Summary
Background
Management of acute coronary syndrome (ACS) patients with non-obstructive epicardial coronary artery disease (CAD) remains poorly understood.
Hypothesis
ACS patients with non-obstructive CAD are less likely to receive effective cardiac medications upon discharge from the hospital.
Methods
We identified patients hospitalized with ACS that underwent coronary angiography and had 6-month follow-up. Patients were grouped by CAD severity: non-obstructive CAD (<50% blockage in all vessels) or obstructive CAD (≥50% blockage in ≥1 vessels). Data were collected on demographics, medications at discharge, and adverse outcomes at 6 months, for all patients.
Results
Of the 2,264 ACS patients included in the study: 123 patients had non-obstructive CAD and 2,141 had obstructive CAD. Cardiac risk factors including hypertension and diabetes were common among patients with non-obstructive CAD. Men and women with non-obstructive CAD were less likely to receive cardiac medications compared to patients with obstructive CAD including aspirin (87.8% vs. 95.0%, p=0.001), beta-blockers (74.0% vs. 89.2%, p<0.001), or statins (69.1% vs. 81.2%, p=0.001). No gender-related differences in discharge medications were observed for patients with nonobstructive CAD. However women with non-obstructive CAD had similar rates of cardiac-related rehospitalization as men with obstructive CAD (23.3% and 25.9%, respectively).
Conclusions
Patients with non-obstructive CAD are less likely to receive evidence-based medications compared to patients with obstructive CAD, despite the presence of CAD risk factors and occurrence of an ACS event. Further research is warranted to determine if receipt of effective cardiac medications among patients with non-obstructive CAD would reduce cardiac related events.
Keywords: Non-obstructive coronary artery disease, Acute Coronary Syndrome, Prevention
INTRODUCTION
Approximately 10-25% of women and 6-10% of men with the acute coronary syndrome (ACS) have “normal” or non-obstructive atherosclerotic CAD defined as < 50% stenosis.1 Although the risk for adverse events post-ACS is lower in non-obstructive CAD patients, this group is not event-free.2 Data from the Thrombolysis in Myocardial Infarction trials (TIMI 11B, TIMI 16, TIMI 22) suggest that 10% of such patients may suffer either myocardial infarction (MI), unstable angina (UA) requiring hospitalization, revascularization, stroke, or death. 1
Currently, data on ACS patients with non-obstructive CAD is limited. Prior studies have observed women admitted for cardiac related diagnoses are more likely to have non-obstructive CAD on coronary angiogram,3-6 however the management of non-obstructive CAD is not well studied. Understanding the risk factor profile, ACS type, and the receipt of use of cardiac medications among women and men with non-obstructive CAD may add insight to current practice patterns and clinical outcomes. Therefore, we evaluated the clinical factors and rate of receipt at discharge for aspirin, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, statins, and clopidogrel or ticlopidine, among men and women ACS patients with non-obstructive epicardial CAD compared to men and women ACS patients with obstructive epicardial CAD.
METHODS
All patients admitted to the University of Michigan Health System’s ACS registry (n=3,514) between January 1999 and August 2004 with a diagnosis of ACS were eligible for study inclusion. Patients who did not receive coronary angiography during the index hospitalization or did not have six-month follow-up data were excluded (n=1,250). ACS was defined as unstable angina (UA), ST-segment elevation myocardial infarction (STEMI), or non-ST-segment elevation myocardial infarction (NSTEMI). The diagnosis of ACS was documented by standardized definitions which included the presence of symptoms consistent with acute coronary insufficiency, increases in cardiac enzymes (CK-MB > 2x upper limit of the hospital’s normal range and/or positive troponin I), and/or positive acute electrocardiographic changes including: 1) transient ST-segment elevations of ≥ 1 mm in 2 or more contiguous leads, 2) ST-segment depressions of ≥ 1 mm, 3) new T-wave inversions of ≥ 1 mm, and 4) new left bundle branch block.7,8 Patients under the age of 18 years were excluded from the study. Full details of the University of Michigan Health System’s ACS registry have been published previously.9
Independent variables included demographics (age, sex, race) and medical history as documented in the patients’ medical records (smoking status, history of angina, myocardial infarction [MI], hyperlipidemia, peripheral vascular disease, diabetes mellitus, hypertension, prior stroke), and CAD family history (defined as having any blood relative [parents, siblings, children] with a history of angina, MI and/or sudden cardiac death before the age of 55). Information regarding ACS type and in-hospital events was collected via chart review as described above. Discharge medications that were assessed included the following: aspirin, beta-blockers, ACE inhibitors, statins, and clopidogrel or ticlopidine. Patients with contraindications to these medications were excluded from the study. Measured outcomes of patients included in-hospital recurrent ischemia (defined as further symptoms of angina with or without ischemic electrocardiographic changes while in the hospital), and six-month outcomes such as rehospitalization for cardiac reasons (defined as any unscheduled rehospitalization[s] for heart disease), non-fatal MI, non-fatal stroke, all-cause death, and major adverse cardiovascular events (MACE) (defined as death from cardiac causes, non-fatal MI, non-fatal stroke, rehospitalization for cardiac causes, and/or unscheduled coronary revascularization).
