Perioperative management of oral anticoagulation

Key points.

• •Warfarin has a slow onset and offset; direct-acting oral anticoagulants are much quicker.
• •Bridging therapy is overprescribed, and the probability of bleeding should be considered against the probability of thromboembolism.
• •Haematoma after neuraxial anaesthesia is a devastating complication. Therefore, neuraxial anaesthesia should only be performed when the systemic anticoagulant activity is low. In emergency situations it is difficult to quantify the level of systemically active direct oral anticoagulant.

Learning objectives.

By reading this article, you should be able to:

• •Estimate the duration that direct oral anticoagulant (DOAC) must be stopped before procedures can be performed.
• •Assess which patients require bridging therapy and devise an appropriate regimen.
• •Manage the anticoagulation reversal in emergency situations for patients receiving warfarin or DOACs.

Past, present, and future

Oral anticoagulants can be split chronologically into two broad groups: warfarin, which was first licenced for clinical use in 1954 in the USA by the Federal Drug Administration (FDA) agency, and the new oral anticoagulants (NOACs). Dabigatran was the first NOAC and was approved by the FDA in 2010. The NOACs have now been reclassified as direct oral anticoagulants (DOACs) because their novelty has diminished.

Warfarin still dominates anticoagulation prescribing and accounts for two thirds of the total number of oral anticoagulant prescriptions. However, DOACs are rapidly gaining ground. The market for DOACs is dominated by rivaroxaban and apixaban. The market share of the three most common DOACs in the USA is apixaban (Eliquis®) 51.3% (which is by far the cheapest DOAC), rivaroxaban (Xarelto®) 41.7%, and dabigatran (Pradaxa®) <5%.¹ Edoxaban (Savaysa® and Lixiana®) is a relatively new DOAC that was approved by the FDA in 2015. Currently, edoxaban accounts for a very small proportion of DOACs prescribed. It was created in an attempt to address current issues relating to DOACs, such as adverse gastrointestinal effects. Even though warfarin has weaknesses, it will continue to be the most commonly prescribed anticoagulant for the foreseeable future, because of its many benefits (Table 1).

Table 1.

Benefits and weaknesses of warfarin compared with DOACs

Advantages	Disadvantages
Wide range of indications Preferred in high-risk patients (especially mechanical valves) Long safety history Cheap, widely available antidote Easy monitoring of degree of anticoagulation No gastrointestinal upset (2% dabigatran/rivaroxaban) Inexpensive Single daily dose	Need for monitoring Highly variable dosing Increased requirement for bridging Food interactions Drug interactions Initially procoagulant Slow onset Long half-life Increased risk of intracranial bleed (50%)2 Possibly increased life-threatening bleed (25%)2

Indications for DOACs

DOACs are still only licenced for a very limited and specific set of indications (Table 2). For patients with atrial fibrillation (AF), there is strong evidence that DOACs are non-inferior for stroke prevention and have a reduced incidence of intracranial haemorrhage in comparison to warfarin.2, 4, 5 DOACs are only licenced in non-valvular AF. This is partly because valvular AF is an exclusion criterion in most DOAC trials. The RE-ALIGN trial included patients with mechanical heart valves (MHVs), and demonstrated increased rates of thromboembolic and bleeding complications when dabigatran was administered to patients with MHVs, when compared with warfarin.⁶ There are robust data substantiating the effectiveness of DOACs for primary prevention of venous thromboembolism (VTE) in knee and hip orthopaedic surgery. Currently DOACs are only advised for secondary prevention and treatment in other VTE circumstances.³

Table 2.

