Dr. Laurent Labaki Dr. Laurent Rousseau CHwapi Février 2014 Les anticoagulants en 2014 Dr. Laurent Labaki Dr. Laurent Rousseau CHwapi Février 2014

History of anticoagulant therapy Oral thrombin and Xa inhibitors Warfarin mechanism elucidated (J. Suttie) Warfarin clinical trials Anticoagulant in spoiled sweet clover (K.P. Link) First clinical use of 4-hydroxycoumarin Warfarin dosing/INR 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 Parenteral anticoagulants – heparin early 20th C. Incredible shrinking drug; heparin derivatives still drugs of choice for treatment of acute VTE, in-hospital prophy Oral anticoagulants – Wisconsin connection Heparin discovered by medical student (McLean) Clinical use of heparin Cont infusion of heparin; aPTT monitoring LMWH trials Requirement for plasma cofactor discovered (K. Brinkhous) LMWH (J. Hirsch) Fondaparinux trials

Anticoagulation orale Quelles molécules? Antivitamines K( AVK) Sintrom Marcoumar Marevan Nouvelles molécules( NOAC) Pradaxa Xarelto Eliquis

Dabigatran given as pro-drug.

Anticoagulant drug mechanisms Indirect inhibitors Direct inhibitors Indirect vs direct inhibitors. Parenteral vs oral. Thrombin vs Xa. Note that warfarin doesn’t block actions of clotting factors but just lowers blood levels. Ansell, 2011 HTRS meeting

Anticoagulant drug targets Heparin VII Fibrin clot X V II IX VIII XI Warfarin Fondaparinux LMWH Heparins get more selective the smaller you make them. Warfarin inhibits proteins C and S, which may cause paradoxical thrombosis in some settings (protein C deficiency, HIT, cancer) The most important targets for antic oagulant therapy are factors X and II – thrombotic potential most heavily dependent on the activities of these two factors

New anticoagulant drug targets VII Fibrin clot X V II IX VIII XI Rivaroxaban Apixaban (More to come) New drugs selectively target IIa and Xa Ximelagatran was the first drug tested; was an effective anticoagulant but eventually withdrawn due to LFT abnormalities in a few pts. Dabigatran

Pharmacology of oral anticoagulant drugs Warfarin Dabigatran Rivaroxaban Apixaban Target Vit K epoxide reductase Thrombin Factor Xa Oral bioavailability 99% 6-7% 60-80% 80% Tmax 72-96 h 2 h 2.5-4 h 3 h Half-life 40 h 14-17 h 5-9 h 9-13 h elderly 8-15 h Metabolism Cytochrome P450 80% renal 20% biliary 66% renal 33% biliary 25% renal 75% biliary Ansell, 2011 HTRS meeting

Drug interactions with new oral anticoagulants Major differences vs warfarin: Rapid onset of action. Shorter half-life so given twice daily for most indications (compliance important). Major component of renal excretion. No specific antidote. Monitoring not routinely required but levels hard to measure if you need them. All susceptible to drug interactions, but substantially less so than warfarin. Genetic and dietary factors do not appear to be important in pharmacology.

Cost per month of oral anticoagulants Rivaroxaban (20 mg/day) : $348 Dabigatran (150 mg bid): $243 Warfarin (7.5 mg/day): $31 About 10x as expensive as warfarin, but much cheaper than LMWH.

Disadvantages of older anticoagulants Warfarin Delayed onset of action Not suitable for initial treatment of acute thrombosis Complex pharmacology (genetics, diet, drug interactions) Need for monitoring

New oral anticoagulant scorecard Plus Rapid onset of action – can use for initial Rx, no bridging Fewer drug interactions No known food interactions Less genetic variation in dose-response Less dependent on liver metabolism than VKAs No routine monitoring, fixed dose Patient convenience More cost-effective? Minus Risk of bleeding in patients with impaired kidney function Harder to determine compliance or overdose Expense (vs VKAs) Short half-life → greater risk of treatment failure with missed doses? Rebound effect? (Doubtful) Antidote or reversing agent? Potential for overuse?

Who are the best candidates for new oral anticoagulants? Patients who have unstable INR on warfarin not due to poor compliance Good renal function No mechanical valve (not enough data) Not pregnant Patients < 75 years old No history of lower GI bleeding

Anticoagulation orale Fibrillation auriculaire non valvulaire Avantages des AVK Bien connu Monitoring possible Antidote existe` Coût ( si tout va bien,…) Seuls anticoagulants utilisables si insuffisance rénale sévère

Anticoagulation orale Fibrillation auriculaire non valvulaire Désavantages des AVK Risque hémorragique(hémorragie cérébrale) Marge thérapeutique étroite (INR entre 2-3) Nécessités de contrôles +/- fréquents de la coagulation (nb:autocontrôle) « régime » apport stable et limité de vitamines K Interactions médicamenteuses Action initiale retardée (HBPM au départ ) et effet prolongé à l’arrêt(48h à 5 j) Perte de cheveux,…..

Circonstances d’usage les plus fréquentes: FA et accidents vasculaires cérébraux Prévention après une chirurgie orthopédique Traitement de la TVP et de l’Embolie Pulmonaire

9/20/10: FDA approval for stroke prevention in non-valvular Afib Dabigatran Pradaxa® 9/20/10: FDA approval for stroke prevention in non-valvular Afib Turning to the individual drugs. Dabigatran was the first to get to market in US.

