REVUE DE L'ANNÉE EN MÉDECINE VASCULAIRE - Le sommet à votre portée

 
REVUE DE L'ANNÉE EN MÉDECINE VASCULAIRE - Le sommet à votre portée
07/05/2019

             REVUE DE L’ANNÉE
      EN MÉDECINE VASCULAIRE
                         VINCENT BERGERON MD FRCPC
                                  7 mai 2019

PLAN
■ Lipides
    – REDUCE-IT               Lignes directrices américaines 2018
                              traitement de l’hypercholestérolémie
    – ODYSSEY OUTCOME
■ Anti-plaquettaires
                              Lignes directrices américaines 2019
    – ASCEND                  prévention primaire
■ AODs
   – LIGNES DIRECTRICES CANADIENNES CAT
   – AVERT
   – CASSINI
   – AUGUSTUS           Mise à jour guide clinique sur la FA
   – MANAGE
■ Diabète
   – DECLARE-TIMI 58
         ■   Sous-étude PAD ACC mars 2019

                                                                             1
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REDUCE-IT
                                                        *
                                                            1,7 mmol/L +/- 10% (1,5 mmol/L)
                                                            2 mmol/L après répartition de
NEJM 2019;380:11-22                                         60% population

                         ICOSAPENT ETHYL vs HUILE VÉGÉTALE
■ Supériorité, multicentrique, internationale, contrôlée, double aveugle, répartition
  aléatoire, 8,000 patients entre novembre 2011 et août 2016
■ Prévention secondaire et primaire (max 30%)
   – * TG 1,7 à 5,6 mmol/L et C-LDL 1 à 2,6 mmol/L sous statine x 4 semaines et
   – 45 ans et maladie CV établie ou
   – Hommes >55 ans ou femmes >65 ans diabétiques ou
     – Diabétiques >50 ans avec facteur de risque additionnel:
         ■   Tabac, HTA, HS-CRP, C-HDL bas, IRC, rétinopathie, MAU ou ITH abaissé
■ Exclusion: défaillance sévère, maladie hépatique sévère, A1c > 10%, PCI prévue,
  pancréatite
■ Amarin Pharma: toutes les étapes de la conduite de l’étude

REDUCE-IT – paramètres d’évaluation
NEJM 2019;380:11-22

■ Critère combiné primaire:
     –   Mortalité cardiovasculaire
     –   Infarctus myocardique non fatal
     –   AVC non fatal
     –   Revascularisation coronarienne
     – Angine instable
■ Critère secondaire principal: MACE traditionnel
■ Critères secondaires

                                                                                                      2
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REDUCE-IT – population
NEJM 2019;380:11-22

Âge médian                                                            64 ans
Femmes                                                                 29%
IMC                                                                 30,8 kg/m2
TG médian                                                           2,44 mmol/L
C-LDL médian                                                        1,91 mmol/L
C-HDL médian                                                        1,03 mmol/L
Caucasiens                                                             90%
Prévention secondaire                                                  71%
Diabète                                                                58%

REDUCE-IT – résultats
NEJM 2019;380:11-22

                                                        n-3           placebo        p
Efficacité primaire                                    17,2%           22%
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REDUCE-IT – effets indésirables
NEJM 2019;380:11-22

                                           n-3   placebo        p
Fibrillation auriculaire                  5,3%    3,9%     Significatif
Hospitalisation pour FA ou flutter        3,1%    2,1%       0,004
Œdème périphérique                        6,5%    5,0%     Significatif
Saignements sérieux                       2,7%    2,1%        0,06

                                     ACCEPTED MANUSCRIPT

                                                               PT
                                                             RI
                                               U         SC

                                                              JACC mars 2019
                                            AN
                                           M

                                                                                  4
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                                                                 Grundy SM, et al.
                                                                 2018 Cholesterol Clinical Practice Guidelines

                                                                      REDUCE-IT – conclusion
                                                                 †The term Hispanics/Latinos in the United States characterizes a diverse population group. This includes white,
                                                                 black, and Native American races. Their ancestry goes from Europe to America, including among these, individuals
                                                                       NEJM
                                                                 from the    2019;380:11-22
                                                                          Caribbean, Mexico, and Central and South America.
                                                                 ASCVD indicates atherosclerotic cardiovascular disease; BP, blood pressure; CAC, coronary artery calcium; CAD,
                                                                 coronary artery disease; CK, creatine kinase; CVD, cardiovascular disease; DASH, Dietary Approaches to Stop
                                                                 Hypertension; DM, type 2 diabetes mellitus; FDA, U.S. Food and Drug Administration; HDL-C, high-density lipoprotein
                                                                       ■ Premier succès dans le traitement du risque résiduel lié à l’hypertriglycéridémie
                                                                 cholesterol; LDL-C, low-density lipoprotein cholesterol; MESA, Multi-Ethnic Study of Atherosclerosis; MetS,
                                                                       ■ Données
                                                                 metabolic syndrome; reproductibles?
                                                                                      and PCE, pooled cohort equations.

                                                                      ■ Spécifique à la formulation utilisée?
                                                                     ■ Hypertriglyceridemia
                                                                 4.5.2. Effet relié à la dose?
                                                                      ■ Mécanisme d’action?
                                                                                          Recommendations for Hypertriglyceridemia
                                                                           – La
                                                                    Referenced    diminution
                                                                               studies         18% de
                                                                                       that support      triglycéridémieare
                                                                                                     recommendations      n’explique pas in
                                                                                                                             summarized   le Online
                                                                                                                                             bénéfice
                                                                                                                                                    Data Supplements 31
                                                                           – Effet indésirable du placebo?          and 32.
                                                                    COR        LOE                                       Recommendations
                                                                      ■ Effets secondaires indésirables: fibrillation auriculaire
                                                                                        1. In adults 20 years of age or older with moderate hypertriglyceridemia
                                                                      ■ « Trop beau pour (fasting
                                                                                            être vrai?
                                                                                                     or »nonfasting triglycerides 175 to 499 mg/dL [1.9 to 5.6 mmol/L]),
                                                                                            clinicians should address and treat lifestyle factors (obesity and metabolic
                                                                      I       B-NR
                                                                                            syndrome), secondary factors (diabetes mellitus, chronic liver or kidney
                                                                                            disease and/or nephrotic syndrome, hypothyroidism), and medications
                                                                                            that increase triglycerides (S4.5.2-1).
                                                                                          2.    In adults 40 to 75 years of age with moderate or severe
                                                                                               hypertriglyceridemia and ASCVD risk of 7.5% or higher, it is reasonable to
Downloaded from http://ahajournals.org by on November 26, 2018

                                                                                               reevaluate ASCVD risk after lifestyle and secondary factors are addressed
                                                                     IIa         B-R
                                                                                               and to consider a persistently elevated triglyceride level as a factor favoring
                                                                                               initiation or intensification of statin therapy (see Section 4.4.2.) (S4.5.2-2–
                                                                                               S4.5.2-6).

                                                                      Lignes directrices            américaines
                                                                             3. In adults 40 to 75 years of age with severe hypertriglyceridemia (fasting
                                                                                triglycerides ≥500 mg/dL [≥5.6 mmol/L]) and ASCVD risk of 7.5% or higher,
                                                                     IIa
                                                                      novembreB-R
                                                                               2018
                                                                                               it is reasonable to address reversible causes of high triglyceride and to
                                                                                               initiate statin therapy (S4.5.2-3–S4.5.2-5, S4.5.2-7, S4.5.2-8).
                                                                                          4. In adults with severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL
                                                                                             [≥5.7 mmol/L]), and especially fasting triglycerides ≥1000 mg/dL (11.3
                                                                                             mmol/L)), it is reasonable to identify and address other causes of
                                                                                             hypertriglyceridemia), and if triglycerides are persistently elevated or
                                                                     IIa        B-NR
                                                                                             increasing, to further reduce triglycerides by implementation of a very low-
                                                                                             fat diet, avoidance of refined carbohydrates and alcohol, consumption of
                                                                                             omega-3 fatty acids, and, if necessary to prevent acute pancreatitis, fibrate
                                                                                             therapy (S4.5.2-7, S4.5.2-9).

