagulation ICH = intracerebral haemorrhage, ECH = extracranial haemorrhage.

for OAC include venous thromboembolic disease and the presence of a mechanical heart valve. With an increasingly elderly population, there has been a dramatic increase in the number of patients receiving long-term warfarin therapy in recent years. This rise is likely to continue, with an estimated 5.6 million patients in America predicted to have atrial fibrillation, and thus potentially require anticoagulation, by 2050.13 In one study, Flaherty et al., demonstrated a quintupling in the incidence of anticoagulant-associated ICH during the 1990s, which was attributed mainly to an increase in warfarin use, with the highest increase in patients aged over 80.14

Table 2

OAC increases the risk of haemorrhagic stroke,3 worsens the severity of the neurological insult,15 and significantly increases the mortality.4 The most desirable level of anticoagulation is that at which the incidence of bleeding, but also thromboembolism is lowest. Cannegieter et al demonstrated that, for patients with mechanical heart valves, this could be found at INR values of 2.5–4.9.16 In another series comparing target INR of 2–3 against 3–4.5 for mechanical prosthetic heart valves, adverse events were reported as 11.2 versus 20.5 events per 100 patient years for all haemorrhagic events, 4.0 versus 5.6 events per 100 patient years for major haemorrhagic events, and 3.1 versus 2.4

ACCP consensus guidelines for antithrombotic therapy.18–20

Condition

Optimal INR

Duration of anticoagulation

DVT post reversible risk factor Idiopathic DVT PE post reversible risk factor Idiopathic PE Paroxysmal AF/CSAF high risk Paroxysmal AF/CSAF medium risk Paroxysmal AF/CSAF low risk Mechanical heart valve (aortic) Mechanical heart valve (mitral)

2–3 (target 2.5) 2–3 (target 2.5) 2–3 (target 2.5) 2–3 (target 2.5) 2–3 (target 2.5) 2–3 (target 2.5) No warfarin, aspirin only 2–3 (target 2.5) 2.5–3.5 (target 3)

3 months 6–12 months 3 months Lifelong Lifelong Lifelong Lifelong Lifelong Lifelong

DVT = deep vein thrombosis, PE = pulmonary embolus, AF = atrial fibrillation, CSAF = chronic stable atrial fibrillation.

Warfarin and intracranial haemorrhage

3

events per 100 patient years for incidence of thromboembolism.17 Maintaining anticoagulation at a lower level, therefore, seems to confer an advantage in terms of bleeding events, with no significant increase in risk of thromboembolic events. Recent guidelines from the American College of Chest Physicians (ACCP) suggest optimal levels of anticoagulation, and duration of treatment.18–20 (Table 2) The British Thoracic Society guidelines suggest 4–6 weeks for PE associated with a temporary risk factor, 3 months for first idiopathic PE, and at least 6 months for other cases, with the risk of bleeding considered in each individual case.21

Pathogenesis ICH is not a static phenomenon. Initial hypotheses that haematoma size was maximal at onset with

Table 3

further increases in size being contained by hydrostatic forces and rising intracranial pressure have been questioned. Further deterioration was initially thought to be due to cerebral oedema and mass effect, but more recent data suggests that early haematoma growth is due to ‘‘ultra-early re-bleeding’’ into areas surrounding the initial haematoma,22 and it is this data which has led to the investigation of ultra-early haemostatic agents in the treatment of ICH. It has now become clear that haematoma expansion is a major predictor of mortality and functional outcome,11,23 and warfarin appears to prolong the time frame over which expansion occurs.6 Inflammation, in addition to ischaemia, is also thought to play a role in a worsened outcome. Several clinical and animal studies have demonstrated that the low-density area that surrounds ICH on the

Reversal of anticoagulation in patients suffering warfarin associated intracranial bleeding.

Reference

Subject

No. of patients

Time AC withheld (days)

No. of thromboembolic events

Widjicks et al.29

Management of AC in patients with PHV and intracranial bleeding Outcome of ACrelated ICH Discontinuation of AC in patients with ICH and high thromboembolic risk Restarting AC in patients with PHV and intracranial haemorrhage Management of AC-associated intracranial haemorrhage Withholding AC in patients with PHV and major bleed ICH in a patient anticoagulated for a PHV Management of AC associated ICH AC following ICH in patients with PHV

39

8 (median)

0

20 (7 PHV)

14.5 (mean)

0

141(52 PHV)

10 (mean)

3

35

0–19. 7 (median)

0

27 (20 PHV)

3

0

28

15 (mean)

0

1

Planned 14 days

1 (fatal day 11)

1

42

0

6

19 (mean)

0

Punthakee et al.30 Phan et al.31

Butler and Tait32

Kawamata et al.33

Ananthasubramaniam et al.34 Shah and Dawson35

Crawley et al.36 Babikian et al.37

AC = anticoagulation, ICH = intracerebral haemorrhage, PHV = prosthetic heart valve.

