New Anticoagulants and Antiplatelet Agents : a Primer for the Clinical Gastroenterologist

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New Anticoagulants and Antiplatelet Agents : A Primer for the Clinical Gastroenterologist

P a r t h J . P a r e k h , M D1 , J o n a t h a n M e r r e l l , M D1 , M e r e d i t h C l a r y , M D1 , J o h n E . B r u s h , M D , F A C C2 , 3 and David A. Johnson , MD, FACG, FASGE 4

The discovery of the ﬁ rst oral anticoagulant, warfarin, was a milestone in anticoagulation. Warfarin’ s well-known limitations, however, have led to the recent development of more effective anticoagulants. The rapidly growing list of these drugs, however, presents a challenge to endoscopists who must treat patients on these sundry medications. This review is intended to summarize the pharmacological highlights of new anticoagulants, with particular attention to suggested “ best-practice ” recommendations for the withholding of these drugs before endoscopic procedures. Am J Gastroenterol 2014; 109:9 – 19; doi: 10.1038/ajg.2013.228

Warfarin was the mainstay of oral anticoagulant therapy The coagulation pathways until the recent discovery of more precise targets for therapy. Endothelium – platelet interactions and the coagulation cascade Although warfarin therapy is plagued by a narrow therapeutic serve as the focal points of hemostasis. In primary hemosta- index, variable individual metabolic responses, and numerous sis, the endothelium of a damaged vessel releases adenosine food and drug interactions, newer agents purport to rise above diphosphate, serotonin, and thromboxane A2. Platelets respond these setbacks. Furthermore, although the safety of these new to these cytokines with expression of glycoprotein IIb / IIIa and drugs compared with traditional therapy has been called into platelet – endothelial cell adhesion molecule 1 to form an initial question (1 ), their ease of use makes it unlikely that they will platelet plug ( 2 ). Th e coagulation cascade unfolds simultane- disappear. ously with its intrinsic and extrinsic pathways that lead to the Th is review will explore the mechanisms of action and phar- formation of fi brin (3 ). Figure 1 depicts both the intrinsic and macokinetics of novel anticoagulants and antiplatelet agents. In extrinsic pathways that comprise the coagulation cascade. addition, recommended withholding periods for these drugs for patients undergoing elective endoscopic procedures as well as options for achieving rapid hemostasis in patients undergoing Xa inhibitors emergent endoscopy. Factor Xa inhibitors competitively inhibit activated factor X. Factor Xa unifi es the intrinsic and extrinsic pathways; therefore, these drugs have an impact on the coagulation cascade as a whole. Methods Normally, factor Xa forms a complex with factor Va called prothrom- Using the keywords “ anticoagulant therapy ” , “ antiplate- binase (4 ). Th is enzyme complex then cleaves prothrombin to form let therapy” , and “ antithrombotic therapy” in the search thrombin (see Figure 2 ). Factor Xa inhibitors bind to the active site engines of PubMed, Cochrane Reviews, and Google, we of factor Xa preventing the formation of prothrombinase ( 5). were able to identify peer-reviewed publications, abstracts, and presentations at national society education meet- ings. Searches were restricted to English and there was no Rivaroxaban (Xarelto) restriction placed on years of publication. In addition, we Rivaroxaban is a direct factor Xa inhibitor approved for use in reviewed the manufacturer ’ s prescribing information per- nonvalvular atrial fi brillation and deep vein thrombosis and pul- taining to each agent. All reviews, protocols, recent trials monary embolism treatment and prophylaxis, following large or publications, and manufacturer recommendations per- joint replacement (6 ). taining to the agents discussed were reviewed and evaluated. We extracted information pertinent to the clinical endo- Pharmacodynamics scopist from these sources and present them in this syste- Dosed as a once or twice daily oral tablet, rivaroxaban attains a matic review. peak concentration 2.5– 4 h aft er dosage with a half-life of 5 – 9 h

1 Eastern Virginia Medical School, Norfolk , Virginia , USA ; 2 Sentara Cardiology Specialists, Norfolk , Virginia , USA ; 3 Cardiology Division, Eastern Virginia Medical School , Norfolk , Virginia , USA ; 4 Gastroenterology Division, Eastern Virginia Medical School, Norfolk , Virginia , USA . Correspondence: David A. Johnson, MD, FACG, FASGE , Eastern Virginia Medical School, Gastroenterology, 885 Kempsville Rd Suite 114, Norfolk , Virginia 23502 , USA. E-mail: [email protected]

Intrinsic pathway Extrinsic pathway

Factor XII Factor XIIa

Factor XI Factor XIa Endothelial injury T* Factor X

Factor IX Factor IXa Tissue factor

Factor VIII Factor VIIIa Factor VIIa Factor VII T* Factor Xa

Factor Va Factor V T*

Prothrombin Thrombin (T*)

Fibrinogen Fibrin

Figure 1 . The intrinsic and extrinsic pathways of coagulation: the coagulation cascade (44 ).

