A clinician’s perspective: novel oral anticoagulants to reduce the risk of stroke in nonvalvular atrial fibrillation – full speed ahead or proceed with caution?

Figures & data

Table 1 Comparison of novel oral anticoagulants

	Dabigatran^Citation6	Rivaroxaban^Citation8	Apixaban^Citation7	Edoxaban^Citation9,Citation10
Mechanism of action Cmax, h Half-life, h	Direct thrombin inhibitor 1a 12–17	Factor Xa inhibitor 2–4b 5–9	Factor Xa inhibitor 3–4 8–15	Factor Xa inhibitor 1–2 5.8–10.7, single dose; 8.75–10.4, multiple dose
Renal excretion	Up to 80%	66%	~25%	35–39
Drug interactions
P-gp and CYP3A4	Avoid coadministration with P-gp inducers (eg, rifampin). Decrease dose if coadministered with P-gp inhibitors dronedarone and systemic ketoconazole in patients with CrCl 30–50 mL/min Do not use concurrently with P-gp inhibitors in patients with CrCl <30 mL/min	Avoid concomitant use with combined P-gp and strong CYP3A4 inducers or inhibitors	Avoid coadministration with strong dual inducers of CYP3A4 and P-gp. Decrease dose if used concurrently with strong dual inhibitors of CYP3A4 and P-gp (2.5 mg bid)c	Edoxaban dosage reduction may be needed when coadministered with strong P-gp inhibitors (eg, verapamil, quinidine, amiodarone, and dronedarone). Interactions have been shown with CYP3A4
Concomitant drugs affecting hemostasis	NSAIDs, antiplatelet agents, heparin, fibrinolytic therapy	Aspirin, platelet aggregation inhibitors, other antithrombotic agents, NSAIDs	NSAIDs used chronically, platelet aggregation inhibitors, or other antithrombotic agents, SSRIs, or SNRIs	Data not available
Approved dosage(s)	150 mg bid (US/Europe) 110 mg bid (Europe) 75 mg bid (US)	20 mg daily with evening meal 15 mg daily with evening meal	5 mg bid 2.5 mg bid	Not currently approved (under review)

Notes:

a Postdose in the fasted state

b coadministration with food increases bioavailability of 20 mg dose (increasing mean AUC and C_max by 39% and 76%, respectively)

c avoid concomitant use with strong dual inhibitors of CYP3A4 and P-gp in patients already taking a reduced dose of apixaban.

Abbreviations: AUC, area under concentration-time curve; bid, twice daily; C_max, maximum plasma concentration; CrCl, creatinine clearance; CYP3A4, cytochrome P450 3A4; NSAIDs, nonsteroidal anti-inflammatory drugs; P-gp, P-glycoprotein; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Table 2 Comparison of novel oral anticoagulant trials

	Dabigatran^Citation11	Rivaroxaban^Citation14	Apixaban^Citation12,Citation13	Edoxaban^Citation16
Key clinical trial(s)	RE-LY	ROCKET-AF	AVERROES, ARISTOTLE	ENGAGE-AF TIMI-48
Trial design	Randomized, double-blind, prospective, open-label (PROBE)	Randomized, prospective double-blind, double-dummy	Randomized, prospective double-blind, double-dummy	Randomized, prospective, double-blind, double-dummy
Primary efficacy endpoint	Stroke or SE	Stroke or SE	Stroke or SE	Stroke or SE
Primary safety endpoint	Major bleeding (ISTH)	Major (ISTH)/CRNM bleeding	Major bleeding (AVERROES,a ARISTOTLEa)	Major bleeding (ISTH)
Trial dose	150 mg bid or 110 mg bid	20 mg/d	5 mg bid	60 mg/d 30 mg/d
Reduced dose for selected patients	NA	15 mg/d (CrCl 30–49 mL/min)	2.5 mg bidb	Dose halved in selected patientsc
Mean CHADS2 score	2.1	3.5	2.1	Not stated
Mean TTR, %	64	55	62.2	64.9

Notes:

a Defined according to ISTH criteria, adjusted for the decrease in hemoglobin level if a blood transfusion is required

b reduced dose if patients met two of the following: age ≥80 years, body weight ≤60 kg, or serum creatinine level ≥1.5 mg/day

c for patients in either group the dose was halved if any of the following symptoms were present at the time of randomization or at any point during the study: estimated creatinine clearance 30–50 mL/min, body weight ≤60 kg, or the concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors). A protocol amendment mandated similar dose modification in the case of concomitant dronedarone use.

Abbreviations: CHADS₂, Congestive heart failure, Hypertension, Age ≥75 years, Diabetes, Stroke (doubled); CrCl, creatinine clearance; CRNM, clinically relevant nonmajor; ISTH, International Society on Thrombosis and Haemostasis; NA, not applicable; SE, systemic embolism; TTR, time in therapeutic range; ARISTOTLE, Apixaban for Reduction In Stroke and Other ThromboemboLic Events in atrial fibrillation; AVERROES, Apixaban Versus Acetylsalicylic acid (ASA) to Prevent Strokes; RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy; ROCKET-AF, Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation; ENGAGE-AF TIMI-48, Edoxaban versus Warfarin in Patients with Atrial Fibrillation; bid, twice daily.

