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Requests for reprints should be addressed to Anthony A. Bavry, MD, MPH, North Florida/South Georgia Veterans Health System, 1600 SW Archer Rd., PO Box 100277, Gainesville, FL 32610-0277.
Aspirin is recommended in stable coronary artery disease based on myocardial infarction and stroke studies. However, benefit among stable coronary artery disease patients who have not suffered an acute ischemic event is uncertain. The objective of this study was to evaluate the impact of aspirin in stable coronary artery disease. We hypothesized that aspirin's benefit would be attenuated among individuals with stable coronary artery disease but no prior ischemic event.
Methods
An observational study was conducted from the INternational VErapamil-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-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 all-cause mortality, myocardial infarction, or stroke.
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 associated with a reduction in risk (hazard ratio [HR] 1.11; 95% confidence interval [CI], 0.97-1.28; P = .13); however, among the “ischemic” group (n = 9485), aspirin was associated with a reduction in risk (HR 0.87; 95% CI, 0.77-0.99; P = .033).
Conclusions
In patients with stable coronary artery disease and hypertension, aspirin use was associated with reduced risk for adverse cardiovascular outcomes among those with prior ischemic events. Among patients with no prior ischemic events, aspirin use was not associated with a reduction in risk.
In a large observational study, we found that some individuals with stable coronary artery disease do not derive appreciable benefit from aspirin.
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Among those with no prior ischemic event, aspirin use was not associated with a reduction in adverse cardiovascular events, but was associated with an increase in strokes.
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Among those with prior ischemic events, aspirin was associated with a reduction in adverse cardiovascular events and all-cause mortality.
Aspirin is used by approximately one-third of the United States population (over 50 million individuals), including over 80% of those with known cardiovascular disease, which makes this a medication of significant public health importance.
AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology.
2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
Aspirin has been documented to be beneficial in reduction of cardiovascular outcomes after coronary ischemic events (unstable angina/myocardial infarction) and cerebrovascular ischemic events (transient ischemic attack/stroke).
Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.
Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
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.
Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
However, it is important to note that stable coronary artery disease is a broad spectrum of disease that also includes patients with no prior ischemic events. Such a patient might have stable angina symptoms with or without percutaneous or surgical revascularization.
With the frequent use of coronary angiogram (and cardiac computed tomography), many patients with signs and symptoms of ischemia are diagnosed with nonobstructive coronary artery disease that does not require revascularization.
AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
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 vs no prior ischemic events. We utilized the INternational VErapamil-SR/Trandolapril 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 coronary artery disease patients with no prior ischemic event.
Methods
Study Cohort
Details about the INVEST protocol and outcomes have been published elsewhere (clinicaltrials.gov NCT00133692).
Rationale and design of the International Verapamil SR/Trandolapril Study (INVEST): an Internet-based randomized trial in coronary artery disease patients with hypertension.
A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial.
Briefly, INVEST was an international 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 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. Target blood pressure was <140/90 mm Hg (<130/85 mm Hg in the presence of diabetes or chronic kidney disease).
Trandolapril or hydrochlorothiazide, or both, could be added as necessary to achieve target blood pressure. Because INVEST was a large, international, contemporary trial with good blood pressure control, this was considered an excellent database to study the effectiveness of aspirin among individuals with hypertension and stable coronary artery disease. The entire INVEST cohort was considered for this analysis because there was no difference in hypertension control or outcomes between treatment strategies.
Coronary artery disease was defined as prior documented myocardial infarction, abnormal coronary angiogram (≥50% stenosis in at least one major coronary artery), concordant abnormalities on 2 different types of cardiac tests (electrocardiogram, echocardiogram, or myocardial perfusion study), or classic angina pectoris. Patients were excluded for current unstable angina; coronary revascularization, or stroke within the last month; myocardial infarction within the last 3 months; beta-blocker use within the last 2 weeks or within 12 months of a myocardial infarction; sinus bradycardia, sick sinus syndrome or type 2 or 3 heart block without permanent pacemaker, Wolff-Parkinson-White syndrome, ventricular tachycardia, or other serious arrhythmias; decompensated heart failure (New York Heart Association class IV); renal or hepatic dysfunction; contraindication to study medication; or limited life expectancy. Participants were classified into “ischemic”/“non-ischemic” sub-groups at the baseline visit according to history of unstable angina, myocardial infarction, transient ischemic attack, or stroke.
