International Journal of Cardiology 188 (2015) 52–53
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Rationale and design of the efficacy of rivaroxaban on renal function in patients with non-valvular atrial fibrillation and chronic kidney disease: The X-NOAC study Makoto Suzuki a,⁎, Seiji Fukamizu b, Jun-ichi Oyama c, Akira Mizukami d, Akihiko Matsumura a, Yuji Hashimoto a, Koichi Node e a
Department of Cardiology, Kameda Medical Center, Chiba, Japan Department of Cardiology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan c Department of Advanced Cardiology, Saga University, Saga, Japan d Department of Cardiology, Awa Regional Medical Center, Chiba, Japan e Department of Cardiovascular Medicine, Saga University, Saga, Japan b
a r t i c l e
i n f o
Article history: Received 3 April 2015 Accepted 5 April 2015 Available online 7 April 2015 Keywords: Atrial fibrillation Chronic kidney disease Non-Vitamin K antagonist oral anticoagulant Oral factor Xa inhibitor Warfarin
Arteriosclerosis and in consequence chronic kidney disease are becoming increasingly prevalent. As it is expected that more patients with atrial fibrillation complicated by arteriosclerosis and chronic renal disease will seek medical treatment in the future, treatment strategies for this population are needed. Arteriosclerosis and chronic kidney disease share lifestyle-related disorders as causal factors, and both are consequences of chronic inflammation, a condition in which macrophage infiltration and endothelial dysfunction are prominent features. In addition to the standard therapy for atrial fibrillation (i.e., warfarin), rivaroxaban, a non-vitamin K oral anticoagulant that selectively inhibits Factor Xa, has attracted much attention due to its efficacy and convenience [1]. Thrombin, a target of rivaroxaban, plays a central role in thrombus formation. Molecular biology studies have shown that it also influences endothelial cell functions and inflammatory reactions [2]. Therefore, anticoagulant therapy is expected not only to inhibit thrombus formation by controlling the coagulation cascade, but also to exert inhibitory effects on arteriosclerosis and chronic renal disease, in both of which chronic inflammation and endothelial dysfunction ⁎ Corresponding author at: Department of Cardiology, Kameda Medical Center, 929 Higashi-chou, Kamogawa-city, Chiba 296-8602, Japan. E-mail address: [email protected] (M. Suzuki).
http://dx.doi.org/10.1016/j.ijcard.2015.04.037 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
play key roles. This has been supported by a report that when rivaroxaban or an alternative inhibitor of thrombus formation was administered to apolipoprotein E-deficient mice, the onset of inflammatory mediators was suppressed and plaques were stabilized [3]. Several clinical studies have provided evidence that rivaroxaban has anti-atherosclerotic activity. In the ATLAS ACS 2-TIMI 51 trial (Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome ACS 2-thrombolysis in myocardial infarction 51), in which recurrence of atherothrombotic events was evaluated in patients with acute coronary syndrome treated with rivaroxaban, it was demonstrated that post-ACS cardiovascular death and myocardial infarction were significantly reduced by rivaroxaban combined with anti-platelet drugs [4]. Additionally, a meta-analysis of large-scale clinical studies of non-vitamin K antagonist oral anticoagulants has confirmed the protective effects of rivaroxaban against coronary events [5]. However, the efficacy of rivaroxaban in relation to renal function has not been evaluated. We are conducting a randomized controlled clinical trial in Japanese hospitals to compare the effects of rivaroxaban and warfarin on renal function in patients with non-valvular atrial fibrillation and chronic kidney disease. The X-NOAC study is the first multicenter study of this type in Japan. After giving informed consent, non-valvular atrial fibrillation patients with estimated glomerular filtration rates N 30 and b 89 mL/ min/1.73 m2 were randomly allocated to either warfarin or rivaroxaban. The allocation method was based on central registration, and eligible patients were assigned to the therapies in a 1:1 ratio via web site access. The randomization factors were age (b 75 years or ≥75 years), gender, anticoagulation pretreatment (none or warfarin), and the CHADS2 score (b2 or ≥ 2). The total sample size is 160 patients. The rationale for setting this size was based on the FRET study [6], in which treatment with a statin for three months was found to improve endothelial dysfunction and reduce urinary albumin excretion by 18.5%. With an estimated difference in percentage change between the rivaroxaban and warfarin groups of 15–25%, it was estimated that the study would require more than 75 patients, and that a sample size of 160 per group would allow a power of 99.9% to detect an incidence rate ratio of 0.90, with a two-sided significance level of 0.05.
