NUEVOS ANTICOAGULANTEScardiologiapuertadehierro.com/wp-content/uploads/DrCastro-r.pdf · Myocardial Infarction 48) trial,321 edoxaban 60 mg once daily and edoxaban 30 mg once daily

Víctor Castro UrdaUnidad de Arritmias

Hospital Universitario Puerta de Hierro Majadahonda

NUEVOS ANTICOAGULANTES¿Qué nos ha enseñado la práctica diaria?

Myocardial Infarction 48) trial,321 edoxaban 60 mg once daily andedoxaban 30 mg once daily (with dose reductions in certain pa-tients, Table 13), were compared with adjusted-dose warfarin.405

Edoxaban 60 mg once daily was non-inferior to warfarin (Table 13).In an on-treatment analysis, edoxaban 60 mg once daily significant-ly reduced stroke or systemic embolism by 21% and significantlyreduced major bleeding events by 20% compared with warfarin,while edoxaban 30 mg once daily was non-inferior to warfarinfor prevention of stroke and systemic embolism but significantlyreduced major bleeding events by 53%. Cardiovascular deathwas reduced in patients randomized to edoxaban 60 mg oncedaily or edoxaban 30 mg once daily compared with warfarin.

Only the higher dose regimen has been approved for stroke pre-vention in AF.

9.2.2.4 RivaroxabanIn the ROCKET-AF (Rivaroxaban Once Daily Oral Direct Fac-

tor Xa Inhibition Compared with Vitamin K Antagonism for Pre-vention of Stroke and Embolism Trial in Atrial Fibrillation) trial,320

patients were randomized to rivaroxaban 20 mg once dailyor VKA, with a dose adjustment to 15 mg daily for those withestimated CrCl 30–49 mL/min by the Cockroft–Gault formula(Table 13). Rivaroxaban was non-inferior to warfarin for the pre-vention of stroke and systemic embolism in the intent-to-treat

Table 13 Characteristics of approved non-vitamin K antagonist oral anticoagulants compared

Dabigatran(RE-LY)

Rivaroxaban(ROCKET-AF)

Apixaban(ARISTOTLE)

Edoxaban(ENGAGE AF-TIMI 48)

Mechanism Oral direct thrombin inhibitor Oral direct factor Xa inhibitor Oral direct factor Xa inhibitor Oral direct factor Xa inhibitor

Bioavailability, % 6 66 fasting, 80–100 with food 50 62

Time to peak levels, hours 3 2–4 3 1–2

Half-life, hours 12–17 5–13 9–14 10–14

Excretion 80% renal 66% liver, 33% renal 27% renal 50% renal

Dose 150 mg twice daily or 110 mg twice daily 20 mg once daily 5 mg twice daily 60 mg once daily or 30 mg once daily

Dose reduction in selected patients

Rivaroxaban 15 mg once daily if CrCl 30-49 mL/min

Apixaban 2.5 mg twice daily if at least2 of age ≥80 years, body weight ≤60 kg or serum creatinine level ≥1.5 mg/dL(133 µmol/L)

Edoxaban 60 mg reduced to 30 mg once daily, and edoxaban 30 mg reduced to 15 mg once daily, if any of the following: creatinine clearance of 30–50 mL/min, body weight ≤60 kg, concomitant use of verapamil or quinidine or dronedarone

Study design Randomized, open-label Randomized, double-blind Randomized, double-blind Randomized, double-blind

Number of patients 18 113 14 264 18 201 21 105

Follow-up period, years 2 1.9 1.8 2.8

Randomized groups Dose-adjusted warfarin vs. blinded doses of dabigatran (150 mg twice daily, 110 mg twice daily)

Dose-adjusted warfarin vs. rivaroxaban 20 mg once daily

Dose-adjusted warfarin vs. apixaban 5 mg twice daily

Dose-adjusted warfarin vs. edoxaban (60 mg once daily, 30 mg once daily)

Age, years 71.5 ± 8.7 (mean ± SD) 73 (65–78) [median (interquartile range)] 70 (63–76) [median (interquartile range)]

72 (64–78) [median (interquartile range)]

Male sex, % 63.6 60.3 64.5 61.9

CHADS2 score (mean) 2.1 3.5 2.1 2.8

Warfarin Dabigatran 150 Dabigatran 110 Warfarin Rivaroxaban Warfarin Apixaban Warfarin Edoxaban 60 Edoxaban 30

n = 6022 n = 6076 n = 6015 n = 7133 n = 7131 n = 9081 n = 9120 n = 7036 n = 7035 n = 7034

Event rate, %/year

Event rate, %/year (RR vs. warfarin)


Event rate, %/year Event rate, %/year (HR vs. warfarin)

Event rate, %/year

Event rate, %/year (HR vs. warfarin)

Event rate, %/year



Stroke/systemic embolism 1.72

1.12 (0.65,0.52–0.81;P for non-inferiority and superiority<0.001)

1.54 (0.89, 0.73–1.09;P for non-inferiority<0.001)

2.4

2.1 (0.88, 0.75–1.03;P for non-inferiority<0.001, P for superiority = 0.12)

1.60

1.27 (0.79, 0.66–0.95;P <0.001 for non-inferiority,P = 0.01 for superiority)

1.80

1.57 (0.87, 0.73–1.04;P <0.001 for non-inferiority, P = 0.08 for superiority)

2.04 (1.13, 0.96–1.34;P = 0.005 for non-inferiority, P = 0.10 for superiority)

Ischaemic stroke 1.220.93 (0.76,0.59–0.97;P = 0.03)

1.34 (1.10,0.88–1.37;P = 0.42)

1.42 1.34 (0.94; 0.75–1.17;P = 0.581) 1.05 0.97 (0.92, 0.74–1.13;

P = 0.42) 1.25 1.25 (1.00, 0.83–1.19;P = 0.97)

1.77 (1.41, 1.19–1.67;P <0.001)

Haemorrhagic stroke 0.380.10 (0.26,0.14–0.49;P <0.001)

0.12 (0.31,0.17–0.56;P <0.001)

0.44 0.26 (0.59; 0.37–0.93;P = 0.024) 0.47 0.24 (0.51, 0.35–0.75;

P <0.001) 0.47 0.26 (0.54, 0.38–0.77;P <0.001)

0.16 (0.33, 0.22–0.50;P <0.001)

Major bleeding 3.613.40 (0.94,0.82–1.08;P = 0.41)

2.92 (0.80, 0.70–0.93;P = 0.003) 3.45 3.60 (1.04; 0.90-2.30;

P = 0.58) 3.09 2.13 (0.69, 0.60–0.80;

P <0.001) 3.43 2.75 (0.80, 0.71–0.91; P <0.001)

1.61 (0.47, 0.41–0.55; P <0.001)

Intracranial bleeding 0.770.32 (0.42,0.29–0.61;P <0.001)

0.23 (0.29 0.19–0.45;P <0.001)

0.74 0.49 (0.67; 0.47–0.93;P = 0.02) 0.80 0.33 (0.42, 0.30–0.58;

P <0.001) 0.85 0.39 (0.47, 0.34–0.63; P <0.001)

0.26 (0.30, 0.21–0.43; P <0.001)

Gastrointestinal major bleeding 1.09

1.60 (1.48,1.19–1.86;P <0.001)

1.13 (1.04, 0.82–1.33;P = 0.74)

1.24 2.00 (1.61; 1.30-1.99; P < 0.001) 0.86 0.76 (0.89, 0.70–1.15;

P = 0.37) 1.23 1.51 (1.23, 1.02–1.50; P = 0.03)

0.82 (0.67, 0.53–0.83; P <0.001)

Myocardial infarction 0.640.81 (1.27,0.94-1.71;P = 0.12)

0.82 (1.29, 0.96-1.75;P = 0.09)

1.12 0.91 (0.81; 0.63–1.06;P = 0.12) 0.61 0.53 (0.88, 0.66–1.17;

P = 0.37) 0.75 0.70 (0.94, 0.74–1.19; P = 0.60)

0.89 (1.19, 0.95–1.49; P = 0.13)

Death from any cause 4.133.64 (0.88,0.77–1.00;P = 0.051)

3.75 (0.91, 0.80–1.03;P = 0.13)

2.21 1.87 (0.85; 0.70–1.02;P = 0.07) 3.94 3.52 (0.89, 0.80–0.99;

P = 0.047) 4.35 3.99 (0.92, 0.83–1.01; P = 0.08)

3.80 (0.87, 0.79–0.96; P = 0.006)

ESC Guidelines2918

Myocardial Infarction 48) trial,321 edoxaban 60 mg once daily andedoxaban 30 mg once daily (with dose reductions in certain pa-tients, Table 13), were compared with adjusted-dose warfarin.405

Edoxaban 60 mg once daily was non-inferior to warfarin (Table 13).In an on-treatment analysis, edoxaban 60 mg once daily significant-ly reduced stroke or systemic embolism by 21% and significantlyreduced major bleeding events by 20% compared with warfarin,while edoxaban 30 mg once daily was non-inferior to warfarinfor prevention of stroke and systemic embolism but significantlyreduced major bleeding events by 53%. Cardiovascular deathwas reduced in patients randomized to edoxaban 60 mg oncedaily or edoxaban 30 mg once daily compared with warfarin.

Only the higher dose regimen has been approved for stroke pre-vention in AF.

