Although the appropriate use criteria incorporate common clinical scenarios for coronary revascularization, a significant proportion of patients with stable coronary artery disease (CAD) cannot be assigned an appropriateness score. Our objective was to characterize these patients and to evaluate whether coronary revascularization is associated with improved outcomes. A population-based cohort of patients aged ≥66 years, who underwent cardiac catheterization in Ontario, Canada, were included. Clinical characteristics were compared between patients with and without an appropriateness score. Clinical outcomes between coronary revascularization and medical therapy in patients with unclassified appropriateness score were compared using the inverse probability of treatment-weighted propensity method for confounder adjustment. Of the 19,228 patients with stable CAD, 11.2% (2,153 patients) were not assigned to an appropriateness score, mostly (92.9%) because of a lack of ischemic evaluation or a noninterpretable test. These patients were older, had higher rate of severe angina, and had more medical co-morbidities compared to patients with an appropriateness score. The 2-year rate of death or myocardial infarction in patients with unclassified appropriateness score was 15.3% in the revascularization group versus 20.7% in the medical therapy group. After propensity weighting, revascularization was associated with significantly lower hazard ratio (0.70; 95% confidence interval 0.61 to 0.79) for death or myocardial infarction compared with medical therapy. In conclusion, in patients aged ≥66 years with stable CAD and unclassified appropriateness score, revascularization is associated with improved outcomes.
Although the appropriate use criteria for coronary revascularization were constructed to incorporate most of the common clinical scenarios encountered in routine clinical practice, studies have demonstrated that as many as 25% of patients with stable coronary artery disease (CAD) cannot be assigned an appropriate score. Patients with stable CAD and unclassified appropriateness score are commonly encountered in clinical practice; however, little is known regarding their clinical characteristics, outcomes, and the impact of revascularization. Accordingly, the first objective of our study was to characterize patients who had unclassified appropriateness score for coronary revascularization. Second, we evaluated whether coronary revascularization is associated with improved clinical outcomes compared to medical therapy in patients with an unclassified appropriateness score. The Cardiac Care Network (CCN) registry, which maintains a prospective clinical registry of all patients undergoing cardiac invasive procedures in Ontario, Canada, was used to achieve our goals.
Methods
All hospitals in Ontario, Canada, are required to collect information prospectively on all cardiac catheterization, percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG) procedures for the CCN registry.
Demographics, clinical characteristics, and procedural information were gathered by clinical coordinators using procedure referral forms and hospital medical records. The registry was linked to the following population-based administrative databases in Ontario using unique encrypted patient health insurance numbers to protect patient confidentiality: the Canadian Institute for Health Information Discharge Abstract Database which captures all hospitalization records, the Ontario Health Insurance Plan database which includes information on physician service claims, the Registered Persons Database which contains vital statistics and demographic information for all Ontarians, and the Ontario Drug Benefit database which includes prescription data for subjects aged ≥65 years. These linked data sets are described elsewhere and have been used extensively in clinical research. The need for informed consent was exempted under Ontario’s legislation regarding privacy of health information because participation in the CCN registry is mandatory. This study was approved by the research ethics board at the Sunnybrook Health Sciences Center.
All patients aged ≥66 years who underwent cardiac catheterization from October 1, 2008, to July 31, 2011, in Ontario, Canada, were eligible for study inclusion. Patients with stable CAD were defined by excluding patients with acute coronary syndrome (unstable angina, myocardial infarction, and cardiogenic shock) in a manner consistent with previous research. Patients undergoing cardiac catheterization before scheduled cardiac operation were not included in the study. We selected patients with CAD, defined as luminal stenosis >50%, because the appropriateness criteria did not consider patients with normal to mild disease. For patients who had multiple cardiac catheterizations during the study period, only the first procedure was considered.
An appropriateness score was assigned to each patient at the time of the cardiac catheterization according to the appropriate use criteria for coronary revascularization guideline, which was based on (1) clinical presentation and symptom severity; (2) intensity of anti-ischemic medical therapy; (3) ischemic burden as determined by noninvasive testing; and (4) extent of coronary artery stenosis on coronary angiography. Patients who could not be assigned an appropriateness score were considered to be in the unclassified appropriateness score category.
The main outcome measure in the analysis comparing coronary revascularization and medical therapy was a composite measure of all-cause mortality or hospitalization for myocardial infarction. Mortality was determined using the Ontario Registered Persons Database. Myocardial infarction requiring hospitalization was identified from the Discharge Abstract Database using International Classification of Disease, Tenth Revision, code I21.