Table 3 Efficacy and safety outcomes in Phase III trials of novel oral anticoagulantsa

	Stroke or SE (%/y)	Major bleeding (%/y)	ICH (%/y)	GI bleeding (%/y)	Mortality (%/y)
RE-LY^Citation11,Citation15
Dabigatran 150 mg bid	1.11	3.32	0.30	1.51	3.64
Dabigatran 110 mg bid	1.54	2.87	0.23	1.12	3.75
Warfarin	1.71	3.57	0.74	1.02	4.13
RR (95% CI): dabigatran 150 mg vs warfarin	0.65 (0.52–0.81); P<0.001	0.93 (0.81–1.07); P=0.31	0.40 (0.27–0.60); P<0.001	1.50 (1.19–1.89); P<0.001	0.88 (0.77–1.00); P=0.051
RR (95% CI): dabigatran 110 mg bid vs warfarin	0.90 (0.74–1.10); P=0.30	0.80 (0.70–0.93); P=0.003	0.31 (0.20–0.47); P<0.001	1.10 (0.86–1.41); P=0.43	0.91 (0.80–1.03); P=0.13
ROCKET-AF^Citation14
Rivaroxaban	2.1	3.6	0.5	3.2	4.5
Warfarin	2.4	3.4	0.7	2.2	4.9
HR (95% CI)	0.88 (0.75–1.03); P<0.001 (noninferiority); P=0.12	1.04 (0.90–1.20); P=0.58	0.67 (0.47–0.93); P=0.02	P<0.001b	0.92 (0.82–1.03); P=0.15
ARISTOTLE^Citation13
Apixaban	1.27	2.13	0.33	0.76	3.52
Warfarin	1.60	3.09	0.80	0.86	3.94
HR (95% CI)	0.79 (0.66–0.95); P<0.01	0.69 (0.60–0.80); P<0.001	0.42 (0.30–0.58); P<0.001	0.89 (0.70–1.15); P=0.37	0.89 (0.80–0.99); P=0.047
AVERROES^Citation12
Apixaban	1.6	1.4	0.4	0.4	3.5
Aspirin	3.7	1.2	0.4	0.4	4.4
HR (95% CI)	0.45 (0.32–0.62); P<0.001	1.13 (0.74–1.75); P=0.57	0.85 (0.38–1.90); P=0.69	0.86 (0.40–1.86); P=0.71	0.79 (0.62–1.02); P=0.07
ENGAGE AF TIMI-48^Citation16
Edoxaban 60 mg	1.57	2.75	0.39	1.51	3.99
Edoxaban 30 mg	2.04	1.61	0.26	0.82	3.80
Warfarin	1.80	3.43	0.85	1.23	4.35
HR (95% CI): high dose vs warfarin	mITT:c 0.79 (0.63–0.99); P<0.001 (noninferiority) ITT:d 0.87 (0.73–1.04); P=0.08	0.80 (0.71–0.91) P<0.001	0.47 (0.34–0.63) P<0.001	1.23 (1.02–1.50) P=0.03	0.92 (0.83–1.01) P=0.08
HR (95% CI): low dose vs warfarin	mITT:c 1.07 (0.87–1.31); P=0.005 (noninferiority) ITT:d 1.13 (0.96–0.34); P=0.10	0.47 (0.41–0.55) P<0.001	0.30 (0.21–0.43) P<0.001	0.67 (0.53–0.83) P<0.001	0.87 (0.79–0.96) P=0.006

Notes:

a All P values are for superiority, unless otherwise stated

b HR was not provided for the outcome of GI bleeding

c included data from patients who underwent randomization and received at least one dose of study drug during the treatment period (from administration of first dose to either 3 days after receipt of last dose or end of double-blind therapy, whichever came first, with interval censoring of events during study drug interruptions that lasted more than 3 days)

d included all primary endpoints during the overall study period from randomization until the end of double-blind treatment.

Abbreviations: CI, confidence interval; GI, gastrointestinal; HR, hazard ratio; ICH, intracranial hemorrhage; ITT, intent-to-treat; mITT, modified intent-to-treat; RR, relative risk; SE, systemic embolism; vs, versus; ARISTOTLE, Apixaban for Reduction In Stroke and Other ThromboemboLic Events in atrial fibrillation; AVERROES, Apixaban Versus Acetylsalicylic acid (ASA) to Prevent Strokes; RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy; ROCKET-AF, Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation; ENGAGE-AF TIMI-48, Edoxaban versus Warfarin in Patients with Atrial Fibrillation; bid, twice daily.

Figure 1 Sites of action for monitoring assays in the coagulation pathway.

Abbreviations: aPTT, activated partial thromboplastin time; dTT, diluted thrombin time; ECT, ecarin clotting time; mPT, modified prothrombin time; PT, prothrombin time; TT, thrombin time.