9.2.2.4 RivaroxabanIn the ROCKET-AF (Rivaroxaban Once Daily Oral Direct Fac-

tor Xa Inhibition Compared with Vitamin K Antagonism for Pre-vention of Stroke and Embolism Trial in Atrial Fibrillation) trial,320

patients were randomized to rivaroxaban 20 mg once dailyor VKA, with a dose adjustment to 15 mg daily for those withestimated CrCl 30–49 mL/min by the Cockroft–Gault formula(Table 13). Rivaroxaban was non-inferior to warfarin for the pre-vention of stroke and systemic embolism in the intent-to-treat

Table 13 Characteristics of approved non-vitamin K antagonist oral anticoagulants compared

Dabigatran(RE-LY)

Rivaroxaban(ROCKET-AF)

Apixaban(ARISTOTLE)

Edoxaban(ENGAGE AF-TIMI 48)

Mechanism Oral direct thrombin inhibitor Oral direct factor Xa inhibitor Oral direct factor Xa inhibitor Oral direct factor Xa inhibitor

Bioavailability, % 6 66 fasting, 80–100 with food 50 62

Time to peak levels, hours 3 2–4 3 1–2

Half-life, hours 12–17 5–13 9–14 10–14

Excretion 80% renal 66% liver, 33% renal 27% renal 50% renal

Dose 150 mg twice daily or 110 mg twice daily 20 mg once daily 5 mg twice daily 60 mg once daily or 30 mg once daily

Dose reduction in selected patients

Rivaroxaban 15 mg once daily if CrCl 30-49 mL/min

Apixaban 2.5 mg twice daily if at least2 of age ≥80 years, body weight ≤60 kg or serum creatinine level ≥1.5 mg/dL(133 µmol/L)

Edoxaban 60 mg reduced to 30 mg once daily, and edoxaban 30 mg reduced to 15 mg once daily, if any of the following: creatinine clearance of 30–50 mL/min, body weight ≤60 kg, concomitant use of verapamil or quinidine or dronedarone

Study design Randomized, open-label Randomized, double-blind Randomized, double-blind Randomized, double-blind

Number of patients 18 113 14 264 18 201 21 105

Follow-up period, years 2 1.9 1.8 2.8

Randomized groups Dose-adjusted warfarin vs. blinded doses of dabigatran (150 mg twice daily, 110 mg twice daily)

Dose-adjusted warfarin vs. rivaroxaban 20 mg once daily

Dose-adjusted warfarin vs. apixaban 5 mg twice daily

Dose-adjusted warfarin vs. edoxaban (60 mg once daily, 30 mg once daily)

Age, years 71.5 ± 8.7 (mean ± SD) 73 (65–78) [median (interquartile range)] 70 (63–76) [median (interquartile range)]

72 (64–78) [median (interquartile range)]

Male sex, % 63.6 60.3 64.5 61.9

CHADS2 score (mean) 2.1 3.5 2.1 2.8

Warfarin Dabigatran 150 Dabigatran 110 Warfarin Rivaroxaban Warfarin Apixaban Warfarin Edoxaban 60 Edoxaban 30

n = 6022 n = 6076 n = 6015 n = 7133 n = 7131 n = 9081 n = 9120 n = 7036 n = 7035 n = 7034

Event rate, %/year



Event rate, %/year Event rate, %/year (HR vs. warfarin)

Event rate, %/year


Event rate, %/year



Stroke/systemic embolism 1.72

1.12 (0.65,0.52–0.81;P for non-inferiority and superiority<0.001)

1.54 (0.89, 0.73–1.09;P for non-inferiority<0.001)

2.4

2.1 (0.88, 0.75–1.03;P for non-inferiority<0.001, P for superiority = 0.12)

1.60

1.27 (0.79, 0.66–0.95;P <0.001 for non-inferiority,P = 0.01 for superiority)

1.80

1.57 (0.87, 0.73–1.04;P <0.001 for non-inferiority, P = 0.08 for superiority)

2.04 (1.13, 0.96–1.34;P = 0.005 for non-inferiority, P = 0.10 for superiority)

Ischaemic stroke 1.220.93 (0.76,0.59–0.97;P = 0.03)

1.34 (1.10,0.88–1.37;P = 0.42)

1.42 1.34 (0.94; 0.75–1.17;P = 0.581) 1.05 0.97 (0.92, 0.74–1.13;

P = 0.42) 1.25 1.25 (1.00, 0.83–1.19;P = 0.97)

1.77 (1.41, 1.19–1.67;P <0.001)

Haemorrhagic stroke 0.380.10 (0.26,0.14–0.49;P <0.001)

0.12 (0.31,0.17–0.56;P <0.001)

0.44 0.26 (0.59; 0.37–0.93;P = 0.024) 0.47 0.24 (0.51, 0.35–0.75;

P <0.001) 0.47 0.26 (0.54, 0.38–0.77;P <0.001)

0.16 (0.33, 0.22–0.50;P <0.001)

Major bleeding 3.613.40 (0.94,0.82–1.08;P = 0.41)

2.92 (0.80, 0.70–0.93;P = 0.003) 3.45 3.60 (1.04; 0.90-2.30;

P = 0.58) 3.09 2.13 (0.69, 0.60–0.80;

P <0.001) 3.43 2.75 (0.80, 0.71–0.91; P <0.001)

1.61 (0.47, 0.41–0.55; P <0.001)

Intracranial bleeding 0.770.32 (0.42,0.29–0.61;P <0.001)

0.23 (0.29 0.19–0.45;P <0.001)

0.74 0.49 (0.67; 0.47–0.93;P = 0.02) 0.80 0.33 (0.42, 0.30–0.58;

P <0.001) 0.85 0.39 (0.47, 0.34–0.63; P <0.001)

0.26 (0.30, 0.21–0.43; P <0.001)

Gastrointestinal major bleeding 1.09

1.60 (1.48,1.19–1.86;P <0.001)

1.13 (1.04, 0.82–1.33;P = 0.74)

1.24 2.00 (1.61; 1.30-1.99; P < 0.001) 0.86 0.76 (0.89, 0.70–1.15;

P = 0.37) 1.23 1.51 (1.23, 1.02–1.50; P = 0.03)

0.82 (0.67, 0.53–0.83; P <0.001)

Myocardial infarction 0.640.81 (1.27,0.94-1.71;P = 0.12)

0.82 (1.29, 0.96-1.75;P = 0.09)

1.12 0.91 (0.81; 0.63–1.06;P = 0.12) 0.61 0.53 (0.88, 0.66–1.17;

P = 0.37) 0.75 0.70 (0.94, 0.74–1.19; P = 0.60)

0.89 (1.19, 0.95–1.49; P = 0.13)

Death from any cause 4.133.64 (0.88,0.77–1.00;P = 0.051)

3.75 (0.91, 0.80–1.03;P = 0.13)

2.21 1.87 (0.85; 0.70–1.02;P = 0.07) 3.94 3.52 (0.89, 0.80–0.99;

P = 0.047) 4.35 3.99 (0.92, 0.83–1.01; P = 0.08)

3.80 (0.87, 0.79–0.96; P = 0.006)

ESC Guidelines2918

Todos

Todos

PenetracióndelosACODs porPaíses

IntroducciónACODsenEspaña(Datos03/2017)

¿A quién debemos indicarle el tratamiento con NACO?

¿A quién NO debemos indicarle el tratamiento con NACO?

ESC GUIDELINES

2016 ESC Guidelines for the management of atrialfibrillation developed in collaboration with EACTSThe Task Force for the management of atrial fibrillation of theEuropean Society of Cardiology (ESC)

Developed with the special contribution of the European HeartRhythm Association (EHRA) of the ESC

Endorsed by the European Stroke Organisation (ESO)

Authors/Task Force Members: Paulus Kirchhof (Chairperson) (UK/Germany),*

Stefano Benussi*1 (Co-Chairperson) (Switzerland), Dipak Kotecha (UK),Anders Ahlsson1 (Sweden), Dan Atar (Norway), Barbara Casadei (UK),Manuel Castella1 (Spain), Hans-Christoph Diener2 (Germany), Hein Heidbuchel(Belgium), Jeroen Hendriks (The Netherlands), Gerhard Hindricks (Germany),Antonis S. Manolis (Greece), Jonas Oldgren (Sweden), Bogdan Alexandru Popescu(Romania), Ulrich Schotten (The Netherlands), Bart Van Putte1 (The Netherlands),and Panagiotis Vardas (Greece)Document Reviewers: Stefan Agewall (CPG Review Co-ordinator) (Norway), John Camm (CPG ReviewCo-ordinator) (UK), Gonzalo Baron Esquivias (Spain), Werner Budts (Belgium), Scipione Carerj (Italy),Filip Casselman (Belgium), Antonio Coca (Spain), Raffaele De Caterina (Italy), Spiridon Deftereos (Greece),Dobromir Dobrev (Germany), Jose M. Ferro (Portugal), Gerasimos Filippatos (Greece), Donna Fitzsimons (UK),

* Corresponding authors: Paulus Kirchhof, Institute of Cardiovascular Sciences, University of Birmingham, SWBH and UHB NHS trusts, IBR, Room 136, Wolfson Drive, BirminghamB15 2TT, United Kingdom, Tel: +44 121 4147042, E-mail: [email protected]; Stefano Benussi, Department of Cardiovascular Surgery, University Hospital Zurich, Ramistrasse100, 8091 Zurich, Switzerland, Tel: +41(0)788933835, E-mail: [email protected] Representing the European Association for Cardio-Thoracic Surgery (EACTS)2 Representing the European Stroke Association (ESO)

ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies Reviewers can be found in the Appendix.

