Continuing Education Activity

Management of perioperative anticoagulation requires an interprofessional approach to determine the duration and discontinuation of temporary interruption of anticoagulation. Parenteral anticoagulation during temporary interruption may be required in certain circumstances based on the patient's and procedure's individualized risks and benefits. This activity explains the recommendations for perioperative management of anticoagulation for patients with nonvalvular atrial fibrillation undergoing non-cardiac surgery.

Objectives:

• Review the basic pharmacology that can affect the homeostasis in patients undergoing non-cardiac elective surgery.

• Review the current indications for antithrombotic and anticoagulation interruption in patients undergoing non-cardiac elective surgery.

• Describe the different emergency anticoagulation reversal treatments and their indications.

• Outline the importance of collaboration and coordination among the interprofessional team that can enhance patient care when dosing and monitoring anticoagulant drugs to improve patient outcomes for patients receiving anticoagulation undergoing non-cardiac elective surgery.

Introduction

The management of patients on anticoagulation and anti-aggregation therapy is a daily challenge for physicians. The interruption of therapy can increase the risk of thrombotic events during and after surgery. However, the non-interruption of these medications can heighten the risk of bleeding during surgery and trigger a sequence of undesirable outcomes ranging from minor to uncontrolled bleeding.

The optimal management of these patients is thus achieved through a balance between thromboembolic and bleeding risks. Several case-based considerations affect the decision of whether or not to interrupt anticoagulation or anti-aggregation therapy before surgery. These include an evaluation of an individual's underlying bleeding risk, the risk of bleeding associated with the surgical procedure, the timing of interruption and resumption of anticoagulation therapy, and whether to use bridging therapy. These are all typical questions that will be addressed in this review.

Etiology

Anticoagulation therapy is most commonly indicated in the presence of atrial fibrillation (AF), deep venous thrombosis (DVT), pulmonary embolism (PE), and after placement of prosthetic heart valves. Patients who have undergone percutaneous coronary interventions are typically on dual antithrombotic therapy, as well as patients with a past medical history of stroke, coronary artery by-pass grafting and essential thrombocytosis could require antithrombotic therapy.

Epidemiology

AF, DVT, and PE are the leading causes of anticoagulation treatment. In the United States (U.S.) alone, approximately 3 to 5 million people suffer from atrial fibrillation, and this number is expected to increase to 8 million by 2050.[1] Likewise, approximately 250,000 patients annually in the U.S. require anticoagulation therapy cessation in order to be considered for surgery.[2]

Pathophysiology

The process of physiologic hemostasis can be altered for several reasons, such as genetic disorders, malignancy, sepsis, surgery, and drugs (those used for anti-aggregation and anticoagulation). From a basic approach to perioperative anticoagulation, a pharmacological review of anticoagulation is essential.

Aspirin (Acetylsalicylic Acid)

This agent is the most commonly prescribed antiplatelet drug for the prevention of cardiovascular disorders. Its mechanism of action is the irreversible inhibition of the cyclooxygenase (COX) 1 and 2 enzymes. The action of COX is necessary for the conversion of arachidonic acid to prostaglandin (PG) H2. The PGH2 is rapidly converted to several bioactive prostanoids, including thromboxane A2, a potent vasoconstrictor, and an inductor of platelet aggregation. Despite the short half-life of aspirin (3 to 6 hours), its irreversible effects will last for the complete lifetime of the platelet (8 to 9 days). After the interruption of aspirin therapy, recovery of platelet function depends on its turnover (approximately 10% per day).[3][4]

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

These drugs act by the inhibition of COX enzymes, depending on the particular drug. Some NSAIDs can selectively inhibit the COX 2 enzyme that mediates pain and inflammation, simultaneously limiting the undesirable effects of COX 1 inhibition. The effect of NSAIDs on platelet function is considered a short-term effect that normalizes within three days; nonetheless, this can vary between drugs in the class. For short-acting drugs like ibuprofen, diclofenac, and indomethacin, 50% of platelet function is restored 6 hours after the last dose and normalized after 24 hours.[4][5]