Study site coordinators, physicians, and cardiology research nurses were trained and given a manual of operations to correctly identify patients eligible for study inclusion and accurately abstract the data from medical charts. Data not within the set limit ranges, inconsistencies, and/or unrecorded fields were flagged and then returned for clarification and correction. Six-month follow-up data were obtained via telephone calls. At least three phone call attempts were made to contact patients to query their health status before any medical record data collection occurred. All aspects of this study were approved by the institutional review board at the University of Michigan and informed consent was obtained from all patients.
ACS patients who underwent cardiac catheterization were divided into two groups: 1) non-obstructive CAD (<50% stenosis in all vessels) and 2) obstructive CAD (≥50% stenosis in ≥ 1 vessels), based on the angiographers’ interpretations. The cut-off of 50% was used based on previous studies.5,10 Within each CAD stratum, differences in characteristics were determined by sex. Differences in characteristics between those with and without non-obstructive CAD were also compared. A p-value of ≤ 0.05 was considered statistically significant. For testing differences between two groups, either the t test or the Wilcoxon–rank sum test for continuous variables was used as indicated by the data. For categorical data, the χ2 statistic was used with Yates’ correction factor as indicated by the data. Fisher’s exact test was used if the expected number of observations in any cell was less than five.
Bivariate analyses among patients in both groups of CAD severity were performed to determine if a relationship existed between prescribing at least 3 of 4 cardiac medications (aspirin, beta-blocker, ACE inhibitor, statin) at the time of discharge and rehospitalization rates for cardiac causes. We opted to evaluate 3 out of 4 of these medications (excluding clopidogrel and ticlopidine) as the evidence to support the prescription of clopidogrel post-ACS had not been published until 2001 - two years after the present study patients were enrolled.11 Statistical Analysis Software (SAS) 8.2 (SAS Institute, Cary, NC, USA) was used for all analyses.
RESULTS
A total of 2,264 ACS patients were included in the study and were followed for 6 months post-hospital discharge. Of these, 67.6% (n=1,530) were men and 93.6% (n=2,119) were white (Table 1). The majority of patients were classified as having obstructive CAD (94.6%) of which 1,473 were men and 668 were women. Non-obstructive CAD was observed in 123 patients (5.4%), of which 57 were men and 66 were women. Women were significantly more likely to have non-obstructive CAD upon angiography compared to men (9.0% vs. 3.7%, p<0.001). Non-obstructive CAD patients averaged 4 years younger, were less likely to be white and less likely to have a prior history of angina or hyperlipidemia, compared to obstructive CAD patients. Rates of traditional cardiovascular risk factors were similar among the two groups including current smoking, family history of CAD, diabetes, hypertension, peripheral vascular disease and stroke. Prevalence of diabetes ranged from 21.2% among women with non-obstructive CAD to 32.2% for women with obstructive CAD. High rates of hypertension were also observed among the women (70.8% for women with non-obstructive CAD and 77.2% for women with obstructive CAD).
Table 1.