ESC entities having participated in the development of this document:

Associations: European Association for Cardiovascular Prevention and Rehabilitation (EACPR), European Association of Cardiovascular Imaging (EACVI), European Heart RhythmAssociation (EHRA), Heart Failure Association (HFA).

Councils: Council on Cardiovascular Nursing and Allied Professions, Council for Cardiology Practice, Council on Cardiovascular Primary Care, Council on Hypertension.

Working Groups: Cardiac Cellular Electrophysiology, Cardiovascular Pharmacotherapy, Grown-up Congenital Heart Disease, Thrombosis, Valvular Heart Disease.

The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESCGuidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford Uni-versity Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC ([email protected]).

Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available atthe time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recom-mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic ortherapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate andaccurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nordo the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competentpublic health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also thehealth professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

& The European Society of Cardiology 2016. All rights reserved. For permissions please email: [email protected].

doi:10.1093/eurheartj/ehw210European Heart Journal (2016) 37, 2893–2962

with increased mortality in patients on dialysis.417 There are norandomized trials assessing OAC in haemodialysis patients,418

and no controlled trials of NOACs in patients with severe CKD(CrCl ,25–30 mL/min).318 – 321 Warfarin use was associated ei-ther with a neutral or increased risk of stroke in database analysesof patients on dialysis,419 – 421 including a population-based ana-lysis in Canada (adjusted HR for stroke 1.14; 95% CI 0.78–1.67,adjusted HR for bleeding 1.44; 95% CI 1.13–1.85).422 In contrast,data from Denmark suggest a benefit of OAC in patients on renalreplacement therapy.423 Hence, controlled studies of anticoagu-lants (both VKAs and NOACs) in AF patients on dialysis areneeded.424

9.2.6 Patients with atrial fibrillation requiring kidneytransplantationThere are no randomized trials assessing OAC in patients after kid-ney transplantation. The prescription of NOAC therapy should be

guided by the estimated GFR of the transplanted kidney. Potentialpharmacokinetic interactions of OAC with immunosuppressiveagents should be considered.

9.2.7 Antiplatelet therapy as an alternative to oralanticoagulantsThe evidence supporting antiplatelet monotherapy for stroke pre-vention in AF is very limited.38,428 – 430 VKA therapy prevents stroke,systemic embolism, myocardial infarction, and vascular death betterthan single or dual antiplatelet therapy with aspirin and clopidogrel(annual risk of 5.6% for aspirin and clopidogrel vs. 3.9% with VKAtherapy).431 Even greater benefits were seen in VKA-treated pa-tients with a high TTR.432 Antiplatelet therapy increases bleedingrisk, especially dual antiplatelet therapy (2.0% vs. 1.3% with antipla-telet monotherapy; P , 0.001),433 with bleeding rates that are simi-lar to those on OAC.354,362,431,434 Thus, antiplatelet therapy cannotbe recommended for stroke prevention in AF patients.

Recommendations for stroke prevention in patients with atrial fibrillation

Recommendations Class a Level b Ref C

Oral anticoagulation therapy to prevent thromboembolism is recommended for all male AF patients with a CHA2DS2-VASc score of 2 or more. I A

38, 318–321, 354, 404

Oral anticoagulation therapy to prevent thromboembolism is recommended in all female AF patients with a CHA2DS2-VASc score of 3 or more. I A

38,318–321, 354, 404

Oral anticoagulation therapy to prevent thromboembolism should be considered in male AF patients with a CHA2DS2-VASc score of 1, considering individual characteristics and patient preferences. IIa B 371,

375–377

Oral anticoagulation therapy to prevent thromboembolism should be considered in female AF patients with a CHA2DS2-VASc score of 2, considering individual characteristics and patient preferences. IIa B 371, 376,

377

Vitamin K antagonist therapy (INR 2.0–3.0 or higher) is recommended for stroke prevention in AF patients with moderate-to-severe mitral stenosis or mechanical heart valves. I B 274,

435–440

When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC (apixaban, dabigatran, edoxaban, or rivaroxaban), a NOAC is recommended in preference to a vitamin K antagonist. I A

39, 318–321,

404

When patients are treated with a vitamin K antagonist, time in therapeutic range (TTR) should be kept as high as possible and closely monitored. I A 395, 432,

441-444

AF patients already on treatment with a vitamin K antagonist may be considered for NOAC treatment if TTR is not well controlled despite good adherence, or if patient preference without contra-indications to NOAC (e.g. prosthetic valve). IIb A

39, 318, 319, 404,

408

Combinations of oral anticoagulants and platelet inhibitors increase bleeding risk and should be avoided in AF patients without another indication for platelet inhibition.

III (harm) B 429, 445

In male or female AF patients without additional stroke risk factors, anticoagulant or antiplatelet therapy is not recommended for stroke prevention.

III (harm) B 368, 371,

376, 377

Antiplatelet monotherapy is not recommended for stroke prevention in AF patients, regardless of stroke risk. III (harm) A 38, 429,

430

NOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) are not recommended in patients with mechanical heart valves (Level of evidence B) or moderate-to-severe mitral stenosis (Level of evidence C).

III (harm) B C 318–321,

400, 404

AF ¼ atrial fibrillation; CHA2DS2-VASc ¼ Congestive Heart failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65–74, and Sex (female);INR ¼ international normalized ratio; NOAC ¼ non-vitamin K antagonist oral anticoagulant; OAC ¼ oral anticoagulation; TTR ¼ time in therapeutic range; VKA ¼ vitamin Kantagonist.aClass of recommendation.bLevel of evidence.cReference(s) supporting recommendations.

ESC Guidelines2920with increased mortality in patients on dialysis.417 There are norandomized trials assessing OAC in haemodialysis patients,418

and no controlled trials of NOACs in patients with severe CKD(CrCl ,25–30 mL/min).318 – 321 Warfarin use was associated ei-ther with a neutral or increased risk of stroke in database analysesof patients on dialysis,419 – 421 including a population-based ana-lysis in Canada (adjusted HR for stroke 1.14; 95% CI 0.78–1.67,adjusted HR for bleeding 1.44; 95% CI 1.13–1.85).422 In contrast,data from Denmark suggest a benefit of OAC in patients on renalreplacement therapy.423 Hence, controlled studies of anticoagu-lants (both VKAs and NOACs) in AF patients on dialysis areneeded.424

9.2.6 Patients with atrial fibrillation requiring kidneytransplantationThere are no randomized trials assessing OAC in patients after kid-ney transplantation. The prescription of NOAC therapy should be

guided by the estimated GFR of the transplanted kidney. Potentialpharmacokinetic interactions of OAC with immunosuppressiveagents should be considered.

9.2.7 Antiplatelet therapy as an alternative to oralanticoagulantsThe evidence supporting antiplatelet monotherapy for stroke pre-vention in AF is very limited.38,428 – 430 VKA therapy prevents stroke,systemic embolism, myocardial infarction, and vascular death betterthan single or dual antiplatelet therapy with aspirin and clopidogrel(annual risk of 5.6% for aspirin and clopidogrel vs. 3.9% with VKAtherapy).431 Even greater benefits were seen in VKA-treated pa-tients with a high TTR.432 Antiplatelet therapy increases bleedingrisk, especially dual antiplatelet therapy (2.0% vs. 1.3% with antipla-telet monotherapy; P , 0.001),433 with bleeding rates that are simi-lar to those on OAC.354,362,431,434 Thus, antiplatelet therapy cannotbe recommended for stroke prevention in AF patients.

Recommendations for stroke prevention in patients with atrial fibrillation

Recommendations Class a Level b Ref C

Oral anticoagulation therapy to prevent thromboembolism is recommended for all male AF patients with a CHA2DS2-VASc score of 2 or more. I A

38, 318–321, 354, 404

Oral anticoagulation therapy to prevent thromboembolism is recommended in all female AF patients with a CHA2DS2-VASc score of 3 or more. I A

38,318–321, 354, 404

Oral anticoagulation therapy to prevent thromboembolism should be considered in male AF patients with a CHA2DS2-VASc score of 1, considering individual characteristics and patient preferences. IIa B 371,

375–377

Oral anticoagulation therapy to prevent thromboembolism should be considered in female AF patients with a CHA2DS2-VASc score of 2, considering individual characteristics and patient preferences. IIa B 371, 376,

377

Vitamin K antagonist therapy (INR 2.0–3.0 or higher) is recommended for stroke prevention in AF patients with moderate-to-severe mitral stenosis or mechanical heart valves. I B 274,

435–440

When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC (apixaban, dabigatran, edoxaban, or rivaroxaban), a NOAC is recommended in preference to a vitamin K antagonist. I A

39, 318–321,

404

When patients are treated with a vitamin K antagonist, time in therapeutic range (TTR) should be kept as high as possible and closely monitored. I A 395, 432,

441-444

AF patients already on treatment with a vitamin K antagonist may be considered for NOAC treatment if TTR is not well controlled despite good adherence, or if patient preference without contra-indications to NOAC (e.g. prosthetic valve). IIb A

39, 318, 319, 404,

408

Combinations of oral anticoagulants and platelet inhibitors increase bleeding risk and should be avoided in AF patients without another indication for platelet inhibition.

III (harm) B 429, 445

In male or female AF patients without additional stroke risk factors, anticoagulant or antiplatelet therapy is not recommended for stroke prevention.