                                                                 Synopsis

                                                                 Two categories of elevated triglycerides consist of moderate hypertriglyceridemia (fasting or nonfasting
                                                                 triglycerides 150-499 mg/dL [1.6-5.6 mmol/L]) and severe hypertriglyceridemia (fasting triglycerides ≥500
                                                                 mg/dL [≥5.6 mmol/L]). In the former, excess triglycerides are carried in VLDL. In the latter, most patients

                                                                                                                      Page 52

                                                                                                                                                                                               5
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             ODYSSEY OUTCOMES
             NEJM 2018;379:2097-2107

                                                                         ALIROCUMAB vs PLACEBO
             ■ Supériorité, multicentrique, internationale, contrôlée, double aveugle, répartition
               aléatoire, 18,000 patients entre novembre 2012 et novembre 2015
             ■ Syndrome coronarien aigu 1 à 12 mois (médiane 2,6 mois):
                – C-LDL > 1,8 mmol/L ou
                – Non-HDL > 2,6 mmol/L ou
                – Apo-lipoprotéine B > 0,8 g/L
             ■ Exclusion: AVC hémorragique, défaillance, TG > 4,5 mM, hépatite, DFG < 30, etc.
             ■ Sanofi et Regeneron Pharmaceuticals
                – Sélection des sites, supervision de l’essai et collecte de données
             ■ Pré-répartition 2 à 16 semaines                                                   > 2 semaines sous:
                – Titration de la statine                                                        Atorvastatine > 40 mg par jour
                                                                                                                                                                   88%
                – Utilisation injecteur                                                          Rosuvastatine > 20 mg par jour
                                                                                                 La plus haute dose tolérée

                 En présence de la PCSK9, le R-LDL est dégradé et ne
                 revient pas à la surface cellulaire

                 Le C-LDL sérique se lie aux récepteurs des LDL. À la suite de
                 cette internalisation, le récepteur  est recyclé.                                                                                                            Plasm a
                                                                                                       LDL

                                                                                                                                        PCSK9
                                                            LDL

                                                                                                                         R-LDL

                                                                                 R-LDL
                                                                                                                  Endocytose
                                                                                                                                                                              Hépatocyte

                                                                                                                                 Autoclivage
                                                                   Endocytose                                                     de PCSK9
                                                                                                      Endosom e

                          Recyclage
                          du R-LDL
                                                           Endosom e

                                                                                                                                                                                  Appareil
                                           Dégradation de LDL                                                                                                                     de Golgi
                                                                                                                                                             Réticulum
                                                                                                                                                           endoplasmique
                                                                        Dégradation par PCSK9,                         Noyau                                    (RE)
                                                                        LDL et R-LDL
                                                                                                                                               © 2013 Amgen Canada Inc. Tous droits réservés
Qian YW, et al. J Lipid Res 2007;48:1488-1498.
Horton JD, et al. J Lipid Res 2009;50(suppl):S172-S177.

                                                                                                                                                                                                       6
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                    L’anticorps monoclonal se lie à la PCSK9 et inhibe la
                    liaison au récepteur des LDL
                 Le fait d’entraver l’activité de la PCSK9 inhibe la                                                                        Anticorps
                                                                                                                                           monoclonal
                 dégradation intracellulaire du R-LDL                                  LDL
                                                                                                                                           anti-PCSK9

                                                                                                                                                                   Plasm a

                                                                                                           R-LDL

                                                                  Recyclage
                                                                  du R-LDL
                                                                                                  Endocytose
                                                                                                                                                                Hépatocyte

                                                                                                                   Autoclivage
                                                                                      Endosome                      de PCSK9

                                                            Lysosome

                                           Dégradation de LDL                                                                                                       Appareil
                                                                                                                                                                    de Golgi
                                                                                                                                               Réticulum
                                                                                                                                             endoplasmique
                                                                                                                    Noyau                         (RE)

                                                                                                                                 © 2013 Amgen Canada Inc. Tous droits réservés
Qian YW, et al. J Lipid Res 2007;48:1488-1498.
Horton JD, et al. J Lipid Res 2009;50(suppl):S172-S177.

             ODYSSEY OUTCOMES – intervention
             NEJM 2018;379:2097-2107

                                  0,4 0,6                                     1,3                1,8
                                                                                    C-LDL (mmol/L)

                                                                                                                                                                                         7
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ODYSSEY OUTCOMES – résultats
NEJM 2018;379:2097-2107

                                                Alirocumab    Placebo       p
Efficacité primaire                               9,5%         11,1%      < 0,001
Critères d’évaluation secondaires
• Événements coronariens                          12,7%        14,3%       0,001
• Décès coronariens et infarctus myocardique       8,4%         9,5%       0,006
• Événements cardiovasculaires (incluent PCI)     13,7%        15,6%      < 0,001
• Décès toute cause, infarctus, AVC               10,3%        11,9%      < 0,001
• Décès coronariens                                2,2%         2,3%        0,38

C-LDL moyen
• 4 mois                                        1,0 mmol/L   2,4 mmol/L
• 12 mois                                       1,2 mmol/L   2,5 mmol/L
• 48 mois                                       1,7 mmol/L   2,7 mmol/L

ODYSSEY OUTCOMES– conclusion
NEJM 2018;379:2097-2107

■ Réduction des événements coronariens non fatals
■ Effet de classe
■ Cible C-LDL: 0,6 à 1,3 mmol/L
   – Éviter C-LDL < 0,4 mmol/L
■ Ratio coûts-bénéfices

                                                                                            8
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dansky, M.D., Andrew Farmer, D.M.,
 scular cause, excluding       Roger McPherson, B.M., F.R.C.Ophth.,                            07/05/2019
 y outcome was the first       Andrew Neil, D.Sc., F.R.C.P., David Simp-
ht-threatening bleeding        son, Richard Peto, F.R.S., F.Med.Sci., Co-
                               lin Baigent, F.F.P.H., F.R.C.P., Rory Collins,
us bleeding). Secondary        F.R.S., F.Med.Sci., Sarah Parish, D.Phil.,
                               and Jane Armitage, F.R.C.P., F.F.P.H.) as-
                               sume responsibility for the overall con-
                 Lignes directrices         américaines
                               tent and integrity  of this article. The affili-
                 novembre 2018
 uring a mean follow-up ations of the members of the writing
                               committee are listed in the           Appendix.
                                                             Très haut risque
ntly lower percentage of Address reprint requests toSCADr.        < 12Armitage
                                                                       mois

group (658 participants at the Medical Research Council,     ATCD Infarctus
                                                             ATCD AVC Popula-
                                                             Maladie artérielle Trial
                                                                                symptomatique
 erval [CI], 0.79 to 0.97; tion Health Research Unit,> 65Clinical  ans
                               Service Unit and Epidemiological           Studies
 4 participants (4.1%) in Unit, Nuffield DepartmentPACofouPopulation
                                                             HF hétérozygote
                                                                     angioplastie

acebo group (rate ratio, Health, Richard Doll Bldg., Old     HTA
                                                             DiabèteRoad Cam-

 ess being gastrointesti- pus, Roosevelt Dr., Oxford OX3     DFGe 157LF,
                                                                       à 59United
                                                             Tabagisme actif
                                                                            mL/L

                               Kingdom, or at ascend@ndph    C-LDL.>ox2,6.ac .uk sous
                                                                          mmol/L   or traitement
 o significant difference jane.armitage@ndph.ox.acATCD         .uk.défaillance

ncidence of gastrointes-T h e n e w e ng l a n d j o u r na l o f m e dic i n e
                               * A complete list of the members of the
 spectively) or all cancers ASCEND Study Collaborative Group is
se outcomes is planned.          provided in Supplementary Appendix 1,
                                               Original
                                          available       Article
                                                    at NEJM.org.
                                         Drs. Bowman and Mafham and Drs. Collins,
 ho had diabetes and no Parish, and Armitage contributed equally
 caused major Effects
                bleedingof toAspirin      for Primary Prevention
                              this article.
                    in Persons
 by the bleeding hazard.            with Diabetes Mellitus
                           This article was published on August 26,
END Current Controlled The 2018,  at NEJM.org.
                              ASCEND   Study Collaborative Group*
er, NCT00135226.)          N Engl J Med 2018;379:1529-39.
                                         DOI: 10.1056/NEJMoa1804988
                                                   A BS T R AC T
                                         Copyright © 2018 Massachusetts Medical Society.
                   BACKGROUND
                   Diabetes mellitus is associated with an increased risk of cardiovascular events.       The members
                   Aspirin use reduces the risk of occlusive vascular events but increases the risk of    (Louise Bowma
                                                                                                          M.D., Karl Wal
                   bleeding; the balance of benefits and hazards for the prevention of first cardiovas-   vens, Ph.D., G
                   cular events in patients with diabetes is unclear.                                     Barton, Kevin
                                                                                                          M.D., Richard H
                   METHODS                                                                                D.Phil., Aleksan
                                                                                                          len Young, Ph
               We randomly assigned adults who had diabetes but no evident cardiovascular dis-            Fang Chen, M.D
                                                                                1529
tober 18, 2018 ease to receive aspirin at a dose of 100 mg daily or matching placebo. The primary         M.B., Ch.B., E
               efficacy outcome was the first serious vascular event (i.e., myocardial infarction,        Amanda Adler,
                                                                                                          dansky, M.D.,
l of Medicine stroke or transient ischemic attack, or death from any vascular cause, excluding            Roger McPher
               any confirmed intracranial hemorrhage). The primary safety outcome was the first           Andrew Neil, D
uary 30, 2019. For  personal use only. No other uses without permission.                                          9
               major bleeding event (i.e., intracranial hemorrhage, sight-threatening bleeding            son, Richard Pe
 l Society. All rights reserved.                                                                          lin Baigent, F.F.
REVUE DE L'ANNÉE EN MÉDECINE VASCULAIRE - Le sommet à votre portée
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ASCEND
NEJM 2018; 379: 1529-39

                                        AAS vs PLACEBO
■ Supériorité, multicentrique, Royaume Uni, contrôlée, double aveugle, répartition
  aléatoire, 15480 patients entre juin 2005 et juillet 2011
■ Hommes et femmes > 40 ans sans maladie cardiovasculaire chez qui il y avait une
  incertitude sur les bénéfices de AAS.
■ Exclusions: indication ou contre-indication claire à utiliser AAS
■ Financée par British Heart Foundation
■ Conception et conduite de l’étude: investigateurs indépendants de l’Université d’Oxford
■ Bayer: comprimés de AAS et placebo. Commentaires sur conception étude et manuscrit
■ Période pré-répartition 8 à 10 semaines
■ AAS 100 mg avec enrobage entérique