Demographic, Medical History, ACS Characteristics, and In-Hospital Events of Coronary Artery Disease Patients Stratified by Severity of Coronary Artery Disease Status (n=2,264)*
| Demographics | Non-Obstructive CAD |
P1 | Obstructive CAD |
P1 | P2 | ||||
|---|---|---|---|---|---|---|---|---|---|
| All Patients (n=123) N (%) |
Men (n=57) N (%) |
Women (n=66) N (%) |
All Patients (n=2141) N (%) |
Men (n=1473) N (%) |
Women (n=668) N (%) |
||||
| Age, mean (SD), y | 58.7 (±15.4) | 54.4 (± 15.0) | 62.3 (± 14.9) | 0.004 | 62.7 (± 12.8) | 61.4 (± 12.4) | 65.4 (± 13.2) | <0.001 | <0.01 |
| Nonwhite race | 12 (16.4) | 5 (13.5) | 7 (19.4) | 0.49 | 133 (8.7) | 79 (7.6) | 54 (11.3) | 0.02 | 0.03 |
| Past Medical History | |||||||||
| Current Smoking | 27 (22.0) | 188 (31.6) | 9 (13.6) | 0.02 | 558 (26.3) | 397 (27.2) | 161 (24.2) | 0.15 | 0.29 |
| Angina | 33 (26.8) | 14 (24.6) | 19 (28.8) | 0.60 | 928 (43.4) | 624 (42.4) | 304 (45.6) | 0.17 | <0.001 |
| Myocardial infarction | 42 (34.1) | 23 (40.4) | 19 (28.8) | 0.18 | 786 (36.7) | 537 (36.5) | 249 (37.3) | 0.72 | 0.57 |
| Hyperlipidemia | 59 (48.4) | 32 (56.1) | 27 (41.5) | 0.11 | 1374 (64.3) | 941 (64.0) | 433 (64.9) | 0.69 | <0.001 |
| CAD Family History | 39 (45.3) | 15 (37.5) | 24 (52.2) | 0.17 | 528 (49.8) | 367 (50.5) | 161 (48.3) | 0.52 | 0.43 |
| PVD | 8 (6.6) | 5 (8.8) | 3 (4.6) | 0.36 | 253 (11.9) | 160 (10.9) | 93 (14.0) | 0.04 | 0.07 |
| Diabetes mellitus | 29 (23.6) | 15 (26.3) | 14 (21.2) | 0.51 | 601 (28.1) | 385 (26.2) | 216 (32.3) | 0.003 | 0.28 |
| Hypertension | 75 (61.5) | 29 (50.9) | 46 (70.8) | 0.02 | 1461 (68.4) | 946 (64.4) | 515 (77.2) | <0.001 | 0.11 |
| Prior Stroke | 9 (7.3) | 2 (3.5) | 7 (10.6) | 0.13 | 186 (8.7) | 106 (7.2) | 80 (12.0) | <0.001 | 0.60 |
| ACS type | |||||||||
| STEMI | 18 (14.6) | 10 (17.5) | 8 (12.1) | 0.40 | 539 (25.2) | 392 (26.6) | 147 (22.0) | 0.023 | 0.008 |
| NSTEMI | 81 (65.9) | 32 (56.1) | 49 (74.2) | 0.04 | 1192 (55.7) | 808 (54.9) | 384 (57.5) | 0.26 | 0.03 |
| UA | 24 (19.5) | 15 (26.3) | 9 (13.6) | 0.08 | 410 (19.1) | 273 (18.5) | 137 (20.5) | 0.28 | 0.92 |
Abbreviations: SD, standard deviation; CAD, coronary artery disease; y, years; STEMI, ST-elevation myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; UA, unstable angina; LV, left ventricular; VF, ventricular fibrillation; PVD, peripheral vascular disease
Data are presented as number (percentage) unless otherwise indicated. Percentages are based on available data.
P1 represents the difference between men and women within each CAD category; P2 represents the difference between CAD categories among all patients.
Among ACS patients with non-obstructive CAD, women were on average older than men (Table 1). Women were more likely to have a prior history of hypertension, but less likely to smoke. Other cardiovascular risk factors were similar between the men and women with non-obstructive CAD.
