- Email: [email protected]
Anticoagulation treatment
THROMBOSIS
Anticoagulation treatment
Key points
Karen A Breen
C
Anticoagulants are used for prevention and treatment of arterial and venous thrombosis
Abstract
C
Current anticoagulants such as unfractionated heparin and warfarin require monitoring owing to their unpredictable pharmacokinetics
C
Anticoagulation is associated with a significant risk of bleeding
C
Direct oral anticoagulants have more predictable pharmacokinetics and do not require monitoring
Anticoagulant therapy using heparins and vitamin K antagonists has been used effectively for prevention and treatment of thromboembolic events for many years. However, therapy is associated with a significant risk of haemorrhagic complications, warranting careful consideration of the need for anticoagulation. Recognized drawbacks of current anticoagulants are their unpredictable pharmacokinetics and the need for laboratory monitoring, which have led in recent years to the development of direct oral anticoagulant agents.
Keywords Anticoagulant monitoring; heparin; reversal of anticoagulation; warfarin
anticoagulants leads to increased haemorrhagic risk, which in some cases can be fatal. Specific antidotes or agents to reverse anticoagulant effect are available for heparin and VKA but dabigatran is currently the only direct anticoagulant agent with a licensed antidote. Antidotes for the anti-Xa agents are currently undergoing Phase III trials.
Introduction Anticoagulation is used for the prevention and treatment of arterial and venous thromboembolism.1 The choice of anticoagulant is influenced by the indication for anticoagulation, mode of administration and duration for which it is required. Anticoagulants currently in use comprise: heparinoids e unfractionated heparin (UFH), lowmolecular-weight heparin (LMWH) and fondaparinux vitamin K antagonists (VKAs) e warfarin, phenindione and acenocoumarol new oral agents e dabigatran, rivaroxaban, apixaban and edoxaban.
Current anticoagulants Unfractionated heparin Heparin’s anticoagulant effect was first discovered in 1916. UFH, the first anticoagulant to be developed in the 1930s, consists of a series of glycosaminoglycan chains and is processed from animal intestinal mucosa, usually of porcine origin, in Europe.
Anticoagulants are one of the most commonly reported drug groups associated with medication errors. Overtreatment with
Mode of action, indications, dosing, drug interactions and monitoring: UFH is administered by intravenous infusion or subcutaneous injection. It causes an anticoagulant effect by potentiating the action of the physiological anticoagulant antithrombin ten thousand-fold. UFH has unpredictable pharmacokinetics and a short elimination half-life, and therefore requires monitoring. There are no specific drug interactions. Indications for its use include prevention of thrombosis of peripheral catheters, haemodialysis, prevention and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), treatment of cardiac ischaemia and critical ischaemia of the lower limb, coronary or peripheral artery angioplasty, and bypass surgery. Adverse effects include allergy, heparin-induced thrombocytopenia, and osteopenia with long-term use. Laboratory monitoring of heparin is performed using the activated partial thromboplastin time (APTT). The APTT ratio (APTTR) provides a measure of anticoagulant effect of UFH; the usual target ratio is two to three times higher than a normal APTT. Dosing of UFH requires a bolus dose for initiation of an UFH infusion, followed by a continuous infusion. APTTR monitoring allows subsequent adjustment of dosage. The dosage of UFH for administration by subcutaneous injection is fixed.
Karen A Breen MB MRCPI FRCPath is a Consultant Haematologist at Guy’s and St Thomas’ NHS Foundation Trust, London, UK. Competing interests: none declared.
Low-molecular-weight heparins LMWHs, first developed in the 1980s, are produced by depolymerization of UFH chains to produce a shorter glycosaminoglycan chain. They have more predictable pharmacokinetics, a
Indications and contraindications to anticoagulants There are multiple indications for anticoagulation, including prevention and treatment of venous thromboembolism1 and stroke prevention in atrial fibrillation. Each agent has a recommended dose according to the indication for which it is required. Contraindications to full anticoagulant therapy include severe uncontrolled hypertension, a recent cerebrovascular accident, a history of inherited or acquired bleeding disorder, thrombocytopenia (<50 109/litre) or a history of active bleeding. Concomitant use of antiplatelet agents and non-steroidal anti-inflammatory agents is not advised because of the increased bleeding risk. UFH is currently the only anticoagulant licensed for use in pregnancy; LMWHs are widely used and accepted to be safe and efficacious although none is licensed for use in pregnancy. Heparin and warfarin are safe for use in breastfeeding mothers.
Reversal of anticoagulation
MEDICINE --:-
1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Breen KA, Anticoagulation treatment, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.01.010
THROMBOSIS
longer half-life and an easier mode of administration (subcutaneous injection) than UFH.
Vitamin K antagonists VKAs were the first oral anticoagulants in use and currently include acenocoumarol, phenindione and warfarin. Only warfarin is discussed in this article.