Thienopyridines (Clopidogrel and Prasugrel)

These are inhibitors of the adenosine diphosphate (ADP) receptor, also called the P2Y12 receptor, in platelets. Physiologically, the union of ADP with its receptor increases levels of intracellular calcium and activates the GpIIB/IIIa platelet receptor that promotes the stabilization of the platelet clot through fibrinogen bonds.[6] Clopidogrel and prasugrel are prodrugs in which active metabolites irreversibly affect the platelet function in a time- and dose-dependent fashion. A clopidogrel dose of 75 mg daily produces a 60% decrease of platelet function in 3 to 5 days; in contrast, a 600 mg loading dose can achieve a steady-state platelet inhibition in 6 to 8 hours.[3] In the same way, a loading dose of prasugrel of 60 mg is enough to produce steady-state platelet inhibition two hours after drug administration. Due to the irreversible mechanism of action, it is recommended to interrupt these drugs 5 to 7 days before non-cardiac elective surgery.[4]

Non-thienopyridines (Ticagrelor and Cangrelor)

These drugs are relatively new with different mechanisms of action from those discussed thus far. Ticagrelor is a reversible, non-competitive ATP analog that binds to a G-protein in the P2Y12 receptor, preventing its activation and signaling. After a loading dose of ticagrelor, the maximum antiplatelet effect is achieved within 2 hours, plasma half-life is 8 to 12 hours, and steady-state concentration in 2 to 3 days. Due to the reversible effect of ticagrelor on platelets, it is recommended to be suspended 5 days before surgery.[4] On the other hand, cangrelor is a direct, reversible, and intravenously administered drug that inhibits the P2Y12 receptor. Cangrelor can inhibit 95% to 100% of platelet activity within the first two minutes of administration; the plasma half-life of cangrelor (3 to 6 minutes) allows recovery of 80% to 90% platelet function within 60 to 90 minutes of discontinuing the intravenous infusion.[7] 

Vitamin K Antagonists (Warfarin, Acenocoumarol, Phenprocoumon)

These are also called coumarins. The most recognized and widely used drug of this group is warfarin, which has been available for more than 50 years. The mechanism of action of warfarin is the inhibition of the 2,3 epoxide reductase enzyme, responsible for the cyclical conversion of oxidized vitamin K to a reduced state. The latter is necessary as a cofactor for the carboxylation of glutamic acid at the N-terminus of coagulation factors. Without gamma carboxyglutamate residues, clotting factors II, VII, IX, and X cannot bind to the divalent calcium necessary for normal activation. However, the inhibition of carboxylation also affects the production of protein C and S anticoagulants. This creates a transient procoagulant state that can be explained by the shorter half-life of these anticoagulants (8 and 30 hours), compared to factor II and factor X (60 and 72 hours). This phenomenon is more frequent, with higher doses of vitamin K antagonists at the beginning of anticoagulation therapy.[8] Warfarin is a racemic mixture of the R and S stereoisomers of the drug; the S isomer is 3-5 times more potent than the R isomer. The half-life of warfarin is 36 to 42 hours (S isomer 29 hours, R isomer 45 hours); nonetheless, it can be altered by several factors. In practice, warfarin is a drug of difficult titration due to the high number of pharmacological interactions and genetic variations that can affect its metabolism.[9]

Direct Inhibitors of Factor Xa (Rivaroxaban, Apixaban, Edoxaban, Betrixaban)

The common mechanism of action these drugs, also known as direct oral anticoagulants (DOACs), is to bind to the active site of factor Xa, thus inactivating it. Factor Xa is considered the rate-limiting step for the progression of the coagulation cascade, thrombin activation, and ultimately clot formation.[10] Some advantages of prescribing DOACs are their short half-life and rapid onset of action, allowing for an easier interruption and re-initiation of anticoagulation therapy after surgery. Furthermore, it seems that the direct inhibitors of factor Xa have a lower bleeding risk compared to vitamin K antagonists, making the use of routine coagulation tests unnecessary.[11] However, the pharmacokinetic properties of each DOAC can vary according to the renal and liver function of the patient (see table 1).