NICE guidelines for DOACs.³ ACS, acute coronary syndrome; DVT, deep vein thrombosis; NICE, National Institute for Health and Care Excellence; PE, pulmonary embolism. Anticoagulants, including non-vitamin K antagonist oral anticoagulants (NOACs). All rights reserved. Subject to notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication

Indication	Apixaban	Rivaroxaban	Dabigatran etexilate
VTE prevention after elective hip or knee replacement	Licenced for this indication	Licenced for this indication	Licenced for this indication
Secondary prevention or management of DVT or PE	Licenced for this indication	Licenced for this indication	Licenced for this indication
Stroke and systemic embolism prevention in patients with non-valvular AF	Possible treatment in specific circumstances	Possible treatment in specific circumstances	Possible treatment in specific circumstances
Prevention of adverse outcomes after acute management of ACS with increased biomarkers	Not licensed for this indication	Possible treatment in specific circumstances	Not licensed for this indication

Pharmacology

Warfarin exerts its effect via inhibition of the epoxide reductase enzyme, which is required to recycle vitamin K and is essential in the production of Ɣ-carboxylated coagulation factors. Because warfarin has an indirect mechanism of action, it can take days to reach therapeutic effect because the existing Ɣ-carboxylated coagulation factor concentrations need to decrease before the reduction in synthesis of new factors becomes apparent. The same is true with offset; levels of new Ɣ-carboxylated coagulation factors are synthesised slowly, but this can be accelerated by the administration of vitamin K.

DOACs have a relatively quick onset and offset, because they have a direct mechanism of action. Dabigatran directly inhibits thrombin (factor II). Dabigatran is a prodrug with minor pharmacological effects, but is hydrolysed to the more active form by carboxylesterases. Rivaroxaban and apixaban are direct inhibitors of factor Xa; Xa inhibitors and thrombin inhibitors reach maximum inhibition concentrations in less than 4 h (Table 3).

Table 3.

Pharmacology of commonly used DOACs and warfarin

	Dabigatran	Rivaroxaban	Apixaban	Warfarin
Mechanism of action	Selective thrombin inhibitor	Selective Xa inhibitor	Selective Xa inhibitor	Vitamin K epoxide reductase inhibitor
Oral bioavailability (%)	6.5	80–100	50	79–100
Half-life (h)	12–17	5–13	8–15	45
Renal elimination (%)	85	66	27	92
Time to maximal inhibition (h)	0.5–2	1–4	1–4	69

Ceasing anticoagulants perioperatively

Warfarin is usually withheld for 5 days, which equates to four missed doses. Bridging is recommended for patients with appropriate risk factors (see below). DOACs are withheld for a variable duration, determined by balancing the estimated risk of haemorrhage against the risk of thromboembolism. For surgery of low bleeding risk in patients with normal or mildly impaired renal function, ceasing a DOAC 24 h before surgery is sufficient.⁷ DOACs should be withheld for 2–4 days for surgery of high bleeding risk (Table 4).⁸

Table 4.

Advised time between last dose of a DOAC and surgery

Renal function and related half-life	DOAC and current dose	Time of last dose before surgery (h)
		Low-bleeding-risk surgery (two to three half-lives between last dose and surgery)	High-bleeding-risk surgery (four to five half-lives between last dose and surgery)
CrCl ≥50 ml min−1 (half-life: 7–8 h)	Apixaban 5 mg twice daily	24	48–72
CrCl 30–49 ml min−1 (half-life: 17–18 h)		48	72
CrCl ≥50 ml min−1 (half-life: 5–9 h)	Rivaroxaban 20 mg once daily	24	48–72
CrCl 30–49 ml min−1 (half-life: 9–13 h)		48	72
CrCl ≥50 ml min−1 (half-life: 12–17 h)	Dabigatran 150 mg twice daily	24	48–72
CrCl 30–49 ml min−1 (half-life: 13–23 h)		48–72	96

Cessation of anticoagulants before neuraxial anaesthesia

Neuraxial anaesthesia, such as intrathecal or epidural anaesthesia, is viewed as a very high-risk intervention because associated bleeding can be devastating, especially neuraxial haematoma. Accordingly, the American Society of Regional Anesthesia (ASRA) produced very conservative guidelines in 2015.⁹ They recommended five half-lives (percentage of drug remaining in system: 3.1%) before neuraxial anaesthesia should be attempted. Further guidelines in April 2018 stated that:

• (i)patients should omit rivaroxaban and apixaban for 72 h before neuraxial block;
• (ii)clinicians should consider checking the level of the anti-factor Xa drug or anti-factor Xa activity level if the interval is less than 72 h;
• (iii)for patients prescribed dabigatran with a creatinine clearance (CrCl) >30 ml min⁻¹, neuraxial block should only be performed 3–5 days after the last dose;
• (iv)in patients with a CrCl <30 ml min⁻¹, ASRA now suggests against the performance of neuraxial blocks.¹⁰

The European and Scandinavian guidelines were less conservative and adopted two half-life intervals (25% drug remaining in the system) between discontinuation of the drug and neuraxial injection.⁹

Warfarin bridging

There has been a shift away from routinely bridging patients. This is because mounting evidence suggests that bridging confers an increase in both major bleeding and major cardiovascular events, but without an appreciable decrease in thromboembolic events.11, 12, 13, 14, 15 Currently, the following key points are widely endorsed:

• (i)Warfarin should not be interrupted for procedures of low bleeding risk.
• (ii)Patients at low risk of VTE should not be bridged.
• (iii)In patients at highest risk of VTE, but not excessive bleeding risk, bridging should be considered.
• (iv)Intermediate-risk cases should be considered on an individual patient basis, with the risk of bleeding vs risk of VTE assessed.

The unnecessary interruption of warfarin therapy can have detrimental effects. Interrupting warfarin has been shown to double the risk of stroke in the first week of reinitiation.¹² This phenomenon may be facilitated by inhibition of anticoagulant proteins C and S, resulting in a hypercoagulable state.

Many procedures may be amenable to continuation of warfarin, such as gastroscopy, endovascular interventions, cardiac device implantation, cataract surgery, dermatologic surgery, dental extractions, minor surgeries, total knee arthroscopy, and arthroscopic surgery.7, 12

Warfarin bridging protocol

The last warfarin dose should be 5 days pre-procedure. A rest day should follow with no anticoagulant to allow the effects of warfarin to diminish and the INR be less than 1.5 before heparin is initiated. Low-molecular-weight heparins (LMWHs) have a more predictable pharmacokinetic profile, which enables less frequent dosing without the requirement for monitoring assays. Consequently, LMWHs have superseded unfractionated heparin because of the reduced cost of administration, greater convenience, and similar efficacy. LMWHs can be administered in an outpatient setting either once a day in a dose of 1.5 mg kg⁻¹ or twice a day dose of 1 mg kg⁻¹. A regimen of 1 mg kg⁻¹ twice daily is more efficacious and should, therefore, be used for high-risk VTE patients and high-risk bleeding patients, as peak concentrations are reduced should bleeding occur. The more convenient daily dose can be contemplated for lower-risk patients.

Both dosage schedules use daily doses that mandate a 24 h period between the last dose of heparin and surgery, to make certain the residual anticoagulant effect has decreased sufficiently. If prescribing the once-a-day schedule, the last 1.5 mg kg⁻¹ dose should also be halved to 0.75 mg kg⁻¹ to allow adequate time for the anticoagulant effects to subside.

DOAC bridging

Bridging is not usually recommended for DOAC drugs, because the duration necessary for the drug to be withheld before surgery is short and the restoration of clinical effect upon re-initiation is rapid, without a procoagulant effect. Bridging may be contemplated in a patient who has a high thrombotic risk and requires prolonged preoperative cessation of the anticoagulant. The PAUSE trial (Perioperative Anticoagulant Use for Surgery Evaluation Study) is currently recruiting to assess if stopping DOACs for between 1 and 4 days before surgery is safe, with acceptably low rates of perioperative major bleeding and arterial thromboembolism.

Thromboembolic risk stratification

The risk of sustaining a perioperative thrombotic event is divided into three pathological groups (Table 5): (i) Mechanical heart valve (MHV); (ii) AF; and (iii) previous/risk of VTE.¹³

Table 5.