Mode of action, indications, dosing, drug interactions and monitoring: like UFH, LMWH binds to antithrombin, but it has a greater inhibitory effect on factor Xa. Because of their longer halflives, LMWHs are suitable for outpatient use and have a lower risk of heparin-induced thrombocytopenia and osteoporosis than UFH. Dosing depends on the LMWH subtype and indication for use, which includes prevention and treatment of DVT and PE, and treatment of severe unstable angina. There are no specific drug interactions. Monitoring is required only in patients with renal failure and those at extremes of body weight, and is performed using anti-Xa concentration. Measurement of peak antiXa concentration is suggested (samples taken 4 hours after administration); target reference ranges depend on heparin type and indication.
Mode of action, indications, dosing, drug interactions and monitoring: warfarin prevents g-carboxylation of vitamin Kdependent clotting factors (II, VII, IX, X), producing an anticoagulant effect by reducing their concentrations. Factor VII has the shortest half-life, whereas factors II, VII, IX and X have half-lives of 8e72 hours, so warfarin takes several days to have full anticoagulant effect. The pharmacokinetics of warfarin are unpredictable, mainly because of its metabolism by enzymes of varied activity in the population. Numerous drug and food interactions contribute to its variable anticoagulant effect. Warfarin requires laboratory monitoring, which is based on the prothrombin time (PT). Variability in reagents used to determine PT has led to international standardization of the assay, now known as the international normalized ratio (INR), a PT-based measure of anticoagulant effect. Warfarin is teratogenic in the first trimester of pregnancy and should be stopped as soon as possible on confirmation of pregnancy. LMWH is a suitable alternative anticoagulant in pregnancy (although none is licensed for use in this setting). The recommended INR varies according to the indication for anticoagulation with warfarin.2 It is difficult to target a specific INR, and the usual aim is to maintain INR within 0.5 of a target INR. Recommended target INRs in relation to different indications for warfarin are shown in Table 1. Dosing regimens for initiation of warfarin therapy vary according to age and indication for anticoagulation. Patients with
Fondaparinux Fondaparinux is a synthetic form of the heparin pentasaccharide molecule. Mode of action, indications, dosing, drug interactions and monitoring: fondaparinux binds and activates antithrombin, resulting in only an anti-Xa effect, and has a half-life of 17e21 hours. It has a marketing authorization in Europe for indications similar to LMWH, but has not been widely used for thromboprophylaxis because of its cost. However, in the management of acute coronary syndrome, it has proved superior to LMWH in many patient groups. The dosage of fondaparinux depends on the indication for use, and as its pharmacokinetics are predictable there is no requirement for monitoring.
Indications for VKAs and recommended target INR Indication
Target INR
Duration
PE
2.5
Proximal DVT
2.5
Calf vein thrombosis Recurrent venous thrombosis on warfarin therapy (with therapeutic INR) Recurrent venous thrombosis in patient taking warfarin therapy with subtherapeutic INR or off anticoagulation Non-rheumatic atrial fibrillation (CHADS2 score >1) Cardioversion Mural thrombus Cardiomyopathy Mechanical prosthetic aortic heart valve Mechanical prosthetic mitral heart valve Bioprosthetic valve
2.5 3.5
At least 3 months e consider extending beyond 3 months if risk of recurrent thrombosis higha At least 3 months e consider extending beyond 3 months if risk of recurrent thrombosis higha 3 months Consider indefinite anticoagulation depending on risk of recurrent thrombosisa Consider indefinite anticoagulation depending on risk of recurrent thrombosisa Indefinite Indefinite Indefinite Indefinite Indefinite Indefinite Indefinite
2.5 2.5 2.5 2.5 2.5 2.5 3.5 2.5
‘CHADS2’ is a mnemonic for a clinical risk prediction tool to estimate risk of stroke associated with atrial fibrillation: C e congestive heart failure, H e hypertension, A e age, D e diabetes mellitus, S2 e previous stroke, transient ischaemic attack or thromboembolism. DVT, deep vein thrombosis; INR, international normalized ratio; PE, pulmonary embolism; VKA, vitamin K antagonist. a Patients with unprovoked DVT or PE should be considered for lifelong anticoagulation, taking into account risk of recurrence balanced against risk of bleeding on anticoagulant therapy. Patients with provoked DVT or PE have lower risk of recurrence and do not warrant lifelong anticoagulation. Provoking factors include recent surgery, immobilization, long-haul flight and oestrogen therapy.
