Fondaparinux (trade name Arixtra), an anticoagulant drug used for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (chemically related to low molecular weight heparins).

Case

A 77-year-old woman with a history of stroke five months prior, bileaflet aortic valve prosthesis, hypertension, and insulin-dependent diabetes is admitted for laparoscopy with lysis of adhesions. The patient stopped her warfarin 10 days prior to admission and initiated enoxaparin five days later. When should the enoxaparin be discontinued?

Intra-operatively, the surgeon converted the case to an open laparotomy for a bowel resection with re-anastomosis; post-operatively, when should the hospitalist reinitiate warfarin and enoxaparin?

Background

Many patients receive chronic oral anticoagulant therapy to minimize their long-term risk of thromboembolic disease. Hospitalists and outpatient providers often care for such patients who need to undergo a medical procedure or operation. The risk of bleeding associated with the medical procedure necessitates an interruption in the patient’s chronic oral anticoagulant therapy. In this scenario, providers are faced with several therapeutic decisions:

How soon before the procedure should patients stop taking oral anticoagulant?

During the period of time when the patient is not taking chronic oral anticoagulant, should the patient receive parenteral bridging anticoagulant therapy?

After the procedure, when should patients restart chronic oral anticoagulant therapy?

‘Bridge’ anticoagulant therapy is the administration of a short-acting parenteral anticoagulant during the peri-operative period, when the patient is not taking chronic oral anticoagulant.¹ The intent of bridge anticoagulant therapy is to minimize both the risk of thromboembolic events and the risk of bleeding during the peri-operative period. Bridging anticoagulant therapy is appropriate for some but not all patients undergoing medical procedures.

The Data

When to discontinue warfarin? Warfarin, the most commonly prescribed oral anticoagulant, achieves its therapeutic effects by antagonizing the actions of endogenous vitamin K-dependent coagulation factors. The decision on when to stop warfarin prior to surgery is dependent on the regeneration time of coagulation factors following the discontinuation of warfarin therapy. Although warfarin’s half-life is typically 36-42 hours, its therapeutic effects typically last up to five days in healthy subjects and often longer in elderly patients.²

Current guidelines recommend the discontinuation of warfarin at least five days prior to surgery (Grade 1C recommendation).³ Despite this recommendation, approximately 7% of patients will still have an international normalized ratio (INR) >1.5 after not taking warfarin for five days.⁴ For this reason, the guidelines recommend that all patients have their INR checked on the day of surgery. For those patients with an INR of 1.5 to 1.9 on the day prior to surgery, there is evidence to show that administration of 1 mg of vitamin K will lower the INR to 1.4 in greater than 90% of cases.⁵

Assessment of peri-procedural thrombotic risk. Knowledge of a patient’s past medical history is critical in helping providers stratify the patient’s peri-procedural thrombotic risk. According to the 2012 American College of Chest Physicians (ACCP) guidelines, a history of atrial fibrillation (Afib), mechanical heart valve(s), and previous VTE are independent risk factors for peri-procedural thrombotic events.³ Hospitalists may risk-stratify their patients based on the anticipated annualized rate of thrombosis or embolization: <5%, 5%-10%, or >15% for the respective low, medium, and high-risk groups.⁶

Patients with Afib history. For these patients, the CHADS2 score helps to stratify the risk of peri-procedural thrombosis. Low risk is defined as a CHADS2 score of zero to two, assuming that the two points were not scored for transient ischemic attack (TIA) or cerebrovascular accident (CVA). Any patient with a TIA or CVA within the previous three months is automatically considered high risk. Medium risk is a score of three or four.

