Management of anticoagulation therapy in the perioperative patient.
Abstract: With the increasing use of oral anticoagulation therapy the appropriate management of perioperative anticoagulation is of surgical importance. There is a delicate balance between the risk of a perioperative thromboembolic event and the risk of operative bleeding from anticoagulation. Whilst there are a range of options available to the clinician, there appears to be no precise agreement about how to best manage this problem.

KEYWORDS Anticoagulation / Surgery / Warfarin / Unfractionated heparin / Low molecular weight heparin
Subject: Anticoagulants (Medicine) (Health aspects)
Perioperative care (Analysis)
Thromboembolism (Drug therapy)
Authors: Dhinsa, Baljinder
Khan, Wasim S.
Tailor, Hiteshkumar
Pub Date: 08/01/2011
Publication: Name: Journal of Perioperative Practice Publisher: Association for Perioperative Practice Audience: Academic Format: Magazine/Journal Subject: Health; Health care industry Copyright: COPYRIGHT 2011 Association for Perioperative Practice ISSN: 1750-4589
Issue: Date: August, 2011 Source Volume: 21 Source Issue: 8
Product: Product Code: 2834310 Anticoagulant Preparations NAICS Code: 325412 Pharmaceutical Preparation Manufacturing SIC Code: 2833 Medicinals and botanicals; 2834 Pharmaceutical preparations
Geographic: Geographic Scope: United Kingdom Geographic Code: 4EUUK United Kingdom
Accession Number: 272168034
Full Text: The management of perioperative anticoagulation is becoming an increasingly important surgical dilemma as the number of people requiring oral anticoagulation therapy rises. Vital to the management of this is an understanding of the risk of a perioperative thromboembolic event from inadequate anticoagulation versus the risk of excessive bleeding from anticoagulation. Both thromboemboli and excessive bleeding can cause significant morbidity and mortality, and also have significant implications on resources.

Oral anticoagulation therapy, commonly warfarin in the UK, is usually given for atrial fibrillation, venous thromboembolism, mechanical heart valves and thrombophilia states such as patients with antiphospholipid antibody syndrome, antithrombion III deficiency, and protein C and protein S deficiency. Those taking oral anticoagulation may be at risk of having a thromboembolic event if this therapy is stopped preoperatively without any cover during the perioperative period. Unfractionated intravenous heparin (UFH) and subcutaneous low molecular weight heparin (LMWH) are commonly used perioperative anticoagulation agents; they are also used in the intensive care setting and in medical patients. The problem that perioperative teams encounter is that there is no agreement on the optimal perioperative anticoagulation management of patients receiving oral anticoagulants, partly due to the individuality of each case. The perioperative team needs to be guided by haematology departments who are involved with the care of the patient.

How anticoagulants work

The coagulation cascade is part of a series of events that leads to haemostasis after a vascular injury. It is illustrated in Figure 1. With a vascular injury there is exposure of sub-endothelial tissue factor and collagen, as well as vasoconstriction. A platelet plug then forms at the site of injury, as a result of platelet adherence and aggregation to the sub-endothelial collagen. Then the coagulation cascade is activated with fibrin production which acts to stabilise the platelet plug. There are four main groups of anticoagulants as described below.

Warfarin

This class of drugs works by blocking the synthesis of the vitamin K-dependent factors. The fat soluble vitamin K, absorbed in the small intestine, is involved in the production of factors II, VII, protein C and protein S that are involved in the extrinsic pathway of the coagulation cascade (Figure 1). The effectiveness of warfarin is monitored by the prothrombin time (PT), measured in seconds, and this is generally expressed as an international normalised ratio (INR). This ratio should be around 1.0 in patients not on oral anticoagulants and without any coagulopathy. In patients at risk of thromboemboli, the ratio generally needs to be kept between 2.0 and 3.5 depending on the indications for anticoagulation.

