Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: Insights from the Everest (efficacy of vasopressin antagonism in heart failure: Outcome study with Tolvaptan) trial

Javed Butler; Haris Subacius; Muthiah Vaduganathan; Gregg C. Fonarow; Andrew P. Ambrosy; Marvin A. Konstam; Aldo Maggioni; Robert J. Mentz; Karl Swedberg; Faiez Zannad; Mihai Gheorghiade

doi:10.1016/j.jacc.2012.10.025

Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: Insights from the Everest (efficacy of vasopressin antagonism in heart failure: Outcome study with Tolvaptan) trial

Javed Butler, Haris Subacius, Muthiah Vaduganathan, Gregg C. Fonarow, Andrew P. Ambrosy, Marvin A. Konstam, Aldo Maggioni, Robert J. Mentz, Karl Swedberg, Faiez Zannad, Mihai Gheorghiade^*

^*Corresponding author for this work

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

Abstract

Objectives: The study investigated whether the number of participants enrolled per site in an acute heart failure trial is associated with participant characteristics and outcomes. Background: Whether and how site enrollment volume affects clinical trials is not known. Methods: A total of 4,133 participants enrolled among 359 sites were grouped on the basis of total enrollment into 1 to 10, 11 to 30, and >30 participants per site and were compared for outcomes (cardiovascular mortality or heart failure hospitalization). Results: Per-site enrollment ranged from 0 to 75 (median 6; 77 sites had no enrollment). Regional differences in enrollment were noted between North and South America, and Western and Eastern Europe (p < 0.001). Participants from sites with fewer enrollments were more likely to be older and male, have lower ejection fraction and blood pressure as well as worse comorbidity and laboratory profile, and were less likely to be on angiotensin-converting enzyme inhibitors or aldosterone antagonists. During a median follow-up of 9.9 months, 1,700 (41%) participants had an outcome event. Compared to event rate at sites with >30 participants (32%), those with 1 to 10 (51%, hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.56 to 2.02) and 11 to 30 (42%, HR: 1.44, 95% CI: 1.28 to 1.62) participants per site groups had worse outcomes. This relationship was comparable across regions (p = 0.43). After adjustment for risk factors, participants enrolled at sites with fewer enrollees were at higher risk for adverse outcomes (HR: 1.26, 95% CI: 1.08 to 1.46 for 1 to 10; HR: 1.22, 95% CI: 1.07 to 1.38 for 11 to 30 vs. >30 participant sites). Higher proportion of participants from site with >30 participants completed the protocol (45.5% for <10, 61.7% for 11 to 30, and 68.4% for sites enrolling >30 participants; p < 0.001). Conclusions: Baseline characteristics, protocol completion, and outcomes differed significantly among higher versus lower enrolling sites. These data imply that the number of participant enrolled per site may influence trials beyond logistics.

Original language	English (US)
Pages (from-to)	571-579
Number of pages	9
Journal	Journal of the American College of Cardiology
Volume	61
Issue number	5
DOIs	https://doi.org/10.1016/j.jacc.2012.10.025
State	Published - Feb 5 2013

Funding

Dr. Butler has a relationship with Takeda, Gambro, Ono Pharma, Trevena, CardioMEMS, Alere, Bayer, AMGEN, Corthera, and Medtronic. Dr. Fonarow receives research support from the Agency for Healthcare Research and Quality and serves as a consultant for Medtronic and Novartis. Dr. Konstam has received research support and/or served as a consultant for Merck, Otsuka, Johnson & Johnson, Amgen, Novartis, and Cardiokine. Dr. Maggioni receives honoraria from Otsuka. Dr. Mentz has received grants from Medtronic and research funding from Gilead Sciences . Dr. Swedberg receives research grants from AstraZeneca , Servier , and Amgen ; honoraria from AstraZeneca, Otsuka, Servier, and Amgen; and is a consultant for Cytokinetics, Servier, and Novartis. Dr. Zannad has received honoraria from and served on advisory boards for Pfizer Inc. Dr. Gheorghiade has a relationship with Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, Corthera, Cytokinetics, CytoPherx, Inc., DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Inc., Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Pharmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, PeriCor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc., and Trevena Therapeutics; and has received support from Bayer Schering Pharma AG, DebioPharm S.A., Medtronic, Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, and Takeda Pharmaceuticals North America, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Keywords