Table 1 MEDICINE --:-
2
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Breen KA, Anticoagulation treatment, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.01.010
THROMBOSIS
Reversal of anticoagulation Anticoagulant
Urgent reversal with major haemorrhage
Urgent reversal without haemorrhage
Reversal for elective procedures
UFH
Stop UFH Measure APTTR Consider protamine sulphate (1 mg per 90e100 units heparin given in previous 2e3 hours)
For immediate procedure: Stop UFH and consider protamine sulphate For procedure delayed >6 hours: C Stop UFH Overanticoagulation without bleeding: C Stop UFH C Restart at a lower dose Stop LMWH Consider protamine sulphate if delay not possible
Stop UFH 4e6 hours before procedure
LMWH
Fondaparinux
Stop LMWH Consider protamine sulphate (only partially reverses LMWH, dose depends on type of LMWH) Stop fondaparinux Consider haemodialysis
Warfarin
Stop warfarin Measure INR PCC 25e50 IU/kg (repeat every 6 hours as needed) and vitamin K 2 mg intravenous Fresh frozen plasma should never be used in this setting
Dabigatran
Stop dabigatran Activated charcoal if within 4 hours of tablet ingestion Measure APTT Consider idarucizumab
Rivaroxaban/ apixaban/ edoxaban
Stop rivaroxaban/apixaban/edoxaban Measure PT Consider PCC/rFVIIa
C
For immediate procedure: Stop fondaparinux For procedure delayed >6 hours: C Stop fondaparinux For immediate procedure: C Stop warfarin C Measure INR C PCC 25e50 IU/kg and vitamin K 1 e2 mg oral or intravenous For procedure delayed >6 hours: C Stop warfarin C Measure INR C Vitamin K 1e2 mg oral or intravenous Overanticoagulation without bleeding: C Stop warfarin C Consider vitamin K 1 mg oral if INR >7 and/or risk of bleeding high For immediate procedure: C Stop dabigatran C Activated charcoal if within 4 hours of tablet ingestion C Measure APTT C Consider PCC For procedure delayed >24 hours: C Stop dabigatran C Measure APTT For immediate procedure: C Stop rivaroxaban/apixaban/ edoxaban C Activated charcoal if within 4 hours of tablet ingestion C Measure PT C Consider PCC For procedure delayed >24 hours: C Stop rivaroxaban/apixaban C Measure PT C
Stop LMWH for >12 hours if prophylactic dose, or for >24 hours if treatment dose before procedure Stop fondaparinux for >24 hours before procedure
Stop warfarin 5 days before procedure Consider bridging with short-acting anticoagulant if risk of thrombosis high Measure INR within 24 hours of procedure
Stop dabigatran within procedure if eGFR >50 Stop dabigatran within procedure if eGFR <50
1e2 days of ml/minute 3e5 days of ml/minute
Stop rivaroxaban/apixaban within 24 hours of procedure (if minor surgery) or 48 hours (if major surgery or impaired renal function)
APTT, activated partial thromboplastin time; APTTR, APTT ratio; eGFR, estimated glomerular filtration rate; INR, international normalized ratio; LMWH, low-molecularweight heparin; PCC, prothrombin complex concentrate; PT, prothrombin time; rFVIIa, recombinant factor FVIIA; UFH, unfractionated heparin.
Table 2
MEDICINE --:-
3
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Breen KA, Anticoagulation treatment, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.01.010
THROMBOSIS
be used to detect the presence of anticoagulant effect resulting from dabigatran. APTT is, however, not sensitive to low concentrations of the drug, and the PT is insensitive to the presence of dabigatran.
acute thrombosis require rapid initiation of anticoagulation using a faster acting anticoagulant, such as UFH or LMWH, until the desired INR range is reached; this is because the initial reduction by warfarin of the concentrations of proteins C and S can lead to an enhanced prothrombotic effect. Initiation regimens such as the Fennerty regimen (using higher doses of 10 mg daily to achieve a therapeutic INR within a short period) have not proved superior to the use of lower doses of 5 mg daily. Initiation of anticoagulation for atrial fibrillation using lower doses of warfarin, such as 3 mg daily (slow-loading regimen), usually achieves a target INR within 3e4 weeks and is acceptable in this setting. The dosage of warfarin is then adjusted according to INR.
Rivaroxaban Mode of action, indications, dosing, and drug interactions: rivaroxaban directly inhibits factor Xa and has a half-life of 4e9 hours. It is currently licensed for thromboprophylaxis after elective knee and hip surgery, prevention of stroke in atrial fibrillation, and the acute treatment and secondary prevention of DVT and PE. Dose reduction is advised in patients with impaired renal function. Important interactions occur with use of potent CYP3A4 inhibitors (e.g. ketoconazole) and P-glycoprotein inhibitors (e.g. protease inhibitors, such as ritonavir and atazanavir), which can increase the plasma concentration of rivaroxaban. PT is more sensitive to rivaroxaban than dabigatran, and can be used to assess for presence of an anticoagulant effect caused by rivaroxaban, whereas APTT is less sensitive to rivaroxaban than dabigatran. There is currently no antidote available for reversal of rivaroxaban, but andexanet alfa, an anti-Xa reversal agent is currently undergoing Phase 3 trials with promising results (see Table 2 for management of bleeding in patients taking rivaroxaban).