[FIGURE 1 OMITTED]

Unfractionated heparin

Unfractionated heparin (UFH) acts by binding to antithrombin III and activating it, which in turn inactivates thrombin, as well as factors VIIa, IXa, Xa and XIa. These factors are primarily involved in the intrinsic pathway of the coagulation cascade (Figure 1). This results in reduced fibrin formation. The use of UFH requires monitoring of the therapeutic level by measuring the activated partial thromboplastin time (aPTT) in seconds. This too can be expressed as a ratio to enable better monitoring. UFH non-specifically binds to a number of proteins and cells, such as macrophages and endothelial cells. This property limits its effect, which can be both variable and unpredictable. UFH has a relatively short half life of between thirty minutes and an hour. It can be used in patients with renal impairment as it is cleared primarily by the reticuloendothelial system. It needs to be administered intravenously and requires frequent monitoring. As the clearance is relatively fast, the therapeutic level can be easily and frequently adjusted (Arbit et al 2006). It can be reversed using protamine sulphate and 1 mg of protamine neutralises approximately 100 units of UFH.

Low molecular weight heparin

Low molecular weight heparin (LMWH) is a class of heparin produced by controlled depolymerisation of unfractionated heparin. This preparation has become more popular than UFH due to its more predictable pharmokinetic profile. The actions of LMWH have greater predictability and reliability than those of UFH due to substantially less non-specific binding to proteins and cells. LMWH can be administered subcutaneously and does not require laboratory monitoring (Arbit el 2006). LMWH has a half life of between four to six hours which is longer than UFH. However, this does vary with renal function (Hirsh et al 1998). Due to the smaller size of LMWH, compared to UFH, it is unable to form the same complex with antithrombin III and thrombin, as described above. Consequently, there is minimal thrombin inhibition with LMWH. The anticoagulant effect of LMWH occurs almost entirely due to factor Xa inactivation and some factor IIa inhibition (Hirsh et al 1998). LMWH generally requires no monitoring, but in renal failure and pregnancy monitoring can be performed with anti-Xa levels. Although UFH and LMWH are frequently used for thromboprophylaxis in hospitalised surgical patients, these agents are not ideal for out-patient use due to their mode of administration. Some hospitals are able to arrange a service for patients to come to the wards for injections or for community nurses to administer LWMH at home.

New oral anticoagulants

Newer oral anticoagulants are continually being developed, and the main difference from warfarin is their direct modes of action against one clotting factor e.g. factor IIa in dabigatran and factor Xa in rivaroxaban (Harbrecht 2011). Although these new anticoagulants have much shorter half lives, specific antidotes are not available. These also benefit from oral bioavailability and the need for minimal or no monitoring (Knepper et al 2011). Although many study patients have already been treated, further information is required on the drugs' safety, efficacy and interactions with other drugs before they can be considered to replace the more established therapies (Harbrecht 2011). Whilst early studies have shown dabigatran to be comparable to LMWH with regards to safety and prevention of venous thromboembolism, further information is required to assess the efficacy and safety balance of a range of doses (Eriksson at al 2005). Another direct thrombin inhibitor, ximelagatran, did not show advantages over other anticoagulants and it was withdrawn from the market. New drugs however are being developed (Lazo-Langner et al 2009).

Complications

A major disadvantage of both UFH and LMWH is that they are administered parenterally, which is a requirement due to the size and charge of the molecules. Other documented side-effects are bleeding, heparin induced thrombocytopenia, and osteoporosis. Their use is contraindicated in those with pre-existing thrombocytopenia, platelet defects, acute peptic ulcer disease, acute cerebrovascular injury, spinal anaesthesia and lumbar puncture (Arbit et al 2006). A meta-analysis performed by Rocha et al (2000) showed a significantly lower incidence of major bleeding with LMWH compared with UFH.

Heparin induced thrombocytopenia (HIT) is a well documented complication of heparin use, and is caused by platelet activating antibodies that recognise chemokine platelet factor 4 when it is bound to heparin (Warkentin et al 2007). Although it had previously been thought that LMWH use conferred a lower incidence of HIT, a meta-analysis by Morris et al (2007) failed to support this and showed no significant difference between the use of LMWH and UFH. This study however included medical as well as surgical patients. In studies looking at venous thromboprophylaxis in orthopaedic surgery, Warkentin et al (2003) and Walenga et al (2004) found a greater incidence of HIT in those using UFH compared to LMWH.

