Perioperative Considerations and Management of Patients Receiving Anticoagulants.

Anticoagulants remain the primary strategy for the prevention and treatment of thrombosis. Unfractionated heparin, low molecular weight heparin (LMWH), fondaparinux, and warfarin have been studied and employed extensively with direct thrombin inhibitors typically reserved for patients with complications or those requiring interventions. Novel oral anticoagulants have emerged from clinical development and are expected to replace older agents with their ease to use and more favorable pharmacodynamic profiles. Increasingly, anesthesiologists are being requested to anesthetize patients who are on some form of anticoagulants and hence it is important to have sound understanding of pharmacology, dosing, monitoring, and toxicity of anticoagulants. We searched the online databases including PubMed Central, Cochrane, and Google Scholar using anticoagulants, perioperative management, anesthetic considerations, and LMWH as keywords for the articles published between 1994 and 2015 while writing this review. In this article, we will review the different classes of anticoagulants and how to manage them in the perioperative settings.

INTRODUCTION

Anticoagulants are commonly prescribed for patients at risk of arterial or venous thromboembolism. The most common indications are atrial fibrillation, venous thromboembolism, and presence of mechanical heart valves. Perioperative management of anticoagulant therapy poses a major problem. Rebound hypercoagulability may occur following abrupt cessation of anticoagulation, whereas perioperative anticoagulation increases the risk of bleeding for many invasive and surgical procedures. The consequences of hematoma formation following neuraxial blockade can be catastrophic for the patient and include permanent paraplegia.

We searched the online databases including PubMed Central, Cochrane, and Google Scholar using anticoagulants, perioperative management, anesthetic considerations, and low molecular weight heparin (LMWH) as keywords for the articles published between 1994 and 2015. The guidelines and evidence-based recommendations in this review are based on the guidelines and recommendations by many reputed agencies including the American Society of Regional Anesthesia (ASRA), the American College of Chest Physicians, and the European Society of Regional Anaesthesia (ESRA).

In 2010, the ASRA and the European and Scandinavian Societies of Anaesthesiology published guidelines for regional anesthesia in patients on anticoagulants.[123] Several new oral anticoagulants (NOACs) have been approved by the US Food and Drug Administration since the guidelines appeared; dabigatran in 2010, rivaroxaban and ticagrelor in 2011, and apixaban in 2012. There is also promising new evidence that novel oral anticoagulants may be more effective in thromboprophylaxis and preventing deep vein thrombosis (DVT). In addition, NOACs offer an advantage of fixed-dose administration, reduced need for monitoring, fewer requirements of dose adjustment, and more favorable pharmacokinetics and pharmacodynamics, which are likely to streamline perioperative management, simplify transitioning of agents, diversify bridging therapy options, and reduce therapy costs.[45]

Classification of Drugs Altering Hemostasis

The drugs altering the hemostasis are summarized as shown in Table 1.

Table 1

Summary of drugs altering hemostasis

Warfarin

Warfarin, a coumarin derivative, acts by inhibiting Vitamin K synthesis and thereby limiting the coagulation factors (II, VII, IX, and X) that are dependent on Vitamin K for its production. It has oral bioavailability of 100%,[6] warfarin is 99% protein bound, which means it is easily displaced by other highly protein-bound drugs. It is almost entirely metabolized in the liver, which exposes it to further drug interactions. The anticoagulant effect can be best measured by prothrombin time (PT) and international normalized ratio (INR). Warfarin is administered orally, and the dosage is based on the indication. Warfarin is started with the initial dose of 2–5 mg/day orally for 1–2 days and maintenance in the range of 2–10 mg once daily depending on the PT and INR values.

Anesthetic management

Anesthetic management of patients anticoagulated perioperatively with warfarin depends on dosage and timing of initiation of therapy. The PT and INR of patients on chronic oral anticoagulants requires 3–5 days to normalize after discontinuation of anticoagulant therapy. Warfarin is stopped 4–5 days preoperatively (±bridging therapy) and INR should be within reference range before initiation of regional anesthesia.[7] Remove the indwelling neuraxial catheters when the INR is <1.5 to assure that adequate levels of Vitamin K-dependent factors are present. With INR >1.5 but <3 removal of neuraxial catheters should be done with caution and neurological status assessed until INR has been stabilized (levels <1.5). In patients with an INR >3.0, warfarin should be withheld/reduced with concurrent neuraxial/deep perineural catheters.[8]

Heparin

Heparin is a naturally occurring mucopolysaccharide with a molecular size of 5000–25,000 daltons. It exists in its unfractionated form or fractionated form.

