Accepted Manuscript Impact of Aspirin According to Type of Stable Coronary Artery Disease: Insights from a Large International Cohort Anthony A. Bavry, MD, MPH Yan Gong, PhD Eileen M. Handberg, PhD Rhonda M. Cooper-DeHoff, PharmD, MS Carl J. Pepine, MD PII:
S0002-9343(14)00907-3
DOI:
10.1016/j.amjmed.2014.09.028
Reference:
AJM 12718
To appear in:
The American Journal of Medicine
Received Date: 25 April 2014 Revised Date:
9 September 2014
Accepted Date: 10 September 2014
Please cite this article as: Bavry AA, Gong Y, Handberg EM, Cooper-DeHoff RM, Pepine CJ, Impact of Aspirin According to Type of Stable Coronary Artery Disease: Insights from a Large International Cohort, The American Journal of Medicine (2014), doi: 10.1016/j.amjmed.2014.09.028. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Impact of Aspirin According to Type of Stable Coronary Artery Disease: Insights from a
Brief Title: Aspirin and stable coronary artery disease
RI PT
Large International Cohort
Cooper-DeHoff, PharmD, MSb,c, Carl J Pepine, MDb
a
SC
Anthony A Bavry, MD, MPHa,b, Yan Gong, PhDc, Eileen M Handberg, PhDb, Rhonda M
M AN U
North Florida/South Georgia Veterans Health System, Gainesville, Florida; bCollege of
Medicine, University of Florida, Gainesville, Florida; cCollege of Pharmacy, University of
TE D
Florida, Gainesville, Florida
*Corresponding author: Anthony A Bavry, MD MPH, 1600 SW Archer Rd, PO Box 100277, Gainesville, FL 32610-0277. Phone: (352) 273-9076; fax: (352) 846-
EP
0314. E-mail: [email protected]
AC C
Funding Sources:
No funding was obtained for this study. The original INVEST study was funded by a grant from BASF Pharma, Ludwigshafen, Germany; Abbott Laboratories, Abbott Park, IL, USA; and the University of Florida Research Foundation and Opportunity Fund. BASF Pharma and Abbott Laboratories had no role in the design or conduct of the study, collection or analysis of data, or preparation or approval of the manuscript.
ACCEPTED MANUSCRIPT 2
Conflict of Interest Statement: Dr Bavry currently receives research support from Novartis Pharmaceuticals, Gilead,
RI PT
and Eli Lilly and serves as a contractor for the American College of Cardiology’s CardioSource, and previously served on an advisory board for Gilead and as a
contractor for Boehringer Ingelheim. Dr Cooper-DeHoff currently receives funding from
SC
the NIH, National Human Genome Research Institute (U01 HG007269); NIH, National Institute of General Medical Sciences (PEAR, 2U01 GM074492); NIH, National Heart,
M AN U
Lung and Blood Institute through a contract with Wake Forest University (WHI, HHSN268201100004C); University of Florida Clinical and Translational Science Institute (UF CTSI, Clinical Research Pilot Award); and Southeast Center for Integrative Metabolomics, UF CTSI (Pilot and Feasibility Project Award). Dr Handberg reported
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receiving grant support from NHLBI, Gilead, and educational grants from AstraZeneca, Daiichi Sankyo, Amarin, Mesoblast, ISIS Pharmaceuticals, Esperion Therapeutics, Vessex, Genentech, Cytori, Daiichi-Sankyo, Medtronic, Baxter, United Therapeutics,
EP
Sanofi/Aventis, Amgen, and Catabasis. Dr Pepine reported receiving research grants from the Abbott, Actelion Pharmaceuticals, Amarin, Amgen, Amorcyte,
AC C
Angioblast/Mesoblast, AstraZeneca, Baxter Healthcare, Brigham and Women’s Hospital, Capricor, Inc., Catabasis Pharmaceuticals, Cytori, Daiichi Sankyo, Esperion Therapeutics, Genentech, Gilead, GlaxoSmithKline, InfraReDx Inc., Isis Pharmaceuticals, Lilly, Medtronic, NeoStem Inc., NIH/NHLBI, Regeneron Pharmaceuticals, Sanofi, United Therapeutics Corp; consulting for Lilly/Cleveland Clinic-DSMB member for a Phase 2 Efficacy and safety study of Ly2484595, Mesoblast
ACCEPTED MANUSCRIPT 3
DSMB, Servier, and SLACK Inc. Dr Pepine receives support in part from the NIH/NCRR Clinical and Translational Science Award to the University of Florida UL1 TR000064. Dr Gong reports that she has no financial disclosures.