Reversal of anticoagulation: dried prothrombin complex (prothrombin complex concentrate; PCC) contains sufficient concentrations of factors II, VII, IX and X to allow reversal of the anticoagulant effects of warfarin and should be administered in combination with factor IV. Parenteral vitamin K administration is also required in patients with life-threatening haemorrhage. Concomitant use of vitamin K is required because PCC only has a half-life of 6 hours. Fresh frozen plasma is no longer used routinely for reversal of warfarin except where PCC is unavailable. For non-major bleeding (or in the setting of overanticoagulation without bleeding), a discontinuation or decrease in dosage of warfarin and/or administration of vitamin K usually suffices. Warfarin has a long half-life (20e60 hours) and should be discontinued 3e4 days in advance of most surgical procedures. Minor procedures associated with low bleeding risk, such as local injections and most dental procedures, do not require cessation of VKA (see Table 2 for reversal of anticoagulation). Protamine can be used for reversal of the anticoagulant effects of UFH but is rarely required in view of its short half-life. As it has only a partial effect on LMWH, it is rarely used for reversal.
Apixaban Apixaban directly inhibits factor Xa and has a half-life of 12 hours. It is currently licensed for thromboprophylaxis after elective knee and hip surgery and prevention of stroke in atrial fibrillation. It is contraindicated in patients with an eGFR below 15 ml/minute. Interactions are the same as those discussed for rivaroxaban, and reversal may also be possible in the future with andexanet alfa.
Direct oral anticoagulants
Edoxaban Edoxaban directly inhibits factor Xa and has a half-life of 10e14 hours. It is currently licensed for thromboprophylaxis after elective knee and hip surgery and prevention of stroke in atrial fibrillation. It is contraindicated in patients with an eGFR of less than 15 ml/minute. Interactions are the same as those discussed for rivaroxaban, and reversal will may also be possible in the future with andexanet alfa.
The new oral anticoagulants antagonize a single target in the clotting cascade; they have predictable pharmacokinetics and few food but some drug interactions, so monitoring is not required. Dabigatran, rivaroxaban, apixaban and edoxaban are direct oral anticoagulants currently in use, and several others are at advanced stages of development. There are currently no safety data for these agents in pregnancy or breastfeeding. Dabigatran Mode of action, indications, dosing, and drug interactions: dabigatran is a direct thrombin inhibitor and has a half-life of 14e17 hours. It is currently licensed for thromboprophylaxis after elective knee and hip surgery and for prevention of stroke in atrial fibrillation. The dosage is dependent on the indication. Dosage reduction is advised in renal impairment, and it should be avoided in those with an estimated glomerular filtration rate (eGFR) under 30 ml/ minute. Important drug interactions include amiodarone and verapamil, which can increase the plasma concentration of dabigatran. Monitoring of dabigatran is not required, but assessment of its anticoagulant effect may be required in an emergency situation. The APTT, which is prolonged in the presence of dabigatran, can
MEDICINE --:-
Reversal of anticoagulation Management of bleeding associated with direct oral anticoagulants is mainly supportive as dabigatran is the only agent to currently have a specific reversal agent (see Table 2 for management of bleeding).3,4 Perioperative management of these agents is dependent on the bleeding risk of the procedure and renal function of the patient.5 A KEY REFERENCES 1 Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(suppl 2): e691Se736.
4
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Breen KA, Anticoagulation treatment, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.01.010
THROMBOSIS
2 Keeling D, Baglin T, Tait C, et al. Guidelines on oral anticoagulation with warfarin e fourth edition. Br J Haematol 2011; 154: 311e24. € ller HR, Falanga A, et al. Managing reversal of direct 3 Ageno W, Bu oral anticoagulants in emergency situations. Anticoagulation Education Task Force White Paper. Thromb Haemost 2016; 116: 1003e10. 4 Heidbuchel H, Verhamme P, Allings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-
vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015; 17: 1467e507. 5 Keeling D, Tait RC, Watson H, British Committee of Standards for Haematology. Peri-operative management of anticoagulation and antiplatelet therapy. Br J Haematol 2016; 175: 602e13.
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here.
Question 1
What is the most appropriate action for her anticoagulation? A. Stop rivaroxaban B. Switch to aspirin C. Switch to edoxaban D. Switch to low-molecular-weight heparin E. Switch to warfarin
A 75-year-old woman was admitted following a head injury. She had a past history of atrial fibrillation. She was taking dabigatran for stroke prevention. On examination, her pulse was 88 beats/minute and irregularly irregular, and her Glasgow Coma Scale score was 7.
Question 3 Investigations CT brain scan showed a subdural haematoma
How A. B. C. D. E.
A 64-year-old man was admitted for laparoscopic cholecystectomy. He was taking edoxaban for long-term prophylaxis in view of recurrent deep vein thrombosis.
should the anticoagulation be managed? Give idarucizumab Give prothrombin complex concentrate Give parenteral vitamin K Give tranexamic acid Stop dabigatran for 3 days
Investigations Estimated glomerular filtration rate 30 ml/minute What is the best advice related to his preoperative anticoagulation? A. Continue it unchanged B. Stop it 1 week before surgery C. Stop it 2 days before surgery and do not restart it D. Stop it 2 days before surgery and recommence it 24 hours after surgery if there is no major bleeding E. Stop it 12 hours before surgery
Question 2 A 27-year-old woman was 4 weeks pregnant. She was taking long-term rivaroxaban for secondary prevention following two unprovoked episodes of venous thromboembolism.
