Bridging anticoagulation: perioperative management of patients on anticoagulants

Currently, approximately 1.3 million patients are prescribed anticoagulant therapy in the UK^[1]
, the majority for atrial fibrillation (AF), venous thromboembolic disease (VTE) and mechanical heart valves^[2]
. The most common oral anticoagulant is warfarin, but increasing numbers of patients are being treated with the direct oral anticoagulants (DOACs): apixaban, dabigatran, edoxaban and rivaroxaban. A small minority of patients are treated with alternative vitamin K antagonists (VKAs): acenocoumarol (Sinthrome) and phenindione.

Around 10–15% of anticoagulated patients undergo surgery or an invasive procedure each year^[3]
,[4]
. Formal bridging anticoagulation involves the substitution of oral anticoagulation with a short-acting alternative, usually low molecular weight heparin (LMWH), during the perioperative period^[3]
,[5]
.

Traditionally, patients on warfarin either had their dose adjusted to maintain a lower international normalized ratio (INR), or were converted to intravenous heparin infusion during the perioperative period^[6]
. This necessitated protracted hospital admissions while warfarin was restarted and restabilised. Managing heparin infusions is notoriously difficult, requires frequent monitoring using blood tests, and many patients are under or over-anticoagulated. In the past ten years or so, LMWH has increasingly been used for management of these patients: subcutaneous injections of LMWH can be administered by the patient, facilitating earlier discharge from hospital in patients who are otherwise fit to go home.

The emergence of more evidence about the need for bridging anticoagulation therapy and the introduction of DOACs have led to changes in how patients are managed, which is the focus of this article.

Risk stratification

The decision about whether to continue or interrupt anticoagulation depends on the patient’s bleeding and thrombotic risks. Previously published guidelines^{[3]
,[6]
,[7]}
have been based on expert consensus, however a meta-analysis^[8]
concluded that bridging increases the risk of post-operative bleeding without reducing the risk of thrombotic events. The evidence base is evolving with the recently published BRIDGE study^[4]
and ongoing PERIOP 2 trial (clinicaltrials.gov, identifier: NCT00432796).

Can anticoagulation be continued for the procedure?

This is the first question to ask. If anticoagulation causes significant blood loss, or bleeding into a critical site (e.g. neurosurgery, spinal or ophthalmic surgery), it could ultimately result in a longer period of time without anticoagulation. If the bleeding risk is low, then the usual anticoagulant can be continued (see ‘Table 1: Common procedures in which oral anticoagulant therapy may be continued’).

Specialist guidelines^{[9]
,[10]
,[11]
,[12]
,[13]
,[14]}
largely refer to warfarin, and there is no published trial data relating to DOACs. Where they have been published, consensus/expert guidelines recommend that if a procedure can be performed on warfarin with an INR in the therapeutic range, then it may also be performed on any anticoagulant^[9]
,[15]
. If the anticoagulant is a VKA, a pragmatic approach is to check the INR a week prior to the procedure to allow for any necessary dose adjustments to be made, with a further INR check on the day before, or day of, the procedure^[14]
.

There are some procedures, such as spinal/neurosurgery and radical prostatectomy, where the bleeding risk is very high and full bridging or even prophylactic LMWH may be considered to be too high risk: in the author’s institution these are considered on a case by case basis.

What is the thrombotic risk?

If anticoagulation cannot be safely continued, the thrombotic risk determines how the anticoagulation is managed (i.e. whether or not bridging is required).

Atrial fibrillation

The BRIDGE study is the first to have examined whether bridging is required in patients with AF by comparing bridging with a placebo^[4]
. It demonstrated that in patients with a CHADS₂ score of 4 or less, bridging provided no benefit in terms of stroke, myocardial infarction, VTE or death, and resulted in increased rates of both major and minor bleeding^[3]
,[5]
. Previous practice has been to risk stratify (see ‘Table 2: Thrombotic risk stratification for mechanical heart valves and VTE’), but these new results will result in a major change in practice. Patients with a CHADS₂ score of 5–6 were under-represented in the BRIDGE study and high risk procedures, such as cardiac surgery, carotid endardectomy, major cancer surgery and neurosurgery, were excluded^[4]
. Clinicians may therefore continue to use bridging for these patients with AF.