In addition to the aforementioned TIA or CVA within the prior three months, high-risk patients also include those with a CHADS2 score of five or six or any patient with a history of rheumatic heart disease.³ Patients with CHADS2 scores less than five but with a TIA or CVA greater than three months in the past are high risk.⁷

Presence of mechanical heart valve(s). For patients with a mechanical heart valve, knowledge of the valve type and location is essential to assist hospitalists in stratifying the risk of peri-procedural thrombosis. The current ACCP guidelines consider patients with bileaflet aortic valve prostheses without additional risk factors for stroke or atrial fibrillation to be low risk.³

The guidelines define the following characteristics as medium risk for patients: the presence of a bileaflet valve with additional risk factors for stroke such as atrial fibrillation, age greater than 75, prior CVA (more than six months prior), hypertension, diabetes mellitus, or congestive heart failure.

Patients at high risk include those with aortic valve prosthesis with a caged-ball or tilting disc, patients with mitral valve prosthesis, and those with a mechanical valve with CVA or TIA during the prior six months.⁷

Hospitalists should identify high-risk patients as those with VTE that has occurred within three months or those with severe thrombophilias such as Protein C or S deficiency, antithrombin III deficiency, or antiphospholipid antibody syndrome.

History of previous VTE. For these patients, the duration of time that has passed since their last VTE event is an important factor in helping to stratify their risk for peri-procedural thrombosis. Hospitalists should consider patients low risk if they had VTE more than one year prior to the procedure.

Medium-risk patients are those with VTE events in the preceding three to twelve months, those with recurrent VTE, those with active cancer who have received cancer therapy within six months, or patients with non-severe thrombophilias (e.g. heterogenous factor V Leiden or prothrombin gene mutation).

Hospitalists should identify high-risk patients as those with VTE that has occurred within three months or those with severe thrombophilias such as Protein C or S deficiency, antithrombin III deficiency, or antiphospholipid antibody syndrome.

Assessment of procedure-related thrombotic risk. The type of anticipated procedure itself conveys peri-procedural thrombotic risk. For example, heart valve replacement, carotid endarterectomy, or other major vascular surgeries automatically stratify patients in the high-risk category, regardless of underlying medication condition.

Assessment of bleeding risk. Hospitalists must identify any preexisting bleeding risk factors (i.e., hemophilias or thrombocytopenia) in addition to the post-procedural bleeding risks. Risk factors for increased post-procedural bleeding include: major surgery with extensive tissue injury, procedures involving highly vascularized organs, removal of large colonic polyps, urological procedures, placement of implantable cardioverter-defibrillator/pacemakers, and procedures at sites where minor bleeding would be clinically devastating, such as the brain or spine.³

Thus, communication with the proceduralist or surgeon regarding the anticipated bleeding risk is vital.

Should the patient receive bridging anticoagulation? Patients considered high risk for peri-procedural thrombosis should receive peri-procedural bridging anticoagulation therapy, while those considered low risk should not. For patients with a moderate peri-procedural risk of thrombosis, hospitalists should base the decision on individual and anticipated pre-surgical/procedural thrombotic risks.

Recent evidence suggests that bridging anticoagulation should be avoided in patients undergoing procedures with high bleeding risk who are not at high thromboembolic risk.⁸

Selection and pre-operative discontinuation of bridging medication. Current ACCP guidelines only support the use of unfractionated heparin (UFH) or low molecular weight heparin (LMWH) as bridging anticoagulants.³ Evidence supports the use of either intravenous UFH (goal aPTT 1.5 to two times control aPTT) or enoxaparin (1 mg/kg BID or 1.5 mg/kg once daily).⁹ UFH is preferred over LMWH in patients with chronic kidney disease stage IV or V due to a more predictable pharmacokinetic profile.

Clinicians should initiate a bridge when a patient’s INR falls to less than 2.0 and discontinue the UFH bridge four to six hours prior to the procedure.¹⁰ The recent update to the guidelines now states that LMWH should be discontinued 24, instead of 12, hours prior to the procedure.³

When to restart UHF or LMWH bridge post-procedure. The type of procedure being performed dictates when bridging anticoagulation should resume. In patients who have undergone surgeries that involve high bleeding risk, LMWH should not be administered until 48-72 hours post-surgery (Grade 2C evidence).³ For those patients undergoing surgeries with low bleeding risk, bridging should be resumed approximately 24 hours after the procedure.

