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

Tetsuo Shoji, Masaaki Inaba, Masafumi Fukagawa, Ryoichi Ando, Masanori Emoto, Hisako Fujii, Akira Fujimori, Mitsuru Fukui, Hiroki Hase, Tetsuya Hashimoto, Hideki Hirakata, Hirokazu Honda, Tatsuo Hosoya, Yuji Ikari, Daijo Inaguma, Toru Inoue, Yoshitaka Isaka, Kunitoshi Iseki, Eiji Ishimura, Noritomo ItamiChiharu Ito, Toshitaka Kakuta, Toru Kawai, Hideki Kawanishi, Shuzo Kobayashi, Junko Kumagai, Kiyoshi Maekawa, Ikuto Masakane, Jun Minakuchi, Koji Mitsuiki, Takashi Mizuguchi, Satoshi Morimoto, Toyoaki Murohara, Tatsuya Nakatani, Shigeo Negi, Shinichi Nishi, Mitsushige Nishikawa, Tetsuya Ogawa, Kazumichi Ohta, Takayasu Ohtake, Mikio Okamura, Senji Okuno, Takashi Shigematsu, Toshitsugu Sugimoto, Masashi Suzuki, Hideki Tahara, Yoshiaki Takemoto, Kenji Tanaka, Yoshihiro Tominaga, Yoshiharu Tsubakihara, Yoshihiro Tsujimoto, Kazuhiko Tsuruya, Shinichiro Ueda, Yuzo Watanabe, Kunihiro Yamagata, Tomoyuki Yamakawa, Shozo Yano, Keitaro Yokoyama, Noriaki Yorioka, Minoru Yoshiyama, Yoshiki Nishizawa

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2325-2334
Number of pages10
JournalJAMA - Journal of the American Medical Association
Volume320
Issue number22
DOIs
Publication statusPublished - 11-12-2018

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Secondary Hyperparathyroidism
Renal Dialysis
Randomized Controlled Trials
Maintenance
Calcitriol Receptors
Parathyroid Hormone
Vitamin D
Control Groups
Mortality
Dialysis
alfacalcidol
Aortic Rupture
Intention to Treat Analysis
Sudden Cardiac Death
Sterols
Infection
Chronic Renal Insufficiency
Amputation
Multicenter Studies
Observational Studies