Table 4 Anticoagulant monitoring assays

	Description	Dabigatran^Citation38,Citation40,Citation41	Rivaroxaban^Citation36,Citation37,Citation39	Apixaban^Citation7,Citation36,Citation42,Citation44
Anti-factor Xa	Measures factor X activation directly using a chromogenic substrate	NA	Quantitative	Quantitative
Activated partial thromboplastin time (aPTT)	Test for the intrinsic system; measures kininogen, prekallikrein, XII, XI, IX, VIII, X, V, and thrombin	Qualitative	Not useful	Not useful
Prothrombin time (PT)	Test of the extrinsic pathway, provides an overview of VII, X, V, thrombin, and fibrinogen	Not useful	Qualitative	Not useful
Thrombin time (TT)	Functional test of fibrinogen concentration and fibrin formation	Qualitative assessment, but values may be abnormally high even at clinically insignificant levels	Not useful	Not useful
Diluted TTa	Uses the Hemoclot Thrombin Inhibitor assay (Hyphen BioMed, Neuville-sur-Oise, France)^Citation40	Quantitative analysis	Not useful	Not useful
Modified PTa	Modification of PT assay by adding calcium chloride to the thromboplastin reagent to increase assay dynamic range and improve sensitivity^Citation42	NA	NA	More sensitive than PT and aPTT^Citation41
Ecarin clotting timea	Specific assay for thrombin generation	Quantitative	NA	NA
Heptest^®a (American Diagnostica, Stamford, CT, USA)	Quantitative heparin clotting test	NA	Prolonged	More sensitive than PT and aPTT^Citation42

Note:

a Not widely available.

Abbreviations: NA, data not available; aPTT, activated partial thromboplastin time; PT, prothrombin time; TT, thrombin time.

Boehringer IngelheimPradaxa^® (dabigatran etexilate) capsules (prescribing information) Available from: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdfAccessed September 18, 2013

 Google Scholar

Janssen PharmaceuticalsXarelto^® (rivaroxaban tablets, prescribing information) Available from: http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf#zoom=100Accessed October 8, 2013

 Google Scholar

Bristol-Myers SquibbEliquis^® (apixaban tablets, prescribing information) Available from: http://packageinserts.bms.com/pi/pi_eliquis.pdfAccessed March 20, 2014

 Google Scholar

MendellJZahirHMatsushimaNDrug-drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitorAm J Cardiovasc Drugs20131333134223784266

 PubMed Web of Science ®Google Scholar

OgataKMendell-HararyJTachibanaMClinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteersJ Clin Pharmacol20105074375320081065

 PubMed Web of Science ®Google Scholar

ConnollySJEzekowitzMDYusufSDabigatran versus warfarin in patients with atrial fibrillationN Engl J Med20093611139115119717844

 PubMed Web of Science ®Google Scholar

PatelMRMahaffeyKWGargJRivaroxaban versus warfarin in nonvalvular atrial fibrillationN Engl J Med201136588389121830957

 PubMed Web of Science ®Google Scholar

ConnollySJEikelboomJJoynerCApixaban in patients with atrial fibrillationN Engl J Med201136480681721309657

 PubMed Web of Science ®Google Scholar

GrangerCBAlexanderJHMcMurrayJJApixaban versus warfarin in patients with atrial fibrillationN Engl J Med201136598199221870978

 PubMed Web of Science ®Google Scholar

GiuglianoRPRuffCTBraunwaldEEdoxaban versus warfarin in patients with atrial fibrillationN Engl J Med20133692093210424251359

 PubMed Web of Science ®Google Scholar

ConnollySJEzekowitzMDYusufSNewly identified events in the RE-LY trialN Engl J Med20103631875187621047252

 PubMed Web of Science ®Google Scholar

LiesenfeldKHSchaferHGTroconizIFEffects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysisBr J Clin Pharmacol20066252753717061960

 PubMed Web of Science ®Google Scholar

StangierJFeuringMUsing the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatranBlood Coagul Fibrinolysis20122313814322227958

 PubMed Web of Science ®Google Scholar

van RynJRuehlDPriepkeHReversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran, by recombinant factor VIIa or activated prothrombin complex concentrateHaematologica200893148

 Web of Science ®Google Scholar

BarrettYCWangZFrostCShenkerAClinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assayThromb Haemost20101041263127120978714

 PubMed Web of Science ®Google Scholar

GarciaDBarrettYCRamacciottiEWeitzJILaboratory assessment of the anticoagulant effects of the next generation of oral anticoagulantsJ Thromb Haemost20131124525223216682

 PubMed Web of Science ®Google Scholar

SamamaMMMartinoliJLLe FlemLAssessment of laboratory assays to measure rivaroxaban – an oral, direct factor Xa inhibitorThromb Haemost201010381582520135059

 PubMed Web of Science ®Google Scholar

WongPCCrainEJXinBApixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studiesJ Thromb Haemost2008682082918315548

 PubMed Web of Science ®Google Scholar

BeckerRCYangHBarrettYChromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban – an oral, direct and selective factor Xa inhibitorJ Thromb Thrombolysis20113218318721516308

 PubMed Web of Science ®Google Scholar