Unfractionated heparin

It is a mucopolysaccharide with an average molecular weight of 15,000–18,000 daltons. It acts by binding reversibly to antithrombin III, accelerating its action on coagulation factors XII, XI, X, IX, plasmin, and thrombin. It also inhibits platelet activation by fibrin.

Unfractionated heparin (UFH) is administered parenterally, both subcutaneous (S/C) for its prophylaxis and as a continuous intravenous (IV) infusion when used therapeutically. IV heparin is usually given as a bolus of 100 U/kg followed by approximately 1000 U/h titrated to achieve an activated partial thromboplastin time (aPTT) of 1.5–2.5 times the control.

The effect of heparin is reversed using protamine in the dose of 1 mg for 100 U of UFH. Six side effects include heparin-induced thrombocytopenia (HIT) and osteoporosis.[9]

Anesthetic management of patients receiving UFH should start with review of medical records to determine any concurrent medications that influence clotting mechanisms. There is no contraindication to regional anesthesia with 5000 units twice daily S/C UFH (prophylaxis). Risk of bleeding are reduced by delaying heparinization until block completion, but may be increased in debilitated patients following prolonged heparin therapy. Safety of neuraxial/deep-peripheral nerve block (PNB) in those receiving UFH >10,000 U/day or twice daily dosing has not been determined, and thrice daily UFH can lead to increased risk of bleeding.[10]

HIT can occur during administration, so it is recommended that patients receiving heparin for more than 4 days be assessed (i.e., platelet count) before deep-PNB/neuraxial blockade or catheter removal.

A study conducted by Warkentin et al., on 665 patients receiving S/C UFH or LMWH for thromboprophylaxis following hip surgery, reported 2.7% incidence of HIT in those receiving UFH and 0% in patients receiving LMWH.[11] This study defined HIT as a decrease in the platelet count in the presence of antiplatelet antibodies.

Intraoperative heparin anticoagulation during vascular surgery combined with neuraxial anesthesia is acceptable with the following:

Avoiding neuraxial techniques in patients with coagulopathies

Delaying heparinization for 1 h following nontraumatic needle placement

Using concentration of local anesthetic that permits neurological evaluation

Monitor patients postoperatively for evidence of neurodeficits

Removing neuraxial catheter 2–4 h following last heparin dose

Assessing coagulation status, then resume 1 h following catheter removal

Occurrence of bloody/difficult neuraxial blockade in vascular surgery and plan for intraoperative heparin can increase bleeding risk. However, there is no data to support mandatory surgery cancellation. Therefore, risk-benefit decision should be conducted with the surgeon and

Using low-dose anticoagulation (5000 U) and delaying administration for 1–2 h

Avoiding full intraoperative heparin 6–12 h

Postponing surgery to the next day should be considered.

At therapeutic doses, UFH should be interrupted at least 4 h before performing neuraxial procedures and/or removal of neuraxial catheter

In situations of full anticoagulation (i.e., cardiac surgery), risk of hematoma is unknown when combined with neuraxial techniques. Therefore, if using neuraxial anesthesia during cardiac surgery, it is suggested to monitor neurologic function and select local anesthetic that minimize motor blockade to facilitate detection of neurodeficits.[7]

Low molecular weight heparin

LMWH include dalteparin, enoxaparin, and tinzaparin.

LMWH has an average molecular weight of 2000–10,000 daltons with a greater ability to inhibit factor Xa, than thrombin.[6] It has a more predictable dose response curve and is administered at fixed dose, based on total body weight.

LMWH has 100% bioavailability and reaches peak levels 2–4 h after S/C administration. It has a half-life of 3–4 h, and is eliminated primarily via renal clearance, necessitating dose reduction in patients with renal insufficiency. Factor Xa levels are used to monitor the effects of LMWH; ideally, factor Xa levels should be obtained 4 h after the administration of LMWH.

LMWH is indicated for thromboprophylaxis and treatment of DVT/pulmonary embolism, myocardial infarction. LMWH has been demonstrated to be efficacious as a bridge therapy for patients anticoagulated with warfarin including parturients, patients with prosthetic heart valves, or preexisting hypercoagulable condition.