Intrinsic activation Extrinsic activation are currently no recommendations on dose adjustment based Surface contact Vessel injury on hepatic function (6,7 ). Th e drug is a substrate of CYP3A4 Factor XII Factor VII and P-glycoprotein transporters. Th erefore, special consideration Factor XI should be given when coadministering medications that inhibit Factor VIII or induce the CYP450 enzymes (see Table 1 for full list) or Factor IXa Factor X P-glycoprotein transport (see Table 2 for full list), as this may change rivaroxaban exposure (8 ).

Prothrombin Reversal agents. Th ere are currently no reversal agents that can be used in the event of an acute bleed in patients taking Factor Xa Rivaroxaban rivaroxaban. Current recommendations are the use of recombinant-activated factor VII and prothrombin complex Thrombin concentrate ( 9 ).

Recommended withholding period before endoscopic procedures. Rivaroxaban should be discontinued at least 24 h before any Fibrinogen Fibrin procedure in individuals with normal kidney function ( 10). Figure 2 . Mechanism of action of rivaroxaban (45 ). An extended washout time of 48 h is recommended for patients with a CrCl < 50 ml / min and elderly patients in general (10,11 ).

(9 – 13 h in elderly). Current manufacturer recommendations are to use with caution in patients with moderate renal impair- Direct thrombin inhibitors ment (defi ned as a CrCl 30 –50 ml / min) and to avoid in patients Th e direct thrombin inhibitors (DTIs) directly inhibit the with severe renal impairment (defi ned as CrCl < 30 ml / min). enzyme thrombin. DTIs are divided into two classes: the bivalents, Regarding hepatic function, there was a noted increase in which bind to both the thrombin active site and exosite-1, and exposure to rivaroxaban when observed in patients with mode- the univalents, which bind solely to the active site (12 ). Figure 3 rate hepatic impairment (Child-Pugh class B); however, there depicts the eff ect of DTIs on thrombin.

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Table 1 . Medications affecting the cytochrome P450 (CYP) Table 2 . Medications requiring P -glycoprotein transporters (47 ) pathway (46 ) Substrates Inhibitors Enzyme Inhibitors Inducers ␤ -Adrenoceptor Immuno- Diverse Antacids antagonist suppressants inhibitors CYP2C9 Amiodarone, capecitabine, Aprepitant, bosentan, cotrimoxazole, etravirine, fl uco- carbamazepine, Cimetidine Bunitrolol Cyclosporine A Verapamil nazole, fl uvastatin, fl uvoxamine, phenobarbital, metronidazole, miconazole, rifampin Ranitidine Carvedilol Sirolimus Quinidine oxandrolone, sulfi npyrazone, Tanilol Tacrolimus Valspodar tigecycline, voriconazole, zafi rlukast Antibiotics Reserpine Cyclosporine CYP1A2 Acyclovir, allopurinol, caffeine, Montelukast, Erythromycin Opioids Ketoconazole cimetidine, ciprofl oxacin, di- moricizine, omeprazole, Tetracycline Calcium channel Loperamide sulfi ram, enoxacin, famotidine, phenobarbital, blockers fl uvoxamine, methoxsalen, phenytoin, cigarette mexiletine, norfl oxacin, oral con- smoke Rifampin Diltiazem Domperidone traceptives, phenylpropanolamine, propafenone, propranolol, Levofl oxacin Mibefradil Morphine terbinafi ne, thiabendazole, Pentazocine ticlopidine, verapamil, zileuton Antiemetic Antiarrhythmics Methadone CYP3A4 Alprazolam, amiiodarone, amlodi- Armodafi nil, pine, amprenavir, aprepitant, amprenavir, aprepitant, Odansetron Dignoxin Asimadoline atorvastatin, atazanavir, bicluta- bosentan, carbama- mide, ciostazol, cimetidine, zepine, efavirenz, Fentanyl ciprofl oxacin, clarithromycin, entravirine, modafi nil, Chemotherapy H1 antagonists conivaptan, cyclosporine, nafcillin, phenytoin, darunavir / ritonavir, diltiazem, pioglitazone, Paclitaxel Fexofenadine Steroids erythromycin, fl uconazole, prednisone, rifampin, fl uoxe tine, fl uvoxamine, fosampre- rufi namide Doxorubicin Terfenadine Dexamethasone navir, imatinib, indinavir, isoni- Daunorubicin Mehylpredni solone azid, itraconazole, ketoconazole, lopinavir / ritonavir, nefazodone, nelfi - Vinblastine HIV protease Aldosterone navir, nilotinib, oral contraceptives, inhibitors posaconazole, ranitidine, ranolazine, Vincristine Amprenavir Progesterone ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton Actinomycin D Indinavir Hydrocortisone Docetaxel Nelfi navir Cortisol Etoposide Saquinavir Corticosterone Imatinib Ritonavir Reversal Teniposide Others Th ere are no clear reversal agents available for DTIs. Blood products, such as fresh frozen plasma or cryoprecipitate are the principle Colchicine agents currently recommended. Prothrombin complex concen- Itraconazole trates and recombinant-activated factor VII can be considered. Phenothiazines Lastly, ultrafi ltration and hemodialysis may be of benefi t (13 – 15 ). Ivermectin