ASCEND – critères d’évaluation
NEJM 2018; 379: 1529-39

■ Critère combiné d’efficacité primaire:
     –   Infarctus myocardiques non fatals
     –   AVC non fatals
     –   * Accidents ischémiques transitoires (ajouté en cours d’étude)
     –   Mortalité de toute cause vasculaire
■ Critère de sécurité primaire:
   – Tout saignement majeur
         ■   Intracrânien
         ■   Intra-oculaire menaçant la vision
         ■   Gastro-intestinal
         ■   Tout saignement sérieux:
             –   Hospitalisation, transfusion, fatal

                                                                                                   10
M.D., Karl Wallendszus, M.Sc., Will Ste-
 ds for the prevention of first cardiovas-                           vens, Ph.D., Georgina Buck, M.Sc., Jil
                                                                                                      07/05/2019
nclear.                                                              Barton, Kevin Murphy, Theingi             Aung
                                                                     M.D., Richard Haynes, D.M., Jolyon Cox
                                                                     D.Phil., Aleksandra Murawska, M.Sc., Al-
betes but no evident cardiovascular dis- len                              Young, Ph.D., Michael Lay, D.Phil.
                                                                     Fang Chen, M.D., Ph.D., Emily Sammons
 daily or matching placebo. The primary M.B., Ch.B., Emma Waters, M.B., B.S.
 cular event (i.e.,ASCEND myocardial        – population
                                                   infarction, Amanda Adler, M.D., Ph.D., Jonathan Bo-
ath from any vascular                  cause, excluding dansky,
                      NEJM 2018; 379: 1529-39                                   M.D., Andrew Farmer, D.M.
                                                                     Roger McPherson,          B.M., F.R.C.Ophth.
 he primary safety    Femmes
                            outcome was the first Andrew Neil,
                      Âge moyen                                                 63 ans
                                                                                 38%
                                                                                       D.Sc., F.R.C.P., David Simp-
 emorrhage, sight-threatening
                      IMC moyen                       bleeding son, Richard    30 kg/mPeto,
                                                                                       2     F.R.S., F.Med.Sci., Co-
                                                                     lin Baigent,55%F.F.P.H., F.R.C.P., Rory Collins
   or other serious          bleeding).
                      Tabagisme (déjà ou actif)
                      AAS avant l’étude
                                                   Secondary         F.R.S., F.Med.Sci.,
                                                                                 35%         Sarah Parish, D.Phil.
ancer.                Durée  médiane  du diabète                                 7 ans
                                                                     and Jane Armitage, F.R.C.P., F.F.P.H.) as-
                      Médications
                      • Statines                                     sume responsibility
                                                                                 75%            for the overall con-
                      • ACEi ou ARB                                  tent and integrity of this article. The affili-
                                                                                 59%
                      • Bêta-bloqueurs                                           13%
  ndomization. During a mean follow-up
                      •  IPP                                         ations   of   the members of the writing
                                                                                 14%
                                                                     committee are listed in the Appendix
  d inAspirin
        a significantly         lower         percentage
              for Primary Prevention in Diabetes Mellitus
                                                               of    Address reprint requests to Dr. Armitage
n the placebo group (658 participants at the Medical Research Council, Popula-
% confidence interval [CI], 0.79 to 0.97; tion Health Research Unit, Clinical Tria
                                                ment to the use of Service
                                                                      aspirin Unit
                                                                              at a and
                                                                                     doseEpidemiological
                                                                                            of 100 mg        Studies
 sDiscussion
    occurred in 314 participants                     (4.1%) in Unit,        Nuffield     Department
                                                daily for 7.4 years resulted   in a risk    of seriousof Population
  3.2%)persons
 olving   in thewhoplacebo
                       had diabetes  group         (rateevents
                                                vascular  ratio,     Health,
                                                                that was  12%Richard
                                                                               lower than Dollthat
                                                                                               Bldg., Old Road Cam-
                                                                                                   with
                                                                     pus, Roosevelt Dr., Oxford OX3 7LF, United
 stmost   of the excess
    cardiovascular              being gastrointesti-
                   disease, assign-             placebo but also in a risk of major bleeding that
                                                                     Kingdom, or at ascend@ndph.ox.ac.uk or
ng. There was no            significant             difference
                      ASCEND – événements vasculaires                jane.armitage@ndph.ox.ac .uk.
  group in the incidence of gastrointes-
  scular Event
                15                                                                         * A complete list of the members of the
nd 158 [2.0%],
        100
               respectively)         or all cancers                                          ASCEND Study Collaborative Group is
         90        Rate ratio, 0.88 (95% CI, 0.79–0.97)
ollow-up for these P=0.01
                    outcomes is planned.                                                     provided in Supplementary
                                                                                                           Placebo     Appendix 1
                                       80
         Participants with Event (%)

                                                 10                                          available at NEJM.org.
                                       70                                                                      Aspirin
                                                                                           Drs. Bowman and Mafham and Drs. Collins
 ts in persons
         60
                who
                 5   had diabetes and no                                                   Parish, and Armitage contributed equally
         50
 ry, but it also caused major bleeding                                                     to this article.
         40
 ounterbalanced 0by the bleeding hazard.                                                   This article was published on August 26
         30
 nd others;
         20
              ASCEND
                   0  Current
                       1    2 Controlled
                                3   4                                                  5   2018,
                                                                                               6 at NEJM.org.
                                                                                                      7     8     9

 rials.gov10 number, NCT00135226.)                                                         N Engl J Med 2018;379:1529-39.
                                                                                           DOI: 10.1056/NEJMoa1804988
                                       0
                                            0    1      2      3        4         5        Copyright
                                                                                             6       ©7 2018 Massachusetts
                                                                                                              8        9 Medical Society.
                                                                     Years of Follow-up

                                                                                                                                    11
                                        7740    7618   7486   7342     7188     7001       5771     3890    2200         1430
d in a significantly lower percentage of Address reprint requests to Dr. Armitage
n the placebo group (658 participants at the Medical Research Council,                            Popula-
                                                                                           07/05/2019
% confidence interval [CI], 0.79 to 0.97; tion Health Research Unit, Clinical Tria
                                                      Service Unit and Epidemiological Studies
 s occurred in 314 participants (4.1%) in Unit, Nuffield Department of Population
  3.2%) in the placebo group (raten eratio,
                                      w e ng l a n d jHealth,
                                                      o u r na l Richard
                                                                 m e dic i n e Doll Bldg., Old Road Cam-
                                                                         The                                                  of

  most of the excess being gastrointesti- pus, Roosevelt Dr., Oxford OX3 7LF, United
                                                      Kingdom, or at ascend@ndph.ox.ac.uk or
ng. There was no significant difference jane.armitage@ndph.ox.ac.uk.
                     Type of Event
                                                                            Aspirin
                                                                           (N=7740)
                                                                                            Placebo
                                                                                           (N=7740)                           Rate Ratio (95% CI)                             P Value
                                                                        no. of participants with event (%)
   group in the incidence of gastrointes-
                     Vascular Outcomes
                     Nonfatal myocardial infarction
                                                      * A complete list of the members of the
                                                                           191 (2.5)       195 (2.5)                                                      0.98 (0.80– 1.19)

nd 158 [2.0%], respectively) or all cancers ASCEND Study Collaborative Group is
                     Nonfatal presumed ischemic stroke
                     Vascular death excluding intracranial hemorrhage
                                                                           202 (2.6)
                                                                           197 (2.5)
                                                                                           229 (3.0)
                                                                                           217 (2.8)
                                                                                                                                                          0.88 (0.73– 1.06)
                                                                                                                                                          0.91 (0.75– 1.10)

ollow-up for these outcomes is planned.
                     Any serious vascular event excluding TIA              542 (7.0)       587 (7.6)                                                      0.92 (0.82–1.03)
                     TIA                                provided in Supplementary Appendix 1
                                                                           168 (2.2)       197 (2.5)                                                      0.85 (0.69– 1.04)
                     Any serious vascular event including TIA              658 (8.5)       743 (9.6)                                                      0.88 (0.79–0.97)     0.01
                     Any arterial revascularization                        340 (4.4)       384 (5.0)            available at NEJM.org.                    0.88 (0.76– 1.02)
                     Any serious vascular event or revascularization       833 (10.8)      936 (12.1)                                                     0.88 (0.80–0.97)