To characterize patients with an unclassified appropriateness score, we compared the demographic and clinical characteristics of patients with and without an assigned appropriateness score. We used the chi-square tests for comparing categorical variables and the Wilcoxon rank-sum test for continuous variables. We further compared patients with unclassified scores with patients who had appropriate score (7 to 9), uncertain score (4 to 6), and inappropriate score (1 to 3) for coronary revascularization. The potential benefit of coronary revascularization in patients with unclassified appropriateness score was evaluated by comparing outcomes of patients who underwent coronary revascularization with those who were treated medically. Patients who received PCI or CABG within 60 days after the index cardiac catheterization were categorized in the coronary revascularization group. To account for potential confounding between the treatment groups, we used the inverse probability of treatment-weighting method to account for systematic differences in baseline covariates between the revascularization and nonrevascularization groups. The propensity score, which was defined to be the probability of receiving coronary revascularization, was estimated with logistic regression analysis. The following characteristics which were selected on the basis of clinical knowledge were included as independent variables: age, gender, severity of angina, extent of coronary artery disease, ischemic evaluation, left ventricular ejection fraction, cardiac risk factors (smoking, hypertension, hyperlipidemia, diabetes), cardiac and medical co-morbidities (myocardial infarction, heart failure, chronic obstructive pulmonary disease, peripheral vascular disease, cerebrovascular disease, renal insufficiency, cancer, anemia, and trauma), cardiovascular medications, and physician (interventional cardiologist) and hospital characteristics (invasive capability).
Patients were then weighted by the inverse of the probability of receiving the treatment that they actually received. The degree of balance between the treatment groups in the weighted cohort was assessed by computing the standardized difference, with differences of <0.1 indicating good balance. Adjusted Kaplan–Meier survival curves were estimated for treated and untreated subjects separately in the weighted sample using a method described by Cole and Hernan. The effect of treatment on the hazard of clinical outcomes was then estimated using Cox proportional hazards model in which survival time was regressed on the recipient coronary revascularization. The inverse probability treatment weights were incorporated, and a robust variance estimator was used. We evaluated the potential benefit of the mode of coronary revascularization on death or repeat hospitalization for myocardial infarction by the inverse probability of treatment-weighting method (i.e., we compared CABG vs medical therapy and PCI vs medical therapy). We also evaluated the potential impact of coronary revascularization on clinical outcomes in predefined subgroups (left main or 3-vessel CAD, 1- or 2-vessel CAD, no ischemic evaluation, uninterpretable ischemic evaluation) by balancing the covariates in each subgroup using the propensity-weighted method.
Several additional analyses were performed to ensure our results were robust. First, we used multivariate proportional hazards models using coronary revascularization as time-varying exposure to account for the potential difference in revascularization time after the index cardiac catheterization. The use of a time-dependent covariate enabled the treatment to vary over time during the observation period after cardiac catheterization and allowed us to estimate the effect of current exposure on the instantaneous hazard of adverse outcomes compared with medical therapy. Second, we repeated the propensity score analysis using a landmark analysis design. In doing so, we excluded patients who had died or were hospitalized for myocardial infarction within 60 days of the cardiac catheterization and used the inverse probability of treatment-weighting method for adjustment. For the landmark analysis, follow-up for outcomes began at 60 days after catheterization.
All 2-sided p values <0.05 were considered statistically significant. SAS version 9.3 (SAS Institute, Cary, North Carolina) was used to conduct the analyses.
Results
After applying inclusion and exclusion criteria, our study cohort included 19,227 patients with stable CAD. Of these patients, 11.2% (2,153 patients) were not assigned to an appropriateness score. The most common reason for not having an appropriateness score was lack of ischemia evaluation: 73.9% (1,547 patients) had no evaluation and 24.8% (540 patients) had no interpretable results, followed by the lack of information about Canadian Cardiovascular Society (CCS) angina severity (7.1%, 153 patients).
The demographics and baseline characteristics of patients with unclassified appropriateness score and the classified group are provided in Table 1 . Patients in the classified group were further stratified into inappropriate, uncertain, and appropriate categories in Supplementary Table 1 . Of the 2,153 patients with unclassified appropriateness score, the mean age was 75.9 years, 34.1% were women, and 29.3% had class III or IV CCS angina ( Table 1 ). Patients with unclassified appropriateness score were slightly older, had more patients experiencing class IV angina, and also had a higher rate of asymptomatic patients without angina compared with patients with classified score. They also had significantly more co-morbidities such as previous myocardial infarction, heart failure, cerebrovascular disease, renal insufficiency, and chronic obstructive pulmonary disease ( Table 1 ). Despite their greater risk characteristics, they were significantly less likely to undergo assessment of left ventricular ejection fraction before cardiac catheterization and were less likely to be prescribed angiotensin receptor enzyme inhibitors or angiotensin receptor blockers, β blockers, and statin medications ( Table 1 ).
