Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years

Mark Y. Chan; Jie Lena Sun; L. Kristin Newby; Yuliya Lokhnygina; Harvey D. White; David J. Moliterno; Pierre Théroux; E. Magnus Ohman; Maarten L. Simoons; Kenneth W. Mahaffey; Karen S. Pieper; Robert P. Giugliano; Paul W. Armstrong; Robert M. Califf; Frans Van De Werf; Robert A. Harrington

doi:10.1016/j.ijcard.2012.01.065

Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years

Mark Y. Chan, Jie Lena Sun, L. Kristin Newby, Yuliya Lokhnygina, Harvey D. White, David J. Moliterno, Pierre Théroux, E. Magnus Ohman, Maarten L. Simoons, Kenneth W. Mahaffey, Karen S. Pieper, Robert P. Giugliano, Paul W. Armstrong, Robert M. Califf, Frans Van De Werf, Robert A. Harrington

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

10 Scopus citations

Abstract

Background: Data are limited on whether clinical trials have randomized higher-risk patients over time and how trends in risk profiles and evidence-based pharmacotherapies have influenced trial outcomes. We quantified changes in baseline risk, treatment, and outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) randomized in 9 phase 3 clinical trials of antithrombotic therapy over 15 years. Methods: We studied 58,771 patients in GUSTO IIb, PURSUIT, PARAGON-A, PARAGON-B, PRISM, PRISM-PLUS, GUSTO IV-ACS, SYNERGY, and EARLY ACS. Patient-level data were mapped to 3 pre-specified 5-year randomization periods. Temporal trends in GRACE score-predicted mortality were compared with trends in observed mortality. Results: Over time, in-hospital and discharge use of thienopyridines (p = 0.001), statins (p < 0.0001), and angiotensin-converting enzyme inhibitors (p < 0.0001) increased, and hospital length-of-stay decreased (p = 0.024). Blood transfusion use increased (8.3% [1994-98], 10.7% [1999-2003], 13% [2004-08], p = 0.0002) despite stable rates of severe bleeding (0.9% [1994-98], 1.4% [1999-2003] and 1.1% [2004-08], p = 0.127) and coronary artery bypass grafting (12.4% [1994-98], 13.7% [1999-2003] 13.1% [2004-08], p = 0.880). Although predicted 6-month mortality increased (6.9% [1994-98], 9.0% [1999-2003], 7.9% [2004-08], p = 0.017), observed 6-month mortality decreased (6.7% [1994-98], 5.8% [1999-2003], 5.1% [2004-08], p = 0.025). Thirty-day myocardial infarction rates remained stable (9.2% [1994-98], 9.3% [1999-2003], 10% [2004-08], p = 0.539). Conclusions: Despite enrolling higher-risk patients into these NSTE ACS trials, with better treatment, observed mortality declined over the past 15 years. The appropriateness of increased blood transfusion despite unchanged bleeding rates deserves further study.

Original language	English
Pages (from-to)	548-554
Number of pages	7
Journal	International Journal of Cardiology
Volume	167
Issue number	2
DOIs	https://doi.org/10.1016/j.ijcard.2012.01.065
State	Published - Jul 31 2013

Bibliographical note

Funding Information:
Robert P. Giugliano: Research grant support, advisory board, and honoraria for lectures, Schering-Plough, Inc., and Merck & Co., Inc; research grant support from Daiichi-Sankyo; consultant/honoraria for lectures from Bristol-Myers Squibb and Sanofi-aventis.

Funding Information:
Mark Y. Chan: Research grants from Eli Lilly and AstraZeneca; consulting honoraria from Eli Lilly and AstraZeneca; New Investigator Grant (NMRC/NIG09may023) and Clinician Scientist Award (NMRC/CSA/028/2010) from the National Medical Research Council, Singapore, Singapore.

Funding Information:
This work was supported by the Merck/Schering-Plough Alliance. Merck/Schering-Plough was not involved in study design, or collection, management, analysis, and interpretation of the data.

Funding Information:
Paul W. Armstrong: Research grant or contract from Schering-Plough Research Institute, Portola Pharmaceutical Inc., AstraZeneca, and Merck & Company Inc., which partially supports his university salary and/or research projects. A complete listing of Dr. Armstrong's relationships with industry is available at http://www.vigour.ualberta.ca .

