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Keywords:

  • low molecular weight heparin;
  • vitamin K antagonist therapy;
  • bridging;
  • anticoagulation;
  • surgical procedures

Summary

  1. Top of page
  2. Summary
  3. Bleeding risks
  4. Procedures that may require bridging therapy to be prescribed
  5. What is the risk of thromboembolism if oral anticoagulation is simply discontinued?
  6. What is the evidence for bridging therapy and do they relate to patient outcomes?
  7. Bridging anticoagulation
  8. Anticoagulant intensity of LMWH
  9. Risk of bleeding and proximity to surgery
  10. Clinical trials that will provide further direction
  11. Novel oral anticoagulants
  12. Experience of NOAC use during the peri-operative period
  13. Conclusion
  14. Author contributions
  15. References

For patients prescribed chronic vitamin K antagonist therapy requiring a surgical or invasive procedure, the question of whether or not to bridge and how to bridge is commonly encountered in clinical practice. Bridging anticoagulation has evolved over the years and the evidence base for current practice is deficient in many areas. Clinical trials currently being completed with conventional anticoagulants should help strengthen the evidence base for future practice. The availability of novel oral anticoagulants is a welcome addition, though their optimal management peri-procedure is yet to be determined. Prospective multi-centre controlled studies that can provide the evidence base for novel oral anticoagulant peri-procedural management are required.

Managing chronic oral anticoagulation therapy during an invasive procedure is commonly encountered within clinical practice. Estimates from North America suggest that this clinical scenario affects up to 250 000 patients each year (Douketis et al, 2012). With an increasing older population, more anticoagulant therapy is likely to be prescribed in the future, particularly when the use of risk stratification tools such as CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex Category) for stroke prevention in patients with atrial fibrillation (AF) are applied (Lip et al, 2010).

When patients require interruption of their chronic anticoagulant therapy, three factors need to be considered; (i) what are the specific risks to the patient if anticoagulant therapy is continued, (ii) what are the risks to the patient, if anticoagulant therapy is discontinued and, (iii) what is the safety and effectiveness of alternative anticoagulant regimens (so called bridging anticoagulation), if oral anticoagulation is discontinued and bridging anticoagulation is prescribed (Ansell, 2003). Due to the significant number of variables involved, and a change in first-line heparin agents from unfractionated heparin (UFH) to low molecular weight heparin (LMWH) over the last 20 years, the evidence base for current bridging practice is deficient in many areas. Experts from the anticoagulation community have reviewed known information and written excellent reviews that provide clinicians with practical direction (Kearon & Hirsh, 1997; Dunn & Turpie, 2003; Spyropoulos, 2010; Douketis, 2011; Gallego et al, 2012; Baron et al, 2013).

The novel oral anticoagulants (NOAC), apixaban, dabigatran and rivaroxaban, provide a welcome addition to the anticoagulation treatment basket. Whilst experience exists regarding the use of NOAC therapy during the post-operative period following elective orthopaedic surgery, there is little published experience on the use of these agents during the peri-operative period. In coming years, undoubtedly they will alter how anticoagulant therapy is managed peri-procedurally in the medium- to long-term (Levy et al, 2010).

The aim of this review is to describe current best practice in managing chronic oral anticoagulation in patients requiring an elective surgical procedure and explores how anticoagulation bridging is likely to alter with the availability of NOAC therapy.

Bleeding risks

  1. Top of page
  2. Summary
  3. Bleeding risks
  4. Procedures that may require bridging therapy to be prescribed
  5. What is the risk of thromboembolism if oral anticoagulation is simply discontinued?
  6. What is the evidence for bridging therapy and do they relate to patient outcomes?
  7. Bridging anticoagulation
  8. Anticoagulant intensity of LMWH
  9. Risk of bleeding and proximity to surgery
  10. Clinical trials that will provide further direction
  11. Novel oral anticoagulants
  12. Experience of NOAC use during the peri-operative period
  13. Conclusion
  14. Author contributions
  15. References

If vitamin K antagonist (VKA) therapy does not require interruption, i.e. when the bleeding risk associated with a procedure is low, then the issue of managing oral anticoagulation is removed. The American College of Chest Physicians (ACCP) currently estimate that 15–20% of all VKA-treated patients assessed for peri-operative anticoagulation require minor dental, dermatological or ophthalmological procedures, which fall into this category (Douketis et al, 2012). Table 1 lists these procedures and briefly describes the relevant issues.

Table 1. Invasive procedures where the bleeding risk is low and oral anticoagulation can often be continued.
ProcedureComments
Minor dental, e.g. tooth extractions and endodontic (root canal)Current UK guidance states that vitamin K antagonist therapy can safely be continued (National Patient Safety Agency, 2007; Perry et al, 2007). A pro-haemostatic agent (e.g. tranexamic acid (5–10%, 5 ml 3–4 times a day), starting 1 d before the procedure and for 1–2 d after the procedure, was found to be associated with a low (<5%) risk of clinically relevant non-major bleeding (Douketis et al, 2012))
Dermatological, e.g. excision of basal and squamous cell skin cancers, actinic keratoses and premalignant or cancerous skin neviThe reported incidence of bleeding complications appears to be low (<5%) when oral anticoagulation is continued
CataractProspective cohort studies report an incidence of clinically relevant bleeding of <3% when oral anticoagulation therapy is continued (Robinson & Nylander, 1989; Roberts et al, 1991; Katz et al, 2003)
Diagnostic oesophagogastroduodenoscopy or colonoscopiesWhere there is no plan to biopsy

Often, these procedures are associated with blood loss that is self-limiting or that can be controlled with local haemostatic measures and oral anticoagulation can simply be continued. However, any bleeding that does occur may cause significant anxiety to the patient and this should be considered in the plan that is formulated for a specific patient. Furthermore, not all dental, dermatological and ophthalmological procedures are associated with self-limiting bleeding and depending on the risk of thromboembolism, bridging anticoagulation may be indicated. Procedures that can be considered in the higher bleeding risk category include reconstructive dental or plastic surgery or vitreo-retinal surgery (Douketis et al, 2012).