| Variable | Unclassified score (n=2,153) | Non-missing score (n=17,074) | P value |
|---|---|---|---|
| Age, mean ± SD (Years) | 75.9 ± 6.4 | 74.7 ± 5.8 | <0.001 |
| Women | 735 (34.1%) | 5,362 (31.4%) | 0.01 |
| CCS angina class | <0.001 | ||
| No angina | 610 (28.3%) | 3,929 (23.0%) | |
| I | 226 (10.5%) | 2,275 (13.3%) | |
| II | 497 (23.1%) | 5,773 (33.8%) | |
| III | 508 (23.6%) | 4,451 (26.1%) | |
| IV | 123 (5.7%) | 646 (3.8%) | |
| Unknown | 189 (8.8%) | 0 | |
| Number of major epicardial arteries narrowed | |||
| 0 | 6 (0.3%) | 236 (1.4%) | <0.001 |
| 1 | 950 (44.1%) | 7,660 (44.9%) | |
| 2 | 720 (33.4%) | 5,353 (31.4%) | |
| 3 | 477 (22.2%) | 3,825 (22.4%) | |
| Left main or 3 vessel | 495 (23.0%) | 5,345 (31.3%) | |
| Myocardial ischemia risk | <0.001 | ||
| High | 51 (2.4%) | 7,670 (44.9%) | |
| Low | 15 (0.7%) | 4,425 (25.9%) | |
| Not done | 1,547 (71.9%) | 4,858 (28.5%) | |
| Unknown | 540 (25.1%) | 121 (0.7%) | |
| Left ventricular ejection fraction | <0.001 | ||
| > 60% | 665 (30.9%) | 8,197 (48.0%) | |
| 40%–59% | 183 (8.5%) | 2,196 (12.9%) | |
| 20%–39% | 105 (4.9%) | 897 (5.3%) | |
| ≤ 20% | 57 (2.6%) | 258 (1.5%) | |
| Unknown | 1,143 (53.1%) | 5,526 (32.4%) | |
| Cardiovascular risk factors | |||
| Current smoker | 346 (16.1%) | 2,614 (15.3%) | 0.357 |
| Hypertension | 1,628 (75.6%) | 13,335 (78.1%) | 0.009 |
| Hyperlipidemia | 1,543 (71.7%) | 13,212 (77.4%) | <0.001 |
| Diabetes mellitus | 715 (33.2%) | 5,675 (33.2%) | 0.979 |
| Other conditions | |||
| Previous myocardial infarction | 665 (30.9%) | 4,306 (25.2%) | <0.001 |
| Prior heart failure | 402 (18.7%) | 1,810 (10.6%) | <0.001 |
| Previous PCI | 312 (14.5%) | 2,346 (13.7%) | 0.341 |
| Cerebrovascular disease | 227 (10.5%) | 1,600 (9.4%) | 0.08 |
| Renal insufficiency | 72 (3.3%) | 355 (2.1%) | <0.001 |
| Peripheral vascular disease | 218 (10.1%) | 1,571 (9.2%) | 0.164 |
| Chronic obstructive pulmonary disease | 171 (7.9%) | 1,145 (6.7%) | 0.032 |
| Cardiac medications | |||
| ACE inhibitors or ARBs | 1,258 (58.4%) | 10,522 (61.6%) | 0.004 |
| Statins | 1,159 (53.8%) | 10,018 (58.7%) | <0.001 |
| Beta blockers | 1,150 (53.4%) | 10,058 (58.9%) | <0.001 |
| Calcium channel blockers | 750 (34.8%) | 6,299 (36.9%) | 0.062 |
| Long acting nitrates | 422 (19.6%) | 3,217 (18.8%) | 0.397 |
| Clopidogrel | 301 (14.0%) | 2,290 (13.4%) | 0.467 |
| Physician and hospital characteristics | |||
| Interventional cardiologist | 1,469 (68.2%) | 11,762 (68.9%) | 0.535 |
| Cardiac catheterization only | 232 (10.8%) | 1,972 (11.5%) | <0.001 |
| Cardiac catheterization and PCI and CABG | 1,539 (71.5%) | 13,114 (76.8%) | |
| Cardiac catheterization, PCI no CABG | 382 (17.7%) | 1,988 (11.6%) | |
In the unclassified appropriateness score group, coronary revascularization was performed in 60.3% (1,298 patients), and 39.7% (855 patients) were treated medically. Patients who received coronary revascularization were slightly younger, more likely to have class III or IV angina, and more likely to have cardiac catheterization performed by an interventional cardiologist and at a full-service facility ( Supplementary Table 2 ).