MEDICINE --:-
5
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Breen KA, Anticoagulation treatment, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.01.010
Anticoagulation treatment
Key points
Karen A Breen
C
Anticoagulants are used for prevention and treatment of arterial and venous thrombosis
Abstract
C
Current anticoagulants such as unfractionated heparin and warfarin require monitoring owing to their unpredictable pharmacokinetics
C
Anticoagulation is associated with a significant risk of bleeding
C
Direct oral anticoagulants have more predictable pharmacokinetics and do not require monitoring
Anticoagulant therapy using heparins and vitamin K antagonists has been used effectively for prevention and treatment of thromboembolic events for many years. However, therapy is associated with a significant risk of haemorrhagic complications, warranting careful consideration of the need for anticoagulation. Recognized drawbacks of current anticoagulants are their unpredictable pharmacokinetics and the need for laboratory monitoring, which have led in recent years to the development of direct oral anticoagulant agents.
Keywords Anticoagulant monitoring; heparin; reversal of anticoagulation; warfarin
anticoagulants leads to increased haemorrhagic risk, which in some cases can be fatal. Specific antidotes or agents to reverse anticoagulant effect are available for heparin and VKA but dabigatran is currently the only direct anticoagulant agent with a licensed antidote. Antidotes for the anti-Xa agents are currently undergoing Phase III trials.
Introduction Anticoagulation is used for the prevention and treatment of arterial and venous thromboembolism.1 The choice of anticoagulant is influenced by the indication for anticoagulation, mode of administration and duration for which it is required. Anticoagulants currently in use comprise: heparinoids e unfractionated heparin (UFH), lowmolecular-weight heparin (LMWH) and fondaparinux vitamin K antagonists (VKAs) e warfarin, phenindione and acenocoumarol new oral agents e dabigatran, rivaroxaban, apixaban and edoxaban.
Current anticoagulants Unfractionated heparin Heparin’s anticoagulant effect was first discovered in 1916. UFH, the first anticoagulant to be developed in the 1930s, consists of a series of glycosaminoglycan chains and is processed from animal intestinal mucosa, usually of porcine origin, in Europe.
Anticoagulants are one of the most commonly reported drug groups associated with medication errors. Overtreatment with
Mode of action, indications, dosing, drug interactions and monitoring: UFH is administered by intravenous infusion or subcutaneous injection. It causes an anticoagulant effect by potentiating the action of the physiological anticoagulant antithrombin ten thousand-fold. UFH has unpredictable pharmacokinetics and a short elimination half-life, and therefore requires monitoring. There are no specific drug interactions. Indications for its use include prevention of thrombosis of peripheral catheters, haemodialysis, prevention and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), treatment of cardiac ischaemia and critical ischaemia of the lower limb, coronary or peripheral artery angioplasty, and bypass surgery. Adverse effects include allergy, heparin-induced thrombocytopenia, and osteopenia with long-term use. Laboratory monitoring of heparin is performed using the activated partial thromboplastin time (APTT). The APTT ratio (APTTR) provides a measure of anticoagulant effect of UFH; the usual target ratio is two to three times higher than a normal APTT. Dosing of UFH requires a bolus dose for initiation of an UFH infusion, followed by a continuous infusion. APTTR monitoring allows subsequent adjustment of dosage. The dosage of UFH for administration by subcutaneous injection is fixed.
Karen A Breen MB MRCPI FRCPath is a Consultant Haematologist at Guy’s and St Thomas’ NHS Foundation Trust, London, UK. Competing interests: none declared.
Low-molecular-weight heparins LMWHs, first developed in the 1980s, are produced by depolymerization of UFH chains to produce a shorter glycosaminoglycan chain. They have more predictable pharmacokinetics, a
Indications and contraindications to anticoagulants There are multiple indications for anticoagulation, including prevention and treatment of venous thromboembolism1 and stroke prevention in atrial fibrillation. Each agent has a recommended dose according to the indication for which it is required. Contraindications to full anticoagulant therapy include severe uncontrolled hypertension, a recent cerebrovascular accident, a history of inherited or acquired bleeding disorder, thrombocytopenia (<50 109/litre) or a history of active bleeding. Concomitant use of antiplatelet agents and non-steroidal anti-inflammatory agents is not advised because of the increased bleeding risk. UFH is currently the only anticoagulant licensed for use in pregnancy; LMWHs are widely used and accepted to be safe and efficacious although none is licensed for use in pregnancy. Heparin and warfarin are safe for use in breastfeeding mothers.
Reversal of anticoagulation
MEDICINE --:-
1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Breen KA, Anticoagulation treatment, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.01.010
THROMBOSIS
longer half-life and an easier mode of administration (subcutaneous injection) than UFH.
Vitamin K antagonists VKAs were the first oral anticoagulants in use and currently include acenocoumarol, phenindione and warfarin. Only warfarin is discussed in this article.