4 initial CT scan is due to extruded serum, rich in thrombin, inflammatory proteins and proteases.24,25 These may provide additional areas for investigational research in the future.

Immediate management In patients who present with ICH, the need to stop the intracranial bleeding outweighs all other considerations; ‘‘time is brain’’.26 The European Society of Cardiology, in its recommendations on patient management following heart valve surgery, states that ‘‘. . .intracranial and, in particular, intracerebral haemorrhage always necessitates reversal of anticoagulation. . .’’.27 There is often a reluctance to reverse warfarin in patients deemed to be at high risk for thrombus generation, for example, patients with mechanical heart valves. This was demonstrated in a recent study, where over 40% of consultants surveyed would not.28 However, the available evidence in this area supports the correction of the coagulopathy.29–37 (Table 3) In one retrospective study of 39 patients with mechanical heart valves who suffered an intracranial bleed, 13 patients died from their haemorrhage within 48 hours; all 26 survivors had had their coagulopathy reversed.29

Strategies for reversal In patients with OAC-related ICH, there is a relatively short window of opportunity for warfarin reversal to avoid an increase in the size of the haematoma. Warfarin inhibits the action of vitamin K within the liver as a cofactor in the production of prothrombin, factors VII, IX and X, and thus treatment options for reversing a coagulopathy are directed towards restoring therapeutic levels of these coagulation factors.38 They include vitamin K, fresh frozen plasma (FFP), prothrombin complex concentrate (PCC) and recombinant activated factor VII (rFVIIa).23,39 (Table 4) In patients with ICH, it is recommended to reverse the INR to 1.2 or less.40

Vitamin K Intravenous vitamin K should be administered to all patients who are warfarinsed and who suffer an ICH.41 It is necessary to support endogenous synthesis of clotting factors, is easy to administer, and has an effect that lasts beyond the relatively short half lives of FFP, PCC and rFVIIa; hence pro-

R. Appelboam, E.O. Thomas ducing a sustained correction of the coagulopathy. The small risk of anaphylaxis associated with the intravenous preparation may be reduced by using the subcutaneous route, though its effect is slower, and less reliable. The time of onset of oral vitamin K is too slow to be therapeutically useful in this situation.42

Fresh frozen plasma FFP contains all coagulation factors in a non-concentrated form, and has been the most widely used method for coagulation factor replacement. It is an effective way of correcting the INR, and it acts more quickly than vitamin K, though it has a shorter half-life. However, the concentration of coagulation factors present in FFP varies considerably, and therefore the efficacy of this treatment may be unpredictable. At the recommended doses of up to 40 ml/kg,43 large volumes may be required leading to difficulties with fluid overload, particularly in elderly patients, or those with cardiovascular co-morbidities. Additionally, factor IX levels may remain low despite adequate correction of other factors, thus leading to incomplete haemostasis.41 FFP takes time to administer, as it needs to be compatibility tested and thawed before use. This further limits its usefulness, as recent evidence demonstrates that time to INR reversal to within the normal range is the most important determinant in reducing haematoma expansion.44 Finally, FFP carries risks associated with transfusion of any blood product, including allergy, blood-borne infection, and transfusion related acute lung injury.

Prothrombin complex concentrate Commercially available PCCs contain a varying combination of prothrombin (factor II), coagulation factors VII, IX and X, protein C, protein S, and protein Z.45 They are formulated in a concentrated form and do not require compatibility testing or thawing before use. Many small studies have shown that PCC is an effective treatment for the urgent reversal of warfarin over-anticoagulation.46–51 However, the preparations vary in the proportion of non-factor IX coagulation factors present, and the optimum dose of PCCs for warfarin reversal has not yet been established; they are often given in a dose dependent manner, according to the INR, body weight, and the individual preparation.52 There is currently no prospective randomised controlled trial in OAC-related ICH comparing FFP

Warfarin and intracranial haemorrhage Table 4

5

Options for reversal in warfarin associated intracerebral haemorrhage.