Dabigatran Dose Affects PT/INR and PTT (but not useful for monitoring) Stroke prevention in A fib: 110-150 mg bid 110 mg dose not available in US For patients with CrCl 15-30: 75 mg bid Not recommended for CrCl < 15 or dialysis dependent Prevention of recurrent VTE*: 150 mg bid Postop VTE prophylaxis*: 110-150 mg once daily Affects PT/INR and PTT (but not useful for monitoring) Drug may degrade over time after exposure to air – must be kept in original packaging Unused tablets should be discarded after 60 days * Not FDA-approved indication

Dabigatran Low bioavailability → high concentration of drug in lower GI tract Prodrug converted to active drug by esterases in gut Higher risk of lower GI bleeding

Dabigatran pharmacokinetics effect of renal function, age, gender, drug interactions Conclusion: Dose adjustment only necessary for impaired renal function 50% dose reduction recommended for patients with CrCl 15-30 mL/min J Thromb Haemost 2011; 9:2168

Rivaroxaban Xarelto® 7/1/11: FDA approval for DVT prophylaxis after hip or knee surgery 9/8/11: FDA approval for stroke prevention in Afib

Rivaroxaban Dose: Post op VTE prophylaxis: 10 mg once daily Stroke prevention in Afib: 20 mg once daily Acute VTE treatment*: 12-15 mg twice daily Secondary prevention of VTE*: 20 mg once daily Acute coronary syndrome*: 2.5-5 mg twice daily Use with caution in moderate renal impairment (CrCL 30-49) Avoid use if CrCl < 30 (not dialyzable) Avoid use in severe liver disease *Not FDA-approved indication Treatment trials have used higher/BID doses of R initially

Eliquis® FDA approval pending (June 2012?) Apixaban Eliquis® FDA approval pending (June 2012?) Likely to be on the market in the next year or so.

Apixaban Dose: Post op VTE prophylaxis: 2.5 mg twice daily Stroke prevention in Afib: 5 mg twice daily Avoid use in severe liver disease Less dependent on renal excretion – safer in pts with renal insuff? Less safe in pts with liver dz?

CLINICAL TRIALS

ATRIAL FIBRILLATION

La fibrillation auriculaire

Le rythme sinusal

La fibrillation auriculaire

AVC embolique sur FA

NEW ORAL ANTICOAGULANTS VS WARFARIN IN NON-VALVULAR ATRIAL FIBRILLATION Drug being compared # subjects CHADS2 (mean) TTR RE-LY Dabigatran (two doses) 18,113 2.1 64% ROCKET-AF Rivaroxaban 14,264 3.5 58% ARISTOTLE Apixaban 18,201 62% All randomized; RE-LY unblinded All designed as non-inferiority trials Primary outcome was stroke or embolism All funded by drug manufacturer NEJM 2009; 361: 1139 NEJM 2011; 365:883 NEJM 2011; 365:981

NEW ORAL ANTICOAGULANTS VS WARFARIN: STROKE RISK

NEW ORAL ANTICOAGULANTS VS WARFARIN: BLEEDING RISK

NEW ORAL ANTICOAGULANTS VS WARFARIN: MORTALITY

Apixaban vs aspirin for atrial fibrillation The AVERROES trial Treatment Stroke or embolism Major bleeding Intracranial hemorrhage Death Apixaban 1.6%/yr 1.4%/yr 0.2% 3.5%/yr Aspirin 3.7%/yr 1.2%/yr 0.3% 4.4%/yr Clearly more effective than ASA in Afib (no surprise) – safety comparable Study stopped early because of clear benefit of apixaban over aspirin NEJM 2011; 364:817

LESSONS FROM AF TRIALS WITH NEW ORAL AGENTS Main result: New agents at least as effective as warfarin, can be given without routine monitoring Other/unexpected findings: Reduction in intracranial bleeding Higher MI rates Higher rates of GI bleeding (active drug in lower intestine) Extracranial bleeding risk higher in older patients

Rivaroxaban: evidence of rebound effect Rivaroxaban: evidence of rebound effect? Events after switching to standard therapy Difference appears > 1 year after stopping rivaroxaban More events after stopping R than W. Reason? Not clear if this is real or a statistical artifact. “Standard therapy” in W group was mainly more W, whereas in R group this required switching drugs (= more risk). Median time to therapeutic INR in R group was 13 days, vs 3 days in W group NEJM 2011; 365:883

PATIENTS WITH ATRIAL FIBRILATION ARE PRESENTLY UNDER-TREATED

MANY PATIENTS WITH AF ARE POORLY CONTROLLED ON WARFARIN

TREATMENT OF VENOUS THROMBOEMBOLISM

Thrombose veineuse profonde

Maladie veineuse Thrombo-embolique

Angio CT Scan pulmonaire

Dabigatran vs warfarin for acute VTE The RE-COVER trial Subjects: 1274 patients with acute VTE Intervention: Standard course of parenteral anticoagulation followed by either dabigatran 150 mg bid or standard warfarin Method: Randomized double blind trial Primary outcome: 6 month incidence of recurrent symptomatic VTE and related death Funded by drug manufacturer “Non-inferiority” trial Warfarin patients spent 60% of time within INR range TTR of around 60% is OK, not great. D given following course of LMWH or UFH – could potentially be used as sole Rx. NEJM 2009; 361: 2342

Dabigatran vs warfarin for acute VTE The RE-COVER trial Treatment VTE recurrence Major bleeding Any bleeding Dabigatran 2.4% 1.6% 16.1% Warfarin 2.1% 1.9% 21.9% Conclusion: A fixed dose of dabigatran is as effective and safe as warfarin for treatment of acute venous thromboembolism NEJM 2009; 361: 2342

Rivaroxaban for acute VTE The EINSTEIN trial Subjects: 3449 patients with acute VTE Intervention: Rivaroxaban 12 mg twice daily x 3 weeks, then 20 mg/d vs enoxaparin (minimum of 5 days) followed by a VKA Treatment duration 3, 6 or 12 mo Method: Open-label randomized “non-inferiority” trial Primary outcome: Recurrent symptomatic VTE and related death Funded by drug manufacturer Warfarin patients spent 58% of time within INR range R vs standard treatment for acute VTE. INR control in the standard treatment arm in this study was not particularly good. NEJM 2010; 363: 2499

Rivaroxaban for acute VTE The EINSTEIN-DVT trial Treatment Recurrent VTE Bleeding Rivaroxaban 2.1% 8.1% Standard treatment 3.0% Conclusion: rivaroxaban is as effective and safe as standard treatment for acute VTE NEJM 2010; 363: 2499

Rivaroxaban to prevent recurrent VTE The EINSTEIN-Extension trial Subjects: 1196 patients who had completed 6-12 months of treatment for DVT Intervention: Rivaroxaban 20 mg/d vs placebo Method: Randomized double-blind trial Primary outcome: recurrent symptomatic VTE NEJM 2010; 363: 2499