Bivalirudin (Angiomax) Bivalirudin is a synthetic peptide analog of hirudin and a bivalent DTI ( 16 ). It is approved for use in patients undergo- Thus, particular consideration should be given to patients ing percutaneous coronary intervention (PCI) with provisional with severe renal impairment or in dialysis-dependent use of glycoprotein IIb/ IIIa inhibitors, patients with or at risk of patients. Current recommendations are to adjust the dose for heparin-induced thrombocytopenia, or in patients with unstable renal impairment in patients with a CrCl of 10 – 29 ml / min angina undergoing percutaneous transluminal coronary angio- undergoing PCI and in patients with a CrCl < 60 ml / min plasty (16 ). being treated for heparin-induced thrombocytopenia. Cur- rent manufacturer recommendations state that dosing Pharmacodynamics modifications are not necessary in patients with hepatic Administered intravenously, bivalirudin achieves an imme- impairment ( 16 ). diate peak plasma concentration with a half-life of 22 min. Approximately 20% of unchanged bivalirudin is renally excre- Reversal agents. Th ere are presently no reversal agents that ted, and the remainder undergoes intracellular proteolysis. can be used in the event of an acute bleed in patients on

Medscape® www.medscape.com Exceite 2

Active Thrombin site

Exceite 1

Thrombin Thrombin Thrombin

Argatroban Dabigatran Bivalirudin Lepirudin

Figure 3 . Mechanism of action of univalent and bivalent DTIs (48 ). DTIs, direct thrombin inhibitors.

bivalirudin. Current guidelines suggest that modifi ed ultra- Table 3. Time of discontinuation before procedure (minimum) fi ltration and hemodialysis may facilitate the removal of ( 20,49) bivalirudin with modifi ed ultrafi ltration (removal of between Renal function Mean half-life Standard risk High risk of 45– 69 % depending on the fi lter type) being superior to hemo- (CrCL ml/ min) (hours) of bleeding bleeding dialysis (removal of 25 % ). Recombinant factor VII can be administered at a dose of 90 mcg / kg intravenously. Lastly, > 80 13 (11 – 22) 24 h 2 – 4 days blood products such as fresh frozen plasma or cryoprecipitate 50 – 80 15 (12 – 34) 24 h 2 – 4 days can be given to work as a competitor to displace bivalirudin 30 – 50 18 (13 – 23) > 48 h > 4 days from thrombin ( 13,17). < 30 27 (22 – 35) 48 – 120 h > 5 days

Recommended withholding period before endoscopic procedures. CrCL, creatinine clearance. Owing to its short half-life, an infusion of bivalirudin needs only to be discontinued before induction of anesthesia in a patient with normal renal function (18 ). Reversal agents. To date, there are no available antidotes for dabigatran. Blood products, such as fresh frozen plasma, Dabigatran (Pradaxa) are the principal agents of reversal. Hemodialysis may be Dabigatran is a monovalent DTI that is currently approved for eff ective in removing as much as 60 % of circulating drug, as the prevention of stroke in nonvalvular atrial fi brillation ( 19 ). the majority of dabigtran is unbound to protein; however, Schulman et al. ( 20 ) recently found dabigatran to be eff ective in there is insuffi cient data to support this as a means of a the extended treatment of venous thromboembolism. Th ere was reversal (15,22 ). a lower risk of major or clinically relevant bleeding when compared with warfarin but a higher risk than compared with Recommended withholding period before endoscopic procedures. placebo. For patients with normal renal function and high risk of bleeding or major surgery, it is recommended to withhold for Pharmacodynamics 2 days, and for otherwise average risks, for 24 h (19 ). Table 3 Dosed as a twice daily oral tablet, dabigatran reaches a peak illustrates manufacturer recommendations for the disconti- plasma concentration aft er 1– 2 h with a half-life of 12– 17 h. nuation of dabigatran before elective surgery, as stratifi ed by Renal clearance accounts for 80– 85 % elimination of dabigatran. renal function. Doses should be reduced in patients with moderate renal impairment (defi ned as CrCl 30 – 50 ml / min) and should be avoided in patients with severe renal impairment (defi ned as CrCl Adenosine diphosphate antagonists (Thienopyridines) 15 – 30 ml / min) and concomitant use of medications requiring During primary hemostasis, damaged endothelium release use of P-glycoprotein (see Table 2 ). Current manufacturer adeno sine diphosphate causing the recruitment and activa- recommendations state that dosing modifi cations are not tion of platelets. Th is aggregation leads to the formation of the necessary in patients with hepatic impairment ( 21). primary platelet plug that must be stabilized by the formation

