Guideline on the management of bleeding in patients on antithrombotic agents

Abstract

The guideline writing group was selected to be representative of UK-based medical experts. The MEDLINE and EMBASE databases were searched systematically for publications in English from 1966 to June 2011 and 1980 to June 2011 respectively, using the following strategy: Approved and proprietary names of the antithrombotic agents described in the guideline were combined with terms relating to antidote, reversal, haemorrhage, (activated) prothrombin complex concentrate, factor VIII inhibitor bypass activity (FEIBA), Beriplex, Octaplex, recombinant activated factor VII (rFVIIa), Novoseven, fresh frozen plasma, tranexamic acid, antifibrinolytic, platelet transfusion, and desmopressin. Identified papers were also searched for additional references. The writing group produced the draft guideline which was subsequently revised by consensus by members of the Haemostasis and Thrombosis task Force of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as outlined in: http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html. The objective of this document is to guide healthcare professionals on the management of patients receiving antithrombotic drugs who experience significant bleeding or who require emergency surgery or an invasive procedure. Guidance on reversal of vitamin K antagonists (VKAs; warfarin, phenprocoumon, acenocoumarol (sinthrome) and phenindione has been described previously (Keeling et al, 2011). Antithrombotic drugs are used increasingly in patient groups at greater bleeding risk. Although major haemorrhage is infrequent, management can be difficult especially with antithrombotics for which there are no specific reversal agents. Bleeding during antithrombotic therapy is associated with high morbidity and mortality (Linkins et al, 2003; Eikelboom et al, 2006; Mannucci & Levi, 2007). Before any antithrombotic treatment is started, the risks and benefits should be carefully considered. In this guideline we consider the management of bleeding in patients on the more widely used antithrombotic agents including heparin, anti-IIa and anti-Xa inhibitors, oral VKAs, anti-platelet drugs as well as the fibrinolytic agents. In many cases, simple non-pharmacological measures and stabilization of the patient whist the antithrombotic is eliminated are sufficient to treat or prevent bleeding (Table 1). Plasmapheresis or haemofiltration may rapidly reduce the plasma concentration of antithrombotic drugs that are not highly protein bound. However, these techniques are often inaccessible in emergency settings outside highly specialized units. Specific antidotes are not always available to reverse antithrombotic drugs in emergencies. However, general pro-haemostatic agents, listed in Table 2 may be useful in some circumstances. Recombinant activated factor VII (rFVIIa, Novoseven®), prothrombin complex concentrates (PCC) and activated PCC [APCC; e.g. factor VIII inhibitor bypass activity (FEIBA)] are often considered as agents for reversal of the effect of antithrombotic drugs. However, off-label use of rFVIIa for critical bleeding was associated with arterial thrombosis in 5·5% vs. 3·2% in placebo in all patient groups and 10·8% vs. 4·1% in placebo in patients >75 years (Levi et al, 2010). Efficacy of rFVIIa as a reversal agent has been demonstrated in vitro, in animal studies and single case reports, which are subject to publication bias. Reversal of the effect of anti-thrombotics is an unlicensed indication for rFVIIa (Sorour et al, 2010) but this agent is often considered as a last resort when all other measures have failed and the risks and benefits are carefully documented. With the exception of the use of PCC to reverse warfarin and other VKAs, there is little evidence supporting the use of PCC and APCC as correction agents for other antithrombotics. PCC and APCC agents may increase thrombosis risk although this has not been evaluated in large-scale meta-analyses. PCC and APCC may be considered in settings of critical or refractory bleeding after thrombosis risk has been considered. The use of rFVIIa, PCC and APCC will be discussed in more detail in subsequent sections. Fresh frozen plasma (FFP) may be a suitable reversal agent for warfarin or other VKA (if PCC is unavailable) and as a source of clotting factors in major haemorrhage. However, FFP has no proven efficacy as a reversal agent for antithrombotics other than warfarin, even those that cause prolonged prothrombin (PT) or activated partial thromboplastin (APTT) times by inhibiting coagulation factors (Crowther & Warkentin, 2009). In the following sections, individual antithrombotics and options for reversal of the anticoagulant effect are discussed. With the exception of VKAs and unfractionated heparin (UFH), the evidence for individual approaches is often weak and limited to small case series and case reports. For some antithrombotics, clinical evidence to guide correction of the anticoagulant effect is absent and recommendations are based on theoretical considerations and animal studies. The characteristics, monitoring and mechanisms