Rivaroxaban to prevent recurrent VTE The EINSTEIN-Extension trial Risk-benefit ratio for R in this setting appears favorable. (But is it significantly better than for warfarin?) Rivaroxaban prevented 34 recurrent events at a cost of 4 major bleeding events 1 recurrence prevented per 15 patients treated; 1 major bleed per 139 patients treated NEJM 2010; 363: 2499

Rivaroxaban for Pulmonary Embolism The EINSTEIN-PE trial Subjects: 4832 patients with acute symptomatic PE Intervention: Rivaroxaban 15 mg bid x 3 weeks, then 20 mg/d vs standard therapy (enoxaparin followed by VKA) for 3-12 mo Method: Randomized open label non-inferiority trial Funded by drug manufacturers Primary outcome: recurrent symptomatic VTE Warfarin patients spent 62.7% of time in target INR range NEJM 2012; 366: 1287

Rivaroxaban for Pulmonary Embolism The EINSTEIN-PE trial Treatment Recurrent VTE Bleeding Major Bleeding Rivaroxaban 2.1% 10.3% 1.1% Standard treatment 1.8% 11.4% 2.2% Conclusion: rivaroxaban as effective as standard treatment for initial and extended treatment of pulmonary embolism, may be safer NEJM 2012; 366: 1287

VTE PROPHYLAXIS

Dabigatran vs enoxaparin prophylaxis after total knee or hip arthroplasty RE-MODEL J Thromb Haemost 2007;5:2178 RE-NOVATE Lancet 2007;370:949 Surgery knee hip # pts 2076 3494 Drug doses Dab: 150 or 220 qd Enox: 40 mg qd Duration (d) 6-10 28-35 VTE or death (%) D150: 40.5 D220: 36.4 E: 37.7 D150: 8.6 D220: 6.0 E: 6.7 Major Bleeding D150: 1.5 D220: 1.3 E: 1.3 D150: 1.3 D220: 2.0 E: 1.6 Two orthopedic trials showed similar outcomes vs LMWH. Knee trial outcomes worse, probably related to not giving the drugs for a sufficient length of time. Both trials showed dabigatran (either dose) had similar efficacy and safety compared to enoxaparin

Rivaroxaban vs enoxaparin prophylaxis after total knee or hip arthroplasty: the RECORD trials NEJM 2008;358:2775 RECORD 2 Lancet 2008;372:31 RECORD 3 NEJM 2008;358:2776 RECORD 4 Lancet 2009;373:1673 Surgery hip knee # pts 4541 2509 2531 3148 Duration (d) 35 Riv: 31-35 Enox: 10-14 14 11-15 VTE or death (%) R: 1.1 E: 3.7 R: 2.0 E: 9.3 R: 9.6 E: 18.9 R: 6.9 E: 10.1 Bleeding R: 0.3 E: 0.1 (major bleed) R: 6.6 E: 5.5 (any bleed) R: 0.6 E: 0.5 R: 0.7 E: 0.3 Four trials of R vs E in high risk ortho surgery all showed better efficacy for R. Note bleeding rates for R are somewhat higher across the board. All trials with rivaroxaban 10 mg/d vs enoxaparin 40 mg/d All had mandatory venography All showed rivaroxaban had superior efficacy vs enoxaparin with similar safety

Apixaban vs enoxaparin prophylaxis after total knee or hip arthroplasty: the ADVANCE trials NEJM 2009;361:594 ADVANCE 2 Lancet 2010;375:807 ADVANCE 3 NEJM 2010;363:2487 Surgery knee hip # pts # evaluable for efficacy 3195 2287 3057 1973 5407 3866 Duration (d) 10-14 35 VTE or death (%) A: 9.0 E: 8.8 A: 15 E: 24 A: 1.4 E: 3.9 Bleeding A: 2.9 E: 4.3 A: 4 E: 5 A: 4.8 E: 5.0 Safer than E in high risk ortho surgery? Meta-analysis of data from ADVANCE-1 and ADVANCE-2 shows that apixaban is non-inferior to enoxaparin with respect to efficacy, and has a “considerable” safety advantage (Huang et al, Thromb Haemost 2011;105: 245)

Monitoring Lotsa luck

Measuring blood levels of new anticoagulants Dabigatran: Modified thrombin time assay (Hemoclot®) Rivaroxaban and apixaban: Anti-Xa activity (similar to LMWH assay) When to consider measuring drug level: Detect/quantify overdose Screen for drug accumulation (eg, impaired renal or liver function) Limited usefulness for assessing compliance due to short drug half-lives Dabigatran assays likely to be available only via send-out for most hospitals. More hospitals doing anti-Xa assays but still not routinely available most places. Compliance testing dicey due to rapid onset and short duration of drug effect. Probably better off counting pills.

Reversing Lotsa luck

No specific antidote for any of the new OACs Activated charcoal will reduce drug absorption if administered within a few hours of ingestion Rivaroxaban & apixaban effect may be reversed by giving prothrombin complex concentrate (PCC) Dabigatran is dialyzable Case reports suggest that recombinant factor VIIa (NovoSeven™) is ineffective vs dabigatran (Thromb Haemost 2012;108:585)

Reversal via dialysis? Dabigatran has low protein binding, is dialyzable 60% removed in 2-3 h No data on efficacy Rivaroxaban has high protein binding, not dialyzable

When to stop drug before surgery Dabigatran CrCl, mL/min Approx half-life, h Standard risk surgery High risk surgery >80 13 24 h 2 days 50-80 15 24h 30-50 18 4 days <30 27 6 days Rivaroxaban CrCl, mL/min Approx half-life, h Standard risk surgery High risk surgery >30 12 24 h 2 days <30 ? 4 days

Thromboembolic risk assessment in medical patients Underlying risk factors Clinical risk factors Molecular risk factors Family history/past history of VTE Factor V Leiden mutation Advanced age Activated protein C resistance Obesity Deficiencies: Varicose veins antithrombin Pregnancy/puerperium protein C Oestrogen therapy protein S Paralysis Antiphospholipid antibody/lupus Immobility anticoagulant Previous or current malignancy Prothrombin gene mutation Chronic heart failure MTHFR mutation* Chronic respiratory failure Inflammatory bowel disease *methylene tetrahydrofolate reductase Adapted from THRIFT II 1998 Although the current clinical condition is an important contributor to overall thromboembolic risk, underlying long-term risk factors appear to be at least as important in determining thromboembolic risk in medical patients [16]. Risk factors are similar to those cited for surgical patients, but unlike surgical patients, in medical settings underlying factors may be more important than the current medical condition in determining overall risk [16]. The THRIFT II document, on which this slide is based, recommends clinical assessment and a series of blood tests to detect congenital and acquired molecular risk factors [6]. The International Consensus Statement suggests a similar series of blood tests for patients with a personal or family history of VTE [7]. 6

Deaths Due to VTE in EU Deaths due to VTE (543,454) Exceed combined deaths due to: AIDS (5,860)1 breast cancer (86,831)1 prostate cancer (63,636)1 transport accidents (53,599)1 1Eurostat statistics on health and safety 2001. Available from: http://epp.eurostat.cec.eu.int.