Properties of LMWH differ from UFH in the following ways:

Lack of monitoring of anticoagulant response (anti-Xa level not predictive of risk)

Prolonged elimination half-life

Anti-Xa activity present 12 h postinjection

Unpredictable response to protamine.[1213]

There is increased risk of hematoma with concomitant use of hemostasis altering medications. Altered coagulation can occur with preoperative LMWH thromboprophylaxis, and it is recommended that deep-PNB/neuraxial placement be delayed 10–12 h after the last dose. In patients receiving therapeutic LMWH, delay of 24 h (minimum) is recommended to ensure adequate hemostasis at the time of regional anesthesia.

It is not recommended to perform neuraxial/deep-PNB techniques in patients receiving LMWH 2 h preoperatively because needle placement would occur at peak anticoagulant activity.

Management of postoperative LMWH thromboprophylaxis and neuraxial/deep-PNB techniques is based upon:

Time to first postoperative dose

Total daily dose

Dosing schedule.

Neuraxial/deep-PNB can be safely performed with LMWH single-daily dosing with first dose administered 6–8 h postoperatively after confirming adequate hemostasis and second dose not sooner than 24 h later. Catheters may be maintained, but should be removed at a minimum of 10–12 h following the last dose of LMWH and subsequent dosing at a minimum of 2 h after catheter removal. Additional hemostasis altering medications should be avoided.

Twice daily postoperative LMWH is associated with increased risk of hematoma formation, so first dose should be delayed postoperatively along with evidence of adequate hemostasis. Catheter should be removed before twice daily LMWH initiation, and subsequent dosing delayed 2 h postcatheter removal.[7]

FACTOR XA INHIBITORS

Fondaparinux

Fondaparinux is a synthetic pentasaccharide that has potent anticoagulant activity. It selectively inhibits factor Xa. It is licensed for use in thromboprophylaxis in medical patients and in patients undergoing major lower limb orthopedic surgery or abdominal surgery. After a single S/C injection, peak plasma concentration occurs after 2 h. The half-life is 17–21 h in healthy patients, but this may be significantly prolonged in renal impairment.

The hematoma risk for patients receiving fondaparinux remains unknown, so management consensus statements are based on sustained and irreversible effects, dosing/timing. Therefore, until further experience becomes available, performing deep-PNB/neuraxial techniques should occur as single needle pass, avoidance of analgesic catheters, and avoiding regional anesthesia with therapeutic dosing. Recent ASRA and ESRA consensus indicates a 3–4 days interval before performing regional anesthesia procedures and then resuming medications 12–24 h postprocedure.[14]

Rivaroxaban

Rivaroxaban is an oral administered factor Xa inhibitor, with maximum effect 1–4 h, terminal elimination half-life of 5–9 h, administered once/day for thromboprophylaxis, first dose 6–8 h postsurgery, but antidote not available. Clinicians should adhere to regulatory recommendations and label inserts, particularly in clinical situations associated with bleeding. The antithrombotic effect can be monitored with PT, aPTT, Heptest, all of which demonstrate linear dose effects.[215] Investigations comparing rivaroxaban LMWH demonstrated similar efficacy and rates of bleeding. Rivaroxaban is cleared by liver, gut, and kidney, but clearance time can be prolonged in the elderly (13 h) secondary to decline of renal function (dose adjustment with renal insufficiency and contraindicated in liver disease).[16]

Recently published interim update to ASRA anticoagulation and recent ESRA/world institute of pain consensus recommend an interval of 3 days before regional anesthesia and delaying drug administration 6 h postprocedure.[1718]

Apixaban

Apixaban is an orally administered reversible direct factor Xa inhibitor. It is rapidly absorbed, attaining peak concentration in 1–2 h elimination half-life of 10–15 h. Elimination is 25% renal and 75% hepatic/biliary with intestinal excretion.[7]

An update to ASRA anticoagulation and recent consensus by ESRA, ASRA, and World Institute of Pain regarding apixaban and regional anesthesia suggest a 3–5-day interval between last apixaban dose and deep-PNB/neuraxial interventions.[1417] As experience with this agent is limited, along with wide-ranging pharmacokinetics of apixaban therapy, it is warranted to delay postprocedure administration by 6 h.[1419]

