Antithrombotic treatment of atrial fibrillation: New insights

Antithrombotic treatment of atrial fibrillation: New insights

Thrombosis Research 130 (2012) S59–S60 Contents lists available at SciVerse ScienceDirect Thrombosis Research journal homepage: www.elsevier.com/loc...

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Thrombosis Research 130 (2012) S59–S60

Contents lists available at SciVerse ScienceDirect

Thrombosis Research journal homepage: www.elsevier.com/locate/thromres

Antithrombotic treatment of atrial fibrillation: New insights J.Y. Le Heuzey ⁎ Georges Pompidou Hospital, René Descartes University, Paris

a r t i c l e

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Keywords: Atrial fibrillation vitamin K antagonists Dabigatran Rivaroxaban Apixaban

a b s t r a c t The incidence and prevalence of atrial fibrillation are quickly increasing, mainly due to the ageing of the population. Atrial fibrillation is, to date, a problem of public health. Atrial fibrillation is associated to a five-fold risk of stroke, which may be identified by score risks, such as CHADS2 score. The classical antithrombotic treatment of atrial fibrillation is based on vitamin K antagonists. Trials made in the 90's have clearly shown that vitamin K antagonists were able to decrease stroke risk by about 60%. New oral anticoagulants are now available on the market to treat patients with atrial fibrillation. These drugs are Dabigatran which has demonstrated an interest in the RE-LY trial. Two doses may be prescribed, 110 mg bid and 150 mg bid. Anti Xa have also demonstrated an interest : Rivaroxaban in the ROCKET AF trial and Apixaban in the AVERROES (versus aspirin) and ARISTOTLE trials. In the future these drugs will have a major place in the armamentarium used to treat patients with atrial fibrillation. In all these trials a decrease in intra cranial haemorrhages has been demonstrated. In the everyday practice it will be necessary to be very cautious in patients with impaired renal function, as all these drugs are eliminated by kidneys. © 2012 Elsevier Ltd. All rights reserved.

Introduction The incidence and prevalence of atrial fibrillation are quickly increasing in western countries. This increase is mainly due to the ageing of the population. Many patients who were dying in the sixties or seventies, mainly due to massive myocardial infarctions, are now surviving but with sequelaes, i.e. heart failure and atrial fibrillation. These increasing incidence and prevalence are accompanied by an increase number of hospitalisations due to atrial fibrillation [1]. To date, atrial fibrillation is becoming a problem of public health with growing costs, mainly due to hospitalisations. Indeed costs of hospitalisations represent about half of the expenditure [2]. One of the major costs induced by atrial fibrillation is the management of stroke, main complication of atrial fibrillation. Stroke risk in atrial fibrillation patients Atrial fibrillation is associated to a five-fold risk of stroke. Atrial fibrillation is responsible for 15 to 20% of all strokes. In the studies made in the 90's (AFASAK, SPAF, BAATAF, CAFA, SPINAF) it has been observed, in the placebo groups, rates of stroke varying from 4.7 (CAFA) to 9.0% per year (SPAF). This stroke rate is directly related to the age of the patients. This risk is the same in different forms of atrial fibrillation : the risk of paroxysmal atrial fibrillation is not lower than the risk of permanent atrial fibrillation. Strokes due to atrial fibrillation are more severe ⁎ Hôpital Georges Pompidou, 20 rue Leblanc, 75015 Paris, France. Tel.: +33 1 56 09 37 01; fax: +33 1 56 09 30 47. E-mail address: [email protected]. 0049-3848/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2012.08.277

than strokes occurring in patients without atrial fibrillation. The risk of death is also higher in patients with atrial fibrillation as compared to patients without. Furthermore the risk of stroke recurrence in patients with atrial fibrillation is very high (20.3% in the placebo group of EAFT trial which was a secondary prevention trial). The risk of stroke may be clearly evaluated by score risks. The best known of these scores is CHADS2 taking into account the presence of congestive heart failure (1 point), hypertension (1 point), age higher than 75 (1 point), diabetes (1 point) and previous stroke (2 points). It can be clearly demonstrated that the mortality is also directly related to CHADS2 [4,5]. More recently CHAD2DS2-VASc (Table 1) score has been proposed [6]. This score takes into account vascular diseases like coronary artery disease. “Classical” antithrombotic treatment of atrial fibrillation with vitamin K antagonists Trials made in the 90's have clearly shown that vitamin K antagonists were able to decrease stroke risk by about 60% [3]. In these trials asprin is not ineffective but this effect is much lower, around 30%. The main difficulty of managing patients treated with vitamin K antagonists is the necessity to remain in the good INR range between 2 and 3. The efficacy window is narrow, the response may be unpredictable, it needs routine coagulation monitoring, vitamin K antagonists have slow onset and offset of action, it needs a frequent dose adjustment, there are numerous food-drug and drug-drug interactions. In clinical trials the rate of patients with a good TTR (Time To Range) is low, around 60% in the best cases. When the TTR is evaluated in real life the proportion is much lower. The recent guidelines from the European

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J.Y. Le Heuzey / Thrombosis Research 130 (2012) S59–S60 Table 1 Factors for establishing the risk of Stroke in the CHADS2 score and the CHAD2DS2-VASc score. The main difference is concerning vascular diseases taken into account in the CHAD2DS2-VASc. Risk Factor

Score

CHADS2 Congestive heart failure Hypertension Age ≥ 75 y Diabetes mellitus Stroke/TIA/thromboembolism Maximum score