Indications for anticoagulants

The main reasons for patients being on warfarin are atrial fibrillation, arterial and venous thromboemboli and prosthetic heart valves. Atrial fibrillation is associated with an increased risk of strokes and thromboembolic complications especially if associated with risk factors including congestive cardiac failure, hypertension, age greater than 75 years, diabetes mellitus and a history of stroke or transient ischaemic attacks (Singer et al 2004). Patients who have had a recent arterial or venous thrombus are at a higher risk of a recurrent thromboembolism (Kearon & Hirsh 1997). The risks of thromboemboli in patients with prosthetic heart valves reduce significantly with anticoagulant therapy. Prosthetic valves in the mitral position have a greater risk of thrombus than aortic valves due to the increased vascular stasis. Older prostheses such as the caged-ball valves pose a greater risk than newer bileaflet valves (Cannegieter et al 1995).

Risk assessment

Perioperative anticoagulation planning should begin in the preoperative assessment clinic and should include input from the surgical, anaesthetic and haematology teams. NICE (2007) and SIGN (2002) have both published guidelines for perioperative thromboprophylaxis in surgical patients. However, these guidelines do not include management of patients who are already on oral anticoagulation. They do recommend the risk assessment of patients preoperatively. This is often done at the preoperative assessment clinic, but can also be done on admission by nurses or doctors. Although no specific risk assessment tool was recommended by NICE, there are tools available. Autar (2003) devised a Risk Assessment Scale for stratifying the risk of deep vein thrombosis in a patient as low, moderate or high risk. More recently, the Department of Health has also published a screening tool (DH 2008). Risk assessment, therefore, is an important guide to using the correct resources for the correct patient risk category. If alterations are to be made to a patient's perioperative anticoagulation, it is important to discuss these risks and benefits with them.

Management of perioperative anticoagulation

As with all surgical patients, mechanical adjuncts should be offered, such as graduated compression stockings from the point of admission, unless contraindicated (NICE 2007). A systematic review by Dunn & Turpie (2003) found that patients taking oral anticoagulation rarely suffered with major bleeding whilst undergoing dental procedures, arthrocentesis, cataract surgery, ureterorenoscopy, and upper endoscopy and colonoscopy with or without biopsy. Thus, for these procedures oral anticoagulants need not be ceased preoperatively, however the International Normalised Ratio (INR) must not be greater than 2.5 (Turna et al 2008). Low, intermediate and high risk procedures are outlined in Figure 2.

The majority of authors suggest that those patients at intermediate and high risk of a thromboembolic event should have the oral anticoagulant stopped four to five days preoperatively, and restarted postoperatively when the surgeon feels it is safe, with heparin administered whilst the INR is sub-therapeutic. Most surgical procedures can be performed safely if the INR is less than 1.5. The last preoperative dose of heparin should be no later than twelve hours prior to surgery with LMWH, and six hours before surgery with UFH. The heparin can be recommenced postoperatively once the surgeon agrees that it is safe to do so. The oral anticoagulant can be restarted on the evening of surgery, dependent on the surgeon's opinion of its safety, and the heparin is stopped once the INR is in therapeutic range. The general opinion is that in surgical procedures with moderate to low risk of postoperative bleeding the oral anticoagulant can be restarted on the evening of surgery, whilst in procedures with a high risk of bleeding it may be recommenced the next day depending on the risk of further bleeding.

[FIGURE 2 OMITTED]

Hewitt et al (1999) suggested that the use of LMWH had been observed to have advantages over the use of UFH in terms of safety and efficiency. It was found that the perioperative use of UFH was justified in those who had had an acute venous thromboembolic event within the last month. UFH use was also justified in the postoperative period if venous thromboembolic event occurred in the previous two to three months. However, the use of UFH was not justified, in light of the potential complications, in those who had had a venous thromboembolic event more than three months prior to surgery. Insertion of a vena caval filter may be considered if the patient is at high risk of either bleeding or a recurrent thromboembolic event, or if surgery is planned within two weeks of an acute venous thromboembolic event. Insertion should follow discussion with the haematologist and interventional radiologist. A temporary filter is preferable as it can be removed following the procedure.

