CLINICAL RESEARCH: CORONARY ARTERY DISEASE
Optimal Medical Therapy With or Without Percutaneous Coronary Intervention in Older Patients With Stable Coronary DiseaseA Pre-Specified Subset Analysis of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation) Trial
Koon K. Teo, MB, BCh, PhD*,
Steven P. Sedlis, MD ,
William E. Boden, MD ,*,
Robert A. O'Rourke, MD ,
David J. Maron, MD||,
Pamela M. Hartigan, PhD¶,
Marcin Dada, MD#,
Vipul Gupta, MBBS, MPH,
John A. Spertus, MD, MPH**,
William J. Kostuk, MD,
Daniel S. Berman, MD,
Leslee J. Shaw, PhD,
Bernard R. Chaitman, MD||||,
G.B. John Mancini, MD¶¶,
William S. Weintraub, MD## COURAGE Trial Investigators
* McMaster University Medical Center, Hamilton, Ontario, Canada
Veterans Affairs (VA) New York Harbor Health Care System and New York University School of Medicine, New York, New York
VA Western New York Health Care System, Buffalo General Hospital, and the University at Buffalo, Buffalo, New York
VA South Texas Health Care System, San Antonio, Texas
|| Vanderbilt University Medical Center, Nashville, Tennessee
¶ VA Cooperative Studies Program Coordinating Center and VA Connecticut Health Care System, West Haven, Connecticut
# Hartford Hospital, Hartford, Connecticut
** Mid America Heart Institute, Kansas City, Missouri
London Health Sciences Centre, London, Ontario, Canada
Cedars-Sinai Medical Center, Los Angeles, California
Emory University School of Medicine, Atlanta, Georgia
|||| St. Louis University, St. Louis, Missouri
¶¶ University of British Columbia, Vancouver, British Columbia, Canada
## Christiana Care Health System, Newark, Delaware
Manuscript received April 24, 2009;
revised manuscript received July 8, 2009,
accepted July 13, 2009.
* Reprint requests and correspondence: Dr. William E. Boden, Division of Cardiology, Buffalo General Hospital, 100 High Street, Buffalo, New York 14203 (Email: wboden{at}kaleidahealth.org).
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Abstract
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Objectives: Our aim was to access clinical effectiveness of percutaneous coronary intervention (PCI) when added to optimal medical therapy (OMT) in older patients with stable coronary artery disease (CAD).
Background: While older patients with CAD are at increased risk for cardiac events compared with younger patients, it is unclear whether PCI may mitigate this risk more effectively than OMT alone or, alternatively, may be associated with more complications.
Methods: We conducted a pre-specified analysis of outcomes in stable CAD patients stratified by age and randomized to PCI + OMT or OMT alone in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation) trial.
Results: A total of 1,381 patients (60%) were <65 years of age (mean 56 ± 6 years) and 904 patients (40%) were  65 years of age (mean 72 ± 5 years). Achieved treatment targets for blood pressure, low-density lipoprotein cholesterol, adherence to diet and exercise, and angina-free status did not differ by age or treatment assignment. Among older patients, there was a 2- to 3-fold higher death rate, but similar rates of myocardial infarction, stroke, and major cardiac events compared with younger patients. The addition of PCI to OMT did not improve or worsen clinical outcomes in patients 65 years of age during a median 4.6 year follow-up.
Conclusions: These data support adherence to American College of Cardiology/American Heart Association clinical practice guidelines that advocate OMT as an appropriate initial management strategy, regardless of age. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE]; NCT00007657
[ClinicalTrials.gov]
)
Key Words: percutaneous coronary intervention • optimal medical therapy • coronary artery disease
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Abbreviations and Acronyms
| | ACC = American College of Cardiology | | ACS = acute coronary syndromes | | AHA = American Heart Association | | BMI = body mass index | | CAD = coronary artery disease | | MI = myocardial infarction | | OMT = optimal medical therapy | | PCI = percutaneous coronary intervention |
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The management of older patients with coronary artery disease (CAD) is challenging since the risk and benefits of treatments are high and influenced by comorbidities. Older patients with acute coronary syndromes (ACS) are at higher risk for cardiac events than younger patients and, although therapies may provide proportionately greater benefit among patients at highest risk (1,2), such patients with advanced age are often subject to a "treatment-risk paradox" since they tend to receive less evidence-based secondary prevention than younger, low-risk patients (3). Whether a disparity in treatment and outcomes exists in older patients with stable CAD who receive optimal medical therapy (OMT) with or without percutaneous coronary intervention (PCI) remains uncertain. While age dichotomized at 65 years was 1 of 8 pre-specified covariates in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation) trial that did not show a difference between PCI and OMT for the primary end point (death or myocardial infarction [MI]) during long-term follow-up, other important cardiovascular outcomes that could vary by treatment assignment in older versus younger patients were not previously reported.