acute heart failure
clinical trials
outcomes assessment
quality of care

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1016/j.jacc.2012.10.025

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Butler, J., Subacius, H., Vaduganathan, M., Fonarow, G. C., Ambrosy, A. P., Konstam, M. A., Maggioni, A., Mentz, R. J., Swedberg, K., Zannad, F., & Gheorghiade, M. (2013). Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: Insights from the Everest (efficacy of vasopressin antagonism in heart failure: Outcome study with Tolvaptan) trial. Journal of the American College of Cardiology, 61(5), 571-579. https://doi.org/10.1016/j.jacc.2012.10.025

Butler, Javed ; Subacius, Haris ; Vaduganathan, Muthiah et al. / Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes : Insights from the Everest (efficacy of vasopressin antagonism in heart failure: Outcome study with Tolvaptan) trial. In: Journal of the American College of Cardiology. 2013 ; Vol. 61, No. 5. pp. 571-579.

@article{78871797c6564e0c99a166d4324d8f7e,

title = "Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: Insights from the Everest (efficacy of vasopressin antagonism in heart failure: Outcome study with Tolvaptan) trial",

abstract = "Objectives: The study investigated whether the number of participants enrolled per site in an acute heart failure trial is associated with participant characteristics and outcomes. Background: Whether and how site enrollment volume affects clinical trials is not known. Methods: A total of 4,133 participants enrolled among 359 sites were grouped on the basis of total enrollment into 1 to 10, 11 to 30, and >30 participants per site and were compared for outcomes (cardiovascular mortality or heart failure hospitalization). Results: Per-site enrollment ranged from 0 to 75 (median 6; 77 sites had no enrollment). Regional differences in enrollment were noted between North and South America, and Western and Eastern Europe (p < 0.001). Participants from sites with fewer enrollments were more likely to be older and male, have lower ejection fraction and blood pressure as well as worse comorbidity and laboratory profile, and were less likely to be on angiotensin-converting enzyme inhibitors or aldosterone antagonists. During a median follow-up of 9.9 months, 1,700 (41%) participants had an outcome event. Compared to event rate at sites with >30 participants (32%), those with 1 to 10 (51%, hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.56 to 2.02) and 11 to 30 (42%, HR: 1.44, 95% CI: 1.28 to 1.62) participants per site groups had worse outcomes. This relationship was comparable across regions (p = 0.43). After adjustment for risk factors, participants enrolled at sites with fewer enrollees were at higher risk for adverse outcomes (HR: 1.26, 95% CI: 1.08 to 1.46 for 1 to 10; HR: 1.22, 95% CI: 1.07 to 1.38 for 11 to 30 vs. >30 participant sites). Higher proportion of participants from site with >30 participants completed the protocol (45.5% for <10, 61.7% for 11 to 30, and 68.4% for sites enrolling >30 participants; p < 0.001). Conclusions: Baseline characteristics, protocol completion, and outcomes differed significantly among higher versus lower enrolling sites. These data imply that the number of participant enrolled per site may influence trials beyond logistics.",

keywords = "acute heart failure, clinical trials, outcomes assessment, quality of care",

author = "Javed Butler and Haris Subacius and Muthiah Vaduganathan and Fonarow, {Gregg C.} and Ambrosy, {Andrew P.} and Konstam, {Marvin A.} and Aldo Maggioni and Mentz, {Robert J.} and Karl Swedberg and Faiez Zannad and Mihai Gheorghiade",