                     Major Bleeding
                                                                                                             Drs. Bowman and1.22
                                                                                                                               Mafham           and Drs. Collins
 ts in persons who had diabetes and no
                     Intracranial hemorrhage
                     Sight-threatening bleeding in eye
                                                                            55 (0.7)
                                                                            57 (0.7)
                                                                                            45 (0.6)
                                                                                            64 (0.8)         Parish, and Armitage
                                                                                                                                   (0.82– 1.81)
                                                                                                                                           contributed equally
                                                                                                                              0.89 (0.62– 1.27)
                     Serious gastrointestinal bleeding                     137 (1.8)       101 (1.3)                          1.36 (1.05– 1.75)
 ry, but it also caused major bleeding
                     Other major bleeding
                     Any major bleeding
                                                                            74 (1.0)
                                                                           314 (4.1)
                                                                                            43 (0.6)
                                                                                           245 (3.2)
                                                                                                             to this article. 1.70 (1.18– 2.44)
                                                                                                                                                          1.29 (1.09–1.52)     0.003

 ounterbalanced by the bleeding hazard.                                                                0.5        0.7         1.0        1.5
                                                                                                             This article was published on August 26
                                                                                                                                                    2.0

 nd others; ASCEND Current Controlled
                                                                                                             Aspirin Better
                                                                                                                      Placebo Better
                                                                                                             2018, at NEJM.org.
                    Figure 2. Effect of Assignment to Aspirin Group on Components of Serious Vascular Events, the Combined Outcome of Serious Vascular
 rials.gov number, NCT00135226.)
                    Event or Revascularization, and Major Bleeding and Its Components.
                                                                                                             N Engl J Med 2018;379:1529-39.
                    The primary outcome was a serious vascular event (a composite of nonfatal myocardial infarction, nonfatal ischemic stroke or transient
                                                                                                             DOI: 10.1056/NEJMoa1804988
                    ischemic attack [TIA], or death from any vascular cause, excluding confirmed intracranial hemorrhage). Secondary outcomes were a seri-
                    ous vascular event or any coronary or noncoronary revascularization procedure. A single participant may have had multiple events and
                    therefore may contribute information to more than one row. The size of eachCopyright               ©ratio
                                                                                                       square for the rate 2018      Massachusetts
                                                                                                                               is proportional  to the amountMedical
                                                                                                                                                               of                       Society.
                    statistical information that was available, the horizontal lines represent 95% confidence intervals, and the dashed vertical line indicates
                    the overall rate ratio for the effect of aspirin use on the first serious vascular event. An arrow on the horizontal line indicates that the
                    confidence interval exceeds the graph area. For composite outcomes, rate ratios and their corresponding 95% confidence intervals are
                    represented by diamonds. Bold entries with diamonds show totals for all data listed above them. The effect of aspirin use on the com-
                    ponents of the primary safety outcome of major bleeding event (a composite of intracranial hemorrhage, sight-threatening bleeding
                    event in the eye, gastrointestinal bleeding, or other major bleeding event) is shown with the use of the same graphic conventions.

                          ANTIPLAQUETTAIRES
                              was 29% higher. The lower risk of serious vascu-            of the participants who underwent randomiza-
                          PRÉVENTION
                              lar events is similar toPRIMAIRE
                                                      the risk that was reported
                              previously in the Antithrombotic Trialists’ Col-
                                                                                          tion have allowed reliable detection of these
                                                                                          moderate but important effects on the incidence
                               laboration meta-analysis of primary prevention of vascular events and on both the severity and
  16   nejm.org       ■ Bénéfice
                    October        mitigé
                                 18,
                               trials  of2018dans une
                                            similar  dosespopulation
                                                            of aspirinà (which
                                                                         faible risque    d’événement
                                                                                  used incidence           (environ
                                                                                                     of bleeding.   10%
                                                                                                                  Our    à 10 do not sup-
                                                                                                                      findings                                                             1529
                        ans) avec   un bon
                               slightly        contrôle
                                           different      des facteurs
                                                      outcome            de risque
                                                                definitions;  see the(lipides,  HTA)
                                                                                          port the  hypothesis that persons with diabetes
                         – Les Methods      section in
                                   événements          Supplementary
                                                     évités sont moins  Appendix
                                                                           solides1). have a resistance to aspirin. Although the pro-
                                                                                      1                                9

New England Journal of MedicineIn contrast to those previous trials, there were portional effects of aspirin use are likely to be
                              ■ Accidents ischémiques transitoires
                               high rates of the use of cardioprotective treat- generalizable to the wider population of persons
L SEC ACQ on January 30, 2019. For personal use only. No other uses without permission.
                              ■ments
                                   Troponine
                                        amongultra    sensible
                                                 the participants  in ASCEND, with with diabetes, the absolute event rates and ad-
 assachusetts Medical Society. All rights reserved.
                      ■ Risquethe    majority of participants
                                 hémorragique                    takingéquivoque
                                                     augmenté sans        statins and herence rates reflect this population of persons
                               blood pressure–lowering therapy. Hence, the pres- with well-treated diabetes. Overall, on the basis
                      ■ NNT = ent
                                NNH    (100)
                                    trial       même
                                           provides     chez assessment
                                                     a direct  populationofà the
                                                                               risque
                                                                                   bal- élevé
                                                                                          of the absolute percentage differences between
                               ance
                      ■ Rôle des IPP? of  the  benefits  and  hazards of  aspirin  use    the groups in the incidence of serious vascular
                               in a contemporary context.                                 events (1.1 percentage points lower in the aspi-
                                   In our trial, factors such as the large number rin group than in the placebo group) and in
                               of participants and clinical outcomes, long dura- bleeding events (0.9 percentage points higher in
                               tion of follow-up, the randomized, blinded design the aspirin group), 91 patients would need to be
                               of the trial, and the almost complete follow-up treated to avoid a serious vascular event over a

                   1536                                                        n engl j med 379;16       nejm.org       October 18, 2018

                                                                     The New England Journal of Medicine
                   Downloaded from nejm.org at BIBLIOTHEQUE UNIV LAVAL SEC ACQ on January 30, 2019. For personal use only. No other uses without permission.
                                                       Copyright © 2018 Massachusetts Medical Society. All rights reserved.

                                                                                                                                                                                          12
efit observed in the entire Primary Prevention Project population,
d 5-year risk of CAD. Similar results were       lesser benefits were noted in the diabetic cohort.138 Further, an
nts (RR 0.82, 95% CI 0.75-0.90; P !
roke (RR 0.86, 95% CI 0.74-1.00; P !
                                                 earlier meta-analysis conducted by the Antithrombotic Trialists’                             07/05/2019
                                                 Collaboration12 failed to demonstrate any benefit for ASA in sub-
  fit was noted. Although the proportional       jects with diabetes, whereas a 22% relative risk reduction was ob-
vents offered by ASA were similar in the         served overall. Similarly, smoking, which is used in most risk strat-
prevention trials, the absolute risk reduc-      ification methods, attenuated the benefit of ASA observed in the
der of magnitude. Absolute annual risk           Women’s Health Study141 and the Physician’s Health Study,134
vents, MI, and ischemic stroke in primary        consistent with data indicating that smoking increases ASA resis-
 .07% (NNT for 1 year 1428), 0.06%               tance.147 An Antithrombotic Trialists’ Collaboration prediction
), and 0.02% (NNT for 1 year 5000),              model of high-risk subjects (ie, those with a 10-year event rate
ociated with a 32% increase in the relative
                                  CCS 2010 – AAS prévention primaire
  ke (RR 1.32, 95% CI 1.00-1.75; P !
  ase 0.01%) and a 54% increase in the
                                                 # 20%) receiving statin therapy suggests that the absolute benefit
                                                 of ASA in primary vascular protection is small and approximately
                                                 equivalent to the risk of major bleeding.66
xtracranial bleeding (RR 1.54, 95% CI
 absolute risk increase 0.03%). The same           RECOMMENDATION (Summarized in Fig. 10 )
ascular risk were also noted to increase
 risk did not differ significantly in the              For men and women without evidence of manifest vas-
   prevention analyses, but the very low           cular disease, the use of ASA at any dose is not recom-
 fit of ASA in primary prevention was              mended for routine use to prevent ischemic vascular events
d by bleeding. In contrast, in second-             (Class III, Level A).
  ascular benefit far outweighed the                   For men and women without evidence of manifest vas-
                                                   cular disease, the use of clopidogrel 75 mg daily plus ASA at
                                                   any dose is not recommended to prevent ischemic vascular
                                                   events (Class III, Level B).
 efit of any intervention is dictated by the           In special circumstances in men and women without
  ted adverse events, and absolute event           evidence of manifest vascular disease in whom vascular risk
ortional treatment effect of ASA is similar        is considered high and bleeding risk is low, ASA 75-162 mg
ry prevention, the low event rate in pri-          daily may be considered (Class IIb, Level C).
shes or possibly nullifies the absolute net
 f the studies considered were conducted
use of other primary risk reduction thera-
nd inhibitors of the RAAS, which would          Use of Antiplatelet Therapy in Patients With
   absolute event rates and net benefit of      Diabetes
 events are likely to have a greater impact         Working Group: Maria E. Kraw, MD, FRCP, and Rémi
 ity than bleeding and the cost of ASA is       Rabasa-Lhoret, MD,ACCEPTED
                                                                        PhD         MANUSCRIPT
 nefit must apply before recommending
                                 Arnett et aal.     Cardiovascular disease is a major cause of mortality and mor-
                                                                                  148
y population. Although many2019   guidelines    bidity foron
                                       ACC/AHA Guideline   patients with diabetes.
                                                             the Primary   PreventionInofaddition to traditional
                                                                                          Cardiovascular         risk
                                                                                                           Disease
A for primary prevention based on age or                            ACCEPTED
                                                factors such as smoking,              MANUSCRIPT
                                                                          systemic hypertension,  dyslipidemia, and
 6,143-145
           the benefit in such populations      dysglycaemia, atherosclerosis in patients with diabetes can be as-
                                2019    ACC/AHA
                                Arnett et al.        Guideline on the Primary Prevention of Cardiovascular
                                2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease
                                                                          Disease
                                4.6. Aspirin
                                 A Report        Use
                                            of the American College of Cardiology/American Heart Association Task Force on
                                                                      Recommendations
                                                                          Clinical Practicefor  Aspirin Use
                                                                                             Guidelines
                                  Referenced studies that support recommendations are summarized in Online Data Supplements 17
                                                                                      and 18.
                                  Endorsed LOE
                                  COR          by the American Association of Cardiovascular    and Pulmonary Rehabilitation, the American
                                                                                          Recommendations
                                   Geriatrics Society, the American Society of Preventive Cardiology, and the Preventive Cardiovascular
                                                       1. Low-dose aspirin (75-100 mg orally daily) might be considered for the
                                                                                 Nurses Association
                                                                                                                  PT