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Irreversible binding Prodrug

Noncompetitive Inactive metabolite reversible binding Intermediate metabolite

Active metabolite

Intestinal absorption Liver

Esterases (85%) CYP CYP isoenzymes isoenzymes or PON-1 Clopidogrel (first step) (second step) Esterases CYP isoenzymes Prasugrel (one step)

Ticagrelor

P2Y12

Platelet

Figure 4 . Mechanism of action of thienopyridines on platelet aggregation (50 ). of fi brin ( 23 ). Th e thienopyridines block the adenosine diphos- the use of clopidogrel in renal or hepatic impairment; therefore, phate-dependent aggregation of platelets by inhibiting the no dose adjustment is necessary in these populations (24 ).

P2Y12 receptor. Figure 4 depicts the eff ect of thienopyridines on platelet aggregation. Reversal agents . To date, there are no available reversal agents that can be used in the event of an acute bleed in patients Reversal on clopidogrel. Current guidelines state that blood products, Th ere are no reversal agents available for the thienopyridines. such as fresh frozen plasma or cryoprecipitate are the primary For treatment of acute bleeding events, platelet transfusion agents of reversal. Several case reports have indicated poten- is the primary medical intervention. Several case reports, tial reversal of clopidogrel with use of methylprednisolone however, have indicated potential reversal of clopidogrel with and desmopressin ( 24 ). methylprednisolone and desmopressin (24 – 26 ). Recommended withholding period before endoscopic procedures. Clopidogrel should be discontinued 5 – 7 days before any Clopidogrel (Plavix) procedure where therapeutic intervention is anticipated or Clopidogrel is a thienopyridine approved for use in patients planned ( 27 ). with acute coronary syndrome who are managed medically or with coronary revascularization. In addition, clopidogrel is indicated following myocardial infarction, stroke, or established Prasugrel (Efﬁ ent) peripheral arterial disease to reduce the risk of new myocardial Prasugrel is a thienopyridine approved for the prevention of infarction, ischemic stroke, and other vascular death ( 24 ). thrombotic cardiovascular events (including stent thrombosis) in patients with unstable angina, non-ST elevation myocardial Pharmacodynamics infarction or segment-elevation myocardial infarction who are to Dosed as a once daily oral tablet, clopidogrel attains peak be managed with PCI (25 ). plasma concentration 1 h after dosage with a half-life of 7– 8 h. Clopidogrel and certain proton pump inhibitors are depend- Pharmacodynamics ent on the CYP2C19 hepatic enzyme for their metabolism. Dosed as a once daily oral tablet, prasugrel attains a peak Because of this, the FDA (Food and Drug Administration) plasma concentration 0.5 h aft er dosage with a half-life of recommends against coadministration of clopidogrel and 2– 15 h. Prasugrel is primarily excreted in the urine; however, omeprazole or esomeprazole. There is limited data regarding current manufacturer recommendations state that dosing

Platelet aggregation

ADP Thrombin Thromboxane A2

Activation

Resting platelets

Fibrinogen

GP llb/llla blocker

Inhibition of platelet aggregation by GP llb/llla blocker

Figure 5 . Mechanism of action of GP IIb/ IIIa inhibitors (51 ). GP, glycoprotein.

modifi cations are not necessary in patients with renal or hepatic function ( 26 ). Ticagrelor is dependent on the CYP3A3 enzyme impairment (25 ). for its metabolism; therefore, inducers and inhibitors should be carefully considered before coadministration (see Table 1 ). As Reversal agents . To date, there are no available reversal agents ticagrelor does not require hepatic activation, it may be more that can be used in the event of an acute bleed in patients on eff ective for patients with CYP2C19 genetic variants than other prasugrel. Current guidelines state that blood products, such as drugs. Current manufacturer recommendations state that dosing fresh frozen plasma or cryoprecipitate are the primary agents of modifi cations are not necessary in patients with renal impairment reversal (25 ). and mild hepatic impairment. In patients with moderate hepatic impairment, current manufacturers recommend exercise caution Recommended withholding period before endoscopic proce- as data is limited, and in patients with severe hepatic impairment dures . Prasugrel should be discontinued at least 7 days before ticagrelor is contraindicated ( 26 ). any procedure where therapeutic intervention is anticipated or planned ( 28 ). Reversal agents . To date, there are no available reversal agents that can be used in the event of an acute bleed in patients on DTIs. Current guidelines state that blood products, such as Ticagrelor (Brillinta) fresh frozen plasma or cryoprecipitate are the primary agents of Ticagrelor is indicated for acute coronary syndrome, preven- reversal (26 ). tion of thrombotic events, and myocardial infarction with ST elevation. Ticagrelor has been found to reduce the risk of Recommended withholding period before endoscopic proce- death and myocardial infarction compared with clopidogrel dures . Ticagrelor should be discontinued a minimum of 5 days in patients with acute coronary syndrome with no diff erence in before any procedure where therapeutic intervention is antici- rates of major bleeding ( 29 ). pated or planned ( 30 ).