III (harm) B 368, 371,

376, 377

Antiplatelet monotherapy is not recommended for stroke prevention in AF patients, regardless of stroke risk. III (harm) A 38, 429,

430

NOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) are not recommended in patients with mechanical heart valves (Level of evidence B) or moderate-to-severe mitral stenosis (Level of evidence C).

III (harm) B C 318–321,

400, 404

AF ¼ atrial fibrillation; CHA2DS2-VASc ¼ Congestive Heart failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65–74, and Sex (female);INR ¼ international normalized ratio; NOAC ¼ non-vitamin K antagonist oral anticoagulant; OAC ¼ oral anticoagulation; TTR ¼ time in therapeutic range; VKA ¼ vitamin Kantagonist.aClass of recommendation.bLevel of evidence.cReference(s) supporting recommendations.

ESC Guidelines2920

Caso clínico. Qué anticoagulante le ofrecería

• 74 años de edad.• HTA.• Insuficiencia mitral severa.• Fibrilación auricular paroxística

Se puede ContraindicadoPrótesis metálicas ✗

EM moderada/severa ✗

Insuf valvulares mod/severas

✔

EAo severa ✔

Prótesis biológicas ✔

Reparación valvular ✔

TAVI ✔

MCH ✔

Rendaet al. Jacc 2017;69. 1363-71

Rendaet al. Jacc 2017;69. 1363-71

Evaluation of Dose-Reduced Direct OralAnticoagulant TherapyMegan E. Barra, PharmD,a John Fanikos, RPh, MBA,a Jean M. Connors, MD,b Katelyn W. Sylvester, PharmD,a

Gregory Piazza, MD, MS,c Samuel Z. Goldhaber, MDcaDepartment of Pharmacy, bHematology Division, Department of Medicine, and cThrombosis Research Group, Cardiovascular Division,Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

ABSTRACT

BACKGROUND: Compared with vitamin K antagonists, direct-acting oral anticoagulants (DOACs) havefixed dosing, limited drug interactions, and do not require therapeutic drug level monitoring. Dose ad-justments are recommended for moderate renal dysfunction, low body weight, and select druginteractions.OBJECTIVES: The aim of our study is to determine if DOAC dose reductions were appropriate based on themanufacturer labeling recommendations for each agent. We also followed patients’ treatment outcomes.METHODS: We retrospectively reviewed patients administered a DOAC at a reduced dose between January2011 and August 2014. The primary outcome was adherence to current manufacturer dose recommenda-tions. The secondary outcome measures were the incidence of thromboembolic events or any bleedingepisodes, regardless of severity, while on therapy.RESULTS: Of 224 patients included in the analysis, 43.3% of patients fit criteria for a dose adjustmentaccording to manufacturer recommendations. Only 3 of 28 (10.7%) patients treated with apixaban met 2 outof 3 clinical criteria required for a dose reduction per manufacturer recommendations. Only 54.7% ofrivaroxaban-treated patients and 32.2% of dabigatran-treated patients had renal insufficiency requiring adose reduction. Half of our patient population received aspirin therapy, with 6.3% of patients on tripleantithrombotic therapy (dual antiplatelet agents plus an anticoagulant). A past medical history significantfor bleeding was prevalent in patients treated with a reduced-dose DOAC (32.1%, 20.4%, and 25.4% ofpatients in the apixaban-, rivaroxaban-, and dabigatran-treated groups, respectively). Thromboembolicevents occurred in 10.7%, 3.6%, and 5.1% of patients in the apixaban, rivaroxaban, and dabigatran groups,respectively. Frequency of bleeding complications, regardless of severity, was 17.9%, 18.2%, and 23.7% ofpatients in the apixaban, rivaroxaban, and dabigatran groups, respectively.CONCLUSION: We found that dose-adjusted DOAC therapy was often prescribed in a dose that was lowerthan package insert recommendations.! 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/). ! The American Journal of Medicine (2016)129, 1198-1204

KEYWORDS: Anticoagulation; Atrial fibrillation; Dose reduction; Drug interactions; Renal dysfunction; Venousthromboembolism

Compared with vitamin K antagonists, direct-acting oralanticoagulants (DOACs) have more predictable pharmaco-dynamics, fewer drug interactions, and do not require lab-oratory coagulation monitoring.1 While current guidelinesdo not recommend a preference for one DOAC overanother, as a group they have similar efficacy and animproved safety profile, with less intracranial bleeding andhemorrhagic stroke in atrial fibrillation and fewer major

Funding: There was no external support for this study.Conflict of Interest: All authors of this article have no conflicts to

disclose.Authorship: All authors participated in the data collection, analysis,

and manuscript preparation.Requests for reprints should be addressed to Samuel Z. Goldhaber, MD,

Cardiovascular Division, Brigham and Women’s Hospital, 75 FrancisStreet, Boston, MA 02115.

E-mail address: [email protected]

0002-9343/! 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).http://dx.doi.org/10.1016/j.amjmed.2016.05.041

CLINICAL RESEARCH STUDY

þÿ D o w n l o a d e d f r o m C l i n i c a l K e y . c o m a t C o n s e j e r í a d e S a n i d a d d e M a d r i d B i b l i o t e c a V i r t u a l J a n u a r y 2 3 , 2 0 1 7 .For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.

Am J Med 2016; 129:1198-1204

• Estudio retrospectivo (2011-2014)• 224 pacientes con NACO a dosis reducida (13.3% de todos los

pacientes a los que se prescribió un NACO)• La indicación más frecuente para ACO era FA/flutter auricular• Seguimiento de 1 año• Sólo el 43.3% cumplía criterios para dosis reducida

Apixaban Rivaroxaban Dabigatrann 28 (12.5%) 137 (61.1%) 59 (26.3%)

Indicación FA 82.1% 88.3% 98.3%

AAS 46.4% 55.5% 50.8%

AP de sangrado 32.1% 20.4% 25.4%

Evento TE 10.7% 3.6% 5.1%

Sangradomayor/menor

17.9% 18.2% 23.7%

JACC 2016; (68) 24:2597-604

ORIGINAL INVESTIGATIONS

Off-Label Dosing of Non-Vitamin KAntagonist Oral Anticoagulants andAdverse OutcomesThe ORBIT-AF II Registry

Benjamin A. Steinberg, MD, MHS,a,b,c Peter Shrader, MA,c Laine Thomas, PHD,c Jack Ansell, MD,d

Gregg C. Fonarow, MD,e Bernard J. Gersh, MB, CHB, DPHIL,f Peter R. Kowey, MD,g Kenneth W. Mahaffey, MD,h

Gerald Naccarelli, MD,i James Reiffel, MD,j Daniel E. Singer, MD,k Eric D. Peterson, MD, MPH,b,c

Jonathan P. Piccini, MD, MHS,b,c for the ORBIT-AF Investigators and Patients

ABSTRACT

BACKGROUND Although non-vitamin K antagonist oral anticoagulants (NOACs) do not require frequent laboratory

monitoring, each compound requires dose adjustments on the basis of certain clinical criteria.

OBJECTIVES This study assessed the frequency of off-label NOAC doses among AF patients and the associations

between off-label dose therapy and clinical outcomes in community practice.

METHODS We evaluated 5,738 patients treated with a NOAC at 242 ORBIT-AF II (Outcomes Registry for Better

Informed Treatment of Atrial Fibrillation phase II) sites. NOAC doses were classified as either underdosed or overdosed,

consistent with Food and Drug Administration labeling. Longitudinal outcomes (median follow-up: 0.99 years)

included stroke or systemic embolism, myocardial infarction, major bleeding (International Society of Thrombosis

and Haemostasis criteria), cause-specific hospitalization, and all-cause mortality.

RESULTS Overall, 541 NOAC-treated patients (9.4%) were underdosed, 197 were overdosed (3.4%), and 5,000 were

dosed according to U.S. labeling (87%). Compared with patients receiving the recommended dose, those who were

receiving off-label doses were older (median: 79 and 80 years of age vs. 70 years of age, respectively; p < 0.0001), more

likely female (48% and 67% vs. 40%, respectively; p < 0.0001), less likely to be treated by an electrophysiologist

(18% and 19% vs. 27%, respectively; p < 0.0001), and had higher CHA2DS2-VASc scores (96% and 97% $2 vs. 86%,

respectively; p < 0.0001) and higher ORBIT bleeding scores (25% and 31% >4 vs. 11%, respectively; p < 0.0001). After

dose adjustment, NOAC overdosing was associated with increased all-cause mortality compared with recommended

doses (adjusted hazard ratio: 1.91; 95% confidence interval [CI]: 1.02 to 3.60; p ¼ 0.04). Underdosing was associatedwith increased cardiovascular hospitalization (adjusted hazard ratio: 1.26; 95% CI: 1.07 to 1.50; p ¼ 0.007).

CONCLUSIONS A significant minority (almost 1 in 8) of U.S. patients in the community received NOAC doses

inconsistent with labeling. NOAC over- and underdosing are associated with increased risk for adverse events.

(Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II [ORBIT-AF II]; NCT01701817)

(J Am Coll Cardiol 2016;68:2597–604) © 2016 The Authors. Published by Elsevier on behalf of the American College of

Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

From the aDivision of Cardiovascular Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah; bDepartment ofMedicine, Duke University Medical Center, Durham, North Carolina; cDuke Clinical Research Institute, Durham, North Carolina;dDepartment of Medicine, Hofstra Northwell School of Medicine, Long Island, New York; eAhmanson-UCLA CardiomyopathyCenter, University of California Los Angeles Division of Cardiology, Los Angeles, California; fDepartment of Medicine, Mayo

Listen to this manuscript’saudio summary byJACC Editor-in-ChiefDr. Valentin Fuster.