Among patients with obstructive CAD, women were older than men and were more likely to be non-white (11.3% vs. 7.6%, p=0.02) (Table 1). Women reported similar rates of current smoking compared to men but were more likely to have a history of peripheral vascular disease, diabetes mellitus, hypertension, or prior stroke, compared to men with obstructive CAD. No sex related differences were observed for a history of angina, prior MI, hyperlipidemia, or family history of CAD, among obstructive CAD patients.
In regards to ACS type, patients with obstructive CAD were more likely to present with a STEMI compared to those with non-obstructive CAD while rates of NSTEMI were higher among those with non-obstructive CAD. Among non-obstructive CAD patients, 57 of the 66 women had positive biomarkers and 42 of the 55 men had positive biomarkers. Rates of unstable angina were similar between the two groups. Among men and women with non-obstructive CAD, women were more likely to present with NSTEMI compared to men, while no statistically significant differences were observed for men and women with obstructive CAD and NSTEMI. Rates of STEMI were higher among men with obstructive CAD compared to women with obstructive CAD.
Receipt of cardiac medications at time of discharge was similar for men and women with non-obstructive CAD, but less frequently prescribed, as compared to those with obstructive CAD (Table 2). Compared to patients with obstructive CAD, patients with non-obstructive CAD were less likely to be discharged on aspirin, beta-blockers, statins, and clopidogrel or ticlopidine with a similar trend observed for receipt of ACE inhibitors. Overall, patients with non-obstructive CAD were significantly less likely to receive 3 of 4 of these EBMs. Of note, women with non-obstructive CAD were less likely to receive aspirin, beta-blockers, ACE inhibitors, and statins upon discharge as compared to the men.
Table 2.
Discharge Medications Administered to Coronary Artery Disease Patients Stratified by Severity of Coronary Artery Disease
| Medications | Non-Obstructive CAD |
P1 | Obstructive CAD |
P1 | P2 | ||||
|---|---|---|---|---|---|---|---|---|---|
| All Patients (n=123) N (%) |
Men (n=57) N (%) |
Women (n=66) N (%) |
All Patients (n=2141) N (%) |
Men (n=1473) N (%) |
Women (n=668) N (%) |
||||
| Aspirin | 108 (87.8) | 51 (89.5) | 57 (86.4) | 0.60 | 2034 (95.0) | 1414 (96.0) | 620 (92.8) | 0.002 | 0.001 |
| Beta blockers | 91 (74.0) | 40 (70.2) | 51 (77.3) | 0.37 | 1910 (89.2) | 1328 (90.2) | 582 (87.1) | 0.04 | <0.001 |
| ACE-inhibitors | 77 (62.6) | 36 (63.2) | 41 (62.1) | 0.91 | 1404 (65.6) | 992 (67.3) | 412 (61.7) | 0.01 | 0.50 |
| Statins | 85 (69.1) | 39 (68.4) | 46 (69.7) | 0.88 | 1739 (81.2) | 1217 (82.6) | 522 (78.1) | 0.01 | 0.001 |
| Clopidogrel or Ticlopidine | 44 (35.8) | 23 (40.4) | 21 (31.8) | 0.33 | 1567 (73.2) | 1088 (73.9) | 479 (71.7) | 0.30 | <0.001 |
| ≥ 3 of 4 medications* | 44 (69.0) | 37 (64.5) | 48 (72.7) | 0.35 | 1839 (85.9) | 1292 (87.7) | 547 (81.9) | <0.001 | <0.001 |
Abbreviations: ACE, angiotensin-converting enzyme; CAD, coronary artery disease.
Four medications considered were aspirin, beta blockers, ACE-inhibitors, and statins.
P1 represents the difference between men and women within each CAD category; P2 represents the difference between CAD categories among all patients.
