10 University of Cape Town The novel oral anti-coagulant

Part I Anaesthesia Refresher Course – 2017 University of Cape Town

10

The novel oral anti-coagulant drugs (NOACs)

Dr Felipe Montoya-Pelaez

UCT Dept of Anaesthesia & Perioperative Medicine

Introduction

Due to changes and improvements in treatment protocols for conditions where a high risk of thrombotic or thromboembolic phenomena exist, it is becoming increasingly common for anaesthetists to care for patients taking a variety of anticoagulant drugs in the perioperative period. Risks of anaesthesia and surgery in this group of patients are self-evident, including the possibility of complications related to the withdrawal or withholding of these drugs pre and post-operatively. Anticoagulant pharmacopoeia was, up until the early 2000s, restricted to warfarin, heparin and its derivatives and aspirin. The limitations of these agents (inter-patient variability in response, the need for ongoing monitoring, thrombocytopaenia and the need for parenteral administration) have necessitated the development of newer agents. Presently, a new variety of drugs, effective orally and targeting novel areas in the coagulation cascade, are in widespread use for conditions such as prophylaxis of thrombo-embolic phenomena in inherited and acquired conditions, atrial fibrillation, patients with mechanical heart valves and prophylaxis and treatment of DVT and pulmonary embolism. This review will discuss only orally ingested drugs introduced into clinical practice within the past 15 years:

1) Anti-platelet agents – P2Y12 receptor antagonists: Clopidogrel, Prasugel and Ticagrelor 2) Anticoagulants – Direct thrombin inhibitors: Dabigatran

Factor Xa inhibitors: Rivaroxaban, Apixaban and Fondaparinux

1) Antiplatelet agents – P2Y12 receptor antagonists Clopidogrel

Clopidogrel is a prodrug. Only a small portion (15%) is metabolised to its active thiol metabolite in a 2 step metabolic pathway involving cytochrome P450 enzymes in the liver (specifically CYP2C19, CYP1A2, CYP2B6, CYP2C9 and CYP3A4). The rest is hydrolysed by carboxylesterase 1(CES-1) to an inactive carboxylic acid derivative that accounts for 85% of clopidogrel-related compounds. Clopidogrel irreversibly inhibits the binding of ADP to the P2Y12 receptor on the platelet membrane. Two receptors, P2Y12 and P2Y1 when activated by ADP, result in the activation of the GPII/IIIa glycoprotein complex which initiates platelet aggregation. Activation via P2Y12 is the more potent pathway (figure 1). This effect lasts for the lifetime of the platelet. Clopidogrel also has anti-inflammatory effects, achieved by decreases in the expression of platelet-dependent inflammatory markers (C-reactive protein etc.)

Clopidogrel bisulfate, a second generation thienopyridine derivative, is a relatively novel anti-platelet agent indicated for the treatment and prevention of arterial thrombosis in patients at high risk of acute myocardial syndromes (ACS), ischaemic stroke and peripheral vascular disease. Clopidogrel may be used as a single agent in preventative treatment of arterio-thrombotic events or as dual anti-thrombotic therapy with aspirin in patients who have had an acute myocardial infarct, or have undergone a percutaneous coronary intervention (PCI) with or without stent insertion.

NOACs Dr F Montoya-Pelaez

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Figure 1

Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral dose. Repeated doses of 75 mg per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg Plavix per day was between 40% and 60%. Peak inhibition may be achieved within 2 hours by administering a loading dose of 300-600mg followed by 75mg to 150mg daily (for patients with ACS undergoing PCI with or without stenting). Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days. Oral administration leads to rapid absorption (>50% of administered dose) which may be enhanced by food intake. After a 75mg oral dose of clopidogrel, 50% is excreted in the urine and 46% in faeces over a period of about 5 days. It has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.

Like aspirin, clopidogrel shows considerable interpatient variability in its pharmacokinetics and dynamics. This is clinical relevant because non-responders are at increased risk of thrombotic events whilst on apparently adequate dosing regimens. The prevalence of clopidogrel resistance varies widely, reported at between 4 and 30%. Potential mechanisms of resistance can be classified as extrinsic or intrinsic (table 1). Pharmacogenetic factors also play a major role in determining whether a patient is a good or poor drug responder. Genetic polymorphisms that affect the pharmacology of clopidogrel include mutations of enzymes involved in its metabolism, the most important being those involving the CYP2C19 enzyme. Genetic polymorphisms affecting the P2Y12 receptor are also thought to result in degrees of resistance to clopidogrel but studies looking into this phenomenon have been inconclusive.