Product

Dose

Time to normalise Notes INR

Vitamin K

5–10 mg intravenous

6–24 h

Replacement of factors IX and X takes >24 h. Unsuitable alone as a reversal strategy Fresh frozen plasma 20–40 ml/kg 12–32 h Large volumes needed, lengthy to administer 15 min following Variable concentration of individual factors. Prothrombin complex Varies according to infusion Short half-life of factor VII requires concentrate preparation. concomitant administration of intravenous Typically 25–50 iU/kg Vitamin K. More expensive than FFP, potentially prothrombotic Recombinant activated 10–50 lg/kg 15 min after bolus Most expensive, short half-life – may require factor VII repeated dosing, corrects PT/INR but not aPTT, does not shorten bleeding time, potentially prothrombotic, currently unlicensed for this indication

and PCC comparing haematoma growth and functional outcome; although one is currently being planned (personal communication Dr Thorsten Steiner). Several small studies have demonstrated that PCC reverses warfarin more rapidly than FFP, with or without supplemental vitamin K.23,46,53 Despite this, there is no evidence to date that correlates this rapidity of effect with improved outcome. A recent Swedish retrospective study demonstrated no advantage in terms of outcome (30 day mortality) in patients treated with PCC instead of FFP.5 Vitamin K should be given at the same time as the PCC, and the INR should be checked 30 min after the initial infusion. If it has not normalised, consideration should be given to a further dose of PCC.49,53,54 There are ongoing concerns relating to PCCs, largely centred on their potential to induce thromboembolism, ranging from superficial thrombophlebitis, to arterial and venous thrombosis, and disseminated intravascular coagulation (DIC).45,46 These phenomena appear to be dose-related, and their incidence in warfarin reversal appears to be low.47–54

Recombinant activated Factor VII (rFVIIa) Recombinant factor VIIa has been used for some time to manage bleeding in haemophiliacs.55 More recently, its has been used in the control of major bleeding associated with blunt trauma,56,57 and in the perioperative setting in patients with liver dysfunction, thrombocytopaenia, and haemostatic abnormalities related to massive transfusion.58,59 Recombinant factor VIIa has been shown to reverse the INR in subjects anticoagulated with war-

farin,60 however it does not shorten the aPTT or bleeding time and does not increase thrombin generation.61,62 In a recent phase II, proof of concept study, it was shown to reduce haematoma expansion and improve functional outcome in patients with spontaneous, non-anticoagulant associated ICH.63 The phase III study was published in April 2008 which showed that rFVIIa, although effective in reducing haematoma expansion, did not result in an outcome benefit and is no longer recommended.64 A number of recent reports have suggested a benefit in patients with warfarin associated ICH,65–68 and some commentators recommend its use,38 but there is currently no strong evidence to support the widespread use of rFVIIa

Table 5 Guidelines for reversal of anticoagulation in patients with warfarin related intracerebral haemorrhage. Organisation

Recommendation

British Committee for Standards in Haematology 1998, 200669,70 Northern Regions Haematologists Group, UK 200471 Australasian Society of thrombosis and haemostasis 200472

5–10 mg intravenous vitamin K plus 50 U/kg PCC

American College of Chest Physicians 6th Consensus group 200173

5 mg intravenous vitamin K plus 30 U/kg PCC 5–10 mg intravenous vitamin K plus 25–50 U/kg PCC and 150–300 ml FFP (reflects lack of factor VII in this PCC) 10 mg intravenous vitamin K plus PCC (dose not specified)

6

R. Appelboam, E.O. Thomas Table 6

Safety of resuming oral anticoagulation in patients with warfarin associated intracranial haemorrhage.

Reference

Subject

No. of patients restarting AC

No. of rebleeds/ICH enlargement

Widjicks et al.29

Management of AC in patients with PHV and intracranial bleeding Outcome of AC related ICH Discontinuation of AC in patients with ICH and high thromboembolic risk Restarting AC in patients with PHV and intracranial haemorrhage Management of AC associated intracranial haemorrhage Management of AC associated ICH AC following ICH in patients with PHV Early AC in patients with PHV and ICH Management of patients with ICH and need for AC

39

0

7 35

0 0

10

1

13

0

1 6 4 13

1 0 0 2

Punthakee et al.30 Phan et al.31 Butler and Tait32 Kawamata et al.33 Crawley et al.36 Babikian et al.37 Leker and Abramsky76 Bertram79