Funding

Robert P. Giugliano: Research grant support, advisory board, and honoraria for lectures, Schering-Plough, Inc., and Merck & Co., Inc; research grant support from Daiichi-Sankyo; consultant/honoraria for lectures from Bristol-Myers Squibb and Sanofi-aventis. Mark Y. Chan: Research grants from Eli Lilly and AstraZeneca; consulting honoraria from Eli Lilly and AstraZeneca; New Investigator Grant (NMRC/NIG09may023) and Clinician Scientist Award (NMRC/CSA/028/2010) from the National Medical Research Council, Singapore, Singapore. This work was supported by the Merck/Schering-Plough Alliance. Merck/Schering-Plough was not involved in study design, or collection, management, analysis, and interpretation of the data. Paul W. Armstrong: Research grant or contract from Schering-Plough Research Institute, Portola Pharmaceutical Inc., AstraZeneca, and Merck & Company Inc., which partially supports his university salary and/or research projects. A complete listing of Dr. Armstrong's relationships with industry is available at http://www.vigour.ualberta.ca .

Funders	Funder number
Eli Lilly and AstraZeneca	NMRC/CSA/028/2010, NMRC/NIG09may023
DuPont Merck Pharmaceutical Company
Schering-Plough Alliance
Schering-Plough Research Institute
Eli Lilly and Company
AstraZeneca
Merck
Schering Plough Co
Portola Pharmaceuticals Inc.
National Health and Medical Research Council Clinical Trials Centre

Keywords

Antithrombotic therapy
Non-ST-segment elevation acute coronary syndromes
Outcomes
Randomized clinical trials
Risk

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

Access to Document

10.1016/j.ijcard.2012.01.065

Cite this

Chan, M. Y., Sun, J. L., Newby, L. K., Lokhnygina, Y., White, H. D., Moliterno, D. J., Théroux, P., Ohman, E. M., Simoons, M. L., Mahaffey, K. W., Pieper, K. S., Giugliano, R. P., Armstrong, P. W., Califf, R. M., Van De Werf, F., & Harrington, R. A. (2013). Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years. International Journal of Cardiology, 167(2), 548-554. https://doi.org/10.1016/j.ijcard.2012.01.065

@article{09e5fa8c680e4c8b8a03b81bd97da17b,

title = "Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years",

abstract = "Background: Data are limited on whether clinical trials have randomized higher-risk patients over time and how trends in risk profiles and evidence-based pharmacotherapies have influenced trial outcomes. We quantified changes in baseline risk, treatment, and outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) randomized in 9 phase 3 clinical trials of antithrombotic therapy over 15 years. Methods: We studied 58,771 patients in GUSTO IIb, PURSUIT, PARAGON-A, PARAGON-B, PRISM, PRISM-PLUS, GUSTO IV-ACS, SYNERGY, and EARLY ACS. Patient-level data were mapped to 3 pre-specified 5-year randomization periods. Temporal trends in GRACE score-predicted mortality were compared with trends in observed mortality. Results: Over time, in-hospital and discharge use of thienopyridines (p = 0.001), statins (p < 0.0001), and angiotensin-converting enzyme inhibitors (p < 0.0001) increased, and hospital length-of-stay decreased (p = 0.024). Blood transfusion use increased (8.3% [1994-98], 10.7% [1999-2003], 13% [2004-08], p = 0.0002) despite stable rates of severe bleeding (0.9% [1994-98], 1.4% [1999-2003] and 1.1% [2004-08], p = 0.127) and coronary artery bypass grafting (12.4% [1994-98], 13.7% [1999-2003] 13.1% [2004-08], p = 0.880). Although predicted 6-month mortality increased (6.9% [1994-98], 9.0% [1999-2003], 7.9% [2004-08], p = 0.017), observed 6-month mortality decreased (6.7% [1994-98], 5.8% [1999-2003], 5.1% [2004-08], p = 0.025). Thirty-day myocardial infarction rates remained stable (9.2% [1994-98], 9.3% [1999-2003], 10% [2004-08], p = 0.539). Conclusions: Despite enrolling higher-risk patients into these NSTE ACS trials, with better treatment, observed mortality declined over the past 15 years. The appropriateness of increased blood transfusion despite unchanged bleeding rates deserves further study.",

