New Anticoagulants and Antiplatelet Agents

A Primer for the Clinical Gastroenterologist

Parth J Parekh MD; Jonathan Merrell MD; Meredith Clary MD; John E Brush MD; FACC; David A Johnson MD; FACG; FASGE

Am J Gastroenterol. 2014;109(1):9-19.

Abstract and Introduction

Abstract

The discovery of the first 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.

Introduction

Warfarin was the mainstay of oral anticoagulant therapy until the recent discovery of more precise targets for therapy. Although warfarin therapy is plagued by a narrow therapeutic index, variable individual metabolic responses, and numerous food and drug interactions, newer agents purport to rise above these setbacks. Furthermore, although the safety of these new drugs compared with traditional therapy has been called into question,^[1] their ease of use makes it unlikely that they will disappear.

This review will explore the mechanisms of action and pharmacokinetics of novel anticoagulants and antiplatelet agents. In addition, recommended withholding periods for these drugs for patients undergoing elective endoscopic procedures as well as options for achieving rapid hemostasis in patients undergoing emergent endoscopy.

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Table 1. Medications affecting the cytochrome P450 (CYP) pathway ⁴⁶
Enzyme	Inhibitors	Inducers
CYP2C9	Amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	Aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	Acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	Montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoke
CYP3A4	Alprazolam, amiiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, biclutamide, ciostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	Armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, entravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table 2. Medications requiring P-glycoprotein transporters ⁴⁷
Substrates			Inhibitors
Antacids	β-Adrenoceptor antagonist	Immunosuppressants	Diverse inhibitors
Cimetidine	Bunitrolol	Cyclosporine A	Verapamil
Ranitidine	Carvedilol	Sirolimus	Quinidine
	Tanilol	Tacrolimus	Valspodar
Antibiotics	Reserpine		Cyclosporine
Erythromycin		Opioids	Ketoconazole
Tetracycline	Calcium channel blockers	Loperamide
Rifampin	Diltiazem	Domperidone
Levofloxacin	Mibefradil	Morphine
		Pentazocine
Antiemetic	Antiarrhythmics	Methadone
Odansetron	Dignoxin	Asimadoline
		Fentanyl
Chemotherapy	H1 antagonists
Paclitaxel	Fexofenadine	Steroids
Doxorubicin	Terfenadine	Dexamethasone
Daunorubicin		Mehylprednisolone
Vinblastine	HIV protease inhibitors	Aldosterone
Vincristine	Amprenavir	Progesterone
Actinomycin D	Indinavir	Hydrocortisone
Docetaxel	Nelfinavir	Cortisol
Etoposide	Saquinavir	Corticosterone
Imatinib	Ritonavir
Teniposide		Others
		Colchicine
		Itraconazole
		Phenothiazines
		Ivermectin

Table 3. Time of discontinuation before procedure (minimum) ^20,49
Renal function (CrCL ml/min)	Mean half-life (hours)	Standard risk of bleeding	High risk of bleeding
>80	13 (11–22)	24 h	2–4 days
50–80	15 (12–34)	24 h	2–4 days
30–50	18 (13–23)	>48 h	>4 days
<30	27 (22–35)	48–120 h	>5 days

CrCL, creatinine clearance.