                                   IIb          A          primary prevention of ASCVD among select adults 40 to 70 years of age who
                                                           are at higher ASCVD risk but not at increased bleeding risk (S4.6-1–S4.6-8).
                                                       2. Low-dose aspirin (75-100 mg orally daily) should not be administered on a
                                   III:                                 WRITING
                                               B-R         routine basis   for the COMMITTEE    MEMBERS
                                                                                   primary prevention    of ASCVD among adults >70 years of
                                                                                                                RI

                                 Harm                            Donna   K. Arnett, PhD, MSPH,   FAHA, Co-Chair
                                                           age (S4.6-9).
                                                               Roger S.
                                                       3. Low-dose       Blumenthal,
                                                                       aspirin  (75-100MD,
                                                                                        mgFACC,
                                                                                            orallyFAHA,
                                                                                                   daily) Co-Chair
                                                                                                          should not be administered for the
                                   III:Michelle A. Albert, MD, MPH, FAHA*
                                               C-LD        primary prevention of ASCVD amongD.adults
                                                                                               Erin    Michos,
                                                                                                             of MD,  MHS,who
                                                                                                                any age     FACC,
                                                                                                                               areFAHA*
                                                                                                                                   at increased
                                                                                                      SC

                                 Harm  Andrew B. Buroker, Esq†                                 Michael D. Miedema, MD, MPH*
                                                           risk of bleeding (S4.6-10).
                                       Zachary D. Goldberger, MD, MS, FACC, FAHA‡              Daniel Muñoz, MD, MPA, FACC*
                                       Ellen J. Hahn, PhD, RN*                                 Sidney C. Smith, Jr, MD, MACC, FAHA*
                                Synopsis
                                       Cheryl D. Himmelfarb, PhD, RN, ANP, FAHA*               Salim S. Virani, MD, PhD, FACC, FAHA*
                                For decades, aspirin has been widely administered for ASCVD prevention. By irreversibly inhibiting
                                                                                     U

                                       Amit Khera, MD, MSc, FACC, FAHA*                        Kim A. Williams, Sr, MD, MACC, FAHA*
                                platelet function, aspirin reduces risk of atherothrombosis but also increases risk of bleeding,
                                       Donald Lloyd-Jones, MD, SCM, FACC, FAHA*                Joseph Yeboah, MD, MS, FACC, FAHA*
                                particularly in the gastrointestinal tract (S4.6-11). Aspirin is well established for secondary prevention of
                                                                                  AN

                                       J. William McEvoy, MBBCh, MEd, MHS*                     Boback Ziaeian, MD, PhD, FACC, FAHA§
                                ASCVD (S4.6-12) and is widely recommended for this indication (S4.6-13). However, in primary
                                prevention, aspirin use is more controversial. Because persons without prior ASCVD are inherently less
                                likely to have future ASCVD events          than are
                                                                        ACC/AHA    TASKthose
                                                                                         FORCEwith  a prior history, it is more challenging for
                                                                                                MEMBERS
                                                                                 M

                                clinicians and patients to balance     benefits
                                                                   Patrick       and harms
                                                                            T. O’Gara,      of prophylactic
                                                                                       MD, MACC,             aspirin for primary prevention. This
                                                                                                    FAHA, Chair
                                uncertainty is reflected in international      guidelines,
                                                                 Joshua A. Beckman,    MD,where,   for example,
                                                                                            MS, FAHA,  Chair-Electaspirin is not recommended in      13
                                European guidelines for   Glennprimary    ASCVD
                                                                  N. Levine,       prevention
                                                                              MD, FACC,  FAHA, (S4.6-13)
                                                                                                ImmediatebutPastisChair║
                                                                                                                   recommended in prior U.S.
07/05/2019

  PIONEER AF PCI
  NEJM 2016;375:2423-34

  ■ Étude ouverte multicentrique internationale
  ■ Patients avec fibrillation auriculaire subissant tuteur coronarien 72 heures avant répartition

                                               Rivaroxaban 2,5 mg BID
                         Rivaroxaban 15 mg die                          AVK + AAS + P2Y12
                                               + AAS + P2Y12                                    p
                         + P2Y12                                        (1, 6 OU 12 mois)
                                               (1, 6 ou 12 mois)

  Saignements
                                16,8%                   18%                   26,7%          < 0,001
  significatifs (TIMI)

  MACE                           6,5%                   5,6%                   6%              NS

  Thromboses tuteur               5                      6                        4            NS

  RE-DUAL PCI
  NEJM 2017;377:1513-24

  ■ Étude ouverte multicentrique internationale
  ■ Patients avec PCI dans les 120 heures avant répartition (SCA ou angor stable) avec
    fibrillation auriculaire non valvulaire
                                                                        AVK + P2Y12 +
                                           DABI 150 +     DABI 110 +
                                                                              AAS       Non infériorité
                                             P2Y12          P2Y12
                                                                         (1 À 3 MOIS)
Saignement majeur (ISTH) ou                  20,2%            15,4%         26,9%            oui
cliniquement significatif

Évén. thromboembolique, décès ou             11,8%            15,2%         13,4%            oui
revascularisation non planifiée

Évén. thromboembolique ou décès               7,9%             11%          8,5%             non

Thromboses de tuteurs                           7              15             8              non

                                                                                                              14
07/05/2019

AUGUSTUS
NEJM mars 2019

                                  APIXABAN vs WARFARINE
                                       AAS vs PLACEBO

■ multicentrique, internationale, ouverte pour le volet AOD vs AVK, aveugle pour le
  volet AAS vs PLACEBO, répartition aléatoire, 4614 patients entre septembre 2015 et
  avril 2018
■ Patients recevant un tuteur coronarien dans les 14 jours avant la répartition                 Temps moyen
                                                                                                  6,6 jours
■ Exclusions: anticoagulation pour une autre raison que FA, etc.
■ Financement par BMS et Pfizer
    – Gestion des données
■ Gestion de l’étude et analyse des données par un centre académique indépendant

AUGUSTUS – paramètre d’évaluation
NEJM mars 2019

■ Saignements majeurs
   – Décès
    – Organe critique
         ■   Intra-crânien, spinal, oculaire, articulaire, péricardique, rétropéritonéal, musculaire
             (compartiment)
    – Chute Hb 20 g/L
    – Transfusion 2 culots globulaires
■ Saignements cliniquement significatifs
   – Hospitalisation, intervention médicale ou chirurgicale, visite médicale non
      planifiée, changement de thérapie anti-thrombotique

                                                                                                                 15
07/05/2019

AUGUSTUS – population
NEJM mars 2019

Âge moyen                                                           70 ans
Femmes                                                                 30%
Caucasiens                                                             92%
CHA2DS2-VASc moyen                                                       4
HASBLED moyen                                                            3
événement index
• SCA et tuteur(s)                                                     38%
• SCA traité médicalement                                              24%
• Tuteur(s) électif(s)                                                 38%
Clopidogrel                                                            93%
AVK: Temps dans l’intervalle thérapeutique                             59%
Délai moyen après événement index                                  6,6 jours

AUGUSTUS – résultats AOD vs AVK
NEJM mars 2019

                                             Apixaban 5 mg BID   AVK             p
Saignements majeurs et cliniquement               10,5%          14,7%
07/05/2019

AUGUSTUS – résultats AAS vs placebo
NEJM mars 2019

                                                       AAS        placebo
Saignements majeurs et cliniquement                    16,1%       9,0%
07/05/2019

                           CCS 2018:
                           CARACTÉRISTIQUES HAUT RISQUE
                           ■ Diabète                                         ■ Multipes tuteurs
                           ■ ATCD SCA                                        ■ Lésion complexe de la bifurcation
                           ■ DFGe < 60 mL/min                                ■ Longueur totale de tuteur > 60 mm
                           ■ ATCD thrombose tuteur                           ■ Intervention sur thrombose
                                                                               chronique
                           ■ Fumeur
                           ■ Maladie multi-vasculaire

226                                                                                                             Canadian Journal of Cardiology
                                                                                                                            Volume 34 2018

                           CCS 2018

                                                                              * Rivaroxaban 15 mg die ou
                                                                              Dabigatran 150 ou 110 mg BID ou
                                                                              AVK

Figure 3. Recommendations for patients with AF without high-risk features who undergo elective PCI. ACS, acute coronary syndrome; AF, atrial
fibrillation; ASA, acetylsalicylic acid; BID, twice daily; BMS, bare-metal stent; CCS, Canadian Cardiovascular Society; CHADS2, Congestive Heart
Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack; DES, drug-eluting stent; INR, international normalized ratio; OAC,18
                                                                                                                                           oral
anticoagulant; PCI, percutaneous coronary intervention; SAPT, single antiplatelet therapy.
antithrombotic management                        07/05/2019

                                                                                                                                                                  Downloaded from http://ahajournals.org by on April 28, 2019
                                                                                                                                 percutaneous coronary interv
                                   Figure 3. Recommendations for patients with AF without high-risk features who undergo elective PCI. ACS, acute coronary syndrome; AF, atrial
                                   fibrillation; ASA, acetylsalicylic acid; BID, twice daily; BMS, bare-metal stent; CCS, Canadian Cardiovascular Society; CHADS , Congestive Heart                                                                                       2

                                   anticoagulant;                                                                                antagonist
                                                        et al percutaneous coronary intervention; SAPT, single antiplatelet therapy.                           oral
                                                                                                                                                      Antithrombotic      anticoagulan
                                   Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack; DES, drug-eluting stent; INR, international normalized ratio; OAC, oral
                                             AngiolilloPCI,                                                                                                          Therapy in AF Patients After PCI