Direct Inhibitors of Thrombin

Dabigatran is the only medication in this group. Its mechanism of action is the direct inhibition of thrombin, preventing the conversion of fibrinogen to fibrin and thus clot formation. Dabigatran has a quick onset of action (0.5 to 2 hours) and is metabolized by non-specific plasma esterases. The plasma half-life is around 12 hours; however, the half-life of this drug is tremendously affected by renal function, as its excretion is 80% by the kidneys and less than 10% by the liver. It is recommended to avoid dabigatran use with creatinine clearance (CrCl) less than 30ml/min, due to the potential for drug accumulation and adverse effect of bleeding (see table.1).

Fondaparinux

This drug is a pentasaccharide that acts as an indirect factor Xa inhibitor. The exact mechanism of action is the reversible binding of the drug to the antithrombin factor, potentiating its activity to inactivate Factor Xa. The plasma half-life of fondaparinux is approximately 15 to 17 hours. Its anticoagulant activity persists even 2 to 4 days after the last dose of the drug in a person with normal renal function.[11]

Heparins

The binding of the heparin molecule to the antithrombin receptor enhances its potency to inactivate factors II and Xa. This drug has been widely used for years, with multiple indications and dosages. One of the most concerning adverse effects of this pharmacological group is the possibility of heparin-induced thrombocytopenia. Fortunately, this complication is infrequent, though it is dependent on the dose, route of administration, and type of heparin. In patients with renal failure and a CrCl < 30 ml/min, low molecular weight heparin (LMWH) should be avoided or adjusted to renal function, the use of unfractionated heparin (UFH) is a suitable option in this case. Heparin can be administered as a therapeutic dose for the patient with high thromboembolic risk (enoxaparin 1 mg/kg twice daily or dalteparin 100 units/kg twice daily) or as the prophylactic dose for patients undergoing bridge therapy (enoxaparin 40 mg once daily or dalteparin 5,000 units once daily).[12]

Evaluation

The approach recommended by several well-known guidelines is based on four considerations that aim to guide the physician in elective surgery cases.[13]

Determine the Thromboembolic Risk of the Patient

The three major conditions related to a higher risk of thromboembolic events are atrial fibrillation, prosthetic heart valves, and recent thromboembolism (venous or arterial). The thromboembolic risk will be estimated through clinical variables in the case of atrial fibrillation with the CHA2DS2VASc score.[14] The localization, type of valve, number of prosthetic valves, and associated cardiac risk factors will lead to the risk stratification of patients with prosthetic valves. Regarding thromboembolism, the time after the episode and risk of recurrence will determine the categorization of risk. The venous thromboembolism (VTE) can be classified as provoked (higher risk of recurrence) when an inciting event is identifiable, or unprovoked when a cause is non-identifiable. An example of provoked VTE is the patient with permanent risk factors such as congestive heart failure, malignancy inherited thrombophilia, or inflammatory bowel disease.[15](see Table.2)

Determine the Procedural Bleeding Risk

When evaluating bleeding risk, it is imperative to consider the type of surgery and clinical characteristics of the patient. These characteristics are assessed with the HAS-BLED (Hypertension, Abnormal liver or kidney function, Stroke, Bleeding history or predisposition, Labile International Normalized Ratio [INR], elderly, drugs, alcohol) score. Each positive item earns 1 point, and a HAS-BLED score > 3 indicates a high bleeding risk. The BNK Online Bridging Registry (BORDER) study assessed the possible predictors of perioperative bleeding in patients undergoing invasive cardiac procedures. They found that the HAS-BLED score is a reliable predictor of perioperative bleeding (HR 11.8, 95% CI 5.6-24.9).[16] As a general guideline, the procedural risk can be divided into low risk (0-2% two-day risk of major bleeding) or high risk (2% to 4% two-day risk of major bleeding). Among the diversity of surgical procedures, intracranial, cardiac, and neuraxial procedures are of special concern due to the localization of potential bleeding and poor patient outcomes in the presence of this complication.[17] (see table 3)