of action of UFH were recently reviewed (Gray et al, 2008). At therapeutic intravenous (IV) doses, the plasma half-life of UFH is 45–90 min because of rapid cellular elimination. However, at higher doses, this mechanism becomes saturated and renal clearance results in a longer half-life (Hirsh et al, 2008). The pharmacokinetic clearance of UFH and pharmacodynamic effect varies between patients due to differences in plasma protein binding. UFH activity may be monitored with the APTT, activated clotting time (ACT) or thromboelastometric assays. Given the short plasma half-life of UFH, treatment or prevention of bleeding can often be achieved by stopping UFH and general measures. UFH can be rapidly reversed with protamine sulphate, which is derived from fish sperm and forms a stable, inactive salt with heparin. Protamine dose may be calculated from the quantity of UFH administered in the 2 h prior to reversal using the assumption that 1 mg protamine neutralizes 80–100 units of UFH. For example, bleeding during an IV infusion of UFH 1250 units/h requires 25 mg protamine. Bleeding soon after a bolus dose of 5000 units requires 50 mg (Hirsh et al, 2008). The half-life of protamine is 7 min, which is shorter than UFH, thus, prolonged protamine administration may be necessary if UFH has been administered subcutaneously, causing entry into the circulation to be delayed (Hirsh et al, 2008). The reversal effect of protamine can be monitored by the APTT. Protamine can cause severe allergic reactions including anaphylaxis, hypotension, bronchospasm and skin reactions in up to 10% of patients. Risk factors are previous exposure to protamine sulphate (including protamine-containing insulin preparations), rate of administration, vasectomy and fish allergy (Porsche & Brenner, 1999). Protamine sulphate should be given slowly over >5 min (Crowther & Warkentin, 2008). Patients at risk may be pre-treated with corticosteroids and antihistamines. At higher doses, protamine may have significant anticoagulant and antiplatelet effects (Ammar & Fisher, 1997; Ni Ainle et al, 2009). Low molecular weight heparins (LMWH) are derived from UFH through chemical or enzymatic depolymerization. The ratios of anti-Xa to anti-IIa activities vary between products depending on LMWH chain length. However the half-life of the anticoagulant activity of LMWH lasts approximately 4 h. The mechanism of action of LMWH and differences from UFH were recently reviewed (Gray et al, 2008). LMWH activity may be monitored with the anti-Xa test. Although LMWH may also prolong the APTT, this test should not be used to assess the extent of drug effect. Protamine reverses approximately 60% of LMWH based on data from animal studies (Bang et al, 1991; Lindblad et al, 1987; Van Ryn-McKenna et al, 1990) and healthy human volunteers (Holst et al, 1994). The largest study using protamine in patients (Van Veen et al, 2011) described three patients requiring emergency surgery and 14 patients that were actively bleeding whilst receiving LMWH and who received protamine at doses suggested by the ACCP guidelines (Hirsh et al, 2008). Protamine prevented excessive bleeding in all the surgical patients and was effective in eight of 12 evaluable patients with active bleeding. Anti-Xa levels after protamine sulphate administration did not correlate with the likelihood of persistent bleeding (Van Veen et al, 2011). Animal studies using rFVIIa for LMWH reversal show contradictory results (Chan et al, 2003; Lauritzen et al, 2008). Registry data indicate the successful use of rFVIIa in six patients with significant bleeding (Ingerslev et al, 2007), two of whom also received PCC but none of whom received protamine. Doses of rFVIIa varied between 20 and 120 μg/kg. Danaparoid is a heparinoid consisting of a mixture of glycosaminoglycans with an anti-Xa/anti-IIa ratio > 20 (Hirsh, 1992). Danaparoid is excreted renally and has a plasma half-life of anti-Xa activity of approximately 24 h (Danhof et al, 1992). Danaparoid may be monitored by anti-Xa assay using a danaparoid standard. Major bleeding occurred in 8·1% of patients treated with danaparoid for heparin-induced thrombocytopenia (HIT) (Magnani & Gallus, 2006). Continued bleeding after cardiopulmonary bypass surgery (CPB) on danaparoid has been reported despite intensive blood product replacement (Schmahl et al, 1997; Westphal et al, 1997; Gitlin et al, 1998; Fernandes et al, 2000; Pamboukian et al, 2000). There is no specific antidote for danaparoid. However, plasmapheresis removes danaparoid effectively from the circulation (Schmahl et al, 1997). An ex vivo study showed partial restoration of thrombin generation when rFVIIa was added at supra-therapeutic doses to plasma spiked with danaparoid, but not with addition of APCC and FFP (Gatt et al, 2008). Fondaparinux is a synthetic pentasaccharide with indirect anti-Xa activity that achieves steady state antithrombotic activity after 3–4 d of use. The plasma half-life is 17–20 h with normal renal function and up to 72 h when creatinine clearance is <30 ml/min (Donat et al, 2002; Samama & Gerotziafas, 2003). There is no specific antidote for fondaparinux. In vitro