Procedures that may require bridging therapy to be prescribed

  1. Top of page
  2. Summary
  3. Bleeding risks
  4. Procedures that may require bridging therapy to be prescribed
  5. What is the risk of thromboembolism if oral anticoagulation is simply discontinued?
  6. What is the evidence for bridging therapy and do they relate to patient outcomes?
  7. Bridging anticoagulation
  8. Anticoagulant intensity of LMWH
  9. Risk of bleeding and proximity to surgery
  10. Clinical trials that will provide further direction
  11. Novel oral anticoagulants
  12. Experience of NOAC use during the peri-operative period
  13. Conclusion
  14. Author contributions
  15. References

For the majority of surgical procedures the risk of bleeding and other complications whilst remaining on VKA therapy is considered significant and thus bridging therapy might be considered, depending on the individual patient's thromboembolic risk. Such procedures include (Douketis et al, 2012):

  1. Surgery of extensive tissue injury (e.g. cancer, joint arthroplasty, reconstructive plastic surgery; Patterson et al, 1989; Hoy et al, 2006)
  2. Surgery in highly vascular organs, i.e. the liver, spleen and kidney
  3. Colonic polyp resection, where bleeding may occur at the transected stalk (Sorbi et al, 2000)
  4. Bowel resection in which bleeding may occur at the bowel anastomosis site
  5. Cardiac, intracranial or spinal surgery, where a bleed can have significant consequences (Lazio & Simard, 1999; Jones et al, 2002; Mangano, 2002)
  6. Pacemaker or implantable cardioverter – defibrillator device implantation, where the risk of haematoma development is significant (Jamula et al, 2009; Robinson et al, 2009; Tischenko et al, 2009; Chow et al, 2010). However, recent results from the BRUISE CONTROL study demonstrated that continuing oral VKA therapy is superior to using UFH or LMWH, in the context of pocket haematoma formation (Birnie et al, 2013)
  7. Procedures associated with the urogenital tract, where endogenous urokinase is thought to promote bleeding (Watson et al, 1990; Nielsen et al, 1997; Ihezue et al, 2005). Such procedures include transurethral prostate resection, bladder resection or tumour ablation, nephrectomy and kidney biopsy

What is the risk of thromboembolism if oral anticoagulation is simply discontinued?

  1. Top of page
  2. Summary
  3. Bleeding risks
  4. Procedures that may require bridging therapy to be prescribed
  5. What is the risk of thromboembolism if oral anticoagulation is simply discontinued?
  6. What is the evidence for bridging therapy and do they relate to patient outcomes?
  7. Bridging anticoagulation
  8. Anticoagulant intensity of LMWH
  9. Risk of bleeding and proximity to surgery
  10. Clinical trials that will provide further direction
  11. Novel oral anticoagulants
  12. Experience of NOAC use during the peri-operative period
  13. Conclusion
  14. Author contributions
  15. References

The published estimates for risk of thromboembolism in patients who discontinue VKA therapy for a surgical procedure are derived indirectly from patients outside of the peri-operative setting and involve patients with mechanical valves (Cannegieter et al, 1994; Hering et al, 2005; Tominaga et al, 2005), chronic AF (Hart et al, 1999; Pearce et al, 2000; Gage et al, 2001, 2004) or venous thromboembolism (VTE; Douketis et al, 2000; White, 2003). These estimates are based on patients who were either not receiving anticoagulation or receiving sub-optimal therapy (e.g. aspirin). Using this information, the ACCP guidelines risk stratify patients according to being high (>10% annual risk of thromboembolism), moderate (5–10% risk of thromboembolism) or low risk (<5% annual risk of thromboembolism). This risk stratification schema is summarized in Table 2.

Table 2. ACCP risk stratification of patients prescribed oral anticoagulation therapy according to anticoagulation indication (Douketis et al, 2012).
Thromboembolic riskMechanical heart valveAtrial fibrillationVenous thromboembolism
  1. CHADS2=congestive heart failure, hypertension, age ≥75 years, diabetes mellitus and Stroke or TIA (Gage et al, 2001).

  2. ACCP, American College of Chest Physicians; TIA, transient ischaemic attack; AF, atrial fibrillation; VTE, venous thromboembolism.

  3. Adapted with permission from the American College of Chest Physicians. Douketis et al 2012, Perioperative Management of Antithrombotic Therapy Perioperative Management of Antithrombotic Therapy Antithrombotic Therapy and Prevention of Thrombosis, 9th ed, American College of Chest Physicians Evidence, Northbrook, Copyright © 2012.

High (>10% annual risk)

Any mitral valve prosthesis

Any caged-ball or tilting disk aortic valve prosthesis

Recent (within 6 months) stroke or TIA

CHADS2 score of 5 or 6

Recent (within 3 months) stroke or TIA

Rheumatic valvular heart disease

Recent (within 3 months) VTE

Severe thrombophilia (e.g. PS, PC, Antithrombin deficiency, antiphosphoshoplipid antibodies, multiple abnormalities)

Moderate (5–10% annual risk)Bi-leaflet aortic valve prosthesis and one or more of the following risk factors: AF, prior stroke or TIA, hypertension, diabetes, congestive heart failure, age >75 yearsCHADS2 score of 3 or 4 (assuming no prior stroke or TIA)

VTE within the past 3–12 months

Non-severe thrombophilia [e.g. heterozygous F5 R506Q (factor V Leiden) or F2 G20210A (prothrombin gene mutation)]

Recurrent VTE

Active cancer (treated within 6 months or palliative)

Low (<5% annual risk)Bi-leaflet aortic valve prosthesis without atrial fibrillation and no other risk factors for strokeCHADS2 score of 0 or 2 (assuming no prior stroke or TIA)VTE >12 months previous and no other risk factors