Determine Whether or Not Interrupt Anticoagulation or Antithrombotic TherapyThe balance between risks and benefits of anticoagulation interruption is the right approach to this decision. Clinical judgment is imperative, as there is no score or calculator to determine the classification of the patient straightforwardly.

As a generalized consideration, patients with a high risk of bleeding will benefit from anticoagulation interruption.[18][19][20] However, those patients with high thromboembolic risk might benefit from bridging therapy and the shortest period of anticoagulation withdrawal as possible. An example of this scenario is the patient undergoing potentially curative cancer surgery. In other scenarios, the delay of the elective surgical procedure after a balance of risks and benefits is a suitable option.

In patients with a recent episode of VTE (less than 1 month ago), the risk of recurrence in the subsequent month can be as high as 40%. An elective surgical procedure should be deferred up to 3 months after an episode of VTE, if possible. For patients with a recent acute ischemic stroke undergoing non-cardiac elective surgical procedures, the risk of having a major cardiovascular event after surgery is high, especially within the first 3 months. The American College of Surgeons recommends deferring the surgery up to 9 months in this scenario when the risk of cardiac events has plateaued after a stroke.[18]

Another common scenario is the patient with coronary stents, most of which are on dual anti-aggregation. Approximately 5% of these patients will require surgery during the next year after coronary stent implantation. If aspirin and thienopyridine need to be suspended during the perioperative period, the elective surgical procedure should be delayed 6 weeks for patients with bare-metal stents and 6 months for drug-eluting stents.[4][12] In case the elective surgery cannot be postponed, the dual anti-aggregation therapy should be continued throughout the perioperative period.[21][22]

Despite limited evidence, there are scenarios where anticoagulation therapy continuation is preferable in patients with low bleeding risk. Dental procedures are considered low bleeding risk procedures. The majority of evidence comes from patients receiving warfarin with a therapeutic INR range. The studies conclude that continuing anticoagulation therapy is safe, not only in dental extraction but in other types of dental procedures and that bridging therapy could be related to even more bleeding associated with these procedures.[23][24] One four-year, cross-sectional study assessed bleeding risk in patients with DOACs, showing no significant bleeding association with continuing anticoagulation therapy.

Endovascular procedures (venous and arterial angioplasty, angiography, catheter ablation for AF, and atherectomy) studies were analyzed in a meta-analysis of 20,000 patients on warfarin anticoagulation.[25][26] The study concluded that rates of complications were low or equivalent between interrupted and uninterrupted warfarin anticoagulation groups. Similar findings have been published with DOACs. The first study was the VENTURE-AF (rivaroxaban vs. VKA in patients with AF undergoing catheter ablation); the number of complications was low and similar between groups.[27] The RE-CIRCUIT study (dabigatran vs. warfarin in patients with AF undergoing catheter ablation); dabigatran had lower rates of major bleeding than warfarin, and there was no difference in stroke or systemic embolism between groups.[28] Uninterrupted apixaban and edoxaban have also been shown to be safe in patients with AF undergoing catheter ablation.