Pharmacodynamics Dosed as a once or twice daily oral tablet, ticagrelor attains a Glycoprotein IIb/ IIIa inhibitors peak plasma concentration of 1.5 h aft er dosage with a half-life Glycoprotein IIb / IIIa antagonists inhibit glycoprotein IIb / IIIa - α β of 7 – 8.5 h. Th e primary route of excretion is via hepatic metabo (also referred to as integrin- IIb 3 ), a complex of integrin found lism; thus, precaution should be given to those with hepatic dys- on platelets. Th e activation of the integrin complex enables the

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binding of fi brinogen, platelet – platelet adhesion, and endothelial eptifi batide. Current guidelines recommend platelet transfusions adherence. Glycoprotein IIb / IIIa inhibitors act on this receptor in adjunct to supportive management ( 33 ). ( 31 ). Figure 5 depicts the eff ect of glycoprotein IIb / IIIa inhibitors on the formation of a platelet plug. Recommended withholding period before endoscopic procedures . E p t i fi batide should be discontinued 2 – 4 h before Reversal any procedure where therapeutic intervention is anticipated or Th ere are no reversal agents currently indicated for glyoco- planned ( 38 ). protein IIb / IIIa inhibitors. Platelet transfusions may be off ered in adjunct to supportive management (32,33 ). Tirofi bran is dialyzable and therefore hemodialysis may also be considered ( 34 ). Tiroﬁ ban (Aggrastat) Tirofi ban is a reversible glycoprotein IIb /IIIa inhibitor approved for use in patients with acute coronary syndrome, including Abciximab (Reopro) patients who are managed medically and those individuals under- Abciximab is approved for its use in individuals undergoing going PCI (with or without stent placement) ( 40 ). PCI (with or without stent placement) ( 32,35 ). Pharmacodynamics Pharmacodynamics Tirofi ban is dosed as an intravenous bolus that is to be contin- Abciximab is dosed as an intravenous bolus administered ued through and following angiography. It reaches a peak plasma 10 – 60 min before PCI, followed by continuous infusion for 12 h concentration 2 h aft er dosage with a half-life of 2 h. Renal (35 ). It attains a peak plasma concentration 2 h aft er dosage pathways account for ~ 65 % of the clearance. Renal dosing with a half-life of 0.5 h (36 ). Th e primary mechanism of drug is therefore required in patients with a CrCl < 30 ml / min. elimination is unknown but catabolism or proteolytic degra- Current manufacturer recommendations state that dosing dation with negligible renal excretion is expected. Current modifi cations are not necessary in patients with hepatic impair- manufacturer recommendations state that dosing modifi ca- ment (40 ). tions are not necessary in patients with renal or hepatic impairment (37 ). Reversal agents . To date, there are no available reversal agents that can be used in the event of an acute bleed in patients on Reversal agents . To date, there are no available reversal agents tirofi ban. Current guidelines recommend platelet transfusions that can be used in the event of an acute bleed in patients on in adjunct to supportive management. In contrast to abciximab, abciximab. Current guidelines recommend platelet transfusions tirofi bran is dialyzable and, therefore, when immediate reversal is in adjunct to supportive management ( 32 ). required hemodialysis should also be considered ( 34 ).

Recommended withholding period before endoscopic proce- Recommended withholding period before endoscopic dures . Abciximab should be discontinued 12 – 24 h before any procedures . T i r o fi ban can be stopped at the start of the proce- procedure, with 24 h being preferred (38 ). dure without harmful hematological eff ects ( 38 ).