and ex vivo studies suggest that rFVIIa may enable at least partial correction as determined by global coagulation assays (Gatt et al, 2008; Desmurs-Clavel et al, 2009). A placebo controlled study in healthy volunteers treated with therapeutic doses of fondaparinux and 90 μg/kg rFVIIa demonstrated correction of prolonged coagulation times and partial restoration of thrombin generation (Bijsterveld et al, 2002). Partial clinical efficacy of rFVIIa has been demonstrated in small case series (Dao et al, 2005; Huvers et al, 2005; Luporsi et al, 2011). Bivalirudin is a recombinant peptide thrombin inhibitor and is the only licensed hirudin in the UK. The lepirudin licence was recently withdrawn and so it is not considered in this guideline. Bivalirudin is cleared predominantly through proteolysis by thrombin (80%) and only 20% is excreted renally. The half-life is approximately 25 min, 1 h in severe renal impairment and 3·5 h in dialysis-dependent patients (Chew, 2002). Bivalirudin activity may be monitored by ACT or by APTT. The PT is minimally prolonged at therapeutic bivalirudin concentrations. The pharmacology and clinical applications of bivalirudin have been reviewed recently (Warkentin et al, 2008). Given the short plasma half-life of bivalirudin, cessation of treatment and general haemostatic measures are often sufficient for correction of the effect except when there is prolonged clearance due to renal impairment. An in vivo study showed that modified ultrafiltration after CPB surgery in patients with normal renal function reduced the half-life by 20% and reduced postoperative blood loss (Koster et al, 2008). Argatroban is a reversible direct thrombin inhibitor that is rapidly eliminated via the hepatic cytochrome P450 3A4/5 enzyme. The plasma half-life is 45 min. Argatroban is usually monitored by APTT ratio. However, argatroban also prolongs the PT, ACT and thrombin time. There is no specific antidote for argatroban but given its short half-life, stopping the drug enables correction of the anticoagulation effect in most cases. Severe bleeding related to reduced elimination of argatroban after cardiac surgery was reported to be unresponsive to blood component treatments alone (Edwards et al, 2003; Gasparovic et al, 2004) and blood components in combination with rFVIIa (Malherbe et al, 2004; Genzen et al, 2010). Treatment with rFVIIa ex vivo restored abnormal thromboelastography parameters in blood samples from two patients treated with argatroban (Young et al, 2007). However, in an animal study of a different direct thrombin inhibitor (melagatran), rFVIIa had no effect on bleeding time whereas APCC reduced bleeding time (Elg et al, 2001). With yet another direct thrombin inhibitor, dabigatran, the drugs rVIIa, APCC and PCC exhibited activity in correcting the coagulopathy in animal models (Van Ryn et al, 2010a; Van Ryn et al, 2008). There are no data on the use of APCC in bleeding during argatroban treatment. Guidelines for the management of patients on warfarin experiencing major or non-major bleeding or over-anticoagulation were included in a recent BCSH guideline on oral anticoagulation with warfarin (Keeling et al, 2011). For completeness, these recommendations have been included below. Whilst warfarin is the main coumarin used in the UK and North America, the VKA drugs phenprocoumon, acenocoumarol (sinthrome) and phenindione are also available and widely used in some countries. All drugs in this class reduce functional levels of the vitamin K-dependent clotting factors (II, VII, IX and X) but have different effective half-lives. Following discontinuation of treatment, the anticoagulant effect of phenprocoumon lasts the longest, and acenocoumarol the shortest. The principles of reversal of the anticoagulant effect with vitamin K and PCC are the same as for warfarin. However, further administration of vitamin K should be considered for correction of VKAs with longer half-lives. The pro-drug dabigatran etexilate is rapidly hydrolysed to the active form dabigatran, a direct thrombin inhibitor. Following oral administration, plasma levels peak within 2–3 h. In individuals with normal renal function, the half-life is 13 h (range 11–22 h; van Ryn et al, 2010b). Dabigatran is 80% eliminated by the kidneys and has a prolonged plasma half-life in patients with renal impairment (plasma half-life 22–35 h with creatinine clearance < 30 ml/min). It is used for surgical thromboprophylaxis at a dose of 150–220 mg once daily and for stroke prevention in atrial fibrillation (AF) at a dose of 110 or 150 mg twice daily. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial of dabigatran in atrial fibrillation the annual risk of major bleeding was 2·71% and 3·11% with the 110 and 150 mg dabigatran doses, respectively, in comparison to 3·36% for patients treated with warfarin (Connolly et al, 2009). It must be appreciated, however, that both these figures are conservative as this pivotal trial excluded many real-life situations of patients with extreme body weights, significant renal impairment or multiple co-morbidities. A major advantage of dabigatran is that its use does not involve monitoring its concentration or effect but this is also a disadvantage because in a bleeding patient it is difficult to be sure of its concentration due to variable effect on the different standard coagulation tests (van Ryn et al, 2010b). A normal thrombin time and a normal APTT imply that a high level of dabigatran is unlikely in the patient. There are no published clinical trials or other high quality evidence addressing the management of bleeding on dabigatran. Van Ryn et al (2009) showed in vitro that activated charcoal was able to bind virtually all the dabigatran etexilate and dabigatran suspended in water, and it would be reasonable to recommend that activated charcoal is given orally to bleeding patients if they have had a dose of the drug within 2 h to prevent further absorption (van Ryn et al, 2010b). In view of the relatively short dabigatran half-life, minor bleeding should be managed by withholding further doses of the drug and using standard measures, such as direct pressure, simple surgical intervention and fluid replacement. In an emergency, dabigatran plasma clearance would be expected to be accelerated using haemodialysis or haemofiltration because it has relatively low plasma protein binding at 35%. Supportive evidence is provided by the fact that haemodialysis effectively reduces the plasma level of dabigatran in patients with end stage renal disease (Stangier et al, 2010; van Ryn et al, 2010b). Van Ryn et al (2010c) also showed that charcoal haemoperfusion using the commercially available Gambro Adsorba Cartridge (containing activated carbon in the form of charcoal) was able to remove c. 85% of dabigatran suspended in bovine blood and circulating in an in vitro system. Only very limited reports on the use of these techniques in bleeding patients on dabigatran are available and the evidence for their support remains preliminary (Warkentin et al, 2012). Furthermore, their rapid deployment in settings outside intensive care units is likely to be challenging. No antidote is available for use in patients with major or life-threatening bleeding on dabigatran. In the absence of this, rFVIIa, PCC and APCC have been investigated in vitro, ex vivo and in animal models. In a rat tail bleeding time model, rFVIIa and FEIBA (Van Ryn et al, 2008), and in a rabbit trauma were effective in correcting the coagulopathy (Van Ryn et al, In an in vitro using the rFVIIa failed to the thrombin generation by dabigatran in spiked plasma samples & 2007). In on healthy rFVIIa failed to the reduced thrombin generation of another direct thrombin inhibitor et al, and more recently this was also with a PCC et al, et al, 2011). At the data on rFVIIa and APCC is preliminary and and not based on bleeding becomes available it is reasonable to these products in patients with life-threatening bleeding on dabigatran, a on an individual A of direct oral factor are in but so only two have been licensed for thromboprophylaxis treatment of and stroke prevention in Following an oral both and a peak at h and have of and h respectively, in patients with normal renal In both cases, are by the and are excreted by the In the with K for of and in the annual risk of major bleeding was for 20 mg once daily and for warfarin et al, 2011). In the for in and in which mg twice daily with warfarin in the annual risks of major bleeding were and et al, 2011). these clinical trials of some patient such as at the extreme of body significant renal impairment and multiple the risk of bleeding in clinical is likely to be these drugs show high plasma protein binding they would not be expected to be For minor in view of the short half-life, measures, such as direct pressure, minor surgical intervention and fluid should be No antidote is available for use in patients with major or life-threatening bleeding on or In the absence of this, rFVIIa and PCC have been investigated in vitro, ex and in animal models. In an in vitro study using the with plasma spiked with the thrombin generation be reversed with rFVIIa & 2007). In a different in vitro using spiked blood and only a correction was following the addition of rFVIIa or PCC to the samples et al, 2009). In a animal the effects of on the bleeding time and coagulation tests be reversed with both rFVIIa and the APCC et al, 2008). In a rabbit both PCC and rFVIIa were able to the parameters but did not reverse bleeding et al, 2012). In a controlled clinical trial in healthy PCC was able to the prolonged prothrombin time and the thrombin generation by et al, et al, 2011). Although so most of the available data reversal of effect are for in view of the of results would be expected for but this remains to be In an in vitro study of and was able to only the by et al, 2011). In the absence of an antidote, based on animal studies rFVIIa and APCC may be after carefully the risks and benefits associated with the use of these drugs have short plasma but may have a prolonged effect because of platelet (Table there are no specific reversal agents, the treatment or prevention of bleeding requires general haemostatic measures, cessation of anti-platelet treatment or reversal of the effect of