Exposure/Outcomes
Protocol-scheduled follow-up visits occurred every 6 weeks for the first 6 months (visits 2 to 5), then twice per year until 2 years after the last patient was enrolled. At the baseline visit and each postbaseline visit, a medication inventory was obtained. The use of aspirin was queried separately from nonaspirin nonsteroidal anti-inflammatory drugs. The primary study outcome was the first occurrence of all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes were the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, and individual components of all-cause mortality, cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, or bleeding. Outcomes were adjudicated by an events committee by review of pertinent patient and hospital records. Nonfatal myocardial infarction was defined as an elevation in cardiac enzymes (troponin I or T, or creatine-kinase myocardial band isoenzyme) greater than the upper limit of normal with ischemic symptoms or ischemic electrocardiographic changes. Nonfatal stroke was defined as a sudden onset of a neurological deficit that persisted for at least 24 hours and was confirmed by neurological imaging or neurology consult.
Statistical Methods
We performed Cox regression analyses by adjusting for time-varying use of aspirin. Confounding was controlled by including statistically significant covariates as suggested by a cut-off P value of .05. The association of aspirin and adverse cardiovascular events was reported as hazard ratio (HR) and 95% confidence interval (CI) (SAS software, version 9.3; SAS Institute, Inc., Cary, NC).
Baseline characteristics were reported as mean and standard deviation or frequencies as appropriate, and continuous and categorical variables were compared with Student's t test and the chi-squared test, respectively. A P value <.05 was considered significant. No funding was obtained for the conduct of this study.
Results
At baseline, slightly more than half of all participants reported use of aspirin, which increased during the course of the study (from 56.7% at baseline to 69.3% at study close out). Use of aspirin was less frequent among the group with no prior ischemic event (n = 5923/13,091; 45.2%) compared with those with a prior ischemic event (n = 6872/9485; 72.5%) (Figure 1). There were many differences in baseline characteristics between aspirin use and no aspirin use within each group of participants. For example, participants with no prior ischemic event and baseline use of aspirin were older, less frequently women, less frequently of black race, and more frequently had coronary revascularization, congestive heart failure, smoking, diabetes, hyperlipidemia, peripheral arterial disease, and chronic kidney disease than nonaspirin users (Table 1).
Figure 1Proportion of aspirin use over time among INVEST participants. The use of aspirin increased during the course of the study, especially among participants with no prior ischemic event.
Among those with no prior ischemic event, over 90% reported use of aspirin during at least one clinic visit. Aspirin classification changed over time, based on reported use of aspirin at follow-up visits. For example, among participants with no prior ischemic event and baseline use of aspirin, 5.5% reported no aspirin at any follow-up visit, 7.7% reported infrequent aspirin use, 27.4% reported frequent aspirin use, and 59.4% reported aspirin use at each follow-up visit (Table 2).
Table 2Aspirin Status during the Course of the Study
In the “non-ischemic” group, aspirin was not associated with reduction in risk for the primary outcome during a mean follow-up of 2.7 years (HR 1.11; 95% CI, 0.97-1.28; P = .13) (Table 3). In the “ischemic” group, aspirin was associated with a 13% reduction in risk for the primary outcome (HR 0.87; 95% CI, 0.77-0.99; P = .033) (Table 4). Figure 2 explored for effect modification among various sub-groups (mean blood pressure, treatment assignment, diabetic status, and sex) on the aspirin and adverse cardiovascular event association. Among participants with no prior ischemic event, there was no evidence for effect modification; however, among those with a prior ischemic event, the use of aspirin was associated with fewer adverse cardiovascular events when coupled with a beta-blocker, but not a calcium antagonist, strategy. The association of aspirin and secondary outcomes is displayed in Table 5. Among the “non-ischemic” group, the use of aspirin was associated with an increase in incident nonfatal stroke. Among the “ischemic” group, the use of aspirin was associated with a reduction in all-cause mortality.