RI PT
Authorship Statement:
All authors had access to the data and a substantive role in writing the manuscript. Dr. Bavry drafted the manuscript, performed research, and analyzed data. All co-authors
SC
assisted in writing the manuscript, revised it critically for important intellectual content, and approved the final version of the manuscript and the decision to submit for
M AN U
publication. Additionally, Dr. Gong analyzed data; Dr. Cooper-DeHoff designed research
AC C
EP
TE D
and analyzed data; and Drs. Handberg and Pepine designed and performed research.
ACCEPTED MANUSCRIPT 4
Abstract Objective: To evaluate the impact of aspirin in stable coronary artery disease. We
coronary artery disease, but no prior ischemic event.
RI PT
hypothesized that aspirin’s benefit would be attenuated among individuals with stable
Background: Aspirin is recommended in stable coronary artery disease based on
myocardial infarction and stroke studies. However, benefit among stable coronary artery
SC
disease patients who have not suffered an acute ischemic event is uncertain.
Methods: An observational study was conducted from the INternational VErapamil-
M AN U
SR/Trandolapril STudy cohort. Ambulatory patients ≥50 years of age with clinically stable coronary artery disease requiring antihypertensive drug therapy (n=22,576) were classified ‘ischemic’ if they had a history of unstable angina, myocardial infarction, transient ischemic attack, or stroke at the baseline visit. All others were classified ‘non-
TE D
ischemic’. Aspirin use was updated at each clinic visit and considered as a time-varying covariate in a Cox regression model. The primary outcome was first occurrence of allcause mortality, myocardial infarction, or stroke.
EP
Results: At baseline, 56.7% of all participants used aspirin, which increased to 69.3% at study close out. Among the ‘non-ischemic’ group (n=13,091) aspirin was not
AC C
associated with a reduction in risk (hazard ratio [HR]=1.11, 95% confidence interval [CI] 0.97–1.28; P=0.13); however, among the ‘ischemic’ group (n=9,485) aspirin was associated with a reduction in risk (HR=0.87, 95%CI 0.77–0.99; P=0.033). Conclusions: In patients with stable coronary artery disease and hypertension, aspirin use was associated with reduced risk for adverse cardiovascular outcomes among
ACCEPTED MANUSCRIPT 5
those with prior ischemic events. Among patients with no prior ischemic events, aspirin
RI PT
use was not associated with a reduction in risk.
Keywords: Aspirin; Adverse cardiovascular events; Ischemic heart disease; Coronary
SC
artery disease
M AN U
Abbreviations
CI = confidence interval
TE D
HR = hazard ratio
AC C
EP
INVEST = INternational VErapamil-SR/Trandolapril Study
ACCEPTED MANUSCRIPT 6
INTRODUCTION Aspirin is used by approximately one-third of the United States population (over 50
RI PT
million individuals), including over 80% of those with known cardiovascular disease, which makes this a medication of significant public health importance.1 Aspirin is widely recommended for patients with stable coronary artery disease.2-5 This recommendation includes patients with hypertension and previous cardiovascular events.6
SC
Aspirin has been documented to be beneficial in reduction of cardiovascular
M AN U
outcomes after coronary ischemic events (unstable angina/myocardial infarction) and cerebrovascular ischemic events (transient ischemic attack/stroke).7-9 Moreover, a large meta-analysis of secondary prevention studies documented the absolute reduction in cardiovascular outcomes to be greater than the absolute excess in major bleeds.10 However, it is important to note that stable coronary artery disease is a broad spectrum
TE D
of disease that also includes patients with no prior ischemic events. Such a patient might have stable angina symptoms with our without percutaneous or surgical revascularization.
EP
With the frequent use of coronary angiogram (and cardiac computed
AC C
tomography), many patients with signs and symptoms of ischemia are diagnosed with non-obstructive coronary artery disease that does not require revascularization.11 For such patients, aspirin is still recommended, although there is a relative paucity of data to guide this recommendation.2,3 Therefore, the aim of this study was to investigate the association between aspirin and adverse cardiovascular events among 2 groups of hypertensive patients with stable coronary artery disease–prior ischemic events versus no prior ischemic events. We utilized the INternational VErapamil-SR/Trandolapril
ACCEPTED MANUSCRIPT 7
STudy (INVEST) cohort where aspirin use was left to provider discretion to test our hypothesis that the magnitude of benefit for aspirin would be attenuated among stable
RI PT
coronary artery disease patients with no prior ischemic event.
METHODS Study Cohort
SC
Details regarding the INVEST protocol and outcomes have been published
elsewhere (clinicaltrials.gov NCT00133692).12,13 Briefly, INVEST was an international
M AN U
randomized trial that compared the effects of a calcium antagonist (verapamil SR)based strategy with a beta-blocker (atenolol)-based strategy for treatment of hypertension among 22,576 patients at least 50 years of age with clinically stable coronary artery disease. Enrollment began September 1997, and follow-up was
TE D
completed in February 2003. The study was conducted according to the principles of the Declaration of Helsinki. Local institutional review boards and ethics committees approved the protocol, and written informed consent was obtained from all subjects.