antithrombotics. However, many patients who are anti-platelet drugs are at high risk of arterial the of drug and pro-haemostatic should be considered carefully through a risk anti-platelet agents are withdrawn they should be as soon as after is et al, et al, et al, 2011). may be considered for emergency reversal of the anti-platelet effect but may a risk of arterial platelet by platelet has a rapid of action after oral administration h but 3–4 h with and has a plasma half-life of c. 20 min. However, evidence of platelet may for 4 d because the effects of on individual is et al, 2012). the risk of surgical bleeding but does not increase the of bleeding for most Given that 10% of are by and the time from to stroke and are and d respectively, is not usually withdrawn surgery et al, studies have demonstrated a of following on low dose et al, 2003; et al, reduced the bleeding time in healthy volunteers et al, However, is relatively in patients with disease and there is no evidence to support efficacy in this patient rFVIIa reverses abnormal thrombin generation in plasma from volunteers et al, but this agent has not been systematically in patients receiving ex vivo with restored abnormal platelet et al, et al, 2012). In infusion of 2–3 doses of is usually effective for emergency reversal of the effect of in There are no specific reversal agents for The antagonists the and and the active drug may show a delayed of platelet of h because it requires by hepatic which requires and anti-platelet effect within h. The active of and have short plasma and c. 7 h although as they are the of platelet may be d et al, et al, 2011) or longer et al, 2012). is a that has a plasma half-life of h and is more reversible than and However, the anti-platelet effect of may for d & 2011). All the antagonists are eliminated by hepatic et al, 2011). the bleeding time in healthy volunteers after exposure to et al, et al, but in patients with disease usually prevent use. treated with antagonists ex vivo with restored abnormal platelet although a higher of was than for correction of the effect et al, et al, 2012). The efficacy of platelet may be reduced in patients who have recently There are no specific reversal agents for the are drugs that prevent platelet and are usually administered with other anti-platelet drugs and to patients with as an to intervention In a of six pivotal controlled clinical the risk of major bleeding associated with antagonists with other was to in placebo or groups et al, 2002). is a that has a rapid of action and a plasma half-life of c. 30 min. is eliminated from plasma by rapid binding to but may for h because of persistent binding to the et al, 1994). thrombocytopenia was reported in and severe thrombocytopenia in of patients receiving and may within h of the of infusion & et al, 1997). within d of cessation of but high bleeding risk. is effective for bleeding after and has been as a for thrombocytopenia & 1999). to is associated with severe thrombocytopenia in of et al, 2001). and are reversible of the binding on that have rapid of action and short plasma c. h; c. agents are eliminated by the kidneys c. renal c. and bleeding risk in patients with renal impairment & 2001). However, in the absence of renal the bleeding risk rapidly after cessation of treatment et al, is in patients receiving and and a has not been proven & 1999). The fibrinolytic agents licensed in the UK and All agents function by generation of which then is recombinant with a plasma half-life of min. It is cleared by in the is a recombinant modified form of with six causing half-life of c. 20 min, to and et al, 2009). It is cleared by in the is a recombinant form of et al, 2006; Van 1999). is specific to than and thus, a greater in The half-life is c. min and it is cleared via and it into an active to other It and greater in plasma fibrinolytic activity 20 min after administration and the plasma half-life of the drug is min. However, the half-life of the antithrombotic effect of is min. is a direct and has partial It is eliminated rapidly from the circulation by in the with a half-life of 20 min. is delayed in patients with disease and Bleeding after treatment with fibrinolytic drugs may through mechanisms including of and antiplatelet et al, et al, et al, 2003; et al, The also reduce plasma of to and of and other clotting factor et al, 1997; et al, The of and factor does not correlate with the of haemorrhage during treatment with fibrinolytic drugs et al, 1997; et al, 2003). Although the of the fibrinolytic drugs are relatively their effect on coagulation parameters is for stroke or was at 2–3 low at 24 h and to normal at h et al, 1998; et al, 2002; et al, 2006). A was with et al, 2000). The factor at approximately 1 h et al, 1997). et al reported on patients who after therapy for had < 1 and only received which included vitamin and However, it is to assess the of these measures due to the very small in There are no clinical data the efficacy of any to reverse fibrinolytic drugs in are derived from and are with previously published guidelines et al, et al, 2011) and 2011). For major bleeding within h of administration we