note = "Funding Information: Dr. Butler has a relationship with Takeda, Gambro, Ono Pharma, Trevena, CardioMEMS, Alere, Bayer, AMGEN, Corthera, and Medtronic. Dr. Fonarow receives research support from the Agency for Healthcare Research and Quality and serves as a consultant for Medtronic and Novartis. Dr. Konstam has received research support and/or served as a consultant for Merck, Otsuka, Johnson & Johnson, Amgen, Novartis, and Cardiokine. Dr. Maggioni receives honoraria from Otsuka. Dr. Mentz has received grants from Medtronic and research funding from Gilead Sciences . Dr. Swedberg receives research grants from AstraZeneca , Servier , and Amgen ; honoraria from AstraZeneca, Otsuka, Servier, and Amgen; and is a consultant for Cytokinetics, Servier, and Novartis. Dr. Zannad has received honoraria from and served on advisory boards for Pfizer Inc. Dr. Gheorghiade has a relationship with Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, Corthera, Cytokinetics, CytoPherx, Inc., DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Inc., Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Pharmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, PeriCor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc., and Trevena Therapeutics; and has received support from Bayer Schering Pharma AG, DebioPharm S.A., Medtronic, Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, and Takeda Pharmaceuticals North America, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. ",

year = "2013",

month = feb,

day = "5",

doi = "10.1016/j.jacc.2012.10.025",

language = "English (US)",

volume = "61",

pages = "571--579",

journal = "Journal of the American College of Cardiology",

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Butler, J, Subacius, H, Vaduganathan, M, Fonarow, GC, Ambrosy, AP, Konstam, MA, Maggioni, A, Mentz, RJ, Swedberg, K, Zannad, F & Gheorghiade, M 2013, 'Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: Insights from the Everest (efficacy of vasopressin antagonism in heart failure: Outcome study with Tolvaptan) trial', Journal of the American College of Cardiology, vol. 61, no. 5, pp. 571-579. https://doi.org/10.1016/j.jacc.2012.10.025

Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: Insights from the Everest (efficacy of vasopressin antagonism in heart failure: Outcome study with Tolvaptan) trial. / Butler, Javed; Subacius, Haris; Vaduganathan, Muthiah et al.
In: Journal of the American College of Cardiology, Vol. 61, No. 5, 05.02.2013, p. 571-579.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes

T2 - Insights from the Everest (efficacy of vasopressin antagonism in heart failure: Outcome study with Tolvaptan) trial

AU - Butler, Javed

AU - Subacius, Haris

AU - Vaduganathan, Muthiah

AU - Fonarow, Gregg C.

AU - Ambrosy, Andrew P.

AU - Konstam, Marvin A.

AU - Maggioni, Aldo

AU - Mentz, Robert J.

AU - Swedberg, Karl

AU - Zannad, Faiez

AU - Gheorghiade, Mihai

N1 - Funding Information: Dr. Butler has a relationship with Takeda, Gambro, Ono Pharma, Trevena, CardioMEMS, Alere, Bayer, AMGEN, Corthera, and Medtronic. Dr. Fonarow receives research support from the Agency for Healthcare Research and Quality and serves as a consultant for Medtronic and Novartis. Dr. Konstam has received research support and/or served as a consultant for Merck, Otsuka, Johnson & Johnson, Amgen, Novartis, and Cardiokine. Dr. Maggioni receives honoraria from Otsuka. Dr. Mentz has received grants from Medtronic and research funding from Gilead Sciences . Dr. Swedberg receives research grants from AstraZeneca , Servier , and Amgen ; honoraria from AstraZeneca, Otsuka, Servier, and Amgen; and is a consultant for Cytokinetics, Servier, and Novartis. Dr. Zannad has received honoraria from and served on advisory boards for Pfizer Inc. Dr. Gheorghiade has a relationship with Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, Corthera, Cytokinetics, CytoPherx, Inc., DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Inc., Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Pharmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, PeriCor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc., and Trevena Therapeutics; and has received support from Bayer Schering Pharma AG, DebioPharm S.A., Medtronic, Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, and Takeda Pharmaceuticals North America, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