Implantation of prosthetic cardiac devices is also considered low bleeding risk procedures. Two studies, the BRUISE CONTROL 1 and 2, have addressed this scenario. The first study examined uninterrupted anticoagulation vs. warfarin interruption and a low therapeutic dose of low molecular weight heparin (LMWH) (1 mg per kg/twice daily of enoxaparin) in patients undergoing pacemaker implantation. The patients with uninterrupted warfarin had a lower incidence of pocket hematoma complications compared with the group that received bridging therapy with LMWH (3.5% vs. 16%, P <0.01).[29] The BRUISE CONTROL 2 study evaluated the safety of performing electrophysiologic device procedures without interrupting DOAC anticoagulation therapy. The study compared uninterrupted DOACs vs. interrupted DOACs (apixaban, rivaroxaban, dabigatran interrupted two days prior to surgery) in patients with high thromboembolic risk. The strategy of continuing DOACs for reducing the complication of pocket hematoma was not superior to the interruption of DOACs 48 hours prior to the procedure.[30] Additionally, there was no statistically significant difference in other outcomes such as stroke, any hematoma, and any adverse event. This trial was terminated early due to futility.

Determine Whether or Not Bridging Anticoagulation

Bridging anticoagulation consists of the substitution of a long-acting anticoagulant (usually with warfarin) for a shorter-acting anticoagulant (usually LMWH) to limit the time of subtherapeutic anticoagulation levels and minimize thromboembolic risk[31]. Despite the growing evidence about the limited to nonexistent benefits of bridging therapy, it is still being used on a case-by-case basis. Clinical scenarios that may benefit from bridging therapy are those involving patients with high thromboembolic risk. In several guidelines, the following scenarios have been proposed:

• The patient with a mechanical heart valve: Mitral valve replacement, aortic valve replacement with additional risk factors (stroke, TIA, cardioembolic event, or intracardiac thrombus), more than 2 mechanical valves.
• Patients with stroke, episode of systemic emboli, or VTE during the last 3 months. Patients presenting with a thromboembolic event after interruption of chronic anticoagulation therapy or those presenting with VTE while on therapeutic anticoagulation.
• Patients with atrial fibrillation and CHA2DS2VASc score > 5 plus additional cardiovascular risk factors (rheumatic valve disease, stroke, or systemic embolism within the last 12 weeks). A CHA2DS2VASc score > 6 with or without additional risk factors.
• Patients with recent coronary stenting (within the previous 12 weeks)

Evidence on bridging therapy follows a trend against its use. Sigeal et al. (2012) performed a meta-analysis of 34 studies, most of them were observational. Despite the criticism of this meta-analysis for its heterogeneity of studies, interesting conclusions were drawn. Regarding the risk of thromboembolism, there was no statistically significant difference between patients that received bridging therapy and those who did not receive bridging therapy(OR:0.80; 95% CI 0.42-1.54). However, the risk of major bleeding had a threefold increase in patients that received bridging therapy compared with patients who did not (OR: 3.60; 95% CI 1.52-8.50).[32]

Large studies of anticoagulation in patients with atrial fibrillation, such as the RE-LY study (warfarin vs. dabigatran), showed that patients on warfarin who received bridging therapy had more thromboembolic events compared with those that did not receive bridging therapy (1.8 vs. 0.3%). Patients that received warfarin plus bridging therapy had a higher risk of major bleeding (warfarin plus bridging therapy 6.8%; warfarin without bridging 1.6%), compared with patients that received dabigatran plus bridging therapy (dabigatran plus bridging therapy 6.5%; dabigatran without bridging therapy 1.8%).[33]

In the BRIDGE (Bridging anticoagulation in patients who require temporary interruption of warfarin therapy for elective surgery) study, 1,884 patients with AF requiring interruption of warfarin anticoagulation therapy were allocated to either a dalteparin or placebo group. There was no difference between groups in arterial thromboembolic events at 30 days after surgery (0.3 vs. 0.4). However, the incidence of major bleeding was higher in the dalteparin bridging group (3.2% vs. 1.3%, P <0.01), as was minor bleeding (20.9% vs. 12.0%, P <0.01). This study was criticized for the exclusion of high thromboembolic risk patients.[34]

The PERIOP-2 study examined whether there is any benefit of bridging therapy after surgery. This study was a randomized clinical trial of 1,471 enrolled patients, 304 of which had a mechanical valve (99 of these had AF at the same time). There were no significant differences for major thromboembolic episodes between dalteparin and placebo (0.71% vs. 1.11%, respectively). For episodes of major bleeding, this study showed no benefit of using dalteparin vs. placebo during the postoperative period (1.46% vs. 2.46%, respectively).

