Antithrombotiques pour les patients de fibrillation auriculaire

La fibrillation auriculaire est un important facteur de risque de l’AVC. Un patient sur six avec AVC ischémique souffre de FA. L’AVC secondaire à la FA peut en grande partie être prévenu par un traitement aux anticoagulants.

• Cliniques de prévention secondaire de l’AVC, notamment par la prise en charge de la FA chez les patients avec AVC ischémique ou AIT (prévention efficace et cohérente par la reconnaissance précoce des facteurs de risque et des interventions ciblées en temps opportun)
• Processus de surveillance approprié du RIN chez les patients ambulants et communications de suivi pour les patients prenant des anticoagulants
• Optimisation des stratégies locales, régionales et provinciales de prévention des récidives de l’AVC
• Sensibilisation à la prévention de l’AVC et formation en prévention secondaire à l’intention des fournisseurs de soins primaires et des spécialistes qui prennent en charge en phase aiguë des patients avec AVC et après leur congé des soins aigus
• L’accès à une clinique spécialisée dans la prise en charge des patients traités avec la warfarine est associé à de meilleurs résultats de santé qu’un suivi médical de routine.

1. Proportion des patients avec AVC ischémique en présence de FA qui reçoivent un traitement anticoagulant, à moins de contre-indication (de base)
2. Proportion des patients avec AVC ou AIT en présence de FA admissibles à qui l'on a prescrit un traitement anticoagulant au congé des soins aigus (de base)
3. Proportion des patients avec AVC ou AIT en présence de FA admissibles à qui l'on a prescrit un traitement anticoagulant après une visite à une clinique de prévention secondaire (de base)
4. Proportion des patients avec FA qui suivent un traitement anticoagulant au moment de leur admission à l’hôpital pour un AVC ischémique ou un AIT
5. Proportion des patients avec FA, victimes d’un AVC ou d’un AIT, qui suivent un traitement antiplaquettaire, auxquels on n’a pas prescrit un traitement anticoagulant
6. Proportion des patients avec FA, victimes d’un AVC ou d’un AIT, continuant à suivre un traitement anticoagulant 3 mois, 6 mois et 1 an après l’amorce de la thérapie
7. Proportion des patients avec FA, qui suivent un traitement à la warfarine dont le RIN se situe dans l’intervalle thérapeutique à 3 mois

Notes relatives à la mesure des indicateurs

• Indicateur 3 : les raisons pour lesquelles les patients avec FA et qui sont victimes d’un AVC ne suivent pas un traitement anticoagulant doivent être recueillies et rapportées, notamment les contre-indications, les questions d’adhésion et les habitudes des médecins en matière d’ordonnances. Ces renseignements supplémentaires aideront à orienter les initiatives d’amélioration de la qualité des soins.
• Si la FA est documentée, le dossier médical devrait être examiné en vue de déterminer les médicaments prescrits au patient au congé, particulièrement la warfarine, le dabigatran, le rivaroxiban, l'apixiban ou l'héparine. Les mesures du rendement devraient être stratifiées de manière à préciser les proportions prescrites de chaque médicament.
• Sources de données : résumés au congé, antécédents et examen physique, ordonnances des médecins, notes du personnel infirmier au dossier du patient hospitalisé, documents de la clinique de prévention et dossiers des patients en soins primaires
• Les rapports de laboratoire ou une autre documentation fiable sont nécessaires pour déterminer si le RIN du patient se situe dans l’intervalle thérapeutique; les RIN devraient être surveillés durant un certain temps plutôt que de se fier à une mesure unique.
• Il est important de noter que le fait de prescrire un médicament ne signifie pas que le patient se conforme à sa médication. Cette adhésion ne peut être signalée que par le patient et peut être déterminée par les mesures consécutives du RIN au fil du temps.
• Pour l'heure, l’adhésion à de nouveaux anticoagulants oraux ne peut être quantifiée de la même manière que le maintien du RIN dans l'intervalle thérapeutique.