AC = anticoagulation, PHV = prosthetic heart valve, ICH = intracerebral haemorrhage.

in this situation. Indeed, the increased incidence of arterial and venous thrombosis seen in patients with non-anticoagulant associated ICH treated with rFVIIa (9% versus 4% in the control group),64 should raise concerns about its use in a group of patients who are already at high risk of thromboembolism. Furthermore, it is unclear whether INR accurately reflects overall coagulation status following administration of rFVIIa,59 and animal studies suggest that PCC is more effective than rFVIIa in restoring haemostatic function.61,62

Recommendations for optimal reversal strategy There are currently no standardised guidelines based on randomised controlled trials for the reversal of the anticoagulant effect in patients with warfarin associated ICH. However, some regional and national guidelines have been published (Table 5); all recommend intravenous vitamin K (5–10 mg) and prothrombin complex concentrate.69–73

Further management The role of neurosurgical intervention in ICH is not well defined – the STICH trial concerned only spontaneous, non-anticoagulated, supratentorial ICH, and showed no overall mortality benefit from surgery.74 It is unlikely that surgical intervention would be considered whilst a coagulopathy still exists. However, these patients should all be admit-

ted to neurosurgical intensive care units, where care directed at controlling haemodynamics, haemostasis, and minimising secondary brain damage has been shown to improve outcome.75

Restarting long term anticoagulation The role of intravenous heparin, and subcutaneous low molecular weight heparin as a ‘bridging’ therapy is unclear. Some studies suggest that it is safe,32,76 whilst others would not recommend it.36 In patients with prosthetic valves, the risk of suffering an ischaemic stroke has been estimated at 4% per year, and the risk of valve thrombosis at 1.8% per year, giving a daily risk of valve thromboembolism of 0.016%, or a risk of 0.2–0.4% over 2 weeks.1,36,43 Given the well-demonstrated increased mortality and morbidity associated with early haematoma expansion, the literature supports withholding all anticoagulation in the acute phase.11,29–31,34(Table 3) Time to re-anticoagulation in these series varied from 3 to 19 days, with a median of 7 days. Both the European Society of Cardiologists and the European Stroke Initiative recommend that withholding all anticoagulation, even in the highest risk cases of mechanical heart valve patients, is safe for at least 7 and up to 14 days.27,43 The decision to re-start long term, OAC in patients who have suffered a warfarin-related ICH is often difficult, and should balance the prevention of thromboembolism and the risk of recurrent ICH. In low risk cases (e.g. past history of deep vein thrombosis or pulmonary embolism), the risk of

Warfarin and intracranial haemorrhage suffering a repeated ICH outweighs the benefit of repeated anticoagulation. In the highest risk cases (e.g. prosthetic heart valves and chronic atrial fibrillation with prior ischaemic events), re-anticoagulation should be considered.77 There is, however, a large group of patients in whom the risks and benefits are less clear, and in which each case needs to be considered individually. A decision analysis tool such as that published by Eckman and colleagues may prove helpful in this situation.78 Although there is no data from controlled trials regarding the rate of ICH recurrence whilst on warfarin, a number of prospective clinical series have demonstrated a low risk of re-bleeding in those patients who were re-anticoagulated.29–33,36,37,76,79 (Table 6)

Conclusion Patients who suffer a warfarin associated intracranial haemorrhage have a high risk of having a poor outcome. In the absence of robust randomised clinical data, management is based around prospective and retrospective case series, and expert opinion. At the present time, not all experts agree.38 Time to normalisation of the INR is critical in minimising haematoma expansion, and a number of therapeutic options exist. Though data exists to favour some therapies over others based on their rapidity in restoring haemostasis, this has yet to be translated into a functional outcome benefit. Whichever strategy is employed, specialist neuro-intensive care to prevent secondary brain injury is of paramount importance, and a period without anticoagulation is indicated in even the highest risk cases. Once the acute phase has passed, consideration should be given to reanticoagulation.

Practice points  Early and aggressive reversal of the INR to within the normal range improves outcome in patients with warfarin related intracranial haemorrhage.  Various strategies to achieve normalisation of the INR exist, but vitamin K 5–10 mg i.v. plus prothrombin complex concentrate is recommended.  The risk of systemic embolisation in the acute phase is low, and oral anticoagulation should be withheld for between 7 and 10 days in all patients.

7  The risk of recurrent haemorrhage after careful reintroduction of oral anticoagulation is low.

Conflicts of interest RA – none EOT – has received honoraria from CSL Behring.

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