J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 6 8 , N O . 2 4 , 2 0 1 6

ª 2 0 1 6 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E A M E R I C A N

C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

T H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .

I S S N 0 7 3 5 - 1 0 9 7

h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j a c c . 2 0 1 6 . 0 9 . 9 6 6

• 5738 pacientes con FA• 542 (9.4%) infradosificados• 197 (3.4%) sobredosificados

• Los pacientes que recibieron dosis off-label eran significativamente mayores (80 vs 70 años), mujeres, y con CHA2DS2-VASc y ORBIT bleeding scores más altos (todas las p < 0.0001)

however, the current clinical data do not support useof these drugs in patients with severe kidney dis-ease. Underdosing also appears to be associated withworse outcomes, but these data should be inter-preted with caution, as the mechanism of the effectis unclear.

STUDY LIMITATIONS. We studied the relationshipbetween off-label doses and outcomes retrospec-tively; dose groups were not randomized. Residualand/or unmeasured confounding may exist andintroduce bias in the results; furthermore, clinicalevents may be associated with off-label use but

not causally related to dosing (e.g., risk factorsfor bleeding and stroke). Additionally, not allconcomitant medicines that might indicate NOACadjustment were collected; however, these arelikely to be uncommon and/or short-term (e.g.,antimicrobial agents). Similarly, trends in off-labeldoses over time were not assessed due to variabilityin the availability of dose criteria (e.g., renal func-tion). The definition of on-label dose was derivedfrom the U.S. FDA-approved PIs, and thus theseresults may not be applicable in other jurisdictions.Last, our multivariate analysis assumed a consistentmagnitude of effect for all off-label doses, which may

TABLE 2 Unadjusted and Adjusted Association Between Appropriateness of NOAC Dosing and Clinical Outcomes

Number of Events

Unadjusted Adjusted

HR (95% CI) p Value Global p Value HR (95% CI) p Value Global p Value

All-cause death <0.0001 0.0674

Appropriately dosed 158 (2.95) Reference Reference

Underdosed 36 (6.30) 2.18 (1.57–3.02) <0.0001 1.25 (0.89–1.76) 0.1975

Overdosed 18 (8.05) 1.43 (0.76–2.67) 0.2650 1.91 (1.02–3.60) 0.0438

First stroke, non-CNS embolism, or TIA 0.4243 0.7580


Underdosed 11 (1.95) 1.50 (0.77–2.94) 0.2369 1.17 (0.61–2.26) 0.6328

Overdosed 5 (2.25) 1.40 (0.39–5.04) 0.6083 1.46 (0.42–5.07) 0.5550

First MI 0.2327 0.4507


Underdosed 6 (1.06) 1.49 (0.68–3.27) 0.3253 1.32 (0.55–3.16) 0.5309

Overdosed 1 (0.45) 0.24 (0.04–1.53) 0.1319 0.31 (0.05–1.96) 0.2142

First all-cause hospitalization 0.0470 0.4258

Appropriately dosed 1,727 (42.77) Reference Reference

Underdosed 212 (48.56) 1.17 (1.02–1.34) 0.0208 1.09 (0.96–1.24) 0.1940

Overdosed 83 (51.52) 0.92 (0.72–1.16) 0.4700 0.98 (0.77–1.23) 0.8378

First CV hospitalization 0.0481 0.0050


Underdosed 129 (26.11) 1.12 (0.92–1.35) 0.2609 1.26 (1.07–1.50) 0.0065

Overdosed 45 (23.82) 0.70 (0.51–0.97) 0.0316 0.73 (0.53–1.02) 0.0625

First bleeding hospitalization 0.0768 0.5742


Underdosed 23 (4.12) 1.60 (1.06–2.41) 0.0247 1.00 (0.63–1.57) 0.9891

Overdosed 15 (6.94) 1.12 (0.61–2.08) 0.7095 1.42 (0.74–2.72) 0.2925

First nonbleeding, non-CV hospitalization 0.0002 0.0978

Recommended dose 568 (11.45) Reference Reference

Underdosed 91 (17.57) 1.57 (1.25–1.96) <0.0001 1.14 (0.90–1.45) 0.2868

Overdosed 34 (16.72) 1.33 (0.87–2.03) 0.1863 1.50 (0.98–2.29) 0.0644

First major bleeding 0.4015 0.1103


Underdosed 23 (4.12) 1.21 (0.78–1.88) 0.4030 0.80 (0.52–1.23) 0.3115

Overdosed 15 (6.92) 1.46 (0.79–2.70) 0.2323 1.71 (0.91–3.24) 0.0980

First bleeding hospitalization or major bleeding 0.5174 0.2087


Underdosed 28 (5.05) 1.23 (0.84–1.81) 0.2825 0.79 (0.54–1.16) 0.2256

Overdosed 18 (8.40) 1.16 (0.69–1.95) 0.5846 1.39 (0.80–2.41) 0.2479

Values are number of events (events per 100 patient-years), unless otherwise indicated. The p values in bold indicate p < 0.05.

CI¼ confidence interval; CNS¼ central nervous system; CV¼ cardiovascular; HR¼hazard ratio;MI¼myocardial infarction;NOAC¼nonvitaminK antagonist oral anticoagulant; TIA¼ transient ischemic attack.

J A C C V O L . 6 8 , N O . 2 4 , 2 0 1 6 Steinberg et al.D E C E M B E R 2 0 , 2 0 1 6 : 2 5 9 7 – 6 0 4 NOAC Dosing and Outcomes in AF

2603





Number of Events

Unadjusted Adjusted




Underdosed 36 (6.30) 2.18 (1.57–3.02) <0.0001 1.25 (0.89–1.76) 0.1975

Overdosed 18 (8.05) 1.43 (0.76–2.67) 0.2650 1.91 (1.02–3.60) 0.0438



Underdosed 11 (1.95) 1.50 (0.77–2.94) 0.2369 1.17 (0.61–2.26) 0.6328

Overdosed 5 (2.25) 1.40 (0.39–5.04) 0.6083 1.46 (0.42–5.07) 0.5550

First MI 0.2327 0.4507


Underdosed 6 (1.06) 1.49 (0.68–3.27) 0.3253 1.32 (0.55–3.16) 0.5309

Overdosed 1 (0.45) 0.24 (0.04–1.53) 0.1319 0.31 (0.05–1.96) 0.2142



Underdosed 212 (48.56) 1.17 (1.02–1.34) 0.0208 1.09 (0.96–1.24) 0.1940

Overdosed 83 (51.52) 0.92 (0.72–1.16) 0.4700 0.98 (0.77–1.23) 0.8378



Underdosed 129 (26.11) 1.12 (0.92–1.35) 0.2609 1.26 (1.07–1.50) 0.0065

Overdosed 45 (23.82) 0.70 (0.51–0.97) 0.0316 0.73 (0.53–1.02) 0.0625



Underdosed 23 (4.12) 1.60 (1.06–2.41) 0.0247 1.00 (0.63–1.57) 0.9891

Overdosed 15 (6.94) 1.12 (0.61–2.08) 0.7095 1.42 (0.74–2.72) 0.2925



Underdosed 91 (17.57) 1.57 (1.25–1.96) <0.0001 1.14 (0.90–1.45) 0.2868

Overdosed 34 (16.72) 1.33 (0.87–2.03) 0.1863 1.50 (0.98–2.29) 0.0644



Underdosed 23 (4.12) 1.21 (0.78–1.88) 0.4030 0.80 (0.52–1.23) 0.3115

Overdosed 15 (6.92) 1.46 (0.79–2.70) 0.2323 1.71 (0.91–3.24) 0.0980



Underdosed 28 (5.05) 1.23 (0.84–1.81) 0.2825 0.79 (0.54–1.16) 0.2256

Overdosed 18 (8.40) 1.16 (0.69–1.95) 0.5846 1.39 (0.80–2.41) 0.2479




2603





Number of Events

Unadjusted Adjusted




Underdosed 36 (6.30) 2.18 (1.57–3.02) <0.0001 1.25 (0.89–1.76) 0.1975

Overdosed 18 (8.05) 1.43 (0.76–2.67) 0.2650 1.91 (1.02–3.60) 0.0438



Underdosed 11 (1.95) 1.50 (0.77–2.94) 0.2369 1.17 (0.61–2.26) 0.6328

Overdosed 5 (2.25) 1.40 (0.39–5.04) 0.6083 1.46 (0.42–5.07) 0.5550

First MI 0.2327 0.4507


Underdosed 6 (1.06) 1.49 (0.68–3.27) 0.3253 1.32 (0.55–3.16) 0.5309

Overdosed 1 (0.45) 0.24 (0.04–1.53) 0.1319 0.31 (0.05–1.96) 0.2142



Underdosed 212 (48.56) 1.17 (1.02–1.34) 0.0208 1.09 (0.96–1.24) 0.1940

Overdosed 83 (51.52) 0.92 (0.72–1.16) 0.4700 0.98 (0.77–1.23) 0.8378



Underdosed 129 (26.11) 1.12 (0.92–1.35) 0.2609 1.26 (1.07–1.50) 0.0065

Overdosed 45 (23.82) 0.70 (0.51–0.97) 0.0316 0.73 (0.53–1.02) 0.0625



Underdosed 23 (4.12) 1.60 (1.06–2.41) 0.0247 1.00 (0.63–1.57) 0.9891

Overdosed 15 (6.94) 1.12 (0.61–2.08) 0.7095 1.42 (0.74–2.72) 0.2925



Underdosed 91 (17.57) 1.57 (1.25–1.96) <0.0001 1.14 (0.90–1.45) 0.2868

Overdosed 34 (16.72) 1.33 (0.87–2.03) 0.1863 1.50 (0.98–2.29) 0.0644



Underdosed 23 (4.12) 1.21 (0.78–1.88) 0.4030 0.80 (0.52–1.23) 0.3115

Overdosed 15 (6.92) 1.46 (0.79–2.70) 0.2323 1.71 (0.91–3.24) 0.0980



Underdosed 28 (5.05) 1.23 (0.84–1.81) 0.2825 0.79 (0.54–1.16) 0.2256

Overdosed 18 (8.40) 1.16 (0.69–1.95) 0.5846 1.39 (0.80–2.41) 0.2479




2603

Caso clínico. Qué dosis indicaría?