Few studies have quantified the risk of thromboembolism prospectively. One of note is the study by Garcia et al (2008), which reported on 1293 episodes of warfarin therapy interruptions in 1024 patients. The main indications for warfarin therapy in their cohort of patients were AF (53·7%), VTE (14·1%) and mechanical prosthetic heart valves (12·9%). The common procedures undertaken were minor (colonoscopy and oral and ophthalmic surgeries). Bridging with UFH or a LMWH was used in only 8·3% of cases, with patients with prosthetic heart valves in-situ more likely to be prescribed bridging therapy. Though the results of this study were published in 2008, the study cohort actually had their procedures completed between 2000 and 2002 and, overall, the authors reported seven patients (0·7% 95% confidence interval (CI): 0·3–1·4%) who experienced post-procedural thromboembolism within 30 d, of which none had received bridging therapy and none were in-patients in whom the primary indication for anticoagulation was a prosthetic mechanical heart valve. In this study, six patients experienced major bleeding (0·6% 95% CI: 0·2–1·3%); 1 spontaneous subdural, four gastrointestinal after colonoscopy and one soft tissue associated with compartment syndrome. Although only 8·6% of the total population received bridging anticoagulation, four of the six major bleeding events occurred in this group, suggestive of an association between bridging anticoagulation and bleeding. The authors of this study concluded that for many patients who undergo a minor outpatient intervention, a brief peri-procedural interruption of warfarin therapy is associated with a low risk of thromboembolism.

It is important to note that, although the ACCP risk stratification schema is helpful in stratifying patients according to their thromboembolic risk, individual patient factors need to be considered when this schema is interpreted. For example, a patient with a prior stroke or transient ischaemic attack (TIA) and one additional risk factor for stroke, would have a CHADS2 (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke or TIA) score of 3, placing them in the moderate risk category according to the ACCP guidelines, although many clinicians might consider such a patient as high risk, if anticoagulant therapy was simply discontinued (Douketis et al, 2012).

What is the evidence for bridging therapy and do they relate to patient outcomes?

  1. Top of page
  2. Summary
  3. Bleeding risks
  4. Procedures that may require bridging therapy to be prescribed
  5. What is the risk of thromboembolism if oral anticoagulation is simply discontinued?
  6. What is the evidence for bridging therapy and do they relate to patient outcomes?
  7. Bridging anticoagulation
  8. Anticoagulant intensity of LMWH
  9. Risk of bleeding and proximity to surgery
  10. Clinical trials that will provide further direction
  11. Novel oral anticoagulants
  12. Experience of NOAC use during the peri-operative period
  13. Conclusion
  14. Author contributions
  15. References

During the last 10 years, two large analyses have been published which address this question; a systematic review (Dunn & Turpie, 2003) and more recently, a systematic review and meta-analysis (Siegal et al, 2012). Dunn and Turpie's analysis reviewed published information of anticoagulation management in 1868 patients undergoing a surgical or invasive procedure. Twenty-nine thromboembolic events were reported from these studies, 1·6% (95% CI: 1·0–2·1%), including seven strokes [0·4% (95% CI: 0·0–0·7%)]. Their analysis did not focus on bleeding outcomes, due to the heterogeneous nature of the population studied (one of its key limitations). However, when the thromboembolic events were analysed according to the specific management strategy employed, the following was found; 0·4% (one of 237) for continuation of oral anticoagulation, 0·6% (six of 996) for discontinuation of oral anticoagulation without administering intravenous UFH, 0% (0 of 166) for discontinuation of oral anticoagulation with administration of intravenous UFH, 0·6% (one of 180) for discontinuation of oral anticoagulation with administration of LMWH and, alarmingly, 8% (21 of 263) for when there was an unclear or unspecified strategy. In their analysis the authors described that, generally, the reports they reviewed were of a poor quality, and there were no identified randomized controlled trials. Within the reports they analysed, the sample sizes were small, often there was no control group and the timing of administration and discontinuation of anticoagulation was not described (Dunn & Turpie, 2003).

More recently, Siegal et al (2012) published their meta-analysis of 34 studies involving >12 000 patients, assessing systematically both the thromboembolism and bleeding events in patients undergoing elective surgical and invasive procedures. The large patient numbers involved in this study provides a valuable insight. Thromboembolic events occurred in 73 of the 7118 bridged patients (pooled incidence, 0·9%; 95% CI: 0–3·4) compared to 32 of 5160 non-bridged patients (pooled incidence, 0·6%; 95% CI: 0–1·2), which is an interesting finding in itself. Bridging was associated with an increased risk of overall bleeding in 13 studies (odds ratio, 5·40; 95% CI: 3·00–9·74) and major bleeding in five studies (odds ratio, 3·60; 95% CI: 1·52–8·50) when comparing bridged and non-bridged patients. Furthermore, the analysis found that therapeutic doses of LMWH were associated with an increased risk of bleeding compared to prophylactic or intermediate dose LMWH, with no difference in the rate of thromboembolic events. The major limitations of Siegel's meta-analysis is the heterogeneity of the data evaluated, including the different bridging strategies employed, the different procedures undertaken (associated with different bleeding risks) and most importantly, the meta-analysis was unable to estimate the baseline risk for thromboembolism or bleeding and the relationship with outcomes, due to the different indications for anticoagulation and the differing use of the term high risk in each study. Acknowledging the limitations of this meta-analysis, it demonstrates a sign, which emerges when therapeutic doses of LMWH are used: there is more chance of post-procedural bleeding complications and that LMWH should be used cautiously, particularly immediately following the procedure.