EP
Target blood pressure was
S0002-9343(14)00907-3
DOI:
10.1016/j.amjmed.2014.09.028
Reference:
AJM 12718
To appear in:
The American Journal of Medicine
Received Date: 25 April 2014 Revised Date:
9 September 2014
Accepted Date: 10 September 2014
Please cite this article as: Bavry AA, Gong Y, Handberg EM, Cooper-DeHoff RM, Pepine CJ, Impact of Aspirin According to Type of Stable Coronary Artery Disease: Insights from a Large International Cohort, The American Journal of Medicine (2014), doi: 10.1016/j.amjmed.2014.09.028. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Impact of Aspirin According to Type of Stable Coronary Artery Disease: Insights from a
Brief Title: Aspirin and stable coronary artery disease
RI PT
Large International Cohort
Cooper-DeHoff, PharmD, MSb,c, Carl J Pepine, MDb
a
SC
Anthony A Bavry, MD, MPHa,b, Yan Gong, PhDc, Eileen M Handberg, PhDb, Rhonda M
M AN U
North Florida/South Georgia Veterans Health System, Gainesville, Florida; bCollege of
Medicine, University of Florida, Gainesville, Florida; cCollege of Pharmacy, University of
TE D
Florida, Gainesville, Florida
*Corresponding author: Anthony A Bavry, MD MPH, 1600 SW Archer Rd, PO Box 100277, Gainesville, FL 32610-0277. Phone: (352) 273-9076; fax: (352) 846-
EP
0314. E-mail: [email protected]
AC C
Funding Sources:
No funding was obtained for this study. The original INVEST study was funded by a grant from BASF Pharma, Ludwigshafen, Germany; Abbott Laboratories, Abbott Park, IL, USA; and the University of Florida Research Foundation and Opportunity Fund. BASF Pharma and Abbott Laboratories had no role in the design or conduct of the study, collection or analysis of data, or preparation or approval of the manuscript.
ACCEPTED MANUSCRIPT 2
Conflict of Interest Statement: Dr Bavry currently receives research support from Novartis Pharmaceuticals, Gilead,
RI PT
and Eli Lilly and serves as a contractor for the American College of Cardiology’s CardioSource, and previously served on an advisory board for Gilead and as a
contractor for Boehringer Ingelheim. Dr Cooper-DeHoff currently receives funding from
SC
the NIH, National Human Genome Research Institute (U01 HG007269); NIH, National Institute of General Medical Sciences (PEAR, 2U01 GM074492); NIH, National Heart,
M AN U
Lung and Blood Institute through a contract with Wake Forest University (WHI, HHSN268201100004C); University of Florida Clinical and Translational Science Institute (UF CTSI, Clinical Research Pilot Award); and Southeast Center for Integrative Metabolomics, UF CTSI (Pilot and Feasibility Project Award). Dr Handberg reported
TE D
receiving grant support from NHLBI, Gilead, and educational grants from AstraZeneca, Daiichi Sankyo, Amarin, Mesoblast, ISIS Pharmaceuticals, Esperion Therapeutics, Vessex, Genentech, Cytori, Daiichi-Sankyo, Medtronic, Baxter, United Therapeutics,
EP
Sanofi/Aventis, Amgen, and Catabasis. Dr Pepine reported receiving research grants from the Abbott, Actelion Pharmaceuticals, Amarin, Amgen, Amorcyte,
AC C
Angioblast/Mesoblast, AstraZeneca, Baxter Healthcare, Brigham and Women’s Hospital, Capricor, Inc., Catabasis Pharmaceuticals, Cytori, Daiichi Sankyo, Esperion Therapeutics, Genentech, Gilead, GlaxoSmithKline, InfraReDx Inc., Isis Pharmaceuticals, Lilly, Medtronic, NeoStem Inc., NIH/NHLBI, Regeneron Pharmaceuticals, Sanofi, United Therapeutics Corp; consulting for Lilly/Cleveland Clinic-DSMB member for a Phase 2 Efficacy and safety study of Ly2484595, Mesoblast
ACCEPTED MANUSCRIPT 3
DSMB, Servier, and SLACK Inc. Dr Pepine receives support in part from the NIH/NCRR Clinical and Translational Science Award to the University of Florida UL1 TR000064. Dr Gong reports that she has no financial disclosures.
RI PT
Authorship Statement:
All authors had access to the data and a substantive role in writing the manuscript. Dr. Bavry drafted the manuscript, performed research, and analyzed data. All co-authors
SC
assisted in writing the manuscript, revised it critically for important intellectual content, and approved the final version of the manuscript and the decision to submit for
M AN U
publication. Additionally, Dr. Gong analyzed data; Dr. Cooper-DeHoff designed research
AC C
EP
TE D
and analyzed data; and Drs. Handberg and Pepine designed and performed research.