PY - 2013/2/5

Y1 - 2013/2/5

N2 - Objectives: The study investigated whether the number of participants enrolled per site in an acute heart failure trial is associated with participant characteristics and outcomes. Background: Whether and how site enrollment volume affects clinical trials is not known. Methods: A total of 4,133 participants enrolled among 359 sites were grouped on the basis of total enrollment into 1 to 10, 11 to 30, and >30 participants per site and were compared for outcomes (cardiovascular mortality or heart failure hospitalization). Results: Per-site enrollment ranged from 0 to 75 (median 6; 77 sites had no enrollment). Regional differences in enrollment were noted between North and South America, and Western and Eastern Europe (p < 0.001). Participants from sites with fewer enrollments were more likely to be older and male, have lower ejection fraction and blood pressure as well as worse comorbidity and laboratory profile, and were less likely to be on angiotensin-converting enzyme inhibitors or aldosterone antagonists. During a median follow-up of 9.9 months, 1,700 (41%) participants had an outcome event. Compared to event rate at sites with >30 participants (32%), those with 1 to 10 (51%, hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.56 to 2.02) and 11 to 30 (42%, HR: 1.44, 95% CI: 1.28 to 1.62) participants per site groups had worse outcomes. This relationship was comparable across regions (p = 0.43). After adjustment for risk factors, participants enrolled at sites with fewer enrollees were at higher risk for adverse outcomes (HR: 1.26, 95% CI: 1.08 to 1.46 for 1 to 10; HR: 1.22, 95% CI: 1.07 to 1.38 for 11 to 30 vs. >30 participant sites). Higher proportion of participants from site with >30 participants completed the protocol (45.5% for <10, 61.7% for 11 to 30, and 68.4% for sites enrolling >30 participants; p < 0.001). Conclusions: Baseline characteristics, protocol completion, and outcomes differed significantly among higher versus lower enrolling sites. These data imply that the number of participant enrolled per site may influence trials beyond logistics.

AB - Objectives: The study investigated whether the number of participants enrolled per site in an acute heart failure trial is associated with participant characteristics and outcomes. Background: Whether and how site enrollment volume affects clinical trials is not known. Methods: A total of 4,133 participants enrolled among 359 sites were grouped on the basis of total enrollment into 1 to 10, 11 to 30, and >30 participants per site and were compared for outcomes (cardiovascular mortality or heart failure hospitalization). Results: Per-site enrollment ranged from 0 to 75 (median 6; 77 sites had no enrollment). Regional differences in enrollment were noted between North and South America, and Western and Eastern Europe (p < 0.001). Participants from sites with fewer enrollments were more likely to be older and male, have lower ejection fraction and blood pressure as well as worse comorbidity and laboratory profile, and were less likely to be on angiotensin-converting enzyme inhibitors or aldosterone antagonists. During a median follow-up of 9.9 months, 1,700 (41%) participants had an outcome event. Compared to event rate at sites with >30 participants (32%), those with 1 to 10 (51%, hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.56 to 2.02) and 11 to 30 (42%, HR: 1.44, 95% CI: 1.28 to 1.62) participants per site groups had worse outcomes. This relationship was comparable across regions (p = 0.43). After adjustment for risk factors, participants enrolled at sites with fewer enrollees were at higher risk for adverse outcomes (HR: 1.26, 95% CI: 1.08 to 1.46 for 1 to 10; HR: 1.22, 95% CI: 1.07 to 1.38 for 11 to 30 vs. >30 participant sites). Higher proportion of participants from site with >30 participants completed the protocol (45.5% for <10, 61.7% for 11 to 30, and 68.4% for sites enrolling >30 participants; p < 0.001). Conclusions: Baseline characteristics, protocol completion, and outcomes differed significantly among higher versus lower enrolling sites. These data imply that the number of participant enrolled per site may influence trials beyond logistics.

KW - acute heart failure

KW - clinical trials

KW - outcomes assessment

KW - quality of care

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UR - http://www.scopus.com/inward/citedby.url?scp=84873095762&partnerID=8YFLogxK

U2 - 10.1016/j.jacc.2012.10.025

DO - 10.1016/j.jacc.2012.10.025

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AN - SCOPUS:84873095762

SN - 0735-1097

VL - 61

SP - 571

EP - 579

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 5

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Butler J, Subacius H, Vaduganathan M, Fonarow GC, Ambrosy AP, Konstam MA et al. Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: Insights from the Everest (efficacy of vasopressin antagonism in heart failure: Outcome study with Tolvaptan) trial. Journal of the American College of Cardiology. 2013 Feb 5;61(5):571-579. doi: 10.1016/j.jacc.2012.10.025

Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: Insights from the Everest (efficacy of vasopressin antagonism in heart failure: Outcome study with Tolvaptan) trial

Abstract

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ASJC Scopus subject areas

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