Bridging anticoagulation

  1. Top of page
  2. Summary
  3. Bleeding risks
  4. Procedures that may require bridging therapy to be prescribed
  5. What is the risk of thromboembolism if oral anticoagulation is simply discontinued?
  6. What is the evidence for bridging therapy and do they relate to patient outcomes?
  7. Bridging anticoagulation
  8. Anticoagulant intensity of LMWH
  9. Risk of bleeding and proximity to surgery
  10. Clinical trials that will provide further direction
  11. Novel oral anticoagulants
  12. Experience of NOAC use during the peri-operative period
  13. Conclusion
  14. Author contributions
  15. References

Historically, intravenous UFH was the most commonly used bridging regimen when peri-procedural anticoagulation was required. Reports from the 1970's provide an insight into how patients with mechanical heart valves were managed with UFH (Katholi et al, 1976, 1978). With the advent and increased use of LMWHs during the 1990s, coupled with the increase in day case procedures, LMWHs have become the main agents of choice for bridging, due to their predictable pharmacokinetic profile, ease of administration (patients self-administering at home) and reduced side-effect profile. Indeed, in an expert review during the 1990s (Kearon & Hirsh, 1997), all the bridging strategies suggested involved the use of either subcutaneous or intravenous UFH. Today UFH is rarely used, reserved for patients where an anticoagulant with a short half-life is required. Cost has also been a key driver. The costs associated with admitting a patient to hospital to receive an UFH infusion has meant that, with time and clinical experience, the balance has tipped in favour of LMWH. In their retrospective study, Spyropoulos et al (2004) reviewed the medical records of patients who had received in-patient intravenous UFH and compared the outcomes and costs to those patients who received out-patient LMWH. Though the patient numbers evaluated in this study were small (n = 66), the authors report that the mean healthcare costs during the peri-procedural period were significantly lower in patients bridged with LMWH compared to UFH. The cost savings were made through the obvious avoidance of an in-patient stay, with the authors reporting no difference in clinical adverse events. In clinical practice today, the skill of maintaining a therapeutic UFH infusion is continually being lost on general medical and surgical wards, and thus LMWH in most cases will be the preferred bridging agent, when required.

What are the outcomes of patients who are bridged with UFH compared to those bridged with LMWH? The multi-centre REGIMEN registry helps to provide an answer to this question. This prospective observational registry from North America enrolled 901 eligible patients on long-term oral anticoagulation who required heparin bridging therapy (Spyropoulos et al, 2006). The study population comprised a mean age of 65·7 years, with the majority of patients having had an arterial indication for chronic oral anticoagulation therapy (either AF or a mechanical heart valve in-situ). Clinical outcomes were compared between patients who received either UFH alone (n = 180) or LMWH alone (n = 721). Treatment doses were prescribed in 129 (72%) of the UFH group and 550 (76%) of the LMWH group. For those prescribed LMWH, the majority received enoxaparin (83%), with LMWH prescribed as a twice-daily treatment dose represented in 80% of these cases. Table 3 summarizes the event rate attributed to both groups.

Table 3. Adverse events suffered by patients in the REGIMEN registry (Spyropoulos et al, 2006).
EventUFH (n = 164)LMWH (n = 668) P-value
  1. UFH, unfractionated heparin; LMWH, low molecular weight heparin.

  2. a

    One cardiac valvular or mural thrombosis, one intracranial event, one transient ischaemic attack (TIA), one peripheral arterial event.

  3. b

    Two intracranial events and two TIAs.

  4. c

    Two deep vein thromboses.

  5. Reproduced with permission from John Wiley and Sons. Spyropoulos et al 2006, Clinical outcomes with unfractionated heparin or low-molecular weight heparin as bridging therapy in patients on long-term oral anticoagulants: the REGIMEN registry1, Journal of Thrombosis and Haemostasis, 4: 1246-52. Copyright © 2006.

Any adverse event, n (%)28 (17·1%)108 (16·2%)0·81
Arterial/venous thromboembolism, major bleed, or death13 (7·9%)28 (4·2%)0·07
Adverse events, n (%)
Arterial thromboembolism4a (2·4)4b (0·6)
Venous thromboembolism0 (0)2c (0·3)
Major bleed9 (5·5)22 (3·3)0·25
Minor bleed15 (9·1)80 (12·0)0·34
Thrombocytopenia2 (1·2)3 (0·4)
Death2 (1·2)4 (0·6)

Those receiving LMWH appeared to fare better than those in the UFH group, though there were significantly more patients in the LMWH group. The strengths of this study include its multi-centre nature, the number of patients included and the fact that a significant proportion of patients included were at high risk of bleeding (11%). In this registry, the authors observed that when bridging heparin is prescribed, it is often prescribed as treatment doses over prophylactic doses (Spyropoulos et al, 2006).

Anticoagulant intensity of LMWH

  1. Top of page
  2. Summary
  3. Bleeding risks
  4. Procedures that may require bridging therapy to be prescribed
  5. What is the risk of thromboembolism if oral anticoagulation is simply discontinued?
  6. What is the evidence for bridging therapy and do they relate to patient outcomes?
  7. Bridging anticoagulation
  8. Anticoagulant intensity of LMWH
  9. Risk of bleeding and proximity to surgery
  10. Clinical trials that will provide further direction
  11. Novel oral anticoagulants
  12. Experience of NOAC use during the peri-operative period
  13. Conclusion
  14. Author contributions
  15. References

Accepting that LMWH is the current preferred bridging agent when bridging is required, what dose should be prescribed? Data are lacking that direct the intensity of LMWH that should be used for the various indications and has therefore been derived indirectly. Use of LMWH as bridging therapy for patients in AF is incomplete; however, one would predict a similar effect to warfarin with the use of therapeutic dose LMWH. Data using prophylactic dose LMWH for AF is lacking. For preventing VTE, there is, of course, a large pool of robust evidence that demonstrates the efficacy of prophylactic doses of LMWH, particularly post-operatively, when evidence from the elective orthopaedic surgical population is considered (Falck-Ytter et al, 2012).