                                   not have AF, ASA used in addition to very low dose OAC
                                                                                                                                 as the oral anticoagulant of c
                                                                                                                      evaluated for long-term stroke prevention in patients with AF.
                                             cally higher
                                   (rivaroxaban
                                             ticagrelor
                                                       2.5 mgamong        patientsmajor
                                                                   BID) reduced
                                                               compared     with
                                                                                     who CV
                                                                                  those
                                                                                            were   treated
                                                                                                 events.
                                                                                           treated   with
                                                                                                         It iswith The
                                                                                                            clopi-
                                                                                                                        Strategy
                                                                                                                                 (oral
                                                                                                                            standard
                                                                                                                        Duration
                                                                                                                                       stroke anticoagulant
                                                                                                                                      (Double
                                                                                                                                      of
                                                                                                                                                 Versus Triple
                                                                                                                                               prevention
                                                                                                                                          Therapy
                                                                                                                                                              dose ofTherapy)
                                                                                                                                                                       rivaroxaban  plus
                                                                                                                                                                                     and
                                                                                                                                                                                                  singl
                                                                                                                                                                                        in patients
STATE OF THE ART

                                   important to note that rivaroxaban 2.5 mg BID has not been                         with AF is 15 mg or 20 mg daily. Consideration could be
                                             dogrel, consistent      CCS       2018
                                                                         with the  data from PLATO and its
                                             higher antiplatelet effect. Thus, more data on the
                                                                                                                                 by
                                                                                                                        Randomized        the
                                                                                                                                          clinical time
                                                                                                                                                   trials have  of     hospital
                                                                                                                                                                   shown
                                                                                                                        of double antithrombotic therapy, consisting of OAC in
                                                                                                                                                   37
                                                                                                                                                                              that a strategy  discha
                                             use of ticagrelor in combination with OAC are war-                                  whereas
                                                                                                                        combination       with a P2Yextending(without aspirin),the    starteduse  at  o                                                     12
                                             ranted. This expert consensus suggests tailoring the                       the time of hospital discharge is associated with sig-
                                             intensity of P2Y -inhibiting therapy according to risk.                             therapy)
                                                                                                                        nificantly                      should
                                                                                                                                     lower risk of bleeding
                                                                                                                                            12
                                                                                                                                                                           be considere
                                                                                                                                                                    complications        without
                                             Therefore, among patients at high ischemic/throm-                          an apparent tradeoff in thrombotic events compared
                                             botic (eg, patients with acute coronary syndromes)                                  thrombotic
                                                                                                                        with triple      therapy.              and low
                                                                                                                                                            Accordingly,               bleeding
                                                                                                                                                                              this consensus                                                         6,7,9,40

                                             and low bleeding risks, ticagrelor may represent a
                                             reasonable treatment option. Ticagrelor should be
                                                                                                                                 present document provides a
                                                                                                                        recommends double therapy for most patients (de-
                                                                                                                        fault strategy; Figure 2). In patients in whom double
                                             administered as a 180-mg loading dose and 90-mg                            therapynew            expert
                                                                                                                                   is considered,      aspirinconsensus–derive
                                                                                                                                                                 is recommended in the
                                             twice daily maintenance dose; a 60-mg twice daily                          peri-PCI phase. Given the irreversible binding of aspirin
                                             maintenance dose regimen immediately after PCI has                         to the management
                                                                                                                                 COX-1 enzyme, residual platelet      of patientsinhibitory ef- with
                                             not been studied.    Circulation
                                                                        This expert  consensus
                                             that if ticagrelor is chosen as the P2Y agent, con-
                                                                                                   recommends           fects   persist   for the
                                                                                                                                 anticoagulation
                                                                                                                        (7–10 days).
                                                                                                                                                    life  span   of   the
                                                                                                                                           However, in selected patients
                                                                                                                                                                            affected
                                                                                                                                                                           undergoing
                                                                                                                                                                                          platelet
                                                                                                                                                                                    considered         p                                    41
                                                                                                                                                           12
                                                                          comitant aspirin not be given (ie, avoid triple thera-                                                                                                at high ischemic/thrombotic risk and low bleeding risk,
                                                                          py), as was done in the RE-DUAL PCI trial.7 Data on                                                                                                    *Rivaroxaban
                                                                                                                                                                                                                                this           2,5 mg diefinds
                                                                                                                                                                                                                                      expert consensus    ou AVK
                                                                                                                                                                                                                                                               it reasonable to continue
                                                                                                                                                                                                                                 puis Rivaroxaban 15 mg die ou
                                                                                       WHITE
                                                                          the combination         PAPER
                                                                                            of prasugrel  with an NOAC are very                                                                                                 with aspirin therapy (ie, triple therapy) for a limited
                                                                                                                                                                                                                                 Dabigatran 150 ou 110 mg BID
                                                                          limited, but 1 small study found a nearly 4-fold in-                                                                                                  period of time after hospital discharge. Although the
                                                                          crease in bleeding with triple therapy with prasugrel,39                                                                                              duration of aspirin treatment is at the discretion of the
                                                                          and thus, the use of this agent is not recommended.              Antithrombotic Therapy in Patients With Atrial                                       treating physician, in these selected patients, it is rea-
                                                                          Furthermore, this expert consensus continues to rec-
                                                                          ommend against the routine use of platelet function              Fibrillation Treated With Oral Anticoagulation                                       sonable to extend aspirin therapy up to 1 month after
                                                                                                                                                                                                                                PCI and rarely beyond this time (Figure 2).
                                                                          or genetic testing to guide the selection of antiplatelet
                                                                          therapy.5
                                                                                                                                           Undergoing Percutaneous Coronary Intervention                                           The duration of the dual-therapy regimen and thus
                                                                                                                                                                                                                                timing of discontinuation of SAPT should also take into
                                                                                                                                           A North American Perspective–2018 Update
                                   Figure 4. Recommendations for patients with AF who undergo PCI for ACS or high-risk elective PCI. ACS, acute coronary syndrome; AF, atrial
                                   fibrillation; ASA, acetylsalicylic acid; BID, twice daily; CCS, Canadian Cardiovascular Society; CHADS2, Congestive Heart Failure, Hypertension, Age,
            Downloaded from http://ahajournals.org by on April 28, 2019

                                   Diabetes, Stroke/Transient Ischemic Attack; DAPT, dual antiplatelet therapy; INR, international normalized ratio; OAC, oral anticoagulant; PCI,
                                   percutaneous coronary ABSTRACT:
                                                            intervention. The optimal antithrombotic treatment regimen for patients                    Dominick J. Angiolillo,
                                                                                            with atrial fibrillation undergoing percutaneous coronary intervention                                          MD, PhD
                                                                                            with stent implantation represents a challenge in clinical practice. In                                     Shaun G. Goodman, MD
                                                                                            2016, an updated opinion of selected experts from the United States and                                     Deepak L. Bhatt, MD,
                                                                                            Canada on the treatment of patients with atrial fibrillation undergoing                                         MPH
                                                                                            percutaneous coronary intervention was reported. After the 2016 North                                       John    W. Eikelboom, MD
                                                                                            American consensus statement on the management of antithrombotic                                            Matthew       J. Price, MD
                                                                                            therapy in patients with atrial fibrillation undergoing percutaneous                                        David     J. Moliterno,    MD
                                                                                                                                                                                                        Christopher P. Cannon,
                                                                                            coronary intervention, results of pivotal clinical trials assessing the type of
                                                                                                                                                                                                            MD
                                                                                            oral anticoagulant agent and the duration of antiplatelet treatment have
                                                                                                                                                                                                        Jean-Francois Tanguay,
                                                                                            been published. On the basis of these results, this focused update on the                                       MD
                                                                                            antithrombotic management of patients with atrial fibrillation undergoing                                   Christopher B. Granger,
                                                                                   Downloaded from http://ahajournals.org by on April 28