Mechanical heart valves

Patients with mechanical heart valves are at risk of valve thrombosis and stroke, and warfarin or other VKAs are used for anticoagulation. The daily thrombosis risk of a non-anticoagulated heart valve is approximately 0.01%^[17]
, although the risk is greater with older more thrombogenic valves and mitral valves rather than aortic valves^[17]
.

Venous thromboembolism

Many patients who have had an idiopathic VTE (i.e. a VTE with no provoking event such as surgery, immobility or illness) continue on long-term anticoagulation to prevent recurrence. Without anticoagulation, the incidence of recurrence is approximately 20% in five years, with a 2.6% incidence of fatal pulmonary embolism^[18]
. ‘Table 2: Thrombotic risk stratification for mechanical heart valves and VTE’ describes the thrombotic risk stratification for patients with mechanical heart valves and VTE.

Anticoagulant bridging

Depending on the outcome of the thrombotic risk assessment, the following action may be needed:

• Low thrombotic risk, or AF with CHADS₂ score 0–4: no bridging required: use prophylactic LMWH only;
• Moderate thrombotic risk: consider bridging (weigh up bleeding risks)^[3]
  – some hospitals use bridging for all moderate risk, some work on a case-by-case basis;
• High thrombotic risk: bridging required.

Even if formal bridging is not required, many surgical procedures will still require the use of prophylactic anticoagulation for the prevention of VTE (e.g. low dose LMWH)^[19]
. The highest risk procedures are major cancer surgery in the abdomen or pelvis (e.g. surgery for bowel, liver, stomach or prostate cancer), hip fracture repair, hip replacement and knee replacement^[19]
: the National Institute for Health and Care Excellence (NICE) recommends that all patients, regardless of previous anticoagulation exposure, should receive extended post-operative VTE prophylaxis (i.e. low dose anticoagulant for up to 35 days post-operatively)^[19]
. In patients who are usually anticoagulated, the prophylactic anticoagulation should continue post-operatively until their usual treatment has resumed and they are fully anticoagulated. This isn’t true bridging, but may be referred to as such.

Bridging for warfarin

‘Table 3: Low molecular weight heparin (LMWH) doses’ outlines suggested LMWH doses, and ‘Table 4: Suggested pre- and post-operative management of LMWH for bridging’ outlines the pre- and post-operative management of LMWH for bridging and warfarin.

Post-operatively, full dose anticoagulation with LMWH should not be started until at least 48 hours after a high bleeding risk procedure or 24 hours after a minor procedure with low bleeding risk^[3]
. Prophylactic LMWH only should be given until then. As further safeguards against bleeding, some centres use an intermediate dose of LMWH on days +3 and +4 post-operatively, and/or spit full dose LMWH into two daily doses^[3]
. Whatever regime is used, it is imperative LMWH is not started, or the dose increased, until the clinicians are satisfied that there is no concern about bleeding. The assessment will include examining the wound site, the amount of fluid collecting in surgical drains, the expected bleeding, and monitoring of the patient’s haemoglobin levels. In some circumstances (e.g. where it is likely that a patient may return to the operating theatre) it may be appropriate to continue prophylactic LMWH for longer than the usual regime.

If the patient has epidural analgesia in situ, LMWH should not be increased above prophylactic doses because of the risk of spinal haematoma causing neurological dysfunction^[20]
. If treatment doses are given, then the epidural catheter must not be removed for at least 24 hours after the last dose: however this is not usually recommended^[20]
.

In patients with severe renal impairment (i.e. a calculated creatinine clearance less than 30ml/min), LMWH is usually not appropriate^[21]
,[22]
. In these circumstances it may be necessary to use an infusion of unfractionated heparin instead^[3]
. This provides full treatment dose anticoagulation and should be stopped 4–5 hours pre-operatively and restarted at least 24–48 hours post-operatively depending on the bleeding risk of the procedure. In the meantime, prophylactic LMWH may be used (some units use adjusted doses for renal impairment).

Warfarin is commonly restarted at the patient’s usual dose, usually on the day after surgery^[3]
. It may be appropriate to give a double dose on the first day^[3]
, but loading doses should be avoided as they introduce the risk of over-anticoagulating the patient in a short time post-op. By continuing the patient’s usual dose, the INR only needs to be checked every 3–4 days, facilitating early discharge from hospital as soon as the patient is otherwise fit to leave. When the INR reaches 2.0, LMWH can be stopped (even if the target INR range is higher): this will usually be within 5–10 days of restarting warfarin.