Cheng et al (2009) looked at patients on oral anticoagulation therapy for mechanical heart valves undergoing pacemaker implantation. They found that excessive bleeding and haematoma formation was associated with preoperative cessation of oral anticoagulation less than three days before surgery and the use of heparin postoperatively. They came to the conclusion that oral anticoagulants should be stopped more than three days prior to surgery, with therapeutic LMWH bridging until twelve hours preoperatively, and oral anticoagulants restarted immediately after surgery without LMWH. It has been shown that if the INR is between 2.0 and 3.0, it falls to less than 1.5 within 4-5 days of the last dose (White et al 1995), but INR testing is recommended preoperatively. LMWH injections can commence thirty one or two days following the last warfarin dose without checking the INR.

If the patient has had an arterial thromboembolic event within a month of planned surgery, the surgery should be deferred beyond a month if possible due to the potential increased risk of a recurrent event (Hewitt et al 1999). In those patients who are at high risk of bleeding, LMWH is preferred to UFH, until the INR becomes therapeutic and the heparin can be ceased.

Some clinicians may consider antiplatelet drugs (e.g. aspirin) as thromboprophylaxis, as many patients are already on such therapy for secondary myocardial infarction and stroke prevention. Aspirin has been shown to reduce the risk of thromboemboli in patients, especially when used as an adjunct with heparin (APT 1994). However, the risk of operative bleeding is increased, albeit small. In addition, NICE (2007) have not recommended the use of antiplatelet drugs alone as prophylaxis.

A summary of management of perioperative anticoagulation is given in Figure 2. In brief, oral anticoagulants need not be stopped preoperatively in low risk procedures but should be stopped four to five days preoperatively for all other surgical procedures. The management following cessation of oral anticoagulants depends on the risk of thromboemboli; whether this is low, intermediate or high risk. Although LMWH can be given in low and intermediate risk patients, UFH should be given in high risk patients. The criteria for thromboembolism risk assessment are also outlined in Figure 2. The authors' hospital protocol coincides with the recommendations mentioned in this article. However, in other trusts, it is likely that there are other protocols specific to surgery-type that will take precedence over any other guidelines. There is also a mutual agreement between nursing staff and the surgical teams where an individual's anticoagulation regime is allowed to deviate from the guidelines; this again highlights patient-specific management. Nevertheless, liaising with the local haematology department in managing patients' anticoagulation is invaluable.

Emergency surgery

In emergency cases, the anticoagulation needs to be reversed. This can be achieved with prothrombin complex concentrate (PCC), fresh frozen plasma (FFP) or recombinant factor VII. PCC contains concentrated factors II, VII, IX and X. It can be administered rapidly in a smaller volume and avoids the need for blood group matching. The coagulation factors contained in it are more predictable. These agents however have a short half-life and require the simultaneous administration of vitamin K. Vitamin K can also be considered in cases where the INR remains high preoperatively despite the cessation of oral anticoagulants. Oral vitamin K administration offers similar efficacy and better safety than intravenous administration.

Conclusion

With increased experience with perioperative anticoagulation, the management of patients with significant risk of perioperative thromboembolic events will improve and become more precise. For medium and high risk invasive surgical procedures, oral anticoagulation needs to be ceased, however the use of UFH or LMWH depends on the individual case and the clinician's own experience. Of importance is that the period of time that the patient's INR is sub-therapeutic should be kept to a minimum in those at high risk of further thromboembolic events. There is limited information in literature to aid this decision process, thus further research studies are required to make an informed decision. More audits should be performed to correlate patients' demographics, management and outcome with regards to anticoagulation via local governance teams. Nevertheless, the best strategy for perioperative management of anticoagulation involves an individual assessment of the patient taking into account the procedure they are undergoing and the reasons for their anticoagulation, and closely liaising with the haematologists.

No competing interests declared

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Correspondence address: Wasim Khan, UCL Institute of Orthopaedics and Musculoskeletal Science, Royal National Orthopaedic Hospital, Stanmore, Middlesex, HA7 4LP. Email: wasimkhan@doctors.org.uk

About the authors

Baljinder Singh Dhinsa MBBS

Senior House Officer in Orthopaedics, UCL Institute of Orthopaedics and Musculoskeletal Science, Royal National Orthopaedic Hospital, Stanmore

Wasim Khan MBChB, MSc, MRCS, PhD

Academic Clinical Fellow, UCL Institute of Orthopaedic & Musculoskeletal Sciences, Royal National Orthopaedic Hospital, Stanmore

Hiteshkumar Tailor BSc

Medical Student, UCL Medical School, London
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