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Shoji, Tetsuo ; Inaba, Masaaki ; Fukagawa, Masafumi ; Ando, Ryoichi ; Emoto, Masanori ; Fujii, Hisako ; Fujimori, Akira ; Fukui, Mitsuru ; Hase, Hiroki ; Hashimoto, Tetsuya ; Hirakata, Hideki ; Honda, Hirokazu ; Hosoya, Tatsuo ; Ikari, Yuji ; Inaguma, Daijo ; Inoue, Toru ; Isaka, Yoshitaka ; Iseki, Kunitoshi ; Ishimura, Eiji ; Itami, Noritomo ; Ito, Chiharu ; Kakuta, Toshitaka ; Kawai, Toru ; Kawanishi, Hideki ; Kobayashi, Shuzo ; Kumagai, Junko ; Maekawa, Kiyoshi ; Masakane, Ikuto ; Minakuchi, Jun ; Mitsuiki, Koji ; Mizuguchi, Takashi ; Morimoto, Satoshi ; Murohara, Toyoaki ; Nakatani, Tatsuya ; Negi, Shigeo ; Nishi, Shinichi ; Nishikawa, Mitsushige ; Ogawa, Tetsuya ; Ohta, Kazumichi ; Ohtake, Takayasu ; Okamura, Mikio ; Okuno, Senji ; Shigematsu, Takashi ; Sugimoto, Toshitsugu ; Suzuki, Masashi ; Tahara, Hideki ; Takemoto, Yoshiaki ; Tanaka, Kenji ; Tominaga, Yoshihiro ; Tsubakihara, Yoshiharu ; Tsujimoto, Yoshihiro ; Tsuruya, Kazuhiko ; Ueda, Shinichiro ; Watanabe, Yuzo ; Yamagata, Kunihiro ; Yamakawa, Tomoyuki ; Yano, Shozo ; Yokoyama, Keitaro ; Yorioka, Noriaki ; Yoshiyama, Minoru ; Nishizawa, Yoshiki. / Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis : The J-DAVID Randomized Clinical Trial. In: JAMA - Journal of the American Medical Association. 2018 ; Vol. 320, No. 22. pp. 2325-2334.
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title = "Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial",
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.",
author = "Tetsuo Shoji and Masaaki Inaba and Masafumi Fukagawa and Ryoichi Ando and Masanori Emoto and Hisako Fujii and Akira Fujimori and Mitsuru Fukui and Hiroki Hase and Tetsuya Hashimoto and Hideki Hirakata and Hirokazu Honda and Tatsuo Hosoya and Yuji Ikari and Daijo Inaguma and Toru Inoue and Yoshitaka Isaka and Kunitoshi Iseki and Eiji Ishimura and Noritomo Itami and Chiharu Ito and Toshitaka Kakuta and Toru Kawai and Hideki Kawanishi and Shuzo Kobayashi and Junko Kumagai and Kiyoshi Maekawa and Ikuto Masakane and Jun Minakuchi and Koji Mitsuiki and Takashi Mizuguchi and Satoshi Morimoto and Toyoaki Murohara and Tatsuya Nakatani and Shigeo Negi and Shinichi Nishi and Mitsushige Nishikawa and Tetsuya Ogawa and Kazumichi Ohta and Takayasu Ohtake and Mikio Okamura and Senji Okuno and Takashi Shigematsu and Toshitsugu Sugimoto and Masashi Suzuki and Hideki Tahara and Yoshiaki Takemoto and Kenji Tanaka and Yoshihiro Tominaga and Yoshiharu Tsubakihara and Yoshihiro Tsujimoto and Kazuhiko Tsuruya and Shinichiro Ueda and Yuzo Watanabe and Kunihiro Yamagata and Tomoyuki Yamakawa and Shozo Yano and Keitaro Yokoyama and Noriaki Yorioka and Minoru Yoshiyama and Yoshiki Nishizawa",
year = "2018",
month = "12",
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doi = "10.1001/jama.2018.17749",
language = "English",
volume = "320",
pages = "2325--2334",
journal = "JAMA - Journal of the American Medical Association",
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Shoji, T, Inaba, M, Fukagawa, M, Ando, R, Emoto, M, Fujii, H, Fujimori, A, Fukui, M, Hase, H, Hashimoto, T, Hirakata, H, Honda, H, Hosoya, T, Ikari, Y, Inaguma, D, Inoue, T, Isaka, Y, Iseki, K, Ishimura, E, Itami, N, Ito, C, Kakuta, T, Kawai, T, Kawanishi, H, Kobayashi, S, Kumagai, J, Maekawa, K, Masakane, I, Minakuchi, J, Mitsuiki, K, Mizuguchi, T, Morimoto, S, Murohara, T, Nakatani, T, Negi, S, Nishi, S, Nishikawa, M, Ogawa, T, Ohta, K, Ohtake, T, Okamura, M, Okuno, S, Shigematsu, T, Sugimoto, T, Suzuki, M, Tahara, H, Takemoto, Y, Tanaka, K, Tominaga, Y, Tsubakihara, Y, Tsujimoto, Y, Tsuruya, K, Ueda, S, Watanabe, Y, Yamagata, K, Yamakawa, T, Yano, S, Yokoyama, K, Yorioka, N, Yoshiyama, M & Nishizawa, Y 2018, 'Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial', JAMA - Journal of the American Medical Association, vol. 320, no. 22, pp. 2325-2334. https://doi.org/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. / Shoji, Tetsuo; Inaba, Masaaki; Fukagawa, Masafumi; Ando, Ryoichi; Emoto, Masanori; Fujii, Hisako; Fujimori, Akira; Fukui, Mitsuru; Hase, Hiroki; Hashimoto, Tetsuya; Hirakata, Hideki; Honda, Hirokazu; Hosoya, Tatsuo; Ikari, Yuji; Inaguma, Daijo; Inoue, Toru; Isaka, Yoshitaka; Iseki, Kunitoshi; Ishimura, Eiji; Itami, Noritomo; Ito, Chiharu; Kakuta, Toshitaka; Kawai, Toru; Kawanishi, Hideki; Kobayashi, Shuzo; Kumagai, Junko; Maekawa, Kiyoshi; Masakane, Ikuto; Minakuchi, Jun; Mitsuiki, Koji; Mizuguchi, Takashi; Morimoto, Satoshi; Murohara, Toyoaki; Nakatani, Tatsuya; Negi, Shigeo; Nishi, Shinichi; Nishikawa, Mitsushige; Ogawa, Tetsuya; Ohta, Kazumichi; Ohtake, Takayasu; Okamura, Mikio; Okuno, Senji; Shigematsu, Takashi; Sugimoto, Toshitsugu; Suzuki, Masashi; Tahara, Hideki; Takemoto, Yoshiaki; Tanaka, Kenji; Tominaga, Yoshihiro; Tsubakihara, Yoshiharu; Tsujimoto, Yoshihiro; Tsuruya, Kazuhiko; Ueda, Shinichiro; Watanabe, Yuzo; Yamagata, Kunihiro; Yamakawa, Tomoyuki; Yano, Shozo; Yokoyama, Keitaro; Yorioka, Noriaki; Yoshiyama, Minoru; Nishizawa, Yoshiki.