Table 1: Potential mechanisms of Clopidogrel resistance ______________________________________________________________________ Extrinsic mechanisms:

1. Patient non-compliance 2. Inappropriate dosing 3. Drug-drug interactions involving CYP3A4 and CYP2C19

Intrinsic mechanisms: 1. Genetic variables

a. Polymorphisms of P2Y12 receptor b. Polymorphisms of CYP2C19

2. Increase release of ADP 3. Alternate pathways of platelet activation

a. Failure to inhibit catecholamine-mediated platelet activation (epinephrine) b. Greater extent of P2Y1 – dependent platelet aggregation c. Up-regulation of P2Y12 -independent pathways (thrombin, thromboxane A2, collagen)


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Prasugrel

Prasugrel is a third generation thienopyridine. After oral ingestion, it is hydrolysed in the gasto-intestinal tract (but not as extensively as clopidogrel) to an intermediary metabolite which is then activated in the liver by the cytochrome P450 system in a one step process. Prasugrel binds irreversibly to the P2Y12 receptor resulting in up to 90% inhibition of platelet aggregation within 2 to 4 hours of administration. The active metabolite has a half-life of approximately 7 hours. Recovery of platelet function takes longer than clopidogrel with 75% of patients returning to baseline platelet reactivity within 7 days. Variability of response to prasugrel is reduced compared to clopidogrel with CYP variants having little influence on the active metabolites of prasugrel. Equipotent doses of prasugrel compared with clopidogrel in dual therapy with aspirin (TRITON-TIMI 38 trial) showed a rate of primary outcomes (death from cardiovascular causes, non-fatal MI and non-fatal stroke, with a safety end-point of major bleeding) that was lower at 15 months for prasugrel (9.9% vs 12.2%, p,0.001)); a reduced rate of in-stent thrombosis (1.1% vs 2.4%, p<0.001) but a higher rate of bleeding (2.4% vs 1.8%, p=0.03).

Ticagrelor

Ticagrelor is a P2Y12 inhibitor that reversibly binds to a site on the receptor distinct from ADP. It acts directly on the receptor site without requiring metabolic activation. It undergoes enzymatic degradation to at least one active metabolite that is as potent as its parent compound. Maximum plasma concentration and platelet inhibition occurs 1 to 3 hours after administration. The drug has a rapid offset of action with a half-life of 12 hours requiring twice daily dosing. Like prasugrel, it exhibits greater platelet inhibition (60%) than clopidogrel. NICE guidelines based the PLATO trial recommends ticagrelor as a treatment option for patients with ACS or patients with unstable angina who are treated with PCI. The trial, comparing ticagrelor to clopidogrel in dual therapy with aspirin in 18000 patients with ACS demonstrated a lower mortality at 12 months for ticagrelor (4.5% vs 5.9%, p<0.001). There was a similar risk of major bleeding in both groups but the rate of both fatal and non-fatal intracranial haemorrhage was higher in the ticagrelor group.


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Table 2 NICE recommendations for P2Y12 receptor inhibitors as dual therapy with aspirin

2) Oral anticoagulants For more than 60 years vitamin K antagonists (VKAs) such as warfarin have been the mainstay of oral anticoagulation for the prevention of atrial fibrillation associated stroke as well as for the treatment and prevention of deep venous thromboembolism and associated pulmonary embolism. Despite its efficacy in preventing stroke and venous hromboembolism, management of anticoagulation with warfarin can be difficult due to its slow onset and offset of action, narrow therapeutic range (requiring frequent monitoring and dose adjusting) and interactions with a variety of drugs that may enhance or hinder its anticoagulant effect. Consequently, new oral anticoagulants with specific advantages and disadvantages compared to VKAs (table 3), have been introduced that aim to address these challenges. These include the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban and edoxaban. Fondaparinux belongs to the same class of drug but is administered parenterally and will not be discussed further.

