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Randomized Controlled Trial
. 2018 Dec 11;320(22):2325-2334.
doi: 10.1001/jama.2018.17749.

Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial

J-DAVID Investigators; Tetsuo Shoji  1   2 , Masaaki Inaba  2   3 , Masafumi Fukagawa  4 , Ryoichi Ando  5 , Masanori Emoto  3 , Hisako Fujii  6 , Akira Fujimori  7 , Mitsuru Fukui  8 , Hiroki Hase  9 , Tetsuya Hashimoto  10 , Hideki Hirakata  11 , Hirokazu Honda  12 , Tatsuo Hosoya  13 , Yuji Ikari  14 , Daijo Inaguma  15 , Toru Inoue  16 , Yoshitaka Isaka  17 , Kunitoshi Iseki  18 , Eiji Ishimura  19 , Noritomo Itami  20 , Chiharu Ito  21 , Toshitaka Kakuta  22 , Toru Kawai  23 , Hideki Kawanishi  24 , Shuzo Kobayashi  25 , Junko Kumagai  26 , Kiyoshi Maekawa  27 , Ikuto Masakane  28 , Jun Minakuchi  29 , Koji Mitsuiki  30 , Takashi Mizuguchi  31 , Satoshi Morimoto  32 , Toyoaki Murohara  33 , Tatsuya Nakatani  34 , Shigeo Negi  35 , Shinichi Nishi  36 , Mitsushige Nishikawa  37 , Tetsuya Ogawa  38 , Kazumichi Ohta  39 , Takayasu Ohtake  25 , Mikio Okamura  40 , Senji Okuno  41 , Takashi Shigematsu  35 , Toshitsugu Sugimoto  42 , Masashi Suzuki  43 , Hideki Tahara  44 , Yoshiaki Takemoto  34 , Kenji Tanaka  45 , Yoshihiro Tominaga  46 , Yoshiharu Tsubakihara  47 , Yoshihiro Tsujimoto  48 , Kazuhiko Tsuruya  49 , Shinichiro Ueda  50 , Yuzo Watanabe  51 , Kunihiro Yamagata  52 , Tomoyuki Yamakawa  53 , Shozo Yano  54 , Keitaro Yokoyama  55 , Noriaki Yorioka  56 , Minoru Yoshiyama  57 , Yoshiki Nishizawa  58
Affiliations
Randomized Controlled Trial

Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial

J-DAVID Investigators et al. JAMA. .

Abstract

Importance: Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels.

Objective: To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis.

Design, setting, and participants: Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015.

Interventions: Treatment with 0.5 μg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481).

Main outcomes and measures: The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death.

Results: Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, -1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52]; P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events.

Conclusions and relevance: Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these.