Warfarin in patients at low thrombotic risk

These patients can have a prophylactic dose of LMWH both pre- and post-operatively until the patient has restarted warfarin and their INR has reached over 2.0. AF patients with a CHADS₂ score of 0-4 may stop LMWH when they are discharged from hospital, provided the procedure they underwent does not require extended thromboprophylaxis^[19]
.

Direct oral anticoagulants

The direct oral anticoagulants have an almost immediate onset of action (peak levels are achieved within 2–4 hours of a dose), and they do not usually require any routine monitoring apart from periodic renal and liver function tests^{[23]
,[24]
,[25]
,[26]
,[27]}
. This potentially makes the perioperative management more straightforward if anticoagulation needs to be stopped. The last dose of DOAC should be timed to achieve normal coagulation status by the time of surgery^[15]
(see ‘Table 5: Timing of last pre-operative doses of direct oral anticoagulants’). The timing depends on the patient’s renal function, as all the DOACs are cleared renally to some extent (dabigatran significantly more so than the factor Xa inhibitors)^{[23]
,[24]
,[25]
,[26]}
. It is important to note that the DOACs are not licensed with renal function below those listed in ‘Table 5: Timing of last pre-operative doses of direct oral anticoagulants’: if the patient has acute kidney injury or chronic renal impairment with a creatinine clearance (CrCl) less than the lower cut off, then it may be necessary to delay surgery for a longer period of time until coagulation tests suggest that clotting has normalised^[28]
.

Post-operatively, the usual DOAC should not be re-started until there are no concerns about bleeding: in practice this will be 24–48 hours post-op depending on the procedure. Prophylactic dose LMWH should be given in the meantime^{[24]
,[25]
,[26]}
. LMWH and DOAC should not overlap: they should be switched directly by giving the DOAC when the next dose of LMWH would have been due^{[23]
,[24]
,[25]
,[26]}
. If the patient remains nil by mouth for an extended period, the LMWH doses can be escalated in the same manner as for patients on warfarin, and then switched to DOAC when the patient is able to take medicines orally.

Emergency surgery

There is not always enough time to manage a patient’s anticoagulation pre-operatively if a patient needs emergency surgery.

For patients on warfarin, 5mg of vitamin K given intravenously will significantly reduce the INR within 6–8 hours^[29]
(giving a bigger dose will not speed up the effect, and oral administration acts more slowly). If surgery cannot be delayed that long, prothrombin complex concentrate (PCC) should also be given for a more rapid reversal^[5]
(see ‘Box 1: Prothrombin complex concentrate’).

Post-operatively, patients may be managed in the same way as elective patients, bearing in mind that it may take longer for the INR to return to therapeutic range because of the effect of having had a large dose of vitamin K immediately pre-op.

At the time of writing, dabigatran is the only DOAC to have a specific reversal agent: idarucizumab was licensed in December 2015^[32]
. It is a humanised monoclonal antibody that selectively binds dabigatran 300 times more potently than dabigatran binds to thrombin. It has an almost immediate onset of action (less than ten minutes), and is licensed for reversal of dabigatran in emergency surgery and in life-threatening or uncontrolled bleeding^[32]
. The manufacturers suggest that dabigatran can be restarted after 24 hours, but this should always be in conjunction with a clinical assessment of the patient, and post-operatively it would be prudent to wait at least 48 hours after major surgery^[32]
.

There are currently no specific reversal agents for the factor Xa inhibitors, but andexanet has been trialled^[33]
and is undergoing review by the Food and Drug Administration for licensing in the United States^[34]
. Wherever possible, surgery should be delayed, waiting 1–2 half lives, to allow renal excretion of the drug. The use of PCC to reverse factor Xa inhibitors is based on healthy volunteer studies and case reports^[35]
. The lack of a specific reversal agent for these drugs should not put patients off being anticoagulated with apixaban, edoxaban or rivaroxaban if they are considered to be the most suitable drug for them. Provided renal and liver function are monitored regularly and doses adjusted as appropriate^[27]
, the bleeding risks are similar to or lower than that of warfarin^{[23]
,[24]
,[25]
,[26]}
and the need for emergency surgery is comparatively uncommon.