Suggested risk stratification for perioperative thromboembolism.¹³ CHA₂DS₂ VASc, congestive heart failure, hypertension, age ≥75 (doubled), diabetes mellitus, prior stroke or transient ischaemic attack (doubled), vascular disease, age 65–74, female; TIA, transient ischaemic attack (range 0-9). VKA, vitamin K antagonist. CHADS₂ score: CHAD=1 point each; S=2 points (range: 0–6)

Risk stratum	Indication for VKA therapy			Bridge?
	MHV	AF	VTE
High	Mitral valve prosthesis: any type Aortic valve prosthesis: caged ball and tilting disc Stroke/TIA <6 months prior	CHA2DS2 VASc score: 7–9 Rheumatic valvular heart disease Stroke/TIA <3 months prior	Severe thrombophilia: deficiency of protein C and protein S, and antithrombin and antiphospholipid antibodies Stroke/TIA <3 months prior	Bridging advised
Moderate	Aortic valve prosthesis: bi-leaflet (and one or more of the following risk factors: AF, prior stroke or TIA, hypertension, diabetes, congestive heart failure, and age >75 yr)	CHA2DS2 VASc score of 5 or 6 (without prior stroke or TIA)	VTE 3–12 months prior Non-severe thrombophilia: heterozygous factor V Leiden and prothrombin gene mutation Recurrent VTE Active cancer	Likely no bridging AF group Consider bridging VTE and MHV
Low	Aortic valve prosthesis: bi-leaflet (without other risk factors)	CHA2DS2 VASc score of 0–4 (without prior stroke or TIA)	VTE >12 months prior and no other risk factors	No bridging

Mechanical mitral valves are considered high risk, whereas aortic valves are categorised by type. The older caged or tilting disc valves are high risk, whereas newer bi-leaflet valves are low or medium risk dependent on additional risk factors. Therefore, not all aortic valves mandate bridging therapy.

Patients at low risk of a thrombotic incident should not cause a clinical dilemma; however, research continuously demonstrates overzealous bridging therapy in patients at low risk of VTE. Surveys demonstrate that approximately 30% of clinicians overestimate the risks of VTE and subsequently bridge low-risk patients.12, 16, 17 Evidence suggests that patients with a low thrombogenic profile are at greater risk of periprocedural bleeding than of VTE when they receive heparin as bridging therapy.¹²

Regarding AF, there is now Level 1 evidence demonstrating that the majority of AF patients are at risk of a major bleed from bridging therapy, with no reduction in incidence of arterial thromboembolism. The BRIDGE trial, a multicentre, randomised, double-blind placebo-controlled trial, demonstrated that bridged AF patients with a CHADS (congestive heart failure, hypertension, age ≥75 yr, diabetes mellitus, and stroke) score of 1–4 were at greater risk of major bleeding than thromboembolism when compared with no bridging. Only 3% of patients recruited to the study had a CHADS score of 5 or 6, limiting the generalisability to higher-risk patients.¹⁵ The American College of Cardiology have recently adopted guidelines to reflect this changing paradigm (Fig. 1).¹⁸

Fig 1.

Selecting perioperative patients who require bridging and appropriate method of bridging.

Mechanical valves were excluded from the BRIDGE trial, but the PERIOP2 trial includes mechanical valves and will add to the evidence comparing bridging with non-bridging in high-risk patients (estimated study completion date: September 2018).

Preoperative anticoagulant testing

The residual effects of warfarin can be reliably tested by measuring the prothrombin time (PT) or international normalised ratio, which are widely available; however, most hospitals do not have the capability to quantify the current DOAC anticoagulant effect.

Rivaroxaban prolongs PT in a linear and concentration-dependent manner. Rivaroxaban also prolongs activated partial thromboplastin time (APTT), but has a ceiling effect, keeping abnormal readings within an APPTr of 2. A normal PT or APTT does not exclude a clinically relevant anticoagulant effect. Anti-factor Xa chromogenic assays have demonstrated a good correlation with plasma concentration of anti-Xa inhibitors and are the preferred test.19, 20 Dabigatran requires a thrombin time (TT) to confirm the absence of a clinically relevant anticoagulant effect, but this can be erroneous if not calibrated correctly. The manufacturers advise using Hemoclot® thrombin inhibitor assay (a diluted TT), a more drug-specific test than the standard TT.