† Thrombosis Interest Group of Canada : www.tigc.org

† Société canadienne de cardiologie : http://www.onlinecjc.ca/article/S0828-282X(12)00046-3/abstract

† Guide de poche pour la FA

• http://www.ccsguidelineprograms.ca/pocket_card/2012_Afib_PG/AtFib_PG_Flipbook/index.html,
• http://www.ccsguidelineprograms.ca/pocket_card/2012_Afib_PG_Fr/index.html(FR)

Atrial fibrillation is a common arrhythmia. The prevalence of atrial fibrillation in the general population increases with age;¹⁵⁷ about 12 percent of people aged over 75 years have atrial fibrillation.¹⁵⁸ The incidence of AF in the general population appears to be increasing over time.¹⁵⁹

Atrial fibrillation is a major risk factor for stroke. The presence of atrial fibrillation increases the risk of stroke approximately five-fold; the relative risk is higher still if there is associated valvular heart disease.¹⁶⁰ Stroke risk also varies according to the presence of other risk factors and can be estimated using a score that takes into account the presence of congestive heart failure, hypertension, age, stroke and systemic embolism.¹⁵⁵

Atrial fibrillation most often causes stroke via embolism of thrombus from the left atrium. Several clinical trials involving many thousands of patients with AF have examined the efficacy of various antithrombotic drug regimens. The majority of the trial evidence concerns prevention of first stroke; the evidence-base for prevention of stroke recurrence in patients with AF is much smaller. Strokes due to atrial fibrillation are generally more severe than those occurring in patients in sinus rhythm. Consequently, atrial fibrillation strokes are associated with higher case-fatality, longer hospitalization, and increased disability.¹⁶¹

To characterize the efficacy and safety of antithrombotic agents for stroke prevention in patients who have atrial fibrillation, conducted a meta-analysis of all randomized trials published between 1966 and March 2007, identified by using the Cochrane Stroke Group search strategy.¹⁶² The analysis included 29 trials involving 28 044 patients who had non-valvular atrial fibrillation (mean age 71 years; mean follow-up 1.5 years). Most trials studied warfarin or aspirin in varying dosages and intensities, but other anticoagulants

(low-molecular-weight heparin, ximelagatran, and dabigatran) and other antiplatelet agents (clopidogrel, dipyridamole, indobufen, and trifusal) were also tested. There were 3003 participants assigned to placebo or control groups in 12 trials. The average stroke rate for these untreated participants was 13 percent per year in trials that were restricted to those who had previous stroke or TIA (secondary prevention trials) and 4.1 percent per year for those in primary prevention trials.

Compared with control, adjusted-dose warfarin (6 trials, 2,900 participants 20 percent of whom had previous stroke or TIA) and antiplatelet agents (8 trials, 4,876 participants 29 percent of whom had previous stroke or TIA) reduced stroke by 64 percent (95% CI 49-74%) and 22 percent (95% CI 6-35%), respectively.¹⁶² Adjusted-dose warfarin was substantially more efficacious than antiplatelet therapy (relative risk reduction, 39 percent [95% CI 22-52%]) (12 trials, 12,963 participants 23 percent of whom had previous stroke or TIA). Adjusted dose warfarin doubled the risk of intracranial and major extracranial hemorrhage; however, absolute rates of these adverse events were only 0.2 percent per year.

The largest trial comparing adjusted-dose warfarin with antiplatelet therapy was ACTIVE-W (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events), which included 6706 participants.¹⁶³ Anticoagulant therapy was superior to the combination of clopidogrel plus aspirin (relative risk reduction, 40 percent [95% CI 18-56%]). The ACTIVE-A trial,¹⁶⁴ published after the meta-analysis by Hart et al,¹⁶² included 7,554 participants in whom warfarin was unsuitable, randomly allocated them to receive clopidogrel plus aspirin or aspirin alone, and followed them for a median of 3.6 years. The results showed that treating 1000 AF patients for one year with clopidogrel plus aspirin prevented eight major vascular events (including two fatal and three disabling strokes) and caused seven major hemorrhages (one fatal).