Danaparoid

Danaparoid is an indirect factor Xa inhibitor with coagulation effects through antithrombin-mediated inhibition of factor Xa. It is a glycosaminoglycan mixture containing 84% heparin sulfate, dermatan sulfate, and chondroitin sulfate resulting in 10% incidence of HIT.[2021] It has a long elimination half-life of 22 h that could be prolonged with renal insufficiency. There is no antidote, coagulation monitoring can be done by measuring anti-Xa activity. It cannot be hemofiltered, but can be removed using plasmapheresis. It is used as an alternative in patients with HIT.[7]

THROMBIN INHIBITORS

Hirudins: Desirudin, lepirudin, and bivalirudin

These recombinant hirudins are first-generation direct thrombin inhibitors and are indicated for thromboprophylaxis (desirudin), prevention of DVT and pulmonary embolism after hip replacement,[16] and DVT treatment in patients with HIT.[22]

They are administered by parenteral route, have an elimination half-life of 30 min to 3 h, can accumulate in renal insufficiency and should be monitored using aPTT and ecarin clotting time (ECT).

Lepirudin has been associated with antibody formation (incidence 40%), delayed elimination, unpredictable and prolonged activity, as well as association with bleeding and anaphylaxis.[23]

No statement regarding risk assessment and patient management can be made owing to the lack of information and application of these agents.

Administration of thrombin inhibitors with other antithrombotics should always be avoided. In those rare circumstances where regional anesthesia would be planned, it is recommended to wait for a minimum of 8–10 h following the last dose, along with evidence of aPTT or ECT within normal limits before proceeding with needle puncture, and then waiting for at least 2–4 h postprocedure before next dosing. However, secondary to potential bleeding issues and route of administration, the trend with these agents have been replaced with factor Xa inhibitors or argatroban for acute HIT.[7]

Argatroban

It is intravenously administered reversible and a direct thrombin inhibitor approved for the management of acute HIT (type II). Advantages or uniqueness over other thrombin inhibitors includes its elimination through the liver (indication in compromising renal dysfunction) and short elimination half-life (35–40 min) that reveals normalization of aPTT in 2–4 h following discontinuation. However, dose reduction should be considered in critically ill patients and those with heart failure or impaired hepatic dysfunction.[7]

Dabigatran

An oral inhibitor approved for thromboprophylaxis (similar efficacy to LMWH and warfarin without increased risk of bleeding). Dabigatran etexilate is a prodrug that specifically and reversibly inhibits both free and bound clot. The prodrug is absorbed from the gastrointestinal tract with a bioavailability of 5%.[24] Once absorbed, it is converted by esterases into active metabolite, dabigatran. Plasma level peaks at 2 h. The half-life is 8 h after single dose and up to 17 h after multiple doses.[5] Eighty percent of the drug is excreted unchanged by the kidneys; it is contraindicated in patients with renal failure. Dabigatran prolongs aPTT but its effect is not linear and reaches plateau at higher doses. However, the ECT and thrombin time are particularly sensitive and display a linear dose response at therapeutic concentrations. Reversal of anticoagulant effect is theoretically possible through administration of recombinant factor VII a, although this has been attempted clinically.[16]

Indeed, product labeling suggests that dialysis can be considered for patients with significant bleeding with dabigatran.[1]

ASRA anticoagulation (2010) interim update and the published consensus by ASRA, ESRA, and World Institute of Pain suggests waiting 4–5 days from last administration before performing regional anesthesia, 6 days to initiate medication post-RA, and 6 h between removal of neuraxial catheter and the next dose.[141719]

Thrombolytics/fibrinolytics

Thrombolytic agents act by converting plasminogen to the natural fibrinolytic agent plasmin. Plasmin lyses the clots by breaking down fibrinogen and fibrin contained in the clot. Clot lysis elevates fibrin split/degradation products.