Risk of bleeding and proximity to surgery

  1. Top of page
  2. Summary
  3. Bleeding risks
  4. Procedures that may require bridging therapy to be prescribed
  5. What is the risk of thromboembolism if oral anticoagulation is simply discontinued?
  6. What is the evidence for bridging therapy and do they relate to patient outcomes?
  7. Bridging anticoagulation
  8. Anticoagulant intensity of LMWH
  9. Risk of bleeding and proximity to surgery
  10. Clinical trials that will provide further direction
  11. Novel oral anticoagulants
  12. Experience of NOAC use during the peri-operative period
  13. Conclusion
  14. Author contributions
  15. References

Evidence published from VTE prophylaxis data suggests that the closer to surgery an anticoagulant is administered, the more likely there is to be bleeding. Unsurprisingly, bleeding is found to be greater when the first dose is given 4–8 h post-operatively and is lower when given at an intermediate interval (12–24 h post-operatively) and lowest when there is a delay of >24 h post-operatively before the first dose is administered (Douketis et al, 2012).

Current ACCP guidelines suggest (Douketis et al, 2012):

  1. LMWH or UFH should not be resumed at a fixed time without a specific review of the bleeding risk and whether adequate haemostasis has been achieved
  2. If therapeutic dose bridging is being used, its initiation should be delayed 48–72 h after surgery, to ensure adequate haemostasis has been achieved

The ACCP guidelines do not specify how to manage patients immediately post-operatively, if the patients' thromboembolic risk is high. Our own practice is to give prophylactic doses of LMWH (once or twice a day – depending on the bleeding risk associated with the procedure) post-operatively, until therapeutic dose LMWH can safely be resumed after 1–2 d.

A Canadian collaborative (Kovacs et al, 2004) published the findings of their prospective multi-centre study of patients requiring interruption of their warfarin therapy and at high risk of arterial embolism (classed as prosthetic valves or AF plus a major risk factor for cardiac embolism, defined as previous stroke or TIA, hypertension, diabetes, age >75 years or left ventricular dysfunction). In their study, warfarin was withheld for 5 d pre-operatively, LMWH was begun 3 d pre-operatively and continued for 4 d post-operatively. Dalteparin was employed pre-operatively, and was prescribed as at a dose of 200 iu/kg sc (maximum, 18 000 iu) on the morning of the third and second days before the procedure. On the morning before surgery, a dalteparin dose of 100 iu/kg (maximum, 9000 iu) was used. No LMWH was given the day of surgery. The day after surgery, patients resumed their preoperative dosage of warfarin and started once-daily dalteparin. This was administered at a dose of 200 iu/kg daily or at a set dose of 5000 iu daily if the physician judged that the patient was at high risk for postoperative bleeding. LMWH was continued for at least 4 d and until the International Normalized Ratio (INR) was ≥1·9.

Patients were then followed for up to 3 months for assessment of thromboembolism and bleeding. In total, 224 patients were enrolled and eight episodes of thromboembolism occurred, of which two were judged to be due to cardioembolism (0·9%; 95% CI: 0·2–3·2). The authors also reported 15 episodes of major bleeding (6·7%; 95% CI: 4·1–10·8); 8 occurred intra-operatively or early post-operatively before dalteparin had been restarted, five occurred in the first week after starting daletparin and two occurred after dalteparin had been stopped (Kovacs et al, 2004). The authors concluded that it is feasible to bridge with LMWH, although they acknowledged that the optimal approach could not be defined from their study (Kovacs et al, 2004).

Halbritter et al (2005) published the findings of their prospective registry of 311 episodes of bridging anticoagulation from Germany. In their registry, 268 patients were evaluated and underwent 311 bridging episodes. The procedures the patients underwent ranged from catheter-based interventions (23%), pacemaker (22%), endoscopy or biopsy (22%), general surgery (10%), orthopaedic surgery (10%) and cardiovascular surgery (1%). LMWH was employed as bridging therapy in 92% of cases, with 41% bridged with full-dose LMWH. Thromboembolic events occurred in 1·3% of cases (95% CI: 0·4–3·2%); three were post-operative deep vein thrombosis and one was a post-procedural stroke. Six cases of bleeding occurred in the early post-procedural period, which the authors attributed to anticoagulation therapy. Whilst specific details on the cases that experienced complications is lacking in their short report, i.e. what the specific thromboembolic risk was in the patients who suffered from an event, their real-world registry provides valuable information.

Another study evaluated the incidence of major bleeding during the peri-operative administration of treatment dose enoxaparin (Dunn et al, 2007). This study comprised 260 patients from 24 North American centres. In all patients, warfarin was withheld and once daily subcutaneous doses of enoxaparin (1·5 mg/kg once daily) was given pre-operatively (on the morning of days -3 to -1). Post-operatively, enoxaparin was re-started 12–24 h post-procedure, provided there was no active surgical bleeding. Major bleeding was observed in nine out of the 260 patients (3·5%, 95% CI: 1·6–6·5). Five thromboembolic events occurred in the cohort, 4 of these were arterial events in 176 patients with AF (2·3%, 95% CI: 0·6–5·7) and one was a venous event in the 96 patients with deep vein thrombosis (1·0%, 95% CI: 0·03–5·7). The authors conclude that once daily treatment doses of enoxaparin have a low incidence of bleeding for patients undergoing invasive procedures and minor surgeries.

An Italian study (Malato et al, 2009) tested the efficacy and safety of fixed doses of LMWH in patients requiring interruption of their chronic oral anticoagulant therapy. This study enrolled patients who discontinued oral anticoagulation for 5 d ± 1 d. In those deemed at low risk of thrombosis, LMWH was given as prophylactic doses of nadroparin (3800 iu) or enoxaparin (4000 iu), once a day, until the night before the procedure. Patients deemed to be at high risk received intermediate doses of LMWH, 3800 iu twice a day and 4000 iu twice a day, of nadroparin and enoxaparin, respectively. Post-operatively, LMWH was reinitiated 12 h after the procedure, with oral anticoagulation being re-commenced the day after the procedure. The primary endpoint of this study was the incidence of thromboembolism and major bleeding, and patients were followed for 30 d post-procedure. A total of 328 patients were enrolled to the study (55·4% were deemed low-risk and 44·6% were deemed high risk). Thromboembolic events occurred in 6 patients (1·8%, 95% CI: 0·4–3·2), five of these patients were in the high-risk group. Major bleeding occurred in seven patients (2·1%, 95% CI: 0·6–3·6), 6 patients belonged to the high-risk group.