                                                                                            percutaneous coronary intervention recommends that a non–vitamin K                                              MD
                                                                                            antagonist oral anticoagulant be preferred over a vitamin K antagonist                                      Laura Mauri, MD
                                                                                            as the oral anticoagulant of choice. Moreover, a double-therapy regimen                                     David R. Holmes, MD
                                                                                            (oral anticoagulant plus single antiplatelet therapy with a P2Y12 inhibitor)                                C. Michael Gibson, MD
                                                                                            by the time of hospital discharge should be considered Circulation.         for most patients,    2018;138:527–536.
                                                                                                                                                                                                        David P. Faxon, MDDOI: 10.1161
                                                                                            whereas extending the use of aspirin beyond hospital discharge (ie, triple
                                                                                            therapy) should be considered only for selected patients at high ischemic/
                                                                                            thrombotic and low bleeding risks and for a limited period of time. The
                                                                                            present document provides a focused updated on the rationale for the
                                                                          Figure 2. Management
                                                                                            new of   antiplatelet
                                                                                                  expert          therapy in patients
                                                                                                           consensus–derived            with atrial fibrillationon
                                                                                                                                      recommendations            undergoing    percutaneous coronary intervention (PCI) treated with
                                                                                                                                                                     the antithrombotic
                                                                          an oral anticoagulant (OAC): 2018 North American expert consensus update.
                                                                                            management of patients with atrial fibrillation treated with oral
                                                                          A double-therapy regimen immediately after hospital discharge should be considered for most patients (default strategy). A non–vitamin K antagonist oral antico-
                                                                                            anticoagulation
                                                                          agulant (NOAC) should be preferred overundergoing       percutaneous
                                                                                                                  a vitamin K antagonist (VKA) unlesscoronary      intervention.
                                                                                                                                                       contraindicated.                                                                     19
                                                                                                                                                                        Single antiplatelet therapy (SAPT), preferably with a P2Y12 inhibitor,
                                                                          should be started as soon as possible, including at hospital discharge. It is reasonable to extend low-dose aspirin therapy (ie, triple therapy) up to 1 month after
3. Intravenous beta blockers are recommended to slow a rapid ventricular
        contraindications to long-term anticoagulation and who are at high risk of thromboembolic events.
                         I                    C
                                    response to AF in patients with ACS who do not display HF, hemodynamic
       Section 6.3.4 - Catheter Ablation
                                    instability,inorHF  bronchospasm.                                                                                  07/05/2019
                                4. If triple therapy (oral anticoagulant, aspirin, and P2Y12 inhibitor) is prescribed
       Catheter ablation of AF isfor reasonable
                                         patients with  in symptomatic
                                                              AF at increased AF risk
                                                                                   patients     with (based
                                                                                         of stroke    HF andonreduced
                                                                                                                   CHA2DSLVEF.
                                                                                                                             2-VASc risk
                                    score of 2 or greater) who have undergone percutaneous coronary intervention
       SectionIIa7.4 - Complicating
                         B-NR           Acute Coronary Syndrome
                                    (PCI) with stenting for ACS, it is reasonable to choose clopidogrel in preference
       If triple therapy is prescribed      post-stent placement, clopidogrel is preferred over prasugrel.
                                    to prasugrel.
                                    NEW: New published data are available.
       Double therapy with a P2Y5. In12  inhibitor
                                      patients    with andAFdose    adjusted
                                                              at increased    riskvitamin
                                                                                   of stroke K (based
                                                                                                antagonist
                                                                                                        on CHAis 2reasonable
                                                                                                                   DS2-VASc risk  post-stenting.
                                                                                                                                     score
                                    of 2 or greater) who have undergone PCI with stenting for ACS, double therapy
       Double therapy with clopidogrel
                                    with a P2Y and12low-dose
                                                       inhibitor rivaroxaban
                                                                   (clopidogrel or   (15ticagrelor)
                                                                                          mg daily)and maydose-adjusted
                                                                                                             be reasonable        post-stenting.
                                                                                                                               vitamin    K

2850
                ACC/AHA 2019
               IIa        B-R
       Double therapy with a P2Y
                                    antagonist is reasonable to reduce the risk of bleeding as compared with triple
                                       12 inhibitor and dabigatran 150 mg twice daily is reasonable post-stenting.
                                    therapy.
                                    NEW:     New    RCT datawith and AF
                                                                      datawho
                                                                            fromare 2 registries   and arisk
                                                                                                         retrospective                                 CardioPulse
       If triple therapy is prescribed for       patients                              at increased            of strokecohort
                                                                                                                            and who study have
                                    are available.
       undergone PCI with stenting         for ACS, a transition to double therapy at 4-6 weeks may be considered.
                                6. In patients with AF at increased risk of stroke (based on CHA2DS2-VASc risk score
                                    of 2 or greater) who have undergone PCI with stenting for ACS, double therapy
       Section 7.12 - Device Detection of AF and Atrial Flutter
               IIa        B-R       with P2Y12 inhibitors (clopidogrel) and low-dose rivaroxaban (15 mg daily) is
                                    reasonable
       In patients with cardiac implantable
                                          AF Pa!ents to  reduce
                                                      electronic  the  risk of with
                                                                    devices,
                                                              presen!ng         bleeding    as compared
                                                                                 atrialElec!ve
                                                                                         high   ratePCI   orwith
                                                                                                     episodes      triple
                                                                                                             ACS(AHREs)   therapy.
                                                                                                                     undergoing shouldPCI prompt
                                                                                                                                             1
                                    NEW: New published data are available.
       further evaluation.
                                7. In patients with AF at increased risk of stroke (based on CHA2DS2-VASc risk
       In patients with cryptogenic score    of 2 or
                                         stroke     ingreater)    who have undergone
                                                        whom long-term                         PCI with stenting
                                                                                external ambulatory                 for ACS,
                                                                                                            monitoring      is double
               IIa        B-R           Concerns
                                    therapy     with about
                                                        a P2Y12 inhibitor (clopidogrel)        and dabigatran     150bleeding
                                                                                                                       mg twice     daily
       inconclusive implantationisofreasonable
                                          a cardiactomonitor                               Concerns    about   high               risk 3
                                        thrombo!c           reduce is
                                                          risk       thereasonable       to detect    silent AF.
                                                               2
                                                                          risk of bleeding     as compared     with
                                                                                                          prevailing  triple  therapy.
                                    NEW: prevailing
                                             New published data are available.
       Section 7.13 - Weight Loss
                                8. If triple therapy (oral anticoagulant, aspirin, and P2Y12 inhibitor) is prescribed

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        Downloaded from https://academic.oup.com/eurheartj/article-abstract/39/31/2847/5076806 by Universite Laval user on 29 April 2019
       Weight loss and risk factor for modification
                                       patients with AF     is recommended
                                                                who are at increasedfor overweight/obese
                                                                                           risk of stroke (based  patients
                                                                                                                     on CHA2with      AF.
                                                                                                                                DS2-VASc
    Time from
    treatment IIb
                                   risk  score    of   2  or  greater)   and   who    have    undergone     PCI  with   stenting     (drug
                          B-R
    ini!a!on                       eluting O or bare
                                                  A Cmetal) for ACS, a transition      O to A double
                                                                                                 C                               O C
                                                                                                        therapy (oral anticoagulant
            I        IIa       IIb and P2YIII 12 inhibitor) at 4 to 6 weeks 1      may    be  considered.
                                        1 mo. Triple Therapy                          mo. Triple Therapy           [Pa!ent at very high bleeding risk]
                                   NEW: New published data are available.
      1mo.
     ACC.org/AFCompare          9. Administration of amiodarone or digoxin may be consideredDual                       to slow
                                                                                                                           Therapya rapid
                                                                                                                                      with OAC plus
               IIb         C        ventricular response in patients with ACS and AF associatedP2Y12                   withinhibitor
                                                                                                                               severeupLVto 12 mo.
                                    dysfunction and HF or hemodynamic instability.
                                                                          5
                                10. Administration of nondihydropyridine calcium
      3mo. IIb                                O A C                                        O C antagonists may be considered
                           C        to slow a rapid ventricular response in patients with ACS and AF only in the
                                            Triple Therapy                   Dual Therapy with     OAC plus
                                    absence     of significant HF or hemodynamic
                                              up to 6 mo.
                                                                                              instability.
                                                                                  up to 6 mo.                                              P2Y12 inhibitor up to 12 mo.
                                                            2850                   (Class IIa)                                                           .                                                                                                                                                                                                              CardioPulse
         CardioPulse                                                                                                                                   2847

       6mo.
         doi:10.1093/eurheartj/ehy396

                           O C                                                                                                      13
        Management of antithrombotic               therapy in AF
        patients presenting with
                          P2Y12      ACS
                                inhibitor up toand/or
                                                12 mo.
                                                                                EUROPE
                          Dual Therapy with OAC plus AF Pa!ents presen!ng with Elec!ve PCI or ACS undergoing PCI1
      12mo.
        undergoing PCI                  .
                                                                    Concerns about
                                                                                                                                                                             Downloaded from https://academic.oup.com/eurheartj/article-abstract/39/31/2847/5076806 by Universite Laval user on 29 April 2019

        A Summary of the Joint Consensus Document of the European Heart Rhythm                                                                                                                                                                                                                                   Concerns about high bleeding risk3
                                                                    thrombo!c
                                                                      Group onrisk
                                                                                   2
        Association (EHRA), European Society of Cardiology Working                                                                                                                                                                                                                                                          prevailing
      Beyond
        Thrombosis,  European Association   of Percutaneous            prevailing
                                                            Cardiovascular InterventionsO
      12mo.

                                                                                                                                                                                                                                                                                                                                                                                      Downloaded from https://academic.oup.com/eurheartj/article-abstract/39/31/2847/5076806 by Universite Laval user
        (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the
                                                                                     OAC alone
        Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), Latin
                                       Time from
        America Heart Rhythm Society (LAHRS),
                                       treatment
                                                   and Cardiac Arrhythmia Society of
        Southern Africa (CASSA)        ini!a!on                        O A C                                                                                                                                                                                                                                    O A C                          O C
                                                           1:Periprocedural
                                                                          administra!on of           aspirin     and clopidogrel during         PCI Therapy
                                                                                                                                                      is recommended
                                                                                                  1 mo.  Triple Therapy                  1 mo. Triple            [Pa!entirrespec!ve       of the
                                                                                                                                                                         at very high bleeding risk]
       OSinceOral an!coagulant with
            VKA (TTR>70%) or NOAC
                                                   treatment1mo.
               publication of the 2014 joint consensus document
                                                                   strategy;
                                                                dealing Michael as dual
                                                                                Haude     therapy,
                                                                                      (Germany), and Kurtpotent    P2Y12
                                                                                                          Huber (Austria).     inhibitors (ticagrelor) may be combined with dabigatran
                                                                                                                           In addition,
                                                                                                                                                                                                                                                                                                                                     Dual Therapy with OAC plus
         with the management of antithrombotic therapy in atrial fibrillation            a group of 22 reviewers co-ordinated by Tatjana Potpara (Serbia)
       A(AF)
           Aspirin                                    : High(ACS)
                                                           2
             patients presenting with acute coronary syndrome  atherothrombo!c
                                                                     and/                  riskintroducing
                                                                          revised the manuscript (For Elec!ve        PCI,and
                                                                                                           many suggestions use     SYNTAX score; for ACS, GRACE score >140; sten!ng of the le"
                                                                                                                               criticisms,
                                                                                                                                                                                                                                                                                                                                     P2Y12 inhibitor up to 12 mo.