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Methods
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The design and main results of the COURAGE trial that randomized 2,287 patients with stable CAD to PCI plus OMT versus OMT alone have been published (4–6). In the present study, we performed a post hoc analysis of baseline characteristics, achieved treatment targets at 60 months of follow-up, and pre-specified cardiovascular outcomes during a 2.5- to 7-year (median 4.6-year) follow-up among patients age <65 versus 65 years at baseline. Outcomes for each age category were further subdivided by randomization status. Outcomes evaluated included the primary efficacy measure of all-cause mortality or nonfatal MI (time to first event); death; hospitalization for ACS; the composite of death, MI, or stroke; and the composite of death, MI, stroke, or hospitalization for ACS. Additional outcomes included the percentage of patients who achieved the target for blood pressure, low-density lipoprotein cholesterol, body mass index (BMI), smoking cessation, adherence to diet, exercise, and medications, as well as angina-free status.
Statistical analysis.
All statistical analyses were performed using the intent-to-treat principle. Data are expressed as numbers and percents, mean ± SD, and where appropriate, as medians and interquartile ranges. Chi-square tests were used to compare categorical variables, while the Student t test or median test was used for continuous variables. Cumulative event rates were estimated by the Kaplan-Meier method, and treatment effects were assessed using the stratified log-rank statistic (7). The Cox proportional hazards model (8) was used to estimate the hazard ratios and confidence limits for the primary and secondary outcomes as well as the interaction between treatment and age for these clinical outcomes. For lifestyle outcomes, a generalized linear model was used to assess the treatment and age effects and interaction between them (9). A level of significance of 0.01 was used for all statistical interactions and subgroup comparisons.
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Results
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Baseline characteristics, by age, are shown in Table 1. There were 1,381 patients in the younger group (mean age 56 ± 6 years) and 904 patients in the older group (mean age 72 ± 5 years). Within each age group, there were no differences in baseline characteristics between the randomized treatment assignment groups (Table 2). Procedural characteristics and outcomes among patients randomized to PCI are shown in Table 3
and were similar for both age groups. Primary and secondary outcomes are shown in Table 4. Among older patients, there was a higher incidence of death or MI (p < 0.001) and a 2- to 3-fold higher death rate (p < 0.001) but similar rates of MI, stroke, and hospitalization for unstable angina compared with younger patients. However, there was no interaction between age and the initial treatment strategy assignment for any pre-specified clinical outcome.
Treatment targets achieved at 60 months of follow-up are shown in Table 5. More younger patients than older patients achieved the target systolic blood pressure <130 mm Hg. There were comparably high rates of achieving the target low-density lipoprotein <85 mg/dl in older patients (78% of OMT patients; 70% of PCI + OMT patients) as in the age <65 years group (69% of OMT patients and 66% of PCI + OMT patients). Achievement of targets at 60 months for smoking cessation, adherence to American Heart Association (AHA) step II diet, exercise, and BMI are summarized in Table 5. More older patients than younger patients achieved target BMI, which may relate more to age-related loss of skeletal muscle mass than to an increased adherence to diet and/or exercise.
The percentage of patients in the younger group who were angina-free at 60 months of follow-up was 70% in both the OMT and PCI + OMT arms, whereas the percentage of angina-free patients in the older group was even higher, with 73% in the OMT arm and 80% in the PCI + OMT arm. Thus, despite the 2- to 3-fold higher rate of death and a 50% higher rate of death, MI, or stroke in the older patients, there was no evidence that PCI, when added to OMT, mitigated this risk, nor was PCI any more effective in achieving angina-free status in older patients. However, in older patients where age-related comorbidities may pose a higher risk for diagnostic coronary angiography and PCI, there were, likewise, no significant excess event rates noted in the PCI + OMT versus OMT alone groups.
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Discussion
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In this pre-specified analysis of clinical outcomes by age from the COURAGE trial, we found an overall 2- to 3-fold higher incidence of death in patients 65 years of age compared with patients <65 years of age but similar rates of MI, stroke, or hospitalization due to ACS in both age groups. There was no evidence that the addition of PCI to OMT was better (or worse) than OMT alone in reducing clinical events. In addition, older patients were angina-free at 60 months of follow-up with similar rates for those treated with PCI (80%) and OMT (73%).
While PCI has been shown to have significant benefits in the treatment of patients with ACS, notably by reducing death or MI during long-term follow-up, its role in the management of stable CAD remains less certain. Although PCI of stenotic coronary arteries relieves symptoms of angina more effectively than medical management alone, it does not prevent "hard" clinical outcomes such as death or MI in stable CAD patients (10), yet it remains one of the most commonly performed procedures in such patients, and accounts for approximately one-third to one-half of all PCIs performed annually in the U.S. (11).