Treatment / Management

How to bridge

Our bridging recommendations follow the AT9 guidelines, which agree with the American Society of Regional Anesthesia (ASRA) 2018 guidelines and are similar to the American College of Surgeons 2018 guidelines.[4][12][18]

During the preoperative period:

• Discontinue warfarin five days before surgery.
• Three days before surgery, start subcutaneous LMWH or unfractionated heparin (UFH), depending on the renal function of the patient at therapeutic doses.
• Two days before surgery assess INR, if greater than 1.5 vitamin K can be administered at a dose of 1 to 2 mg.
• Discontinue LMWH 24 hours before surgery or 4 to 6 hours before surgery if UFH.

During the postoperative period:

• If the patient is tolerating oral intake, and there are no unexpected surgical issues that would increase bleeding risk, restart warfarin 12 to 24 hours after surgery.
• If the patient received preoperative bridging therapy (high thromboembolic risk) and underwent a minor surgical procedure, resume LMWH or UFH 24 hours after surgery. If the patient underwent a major surgical procedure, resume LMWH or UFH 48 to 72 hours after surgery.
• Always assess the bleeding risk and adequacy of homeostasis before the resumption of LMWH or UFH[35]

How to Manage Patients on DOAC Anticoagulation Therapy Undergoing Elective Surgery

It is important to note that bridging therapy is not indicated in patients on DOACs. The predictable pharmacological effect of DOACs allows a properly timed interruption of anticoagulation therapy before surgery. Various societies have issued recommendations about the timing of DOAC interruption. Our recommendations are based on the American College of Cardiology Expert Consensus (2017), European Heart and Rhythm Association (2018), American Society of Regional Anesthesia (ASRA) (2018).[4][19][20]

The appropriate timing interruption for patients on DOAC anticoagulation is based on the invasiveness and bleeding risk of the procedure, pharmacokinetic profile of the DOAC, and clinical characteristics of the patient (renal function and liver function, see Table.4). As a common recommendation among guidelines, DOACs should be held 3 half-life times before low-risk procedures and 5 half-life times before high-risk procedures. Nevertheless, there are some procedures considered less than low bleeding risk, such as a colonoscopy without biopsy, where DOAC therapy may be continued.(see table.4)

Betrixaban is a new inhibitor of factor Xa. Though many aspects of the clinical use of this drug are still under study, ASRA (2018) recommends betrixaban interruption at least 72 hours before a neuraxial block. ASRA also recommends at least 5 hours between catheter removal and reinitiation of the drug.[36]

In 2019, a new strategy was published in the PAUSE study, a prospective clinical trial evaluating a standardized approach for perioperative management of DOACs. The interruption scheme used in this study was simple. For high bleeding risk procedures, rivaroxaban, apixaban, and dabigatran were suspended 48 hours before surgery in patients with CrCl>50 ml/min. If the renal function was compromised (CrCl< 50 ml/min), these drugs were interrupted for four days before surgery. For low bleeding risk procedures, rivaroxaban, apixaban, and dabigatran were interrupted 24 hours before surgery in patients with CrCl>50 ml/min. If the renal function was compromised (CrCl <50 ml/min), drugs were suspended two days before the procedure. Regardless of renal function, all drugs were reinitiated at 48 hours for high bleeding risk surgical procedures and 24 hours for low bleeding risk procedures. The 30-day postoperative rate of major bleeding was 1.35% (95% CI, 0%-2.00%) and rate of arterial thromboembolism of 0.16% (95% CI, 0%-0.48%). However, more studies are needed in patients with high surgical bleeding risk.[37]