It is clear to see that the studies published to date are observational, with apparent bias and a lack of uniform definitions for procedure-related thromboembolic and bleeding risks, and a wide variation in the time frame for capturing these events. This has largely made it difficult to define the best course of action in the different clinical scenarios. To address this issue, the International Society of Thrombosis and Haemostasis (ISTH) subcommittee on the control of anticoagulation have recently produced recommendations for the reporting of future studies in this area, with a particular emphasis on those patients requiring anticoagulation for arterial indications (Spyropoulos et al, 2012). They recommend:

  1. A standardized description of the patients thromboembolic risk based on the ACCP risk stratification
  2. A general description of the type of surgery/intervention being conducted
  3. A detailed description of antithrombotic therapy used, both pre- and post-operatively, and this should also consider the NOAC
  4. The primary outcome of arterial thromboembolism should be defined as stroke, TIA, and systemic embolism. ST elevation myocardial infarction and acute coronary syndromes may be considered as secondary outcomes
  5. The ISTH surgical definitions of major bleeding (Schulman & Kearon, 2005) should be used
  6. A 30-d post-procedural follow-up period should be used to report events, including major bleeding, which should be linked to a specific patient group as per thromboembolic risk and procedure as per bleed risk

Clearly, these aforementioned recommendations would be valuable considerations when collating future information on peri-procedural bridging therapy. Our guidelines for elective peri-procedural anticoagulation at King's College Hospital are outlined in Table 4.

Table 4. Guidelines applied at King's College Hospital for oral VKA therapy.
Time lineAction
  1. The information in the table assumes a normal renal function for LMWH dosing and no clinically relevant post-operative bleeding.

10–14 d pre-procedurePatient risk assessed for the need for bridging therapy and a specific plan formulated for patient, depending on their specific circumstances
4–5 d pre-procedurePatient stops oral anticoagulation
Days 3–1 pre-procedureIf patient requires pre-procedure bridging, patients injects low molecular weight heparin (LMWH; either treatment or prophylactic doses) depending on thromboembolic risk. Patient specifically instructed to inject LMWH in the morning
Morning of the procedureOmit LMWH (if injecting pre-operatively)
Evening of the procedureIf no bleeding and procedure bleeding risk low, consider re-starting oral vitamin K antagonist therapy. If high risk of thromboembolism, administration of a prophylactic dose of LMWH is considered.
Day 1 and 2 post-procedureTwice-daily prophylactic doses of LMWH with oral anticoagulation if high risk of thromboembolism, otherwise once daily prophylactic dose of LMWH, if thromboembolism risk is moderate. If thromboembolism risk is low, then no LMWH, oral anticoagulation simply re-started
Day 3 + post-procedureBack to treatment dose LMWH (if high risk of thromboembolism) and continue oral anticoagulation until INR therapeutic is reached

Clinical trials that will provide further direction

  1. Top of page
  2. Summary
  3. Bleeding risks
  4. Procedures that may require bridging therapy to be prescribed
  5. What is the risk of thromboembolism if oral anticoagulation is simply discontinued?
  6. What is the evidence for bridging therapy and do they relate to patient outcomes?
  7. Bridging anticoagulation
  8. Anticoagulant intensity of LMWH
  9. Risk of bleeding and proximity to surgery
  10. Clinical trials that will provide further direction
  11. Novel oral anticoagulants
  12. Experience of NOAC use during the peri-operative period
  13. Conclusion
  14. Author contributions
  15. References

Two clinical trials are underway to try and address some of the uncertainties in managing peri-procedural anticoagulation for patients prescribed oral VKA therapy. The PERIOP2 study (clinicaltrials.gov: NCT00432796) was completed in March 2013 and from which the results are eagerly awaited, is a randomized double-blind controlled trial across 11 teaching hospitals in Canada. The study aimed to enrol 1773 patients with either prosthetic heart valves or patients with AF with a major risk factor for stroke, on long-term anticoagulation requiring a surgical procedure that necessitated cessation of their anticoagulant therapy. In this study, all patients stopped warfarin 5 d prior to the procedure. Dalteparin was then commenced 3 d prior to the procedure at a dose of 200 iu/kg daily, except on the day prior to the procedure when a dose of 100 iu/kg was given. Warfarin was resumed the evening of the procedure. Dalteparin or placebo (starting the morning after the procedure), was started at a dose of 5000 iu daily or placebo in those considered at high bleeding risk or 200 iu/kg daily or placebo in those considered at low bleeding risk. The study's primary outcome is the frequency of major thromboembolism over a 90-d follow-up period following randomization. Secondary outcomes include major bleeding.

The BRIDGE study (clinicaltrials.gov: NCT00786474), is a randomized double-blind trial evaluating the outcomes in patients who stop anticoagulation therapy temporarily for a surgical procedure and receive either dalteparin or placebo injections twice a day, as part of their peri-operative anticoagulation, 3 d prior to the procedure and for 6 d afterwards. The primary aim of this study is to determine whether bridging anticoagulation is required in patients with AF for patients prescribed chronic warfarin therapy, requiring surgery. The study is due for completion in January 2015. The BRIDGE investigators aim to recruit >3600 patients in >90 clinical centres in the USA, Canada and Brazil (BRIDGE study investigators, 2012).

Novel oral anticoagulants

  1. Top of page
  2. Summary
  3. Bleeding risks
  4. Procedures that may require bridging therapy to be prescribed
  5. What is the risk of thromboembolism if oral anticoagulation is simply discontinued?
  6. What is the evidence for bridging therapy and do they relate to patient outcomes?
  7. Bridging anticoagulation
  8. Anticoagulant intensity of LMWH
  9. Risk of bleeding and proximity to surgery
  10. Clinical trials that will provide further direction
  11. Novel oral anticoagulants
  12. Experience of NOAC use during the peri-operative period
  13. Conclusion
  14. Author contributions
  15. References

At the time of writing, three NOAC were available for clinical use in the UK; apixaban, dabigatran and rivaroxaban. The NOAC combine the advantages of both VKA and LMWH, in that they are orally active, have a rapid onset of action and have a relatively predictable pharmacokinetic profile (Baglin, 2013). Some well-documented key properties of these agents are described in Table 5. One significant disadvantage of the NOAC is that there are currently no antidotes, should immediate anticoagulation reversal be required, although promising agents are being investigated for both dabigatran (Schiele et al, 2013) and the direct coagulation factor Xa inhibitors (Lu et al, 2013).