keywords = "Antithrombotic therapy, Non-ST-segment elevation acute coronary syndromes, Outcomes, Randomized clinical trials, Risk",

author = "Chan, {Mark Y.} and Sun, {Jie Lena} and Newby, {L. Kristin} and Yuliya Lokhnygina and White, {Harvey D.} and Moliterno, {David J.} and Pierre Th{\'e}roux and Ohman, {E. Magnus} and Simoons, {Maarten L.} and Mahaffey, {Kenneth W.} and Pieper, {Karen S.} and Giugliano, {Robert P.} and Armstrong, {Paul W.} and Califf, {Robert M.} and {Van De Werf}, Frans and Harrington, {Robert A.}",

note = "Funding Information: Robert P. Giugliano: Research grant support, advisory board, and honoraria for lectures, Schering-Plough, Inc., and Merck & Co., Inc; research grant support from Daiichi-Sankyo; consultant/honoraria for lectures from Bristol-Myers Squibb and Sanofi-aventis. Funding Information: Mark Y. Chan: Research grants from Eli Lilly and AstraZeneca; consulting honoraria from Eli Lilly and AstraZeneca; New Investigator Grant (NMRC/NIG09may023) and Clinician Scientist Award (NMRC/CSA/028/2010) from the National Medical Research Council, Singapore, Singapore. Funding Information: This work was supported by the Merck/Schering-Plough Alliance. Merck/Schering-Plough was not involved in study design, or collection, management, analysis, and interpretation of the data. Funding Information: Paul W. Armstrong: Research grant or contract from Schering-Plough Research Institute, Portola Pharmaceutical Inc., AstraZeneca, and Merck & Company Inc., which partially supports his university salary and/or research projects. A complete listing of Dr. Armstrong's relationships with industry is available at http://www.vigour.ualberta.ca . ",

year = "2013",

month = jul,

day = "31",

doi = "10.1016/j.ijcard.2012.01.065",

language = "English",

volume = "167",

pages = "548--554",

number = "2",

}

Chan, MY, Sun, JL, Newby, LK, Lokhnygina, Y, White, HD, Moliterno, DJ, Théroux, P, Ohman, EM, Simoons, ML, Mahaffey, KW, Pieper, KS, Giugliano, RP, Armstrong, PW, Califf, RM, Van De Werf, F & Harrington, RA 2013, 'Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years', International Journal of Cardiology, vol. 167, no. 2, pp. 548-554. https://doi.org/10.1016/j.ijcard.2012.01.065

TY - JOUR

T1 - Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years

AU - Chan, Mark Y.

AU - Sun, Jie Lena

AU - Newby, L. Kristin

AU - Lokhnygina, Yuliya

AU - White, Harvey D.

AU - Moliterno, David J.

AU - Théroux, Pierre

AU - Ohman, E. Magnus

AU - Simoons, Maarten L.

AU - Mahaffey, Kenneth W.

AU - Pieper, Karen S.

AU - Giugliano, Robert P.

AU - Armstrong, Paul W.

AU - Califf, Robert M.

AU - Van De Werf, Frans

AU - Harrington, Robert A.

N1 - Funding Information: Robert P. Giugliano: Research grant support, advisory board, and honoraria for lectures, Schering-Plough, Inc., and Merck & Co., Inc; research grant support from Daiichi-Sankyo; consultant/honoraria for lectures from Bristol-Myers Squibb and Sanofi-aventis. Funding Information: Mark Y. Chan: Research grants from Eli Lilly and AstraZeneca; consulting honoraria from Eli Lilly and AstraZeneca; New Investigator Grant (NMRC/NIG09may023) and Clinician Scientist Award (NMRC/CSA/028/2010) from the National Medical Research Council, Singapore, Singapore. Funding Information: This work was supported by the Merck/Schering-Plough Alliance. Merck/Schering-Plough was not involved in study design, or collection, management, analysis, and interpretation of the data. Funding Information: Paul W. Armstrong: Research grant or contract from Schering-Plough Research Institute, Portola Pharmaceutical Inc., AstraZeneca, and Merck & Company Inc., which partially supports his university salary and/or research projects. A complete listing of Dr. Armstrong's relationships with industry is available at http://www.vigour.ualberta.ca .