How to Manage Antithrombotic Therapy in Patients Undergoing Elective Surgery

Ideally, patients with recent coronary stent implantation should postpone elective surgery during critical periods post-placement (6 weeks for bare metal stents and 6 months for drug-eluting stents). If elective surgery cannot be postponed, dual antithrombotic therapy should be continued throughout the perioperative period. In patients at high risk of cardiac events, aspirin should be continued throughout the perioperative period, with clopidogrel and prasugrel discontinued 5 days prior to surgery and resumed 24 hours postoperatively. For patients at low risk of cardiac events, dual antiplatelet therapy can be discontinued 7 to 10 days before surgery and restarted 24 hours postoperatively.[4]

Considerations for Patients Undergoing Neuraxial Anesthesia

The following recommendations for neuraxial puncture and catheter removal are based on the European Society of Anesthesiology and ASRA. Included in these recommendations are the timelines for interrupting and resuming anticoagulation after the puncture, catheter manipulation, or removal.

For patients treated with intravenous UFH, the infusion should be interrupted 4-6 hours before puncture or catheter removal/manipulation. However, if the patient is receiving UFH subcutaneously, the drug should be interrupted 8-12 hours before puncture or catheter removal/manipulation. Independent of the route of UFH administration, the drug can be restarted 1 hour after puncture or catheter removal/manipulation.

For patients receiving a prophylactic dose of LMWH, the drug should be interrupted for 12 hours before puncture or catheter removal/manipulation and 24 hours if the dose is therapeutic. Independent of LMWH dose, the drug may be restarted 4 hours after puncture or catheter removal/manipulation. If the patient is receiving fondaparinux at a prophylactic dose (2.5 mg/day), it should be stopped 36-42 hours before any neuraxial approach and might be resumed 6 to 12 hours post-procedure.

For patients receiving DOACs, the time of interruption will vary according to the specific drug. Patients on rivaroxaban at a prophylactic dose (less than 10 mg/day) should have the drug interrupted 22 to 26 hours before a neuraxial approach. If the patient is on apixaban at a prophylactic dose, it should be discontinued 26 to 30 hours before a neuraxial puncture or catheter placement. Both of these drugs may be restarted 4 to 6 hours after the puncture or catheter removal/manipulation. If the patient is on coumarin anticoagulation, the INR should be less than 1.4 before any neuraxial approach.

Drugs such as NSAIDs, including aspirin, do not require interruption for neuraxial anesthetic interventions. However, others such as cilostazol will require 42 hours of an interruption prior to neuraxial anesthesia and can be resumed 5 hours after the puncture or catheter removal.[4]

How to Perform Emergency Reversal of Anticoagulation

Definitions of emergency and urgent surgery can vary slightly between guidelines. An urgent procedure is defined as one that can be delayed up to 24 hours, giving time to the physician to conduct anticoagulation reversal based on repeated coagulation tests. On the other hand, the emergent scenario can be defined as one in which the patient requires surgical intervention in less than 1 hour or is experiencing life-threatening bleeding. In emergent cases, the amount of time, number of coagulation tests that can be performed, and opportunities to delay the procedure until the bleeding risk is lower are limited.[38]

Reversal of warfarin: For non-significant bleeding with alterations of the INR, conservative strategies such as interruption of the drug and oral vitamin K are suitable options. In the emergent scenario, the reversal of warfarin anticoagulation is based on prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP) administration as follows: 

• INR 2-4: PCC 25 IU/kg IV
• INR ≥4-6: PCC 35 IU/kg IV
• INR >6: PCC 50 IU/kg IV

• Vitamin K: 10 mg IV administered slowly
• FFP: 10 to 20 ml/kg
• Trauma patients: 1 gm of tranexamic acid can be used at arrival and repeat dose of 1 gm in 8 hours
• PCC is commercially available as prothrombin complex concentrate both contain heparin and are thus contraindicated in patients with a past medical history of heparin-induced thrombocytopenia.[13]