As expected, six-month cardiac outcomes were lower among those with non-obstructive CAD (Table 3). No statistical difference was noted for six-month mortality when comparing ACS patients with non-obstructive CAD and obstructive CAD, however the event rate was low for both groups. The rates of rehospitalization among women with non-obstructive CAD (23.2%) were similar to that observed for men with obstructive CAD (25.9%), and significantly higher then that of men with non-obstructive CAD. In terms of discharge medications and rates of cardiac-related rehospitalization, no significant differences were observed among men and women who received ≥ 3 of 4 EBMs (aspirin, beta-blockers, ACE inhibitors, and statins) compared to those who did not. Of the 17 patients with non-obstructive CAD, who were rehospitalized within 6-months, approximately, 1/3 did not receive 3 of 4 EBMs (64.7% vs. 35.3%); however the numbers of subjects rehospitalized were extremely small which limited our power to detect meaningful differences.
Table 3.
Six-month Follow-Up Events Among Coronary Artery Disease Patients Stratified by Severity of Coronary Artery Disease Status
| Six-month outcomes | Non-Obstructive CAD |
P1 | Obstructive CAD |
P1 | P2 | ||||
|---|---|---|---|---|---|---|---|---|---|
| All Patients (n=123) N (%) |
Men (n=57) N (%) |
Women (n=66) N (%) |
All Patients (n=2141) N (%) |
Men (n=1473) N (%) |
Women (n=668) N (%) |
||||
| Rehospitalization | 17 (15.6) | 4 (7.5) | 13 (23.2) | 0.02 | 547 (29.1) | 335 (25.9) | 212 (36.0) | <0.001 | 0.002 |
| Myocardial infarction | 1 (1.0) | 1 (2.0) | 0 (0.0) | 0.31 | 106 (7.0) | 65 (6.3) | 41 (8.5) | 0.12 | 0.02 |
| Stroke | 0 (0.0) | 0 (0.0) | 0 (0.0) | ------ | 20 (1.1) | 14 (1.1) | 6 (1.0) | 0.91 | 0.27 |
| Revascularization (unscheduled) |
1 (1.0) | 1 (2.2) | 0 (0.0) | ------ | 145 (8.3) | 83 (6.9) | 62 (11.4) | 0.002 | 0.009 |
| Death | 5 (4.1) | 2 (3.5) | 3 (4.5) | 0.77 | 80 (3.7) | 44 (3.0) | 36 (5.4) | <0.01 | 0.85 |
| MACE | 21 (17.1) | 7 (12.3) | 14 (21.2) | 0.19 | 634 (29.6) | 388 (26.3) | 246 (36.8) | <0.001 | 0.003 |
Abbreviations: CAD, coronary artery disease; MACE, major adverse cardiovascular events including death from cardiac causes, non-fatal myocardial infarction, and non-fatal stroke
P1 represents the difference between men and women within each CAD category; P2 represents the difference between CAD categories among all patients.
DISCUSSION
In this large cohort from a single academic center, we observed approximately 6% of men and women admitted with ACS had non-obstructive CAD by coronary angiography, with a higher proportion among women compared to men. Both men and women with non-obstructive CAD had significant rates of cardiovascular risk factors, and were less likely to receive cardiac medications including aspirin, beta-blockers, statins, and clopidogrel or ticlopidine, at the time of discharge compared to patients with obstructive CAD. Furthermore, women with non-obstructive CAD had similar rates of cardiac-related rehospitalization as men with obstructive CAD within the first 6 months of discharge from the index hospitalization.
The incidence of ACS patients with non-obstructive CAD in our study is similar to what has been observed in previous reports of ACS.1,3,10 The higher rates of non-obstructive CAD among women patients has been observed in several other studies as well.10,12 Data from 3 TIMI trials noted rates of non-obstructive CAD between 9-25%1, while the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) Quality Improvement Initiative observed 8.6% of the study population had non-obstructive CAD.13 The Women’s Ischemia Syndrome Evaluation Study (WISE) and Global Utilization for Streptokinase and TPA for Occluded Coronary Arteries (GUSTO) IIb studies also reported significant rates of non-obstructive CAD among women referred for angiography.5,6 In our investigation, women with non-obstructive CAD were more likely to be older and were more likely to have chronic hypertension compared to the men, while both men and women similar rates of diabetes. However, our observations are consistent with prior studies which have examined gender differences in ACS patients, where women were older and have a higher prevalence of hypertension compared to mens.6,14-18
We observed a significantly lower rate of receipt for cardiac medication among patients who were found to have non-obstructive CAD, despite the high prevalence of cardiovascular risk factors. In a similar study, 180 ACS patients with non-obstructive CAD were observed to have lower rates of receipt for aspirin, ACE-inhibitors, beta-blockers and clopidogrel.12 In our cohort, almost 40% of patients with non-obstructive CAD did not receive ACE-inhibitors at the time of discharge, despite the diagnosis of ACS and high rates of hypertension and diabetes in this group.
