Investigation on Dabigatran Etexilate and Worsening of Renal Function in Patients with Atrial fibrillation: The IDEA Study
- 64 Downloads
Background and Objectives
Warfarin-related nephropathy is an unexplained acute kidney injury, and may occur in patients with supratherapeutic INR, in the absence of overt bleeding. Similar findings have been observed in rats treated with dabigatran etexilate. We conducted a prospective study in dabigatran etexilate-treated patients to assess the incidence of dabigatran-related nephropathy and to investigate the possible correlation between dabigatran plasma concentration (DPC) and worsening renal function.
One hundred and seven patients treated long term with dabigatran etexilate for non-valvular atrial fibrillation (NVAF) were followed up for 90 days. DPC, serum creatinine (SCr) and serum cystatin C were prospectively measured. Ninety five patients had complete follow-up data and were evaluable for primary endpoint.
Eleven patients had supratherapeutic DPC, defined as DPC higher than 200 ng/ml at study enrolment, but at the end of follow-up no patient showed a persistent increase in SCr. No patients experienced acute kidney injury.
Our study shows that no persistent renal detrimental effect is associated with dabigatran treatment. An increase in SCr during dabigatran treatment is reversible and it seems to be unrelated to dabigatran itself.
We are grateful to Dr. Maria Cristina Straface and Giuseppina Caiazzo for laboratory measurements, and to the nurses of the medical ward “Tulipano Rosso” of Vimercate Hospital, for harvesting blood samples.
CC, MM, HPF and MC drafted the design of the trial and the planning of the analyses. PB, GM and AO performed the statistical analyses. PT and MC performed the laboratory analysis. All the other authors enrolled patients and led the clinical follow-up. CC, MM and MC wrote the first draft of the manuscript, and all the authors participated in subsequent revisions and approved the final version of the manuscript.
Compliance with Ethical Standards
This research did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Conflict of interest
Dr. Mauro Molteni has received consultancy, lectures and research fees from Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Portola and Sanofi. Dr. Matteo Crippa has no conflicts of interest to disclose. Dr. Annalisa Orenti has no conflicts of interest to disclose. Dr. Polo Friz has received personal fees for collaborations as a medical writer, consultant, sponsored conferences and lectures by Sanofi, Bayer, Daiichi Sankyo, Pfizer, Boehringer Ingelheim, Health and Life, Clinical Forum, Xcape Srl, McCann Complete Medical Srl, IMSHealth London. Dr. Anna Menghini has no conflicts of interest to disclose. Dr. Pierluigi Tramacere has no conflicts of interest to disclose. Dr. Giuseppe Marano has no conflicts of interest to disclose. Dr. Patrizia Boracchi has no conflicts of interest to disclose. Dr. Claudio Cimminiello has received consultancy/lectures fees from Bayer, BMS/Pfizer, Boehringer Ingelheim, Sanofi, and MSD.
The local Ethics Committee approved the study.
All patients provided written informed consent.
- 2.Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials. Lancet. 2014;383:955–62.CrossRefGoogle Scholar
- 17.Ryan M, Ware K, Qamri Z, Satoskar A, Wu H, Nadasdy G, Rovin B, Hebert L, Nadasdy T, Brodsky SV. Warfarin-related nephropathy is the tip of the iceberg: direct thrombin inhibitor dabigatran induces glomerular hemorrhage with acute kidney injury in rats. Nephrol Dial Transpl. 2014;29:2228–34.CrossRefGoogle Scholar
- 21.Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P, Association European Heart Rhythm. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15:625–51.CrossRefGoogle Scholar
- 24.Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol. 2011;57:173–80.CrossRefGoogle Scholar
- 27.Brodsky SV, Mhaskar NS, Thiruveedi S, Dhingra R, Reuben SC, Calomeni E, Ivanov I, Satoskar A, Hemminger J, Nadasdy G, Hebert L, Rovin B, Nadasdy T. Acute kidney injury aggravated by treatment initiation with apixaban: another twist of anticoagulant-related nephropathy. Kidney Res Clin Pract. 2017;36:387–92.CrossRefGoogle Scholar
- 28.Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L, RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.CrossRefGoogle Scholar
- 29.Böhm M, Ezekowitz MD, Connolly SJ, Eikelboom JW, Hohnloser SH, Reilly PA, Schumacher H, Brueckmann M, Schirmer SH, Kratz MT, Yusuf S, Diener HC, Hijazi Z, Wallentin L. Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY trial. J Am Coll Cardiol. 2015;65:2481–93.CrossRefGoogle Scholar
- 32.Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J, Yang S, Alings M, Kaatz S, Hohnloser SH, Diener HC, Franzosi MG, Huber K, Reilly P, Varrone J, Yusuf S. 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 anti-coagulant therapy (RE-LY) trial. Circulation. 2011;123:2363–72.CrossRefGoogle Scholar
- 34.Pradaxa. Dabigatran etexilate: summary of the European public assessment report. https://www.ema.europa.eu/en/medicines/human/EPAR/pradaxa. Accessed 24 Jan 2019.