1 1 1 1 2 6

CHA2DS2-VASc Congestive heart failure Hypertension Age ≥ 75 y Diabetes mellitus Stroke/TIA/thromboembolism Vascular disease Age 65–74 y Female Maximum score

1 1 2 1 2 1 1 1 9

When looking at the on treatment population it was possible to demonstrate a superiority. Like in RE-LY it has been possible to observe a significant decrease in intra cranial haemorrhage. There was also a slight increase in the number of gastro intestinal bleedings. Apixaban The development of Apixaban has been made with two trials, AVERROES versus aspirin and ARISTOTLE versus Warfarin. Apixaban is also an anti Xa drug, prescribed at the dose of 5 mg bid. In these two trials the dose of 2.5 was given to selected patients with renal failure. In AVERROES the mean CHADS2 score was 2.1. The trial has been stopped prematurely due to a clear demonstration of APIXABAN superiority. The rate of major bleedings was not different in the two groups. In ARISTOTLE the mean CHADS2 score was also 2.1 and it has been observed an interest of the drug with a 11% decrease in mortality, 21% decrease in the primary outcome which was, as in the other trials, stroke or systemic embolism and 31% decrease in major bleedings. Once again it has been demonstrated that the drug was able to decrease intra cranial haemorrhage as compared to Warfarin. In conclusion

Society of Cardiology in 2010 proposed to treat by an antithrombotic therapy all patients with atrial fibrillation except those at low risk, i.e. lone atrial fibrillation with an age lower than 65 years, or of course patients with contra indication to anticoagulation. The difficulty to manage vitamin K antagonists treatment in clinical practice and in real life implies that many researches have been made, in the previous years, on the development of new oral anticoagulants (NOACs). New oral anticoagulants The effects of these new drugs are based on their action on factor IIa and factor Xa. The thrombin inhibitors (anti IIa) which has been developed are Ximelagatran and Dabigatran. Ximelagatran has demonstrated a therapeutic interest but has been withdrawn from the market due to a liver toxicity. Dabigatran has demonstrated its therapeutic interest in the RE-LY trial [7]. For anti Xa, the drugs are Rivaroxaban studied in the ROCKET-AF trial [8] and Apixaban in 2 trials, AVERROES versus aspirin [9] and ARISTOTLE versus Warfarin [10]. A fifth drug is still in development, Edoxaban tested in ENGAGE AF TIMI 48 trial. Dabigatran The RE-LY trial was an open label trial comparing two doses of Dabigatran (110 mg bid and 150 mg bid) versus Warfarin. This trial shows a non inferiority for the 110 mg dose and a superiority for the 150 dose. The mean CHADS2 score was 2.1. The rate of bleeding was lower in the Dabigatran groups but gastro-intestinal major bleedings were more frequent. A very interesting point is the demonstration of the decreasing in intracranial bleeding as compared to Warfarin. The rate of myocardial infarction, in the first publication, was higher and this point has been discussed by many authors. In fact the difference is depending on the definition of myocardial infarction. The main side effect observed with Dabigatran is dyspepsia, seen in about 10% of patients. Rivaroxaban A comparable trial has been made with Rivaroxaban which is an anti Xa drug. The main difference is the design of the trial, which was a double blind. The trial compared Warfarin with INR target between 2 and 3 to 20 mg Rivaroxaban once a day. Some patients with a low creatinin clearance were receiving 15 mg. The mean CHADS2 score was higher than in the previous trial, i.e. 3.47. The result of the trial was a demonstration of a non inferiority in intention to treat.

It is clear than in the future these drugs will have a major place in the armamentarium used to treat patients with atrial fibrillation. It is possible to consider that all patients with atrial fibrillation could be candidate for these drugs, except those with contra indications to anticoagulants (haemorrhagic syndromes), patients with valvular atrial fibrillation (including prosthetic valves), patients with severe renal failure (including elderly patients : the cut-off point of 30 ml/mn for creatinin clearance measured by the Cockroft method is proposed), patients without any indication to anticoagulants (with a CHADS2 score equal to 0) and finally patients with very stable INR without any thromboembolic or haemorrhagic previous event, if they are not willing to change. Conflict of interest statement Consultant / Conferences / Advisory board : Boehringer - Ingelheim, Bayer, BMS/Pfizer, Daiichi - Sankyo. References [1] Charlemagne A, Blacher J, Cohen A, Collet JP, Dievart F, De Groote P, et al. Epidemiology of atrial fibrillation in France : extrapolation of international epidemiological data to France and analysis of french hospitalisation data. Arch Cardiovasc Dis 2011;104:115-24. [2] Le Heuzey JY, Paziaud O, Piot O, Ait Said M, Copie X, Lavergne T, et al. Cost Of Care distribution in Atrial Fibrillation patients : the COCAF study. Am Heart J 2004;147: 121-6. [3] Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131:492-501. [4] Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864-70. [5] Friberg L, Hammar N, Pettersson H, Rosenqvist M. Increased mortality in paroxysmal atrial fibrillation: report from the Stockholm Cohort-Study of Atrial Fibrillation (SCAF). Eur Heart J 2007;28:2346-53. [6] Camm AJ, Kirchhof P, Schotten U, Savelieva I, Ernst S, et al. Lip Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369-429. [7] Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus Warfarin in patients with atrial fibrillation. N Engl J Med 2009;17:1139-51. [8] Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus Warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91. [9] Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, et al. AVERROES committees and investigators. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17. [10] Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. ARISTOTLE committees and investigators Apixaban versus Warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.