Table 4. Best practice recommendations
Class	Agent	Peak (hours)	Half-life (hours)	Bioavailability (%)	Dosing	Reversal agents (see below for HASHTI (52))	Recommendations to discontinue before procedure
Vitamin K antagonist	Warfarin	72–96	20–60	100	Daily	1. Vitamin K (IV/PO) 1–10 mg ^*Takes 6 (IV) to 24 (PO) hours to reverse 2. Fresh Frozen Plasma 10–30 ml/kg (1 unit=~250 ml) 3. Prothombin Complex Concentrates 25–50 units/kg IV	Discontinue 5 days before procedure
Xa inhibitor	Rivaroxaban (Xarelto)	2.5–4	5–9 (9–13 if elderly)	80	Daily or b.i.d.	1. Supportive Treatment 2. Factor VIIa 3. Prothombin Complex Concentrates 25–50 units/kg IV	Discontinue 24 h before procedure
	Apixaban (Eliquis)	3	8–13	~66	b.i.d.	1. Supportive Treatment 2. Factor VIIa 3. Prothombin Complex Concentrates 25–50 units/kg IV	Discontinue 24 h before procedure if low risk of bleeding or 48 h before procedure if high risk bleeding
Direct thrombin inhibitor	Dabigatran (Pradaxa)	2–3	13–27 (Depending on CrCl—refer to Table 3)	6.5	Daily or b.i.d.	1. Supportive Blood Products/HASHTI (52) 2. Prothombin Complex Concentrates 3. Consider rVIIa 4. Hemodialysis	Refer to Table 3
	Bivalirudin (Angiomax)	0.5–3	0.5	100	Intravenous	1. Supportive Blood Products/HASHTI (52) 2. Consider rVIIa (90 mcg/kg for up to 2 doses) 3. Hemodialysis	Discontinue before induction of anesthesia in a patient with normal renal function
	Argatroban	1–3	39–51 min	100	Intravenous	1. Supportive Blood Products/HASHTI (52) 2. Prothombin Complex Concentrates 3. Consider rVIIa 4. Hemodialysis	Discontinue 4–6 h before induction of anesthesia in a patient with normal hepatic function
Thienopyridine antiplatelet agent	Clopidogrel (Plavix)	1	7–8	>50	Daily	1. HASHTI (52) 2. Platelet Transfusion 3. Case Reports of Methylprednisolone and desmopressin	Discontinue 5–10 days before procedure
	Ticlopidine (Ticlid)	2	12	>80	b.i.d.	1. HASHTI (52) 2. Platelet Transfusion	Discontinue 5–10 days before procedure
	Prasugrel (Effient)	0.5	2–15	>79	Daily	1. HASHTI (52) 2. Platelet Transfusion	Discontinue 5–10 days before procedure
	Ticagrelor (Brillinta)	1.5	7–8.5	>36	Daily or BID	1. HASHTI (52) 2. Platelet Transfusion	Discontinue 5–10 days before procedure
	Dipyrimadole (Persantine)	1.25	7–10	50–75	q.i.d.	1. HASHTI (52) 2. Platelet Transfusion 3. Aminophylline for Dipyrimadole overdose	Discontinue 7 days before procedure
	(Aggrenox (Extrended release dipyrimadole+aspirin)	2	13.6	50–75	b.i.d.	1. HASHTI (52) 2. Platelet Transfusion	Discontinue 7 days before procedure
Glycoprotein IIB/IIIA inhibitors	Abciximab (ReoPro)	2	0.5	100	Intravenous	1. HASHTI (52) 2. Platelet Transfusion	12–24 h before procedure (24 ideal)
	Eptifibatide (Integrilin)	4–6	2.5	100	Intravenous	1. HASHTI (52) 2. Platelet Transfusion	2–4 h before procedure
	Tirofiban (Aggrastat)	2	2	100	Intravenous	1. HASHTI (52) 2. Platelet Transfusion 3. Dialysis	Can be stopped at the moment of skin incision without harmful effects
Low-molecular weight heparin	Dalteparin (Fragmin)	3–5	2.2	87	Subcutaneous	1. HASHTI (52) 2. Protamine sulfate (1 mg/100 units Dalteparin in previous 8 h) 3. Consider rVIIa	Last dose should be given 24 h before procedure
	Tinzaparin (Innohep)	4–5	3.9	90 for Xa 67 for IIa	Subcutaneous	1. HASHTI (52) 2. Protamine sulfate (1 mg/100 units Tinzaparin in previous 8 h) 3. Consider rVIIa	Last dose should be given 24 h before procedure
	Fondaparinux (Arixtra)	2	17–21	100	Subcutaneous	1. HASHTI (52) 2. Protamine sulfate 3. Consider rVIIa	Last dose should be given 24 h before 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 Hemostatic 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 (150 mg) (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 embolism^a	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 unspecified 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 benefit 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 benefit outcome" was the composite of stroke, systemic embolism, pulmonary embolism, MI, death, or major bleeding.
^c "Major bleeding" was defined 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.

Table 6. Major bleeding by site comparing rivaroxaban to warfarin ⁴³
Major bleeding by site^a	Rivaroxaban (n=7,111)	Warfarin (n=7,125)
Major bleeding, no. (%)	395 (5.55)	386 (5.42)
Gastrointestinal (upper, lower, and rectal)^b	224 (3.15)	154 (2.16)
Intracranial^c	55 (0.77)	84 (1.18)
Intraparenchymal^c	37 (0.52)	56 (0.79)
Non-traumatic^c	33 (0.46)	54 (1.76)
Traumatic	4 (0.06)	2 (0.03)
Intraventricular	2 (0.03)	4 (0.06)
Subdural hematoma	0	1 (0.01)
Subarachnoid	4 (0.06)	1 (0.01)
Epidural hematoma	0	1 (0.01)
Macroscopic hematuria	26 (0.37)	21 (0.29)
Bleeding associated with non-cardiac surgery	19 (0.27)	26 (0.36)
Intraocular/retinal	17 (0.24)	24 (0.34)
Intra-articular	16 (0.23)	21 (0.29)
Epistaxis	13 (0.18)	14 (0.20)

^a Site based on blinded adjudication.
^b Combined gastrointestinal bleed rate P<0.001.
^c P<0.05.

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New Anticoagulants and Antiplatelet Agents

A Primer for the Clinical Gastroenterologist

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

Tables

Tables

Tables

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Authors and Disclosures

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