M. Suzuki et al. / International Journal of Cardiology 188 (2015) 52–53
53
Fig. 1. Flow chart of the study timeline. o.d., once daily.
In the warfarin group, the dose was adjusted such that PT-INR would become 2.0–3.0 in patients aged b70 years or 1.6–2.6 in those aged ≥70 years. In the rivaroxaban group, 15 mg rivaroxaban was given orally once daily after a meal. In addition, in cases where the creatinine clearance was 30–49 mL/min, 10 mg was given orally once daily after a meal. The design of the study is shown in Fig. 1. When warfarin was switched to rivaroxaban, treatment with rivaroxaban was initiated when the PT-INR result on warfarin was at the lower limit of the appropriate range (2.0 for those aged b70 years, 1.6 for those aged ≥70 years). At registration and after three months, markers of renal function, endothelial cell function, blood coagulation/fibrinolysis, and inflammation were measured together with other parameters. The primary endpoint is the change in urinary albumin excretion, and the secondary endpoints are changes in endothelial cell function, blood coagulation/fibrinolysis, inflammation, and renal function three months after registration. The X-NOAC study is the first multicenter trial to evaluate the clinical effectiveness of rivaroxaban in non-valvular atrial fibrillation patients with chronic kidney disease in Japan. The results will address the treatment strategy for non-valvular atrial fibrillation patients with moderate chronic kidney disease. The study was funded by Bayer Yakuhin, Ltd (Osaka, Japan). Conflict of interest Dr. Suzuki received lecturer fees from Otsuka Pharmaceutical Co., Ltd (Tokyo, Japan), Bayer Yakuhin, Ltd. (Osaka, Japan), Nippon Boehringer
Ingelheim Co., Ltd. (Tokyo, Japan), Medtronic Japan Co., Ltd. (Tokyo, Japan), Boston Scientific Japan Co., Ltd. (Tokyo, Japan), and Fukuda Denshi Co., Ltd. (Tokyo, Japan).
References [1] M.R. Patel, Kenneth W. Mahaffey, J. Garg, G. Pan, D.E. Singer, W. Hacke, G. Breithardt, J.L. Halperin, G.J. Hankey, J.P. Piccini, R.C. Becker, C.C. Nessel, J.F. Paolini, S.D. Berkowitz, the ROCKET AF Steering Committee, for the ROCKET AF Investigators, et al., Rivaroxaban versus warfarin in non-valvular atrial fibrillation, N. Engl. J. Med. 365 (2011) 883–891. [2] M. Eto, C. Barandiér, L. Rathgeb, T. Kozai, H. Joch, Z. Yang, T.F. Lüscher, Thrombin suppresses endothelial nitric oxide synthase and up-regulates endothelin-converting enzyme-1 expression by distinct pathways. Role of Rho/ROCK and mitogenactivated protein kinase, Circ. Res. 89 (2001) 583–590. [3] Q. Zhou, F. Bea, M. Preusch, H. Wang, B. Isermann, K. Shahzad, H.A. Katus, E. Blessing, Evaluation of plaque stability of advanced atherosclerotic lesions in apo E-deficient mice after treatment with the oral factor Xa inhibitor rivaroxaban, Mediators Inflamm. 2011 (2011) 9. [4] J.L. Mega, E. Braunwald, S.D. Wiviott, J.-P. Bassand, D.L. Bhatt, C. Bode, P. Burton, M. Cohen, N. Cook-Bruns, K.A.A. Fox, S. Goto, S.A. Murphy, A.N. Plotnikov, D. Schneider, X. Sun, for the ATLAS ACS 2–TIMI 51 Investigators, et al., Rivaroxaban in patients with a recent acute coronary syndrome, N. Engl. J. Med. 366 (2011) 9–19. [5] K.H. Mak, Coronary and mortality risk of novel oral antithrombotic agents: a metaanalysis of large randomized trials, BMJ Open 2 (2012) e001592. [6] T. Inoue, H. Ikeda, T. Nakamura, S. Abe, I. Taguchi, M. Kikuchi, S. Toyoda, M. Miyazono, T. Kishi, T. Sanai, K. Node, Potential benefit of statin therapy for dyslipidemia with chronic kidney disease: Fluvastatin Renal Evaluation Trial (FRET), Intern. Med. 50 (2011) 1273–1278.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Rationale and design of the efficacy of rivaroxaban on renal function in patients with non-valvular atrial fibrillation and chronic kidney disease: The X-NOAC study Makoto Suzuki a,⁎, Seiji Fukamizu b, Jun-ichi Oyama c, Akira Mizukami d, Akihiko Matsumura a, Yuji Hashimoto a, Koichi Node e a
Department of Cardiology, Kameda Medical Center, Chiba, Japan Department of Cardiology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan c Department of Advanced Cardiology, Saga University, Saga, Japan d Department of Cardiology, Awa Regional Medical Center, Chiba, Japan e Department of Cardiovascular Medicine, Saga University, Saga, Japan b