Table 3


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In phase III clinical trials involving patients with AF, the direct acting oral anticoagulant agents (DOACs) were at least as effective in preventing stroke and systemic embolic events as warfarin with a reduced all-cause mortality and incidence of intra-cranial haemorrhage. However, non-fatal GI bleeding was increased relative to warfarin. This may be attributed to the lower absorption of DOACs across the GI mucosa compared to warfarin, which may increase the rate of bleeding of susceptible lesions in the GI tract. In the treatment of venous thromboembolism (DVT and PE) DOACs are just as effective as standard therapy with lead-in LMWH or unfractionated heparin followed by oral coumadin drugs. Rates of bleeding were lower with DOACs. Unlike the VKAs, the new oral anticoagulants do not presently have specific reversal agents. Non-specific agents like prothrombin complex concentrates and factor VIIa are effective in a dose dependent fashion. Dialysis may be helpful for removal of dabigatran but not for the factor Xa inhibitors. Several potential antidotes are currently in development. Andexanet alfa is a modified recombinant factor X produced from Chinese hamster ovary cells. It lacks intrinsic procoagulant effects and is able to bind direct factor Xa inhibitors without interfering with the coagulation cascade. Another promising antidote under development is aripazine. It binds non-covalently to and inhibits the activity of both direct and indirect anticoagulants, including both oral and parenteral agents. Dabigatran

Rivaroxaban

Rivarobaxan

R hances absorption.

Dabigatran etixalate is a competitive, highly specific direct thrombin inhibitor. It is administered as an inactive drug and converted to its active form by ester hydrolysis. It has a rapid onset of action (1-2 hours) and has a half-life of 12-17 hours. It is 35% bound to plasma proteins with 80% of an administered dose excreted by the kidneys. Recommended dosages are 150mg BD and 110mg BD for patients over 80 years old or those at a high risk of bleeding. Lower doses are recommended for patients with reduced renal function. Dabigatran etexilate is a substrate for the transmembrane transporter P-glycoprotein (P-gp). Drugs that inhibit P-gp (e.g verapamil and amiodarone) increase the bioavailability of dabigatran

Rivaroxaban is a direct, competitive and dose dependent inhibitor of factor Xa. It is rapidly absorbed and reaches peak plasma concentrations within 2-4 hours and has a half-life of 9-13 hours. It is highly protein bound (up to 95%). 35% of an administered drug is cleared by the kidney, the rest is metabolised in the liver by the cytochrome P450 enzyme complex (CYP3A4 and CYP2J2). Treatment with P450 iso-enzymes and P-gp inhibitors such as itraconazole and voriconazole is contraindicated due to an increased risk of bleeding. Enzyme inducers such as carbamazepine, phenytoin and St John’s Wort are liable decrease anticoagulant effect. Recommended dosing for stroke prevention in AF is 20 mg daily with VTE prophylaxis at 10mg daily. Renal dysfunction mandates dose reduction. Food enhances absorption.


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Apibaxan

Edoxaban

Edoxaban

Edoxaban is another direct factor inhibitor. Peak plasma concentrations of the drug occur 1-2 hours following oral administration. It has a bioavailability of 62% and is 55% protein bound. Most of the drug remains unchanged in the plasma although there is minimal metabolism via hydrolysis, conjugation and oxidation by CYP3A4. 50% of the drug is eliminated unchanged in faeces with approximately 50% the urine. Over70% of the drug is eliminated unchanged with an elimination half-life of 9-11 hours. Dosing ranges from 60mg daily to 30mg daily in patients with reduced creatinine clearance (less than 50ml/min). Interestingly edoxaban is not recommended in patients with creatinine clearances of >95mls/min due to an increased incidence of stroke compared to patients on warfarin. Although edoxaban appears to have fewer drug interactions than other direct Xa inhibitors it still has potentially clinically important interactions with inhibitors or inducers of the P-gp efflux transporter.

Table 4: Pharmacology of the novel oral anti-coagulants

Apibaxan is a direct, competitive and selective inhibitor of factor Xa and, like the dabigatran and rivaroxaban, it is approved for stroke prevention in AF and VTE prophylaxis in orthopaedic surgery. It is well absorbed, achieving peak plasma concentrations in 1-4 hours. Plasma half-life is approximately 12 hours. 50% is faecally excreted, 25 percent via the kidney. Apixaban is a substrate for both P-gp and CYP3A4. It is administered orally in a dose of 5mg twice daily with half this regimen recommended for patients aged over 80 years, patients weighing less than 60 kg and those with a serum creatinine of > 133μmol/L.


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Management of patients presenting for elective surgery There is a paucity of evidence available to guide the management of these new medications around the time of surgery. Because of the large inter-patient variability in drug handling and the unpredictability of residual anticoagulant effect, decisions in the perioperative period must be tailored to individual patients balancing the risk of significant bleeding against that of thromboembolic events. If the patient is undergoing a procedure with a low or minor risk of bleeding then it is reasonable to continue treatment; conversely, if a patient is at a low-risk of thrombosis undergoing a procedure with a high-risk of bleeding then the treatment can be suspended perioperatively. Obviously, the problem arises with patients who are at high-risk for thrombosis undergoing high bleeding risk procedures.