We found no significant differences in all-cause mortality between men and women with non-obstructive CAD. We noted 4% of patients with non-obstructive CAD died during the 6-month follow-up, in contrast to a similar study by Dwyer, et al, which observed no deaths or recurrent myocardial infarction among ACS patients with non-obstructive CAD.12 However, rates of readmissions were similar between the two studies.
Women with non-obstructive CAD were more than 3 times more likely to be rehospitalized for cardiac causes than men. Furthermore, women with non-obstructive CAD had comparable rehospitalization rates to that of men with obstructive CAD. While the presented data do not provide definitive reasons for these observations, it is plausible that rehospitalization was due to recurrent episodes of chest pain from microvascular disease, particularly given the CAD risk factor burden observed in the group with non-obstructive CAD. Unfortunately given the small numbers of patients with non-obstructive CAD in this cohort, it is not possible to examine multiple factors via multivariate analysis. Prior studies suggest a significant benefit to the receipt of medications in ACS patients in terms of recurrent cardiac events and progression of coronary atherosclerosis.19-21 It remains to be seen whether risk factor modification among men and women with non-obstructive CAD would result in decreased rehospitalization.
Several limitations of this study exist. This study included patients with documented ACS who were part of a large ongoing registry in one academic medical center; however the numbers of men and women with non-obstructive CAD is small. This cohort includes a spectrum of ACS patients and as such offers a “real-life” perspective of ACS treatment by including a heterogeneous study population as compared with randomized control trial study populations. However, as this study has an observational design, inherent limitations and potential biases (including selection bias) may exist. For the present analysis, only patients who underwent coronary angiography were included and therefore this information may not be generalizable to patients who do not receive cardiac angiography. Angiographic data was based on clinical report and was not adjudicated by a core lab, and thus may be subject to some degree of between-person variability. Second, while we do follow patients for up to 6 months, we do not have information regarding adherence to medications which can certainly play a factor in clinical outcomes. Finally, categorizing of CAD severity as obstructive CAD based on our criteria meant grouping ACS patients with less severe disease together with patients with multiple and/or more severely stenotic lesions; however the primary aim of this study was to examine management among ACS patients with non-obstructive CAD. In addition, this type of categorization of CAD severity has been done in prior studies.4, 10, 21
Conclusion
Significant improvements in the management of patients presenting with the acute coronary syndrome have occurred over the past several decades. However, we observed lower rates of receipt of cardiac medications at the time of discharge among men and women ACS patients with non-obstructive disease. Increased use of cardiac medications and modification of risk factors among patients with non-obstructive CAD may reduce their rehospitalization rates and decrease their progression of coronary atherosclerosis, though larger, long-term studies are needed to further examine this hypothesis.
Condensed Abstract.
Data from a large acute coronary syndrome (ACS) registry were used to examine receipt of cardiac medications among ACS patients with non-obstructive coronary artery disease (CAD). These patients were less likely to receive aspirin, beta blockers, and statins at time of discharge compared to ACS patients with obstructive CAD. Women with non-obstructive disease had similar rates of rehospitalization at six month as did men with obstructive disease. These data suggest the need for further research to determine if effective cardiac medications among ACS patients with non-obstructive CAD would reduce secondary cardiac events.
Acknowledgments
This study was partly supported by unrestricted grants from the Mardigan Fund and the Hewlett Foundation. Dr. Jackson receives support from the NHLBI (K23 HL073310-01)
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