a r t i c l e
i n f o
Article history: Received 3 April 2015 Accepted 5 April 2015 Available online 7 April 2015 Keywords: Atrial fibrillation Chronic kidney disease Non-Vitamin K antagonist oral anticoagulant Oral factor Xa inhibitor Warfarin
Arteriosclerosis and in consequence chronic kidney disease are becoming increasingly prevalent. As it is expected that more patients with atrial fibrillation complicated by arteriosclerosis and chronic renal disease will seek medical treatment in the future, treatment strategies for this population are needed. Arteriosclerosis and chronic kidney disease share lifestyle-related disorders as causal factors, and both are consequences of chronic inflammation, a condition in which macrophage infiltration and endothelial dysfunction are prominent features. In addition to the standard therapy for atrial fibrillation (i.e., warfarin), rivaroxaban, a non-vitamin K oral anticoagulant that selectively inhibits Factor Xa, has attracted much attention due to its efficacy and convenience [1]. Thrombin, a target of rivaroxaban, plays a central role in thrombus formation. Molecular biology studies have shown that it also influences endothelial cell functions and inflammatory reactions [2]. Therefore, anticoagulant therapy is expected not only to inhibit thrombus formation by controlling the coagulation cascade, but also to exert inhibitory effects on arteriosclerosis and chronic renal disease, in both of which chronic inflammation and endothelial dysfunction ⁎ Corresponding author at: Department of Cardiology, Kameda Medical Center, 929 Higashi-chou, Kamogawa-city, Chiba 296-8602, Japan. E-mail address: [email protected] (M. Suzuki).
http://dx.doi.org/10.1016/j.ijcard.2015.04.037 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
play key roles. This has been supported by a report that when rivaroxaban or an alternative inhibitor of thrombus formation was administered to apolipoprotein E-deficient mice, the onset of inflammatory mediators was suppressed and plaques were stabilized [3]. Several clinical studies have provided evidence that rivaroxaban has anti-atherosclerotic activity. In the ATLAS ACS 2-TIMI 51 trial (Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome ACS 2-thrombolysis in myocardial infarction 51), in which recurrence of atherothrombotic events was evaluated in patients with acute coronary syndrome treated with rivaroxaban, it was demonstrated that post-ACS cardiovascular death and myocardial infarction were significantly reduced by rivaroxaban combined with anti-platelet drugs [4]. Additionally, a meta-analysis of large-scale clinical studies of non-vitamin K antagonist oral anticoagulants has confirmed the protective effects of rivaroxaban against coronary events [5]. However, the efficacy of rivaroxaban in relation to renal function has not been evaluated. We are conducting a randomized controlled clinical trial in Japanese hospitals to compare the effects of rivaroxaban and warfarin on renal function in patients with non-valvular atrial fibrillation and chronic kidney disease. The X-NOAC study is the first multicenter study of this type in Japan. After giving informed consent, non-valvular atrial fibrillation patients with estimated glomerular filtration rates N 30 and b 89 mL/ min/1.73 m2 were randomly allocated to either warfarin or rivaroxaban. The allocation method was based on central registration, and eligible patients were assigned to the therapies in a 1:1 ratio via web site access. The randomization factors were age (b 75 years or ≥75 years), gender, anticoagulation pretreatment (none or warfarin), and the CHADS2 score (b2 or ≥ 2). The total sample size is 160 patients. The rationale for setting this size was based on the FRET study [6], in which treatment with a statin for three months was found to improve endothelial dysfunction and reduce urinary albumin excretion by 18.5%. With an estimated difference in percentage change between the rivaroxaban and warfarin groups of 15–25%, it was estimated that the study would require more than 75 patients, and that a sample size of 160 per group would allow a power of 99.9% to detect an incidence rate ratio of 0.90, with a two-sided significance level of 0.05.