The American College of Cardiology (ACC)/AHA clinical practice guidelines for the treatment of ACS do not alter therapeutic recommendations based on age, apart from encouraging appropriate risk stratification, attention to comorbidities, and appropriate dosing of medications (12,13). Alexander et al. (2) demonstrated that the use of recommended therapies in the elderly was significantly lower than in younger patients in the 56,963 patient CRUSADE ACS (Evolution in Cardiovascular Care for Elderly Patients With Non–ST-Segment Elevation Acute Coronary Syndromes) registry. After adjustment for age-related differences in treatments, contraindications, and comorbidities, elderly ACS patients were significantly less likely to receive antiplatelet and antithrombin therapy within the first 24 h, undergo early catheterization or revascularization, and receive clopidogrel and statins at hospital discharge. Importantly, while in-hospital mortality and complication rates increased with advancing age, patients age 65 years who received more ACC/AHA guideline-recommended therapies had lower in-hospital mortality even after adjustment than those who did not (2). Similar data from another large international registry of patients with ACS with or without ST-segment elevation reported significantly decreased use of recommended therapies in the elderly (14). Thus, concordant findings from 2 ACS registries emphasize that even short-term outcomes in the elderly may be favorably impacted by more widespread use of proven secondary prevention therapies. Little evidence, however, is available regarding the potential long-term benefits associated with the use of evidence-based medical therapies in older patients with stable ischemic heart disease.
In the TIME (Trial of Invasive versus Medical Therapy in Elderly patients) study, 1-year outcomes in elderly patients with chronic angina were similar with regard to symptoms, quality of life, and death or nonfatal infarction with invasive versus optimized medical strategies (15). In stable elderly patients (age >80 years) recovering from ST-segment elevation MI, Setoguchi et al. (16) showed a 10-year time trend in mortality improvement that was completely abolished after adjustment for the use of statins, beta-blockers, angiotensin inhibitors, and antiplatelet drugs, indicating that the more favorable outcome in long-term post-MI mortality was likely due to the increased use of proven secondary prevention medications after discharge. While there was evidence that post-MI PCI procedures may have also contributed to improved survival, after adjusting for post-MI PCI procedural use during the index MI hospitalization, the temporal change associated with improved prognosis was largely attenuated. This suggests that, in post-MI patients, improved short-term outcomes may have been attributable to PCI, whereas evidence-based secondary prevention therapies provided significant long-term prognostic benefit (17).
The results of the current COURAGE trial subset analysis provide important, new information on the clinical benefit of OMT in a cohort of patients age 65 years who have chronic angina and stable CAD and who comprised 40% of all enrolled patients. OMT is remarkably effective in achieving angina-free status during long-term follow-up, even acknowledging the expected reduction of physical activity, which goes along with advanced age, and is as effective as PCI in reducing rates of death, MI, stroke, and hospitalization for ACS. The present analysis demonstrates that not only can high rates of effective treatment be achieved in older subjects with the use of aggressive pharmacologic therapy and lifestyle intervention during long-term follow-up, but clinical events can be, likewise, favorably impacted.
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Conclusions
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OMT is as effective in stable CAD patients age 65 years as in patients age <65 years, and PCI, when added to OMT, does not reduce clinical events or improve angina relief during long-term follow-up. While, as expected, older patients have significantly higher overall rates of death and the composite of death or MI than younger patients, our results demonstrate that the addition of PCI does not mitigate this risk. While it is also true that older patients undergoing PCI did not display higher event rates (as might be anticipated in such patients with clinical comorbidities such as reduced kidney function), it nonetheless appears difficult to justify PCI as an initial treatment strategy in the majority of older patients with stable CAD, since clinical outcomes (including angina relief) appeared similar in OMT-treated and PCI + OMT-treated patients. Thus, these data support continued adherence to the published ACC/AHA treatment guidelines, which endorse OMT as the preferred initial management strategy for stable CAD patients, regardless of age.
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Footnotes
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This study was supported by the Cooperative Studies Program of the U.S. Department of Veterans Affairs Office of Research and Development, in collaboration with the Canadian Institutes of Health Research; and by unrestricted research grants from Merck, Pfizer, Bristol-Myers Squibb, Fujisawa, Kos Pharmaceuticals, Datascope, AstraZeneca, Key Pharmaceutical, Sanofi-Aventis, First Horizon, and GE Healthcare, including in-kind support with Food and Drug Administration-approved drugs used by study participants. All industrial funding in support of the trial was directed through the U.S. Department of Veterans Affairs. Dr. Teo has received honoraria from Boehringer Ingelheim. Dr. Spertus has received grants from Bristol-Myers Squibb/Sanofi, Amgen, Lilly, and Johnson & Johnson; has served on the scientific advisory board for United Healthcare; and has served as a consultant for Amgen and St. Jude Medical. Dr. Chaitman has done consulting and served on the Speakers' Bureau for Gilead, and has done consulting for Pfizer and Merck. Dr. Mancini has received honoraria (<$10,000) from GlaxoSmithKline, Merck, Pfizer, Sanofi-Aventis, and AstraZeneca. Dr. Weintraub has received grants from Abbott, AstraZeneca, Bristol-Myers Squibb, CVT, Otsuka, and Sanofi-Aventis; has provided expert testimony for AstraZeneca, Bayer, and Pfizer; and has served as a consultant for CVT, Cardionet, Eli Lilly, and Humana.
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References
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Abstract
Methods