• 80 años de edad.• HTA.• Fibrilación auricular paroxística• Peso 70 kgs• Cr 1,4 mg/ml

Selección de dosis

Selección de dosis

• Rivaroxaban 20 mg UNA vez al día– Siempre CON la comida

• Rivaroxaban 15 mg UNA vez al día: – Insuficiencia renal moderada o grave (ClCreat 15 – 50 ml/min)

Selección de dosis

• Apixaban 5 mg dos veces al día

• Apixaban 2,5 mg dos veces al día si ≥ 2: – Edad ≥ 80 años– Peso corporal ≤ 60 kg– Creatinina sérica ≥ 1,5 mg/dl

Selección de dosis

• Edoxaban 60mg/30mg 30mg/15mg

• Reducir dosis si uno o más de los siguientes:– CrCl 15-49ml/min– Peso corporal ≤ 60 kg– Inhibidores potentes GPp

Selección de dosis

CRCl (ml/min) DABIGATRAN APIXABAN RIVAROXABAN EDOXABAN

>50 ml/min 150 mg/12h 5 mg/12h 20 mg/24h 60 mg/24h

30–50 ml/min 110mg/12h 5 mg/12h 15 mg/24h 30 mg/24h

15–29 ml/minCONTRAINDICADO

No debería ser la primera elección en pacientes con ERC.

2,5 mg/12hSi cumple 2 o más…

C≥1,5mg/dl ≥80 años W≤60Kg

15 mg/24h 30 mg/24h

<15 ml/minLos tres están CONTRAINDICADOS si

ClCreat <15ml/min

CONTROLES DE FUNCIÓN RENAL: ClCreat ≥60ml/min: C/ año. ClCreat < 60ml/min: CrCl/10 meses>75-80 años o fragilidad (especialmente dabigatran o edoxaban): 6 meses

Selección de dosis en IRC

INDUCTORES DE LA gp–p y del CYP3A4Disminuyen su [pl]:- Rifampicina- Carbamacepina- Fenitoina- Hierba de San Juan

INHIBIDORES DE LA gp–p é [pl]:

- Amiodarona, dronedarona

- Verapamilo

- Antimicóticos azólicos

- Ciclosporina, tacrólimus

- Antiretrovirales

INTERACCIONES FARMACOLOGICAS

INHIBIDORES del CYP3A4 é [pl]:- Antimicóticos azólicos- Ritonavir

Heidbuchel et al.EHJ. In press. June 2016

Caso clínico. Qué dosis indicaría?

• 76 años de edad.• DM tipo 2• Fibrilación auricular paroxística• Tto con Amiodarona• Peso 70 kgs• CrCl 55 ml/min

Caso clínico. Monitorización de efecto

• 66 años de edad.• HTA.• Reparación valvular mitral hace dos

años• Hallazgo en ETE durante el

seguimiento

VIDEO

¿Cuando me interesa monitorizar?

• Cirugía urgente.• Evento hemorrágico• Evento isquémico. Fibrinolisis?• Dudas de cumplimiento terapéutico• Pre CVE?

DABIGATRAN APIXABAN EDOXABANRIVAROXABAN

APTT: Relación curvilínea. No relación cuantitativaValores normales no descartan presencia de fármaco

X2. No descarta alto riesgo de sangrado quirúrgico

APTT: No útil APTT: No util

TT: Muy sensible pero inespecífico

Si es normal à No hay efecto de fármaco

TP : No útil TP: Relación curvilínea

No disponibles:TE (Tº Ecarina) à Dosis dpdte. Niveles plasm del fármaco.

Hemoclot (TTd) à Determina la [pl] = si >200 mayor riesgo de sangrado

Medición actividadanti Xadirectamente proporcional a la [pl] (Sobredosis y Cx Urg)

Medición actividad anti Xa

Resultados Estudio CALIFA

13,60%

30%

21,70%

34,70%

0,00%

5,00%

10,00%

15,00%

20,00%

25,00%

30,00%

35,00%

40,00%

% pacientes

M.AnguitaSánchez etal..RevEsp Cardiol.2015;68(9):761-768.

AVK Dabigatrán o Anti Xa

Cuando el INR sea <2, <3 Rivaroxaban, <2.5 EdoxabanIr determinando INR

DíasS

Cambio de tratamiento

Cambio de tratamiento

Intervención quirúrgica

Caso clínico. Cuando suspender?

• 70 años de edad.• Tto con Dabigatrán• Cr Cl 45 ml/min• PANCREATITIS. Programado para Colecistectomía• Cuando suspender Dabigatrán?

Riesgo hemorrágico

Intervención quirúrgica

Bajo•Exodoncia de una sola pieza dentaria.•Cataratas con anestesia local.•Punción de partes blandas.•Artrocentesis.•Estudios de médula ósea•PAAF en lugares de bajo riesgo.•Endoscopias sin biopsia, polipectomía, esfinterotomía. Muy poca información y experiencia en este caso. Valorar.

Medio•Extracciones dentarias múltiples.•Implantes dentarios.•Curetajes.•Endoscopia digestiva con biopsia.•Cateterismo arterial vía femoral.•Implantación de marcapasos.•Biopsia de próstata.•Toracocentesis y broncoscopia.•Artroscopia terapéutica.•Legrado uterino.•Polipectomía (pólipos de <20 mm de base).

Alto•Biopsia hepática o renal.•Polipectomía (pólipos de >20 mm de base).•CPRE.•Cataratas con anestesia retrobulbar.•Cirugía de desprendimiento de retina.•Cualquier cirugía mayor: abdominal, urológica, traumatológica, ginecológica...•Punción lumbar.•Anestesia neuroaxial.

Cirugía y procedimientos invasivosDABIGATRAN Xa INHIBIDORES

Sin riesgo importante y hemostasia local adecuada. Realizar en niveles valle (12-24h tras ultima toma)

Medio riesgo Alto riesgo Medio riesgo Alto riesgo

CrCl ≥ 80ml/min

≥24h ≥48h ≥24h ≥48h

CrCl 50-80 ml/min

≥36h ≥72h ≥24h ≥48h

CrCl 30-50 ml/min

≥48h ≥96h ≥24h ≥48h

CrCl 15-30 ml/min

No indicado ≥36h ≥72h

CrCl < 15 ml/min

No indicado

NUNCA TERAPIA PUENTE CON HEPARINA!!!!!

Hemorragias

Antídotos

Sí, sí. Pero me han dicho que si tengo un sangrado no hay antídoto

Esta pastilla que le mando es muy buena. Ya verá usted

Antídotos

Publication of ANNEXA™-A and ANNEXA™-R Studies

▸ Greater than 90% reversal of anti-fXa activity▸ No serious or severe adverse events were reported in any subject▸ No thrombotic events, antibodies to FX or FXa, or neutralizing antibodies to andexanet

Siegal et al. NEJM 2015;373:2413-24

Olvido de medicación

NO ME ACUERDO SI ME TOME LA PASTILLA

????????????????????????????????????????????????????????

Olvidos de medicación

• Se puede tomar la dosis olvidado cuando hatranscurido menos del 50% del intervalo entredosis (6 o 12h)

• Doble dosis.– Si toma cada 12 h. Saltarse la siguiente toma– Si toma cada 24 h: No saltarsela

Conclusiones

• Se usan poco. Pensar en ellos como primeraelección. ¿por qué no?.

• Dosis adecuada. CrCl, edad, peso, IF• El tiempo de suspensión preQx se basa en la

clase de fármaco, tipo de Qx y función renal• El mejor tto para la hemorragia es el tiempo.

Sin embargo hay antídotos

Muchas gracias!!!

Muchas gracias!!!

¿Que NACO para quién?

IR moderada/grave APIXABAN/RIVAROXABAN/EDOXABAN

Alto riesgo isquémico DABIGATRAN 150/APIXABAN

Alto riesgo de sangrado APIXABAN/EDOXABAN/DABIGATRAN 110

Antec sangrado GI APIXABAN/DABIGATRAN 110/EDOXABAN

Preferencia de una sóladosis

RIVAROXABAN/EDOXABAN

Cardiopatía isquémica. Stent RIVAROXABANPeri CVE RIVAROXABAN/EDOXABAN

Nuevo IPT

Publicado el 21 de noviembre de 2016 sin grandes cambios y sin tener en cuenta las recomendaciones de las sociedades científicas:

•Cambio de denominación. NACO a ACOD•Para la evaluación del riesgo tromboembólico, sustituye la escalaCHADS2 por la CHA2DS2-VAS y considera que el mínimo comúndenominador de las recomendaciones clínicas existentes para iniciar laTAO es una puntuación CHA2DS2-VASc ≥ 2.•Las situaciones para iniciar esta TAO con un ACOD son las mismas que enel anterior IPT.•Finalmente, el IPT no ha entrado en valorar situaciones temporalesespecíficas como la cardioversión o la ablación por catéter.