PY - 2013/7/31

Y1 - 2013/7/31

N2 - Background: Data are limited on whether clinical trials have randomized higher-risk patients over time and how trends in risk profiles and evidence-based pharmacotherapies have influenced trial outcomes. We quantified changes in baseline risk, treatment, and outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) randomized in 9 phase 3 clinical trials of antithrombotic therapy over 15 years. Methods: We studied 58,771 patients in GUSTO IIb, PURSUIT, PARAGON-A, PARAGON-B, PRISM, PRISM-PLUS, GUSTO IV-ACS, SYNERGY, and EARLY ACS. Patient-level data were mapped to 3 pre-specified 5-year randomization periods. Temporal trends in GRACE score-predicted mortality were compared with trends in observed mortality. Results: Over time, in-hospital and discharge use of thienopyridines (p = 0.001), statins (p < 0.0001), and angiotensin-converting enzyme inhibitors (p < 0.0001) increased, and hospital length-of-stay decreased (p = 0.024). Blood transfusion use increased (8.3% [1994-98], 10.7% [1999-2003], 13% [2004-08], p = 0.0002) despite stable rates of severe bleeding (0.9% [1994-98], 1.4% [1999-2003] and 1.1% [2004-08], p = 0.127) and coronary artery bypass grafting (12.4% [1994-98], 13.7% [1999-2003] 13.1% [2004-08], p = 0.880). Although predicted 6-month mortality increased (6.9% [1994-98], 9.0% [1999-2003], 7.9% [2004-08], p = 0.017), observed 6-month mortality decreased (6.7% [1994-98], 5.8% [1999-2003], 5.1% [2004-08], p = 0.025). Thirty-day myocardial infarction rates remained stable (9.2% [1994-98], 9.3% [1999-2003], 10% [2004-08], p = 0.539). Conclusions: Despite enrolling higher-risk patients into these NSTE ACS trials, with better treatment, observed mortality declined over the past 15 years. The appropriateness of increased blood transfusion despite unchanged bleeding rates deserves further study.

AB - Background: Data are limited on whether clinical trials have randomized higher-risk patients over time and how trends in risk profiles and evidence-based pharmacotherapies have influenced trial outcomes. We quantified changes in baseline risk, treatment, and outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) randomized in 9 phase 3 clinical trials of antithrombotic therapy over 15 years. Methods: We studied 58,771 patients in GUSTO IIb, PURSUIT, PARAGON-A, PARAGON-B, PRISM, PRISM-PLUS, GUSTO IV-ACS, SYNERGY, and EARLY ACS. Patient-level data were mapped to 3 pre-specified 5-year randomization periods. Temporal trends in GRACE score-predicted mortality were compared with trends in observed mortality. Results: Over time, in-hospital and discharge use of thienopyridines (p = 0.001), statins (p < 0.0001), and angiotensin-converting enzyme inhibitors (p < 0.0001) increased, and hospital length-of-stay decreased (p = 0.024). Blood transfusion use increased (8.3% [1994-98], 10.7% [1999-2003], 13% [2004-08], p = 0.0002) despite stable rates of severe bleeding (0.9% [1994-98], 1.4% [1999-2003] and 1.1% [2004-08], p = 0.127) and coronary artery bypass grafting (12.4% [1994-98], 13.7% [1999-2003] 13.1% [2004-08], p = 0.880). Although predicted 6-month mortality increased (6.9% [1994-98], 9.0% [1999-2003], 7.9% [2004-08], p = 0.017), observed 6-month mortality decreased (6.7% [1994-98], 5.8% [1999-2003], 5.1% [2004-08], p = 0.025). Thirty-day myocardial infarction rates remained stable (9.2% [1994-98], 9.3% [1999-2003], 10% [2004-08], p = 0.539). Conclusions: Despite enrolling higher-risk patients into these NSTE ACS trials, with better treatment, observed mortality declined over the past 15 years. The appropriateness of increased blood transfusion despite unchanged bleeding rates deserves further study.

KW - Antithrombotic therapy

KW - Non-ST-segment elevation acute coronary syndromes

KW - Outcomes

KW - Randomized clinical trials

KW - Risk

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Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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