Trial registration: UMIN-CTR Identifier: UMIN000001194.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Shoji reports grants from The Kidney Foundation, Japan, during the conduct of the study and personal fees from Chugai Pharmaceutical, personal fees from Kyowa Hakko Kirin, personal fees from Kissei Pharmaceutical, grants and personal fees from Bayer and Ono Pharmaceutical, and personal fees from Torii Pharmaceutical outside the submitted work. Dr Inaba reports receiving grants from The Kidney Foundation, Japan, during the conduct of the study and personal fees from Chugai Pharmaceutical, grants and personal fees from Kyowa Hakko Kirin, personal fees from Teijin, personal fees from Taisho Tomiyama, personal fees from Kissei Pharmaceutical, personal fees from Fuso, personal fees from Bayer, grants and personal fees from Astellas, personal fees from Torii, and personal fees from Ono Pharmaceutical outside the submitted work. Dr Fukagawa reports grants and personal fees from Kyowa Hakko Kirin, personal fees from Chugai Pharmaceutical, grants and personal fees from Ono Pharmaceutical, grants and personal fees from Bayer Japan, personal fees from Torii Pharmaceutical, and personal fees from Kissei Pharmaceutical outside the submitted work. Dr Ando reports personal fees from Chugai Pharmaceutical, personal fees from Kyowa Hakko Kirin, personal fees from Kissei Pharmaceutical, personal fees from Torii Pharmaceutical, personal fees from Bayer Yakuhin, and personal fees from Astellas Pharmaceutical outside the submitted work. Dr Hase reports grants from Chugai Pharmaceutical, personal fees from Chugai Pharmaceutical, grants and personal fees from Kyowa Hakko Kirin, and personal fees from Pfizer Japan Inc outside the submitted work. Dr Hashimoto reports personal fees and grants from Kyowa Hakko Kirin, personal fees from Kissei Pharmaceutical, grants from Bayer Yakuhin, and personal fees from Ono Pharmaceutical outside the submitted work. Dr Hirakata reports personal fees from Chugai Pharmaceutical, personal fees from Kyowa Hakko Kirin, personal fees from Fuso Pharmaceutical, personal fees from Bayer Japan, personal fees from Torii Pharmaceutical, and personal fees from Ono Pharmaceutical outside the submitted work. Dr Honda reports personal fees from Kissei Pharmaceutical and Torii Pharmaceutical outside the submitted work. Dr Hosoya reports grants and personal fees from Sanwa Kagaku Kenkyusho, grants and personal fees from Teijin Pharmaceutical, grants and personal fees from Fuji Yakuhin, grants and personal fees from Chugai Pharmaceutical, personal fees from Pfizer, grants from Baxter, grants from Yayoikai, personal fees from Mochida Pharmaceutical, personal fees from Nippon Chemiphar, and grants from Torii Pharmaceutical outside the submitted work. Dr Isaka reports grants and personal fees from Chugai, grants and personal fees from Kyowa Hakko Kirin, and personal fees from Kissei Pharmaceutical outside the submitted work. Dr Kobayashi reports personal and consultant fees from Chugai Pharmaceutical, personal and consultant fees from Kyowa Hakko Kirin, personal fees from Taisho Toyama, personal fees from Kissei Pharmaceutical, personal fees from Bayer, personal fees from Astellas, consultant fees from Ono Pharmaceutical, and consultant fees from Kaneka outside the submitted work. Dr Masakane reports personal fees from Chugai Pharmaceutical and personal fees from Kyowa Hakko Kirin outside the submitted work. Dr Mitsuiki reports personal fees from Kyowa Hakko Kirin, personal fees from Kissei Pharmaceutical, personal fees from Bayer Pharmaceutical, personal fees from Torii Pharmaceuticals, and personal fees from Chugai Pharmaceuticals outside the submitted work. Dr Murohara reports grants from Pfizer, grants from Daiichi-Sankyo, grants from Mitsubishi-Tanabe, grants from Astellas Pharmaceutical, grants from Bayer Yakuhin, grants from Takeda, grants from Boehlinger Ingelheim Japan, personal fees from Daiichi-Sankyo, personal fees from Mitsubishi-Tanabe, personal fees from Boehringer Ingelheim Japan, personal fees from Bayer Yakuhin, and personal fees from Merck-Sharpe-Dohme outside the submitted work. Dr Sugimoto reports grants and personal fees from Chugai Pharmaceutical, grants and personal fees from Taisho Toyama Pharmaceutical, grants from Astellas Pharmaceutical, and grants from Ono Pharmaceutical outside the submitted work. Dr Tahara reports personal fees from Chugai Pharmaceutical, personal fees from Kyowa Hakko Kirin, grants from Teijin, personal fees from Kissei Pharmaceutical, grants and personal fees from Bayer, personal fees from Astellas, and personal fees from Ono Pharmaceutical outside the submitted work. Dr Tsubakihara reports personal fees from Chugai Pharmaceutical and personal fees from Kyowa Hakko Kirin outside the submitted work. Dr Tsuruya reports grants and personal fees from Chugai Pharmaceutical, grants and personal fees from Kyowa Hakko Kirin, grants and personal fees from Kissei Pharmaceutical, grants from Teijin, personal fees from Bayer, grants and personal fees from Astellas Pharmaceutical, grants and personal fees from Torii Pharmaceutical, and grants and personal fees from Ono Pharmaceutical outside the submitted work. Dr Ueda reports grants from Bristol-Myers Squibb, grants from Bayer, personal fees from Chugai Pharmaceutical, personal fees from Boehringer Ingelheim, personal fees from Merck-Sharpe-Dohme, grants from Kowa, grants from Takeda Pharmaceutical, and grants from Pfizer outside the submitted work. Dr Yamagata reports personal fees from Chugai Pharmaceutical, personal fees from Dainihon Sumitomo, personal fees from Daiichi Sankyo, personal fees from Kyowa Hakko Kirin, personal fees from Asteras, personal fees from Pfizer, personal fees from Takeda, personal fees from Asahi Kasei Pharmaceutical, personal fees from Japan Medtronic, personal fees from Mochida, and personal fees from Kowa outside the submitted work. Dr Yamakawa reports nonfinancial support from Torii Pharmaceutical, Chugai Pharmaceutical, Otsuka Pharmaceutical, Kissei Pharmaceutical, and Kyowa Hakko Kirin outside the submitted work. Dr Nishizawa reports grants from The Kidney Foundation, Japan, during the conduct of the study and personal fees from Chugai Pharmaceutical, personal fees from Ono Pharmaceutical, personal fees from Astella, and personal fees from Kyowa Hakko Kirin outside the submitted work. Drs Emoto, Fujii, Fujimori, Fukui, Ikari, Inaguma, Inoue, Iseki, Ishimura, Itami, Ito, Kakuta, Kawai, Kawanishi, Kumagai, Maekawa, Minakuchi, Mizuguchi, Morimoto, Negi, Nishi, Nishikawa, Ogawa, Ohta, Ohtake, Okamura, Okuno, Shigematsu, Suzuki, Takemoto, Tanaka, Nakatani, Tominaga, Tsujimoto, Watanabe, Yano, Yokoyama, Yorioka, and Yoshiyama report nothing to disclose.

Figures

Figure 1.
Figure 1.. Flow of the Participants in a Study of the Effect of Oral Alfacalcidol in Patients Receiving Hemodialysis
The participants who were lost to follow-up were censored on the last day of follow-up. No imputation was performed. The numbers analyzed are the same for the full analysis set, the per-protocol set, and the modified per-protocol set. These analysis sets differ only in the method of censoring of participants who discontinued their assigned treatment. Such participants were censored at the time of discontinuation in the per-protocol set, whereas participants in the intervention group who switched from oral alfacalcidol to another vitamin D receptor activator (VDRA) were not censored in the modified per-protocol set.
Figure 2.
Figure 2.. Primary and Secondary Outcomes
A, For the primary outcome, the median (interquartile range [IQR]) observation time was 4.0 (2.6-4.0) years for the intervention group and 4.0 (3.5-4.0) years for the control group. B, For the secondary outcome, the median (IQR) observation time was 4.0 (4.0-4.0) years for the intervention group and 4.00 (4.0-4.0) years for the control group. The primary outcome (A) included fatal and nonfatal cardiovascular events, coronary revascularization, and leg artery revascularization. The secondary outcome (B) was all-cause mortality.
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