In: JAMA - Journal of the American Medical Association, Vol. 320, No. 22, 11.12.2018, p. 2325-2334.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis

T2 - The J-DAVID Randomized Clinical Trial

AU - Shoji, Tetsuo

AU - Inaba, Masaaki

AU - Fukagawa, Masafumi

AU - Ando, Ryoichi

AU - Emoto, Masanori

AU - Fujii, Hisako

AU - Fujimori, Akira

AU - Fukui, Mitsuru

AU - Hase, Hiroki

AU - Hashimoto, Tetsuya

AU - Hirakata, Hideki

AU - Honda, Hirokazu

AU - Hosoya, Tatsuo

AU - Ikari, Yuji

AU - Inaguma, Daijo

AU - Inoue, Toru

AU - Isaka, Yoshitaka

AU - Iseki, Kunitoshi

AU - Ishimura, Eiji

AU - Itami, Noritomo

AU - Ito, Chiharu

AU - Kakuta, Toshitaka

AU - Kawai, Toru

AU - Kawanishi, Hideki

AU - Kobayashi, Shuzo

AU - Kumagai, Junko

AU - Maekawa, Kiyoshi

AU - Masakane, Ikuto

AU - Minakuchi, Jun

AU - Mitsuiki, Koji

AU - Mizuguchi, Takashi

AU - Morimoto, Satoshi

AU - Murohara, Toyoaki

AU - Nakatani, Tatsuya

AU - Negi, Shigeo

AU - Nishi, Shinichi

AU - Nishikawa, Mitsushige

AU - Ogawa, Tetsuya

AU - Ohta, Kazumichi

AU - Ohtake, Takayasu

AU - Okamura, Mikio

AU - Okuno, Senji

AU - Shigematsu, Takashi

AU - Sugimoto, Toshitsugu

AU - Suzuki, Masashi

AU - Tahara, Hideki

AU - Takemoto, Yoshiaki

AU - Tanaka, Kenji

AU - Tominaga, Yoshihiro

AU - Tsubakihara, Yoshiharu

AU - Tsujimoto, Yoshihiro

AU - Tsuruya, Kazuhiko

AU - Ueda, Shinichiro

AU - Watanabe, Yuzo

AU - Yamagata, Kunihiro

AU - Yamakawa, Tomoyuki

AU - Yano, Shozo

AU - Yokoyama, Keitaro

AU - Yorioka, Noriaki

AU - Yoshiyama, Minoru

AU - Nishizawa, Yoshiki

PY - 2018/12/11

Y1 - 2018/12/11

N2 - 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.

AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85058603045&partnerID=8YFLogxK

U2 - 10.1001/jama.2018.17749

DO - 10.1001/jama.2018.17749

M3 - Article

C2 - 30535217

AN - SCOPUS:85058603045

VL - 320

SP - 2325

EP - 2334

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 22

ER -