Mode of action, indications, dosing, drug interactions and monitoring: like UFH, LMWH binds to antithrombin, but it has a greater inhibitory effect on factor Xa. Because of their longer halflives, LMWHs are suitable for outpatient use and have a lower risk of heparin-induced thrombocytopenia and osteoporosis than UFH. Dosing depends on the LMWH subtype and indication for use, which includes prevention and treatment of DVT and PE, and treatment of severe unstable angina. There are no specific drug interactions. Monitoring is required only in patients with renal failure and those at extremes of body weight, and is performed using anti-Xa concentration. Measurement of peak antiXa concentration is suggested (samples taken 4 hours after administration); target reference ranges depend on heparin type and indication.
Mode of action, indications, dosing, drug interactions and monitoring: warfarin prevents g-carboxylation of vitamin Kdependent clotting factors (II, VII, IX, X), producing an anticoagulant effect by reducing their concentrations. Factor VII has the shortest half-life, whereas factors II, VII, IX and X have half-lives of 8e72 hours, so warfarin takes several days to have full anticoagulant effect. The pharmacokinetics of warfarin are unpredictable, mainly because of its metabolism by enzymes of varied activity in the population. Numerous drug and food interactions contribute to its variable anticoagulant effect. Warfarin requires laboratory monitoring, which is based on the prothrombin time (PT). Variability in reagents used to determine PT has led to international standardization of the assay, now known as the international normalized ratio (INR), a PT-based measure of anticoagulant effect. Warfarin is teratogenic in the first trimester of pregnancy and should be stopped as soon as possible on confirmation of pregnancy. LMWH is a suitable alternative anticoagulant in pregnancy (although none is licensed for use in this setting). The recommended INR varies according to the indication for anticoagulation with warfarin.2 It is difficult to target a specific INR, and the usual aim is to maintain INR within 0.5 of a target INR. Recommended target INRs in relation to different indications for warfarin are shown in Table 1. Dosing regimens for initiation of warfarin therapy vary according to age and indication for anticoagulation. Patients with
Fondaparinux Fondaparinux is a synthetic form of the heparin pentasaccharide molecule. Mode of action, indications, dosing, drug interactions and monitoring: fondaparinux binds and activates antithrombin, resulting in only an anti-Xa effect, and has a half-life of 17e21 hours. It has a marketing authorization in Europe for indications similar to LMWH, but has not been widely used for thromboprophylaxis because of its cost. However, in the management of acute coronary syndrome, it has proved superior to LMWH in many patient groups. The dosage of fondaparinux depends on the indication for use, and as its pharmacokinetics are predictable there is no requirement for monitoring.
Indications for VKAs and recommended target INR Indication
Target INR
Duration
PE
2.5
Proximal DVT
2.5
Calf vein thrombosis Recurrent venous thrombosis on warfarin therapy (with therapeutic INR) Recurrent venous thrombosis in patient taking warfarin therapy with subtherapeutic INR or off anticoagulation Non-rheumatic atrial fibrillation (CHADS2 score >1) Cardioversion Mural thrombus Cardiomyopathy Mechanical prosthetic aortic heart valve Mechanical prosthetic mitral heart valve Bioprosthetic valve
2.5 3.5
At least 3 months e consider extending beyond 3 months if risk of recurrent thrombosis higha At least 3 months e consider extending beyond 3 months if risk of recurrent thrombosis higha 3 months Consider indefinite anticoagulation depending on risk of recurrent thrombosisa Consider indefinite anticoagulation depending on risk of recurrent thrombosisa Indefinite Indefinite Indefinite Indefinite Indefinite Indefinite Indefinite
2.5 2.5 2.5 2.5 2.5 2.5 3.5 2.5
‘CHADS2’ is a mnemonic for a clinical risk prediction tool to estimate risk of stroke associated with atrial fibrillation: C e congestive heart failure, H e hypertension, A e age, D e diabetes mellitus, S2 e previous stroke, transient ischaemic attack or thromboembolism. DVT, deep vein thrombosis; INR, international normalized ratio; PE, pulmonary embolism; VKA, vitamin K antagonist. a Patients with unprovoked DVT or PE should be considered for lifelong anticoagulation, taking into account risk of recurrence balanced against risk of bleeding on anticoagulant therapy. Patients with provoked DVT or PE have lower risk of recurrence and do not warrant lifelong anticoagulation. Provoking factors include recent surgery, immobilization, long-haul flight and oestrogen therapy.