Also published after the meta-analysis by Hart et al was the BAFTA trial (the Birmingham Atrial Fibrillation Treatment of the Aged study) which recruited 973 patients (12.5 percent of whom had previous stroke or TIA) aged 75 years or more (mean 81.5 years) from primary care, randomly assigned them to adjusted-dose warfarin (INR 2.0 - 3.0) or aspirin 75 mg once daily, and followed them for a mean of 2.7 years.¹⁶⁵ The primary endpoint was fatal or disabling stroke (ischemic or hemorrhagic), other intracranial hemorrhage, or clinically significant systemic embolism. There were 24 primary events (21 strokes, two other intracranial hemorrhages, and one systemic embolus) among participants assigned warfarin and 48 primary events (44 strokes, one other intracranial hemorrhage, and three systemic emboli) among those assigned aspirin (annual risk 1.8% vs. 3.8%, relative risk reduction 52 percent [95% CI 20-72%], p=0.003; treat 50 patients for one year to prevent one event). The annual risk of extracranial hemorrhage was 1.4 percent for patients assigned warfarin and 1.6 percent for those assigned aspirin.

Two trials in the meta-analysis by Hart et al included only patients who recently had a stroke or TIA. The European Atrial Fibrillation Trial (EAFT) involved 455 patients who were within three months of TIA or minor stroke, randomly assigned them to warfarin (INR 2.5 to 4.0) or aspirin (300 mg/day), and followed them for a mean of 2.3 years.¹⁶⁶ In the Studio Italiano Fibrillazione Atriale (SIFA) trial,916 patients within 15 days of TIA or minor stroke were randomized to open-label warfarin (INR 2.0 to 3.5) or indobufen (a reversible platelet cyclooxygenase inhibitor, 100 or 200 mg twice a day), and followed for one year.¹⁶⁷ The combined results showed that anticoagulants were significantly more effective than antiplatelet therapy for the prevention of all ischemic vascular events (odds ratio 0.67, 95% CI 0.50–0.91) and for the prevention of stroke recurrence (odds ratio 0.49, 95% CI 0.33–0.72). Warfarin did not significantly increase the frequency of intracranial bleeding.¹⁶⁸ Although major extracranial bleeding complications occurred more often in patients on warfarin (odds ratio 5.16, 95% CI 2.08–12.83), the absolute difference was small (2.8 percent per year versus 0.9 percent per year in EAFT and 0.9 percent per year versus zero percent in SIFA). Heparin anticoagulation confers no net benefit over antiplatelet therapy in patients with AF and recent (within 14 days) acute ischemic stroke.¹⁶⁹

A Danish cohort study investigated the risks of bleeding on monotherapy compared to combined therapy in patients with atrial fibrillation.¹⁷⁰ Records from nation-wide registries were used to identify patients with a first-time hospitalization for AF between 1997 and 2006. A total of 82 854 of 118 606 patients (69.9 percent) surviving AF hospitalization had at least 1 prescription filled for warfarin, aspirin, or clopidogrel after discharge. During mean (SD) follow-up of 3.3 (2.6) years, 13 573 patients (11.4 percent) experienced a nonfatal or fatal bleeding. The crude incidence rate for bleeding was highest for dual clopidogrel and warfarin therapy (13.9 percent per patient-year) and triple therapy (15.7 percent per patient- year). Using warfarin monotherapy as a reference, the hazard ratio (95% confidence interval) for the combined end

point was 0.93 (0.88-0.98) for aspirin, 1.06 (0.87-1.29) for clopidogrel, 1.66 (1.34-2.04) for aspirin-clopidogrel, 1.83 (1.72-1.96) for warfarin-aspirin, 3.08 (2.32-3.91) for warfarin-clopidogrel, and 3.70 (2.89- 4.76) for warfarin-aspirin-clopidogrel. Triple therapy posed a bleeding risk, which was three times higher than the risk of bleeding for warfarin alone.