ACCEPTED MANUSCRIPT 4
Abstract Objective: To evaluate the impact of aspirin in stable coronary artery disease. We
coronary artery disease, but no prior ischemic event.
RI PT
hypothesized that aspirin’s benefit would be attenuated among individuals with stable
Background: Aspirin is recommended in stable coronary artery disease based on
myocardial infarction and stroke studies. However, benefit among stable coronary artery
SC
disease patients who have not suffered an acute ischemic event is uncertain.
Methods: An observational study was conducted from the INternational VErapamil-
M AN U
SR/Trandolapril STudy cohort. Ambulatory patients ≥50 years of age with clinically stable coronary artery disease requiring antihypertensive drug therapy (n=22,576) were classified ‘ischemic’ if they had a history of unstable angina, myocardial infarction, transient ischemic attack, or stroke at the baseline visit. All others were classified ‘non-
TE D
ischemic’. Aspirin use was updated at each clinic visit and considered as a time-varying covariate in a Cox regression model. The primary outcome was first occurrence of allcause mortality, myocardial infarction, or stroke.
EP
Results: At baseline, 56.7% of all participants used aspirin, which increased to 69.3% at study close out. Among the ‘non-ischemic’ group (n=13,091) aspirin was not
AC C
associated with a reduction in risk (hazard ratio [HR]=1.11, 95% confidence interval [CI] 0.97–1.28; P=0.13); however, among the ‘ischemic’ group (n=9,485) aspirin was associated with a reduction in risk (HR=0.87, 95%CI 0.77–0.99; P=0.033). Conclusions: In patients with stable coronary artery disease and hypertension, aspirin use was associated with reduced risk for adverse cardiovascular outcomes among
ACCEPTED MANUSCRIPT 5
those with prior ischemic events. Among patients with no prior ischemic events, aspirin
RI PT
use was not associated with a reduction in risk.
Keywords: Aspirin; Adverse cardiovascular events; Ischemic heart disease; Coronary
SC
artery disease
M AN U
Abbreviations
CI = confidence interval
TE D
HR = hazard ratio
AC C
EP
INVEST = INternational VErapamil-SR/Trandolapril Study
ACCEPTED MANUSCRIPT 6
INTRODUCTION Aspirin is used by approximately one-third of the United States population (over 50
RI PT
million individuals), including over 80% of those with known cardiovascular disease, which makes this a medication of significant public health importance.1 Aspirin is widely recommended for patients with stable coronary artery disease.2-5 This recommendation includes patients with hypertension and previous cardiovascular events.6
SC
Aspirin has been documented to be beneficial in reduction of cardiovascular
M AN U
outcomes after coronary ischemic events (unstable angina/myocardial infarction) and cerebrovascular ischemic events (transient ischemic attack/stroke).7-9 Moreover, a large meta-analysis of secondary prevention studies documented the absolute reduction in cardiovascular outcomes to be greater than the absolute excess in major bleeds.10 However, it is important to note that stable coronary artery disease is a broad spectrum
TE D
of disease that also includes patients with no prior ischemic events. Such a patient might have stable angina symptoms with our without percutaneous or surgical revascularization.
EP
With the frequent use of coronary angiogram (and cardiac computed
AC C
tomography), many patients with signs and symptoms of ischemia are diagnosed with non-obstructive coronary artery disease that does not require revascularization.11 For such patients, aspirin is still recommended, although there is a relative paucity of data to guide this recommendation.2,3 Therefore, the aim of this study was to investigate the association between aspirin and adverse cardiovascular events among 2 groups of hypertensive patients with stable coronary artery disease–prior ischemic events versus no prior ischemic events. We utilized the INternational VErapamil-SR/Trandolapril
ACCEPTED MANUSCRIPT 7
STudy (INVEST) cohort where aspirin use was left to provider discretion to test our hypothesis that the magnitude of benefit for aspirin would be attenuated among stable
RI PT
coronary artery disease patients with no prior ischemic event.
METHODS Study Cohort
SC
Details regarding the INVEST protocol and outcomes have been published
elsewhere (clinicaltrials.gov NCT00133692).12,13 Briefly, INVEST was an international
M AN U
randomized trial that compared the effects of a calcium antagonist (verapamil SR)based strategy with a beta-blocker (atenolol)-based strategy for treatment of hypertension among 22,576 patients at least 50 years of age with clinically stable coronary artery disease. Enrollment began September 1997, and follow-up was
TE D
completed in February 2003. The study was conducted according to the principles of the Declaration of Helsinki. Local institutional review boards and ethics committees approved the protocol, and written informed consent was obtained from all subjects.
EP
Target blood pressure was