                                                           main, proximal manuscript.
        or undergoing percutaneous coronary (PCI) or valve interventions,
         which represented an effort of the European Society of Cardiology
                                                                          LAD, proximal bifurca!on; recurrent MIs; stent thrombosis etc.) and low bleeding risk
                                                                          which contributed to the quality and comprehensiveness of the

       CWorking
          Clopidogrel                                   3mo.
                  Group (ESC) on Thrombosis, European Heart
                                               3: Bleeding
        Association (EHRA), European Association
                                                            Rhythm                      O A C                      O C
                                                               risk can be es!mated using the HAS-BLED score; correct modifiable bleeding risk factors
                                                   of Percutaneous
                                                                                                                                     Triple Therapy                        Dual Therapy with OAC plus
         Cardiovascular Interventions (EAPCI) and European Association of
                                                                                                                                       up to 6 mo.                         P2Y12 inhibitor up to 12 mo.
         Acute Cardiac Care (ACCA),1 endorsed by the Heart Rhythm
         Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS)                                                                    (Class IIa)                                      .
         there have been additional data from observational cohorts,
         randomized controlled trials and advances in percutaneous
                                                                      6mo.
                   Gregory Y.H. Lip
         interventions.
                   Professor  of Cardiovascular   Medicine
            New guidelines have also been published, as well as new drugs, devi-
                                                                                                                                  C
                                                                                                                               OJean-Philippe Collet (France)
                   University of Birmingham, UK                                                                                  ACTION Study Group Institut de Cardiologie
         ces, and interventional techniques in AF, ACS management, and PCI.2,3                                             Dual Therapy with OAC plus
                                                                                                                             Groupe Hospitalier Pitié-Salpêtrière 47-83,
                   E-mail: g.y.h.lip@bham.ac.uk
                                                                                                                           P2Y12  inhibitor up to 1275013,
                                                                                                                                                      mo. Paris, France.                                                                                                                                                               Michael Haude (Germany)
         Atrial fibrillation management
                   Price-Evans             has also evolved
                                 Chair of Cardiovascular     towards a more inte-
                                                         Medicine                                                            Boulevard  de l'Hôpital,
         grated or(from
                    holistic approach
                           1 Feb                                    12mo.
                                 2019)that includes the following components:                                                             .
                                                                                                                             Tel: +33.1.42.16.29.62
                                                                                                                                                                                                                                                                                                                                       Email: michael.haude@uni-due.de
                   University of Liverpool, UK                                                                                   Fax : +33.1.42.16.29.31
         • ‘A’ Avoid    stroke
                   Email:      with Anticoagulation;
                           gregory.lip@liverpool.ac.uk
         • ‘B’ Better    symptom
                   Tel: +44        management, with patient centred decisions on
                             121 5075080
                                                                                                                                 Email: jean-philippe.collet@aphp.fr
            rate or rhythm control; and
         • ‘C’ Cardiovascular and comorbidity risk management, Beyond
                                                                                       The full version of this important consensus document is pub-                        O
                                                                     including life-
                                                                                   lished in EP Europace.4 We hope this consensus document is user-
            style changes.4                                         12mo.          friendly, based on ranking using the EHRA ‘coloured hearts’ system
                                                                                                                                                                        OAC alone
            In recognizing this new information since the last consensus docu-
         ment, a Task Force was convened by EHRA, WG Thrombosis, EAPCI,            the evidence and offer consequent guidance. The ultimate aim of
                                                                                                                                                   Astra-Zeneca, Bayer, Lead-Up, WebMD. MH: Grant support:
                                                                                   that should allow physicians to easily assess the current status of

                                                                                   the Task Force was 1to:Periprocedural
                                                                                                              prepare an expert administra!on          of aspirin and clopidogrel during PCI is recommended irrespec!ve of the
         and ACCA, with additional contribution from HRS, APHRS, Latin
         America Heart Rhythm Society (LAHRS), and Cardiac O           Oral an!coagulant
                                                                    Arrhythmia
                                                                                                                                                   Biotronik, Orbus Neich, Abbott, Medtronic, Cardiac Dimensions
                                                                                                                                   consensus and evidence-
                                                                                               with reviewing the best available scientific evidence on
                                                                                   based document         treatment strategy; as dual therapy, potent P2Y12 inhibitors (ticagrelor) may be combined with dabigatran
                   Kurt   Huber     (Austria)                          VKA    (TTR>70%)    or NOAC
         Society of Southern Africa (CASSA), to produce an updated consen-
                   Email:withkurt.huber@meduniwien.ac.at
                                                                                   this growing  issue, and
                                                                                                          2
                                                                                                             to update  the
                                                                                                           : Highcommunity
                                                                                                                             current
                                                                                                                   atherothrombo!c                 Speaker’s bureau: Biotronik, Orbus Neich, Abbott, Medtronic, Lilly,
                                                                                                                                      knowledge in this field,
                                                                                                                                               riskspecialists
                                                                                                                                                    (For Elec!ve PCI, use SYNTAX score; for ACS, GRACE score >140; sten!ng of the le"
         sus document,                                              A theAspirin
                                the remit of comprehensively reviewing     avail-  not only for the cardiology                 but also for other
         able evidence and providing up-to-date consensus recommendations          who see patients with  main,   proximal
                                                                                                             AF and   acute or LAD,
                                                                                                                                 stable proximal    bifurca!on;   recurrent MIs; stent thrombosis etc.) and low bleeding risk
                                                                                                                                                   Philips / Volcano, Cardiac Dimensions (Proctor)Consultant: Biotronik,
                                                                                                                                        coronary artery   dis-
         for use in clinical practice.                              C  Clopidogrel ease, particularly  cardiologists, general   internists, and general prac-
                                                                                                         3: Bleeding risk can be es!mated using the HAS-BLED score; correct modifiable bleeding risk factors
            The consensus document has been written by 16 authors, chaired by      titioners, which   have  to  make   daily  decisions  on  such  Orbus Neich, Abbott. KH: Lecture fees from AstraZeneca, Bayer,
                                                                                                                                                  patients  in
         Gregory Y.H. Lip (UK) and co-chaired by Jean-Philippe Collet (France),    clinical routine.

Conflict of interest: GYHL: Consultant for Bayer/Janssen, BMS/                                                                                     Boehringer INgelheim, Bristol Myers Squibb, Daiichi Sankyo, Pfizer,
Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon and Daiichi-         Gregory Y.H. Lip                                                   Sanofi Aventis,          The Medicines Company.
                                                                                                                                                          Jean-Philippe Collet (France)

                                                                                                                                                                                                                                                                                                                                                                                                          20
                                                                                Professor of Cardiovascular Medicine
                                                                                University of Birmingham, UK                                                    ACTION Study Group Institut de Cardiologie

Sankyo. Speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer                    E-mail: g.y.h.lip@bham.ac.uk
                                                                                Price-Evans Chair of Cardiovascular Medicine
                                                                                                                                                                Groupe Hospitalier Pitié-Salpêtrière 47-83,
                                                                                                                                                                Boulevard de l'Hôpital, 75013, Paris, France.
                                                                                                                                                                                                                                                                                                                                              Michael Haude (Germany)

Ingelheim, and Daiichi-Sankyo. No fees are directly received personally.
                                                                                (from 1 Feb 2019)
                                                                                University of Liverpool, UK
                                                                                Email: gregory.lip@liverpool.ac.uk
                                                                                                                                                   References   Tel: +33.1.42.16.29.62
                                                                                                                                                                Fax : +33.1.42.16.29.31
                                                                                                                                                                                                                                                                                                                                              Email: michael.haude@uni-due.de

                                                                                Tel: +44 121 5075080
                                                                                                                                                                Email: jean-philippe.collet@aphp.fr
07/05/2019

                                            TEV et cancer

                                            ■ Prévalence multipliée par 5 par rapport à population générale
                                            ■ Deuxième cause de décès chez patients avec cancer (9% des décès)
                                            ■ Mortalité multipliée par 5 par rapport à population générale
                                            ■ Impact sur le traitement du cancer
                                            ■ Hospitalisations non prévues
                                            ■ Risque élevé de récidive et de saignement sous traitement

          Edoxaban for Cancer-Associated Venous Thromboembolism
                                            Hokusai VTE cancer: récidive TEV
A
                                           100             20
                                           90
                                                           15
          Patients with Recurrent Venous

                                           80                                                                         Dalteparin
              Thromboembolism (%)

                                           70
                                                           10
                                           60
                                                                                                                      Edoxaban
                                           50
                                                            5
                                           40

                                           30               0
                                                                0    30     60    90   120 150 180 210 240 270 300 330 360
                                           20

                                            10
                                                                                                                              NEJM 2018; 378: 615-24
                                            0
                                                 0   30         60    90         120   150   180    210   240   270    300     330   360
                                                                                             Days
    No. at Risk
    Edoxaban                                 522     480    437       415        395   370   356    340   320   307    281     245   168
    Dalteparin                               524     488    452       423        389   370   358    348   333   321    282     246   174               21
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