Maladie thromboembolique veineuse: Fréquence en fonction de l'âge Slide A25 Maladie thromboembolique veineuse: Fréquence en fonction de l'âge USA, l'incidence annuelle TVP est approximativement 0.1% NIH Consensus Statements 1986; 6:1–8. TVP et EP sont responsable de 300,000 – 600,000 hospitalisations par an Silverstein MD, et al. Arch. Int. Med. 1998; 158:585–593. Annual incidence 0.5 0.4 0.3 Key marketing messages DVT is a common condition, particularly in the elderly as the incidence increases with age. PE is responsible for a large number of hospital admissions. At the same time, the incidence of PE among patients already in hospital is even higher than the number of patients who are admitted to hospital with PE. (% hospital admissions) Incidence of PE 0.2 0.1 DVT is a relatively common condition, with an annual incidence of 1 in 1,000 in the USA. Venous thrombosis is an important cause of morbidity and mortality, and is responsible for 300,000–600,000 hospitalisations in the USA each year. PE is potentially the most serious complication of VTE. Although uncommon in younger life, the incidence of PE rises through adulthood and confirmed PE is responsible for nearly 1 in every 200 (0.5%) hospital admissions among elderly patients (>80 years of age). PE is an important cause of mortality. For example, each year in the USA 600,000 people develop PE and 60,000 die as a result. The 3-month mortality for PE patients is 17%. NIH Consensus Statements 1986; 6:1–8. Silverstein MD, et al. Arch. Int. Med. 1998; 158:585-593. Stein PD, et al. Chest 1999; 116:909–913. Goldhaber SZ, et al. Lancet 1999; 353:1386–1389. DVT: an important cause of morbidity and mortality 0–9 10–19 20–29 30–39 40–49 50–59 60–69 70–79 80–89 Age (years) PE: the most common cause of preventable hospital deaths Stein PD, et al. Chest 1999; 116:909–913. Silverstein MD, et al. Arch. Int. Med. 1998; 158:585-593. For further slides on this topic, see the CD-ROM databank: Slides A6, A26–A29

Evaluation individuelle du risque

Anticoagulation orale Fibrillation auriculaire non valvulaire Utilisation des nouveaux anticoagulants oraux Pradaxa en 2 prises (gelules) Tous les jours aux mêmes heures Toutes les 12 heures De préférence avec les aliments(dyspepsie) En général 2*150mg 2*110 mg si > 80 ans ou++ par isoptine ou insuffisance rénale Xarelto En 1 prises (comprimé) Tous les jours à la même heure En général 20mg/j Dose de 15mg/j si insuffisance rénale relative

Anticoagulation orale Contre-indications générales Grossesse (Sintrom---Teratogène) Patients incapables de collaborer Insuffisance hépatique ,alcoolisme risque hémorragique =ulcère gastrique Lésions des voies digestives ,urinaires, respiratoires , tumeurs, métastases Epanchement péricardique, pericardite Injections intra-musculaires Infiltrations articulaires,…ou péridurales,… HTA sévère non contrôlée

Anticoagulation orale Précautions générales Grossesse Interactions medicamenteuses… Antiinflamatoires,…aspirine,…antiaggregants plaquettaires,… Millepertuis,Tavonin,…Tanakan,…(ginkgo Biloba) Ne pas modifier le traitement sans avis médical Pas de distraction si bricolage dangereux Pas de sport violents Rasoir électrique plutôt que lames,… Brosse à dents souple Carte de groupe sanguin en poche Ajouter sous anticoagulant ( préciser) Prévenir toutes les personnes qui vous soignent (généraliste, spécialistes, infirmières, pharmaciens,kinésthérapeute,dentiste, pédicure, podologue,urgentiste,… Stopper les anticoagulants oraux avant chirurgie programmée, soins dentaires ou infiltrations

Anticoagulation orale Symptômes suspects de surdosage Saignements visibles Saignements internes non visibles Saignements des gencives Saignement du nez ou œil rouge Apparition de “bleus “ (ecchymoses,…) Présence de sang dans les urines Règles anormalement abondantes Présence de sang rouge dans les selles ou selles noires Vomissements ou crachats sanglants Saignements qui ne s’arrête pas Fatigue inhabituelle Essoufflement anormal Pâleur inattendue Mal de tête ne cédant pas au traitement Malaise inexpliqué Si un ou plusieurs de ces symptômes se déclarent, contactez sans tarder votre médecin afin d’effectuer éventuellement des examens complémentaires

Anticoagulation orale par NOAC’s Précautions spécifiques(xarelto/pradaxa) Prise de sang (fonction rénale) avant début du traitement Avaler entièrement les gelules ou comprimés Ne pas macher, couper ou ouvrir (risque hémorragique) Respecter l’horaire de la (des ) prise(s) Que faire en cas d’oubli? Xarelto : si moins de 8h de retard --prise immédiate(dose normale le lendemain) Si plus de 8 h de retard ---- passer une dose Pradaxa: idem mais délai de 6 h Ne jamais prendre une double dose en cas d’oubli Astuces: alarmes, réveil, gsm,…. Eviter le jus de pamplemouse Interactions médicamenteuses ----(nb: pradaxa---vérapamil) Suivi fonction rénale…..(déshydratation ,gastroentérite, infection,..)