1) Dual anti-platelet therapy (DAPT) In patients with ACS who have had a PCI with the placement of a stent (drug eluting or bare metal) elective surgery should be delayed and DAPT continued for 12 months with a drug eluting and 4-6 weeks for a bare meta stent. The risk of in-stent thrombosis is highest for bare metal stents in the first 6 weeks and for drug eluting stents within the first 6 months. In the 5% of patients undergoing PCI and stent placement that present for non-cardiac surgery, aspirin should be continued and the P2Y12 anti-platelet agent discontinued if the procedure involves areas such as intra-cranial, intra-spinal, intra-ocular, pericardial and neuraxial locations. If appropriate, the patient should be bridged with LMWH or unfractionated heparin. Guidelines for patients with bare metal or drug eluting stents on DAPT who present for elective and emergency surgery are illustrated below (figure 2). Figure 2


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Management of bleeding Although the new anti-platelet agents generally have short half-lives, their effects are long lasting (i.e. the life if the platelet). As no reversal agents exist, the mainstay of treatment is to institute general resuscitative measures as required, withdraw anti-platelet medication and, in extreme circumstances, transfuse platelet concentrates, blood products and FFP.

2) Anticoagulants Similar principles regarding risk of thrombosis against that of bleeding apply to the novel anticoagulants. Although no antidotes exist clinically at present, these drugs generally have a rapid onset and offset so should be easier to manage. The necessity for bridging patients on these drugs prior to surgery can be defined by scoring patients on the CHADS2 and CHA2DS2-VASc scales that assess thrombosis risk in patients with atrial fibrillation.

A patient with a CHADS2 score of 2 and above or a CHA2DS2-VASc score of 5 and above should be bridged with therapeutic LMWH. The oral anticoagulant should be stopped 5 days prior to surgery with therapeutic LMWH started three days prior to surgery. A prophylactic risk surgery in patients with normal renal function, the anticoagulant can be stopped 2 days before surgery with the administration f a prophylactic dose of LMWH the evening prior to surgery. In patients with impaired renal function, (eGFR <80mls/min), treat as for major surgery. Management of bleeding (table 5)

Table 5


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Management of patients presenting for emergency surgery (see above for patients on DAPT). Emergency surgery should be started at least 2 half-lives after the last dose of anticoagulant if time and circumstance permits (>12 hours for dabigatran and >24 hours for rivaroxaban and apixaban). If surgery must happen sooner than suggested above for each drug, treatment should follow the guidelines set out in table 5 above.

Timing of neuraxial block Clopidogrel and prasugel bind irreversibly to the P2Y12 receptor and thus has antiplatelet effects that last for the life of the platelet. Clopidogrel and prasugel should be stopped for at least 7 days before neuraxial anaesthesia. Clopidogrel may be re-started 2 hours and prasugel 6 hours after epidural catheter removal.

Table 6: Timing of Central Neuraxial Block in patients taking novel anticoagulants


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References:

1) Smith F, Telford R. ATOTW-Novel anti-platelet agents and anti-coagulants, 22/09/2014 2) Arora H. New Anticoagulants and Emerging Trends in Regional Anesthesia. Anesthesiologynews.com 3) Thuy Anh Nguyen, Jean Diodati, Chantal Pharand. Resistance to Clopidogrel: A Review of the Evidence. JACC Vol.

45, No. 8, April 19, 2005: 1157-64 4) Xi-Ling Jiang, Snehal Samant, Lawrence Lesko et al. Clinical Pharmacokinetics and Pharmacodynamics of

Clopidogrel. Clin Pharmacokinet (2015) 54: 147-166 5) Guidelines for Neuraxial Anesthesia and Anticoagulation. Intermountain Guidelines.

https://kr.ihc.com/ext/Dcmnt?ncid=520499512&tfrm=default 6) Frank Peacock, Zubaid Rafique, Adam Singer. Direct-Acting Oral Anticoagulants: Practical Considerations for

Emergency Medicine Physicians. Emergency Medicine International, Volume 2016. 7) Joseph John, Sandeep Chopra. “Management of Patients on Antiplatelet Drugs Undergoing Surgery” To Stop OR Not

TO Stop. Medicine Update 2012: Vol 22

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10 University of Cape Town The novel oral anti-coagulant