Eptiﬁ batide (Integrilin) Discussion Eptifi batide is approved for use in patients with acute coronary The development and introduction of new anticoagulants syndrome, including both those patients who are to be managed and antiplatelet therapies has been explosive. As patients medically and those undergoing PCI (with or without stent place- who use the medications have gastrointestinal (GI) disease or ment) ( 39 ). need emergent or elective endoscopic procedures, it is critical for patient safety that gastroenterologists fully understand Pharmacodynamics the pharmacology so as to best manage the clinical impact Eptifibatide is dosed as an intravenous bolus followed by of usage from a gastrointestinal perspective. The pharmaco- continuous infusion and attains a peak plasma concentration kinetics, dosing, reversal agents, and recommendations on within 4 – 6 h after dosage. It has a half-life of 2.5 h. The kid- pre-procedural withholding periods for warfarin and the neys account for ~ 50 % of drug clearance; therefore, dosing more modern agents are summarized as best-practice recom- should be adjusted for renal impairment as defined as a mendations in Table 4 . CrCl < 50 ml / min. Current manufacturer recommendations A recent meta-analysis found that new anticoagulant and state that dosing modifications are not necessary in patients antiplatelet drugs carry an increased risk of GI bleed over tradi tional with hepatic impairment (39 ). therapy (1 ). Th erefore, as the use of these new agents increases, so does the need for greater collaboration between cardiologists Reversal agents . To date, there are no available reversal agents and gastroenterologists. Th e challenges inherent to managing that can be used in the event of an acute bleed in patients on patients requiring chronic anticoagulation and gastro intestinal

Table 4 . Best practice recommendations

Recommendations Peak Half-life Bioavail- Reversal agents (see below to discontinue Class Agent (hours) (hours) ability (% ) Dosing for HASHTI ( 52 ) ) before procedure

Vitamin K Warfarin 72 – 96 20 – 60 100 Daily 1. Vitamin K (IV/ PO) 1– 10 mg Discontinue 5 days antagonist *Takes 6 (IV) to 24 (PO) before procedure hours to reverse 2. Fresh Frozen Plasma 10 – 30 ml / kg (1 unit=~ 250 ml) 3. Prothombin Complex Con- centrates 25– 50 units / kg IV Xa inhibitor Rivaroxaban (Xarelto) 2.5 – 4 5 – 9 (9 – 13 if 80 Daily or b.i.d. 1. Supportive Treatment Discontinue 24 h elderly) 2. Factor VIIa before procedure 3. Prothombin Complex Con- centrates 25– 50 units / kg IV Apixaban (Eliquis) 3 8 – 13 ~ 66 b.i.d. 1. Supportive Treatment Discontinue 24 h 2. Factor VIIa before procedure if 3. Prothombin Complex low risk of bleed- Concentrates ing or 48 h before 25 – 50 units / kg IV procedure if high risk bleeding Direct thrombin Dabigatran (Pradaxa) 2 – 3 13 – 27 6.5 Daily or b.i.d. 1. Supportive Blood Refer to Table 3 inhibitor (Depending Products / HASHTI (52 ) on CrCl— refer 2. Prothombin Complex to Table 3 ) Concentrates 3. Consider rVIIa 4. Hemodialysis Bivalirudin 0.5 – 3 0.5 100 Intravenous 1. Supportive Blood Discontinue before (Angiomax) Products / HASHTI (52 ) induction of anesthe- 2. Consider rVIIa sia in a patient with (90 mcg / kg for up to 2 doses) normal renal function 3. Hemodialysis Argatroban 1 – 3 39 – 51 min 100 Intravenous 1. Supportive Blood Discontinue 4– 6 h Products / HASHTI (52 ) before induction 2. Prothombin Complex of anesthesia in a Concentrates patient with normal 3. Consider rVIIa hepatic function 4. Hemodialysis Thienopyridine Clopidogrel (Plavix) 1 7 – 8 > 50 Daily 1. HASHTI ( 52 ) Discontinue 5– 10 antiplatelet 2. Platelet Transfusion days before proce- agent 3. Case Reports of Methyl- dure prednisolone and desmopressin Ticlopidine (Ticlid) 2 12 > 80 b.i.d. 1. HASHTI ( 52 ) Discontinue 5– 10 2. Platelet Transfusion days before procedure Prasugrel (Efﬁ ent) 0.5 2 – 15 > 79 Daily 1. HASHTI ( 52 ) Discontinue 5 –10 2. Platelet Transfusion days before procedure Ticagrelor (Brillinta) 1.5 7 – 8.5 > 36 Daily or BID 1. HASHTI ( 52 ) Discontinue 5– 10 2. Platelet Transfusion days before procedure Dipyrimadole (Per- 1.25 7 – 10 50 – 75 q.i.d. 1. HASHTI ( 52 ) Discontinue 7 days santine) 2. Platelet Transfusion before procedure 3. Aminophylline for Dipyrimadole overdose (Aggrenox 2 13.6 50 – 75 b.i.d. 1. HASHTI ( 52 ) Discontinue 7 days (Extrended release 2. Platelet Transfusion before procedure dipyrimadole + aspirin)) Glycoprotein Abciximab (ReoPro) 2 0.5 100 Intravenous 1. HASHTI ( 52 ) 12 – 24 h before IIB / IIIA 2. Platelet Transfusion procedure (24 ideal) inhibitors Table 4 continued on the following page