Anticoagulation orale par NOAC’s Gestion péri.interventionnelle Délai entre la dernière dose et la procédure avant l’opération Après l’opération procédures programmées soins dentaires-endoscopies infiltrations-artériographie chir à faible risque hémorragique ≥24h chir à risque hémorragique patient standard ≥24h élevé patient à haut risque ≥ 48h ≥48h (HBPM) procédure d’urgence de préference 24h ≥48h (HBPM)

Anticoagulation orale par AVK Précautions spécifiques Alimentation “contrôlée » en vit K Avant soins dentaires simple pas d’arrêt Avant extractions dentaires endoscopies, biopsies, artériographies -stop 3jours avant(HBPM si nécessaire) infiltrations avant chirurgie programmée -- stop 3à 5 jours (HBPM si nécessaire) si chirurgie urgente --- antidotes(ppsb, vit K)

Alimentation du patient sous traitement anticoagulant par AVK Permis occassionnellement sans excès persil,ciboulette,chou-fleur,chou rouge,choux de bruxelles, laitues,épinards,brocolis,céleri-rave,carottes,crudités,foie de veau, germes de blé, thé vert Permis sans excès: Asperges,avocats,concombres,haricots verts,petits pois,tomates,pommes de terre,fraises,oranges,beurre,fromage blanc gras,œufs,viande et foie de porc ou de bœuf Permis sans restrictions: Ail, artichauds, aubergines,céleri en branche,chicorée, courges,cresson, fenouil, oignons, poireaux, radis,salsifis, pousses de soja remarques: attention aux boissons alcoolisées

The End

Gestion de l’anticoagulation dans la fibrillation auriculaire Docteur Laurent Rousseau Cardiologie - CHwapi

AF is a common disorder Responsible for a third of all hospitalizations for cardiac rhythm disturbances1 Estimated prevalence: Europe: 4.5 million1 USA: 5.1 million2 Affects approximately 2.5% of the US population2 Nearly one in four people at age 55 years will go on to develop AF (24% of men and 22% of women)3 1. ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030; 2. Miyasaka Y et al. Circulation 2006;114:119–25; 3. Heeringa J et al. Eur Heart J 2006;27:949–53

Prevalence of AF increases with age 20 Women (n=4053) Men (n=2590) 15 Prevalence (%) 10 5 55–59 60–64 65–69 70–74 75–79 80–84 >85 Age (yrs) Prevalence at baseline assessed in 6808 participants in a European population-based study Data from Heeringa J et al. Eur Heart J 2006;27:949–53

Consequences of AF Formation of blood clots (thrombosis) on the atrial walls that can dislodge (embolize), leading to stroke and systemic embolism Reduction in cardiac output can precipitate heart failure, leading to distinctive symptoms such as: Peripheral oedema Dyspnoea Pulmonary oedema Fatigue Chest pain

Management of AF has two broad objectives Prevention of complications, including thromboembolism (particularly ischaemic stroke) and heart failure Relief of symptoms Choice of antithrombotic therapy should be tailored to the patient based on: Management of AF patients is aimed at reducing symptoms and at preventing severe complications associated with AF Prevention of AF-related complications relies on antithrombotic therapy, control of ventricular rate, and adequate therapy of concomitant cardiac diseases Reference ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429 Risk of thromboembolism Risk of bleeding ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429; ACCF/AHA/HRS Focused Update Guidelines: Fuster V et al. J Am Coll Cardiol 2011;57:e101–98

Overview of traditional antithrombotic treatments Presentation category: Overview of traditional antithrombotic treatments The following slides note the main objectives in managing AF and list the key clinical trials that have evaluated traditional antithrombotic treatments in AF. Key words ASA Aspirin ESC guidelines Guidelines ESC Primary stroke prevention VKA

Warfarin reduces the risk of stroke in patients with AF Favours warfarin Favours placebo AFASAK SPAF BAATAF CAFA SPINAF EAFT RRR 64%* (95% CI: 4974%) All trials 100 50 –50 –100 RRR (%)† When only ischaemic stroke was considered, dose-adjusted warfarin was associated with a 67% RRR (95% CI: 54–77%) Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic), for ischaemic stroke only, the RRR was 67% (95% CI: 54–77%) VKA = vitamin K antagonist Hart RG et al. Ann Intern Med 2007;146:857–67

Limited efficacy of ASA in reducing the risk of stroke in patients with AF RRR (%)† 100 –100 50 –50 AFASAK SPAF EAFT ESPS II ASA better Placebo better LASAF 125 mg/d 125 mg QOD UK-TIA 300 mg/d 1200 mg/d JAST All trials Only the SPAF trial showed a benefit of ASA over placebo for reducing stroke risk RRR: 19%* (95% CI: –1 to 35%) *Random effects model; error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic); for ischaemic stroke only, RRR was 21% (95% CI: −1 to 38%) ASA = acetylsalicylic acid; QOD = every other day Hart RG et al. Ann Intern Med 2007;146:857–67

ASA inferior to warfarin for stroke prevention in AF RRR (%)† 100 –100 50 –50 AFASAK I AFASAK II EAFT PATAF Warfarin better ASA better Chinese ATAFS SPAF II Age 75 yrs Age >75 yrs All trials RRR: 38%* (95% CI: 18–52%) Random effects model; error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic); ASA = acetylsalicylic acid Hart RG et al. Ann Intern Med 2007;146:857–67

Inconvénients des AVK Etroitesse de la fenêtre thérapeutique Prises de sang fréquentes (suivi INR) Intéractions alimentaires et médicamenteuses Hémorragies (gastro-intestinales et cérébrales)

Novel agents for stroke prevention in patients with atrial fibrillation Disclaimer: Dabigatran etexilate, rivaroxaban, and apixaban are now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details

Novel agents target specific molecules in the coagulation cascade Tissue factor/VIIa X IX Vitamin K antagonists VIIIa IXa Direct Factor Xa inhibitors Apixaban Rivaroxaban Edoxaban Va Xa AT Direct thrombin inhibitors Dabigatran II Thrombin Vitamin K antagonists inhibit coagulation by depleting available clotting factors. Novel agents inhibit specific molecules within the coagulation cascade. Direct Factor Xa inhibitors exert their anticoagulant effect by preventing Factor Xa from binding to its substrates, thereby blocking the conversion of prothrombin to thrombin. Direct thrombin inhibitors exert their anticoagulant effect by preventing thrombin from catalysing the conversion of fibrinogen to fibrin. Weitz J, Bates S. J Thromb Haemost 2005;3:1843–53 Monroe D, Hoffman M. Arterioscler Thromb Vasc Biol 2006;26:41–8 Crawley J et al. J Thromb Haemost 2007;5 (Suppl 1):95–101 Fibrinogen Fibrin Weitz J, Bates S. J Thromb Haemost 2005;3:1843–53; Monroe D, Hoffman M. Arterioscler Thromb Vasc Biol 2006;26:41–8; Crawley J et al. J Thromb Haemost 2007;5 (Suppl 1):95–101