Thrombolytic therapy will maximally depress fibrinogen and plasminogen for 5 h following therapy and remain depressed for 27 h.[25]

Original recommendations to initiate thrombolytic therapy was contraindicated within 10 days following neuraxial/deep-PNB procedures and surgery, but in a recent consensus statement by ASRA and ESRA, it was reduced to 2 day minimum and performing assessments every 2 h for neurological deficits. The 2 day minimum is based on prolonged plasminogen depression for 27 h.[14]

Definitive data are not available on when to discontinue these agents and safe time to neuraxial/deep-PNB placement which ranges from 24 h to 10 days,[25] but it should be noted that clots are stable for 10 days postthrombolytic therapy.[14]

There are no recommendations for the removal of analgesic catheters for patients receiving fibrinolytic/thrombolytic medications, but fibrinogen levels can provide guidance on thrombolytic effect and timing of catheter removal.

Antiplatelet medications

Aspirin and other nonsteroidal anti-inflammatory drugs when administered alone during perioperative period are not considered a contraindication to regional anesthesia.[7] In patients on combination therapy with medication that affect coagulation, clinicians should be conscious about neuraxial and deep-PNB techniques due to increased risk of bleeding.[262728] Cyclooxygenase 2 inhibitors have shown minimal effect on platelet function, consider safe for patients receiving regional anesthesia, and without additive effects in the presence of anticoagulation therapy.[1429]

Thienopyridine derivatives include clopidogrel, prasugrel, and ticagrelor which act by inhibiting P2Y12 receptor. The use of aspirin and a P2Y12 receptor inhibitor, the so-called dual antiplatelet therapy (DAPT), has dramatically reduced atherothrombotic events in patients with acute coronary syndrome and those who undergo percutaneous coronary intervention (PCI).[3031] A minimum of 6 weeks DAPT after bare metal stent insertion and at least 12 months after drug-eluting stent placement is recommended to avoid thrombotic complications.[32]

Invasive procedures are occasionally considered for patients with coronary stents on DAPT. If at all possible, such procedures should be differed for at least 6 weeks in those with bare metal stents and 6 months in those with drug-eluting stents.[33] If surgery cannot be delayed, consultation with a cardiologist is strongly recommended before any planned interruption of treatment. In these scenarios, PNBs or general anesthesia might be preferable.[33]

Platelet dysfunction is present for 5–7 days after discontinuation of clopidogrel and 10–14 days for ticlopidine. Prasugrel is a new thienopyridine which inhibits platelets more rapidly, more consistently, and to a greater extent than do standard and high doses of clopidogrel. The platelet aggregation normalizes in 7–9 days after discontinuation of prasugrel.[15]

Glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonist such as abciximab, eptifibatide, and tirofiban are primarily used in a management of acute coronary syndrome and PCI.

Antiplatelet medication including thienopyridine derivatives and platelet GPIIb/IIIa antagonist can have diverse pharmacologic effects on coagulation and platelet function. Such variable differences cause difficulty when considering regional anesthesia, as there are no acceptable tests that will guide antiplatelet therapy. Therefore, preoperative assessment should search for health considerations that contribute to altered coagulation. Risk of hematoma formations with these drugs in combination with regional anesthesia is unknown. Therefore, management is based on labeling and surgical reviews.

Time between discontinuation of therapy and neuraxial/deep-PNB is 14 days for ticlopidine and 5–7 days for clopidogrel.

If performing regional anesthesia is indicated before completing suggested time interval, then normalization of platelet function should be demonstrated.

GPIIb/IIIa inhibitors exert an effect on platelet aggregation and time to normal platelet aggregation is 24–48 h for abciximab and 4–8 h for eptifibatide and tirofiban following discontinuation.[15] GPIIb/IIIa antagonists are contraindicated within 4 weeks of surgery and patients need to be monitored neurologically if such medications are administered in the postoperative period subsequent to neuraxial/deep-PNB.[7]

Summary

The clinical guidelines and protocols are helpful in deciding the plan of anesthetic management tailored to each patient. These clinical guidelines and protocols are summarized in Table 2.[715]

Table 2

Summary of clinical guidelines and protocols

CONCLUSION

The management of anticoagulants in the perioperative period is based on their pharmacokinetics and pharmacodynamic profile. Understanding clinical indications for the drugs will make an anesthesiologist more aware of the risks of discontinuation. Several NOACs offer oral routes of administration, simple dosing regimen, efficacy with less bleeding risks, reduced requirement for clinically monitoring. Due to safety concerns of bleeding risks, guidelines, and recommendations have been designed to reduce patient morbidity/mortality during regional anesthesia. Patient-specific factors and surgery-related issues should be considered to improve patient-oriented outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.