Emergency management

In the emergency setting, it is often not known when the last dose of an anticoagulant was ingested, because of diminished consciousness, delirium, or other factors. It should also be remembered that the effects of most DOACs, especially dabigatran, are prolonged with renal failure—a common finding in many emergency admissions. In these circumstances, DOAC concentrations may guide management.

Reversal of anticoagulants

The approach to reversal of both warfarin and DOACs depends on the degree of bleeding and if this bleeding is life-threatening

No bleeding/minor bleeding

• (i)Discontinue anticoagulant.
• (ii)Spontaneous resolution over time is an option with all anticoagulants.
• (iii)Vitamin K for warfarin.

Severe bleeding

• (i)Discontinue anticoagulant.
• (ii)Supportive care (i.v. fluids and blood products).
• (iii)Activated charcoal (if within 3 h of ingestion).
• (iv)Consider dialysis (dabigatran only).
• (v)Consider DOAC reversal agent.
• (vi)Consider prothrombin complex concentrate (PCC) (rivaroxaban or apixaban only).
• (vii)Prothrombin complex concentrate and vitamin K (warfarin reversal).
• (viii)Consider recombinant factor VIIa.
• (ix)Consider tranexamic acid.

Fresh frozen plasma is not recommended for the reversal of the effects of warfarin. PCC has a relatively short duration of action (half-life of 6 h), so vitamin K is essential to maintain the corrected coagulation profile if haemostasis is desired after this 6 h window.

Reversal agents for DOACs (see Table 6)²²

Table 6.

American College of Cardiology summary of available reversal agents and suggested use.²¹ aPCC, activated PCC; 4F-PCC, four-factor PCC

Reversal agent	Vitamin K antagonist (warfarin)	Factor IIa inhibitor (dabigatran)	Factor Xa inhibitor (apixaban, edoxaban, and rivaroxaban)
4F-PCC	First line	Second line	First line
aPCC	Not indicated	Second line	Second line
Idarucizumab	Not Indicated	First line	Not indicated
Plasma	If 4-PCC is unavailable	Not indicated	Not indicated

Dabigatran: idarucizumab (Praxbind®) (licensed)

A humanised monoclonal antibody fragment (Fab), idarucizumab binds dabigatran with about 350 times the avidity that dabigatran binds to thrombin. In emergency situations, idarucizumab can rapidly, durably, and safely reverse the anticoagulant effect of dabigatran. There is no evidence of hypersensitivity reactions. The full reversal dose is 5 g and costs £2400 in the UK.²¹

Rivaroxaban/apixaban: andexanet (AndexXa^®) (not licensed)

Andexanet is a Xa inhibitor reversal drug. It is a genetically engineered version of human factor Xa that binds Xa inhibitors, but the active sites have been removed so it does not interfere with coagulation. The terminal half-life is 1 h. Therefore, to achieve a short duration of reversal (i.e. 1–2 h), a bolus may be adequate, but for a sustained effect, an infusion should be administered.²³

Universal anticoagulant reversal agent: ciraparantag (Aripazine) (currently being fast tracked through phase III testing)

An investigational factor Xa and IIa inhibitor, ciraparantag was first developed as a ‘universal’ antidote to reverse the anticoagulant effects of both factor Xa inhibitors and factor IIa inhibitors. It also binds to fondaparinux and heparins, but does not bind to blood clotting factors, albumin, or other blood proteins. Ciraparantag decreases bleeding by more than 90%. There was no evidence of prothrombotic effects.²⁴

Declaration of interest

The authors declare that they have no conflicts of interest.

MCQs

The associated MCQs (to support CME/CPD activity) will be accessible at www.bjaed.org/cme/home by subscribers to BJA Education.

Biographies

Keir McIlmoyle FANZCA FRCA is a consultant anaesthetist at Toowoomba Hospital and director of Toowoomba Anaesthesia Services. His major clinical and research interests are in perioperative anticoagulation medicine.

Huyen Tran MClinEpi FRACP FRCPA is a consultant haematologist, head of the Haemostasis and Thrombosis Unit, and director of the Haemophilia Centre at the Alfred Hospital, Melbourne. He is the current president of the Australian Society of Thrombosis and Haemostasis.

Matrix codes: 1E05, 2A03, 3I00