Table 3Cox Regression Model for Participants with No Prior Ischemic Event: Association of Aspirin Use and Adverse Cardiovascular Outcomes
Characteristic
Parameter Estimate
Standard Error
Chi-squared
HR
95% CI
P Value
Time varying aspirin use
0.11
0.07
2.25
1.11
0.97-1.28
0.13
Age
0.06
0.003
259.21
1.06
1.06-1.05
<.0001
Male sex
0.24
0.073
11.15
1.28
1.11-1.48
.0008
BMI
−0.03
0.007
22.78
0.97
0.95-0.98
<.0001
SBP
0.01
0.002
38.68
1.01
1.01-1.02
<.0001
Heart rate
0.03
0.004
42.79
1.03
1.02-1.04
<.0001
CHF
0.56
0.119
22.36
1.76
1.39-2.23
<.0001
Smoking
0.46
0.073
39.18
1.58
1.37-1.83
<.0001
Diabetes
0.51
0.072
51.50
1.67
1.45-1.93
<.0001
Hyperlipidemia
−0.15
0.070
4.97
0.85
0.74-0.98
.0257
PAD
0.23
0.091
6.75
1.26
1.06-1.51
.0094
CKD
0.79
0.176
20.36
2.21
1.56-3.13
<.0001
Variables not included in the final model: race, history of left ventricular hypertrophy, treatment strategy, nonsteroidal anti-inflammatory drug use, and history of arrhythmia.
BMI = body mass index; CHF = congestive heart failure; CI = confidence interval; CKD = chronic kidney disease; HR = hazard ratio; PAD = peripheral arterial disease; SBP = systolic blood pressure.
Figure 2Interaction of aspirin and adverse cardiovascular events (all-cause death, myocardial infarction, or stroke) among participant subgroups. The hazard ratio is the risk for adverse cardiovascular events for aspirin vs no aspirin use. SBP = systolic blood pressure.
We found that the impact of aspirin among hypertensive individuals with stable coronary artery disease is variable depending upon presence or absence of prior ischemic events. Among those with no prior ischemic event, aspirin use was not associated with a reduction in adverse cardiovascular events, but was associated with an increase in strokes. Conversely, aspirin was associated with a reduction in adverse cardiovascular events and all-cause mortality among those with a prior coronary or cerebrovascular ischemic event. Among ischemic participants assigned to a beta-blocker strategy, aspirin was associated with fewer adverse cardiovascular events compared with a calcium antagonist strategy.
Among the “non-ischemic” group, aspirin was associated with a nonsignificant increase in composite adverse events, including an 86% increase in the risk of stroke. In part, this stroke hazard could be due to an increased risk of hemorrhagic stroke from the use of aspirin.
Also, the Antithrombotic Trialists' Collaboration documented a harmful association between the use of aspirin and ischemic stroke in the setting of primary prevention. This harmful association was not apparent among low-risk individuals (ie, estimated 5-year risk of a coronary heart disease event <2.5%), but it was among high-risk individuals (ie, estimated 5-year risk of a coronary heart disease event >10%; P for trend = .05).
Antithrombotic Trialists' (ATT) Collaboration Supplementary webappendix. Supplement to: Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
Lancet.2009; 373 (Available at:) (Accessed January 17, 2014): 1849-1860
This high-risk group may resemble the INVEST cohort that had no prior ischemic event, because their 5-year risk of a coronary event was approximately 13%.
Among the “ischemic” group, aspirin was associated with a 13% relative reduction in risk for adverse cardiovascular events. The association between aspirin use and reduced risk was driven by a reduction in all-cause mortality, but not cardiovascular mortality. This finding is consistent with an updated meta-analysis (included 12 primary prevention trials and 39 secondary prevention trials) that documented a reduction in nonvascular deaths with the use of aspirin, possibly by decreasing cancer-related deaths.
Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials.
