New antithrombotic drugs for atrial fibrillation: caution is needed – Authors' reply

Abstract

We thank Sarah Bell and colleagues for reinforcing the point that approval processes should be optimised, in terms of delay, without decreasing the rigour of these processes. We are aware of several recently published cases emphasising that prescription of dabigatran could be deleterious, particularly in elderly patients with poor renal function and low bodyweight.1Legrand M Mateo J Aribaud A et al.The use of dabigatran in elderly patients.Arch Intern Med. 2011; 171: 1285-1286Crossref PubMed Scopus (183) Google Scholar Guideline developers should consider exclusion criteria as well as the characteristics of patients enrolled in randomised controlled trials. Bell and colleagues legitimately underline that patients with a calculated creatinine clearance lower than 30 mL/min were excluded from the RE-LY trial, and that the study recruited very few patients older than 80 years.2Connolly SJ Ezekowitz MD Yusuf S et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8588) Google Scholar We would add that this was the case for all trials of new antithrombotic drugs in atrial fibrillation,2Connolly SJ Ezekowitz MD Yusuf S et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8588) Google Scholar, 3Connolly SJ Eikelboom J Joyner C et al.Apixaban in patients with atrial fibrillation.N Engl J Med. 2011; 364: 806-817Crossref PubMed Scopus (1986) Google Scholar, 4Patel MR Mahaffey KW Garg J et al.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (6888) Google Scholar and that additionally, in RE-LY, only 0·02% had a bodyweight less than 50 kg,2Connolly SJ Ezekowitz MD Yusuf S et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8588) Google Scholar whereas in other trials, a reduced dose of antithrombotic drugs was considered when the creatinine clearance was between 30 and 49 mL/min,4Patel MR Mahaffey KW Garg J et al.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (6888) Google Scholar as well as for patients who met two of the following criteria: age 80 years or older, bodyweight 60 kg or less, or a serum creatinine concentration of 133 μmol/L or higher.3Connolly SJ Eikelboom J Joyner C et al.Apixaban in patients with atrial fibrillation.N Engl J Med. 2011; 364: 806-817Crossref PubMed Scopus (1986) Google Scholar Taken together, there are also substantial data to support the need for special caution or even contraindication for their use in elderly patients, those with a low bodyweight, and, more importantly, in those with renal failure, even it is mild. The effect of each of these factors has been shown.5Eikelboom JW Wallentin L Connolly SJ et al.Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.Circulation. 2011; 123: 2363-2372Crossref PubMed Scopus (962) Google Scholar We totally agree that observational studies, based on the “real life” use of dabigatran, can add substantial complementary information about its adverse effects, and should therefore be started early. However, such registries would only be possible if the prescription of dabigatran is possible. Finally, we have to admit that any antithrombotic drugs have been and will be responsible for haemorrhagic complications, irrespective of adherence to the prescription guidelines. To the best of our knowledge, the delay since the publication of the first results of the RE-LY trial was not related to the need for a further assessment of the drug, particularly safety and benefit/risk concerns. The cause of the delay was rather negotiation of the price of the drug, and it seems likely that this delay resulted in a loss of chance for a substantial number of patients. EM has no conflicts of interest. LF has served as a consultant for Bayer, Medtronic, and Sanofi-Aventis, and has received funding for conference travel and educational symposia from Boehringer Ingelheim, Bayer, Medtronic, and Sanofi-Aventis. J-YLH has served as a consultant for Boehringer Ingelheim, Bayer, BMS/Pfizer, and Daiichi-Sankyo. New antithrombotic drugs for atrial fibrillation: caution is neededThe Correspondence letter by Eloi Marijon and others (Aug 20, p 662)1 chastises the drug regulation authorities in Europe for the slowness of their assessment processes in the approval of new antithrombotic drugs for use in atrial fibrillation. They claim that the ROCKET-AF2 and RE-LY3 studies have shown these new drugs to be superior to vitamin K antagonists. Marijon and colleagues then go on to extrapolate the claimed advantages to the European population with atrial fibrillation and calculate the number of strokes that might have been saved by earlier introduction of these drugs. Full-Text PDF