Table 5. Properties of novel oral anticoagulants.
PropertyDabigatranApixabanRivaroxaban
  1. P-gp: potent P-glycoprotein inhibitors and inducers; P-gp and CYP3A4: combined P-gp and CYP3A4 inhibitors and inducers.

  2. a

    The values listed here assume normal renal function.

  3. Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Nephrology, Hart et al 2012, Anticoagulants in atrial fibrillation patients with chronic kidney Disease, 8: 569-78. Copyright © 2012.

TargetIIaXaXa
Bioavailability (%)67080
Protein binding (%)359090
Peak onset (h)1·5–23–42–4
Half life (h)a12–14127–11
Renal clearance (%)802535
Drug interactionsP-gpP-gp and CYP3A4P-gp and CYP3A4

For patients prescribed chronic NOAC therapy, the issue of discontinuing the oral agent and commencing a parenteral agent (risk permitting) will no longer be there; due to their short half-life, they can simply be omitted before surgery, just like LMWH.

Experience of NOAC use during the peri-operative period

  1. Top of page
  2. Summary
  3. Bleeding risks
  4. Procedures that may require bridging therapy to be prescribed
  5. What is the risk of thromboembolism if oral anticoagulation is simply discontinued?
  6. What is the evidence for bridging therapy and do they relate to patient outcomes?
  7. Bridging anticoagulation
  8. Anticoagulant intensity of LMWH
  9. Risk of bleeding and proximity to surgery
  10. Clinical trials that will provide further direction
  11. Novel oral anticoagulants
  12. Experience of NOAC use during the peri-operative period
  13. Conclusion
  14. Author contributions
  15. References

Very little published information is currently available. In their summary of product characteristics, the manufacturers of dabigatran do state that patients who undergo surgery or invasive procedures are at increased risk for bleeding and may require discontinuation of dabigatran, and make suggestions as outlined in Table 6.

Table 6. Suggested time to discontinue dabigatran pre-operatively (http://www.medicines.org.uk/emc/medicine/24839/SPC/Pradaxa+150+mg+hard+capsules/).
  Timing of discontinuation of dabigatran before surgery
Renal function [CrCl (ml/min)]Half-life (h)Standard risk of bleedingHigh risk of bleeding
  1. a

    Not licensed for use in the UK if creatinine clearance (CrCl) <30 ml/min – this recommendation taken from Weitz et al (2012). In the US, dabigatran is licensed for stroke prevention in atrial fibrillation when CrCl <30 ml/min.

>801324 h before2 d before
>50–≥80151–2 d2–3 d
>30–≤50182–3 d before4 d
≤30a272–3 d4–6 d

Due to the significant renal excretion of dabigatran, the time between surgery and omitting the dabigatran is dictated by renal function. Weitz et al (2012) have recently published their suggestions for managing dabigatran during the peri-operative period. In their review, they suggest that dabigatran need not be stopped in patients undergoing minor procedures, such as dental cleaning, extraction, skin biopsy or cataract extraction, similar to what is currently recommended for VKA therapy. However, they do suggest that the procedures should ideally be performed ≥10 h after the last dose of dabigatran, when the plasma concentration of dabigatran is at its lowest.

The timing of re-starting dabigatran needs to be considered. Following oral ingestion, dabigatran has a rapid onset of action (within 1·5 h) and given the experience of using LMWH, that re-starting soon after the procedure can increase the risk of bleeding, this needs consideration when dabigatran is re-started. There may, of course be a utility for using prophylactic doses of dabigatran in appropriate cases, particularly the 75 mg dose for the first couple of days, before reverting back to full treatment dose. There is no evidence to support such practice, and further clinical experience will determine how best to manage dabigatran peri-operatively.

More recently, Healey et al (2012) retrospectively analysed the peri-procedural bleeding risk in patients from the RE-LY study treated with warfarin or dabigatran (Connolly et al, 2009). During the RE-LY study, all patients who required a procedure had the details of their peri-operative management of anticoagulation prospectively recorded. During the trial, 4591 patients had their anticoagulant therapy interrupted at least once to undergo surgery or another invasive procedure, representing approximately 25% of patients in each arm of the trial [110 mg dabigatran, 150 mg dabigatran and warfarin (target INR 2–3)]. The most common reasons for discontinuing dabigatran was pacemaker or defibrillator insertion (10·3%), dental procedures (10·0%), diagnostic procedures (10·0%), cataract removal (9·3%), colonoscopy (8·6%) and joint replacement (6·2%). Interestingly, when peri-procedural bridging was used, it was used in 15·3% of patients assigned to dabigatran 110 mg, 17·0% of patients assigned to dabigatran 150 mg and 28·5% of patients to warfarin (P < 0·001). Among patients assigned to either dose of dabigatran, the last dose of the study drug was given 49 h (range 35–85) before the procedure in comparison to 114 h (range 87–144) for patients prescribed warfarin, illustrating that dabigatran facilitated a shorter interruption of oral anticoagulation. The authors' analysis found that there were no significant differences in the rates of peri-procedural major bleeding between those patients receiving dabigatran 110 mg (3·8%), dabigatran 150 mg (5·1%) or warfarin (4·6%; Healey et al, 2012). For those patients in the RE-LY study who required urgent surgery, major bleeding occurred in 17·8% in the dabigatran 110 mg group, 17·7% in the dabigatran 150 mg group and 21·6% in the warfarin group. The authors concluded that both dabigatran and warfarin were associated with similar rates of peri-procedural bleeding.