Properties of novel agents for stroke prevention Dabigatran Rivaroxaban Apixaban Target Thrombin Factor Xa Dosing Fixed, twice daily Fixed, once daily Half-life in hours 12–14 7–13 8–13 Routine monitoring No Renal clearance 80% 66% 25% Involvement of CYP Yes (CYP3A4) The novel agents have numerous advantages over vitamin K antagonists, including a rapid onset of action, no significant food interactions, low potential for drug interactions, and a predictable anticoagulant effect that removes the requirement for routine coagulation monitoring. Eriksson B et al. Annu Rev Med 2011;62:41–57 CYP = cytochrome P450 Adapted from Eriksson B et al. Annu Rev Med 2011;62:41–57

Dabigatran etexilate for stroke prevention in patients with atrial fibrillation RE-LY®

Dabigatran 150 mg BID vs warfarin Dabigatran 150 mg BID was superior to warfarin for the prevention of stroke and systemic embolism Dabigatran 150 mg BID vs warfarin Rate (%/yr) Dabigatran Warfarin Stroke or systemic embolism 1.11 1.71 Stroke 1.01 1.58 Haemorrhagic stroke 0.10 0.38 Ischaemic 0.92 1.21 Non-disabling stroke 0.37 0.58 Disabling or fatal stroke 0.66 RR (95% CI); P value 0.65 (0.52, 0.81); P<0.001 0.64 (0.51, 0.81); P<0.001 0.26 (0.14, 0.49); P<0.001 0.76 (0.59, 0.97); P=0.03 0.62 (0.43, 0.91); P=0.01 Dabigatran 150 mg BID was found to be superior to warfarin for the primary efficacy endpoint of stroke and systemic embolism:1 35% relative risk reduction versus warfarin. Dabigatran 150 mg BID was also superior to warfarin for the secondary endpoints of stroke, haemorrhagic stroke, non-disabling stroke, disabling or fatal stroke and ischaemic stroke:1 74% relative risk reduction versus warfarin for haemorrhagic stroke 24% relative risk reduction versus warfarin for ischaemic stroke. The majority of strokes associated with AF are ischaemic.2 Additional information The mean time in therapeutic range for the warfarin arm of the trial was 64%, demonstrating that dabigatran 150 mg BID achieved superiority over well-controlled warfarin for the primary endpoint.1 In routine clinical practice time in therapeutic range tends to be much lower than that achieved in the RE-LY® trial (~50%).3 Connolly SJ et al. N Engl J Med 2009;361:1139–5 Andersen KK et al. Stroke 2009;40:2068–72 Samsa GP et al. Arch Intern Med 2000;160:967–73 0.66 (0.50, 0.87); P=0.004 0.5 1.0 1.5 2.0 Favours dabigatran Favours warfarin Error bars = 95% CI; BID = twice daily; Intention-to-treat population Connolly SJ et al. N Engl J Med 2009;361:1139–51; Connolly SJ et al. N Engl J Med 2010;363:1875–6; Pradaxa® EU SmPC, June 2012

Dabigatran 110 mg BID vs warfarin Dabigatran 110 mg BID was non-inferior to warfarin for the prevention of stroke and systemic embolism Rate (%/yr) Dabigatran Warfarin Stroke or systemic embolism 1.54 1.71 Stroke 1.44 1.58 Haemorrhagic stroke 0.12 0.38 Ischaemic 1.34 1.21 Non-disabling stroke 0.50 0.58 Disabling or fatal stroke 0.94 1.01 Dabigatran 110 mg BID vs warfarin RR (95% CI); P value 0.90 (0.74, 1.10); P<0.001* 0.91 (0.74, 1.12); P=0.38 0.31 (0.17, 0.56); P<0.001 1.11 (0.88, 1.39); P=0.35 0.86 (0.61, 1.22); P=0.40 Dabigatran 110 mg BID was found to be non-inferior to warfarin for the primary endpoint of stroke and systemic embolism. Dabigatran 110 mg BID was found to significantly reduce the risk of haemorrhagic stroke compared with warfarin: 69% relative risk reduction. Connolly SJ et al. N Engl J Med 2009;361:1139–5 0.93 (0.72, 1.21); P=0.61 0.5 1.0 1.5 2.0 Favours dabigatran Favours warfarin *P value for non-inferiority; Error bars = 95% CI; BID = twice daily; Intention-to-treat population Connolly SJ et al. N Engl J Med 2009;361:1139–51; Connolly SJ et al. N Engl J Med 2010;363:1875–6; Pradaxa® EU SmPC, June 2012

RE-LY®: bleeding outcomes Characteristic Dabigatran 110 mg BID (n=6015) Dabigatran 150 mg BID (n=6076) Warfarin (n=6022) P value D 110 mg vs W P value D 150 mg vs W Major bleeding 2.87 3.32 3.57 0.003 0.31 – Life-threatening 1.24 1.49 1.85 <0.001 0.03 – Non-life threatening 1.83 2.06 1.92 0.65 0.39 – Gastrointestinal 1.15 1.56 1.07 0.52 0.001 Intracranial bleeding 0.23 0.32 0.76 Dabigatran 150 mg BID was found to result in a similar rate of major bleeding compared with warfarin. There was a significant increase in the risk of gastrointestinal bleeding with dabigatran 150 mg BID compared with warfarin. Dabigatran 110 mg BID was found to significantly reduce the rate of major bleeding compared with warfarin. Both doses of dabigatran significantly reduced the rate of intracranial bleeding (the most feared complication of antithrombotic therapy) compared with warfarin. Connolly SJ et al. N Engl J Med 2009;361:1139–5 Data represent %/year D = dabigatran; W = warfarin; Intention-to-treat population Connolly SJ et al. N Engl J Med 2010;363:1875–6