The required time for anticoagulant reversal and INR correction with vitamin K and PCC are 6 to 24 hours and 15 minutes after 10-minute to 1-hour infusion, respectively. FFP should be administered if there is ongoing bleeding or PCC is not available. The timing of anticoagulation reversal depends on the timing to complete infusion. Complete reversal usually takes up to 32 hours. PCC must be administered with vitamin k. [39]

Reversal of DOACs: The FDA recently approved andexanet alfa for the reversal of the anticoagulative effects of apixaban and rivaroxaban.[40] The effects of andexanet alfa also seem to be extended to betrixaban and edoxaban; however, more studies are needed. DOAC anticoagulation represents a problem for the clinician. For several years, the first-line option for the reversal of anticoagulation was PCC. However, evidence about prothrombin complex concentrate effectiveness is controversial, and with the approval of new specific reversal medications, its future use is uncertain (see table 5). What is known is that the cost of the specific new reversal drugs is still high, limiting their use and widespread availability. A complete reversal treatment with andexanet alfa can cost around $50,000, compared to the cost of full treatment with prothrombin complex concentrate, about $5,000.[41]

Differential Diagnosis

• Acute Anemia

• Afibrinogenemia

• Child abuse

• Dysfibrinogenemia

• Epistaxis

• Factor V deficiency

• Factor X deficiency

• GI bleeding

• Idiopathic Thrombocytopenic Purpura

• Liver failure

• Munchausen syndrome

• Subdural hematoma

• Type A haemophilia

• Type B haemophilia

Complications

There are two major complications of poor management of perioperative anticoagulation. The first is bleeding, which occurs if the provider fails to interrupt anticoagulation therapy in an appropriate timeframe. On the other hand, however, patients who have their anticoagulation interrupted too early in the perioperative period are at high risk of thromboembolic events, as surgical procedures themselves induce a hypercoagulable state. Thus, appropriate interruption of anticoagulation in the perioperative period is a delicate balancing act between the potentially severe complications of bleeding and thrombosis, requiring strict attentiveness of the managing provider.

Enhancing Healthcare Team Outcomes

Managing perioperatively the patient receiving anticoagulation therapy is the responsibility across all disciplines of the healthcare team. First, it is the responsibility of the nurse to ensure the information on anticoagulation therapy and diagnoses is correct for the patient upon admission for preoperative testing/physical exam. During the preoperative visit, the surgeon and anesthesiologist in charge then have the responsibility of ensuring this information is correct and then deciding how the patient will be managed perioperatively. Once that decision is made, it is the responsibility of the physician to explain this information in detail, the nurse to review this before discharge, and finally, the pharmacist to answer any questions and/or reiterate this information.

On the day of surgery, operative nurses, physicians, and pharmacy personnel have their usual duties of ensuring the patient receives appropriate operative care per protocol for the procedure. Postoperatively, the physician has the responsibility of placing orders for either continuing to hold to administering the anticoagulation agent, depending on the drug and the patient scenario. However, it is the duty of the recovery room and hospitalization floor nurses to re-check each prescription before administration according to the diagnoses of the patient. Additionally, pharmacy personnel will be in charge of review the pharmacological conciliation of the patient.

Finally, it will be time for the patient to be discharged. The physician will be responsible for writing discharge orders, which may consist of continuing the same anticoagulation regimen that was prescribed preoperatively, changes to the dosage, or even holding medication for some time. Such orders will again be checked by pharmacy personnel. In general, it is the responsibility of the nurse to ensure that discharge instructions are received and understood by the patient, thus completing the interdisciplinary care circle for the patient receiving anticoagulation perioperatively. Only by working as an interprofessional team can the morbidity and mortality related to anticoagulation treatments and physicians errors be diminished. [Level 5]