It must be remembered that the RE-LY study was not designed to answer the question of how best to manage dabigatran during the peri-procedural period. The large study size however, does mean the analysis from this study provides valuable information, despite the majority of procedures the patients underwent being classed as minor.

A further study by Lakkireddy et al (2012), explored the feasibility and safety of dabigatran versus warfarin for peri-procedural anticoagulation in patients undergoing radiofrequency ablation for AF. In this study, the authors found that dabigatran significantly increased the risk of major bleeding (6% vs. 1%, P = 0·031) and, in some ways, contradicts some of the findings from the RE-LY study. A more recently published study (Bassiouny et al, 2013) compared warfarin with dabigatran for the same indication and found no differences in the rates of bleeding or thromboembolic events. However, in this study, warfarin was continued, as usual, whereas 1–2 doses of dabigatran were omitted pre-procedure.

In the absence of controlled studies, registries such as GLORIA AF (clinicaltrials.gov NCT01468701), where patients prescribed dabigatran for non-valvular AF will be followed long-term, might provide future direction, although there are of course limitations to registry type data. Ideally, clinical trials similar to PERIOP2 (NCT00432796) and the BRIDGE (NCT00786474) studies would be completed, to objectively define how best to manage dabigatran (and other NOAC) during a surgical challenge.

Very little clinical experience has been published evaluating the peri-procedural use of rivaroxaban. The manufacturers of rivaroxaban suggest that it should be stopped at least 24 h before surgery, based on clinical judgement and re-started when the clinical situation allows and adequate haemostasis has been established (http://www.medicines.org.uk/emc/medicine/25586/SPC/Xarelto+20mg+film-coated+tablets/). The manufacturers were also contacted to see if there was any data from patients who might have stopped oral anticoagulation temporarily during the ROCKET-AF (Patel et al, 2011) study (personal communication with the medical information department, Bayer UK, Newbury, Berkshire, UK 30/05/2013); they were unaware of any work planned to analyse such information.

For apixaban, the manufacturers suggest to discontinue the drug at least 48 h prior to elective surgery or invasive procedures with a moderate to high risk of bleeding. For elective surgery with a low risk of bleeding, apixaban should be discontinued 24 h prior to the procedure. Again, the manufacturers suggest that apixaban should be re-started when it is clinically safe to do so (http://www.medicines.org.uk/emc/medicine/27220/SPC/Eliquis+5+mg+film-coated+tablets/).

The manufacturers of apixaban were contacted to share any unpublished data they may have from the ARISTOTLE study (Granger et al, 2011; personal communication with Bristol-Myers-Squibb, Uxbridge, Middlesex, UK 05/06/2013). This phase III study compared warfarin (n = 9081) with apixaban (n = 9120) for the prevention of stroke in patients with non-valvular AF, during the course of which 11 417 invasive procedures were conducted in 6162 subjects (apixaban, n = 5660; warfarin, n = 5757). The majority of the procedures were non-major and non-emergency as defined by investigators. In approximately one-third of the procedures, the study drug was not discontinued, but it was temporarily discontinued for a median time of 4 d prior to the procedure in the remaining two-thirds of the procedures. A bridging anticoagulant was used in 11·7% of procedures, with LMWH as the most commonly used agent. The 30-d rate of stroke/systemic embolism was 0·43% (95% CI: 0·29–0·64) in the apixaban arm, compared to 0·56% (95% CI: 0·40–0·79) in the warfarin arm. The rate of major bleeding was 1·55% (95% CI: 1·24–1·92) in the apixaban arm, compared to 1·80% (95% CI: 1·47–2·20) in the warfarin arm.

Although this analysis provides valuable information, as most procedures were non-major, further information is required to determine the optimal management of apixaban, peri-procedurally in various clinical scenarios.

Due to their rapid onset of action, it is important that consideration is given as to how quickly the NOAC is re-introduced post-operatively. With the NOAC, there is an opportunity to use a lower dose (i.e. 75 mg dabigatran, 10 mg rivaroxaban and 2·5 mg apixaban) and such doses use may well circumvent bleeding problems; further clinical experience will dictate if such strategies are reasonable. Based on current information, we currently follow the manufacturer's recommendations of when to stop and start these agents peri-operatively.

Conclusion

  1. Top of page
  2. Summary
  3. Bleeding risks
  4. Procedures that may require bridging therapy to be prescribed
  5. What is the risk of thromboembolism if oral anticoagulation is simply discontinued?
  6. What is the evidence for bridging therapy and do they relate to patient outcomes?
  7. Bridging anticoagulation
  8. Anticoagulant intensity of LMWH
  9. Risk of bleeding and proximity to surgery
  10. Clinical trials that will provide further direction
  11. Novel oral anticoagulants
  12. Experience of NOAC use during the peri-operative period
  13. Conclusion
  14. Author contributions
  15. References

Management of chronic oral anticoagulation and whether or not to bridge has evolved over the years, and will continue to evolve as NOAC are used in clinical practice. Current recommended practice is based on a weak evidence base (mainly level 2c recommendations). Clinical trials currently underway should provide a better evidence base for the anticoagulation management of oral VKA in this commonly encountered scenario. However, the increasing use of NOAC in clinical practice will mean that the management of anticoagulation therapy peri-procedurally will alter once again. In all situations however, although guidelines can provide a broad overview of how to manage patients, individual decisions should be made on a case-by-case basis.

References

  1. Top of page
  2. Summary
  3. Bleeding risks
  4. Procedures that may require bridging therapy to be prescribed
  5. What is the risk of thromboembolism if oral anticoagulation is simply discontinued?
  6. What is the evidence for bridging therapy and do they relate to patient outcomes?
  7. Bridging anticoagulation
  8. Anticoagulant intensity of LMWH
  9. Risk of bleeding and proximity to surgery
  10. Clinical trials that will provide further direction
  11. Novel oral anticoagulants
  12. Experience of NOAC use during the peri-operative period
  13. Conclusion
  14. Author contributions
  15. References
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