Rivaroxaban for stroke prevention in patients with atrial fibrillation ROCKET AF

Rivaroxaban vs warfarin ROCKET AF: rivaroxaban was non-inferior to warfarin for the primary outcome of stroke and systemic embolism Rate (%/yr) Rivaroxaban Warfarin Stroke or systemic embolism 2.1 2.4 Vascular death, stroke, embolism 3.11 3.63 Haemorrhagic stroke 0.26 0.44 Ischaemic stroke 1.34 1.42 Unspecified stroke 0.06 0.10 Non-CNS embolism 0.04 0.19 Rivaroxaban vs warfarin HR (95% CI); P value 0.88 (0.74, 1.03); P<0.001* 0.86 (0.74, 0.99); P=0.034 0.59 (0.37, 0.93); P=0.024 0.94 (0.75, 1.17); P=0.581 0.65 (0.25, 1.67); P=0.366 Rivaroxaban was found to be non-inferior to warfarin for the primary endpoint of stroke and systemic embolism. Superiority was tested in the intention-to-treat population but was not achieved (hazard ratio [HR] 0.88; 95% CI 0.75–1.03; P=0.12). Non-central nervous system embolism was significantly reduced with rivaroxaban compared with warfarin (HR 0.23; 95% CI 0.09–0.61; P=0.003). Rivaroxaban also significantly reduced the risk of haemorrhagic stroke compared with warfarin (HR 0.59; 95% CI 0.37–0.93; P=0.024). Rivaroxaban did not reduce the rate of ischaemic stroke compared with warfarin (HR 0.94; 95% CI 0.75–1.17; P=0.581). Additional information The mean time in therapeutic range for warfarin treated patients was 55%. Patel MR et al. N Engl J Med 2011;365:883–91 0.23 (0.09, 0.61); P=0.003 0.5 1.0 1.5 2.0 Favours rivaroxaban Favours warfarin *P value for non-inferiority, intention-to-treat population, all other results based on safety on-treatment population Error bars = 95% confidence intervals; CNS = central nervous system; HR = hazard ratio Patel MR et al. N Engl J Med 2011;365:883–91

ROCKET AF: bleeding outcomes Event rate/100 patient-yrs HR (95% CI) P value Rivaroxaban Warfarin Major and non-major clinically relevant bleeding 14.9 14.5 1.03 (0.96–1.11) 0.44 Major bleeding 3.6 3.4 1.04 (0.90–1.20) 0.58 ≥2 g/dL Hb drop 2.8 2.3 1.22 (1.03–1..44 0.02 Transfusion 1.6 1.3 1.25 (1.01–1.55) 0.04 Critical bleeding 0.8 1.2 0.69 (0.53–0.91) 0.007 Fatal bleeding 0.2 0.5 0.50 (0.31–0.79) 0.003 Intracranial haemorrhage 0.7 0.67 (0.47–0.93) Gastrointestinal bleeding (upper, lower, and rectal) 3.15 2.16 Data not provided <0.001 Non-major clinically relevant bleeding 11.8 11.4 1.04 (0.96–1.13) 0.35 Rivaroxaban resulted in similar levels of the composite of major and clinically relevant non-major bleeding when compared with warfarin. Rivaroxaban provided a relative risk reduction of 33% (hazard ratio 0.67; 95% CI 0.47–0.93; P=0.02) in the rate of intracranial haemorrhage when compared with warfarin. Rivaroxaban was associated with less fatal bleeding than warfarin. However, decreases in haemoglobin levels of ≥2g/dL and transfusions were significantly more common among patients treated with rivaroxaban compared with warfarin. The incidence of gastrointestinal bleeding was significantly higher in the rivaroxaban group than in the warfarin group (P<0.001). Patel MR et al. N Engl J Med 2011;365:883–91. Based on safety on-treatment population Hb = haemoglobin; HR = hazard ratio Patel MR et al. N Engl J Med 2011;365:883–91

Apixaban for stroke prevention in patients with atrial fibrillation ARISTOTLE

ARISTOTLE: apixaban was found to be superior to warfarin for the primary outcome of stroke or systemic embolism Rate (%/yr) Apixaban Warfarin Stroke or systemic embolism* 1.27 1.60 Stroke 1.19 1.51 Ischaemic or uncertain 0.97 1.05 Haemorrhagic 0.24 0.47 Systemic embolism 0.09 0.10 All cause death* 3.52 3.94 Stroke, systemic embolism, or all-cause death 4.49 5.04 Myocardial infarction 0.53 0.61 Apixaban vs warfarin HR (95% CI); P value 0.79 (0.66, 0.95); P=0.011 0.79 (0.65, 0.95); P=0.012 0.92 (0.74, 1.13); P=0.42 0.51 (0.35, 0.75); P<0.001 0.87 (0.44, 1.75); P=0.70 0.89 (0.80, 0.998); P=0.047 Apixaban was found to be superior to warfarin for the primary endpoint of stroke and systemic embolism: 21% relative risk reduction. Apixaban was found to significantly reduce the rate of haemorrhagic stroke compared with warfarin: 49% relative risk reduction. Apixaban was found to significantly reduce all-cause death compared with warfarin: 11% relative risk reduction. Apixaban did not significantly reduce the rate of ischaemic stroke compared with warfarin (P=0.42). Additional information The mean time in therapeutic range for patients treated with warfarin was 62%. Granger CB et al. N Engl J Med 2011;365:981–92 0.89 (0.81, 0.98); P=0.019 0.88 (0.66, 1.17); P=0.37 0.5 1.0 1.5 2.0 Favours apixaban Favours warfarin *Part of sequential testing sequence preserving the overall type I error; CI = confidence interval; HR = hazard ratio Granger CB et al. N Engl J Med 2011;365:981–92