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Table 4 . (Continued)

Recommendations Peak Half-life Bioavail- Reversal agents (see below to discontinue Class Agent (hours) (hours) ability ( % ) Dosing for HASHTI ( 52 ) ) before procedure

Eptiﬁ batide 4 – 6 2.5 100 Intravenous 1. HASHTI ( 52 ) 2 – 4 h before (Integrilin) 2. Platelet Transfusion procedure Tiroﬁ ban (Aggrastat) 2 2 100 Intravenous 1. HASHTI ( 52 ) Can be stopped at 2. Platelet Transfusion the moment of skin 3. Dialysis incision without harmful effects Low-molecular Dalteparin (Fragmin) 3 – 5 2.2 87 Subcutaneous 1. HASHTI ( 52 ) Last dose should be weight heparin 2. Protamine sulfate given 24 h before (1 mg / 100 units Dalteparin procedure in previous 8 h) 3. Consider rVIIa Tinzaparin (Innohep) 4 – 5 3.9 90 for Xa Subcutaneous 1. HASHTI ( 52 ) Last dose should be 67 for IIa 2. Protamine sulfate given 24 h before (1 mg / 100 units Tinzaparin procedure in previous 8 h) 3. Consider rVIIa Fondaparinux 2 17 – 21 100 Subcutaneous 1. HASHTI ( 52 ) Last dose should be (Arixtra) 2. Protamine sulfate given 24 h before 3. Consider rVIIa procedure and resume 6 h after procedure

b.i.d., twice daily dosing; IV, intravenous; p.o., oral; rVIIa, recombinant factor VIIa. HASHTI: (1) Hold further doses of anticoagulant; (2) consider Antidote; (3) Supportive treatment: volume resuscitation, inotropes as needed; (4) local or surgical Hemo- static measures: topical agents (aminocaproic acid, tranexamic acid); (5) Transfusion (red cells, platelets, FFP as indicated); (6) Investigate for bleeding source. Courtesy: Cushman MD, Mary, et al. ( 52 ).

Table 5 . Select outcomes of the RE-LY trial (53 )

Outcome Dabigatran (150mg) ( n =6,076) Warfarin (n =6,022) Dabigatran 150 mg vs. warfarin No. of patients (% ) No. of patients (% ) Relative risk (95 % CI) P -value

Stroke or systemic embolisma 134 (2.21) 202 (3.35) 0.65 (0.52 – 0.81)b < 0.001 Hemorrhagic stroke 12 (0.20) 45 (0.75) 0.26 (0.14– 0.49) < 0.001 Ischemic or unspeciﬁ ed stroke 111 (1.83) 142 (2.36) 0.76 (0.60– 0.98) 0.03 Major bleeding a,c 399 (6.47) 421 (6.99) 0.93 (0.81 – 1.07)b 0.32 Major GI bleeding 182 (3.00) 120 (1.99) 1.50 (1.19– 1.89) < 0.001 Intracranial bleeding 36 (0.59) 87 (1.44) 0.40 (0.27– 0.60) < 0.001 Myocardial infarction (MI) a 97 (1.60) 75 (1.25) 1.27 (0.94 – 1.71)b 0.12 Net clinical beneﬁ t outcome b 832 (13.70) 901 (14.96) 0.91 (0.82– 1.00) 0.04 Dyspepsia 688 (11.3) 348 (5.8) Not provided < 0.001 ALT or AST > 3 ULN 117 (1.9) 132 (2.2) Not provided Not provided Hepatobiliary disorder 143 (2.4) 145 (2.4) Not provided Not provided

IM, intramuscular; MI, myocardial infarction; ULN, upper limit of normal. a Based on revised data. b “ Net clinical beneﬁ t outcome ” was the composite of stroke, systemic embolism, pulmonary embolism, MI, death, or major bleeding. c “ Major bleeding” was deﬁ ned as one or more of the following: bleeding associated with a reduction in hemoglobin of at least 2 g / dl or leading to a transfusion of at least 2 U of blood, or symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal, or IM with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding. d “ Intracranial bleeding” included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.