Of note, enoxaparin administered in one single daily dose, as compared to divided doses, is associated with a greater risk of post-operative bleeding. UFH bridging should resume post-operatively without a bolus dose at 24 hours in low-risk bleeding cases or 48-72 hours in high-risk bleeding cases (Grade 2C evidence).³

On occasion, unanticipated adjustments to surgical cases—or complications—change the previously determined post-operative bleeding risk. In these instances, the hospitalist and surgeon/proceduralist should review the case and reassess the bleeding risk prior to employing bridging anticoagulation protocols.

When to restart long-term vitamin K antagonists (VKA) post-procedure. In most instances, regardless of pre-operative bleeding risk stratification, the resumption of VKA may occur once post-operative hemostasis has been achieved and the patient has been instructed to resume eating by the proceduralist or surgeon. This most often occurs on the calendar day following surgery, because it takes approximately five days for an INR to achieve therapeutic levels.

Back to the Case

The patient’s history of prosthetic valve with stroke within the preceding six months stratified her to a high thrombotic risk category. Given the high risk of thrombosis, the decision was made to bridge with LMWH. The hospitalist discontinued LMWH 24 hours prior to surgery, and INR was checked on the morning of the procedure.

Although the patient underwent the operation without significant bleeding, the adjustment from an exploratory laparoscopy to an open laparotomy increased her post-operative bleeding risk from medium to high. Therefore, bridging anticoagulation with LMWH was resumed no sooner than 48 hours after the operation. Her warfarin was restarted on the day following surgery, once she resumed her diet.

Bottom Line

Hospitalists must understand both the pre- and post-procedure thrombotic risks, as well as the pre- and post-procedural bleeding risks, when determining the selection and logistics of initiation and cessation of antithrombotic bridging for inpatients.

Drs. McCormick, Carbo, and Li are hospitalists at Beth Israel Deaconess Medical Center in Boston. Dr. Kerbel is a hospitalist at the University of California Los Angeles.

Key Points

The CHADS2 score, the presence of heart valve type and location, and the duration of time since previous VTE events help guide our understanding of the peri-procedural thrombotic risk in patients with atrial fibrillation, mechanical heart valves, and prior VTE. The type of procedure and the presence of inherited or acquired bleeding diatheses guides our understanding of the bleeding risk.

Patients at high risk for thrombotic events should receive bridging anticoagulation, while patients at low risk do not require bridging anticoagulation. There is insufficient evidence to guide the use of bridging anticoagulation in patients with medium risk for thrombotic events. Hospitalists will need to use their own best judgment in these patients.

The bleeding risk associated with medical procedures or surgery dictates when to resume bridging anticoagulation. Communication with the proceduralist or surgeon is essential.

References

BRIDGE Study Investigators. Bridging anticoagulation: is it needed when warfarin is interrupted around the time of a surgery or procedure? Circulation. 2012;125(12):e496-498.

Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):160S-198S.

Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e326S-350S.

Kovacs MJ, Kearon C, Rodger M, et al. Single-arm study of bridging therapy with low-molecular-weight heparin for patients at risk of arterial embolism who require temporary interruption of warfarin. Circulation. 2004;110(12):1658-1663.

Woods K, Douketis JD, Kathirgamanathan K, Yi Q, Crowther MA. Low-dose oral vitamin K to normalize the international normalized ratio prior to surgery in patients who require temporary interruption of warfarin. J Thromb Thrombolysis. 2007;24(2):93-97.

Ortel TL. Perioperative management of patients on chronic antithrombotic therapy. Blood. 2012;120(24):4699-4705.

Kaatz S, Douketis JD, Zhou H, Gage BF, White RH. Risk of stroke after surgery in patients with and without chronic atrial fibrillation. J Thromb Haemost. 2010;8(5):884-890.

Siegal D, Yudin J, Kaatz S, Douketis JD, Lim W, Spyropoulos AC. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates. Circulation. 2012;126(13):1630-1639.

Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-153.

Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):188S-203S.

Which Patients Should Receive Bridging Anticoagulation?