Table 1 MEDICINE --:-
2
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Breen KA, Anticoagulation treatment, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.01.010
THROMBOSIS
Reversal of anticoagulation Anticoagulant
Urgent reversal with major haemorrhage
Urgent reversal without haemorrhage
Reversal for elective procedures
UFH
Stop UFH Measure APTTR Consider protamine sulphate (1 mg per 90e100 units heparin given in previous 2e3 hours)
For immediate procedure: Stop UFH and consider protamine sulphate For procedure delayed >6 hours: C Stop UFH Overanticoagulation without bleeding: C Stop UFH C Restart at a lower dose Stop LMWH Consider protamine sulphate if delay not possible
Stop UFH 4e6 hours before procedure
LMWH
Fondaparinux
Stop LMWH Consider protamine sulphate (only partially reverses LMWH, dose depends on type of LMWH) Stop fondaparinux Consider haemodialysis
Warfarin
Stop warfarin Measure INR PCC 25e50 IU/kg (repeat every 6 hours as needed) and vitamin K 2 mg intravenous Fresh frozen plasma should never be used in this setting
Dabigatran
Stop dabigatran Activated charcoal if within 4 hours of tablet ingestion Measure APTT Consider idarucizumab
Rivaroxaban/ apixaban/ edoxaban
Stop rivaroxaban/apixaban/edoxaban Measure PT Consider PCC/rFVIIa
C
For immediate procedure: Stop fondaparinux For procedure delayed >6 hours: C Stop fondaparinux For immediate procedure: C Stop warfarin C Measure INR C PCC 25e50 IU/kg and vitamin K 1 e2 mg oral or intravenous For procedure delayed >6 hours: C Stop warfarin C Measure INR C Vitamin K 1e2 mg oral or intravenous Overanticoagulation without bleeding: C Stop warfarin C Consider vitamin K 1 mg oral if INR >7 and/or risk of bleeding high For immediate procedure: C Stop dabigatran C Activated charcoal if within 4 hours of tablet ingestion C Measure APTT C Consider PCC For procedure delayed >24 hours: C Stop dabigatran C Measure APTT For immediate procedure: C Stop rivaroxaban/apixaban/ edoxaban C Activated charcoal if within 4 hours of tablet ingestion C Measure PT C Consider PCC For procedure delayed >24 hours: C Stop rivaroxaban/apixaban C Measure PT C
Stop LMWH for >12 hours if prophylactic dose, or for >24 hours if treatment dose before procedure Stop fondaparinux for >24 hours before procedure
Stop warfarin 5 days before procedure Consider bridging with short-acting anticoagulant if risk of thrombosis high Measure INR within 24 hours of procedure
Stop dabigatran within procedure if eGFR >50 Stop dabigatran within procedure if eGFR <50
1e2 days of ml/minute 3e5 days of ml/minute
Stop rivaroxaban/apixaban within 24 hours of procedure (if minor surgery) or 48 hours (if major surgery or impaired renal function)
APTT, activated partial thromboplastin time; APTTR, APTT ratio; eGFR, estimated glomerular filtration rate; INR, international normalized ratio; LMWH, low-molecularweight heparin; PCC, prothrombin complex concentrate; PT, prothrombin time; rFVIIa, recombinant factor FVIIA; UFH, unfractionated heparin.
Table 2
MEDICINE --:-
3
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Breen KA, Anticoagulation treatment, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.01.010
THROMBOSIS
be used to detect the presence of anticoagulant effect resulting from dabigatran. APTT is, however, not sensitive to low concentrations of the drug, and the PT is insensitive to the presence of dabigatran.
acute thrombosis require rapid initiation of anticoagulation using a faster acting anticoagulant, such as UFH or LMWH, until the desired INR range is reached; this is because the initial reduction by warfarin of the concentrations of proteins C and S can lead to an enhanced prothrombotic effect. Initiation regimens such as the Fennerty regimen (using higher doses of 10 mg daily to achieve a therapeutic INR within a short period) have not proved superior to the use of lower doses of 5 mg daily. Initiation of anticoagulation for atrial fibrillation using lower doses of warfarin, such as 3 mg daily (slow-loading regimen), usually achieves a target INR within 3e4 weeks and is acceptable in this setting. The dosage of warfarin is then adjusted according to INR.
Rivaroxaban Mode of action, indications, dosing, and drug interactions: rivaroxaban directly inhibits factor Xa and has a half-life of 4e9 hours. It is currently licensed for thromboprophylaxis after elective knee and hip surgery, prevention of stroke in atrial fibrillation, and the acute treatment and secondary prevention of DVT and PE. Dose reduction is advised in patients with impaired renal function. Important interactions occur with use of potent CYP3A4 inhibitors (e.g. ketoconazole) and P-glycoprotein inhibitors (e.g. protease inhibitors, such as ritonavir and atazanavir), which can increase the plasma concentration of rivaroxaban. PT is more sensitive to rivaroxaban than dabigatran, and can be used to assess for presence of an anticoagulant effect caused by rivaroxaban, whereas APTT is less sensitive to rivaroxaban than dabigatran. There is currently no antidote available for reversal of rivaroxaban, but andexanet alfa, an anti-Xa reversal agent is currently undergoing Phase 3 trials with promising results (see Table 2 for management of bleeding in patients taking rivaroxaban).
Reversal of anticoagulation: dried prothrombin complex (prothrombin complex concentrate; PCC) contains sufficient concentrations of factors II, VII, IX and X to allow reversal of the anticoagulant effects of warfarin and should be administered in combination with factor IV. Parenteral vitamin K administration is also required in patients with life-threatening haemorrhage. Concomitant use of vitamin K is required because PCC only has a half-life of 6 hours. Fresh frozen plasma is no longer used routinely for reversal of warfarin except where PCC is unavailable. For non-major bleeding (or in the setting of overanticoagulation without bleeding), a discontinuation or decrease in dosage of warfarin and/or administration of vitamin K usually suffices. Warfarin has a long half-life (20e60 hours) and should be discontinued 3e4 days in advance of most surgical procedures. Minor procedures associated with low bleeding risk, such as local injections and most dental procedures, do not require cessation of VKA (see Table 2 for reversal of anticoagulation). Protamine can be used for reversal of the anticoagulant effects of UFH but is rarely required in view of its short half-life. As it has only a partial effect on LMWH, it is rarely used for reversal.