M. Suzuki et al. / International Journal of Cardiology 188 (2015) 52–53
53
Fig. 1. Flow chart of the study timeline. o.d., once daily.
In the warfarin group, the dose was adjusted such that PT-INR would become 2.0–3.0 in patients aged b70 years or 1.6–2.6 in those aged ≥70 years. In the rivaroxaban group, 15 mg rivaroxaban was given orally once daily after a meal. In addition, in cases where the creatinine clearance was 30–49 mL/min, 10 mg was given orally once daily after a meal. The design of the study is shown in Fig. 1. When warfarin was switched to rivaroxaban, treatment with rivaroxaban was initiated when the PT-INR result on warfarin was at the lower limit of the appropriate range (2.0 for those aged b70 years, 1.6 for those aged ≥70 years). At registration and after three months, markers of renal function, endothelial cell function, blood coagulation/fibrinolysis, and inflammation were measured together with other parameters. The primary endpoint is the change in urinary albumin excretion, and the secondary endpoints are changes in endothelial cell function, blood coagulation/fibrinolysis, inflammation, and renal function three months after registration. The X-NOAC study is the first multicenter trial to evaluate the clinical effectiveness of rivaroxaban in non-valvular atrial fibrillation patients with chronic kidney disease in Japan. The results will address the treatment strategy for non-valvular atrial fibrillation patients with moderate chronic kidney disease. The study was funded by Bayer Yakuhin, Ltd (Osaka, Japan). Conflict of interest Dr. Suzuki received lecturer fees from Otsuka Pharmaceutical Co., Ltd (Tokyo, Japan), Bayer Yakuhin, Ltd. (Osaka, Japan), Nippon Boehringer
Ingelheim Co., Ltd. (Tokyo, Japan), Medtronic Japan Co., Ltd. (Tokyo, Japan), Boston Scientific Japan Co., Ltd. (Tokyo, Japan), and Fukuda Denshi Co., Ltd. (Tokyo, Japan).
References [1] M.R. Patel, Kenneth W. Mahaffey, J. Garg, G. Pan, D.E. Singer, W. Hacke, G. Breithardt, J.L. Halperin, G.J. Hankey, J.P. Piccini, R.C. Becker, C.C. Nessel, J.F. Paolini, S.D. Berkowitz, the ROCKET AF Steering Committee, for the ROCKET AF Investigators, et al., Rivaroxaban versus warfarin in non-valvular atrial fibrillation, N. Engl. J. Med. 365 (2011) 883–891. [2] M. Eto, C. Barandiér, L. Rathgeb, T. Kozai, H. Joch, Z. Yang, T.F. Lüscher, Thrombin suppresses endothelial nitric oxide synthase and up-regulates endothelin-converting enzyme-1 expression by distinct pathways. Role of Rho/ROCK and mitogenactivated protein kinase, Circ. Res. 89 (2001) 583–590. [3] Q. Zhou, F. Bea, M. Preusch, H. Wang, B. Isermann, K. Shahzad, H.A. Katus, E. Blessing, Evaluation of plaque stability of advanced atherosclerotic lesions in apo E-deficient mice after treatment with the oral factor Xa inhibitor rivaroxaban, Mediators Inflamm. 2011 (2011) 9. [4] J.L. Mega, E. Braunwald, S.D. Wiviott, J.-P. Bassand, D.L. Bhatt, C. Bode, P. Burton, M. Cohen, N. Cook-Bruns, K.A.A. Fox, S. Goto, S.A. Murphy, A.N. Plotnikov, D. Schneider, X. Sun, for the ATLAS ACS 2–TIMI 51 Investigators, et al., Rivaroxaban in patients with a recent acute coronary syndrome, N. Engl. J. Med. 366 (2011) 9–19. [5] K.H. Mak, Coronary and mortality risk of novel oral antithrombotic agents: a metaanalysis of large randomized trials, BMJ Open 2 (2012) e001592. [6] T. Inoue, H. Ikeda, T. Nakamura, S. Abe, I. Taguchi, M. Kikuchi, S. Toyoda, M. Miyazono, T. Kishi, T. Sanai, K. Node, Potential benefit of statin therapy for dyslipidemia with chronic kidney disease: Fluvastatin Renal Evaluation Trial (FRET), Intern. Med. 50 (2011) 1273–1278.