TAO: terapia anticoagulante oralNACO: nuevos anticoagulantes oralesACOD: anticoagulantes orales directos

1.Situaciones clínicas:• Pacientes con hipersensibilidad conocida o con contraindicación

específica al uso acenocumarol o warfarina.

• Pacientes con antecedentes de hemorragia intracraneal (HIC)

• Pacientes con ictus isquémico que presenten criterios clínicos y de neuroimagen de alto riesgo de HIC.

• Pacientes en tratamiento con AVK que sufren episodios tromboembólicos arteriales graves a pesar de un buen control de INR.

Situaciones en pacientes con fibrilación auricular no valvular en las que los ACOD pueden considerarse una opción terapéutica en el marco del SNS

Articles

www.thelancet.com Vol 383 March 15, 2014 955

Comparison of the effi cacy and safety of new oral anticoagulants with warfarin in patients with atrial fi brillation: a meta-analysis of randomised trialsChristian T Ruff , Robert P Giugliano, Eugene Braunwald, Elaine B Hoff man, Naveen Deenadayalu, Michael D Ezekowitz, A John Camm, Jeff rey I Weitz, Basil S Lewis, Alexander Parkhomenko, Takeshi Yamashita, Elliott M Antman

SummaryBackground Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fi brillation; however, the balance between effi cacy and safety in subgroups needs better defi nition. We aimed to assess the relative benefi t of new oral anticoagulants in key subgroups, and the eff ects on important secondary outcomes.

Methods We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fi brillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both effi cacy and safety outcomes were reported. We did a prespecifi ed meta-analysis of all 71 683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF–TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether diff erences in patient and trial characteristics aff ected outcomes. We used a random-eff ects model to compare pooled outcomes and tested for heterogeneity.

Findings 42 411 participants received a new oral anticoagulant and 29 272 participants received warfarin. New oral anticoagulants signifi cantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73–0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38–0·64; p<0·0001). New oral anticoagulants also signifi cantly reduced all-cause mortality (0·90, 0·85–0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39–0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01–1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0·69, 0·59–0·81 vs 0·93, 0·76–1·13; p for interaction 0·022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1·03, 0·84–1·27; p=0·74), and a more favourable bleeding profi le (0·65, 0·43–1·00; p=0·05), but signifi cantly more ischaemic strokes (1·28, 1·02–1·60; p=0·045).

Interpretation This meta-analysis is the fi rst to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fi brillation. New oral anticoagulants had a favourable risk–benefi t profi le, with signifi cant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative effi cacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our fi ndings off er clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population.

Funding None.

IntroductionAtrial fi brillation, the most common sustained cardiac arrhythmia, predisposes patients to an increased risk of embolic stroke and has a higher mortality than sinus rhythm.1,2 Until 2009, warfarin and other vitamin K antagonists were the only class of oral anticoagulants available. Although these drugs are highly eff ective in prevention of thromboembolism, their use is limited by a narrow therapeutic index that necessitates frequent monitoring and dose adjustments resulting in substantial

risk and inconvenience. This limitation has translated into poor patient adherence and probably contributes to the systematic underuse of vitamin K antagonists for stroke prevention.3,4

Several new oral anticoagulants have been developed that dose-dependently inhibit thrombin or activated factor X (factor Xa) and off er potential advantages over vitamin K antagonists, such as rapid onset and off set of action, absence of an eff ect of dietary vitamin K intake on their activity, and fewer drug interactions. The

Lancet 2014; 383: 955–62

Published OnlineDecember 4, 2013http://dx.doi.org/10.1016/S0140-6736(13)62343-0

See Comment page 931

Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA (C T Ruff MD, R P Giugliano MD, Prof E Braunwald MD, E B Hoff man PhD, N Deenadayalu MPH, Prof E M Antman MD); Jeff erson Medical College, Philadelphia, PA, and Cardiovascular Research Foundation, New York, NY, USA (Prof M D Ezekowitz MBChB); St George’s University, London, UK (Prof A J Camm MD); McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada (Prof J I Wetiz MD); Lady Davis Carmel Medical Center, Haifa, Israel (Prof B S Lewis MD); Institute of Cardiology, Kiev, Ukraine (Prof A Parkhomenko MD); and The Cardiovascular Institute, Tokyo, Japan (Prof T Yamashita MD)

Correspondence to:Dr Christian T Ruff , Thrombolysis in Myocardial Infarction (TIMI) Study Group, 350 Longwood Avenue, 1st Floor Offi ces, Boston, MA 02115, USAcruff @partners.org


Articles


Statistical analysisWe obtained information about the following out comes from the main trial publications, supplemental appen-dices, and relevant subsequent analyses:5–8,15–23 stroke and systemic embolic events, ischaemic stroke, haemor rhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage (including haemor rhagic stroke, epidural, subdural, and subarachnoid haemorrhage), and gastrointestinal bleeding. When poss ible, we did analyses with the intention-to-treat population for effi cacy outcomes and with the safety population for bleeding outcomes. In RE-LY5 and ENGAGE AF–TIMI 48,8 two doses of dabigatran and edoxaban, respectively, were compared with warfarin. Rather than combining data with both doses into one meta-analysis, which would merge the benefi t and risk of diff erent doses, potentially com-promising interpretability, we undertook a meta-analysis with both higher doses (dabigatran 150 mg twice daily for RE-LY and edoxaban 60 mg once daily for ENGAGE AF–TIMI 48) combined with the single doses studied in ROCKET AF6 (rivaroxaban 20 mg once daily) and ARISTOTLE7 (5 mg twice daily). In a separate analysis we undertook a meta-analysis of the two lower doses (dabigatran 110 mg twice daily for RE-LY and edoxaban 30 mg once daily for ENGAGE AF–TIMI 48). We did two sensitivity analyses including a meta-analy-sis of only the factor Xa inhibitors, with removal of the thrombin inhibitor dabigatran, and an analysis com-bining all doses of all drugs (both high and low doses of dabigatran and edoxaban with rivaroxaban and apixa-ban). We did not use any data from phase 2 dose-ranging studies because of their small sample size and short follow-up, which precluded comparable ascertain-ment for all the outcomes analysed.

We calculated relative risks (RRs) and corresponding 95% CIs for each outcome and trial separately and checked fi ndings against published data for accuracy. When necessary, we calculated numbers of outcome events on the basis of event rates, sample size, and duration of follow-up. Outcomes were then pooled and compared with a random-eff ects model.24 We assessed the appropriateness of pooling of data across studies with use of the Cochran Q statistic and I² test for heterogeneity.25

We assessed comparative effi cacy and safety for stroke or systemic embolic events and for major bleeding (the primary effi cacy and safety outcomes) in important clinical subgroups: age (<75 vs ≥75 years), sex, history of previous stroke or transient ischaemic attack, history of diabetes, renal function (creatinine clearance <50 mL/min, 50–80 mL/min, >80 mL/min), CHADS2 risk score (0–1, 2, 3–6), vitamin K antagonist status at study entry (naive or experienced), and centre-based time in therapeutic range (threshold of <66% vs ≥66%). The centre-based time in therapeutic range is the mean time in therapeutic range at each enrolling centre achieved in its patients randomised to warfarin. The range is used as a surrogate of the quality of control of international normalised ratio for all the patients receiving warfarin at that site. All four of the trials reported the centre-based time in therapeutic range achieved in their respective warfarin groups by quartiles. We selected our threshold of centre-based time in therapeutic range because RE-LY, ROCKET AF, and ARISTOTLE all had a quartile boun dary near 66% and because the threshold diff erentiates the effi cacy and safety of oral anticoagulants from dual antiplatelet therapy.6,16,22 Because we had access to the clinical database in ENGAGE AF–TIMI 48, we could run this analysis at a threshold of 66%. We did all analyses with Comprehensive Meta-Analysis software (version 2).

Role of the funding sourceThere was no funding source for this study. All authors had full access to all the data in the study and had fi nal responsibility for the decision to submit for publication.

Results42 411 participants received a new oral anticoagulant and 29 272 participants received warfarin. The table shows base line characteristics for each study. The average age of patients was similar between trials as was the proportion of women recruited (table). However, the underlying risk for stroke diff ered signifi cantly across the trials as shown by the proportion of patients with CHADS2 scores of 3–6 (table). Median follow-up ranged from 1·8 years to 2·8 years and the median time in

Figure 1: Stroke or systemic embolic eventsData are n/N, unless otherwise indicated. Heterogeneity: I²=47%; p=0·13. NOAC=new oral anticoagulant. RR=risk ratio. *Dabigatran 150 mg twice daily. †Rivaroxaban 20 mg once daily. ‡Apixaban 5 mg twice daily. §Edoxaban 60 mg once daily.