Rate of bleeds with Pradaxa 150 mg vs Table 6 . Major bleeding by site comparing rivaroxaban to warfarin Bleeding events warfarin ( 43 ) (per 100 patient-years) 2166 warfarin 18.4% Rivaroxaban Warfarin 1993 (n=6022; patient -years = 11,794) a 16.6% Major bleeding by site (n =7,111) (n =7,125) PRADAXA 150 mg BID HR 0.91 (n=6076; patient-years =12,033) Major bleeding, no. (% ) 395 (5.55) 386 (5.42) 95% CI (0.85, 0.96) Gastrointestinal (upper, lower, and 224 (3.15) 154 (2.16) rectal) b

c Intracranial 55 (0.77) 84 (1.18) Primary Safety Endpoint HR 0.93 c Intraparenchymal 37 (0.52) 56 (0.79) 95% CI (0.81, 1.07) HR 0.80 95% CI (0.66, 0.98) HR 1.50 Non-traumaticc 33 (0.46) 54 (1.76) 421 399 95% CI (1.2, 1.9) 3.6% 3.3% 218 Traumatic 4 (0.06) 2 (0.03) 179 125 186 1.9% 1.5% 1.1% 1.6% Intraventricular 2 (0.03) 4 (0.06) Subdural hematoma 0 1 (0.01) Total bleeds Major bleeds Life-threatening bleeds Major GI bleeds

Subarachnoid 4 (0.06) 1 (0.01) Figure 6 . Adverse outcomes from RE-LY trial (54 ). RE-LY, Randomized Epidural hematoma 0 1 (0.01) Evaluation of Long Term Anticoagulant Therapy. Macroscopic hematuria 26 (0.37) 21 (0.29) Bleeding associated with 19 (0.27) 26 (0.36) GI bleeds were more common in the rivaroxaban group, with 224 non-cardiac surgery events (3.2 % ) as compared with the 154 events in the warfarin Intraocular / retinal 17 (0.24) 24 (0.34) group (2.2% , P < 0.001) ( 43 ) (see Table 6). Th e recent trial data have (42,43 ) clarifi ed the best-practice- Intra-articular 16 (0.23) 21 (0.29) targeted strategy for the use of these new oral anticoagulants. Epistaxis 13 (0.18) 14 (0.20) Th ese newer regimens appeal to clinicians, as well as patients, a Site based on blinded adjudication. because of the ease of use, as they off er less oversight than that b Combined gastrointestinal bleed rate P < 0.001. required for the use of warfarin. Endoscopists, however, need c P < 0.05. to be cognizant that these new agents seem to have higher pre- dilection of GI bleeding (42,43 ). Unfortunately, to date there is only anecdotal evidence supporting the use of any reversal agents in the setting of an acute GI bleed for these newer anti- care have even prompted a recent call for a fi eld of “ cardio-gastro- coagulants or antiplatelet agents. Although reversal agents enterology ” ( 41 ). may be in the pipeline, these agents are not available, and the Th e development of targeted anticoagulant and antiplatelet pragmatic issue is that gastroenterologists continue to witness agents has revolutionized the fi eld of anticoagulation. Th e RE-LY major GI bleeding on these newer anticoagulants, and therefore (Randomized Evaluation of Long Term Anticoagulant Th erapy) best-practice strategies for management are needed not only for trial, which randomized over 18,000 patients, demonstrated that prevention for elective procedures but also for management of a 150-mg dose of dabigatran was superior to warfarin for over- acute events. all stroke and systemic embolism prevention (42 ). Table 5 below Clearly, it is well recognized that the temporary discontin- depicts the notable outcomes from the RE-LY trial and particular uance of these agents is safe for elective procedures when at attention should be given to bleeding risk. Further evaluation of least 6 months aft er stent placement, but at least for diagnostic bleeding risk shows dabigatran to be safer when compared with procedures the cardiovascular complications of stopping these warfarin in terms of total bleeds, major bleeds, and life-threaten- agents may outweigh the bleeding risks. It is therefore strongly ing bleeds; however, dabigatran is associated with a higher risk of recommended that the gastroenterologist / endoscopist never major GI bleeds, as illustrated in Figure 6. Th e RE-LY trial was a be the one to instruct the patient to stop any anticoagulant or landmark trial that led to the approval of dabigatran in patients antiplatelet therapy. Th is should be a recommendation pend- with nonvalvular atrial fi brillation and heralded the entry of other ing the patient fi nalizing approval by the prescriber of these anticoagulants. agents — typically the cardiologist, neurologist, and vascular Similarly, the Rivaroxaban Once Daily Oral Direct Factor Xa surgeon or primary care provider. In addition, the necessity for Inhibition Compared with Vitamin K Antagonism for Prevention approved reversal agents for these new drugs remains of utmost of Stroke and Embolism Trial in Atrial Fibrillation trial , which concern, particularly in dealing with emergent bleeding com- randomized 14,264 patients with a primary end point of stroke or plications. Th e recommendations presented in this review are embolism prevention in patients with atrial fi brillation, demon- based on the best evidence available at this time. Clearly, new strated rivaroxaban was noninferior to warfarin. Further evalua- guidelines for best-practice recommendations from both the tion of bleeding outcomes from this study trial showed that major cardiology and gastrointestinal national societies addressing

The American Journal of GASTROENTEROLOGY VOLUME 109 | JANUARY 2014 www.amjgastro.com THE RED SECTION 19

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