The beneficial effect of aspirin was not apparent among participants assigned to a calcium antagonist strategy compared with a beta-blocker strategy. This could be explained by the known antiplatelet effects of calcium antagonists.
There are multiple strengths of the current analysis. One is the use of a large international cohort of patients with documented coronary artery disease and multiple follow-up visits with repeated ascertainment of aspirin use. The latter is important because patients might temporarily stop aspirin therapy due to intolerance or an adverse event such as a gastrointestinal hemorrhage. In fact, there was some change in aspirin classification, from use to disuse and vice versa, over the course of the study. Another strength is the excellent blood pressure control achieved in INVEST.
It is plausible that aspirin may not be helpful or may even be harmful among stable coronary artery disease patients with no prior ischemic events. In the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, participants at high risk for atherothrombotic events were randomized to dual antiplatelet therapy (aspirin and clopidogrel), compared with mono antiplatelet therapy (aspirin and placebo).
Among asymptomatic participants, aspirin and clopidogrel was associated with an increase in all-cause mortality (P = .04) and cardiovascular mortality (P = .01).
While the INVEST analysis only explored aspirin monotherapy, the CHARISMA trial supports that there are certain subgroups of patients in whom potent antiplatelet therapy may be harmful. It is possible that antiplatelet therapy could result in hemorrhage into atherosclerotic plaques, and thus result in plaque instability.
Limitations
Unfortunately, INVEST did not record stroke type (hemorrhagic vs ischemic) separately; however, based on epidemiological data, the proportion of ischemic strokes is approximately 90%.
We attempted to examine gastrointestinal hemorrhage as an adverse event and a possible reason for termination in aspirin therapy; however, there were only 176 such events, which precluded meaningful analysis of this outcome. The period of enrollment predates drug-eluting stents, which are known to have a unique side-effect profile.
Although the use of aspirin was carefully recorded during the study, the dose of aspirin therapy was not captured. This is likely of minimal significance because 300 to 325 mg of aspirin has not been shown to be superior to 75 to 100 mg of aspirin.
Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.
Although we performed a rigorous Cox regression analysis to account for known confounders and controlled for the use of aspirin as a time-varying covariate, issues of residual confounding within an observational study remain.
Conclusions
In conclusion, among patients with stable coronary disease and no prior ischemic event, the benefit of aspirin appears limited. The contemporary use of aspirin in stable coronary artery disease patients deserves further study.
References
Ajani U.A.
Ford E.S.
Greenland K.J.
Giles W.H.
Mokdad A.H.
Aspirin use among U.S. adults: Behavioral Risk Factor Surveillance System.
AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology.
2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.
Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
Rationale and design of the International Verapamil SR/Trandolapril Study (INVEST): an Internet-based randomized trial in coronary artery disease patients with hypertension.
A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial.
Supplementary webappendix. Supplement to: Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
Lancet.2009; 373 (Available at:) (Accessed January 17, 2014): 1849-1860
Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials.
Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.
Funding: 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.
Conflict of Interest: AAB currently receives research support from Novartis Pharmaceuticals, Gilead, 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. RMC currently receives funding from the National Institutes of Health (NIH), National Human Genome Research Institute (U01 HG007269); NIH, National Institute of General Medical Sciences (PEAR, 2U01 GM074492); NIH, National Heart, Lung and Blood Institute (NHLBI) 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). EMH reported 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, Sanofi/Aventis, Amgen, and Catabasis. CJP reported receiving research grants from Abbott, Actelion Pharmaceuticals, Amarin, Amgen, Amorcyte, 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-Data Safety Monitoring Board (DSMB) member for a Phase 2 Efficacy and safety study of Ly2484595, Mesoblast DSMB, Servier, and SLACK Inc. CJP receives support in part from the NIH/NCRR Clinical and Translational Science Award to the University of Florida UL1 TR000064. YG reports that she has no financial disclosures.
Authorship: All authors had access to the data and a substantive role in writing the manuscript. AAB drafted the manuscript, performed research, and analyzed data. All co-authors 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 publication. Additionally, YG analyzed data; RNC designed research and analyzed data; and EMH and CJP designed and performed research.
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