RR (95% CI) pNOAC (events) Warfarin (events)

RE-LY5* ROCKET AF6† ARISTOTLE7‡ ENGAGE AF–TIMI 488§ Combined (random)

134/6076 269/7081 212/9120 296/7035 911/29 312

199/6022 306/7090 265/9081 337/7036 1 107/29 229

0·66 (0·53–0·82) 0·0001 0·88 (0·75–1·03) 0·12 0·80 (0·67–0·95) 0·012 0·88 (0·75–1·02) 0·10 0·81 (0·73–0·91) <0·0001

1·00·5 2·0

Favours warfarinFavours NOAC


End-point primario (ictus o embolismo sistémico)

Lancet 2014; 383:955-62

• El beneficio se obtiene principalmente de una reducción en el ictus hemorrágico• Globalmente disminuyen la mortalidad y el sangrado intracraneal, pero aumentan

significativamente el riesgo de sangrado GI

Articles


Comparison of the effi cacy and safety of new oral anticoagulants with warfarin in patients with atrial fi brillation: a meta-analysis of randomised trialsChristian T Ruff , Robert P Giugliano, Eugene Braunwald, Elaine B Hoff man, Naveen Deenadayalu, Michael D Ezekowitz, A John Camm, Jeff rey I Weitz, Basil S Lewis, Alexander Parkhomenko, Takeshi Yamashita, Elliott M Antman

SummaryBackground Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fi brillation; however, the balance between effi cacy and safety in subgroups needs better defi nition. We aimed to assess the relative benefi t of new oral anticoagulants in key subgroups, and the eff ects on important secondary outcomes.

Methods We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fi brillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both effi cacy and safety outcomes were reported. We did a prespecifi ed meta-analysis of all 71 683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF–TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether diff erences in patient and trial characteristics aff ected outcomes. We used a random-eff ects model to compare pooled outcomes and tested for heterogeneity.

Findings 42 411 participants received a new oral anticoagulant and 29 272 participants received warfarin. New oral anticoagulants signifi cantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73–0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38–0·64; p<0·0001). New oral anticoagulants also signifi cantly reduced all-cause mortality (0·90, 0·85–0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39–0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01–1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0·69, 0·59–0·81 vs 0·93, 0·76–1·13; p for interaction 0·022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1·03, 0·84–1·27; p=0·74), and a more favourable bleeding profi le (0·65, 0·43–1·00; p=0·05), but signifi cantly more ischaemic strokes (1·28, 1·02–1·60; p=0·045).

Interpretation This meta-analysis is the fi rst to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fi brillation. New oral anticoagulants had a favourable risk–benefi t profi le, with signifi cant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative effi cacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our fi ndings off er clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population.

Funding None.

IntroductionAtrial fi brillation, the most common sustained cardiac arrhythmia, predisposes patients to an increased risk of embolic stroke and has a higher mortality than sinus rhythm.1,2 Until 2009, warfarin and other vitamin K antagonists were the only class of oral anticoagulants available. Although these drugs are highly eff ective in prevention of thromboembolism, their use is limited by a narrow therapeutic index that necessitates frequent monitoring and dose adjustments resulting in substantial

risk and inconvenience. This limitation has translated into poor patient adherence and probably contributes to the systematic underuse of vitamin K antagonists for stroke prevention.3,4

Several new oral anticoagulants have been developed that dose-dependently inhibit thrombin or activated factor X (factor Xa) and off er potential advantages over vitamin K antagonists, such as rapid onset and off set of action, absence of an eff ect of dietary vitamin K intake on their activity, and fewer drug interactions. The

Lancet 2014; 383: 955–62

Published OnlineDecember 4, 2013http://dx.doi.org/10.1016/S0140-6736(13)62343-0

See Comment page 931

Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA (C T Ruff MD, R P Giugliano MD, Prof E Braunwald MD, E B Hoff man PhD, N Deenadayalu MPH, Prof E M Antman MD); Jeff erson Medical College, Philadelphia, PA, and Cardiovascular Research Foundation, New York, NY, USA (Prof M D Ezekowitz MBChB); St George’s University, London, UK (Prof A J Camm MD); McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada (Prof J I Wetiz MD); Lady Davis Carmel Medical Center, Haifa, Israel (Prof B S Lewis MD); Institute of Cardiology, Kiev, Ukraine (Prof A Parkhomenko MD); and The Cardiovascular Institute, Tokyo, Japan (Prof T Yamashita MD)

Correspondence to:Dr Christian T Ruff , Thrombolysis in Myocardial Infarction (TIMI) Study Group, 350 Longwood Avenue, 1st Floor Offi ces, Boston, MA 02115, USAcruff @partners.org


Articles

958 www.thelancet.com Vol 383 March 15, 2014

therapeutic range in patients in the warfarin groups ranged from 58% to 68% (table).

Figure 1 shows the comparative effi cacy of high-dose of new oral anticoagulants and warfarin. Allocation to a new oral anticoagulant signifi cantly reduced the com-posite of stroke or systemic embolic events by 19% compared with warfarin (fi gure 1). The benefi t was mainly driven by a large reduction in haemorrhagic stroke (fi gure 2). New oral anticoagulants were also asso ciated with a signifi cant reduction in all-cause mortality (fi gure 2). The drugs were similar to warfarin in the prevention of ischaemic stroke and myocardial infarction (fi gure 2).

Randomisation to a high-dose new oral anticoagulant was associated with a 14% non-signifi cant reduction in major bleeding (fi gure 3). In line with the reduction in haemorrhagic stroke, a substantial reduction in intra-cranial haemorrhage was observed, which included haemorrhagic stroke, and subdural, epidural, and sub-arachnoid bleeding (fi gure 2). New oral anticoagulants were, however, associated with increased gastrointestinal bleeding (fi gure 2).

The benefi t of new oral anticoagulants compared with warfarin in reducing stroke or systemic embolic events was consistent across all subgroups examined (fi gure 4). The safety of new oral anticoagulants compared with

warfarin was generally consistent for the reduction of major bleeding across subgroups, with the exception of a signifi cant interaction for centre-based time in thera-peutic range (fi gure 4). We noted a greater relative reduction in bleeding with new oral anticoagulants at centres that achieved a centre-based time in therapeutic range of less than 66% than at those achieving a time in therapeutic range of 66% or more (fi gure 4).

The low-dose new oral anticoagulant regimens had similar effi cacy to warfarin for the composite of stroke or systemic embolic events (appendix). When diff eren-tiated by stroke type, the low-dose regimens were asso-ciated with an increase in ischaemic stroke compared with warfarin, which was balanced by a large decrease in haemorrhagic stroke (appendix). Similar to the higher-dose regimens, the low doses showed a signifi -cant reduc tion in all-cause mortality (appendix). Signifi -cantly more myocardial infarctions were reported with the low-dose regimens than with warfarin (appen dix). The low-dose regimens were associated with a non-signifi cant reduction in major bleeding, but with a signifi cant reduction in intracranial haemor rhage. Gastro intestinal bleeding was similar between low-dose new oral anti coagulants and warfarin (appendix).

A meta-analysis of only the factor Xa inhibitors , with removal of dabigatran, showed similar results to the

Figure 2: Secondary effi cacy and safety outcomesData are n/N, unless otherwise indicated. Heterogeneity: ischaemic stroke I²=32%, p=0·22; haemorrhagic stroke I²=34%, p=0·21; myocardial infarction I²=48%, p=0·13; all-cause mortality I²=0%, p=0·81; intracranial haemorrhage I²=32%, p=0·22; gastrointestinal bleeding I²=74%, p=0·009. NOAC=new oral anticoagulant. RR=risk ratio.

Figure 3: Major bleedingData are n/N, unless otherwise indicated. Heterogeneity: I²=83%; p=0·001. NOAC=new oral anticoagulant. RR=risk ratio. *Dabigatran 150 mg twice daily. †Rivaroxaban 20 mg once daily. ‡Apixaban 5 mg twice daily. §Edoxaban 60 mg once daily.

RR (95% CI) pPooled NOAC (events)

Pooled warfarin (events)

EfficacyIschaemic strokeHaemorrhagic strokeMyocardial infarctionAll-cause mortality

665/29 292 130/29 292 413/29 292 2022/29 292

724/29 221 263/29 221 432/29 221 2245/29 221

0·92 (0·83–1·02) 0·10 0·49 (0·38–0·64) <0·0001 0·97 (0·78–1·20) 0·77 0·90 (0·85–0·95) 0·0003

SafetyIntracranial haemorrhageGastrointestinal bleeding

204/29 287 751/29 287

425/29 211 591/29 211

0·48 (0·39–0·59) <0·0001 1·25 (1·01–1·55) 0·043

10·2 20·5


RR (95% CI) pNOAC (events) Warfarin (events)

RE-LY5* ROCKET AF6† ARISTOTLE7‡ ENGAGE AF–TIMI 488§ Combined (random)

375/6076 395/7111 327/9088 444/7012 1 541/29 287

397/6022 386/7125 462/9052 557/7012 1 802/29 211

0·94 (0·82–1·07) 0·34 1·03 (0·90–1·18) 0·72 0·71 (0·61–0·81) <0·0001 0·80 (0·71–0·90) 0·0002 0·86 (0·73–1·00) 0·06

1·00·5 2·0


See Online for appendix


Lancet 2014; 383:955-62

NUEVOS ANTICOAGULANTEScardiologiapuertadehierro.com/wp-content/uploads/DrCastro-r.pdf · Myocardial Infarction 48) trial,321 edoxaban 60 mg once daily and edoxaban 30 mg once daily

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