Apixaban Apixaban directly inhibits factor Xa and has a half-life of 12 hours. It is currently licensed for thromboprophylaxis after elective knee and hip surgery and prevention of stroke in atrial fibrillation. It is contraindicated in patients with an eGFR below 15 ml/minute. Interactions are the same as those discussed for rivaroxaban, and reversal may also be possible in the future with andexanet alfa.
Direct oral anticoagulants
Edoxaban Edoxaban directly inhibits factor Xa and has a half-life of 10e14 hours. It is currently licensed for thromboprophylaxis after elective knee and hip surgery and prevention of stroke in atrial fibrillation. It is contraindicated in patients with an eGFR of less than 15 ml/minute. Interactions are the same as those discussed for rivaroxaban, and reversal will may also be possible in the future with andexanet alfa.
The new oral anticoagulants antagonize a single target in the clotting cascade; they have predictable pharmacokinetics and few food but some drug interactions, so monitoring is not required. Dabigatran, rivaroxaban, apixaban and edoxaban are direct oral anticoagulants currently in use, and several others are at advanced stages of development. There are currently no safety data for these agents in pregnancy or breastfeeding. Dabigatran Mode of action, indications, dosing, and drug interactions: dabigatran is a direct thrombin inhibitor and has a half-life of 14e17 hours. It is currently licensed for thromboprophylaxis after elective knee and hip surgery and for prevention of stroke in atrial fibrillation. The dosage is dependent on the indication. Dosage reduction is advised in renal impairment, and it should be avoided in those with an estimated glomerular filtration rate (eGFR) under 30 ml/ minute. Important drug interactions include amiodarone and verapamil, which can increase the plasma concentration of dabigatran. Monitoring of dabigatran is not required, but assessment of its anticoagulant effect may be required in an emergency situation. The APTT, which is prolonged in the presence of dabigatran, can
MEDICINE --:-
Reversal of anticoagulation Management of bleeding associated with direct oral anticoagulants is mainly supportive as dabigatran is the only agent to currently have a specific reversal agent (see Table 2 for management of bleeding).3,4 Perioperative management of these agents is dependent on the bleeding risk of the procedure and renal function of the patient.5 A KEY REFERENCES 1 Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(suppl 2): e691Se736.
4
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Breen KA, Anticoagulation treatment, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.01.010
THROMBOSIS
2 Keeling D, Baglin T, Tait C, et al. Guidelines on oral anticoagulation with warfarin e fourth edition. Br J Haematol 2011; 154: 311e24. € ller HR, Falanga A, et al. Managing reversal of direct 3 Ageno W, Bu oral anticoagulants in emergency situations. Anticoagulation Education Task Force White Paper. Thromb Haemost 2016; 116: 1003e10. 4 Heidbuchel H, Verhamme P, Allings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-
vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015; 17: 1467e507. 5 Keeling D, Tait RC, Watson H, British Committee of Standards for Haematology. Peri-operative management of anticoagulation and antiplatelet therapy. Br J Haematol 2016; 175: 602e13.
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here.
Question 1
What is the most appropriate action for her anticoagulation? A. Stop rivaroxaban B. Switch to aspirin C. Switch to edoxaban D. Switch to low-molecular-weight heparin E. Switch to warfarin
A 75-year-old woman was admitted following a head injury. She had a past history of atrial fibrillation. She was taking dabigatran for stroke prevention. On examination, her pulse was 88 beats/minute and irregularly irregular, and her Glasgow Coma Scale score was 7.
Question 3 Investigations CT brain scan showed a subdural haematoma
How A. B. C. D. E.
A 64-year-old man was admitted for laparoscopic cholecystectomy. He was taking edoxaban for long-term prophylaxis in view of recurrent deep vein thrombosis.
should the anticoagulation be managed? Give idarucizumab Give prothrombin complex concentrate Give parenteral vitamin K Give tranexamic acid Stop dabigatran for 3 days
Investigations Estimated glomerular filtration rate 30 ml/minute What is the best advice related to his preoperative anticoagulation? A. Continue it unchanged B. Stop it 1 week before surgery C. Stop it 2 days before surgery and do not restart it D. Stop it 2 days before surgery and recommence it 24 hours after surgery if there is no major bleeding E. Stop it 12 hours before surgery
Question 2 A 27-year-old woman was 4 weeks pregnant. She was taking long-term rivaroxaban for secondary prevention following two unprovoked episodes of venous thromboembolism.
MEDICINE --:-
5
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Breen KA, Anticoagulation treatment, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.01.010