Table 2 reports the baseline characteristics of the study population after application of inverse probability weights. All demographics and clinical characteristics were well balanced after propensity weight with all variables having a standardized difference of <0.1. The median follow-up of the unclassified appropriateness score study cohort was 3 years in the coronary revascularization group and 2.7 years in the medical therapy group. The rate of death or myocardial infarction was significantly lower in the coronary revascularization group compared to the medical therapy group (2-year rates 15.3% for revascularization vs 20.8% for medical therapy, p <0.001; Table 3 ). Difference in outcomes was driven mainly by a difference in death as the rate of myocardial infarction did not differ significantly. Clinical outcomes between the coronary revascularization and medical therapy groups began to diverge a month after the cardiac catheterization and continued to diverge over time ( Figure 1 ).
| Variable | Medical therapy (n=855) | Revascularization (n=1,298) | Standardized difference |
|---|---|---|---|
| Age, mean ± SD (Years) | 75.9 ± 10.4 | 75.9 ± 8.3 | 0.0117 |
| Women | 288 (33.7%) | 440 (33.9%) | 0.0036 |
| CCS angina class | |||
| No angina | 244 (28.5%) | 373 (28.8%) | 0.0084 |
| I | 89 (10.4%) | 135 (10.4%) | 0.0017 |
| II | 197 (23.1%) | 293 (22.6%) | 0.0113 |
| III | 208 (24.3%) | 306 (23.6%) | 0.0182 |
| IV | 45 (5.3%) | 78 (6%) | 0.032 |
| Unknown | 72 (8.4%) | 110 (8.5%) | 0.0029 |
| Number of major epicardial arteries narrowed | |||
| 1 | 378 (44.2%) | 578 (44.5%) | 0.0056 |
| 2 | 284 (33.2%) | 430 (33.1%) | 0.002 |
| 3 | 192 (22.4%) | 287 (22.1%) | 0.0073 |
| Myocardial ischemia risk | |||
| High | 19 (2.2%) | 30 (2.3%) | 0.0032 |
| Low | 6 (0.7%) | 8 (0.6%) | 0.0103 |
| Not done | 616 (72.1%) | 936 (72.1%) | 0.001 |
| Unknown | 215 (25.1%) | 326 (25.1%) | 0.001 |
| Left ventricular ejection fraction | |||
| > 60% | 265 (31%) | 400 (30.8%) | 0.0053 |
| 40%–59% | 70 (8.2%) | 106 (8.2%) | 0.0016 |
| 20%–39% | 41 (4.8%) | 62 (4.8%) | 0.0015 |
| ≤ 20% | 23 (2.7%) | 41 (3.2%) | 0.0313 |
| Unknown | 455 (53.2%) | 687 (52.9%) | 0.006 |
| Cardiovascular risk factors | |||
| Current smoker | 135 (15.8%) | 208 (16%) | 0.0053 |
| Hypertension | 651 (76.1%) | 979 (75.4%) | 0.0164 |
| Hyperlipidemia | 614 (71.8%) | 932 (71.8%) | 0.0018 |
| Diabetes mellitus | 286 (33.5%) | 435 (33.5%) | 0.001 |
| Other conditions | |||
| Previous myocardial infarction | 262 (30.6%) | 393 (30.3%) | 0.0053 |
| Prior heart failure | 159 (18.6%) | 245 (18.9%) | 0.0077 |
| Previous percutaneous coronary intervention | 127 (14.8%) | 196 (15.1%) | 0.0074 |
| Cerebrovascular disease | 91 (10.7%) | 141 (10.9%) | 0.0074 |
| Renal insufficiency | 28 (3.3%) | 43 (3.3%) | 0.0018 |
| Peripheral vascular disease | 88 (10.3%) | 139 (10.7%) | 0.014 |
| Chronic obstructive pulmonary disease | 68 (7.9%) | 108 (8.3%) | 0.0138 |
| Cardiovascular medications | |||
| ACE inhibitors or ARBs | 497 (58.1%) | 758 (58.4%) | 0.0045 |
| Statins | 460 (53.8%) | 696 (53.6%) | 0.0033 |
| Beta blockers | 453 (53%) | 689 (53.1%) | 0.0027 |
| Calcium channel blockers | 308 (36%) | 454 (35%) | 0.0213 |
| Long acting nitrates | 171 (20%) | 257 (19.8%) | 0.0045 |
| Clopidogrel | 124 (14.5%) | 179 (13.8%) | 0.0197 |
| Physician and hospital characteristics | |||
| Interventional cardiologist | 581 (68%) | 881 (67.9%) | 0.0026 |
| Cardiac catheterization only | 90 (10.5%) | 141 (10.9%) | 0.0128 |
| Cardiac catheterization and PCI and CABG | 610 (71.4%) | 928 (71.5%) | 0.001 |
| Cardiac catheterization, PCI no CABG | 155 (18.1%) | 228 (17.6%) | 0.0114 |
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