In spite of convincing evidence linking AF to stroke, and the benefits of warfarin therapy in reducing this risk, AF patients are often not optimally managed. A recent analysis by Gladstone and colleagues using data from the Registry of the Canadian Stroke Network (RCSN) examined this issue in a cohort of 597 patients presenting to hospital with an ischemic stroke and previously known atrial fibrillation.¹⁷¹ They found that on admission for stroke, only 40 percent of patients were on warfarin, 30 percent on antiplatelet therapy, and 29% were not on any antithrombotics. Of those taking warfarin, three fourths had a subtherapeutic INR (<2.0) at the time of stroke admission. Overall, only 10 percent of patients with acute stroke and previously known atrial fibrillation were therapeutically anticoagulated (INR >2.0) at admission. Among the high-risk subgroup of stroke patients with a history of atrial fibrillation and a previous TIA or ischemic stroke (n=323), only 18 percent were taking warfarin with a therapeutic INR at the time of admission for their recurrent stroke; 39 percent were taking warfarin with a subtherapeutic INR, and 15 percent were on no antithrombotic therapy. These findings are particularly troublesome given that all subjects selected for inclusion in this study were considered high risk for stroke according to published criteria (low and moderate risk patients were not included), were living independently, and were considered ideal candidates for warfarin therapy (patients with known contraindications to warfarin were excluded from the study).

The problems associated with warfarin therapy have stimulated the development of oral agents that produce more predictable anticoagulation and do not require frequent monitoring. Most of the trial evidence concerns dabigatran, an oral thrombin inhibitor that does not have the drug and food interactions of warfarin or the inconvenience of INR monitoring.

The RE-LY (Randomized Evaluation of Long-term anticoagulant therapy) study tested two doses of dabigatran against warfarin in a non-inferiority trial with a prospective, randomized, open-label (warfarin only), blinded-end-point (PROBE) design.¹⁵⁶ Collaborators in 44 countries enrolled 18,1130 patients (mean age 71 years, 64 percent men) who had AF and at least one of: past stroke or TIA (20 percent of participants), left ventricular ejection fraction less than 40 percent, heart failure symptoms within six months (New York Heart Association class II or higher), age 75 years or higher, or 65-74 years of age plus diabetes mellitus, hypertension, or coronary heart disease. Exclusion criteria included severe valvular heart disease (including prosthetic valves), stroke within 14 days or severe stroke within six months, conditions that increase risk for hemorrhage, creatinine clearance less than 30 mL/min, active liver disease, and pregnancy. Participants were randomly allocated to receive dabigatran, 110 mg (n=6015) or 150 mg (n=6076) twice daily, or warfarin adjusted to an INR of 2.0-3.0 (n=6022), and followed for a median of two years (follow-up was 99.9 percent complete). The primary outcome was a composite of stroke or systemic embolism. Other outcomes included major hemorrhage, stroke, and death.

Dabigatran 150 mg twice daily reduced the risk of stroke or systemic embolism more than warfarin or dabigatran 110 mg twice daily. Rates of major hemorrhage were similar for warfarin and dabigatran 150 mg twice daily; dabigatran 110 mg twice daily was associated with lower rates of major hemorrhage than warfarin. Specifically, the rates of the primary outcome were 1.69 percent per year in the warfarin group, as compared with 1.53 percent per year in the group that received 110 mg bid of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P

The only adverse effect that was significantly more common with dabigatran than with warfarin was dyspepsia. Dyspepsia occurred in 348 patients (5.8 percent) in the warfarin group and in 707 patients (11.8 percent) and 688 patients (11.3 percent) in the 110-mg and 150-mg dabigatran groups, respectively

(p

Warfarin patients in the RE-LY trial had a therapeutic INR only about 64 percent of the time.¹⁷¹ This is consistent with other clinical trials and underscores the problems with warfarin therapy.¹⁷² To have a stroke rate similar to that of he dabigatran 150 mg twice daily group, patients assigned to warfarin in RE-LY needed to have a therapeutic INR 80 percent of the time.¹⁷³This degree of control is unlikely to be achieved in clinical trials or clinical practice.¹⁷⁴

Ongoing questions remain about dabigatran.¹⁷⁵These include: a) the potential safety and utility of the lower, 100 mg twice daily, dose in older patients with renal impairment; b) the safety and efficacy of dabigatran in the longer term, beyond the mean follow-up of two years, which is being evaluated in an ongoing follow-up study of RE-LY patients (NCT00808067); c) the implications, if any, of there being no antidote to dabigatran; and d) the cost of dabigatran.