ARISTOTLE: bleeding outcomes Events, n (%/yr) HR (95% CI) P value Apixaban (n=9088) Warfarin (n=9052) Primary safety outcome: ISTH major bleeding* 327 (2.13) 462 (3.09) 0.69 (0.60–0.80) <0.001 Intracranial 52 (0.33) 122 (0.80) 0.42 (0.30–0.58) Other location 275 (1.79) 340 (2.27) 0.79 (0.68–0.93 0.004 Gastrointestinal 105 (0.76) 119 (0.86) 0.89 (0.70–1.15) 0.37 Major or clinically relevant non-major bleeding 613 (4.07) 877 (6.01) 0.68 (0.61–0.75) Any bleeding 2356 (18.1) 3060 (25.8) 0.71 (0.68–0.75) Apixaban was associated with a significantly lower rate of major bleeding compared with warfarin: 31% relative risk reduction. Apixaban was found to significantly reduce the rate of intracranial bleeding compared with warfarin: 58% relative risk reduction. The rate of gastrointestinal bleeding was similar in patients treated with apixaban and warfarin. Granger CB et al. N Engl J Med 2011;365:981–92 *Part of sequential testing sequence preserving the overall type I error HR = hazard ratio; ISTH = International Society on Thrombosis and Haemostasis Granger CB et al. N Engl J Med 2011;365:981–92

Goals for anticoagulation therapy in AF Prevent ischaemic stroke Minimize haemorrhagic stroke (minimize risk of ICH) The goals of anticoagulation/antithrombotic therapy in AF can be summarised as preventing ischaemic stroke (prevent the formation of clots that subsequently block vessels in the brain) and minimizing the risk of haemorrhagic stroke and of intracranial bleeding (caused by the therapy itself)

Assessing stroke risk: CHADS2 Annual stroke rate (%)* CHADS2 score 30 2 3 4 5 6 10 15 20 25 1 CHADS2 criteria Score CHF 1 Hypertension Age ≥75 yrs Diabetes mellitus Stroke/TIA 2 The CHADS2 score is a simple system for stratifying patients with atrial fibrillation according to their risk of stroke.1 It has been validated in a large national registry of patients with atrial fibrillation1 This system of stroke risk scoring has traditionally been recommended in treatment guidelines.2 Gage BF et al. JAMA 2001;285:2864–70 ACCF/AHA/HRS Focused Update Guidelines: Fuster V et al. J Am Coll Cardiol 2011;57:e101–98 CHF = congestive heart failure; TIA = transient ischaemic attack Gage BF et al. JAMA 2001;285:2864–70

Assessing stroke risk: CHA2DS2-VASc CHA2DS2-VASc criteria Score CHF/LV dysfunction 1 Hypertension Age 75 yrs 2 Diabetes mellitus Stroke/TIA/TE Vascular disease Age 65–74 yrs Sex category (i.e. female gender) Total score Patients (n=7329) Adjusted stroke rate (%/year)* 1 0.0 422 1.3 2 1230 2.2 3 1730 3.2 4 1718 4.0 5 1159 6.7 6 679 9.8 7 294 9.6 8 82 9 14 15.2 The CHADS2 score has been criticized for being too simplistic and for predominately classifying patients as at intermediate risk of stroke.1 The CHA2DS2-VASc score was developed to more accurately predict patients’ stroke risk by taking additional stroke risk factors into account.1 The CHA2DS2-VASc score has since been validated in multiple cohorts.2 The accumulated evidence shows that CHA2DS2-VASc is better at identifying ‘truly low-risk’ patients with AF and is as good as, and possibly better than, scores such as CHADS2 in identifying patients who develop stroke and thromboembolism.2 Lip G et al. Chest 2010;137:263-72 Camm AJ et al. Eur Heart J 2012;33:2719–47 *Theoretical rates without therapy; assuming that warfarin provides a 64% reduction in stroke risk, based on Hart RG et al. 2007; TE = thromboembolism; TIA = transient ischaemic attack; LV = left ventricular Lip G et al. Chest 2010;137:263-72; Lip G et al. Stroke 2010;41:2731–8; Camm J et al. Eur Heart J 2010; 31:2369–429; Hart RG et al. Ann Intern Med 2007;146:857–67

Assessing bleeding risk: HAS-BLED HAS-BLED risk criteria Score Hypertension 1 Abnormal renal or liver function (1 point each) 1 or 2 Stroke Bleeding Labile INRs Elderly (e.g. age >65 yrs) Drugs or alcohol (1 point each) HAS-BLED total score N Number of bleeds Bleeds per 100 patient-yrs* 798 9 1.13 1 1286 13 1.02 2 744 14 1.88 3 187 7 3.74 4 46 8.70 5 8 12.5 6 0.0 – A number of bleeding risk scoring systems have been developed for use in patients with atrial fibrillation including HAS-BLED, HEMORR2AGES and ATRIA. The HAS-BLED score has been validated in several independent cohorts and has recently been included in the updated ESC guidelines as a formal bleeding risk assessment tool for all patients with atrial fibrillation. Camm AJ et al. Eur Heart J 2012;33:2719–47 *P value for trend = 0.007; INR = international normalized ratio Pisters R et al. Chest 2010;138:1093–100; ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429

ESC 2012 focused update: choice of anticoagulant Yes Atrial fibrillation Valvular AF* <65 years and lone AF (including females) Assess risk of stroke CHA2DS2-VASc score No antithrombotic therapy Oral anticoagulant therapy NOAC VKA 1 No (i.e. non-valvular) No ≥2 Assess bleeding risk (HAS-BLED score) Consider patient values and preferences = CHA2DS2-VASc 0 = best option = CHA2DS2-VASc 1 = CHA2DS2-VASc ≥2 = alternative option The process of choosing anticoagulant therapy, based on the ESC 2012 update, can be summarized in this flow diagram. A key point to note is that antiplatelet therapy with ASA plus clopidogrel or – less effectively – ASA only should be considered in patients who refuse any OAC or cannot tolerate anticoagulation for reasons unrelated to bleeding. Camm AJ et al. Eur Heart J 2012;33:2719–47 *Includes rheumatic valvular disease and prosthetic valves; NOAC = novel oral anticoagulant; VKA = vitamin K antagonist; Camm AJ et al. Eur Heart J 2012;33:2719–47

Avantages des DOAC Efficacité au moins équivalente voire supérieure au traitement de référence Sécurité et facilité d’emploi Rapidité d’action. Pas de bridging Doses fixes Pas de suivi biologique Intéractions médicamenteuses limitées Pas d’intéractions alimentaires

Inconvénients des DOAC Elimination rénale (25-80%) Variabilité pharmacocinétique interindividuelle Pas de retentissement sur les tests courants de coagulation, en particulier l’INR Pas d’antidote Gestion des saignements et des procédures en urgence