We sought to determine the effectiveness of angiotensin-converting enzyme (ACE) inhibition and β-blocker treatment as a function of the degree of coronary artery disease (CAD) obstruction at angiography. The Evaluation of Methods and Management of Acute Coronary Events registry enrolled patients who had been hospitalized for an acute coronary syndrome. There were 1,602 patients who had cardiac catheterization that were used for this analysis. The main outcome measures were evidence-based therapies prescribed at discharge and 6-month incidence of all-cause mortality. The cohort consisted of 1,252 patients with obstructive CAD (>50% luminal diameter obstructed) and 350 patients with nonobstructive CAD. Multivariate logistic regression analysis adjusted for further medications and other clinical factors was performed. Patients with nonobstructive CAD had significantly (p <0.001) higher rates of β-blocker (77.8% vs 63.3%) and lower rates of ACE-inhibitor (57.7% vs 66.4%) prescriptions. In patients with nonobstructive CAD, ACE-inhibitor therapy was clearly associated with a lower 6-month mortality (odds ratio [OR] 0.31, 95% confidence interval [CI] 0.03 to 0.78, p = 0.004). No significant association between β-blocker use and death was found. In patients with obstructive CAD, both β blockers (OR 0.47, 95% CI 0.32 to 0.67, p <0.001) and ACE inhibitors (OR 0.47, 95% CI 0.26 to 0.87, p = 0.01) were significantly associated with a reduced risk of 6-month mortality. In conclusion, ACE-inhibitor therapy seems to be an effective first-line treatment for preventing the occurrence of mortality in patients with nonobstructive CAD
Patients with nonobstructive coronary arteries on coronary angiography represent 5% to 20% of all patients with acute coronary syndrome (ACS). Women are more likely to have nonobstructive coronary artery disease (CAD). Recently, it has been show that these patients have a substantial risk of subsequent coronary events. Despite this evidence, it is still unsolved the question of whether patients with nonobstructive CAD derive benefit in prognosis from use of conventional guideline-recommended therapies.
To address this gap in knowledge, we used the Evaluation of Methods and Management of Acute Coronary Events (EMMACE-2) registry to evaluate the rates of secondary prevention therapies at discharge in patients with ACS as a function of the degree of CAD obstruction at angiography. Additionally, we compared the impact of β blockers and angiotensin-converting enzyme (ACE)–inhibitor therapy on future risk of adverse outcomes in nonobstructive CAD compared with patients with obstructive CAD over a 6-month follow-up period.
Methods
The study design of the EMMACE-2 registry has been reported previously. In brief, the registry has been designed to examine outcomes in consecutively admitted unselected patients with confirmed ACS (within the catchments’ area of 1 tertiary center, performing all interventional procedures) in Yorkshire, United Kingdom. Patients were potentially eligible if they were admitted to hospital with an admission diagnosis of suspected ACS. Appropriateness of inclusion was judged by a board-certified cardiologist taking into account clinical history, examination, electrocardiograms, and cardiac biomarkers. Specifically, patients were included in the study if they fulfilled the European Society of Cardiology/American College of Cardiology definition of myocardial infarction. Unstable angina was diagnosed when serum biochemical markers indicative of myocardial necrosis were within the normal range but chest pain and electrocardiographic changes (ST-segment depression, T-wave changes, left bundle branch block, and other abnormalities) were considered compatible with this diagnosis. Data of patients with ACS who did not receive coronary angiography during the index hospitalization were excluded. Patients who underwent cardiac catheterization were divided into 2 groups: (1) nonobstructive CAD (<50% stenosis in all vessels) and (2) obstructive CAD (≥50% stenosis in ≥1 vessel), based on the interpretation of angiograms by visual analysis. Patients were also excluded if they had active cancer or autoimmune inflammatory disease.
Demographic and medical data were collected for all patients during hospitalization. Follow-up assessment of survival was determined through the Office for National Statistics 6 months from the time of discharge. The clinical outcome was 6-month incidence of all-cause mortality. Measures of interest were discharge prescription of evidence-based therapies (aspirin, β blockers, statins, and ACE inhibitors).
The study was approved by the Multicentre Research Ethics Committee (MREC, Cambridge) and the Local Research Ethics Committees for each of the participating hospitals (MREC03/5/08 [Cambridge 2003]). Patients provided written consent for evaluation of their medical notes and monitoring of their health status.
Statistical testing was performed using the chi-square test for categorical variables and the Wilcoxon rank sum test for continuous variables. The potential benefit of β-blocker use and ACE-inhibitor therapy was estimated by odds ratios (ORs) and associated 95% confidence intervals (CIs) obtained using the logistic regression analysis. For the multivariate analysis, no automatic selection process was used because of the limited size of the sample. All the variables that were significant (p value <0.05) at univariate analysis were included. A post hoc sample size calculation revealed that there was sufficient power to detect differences in survival across β-blocker and ACE-inhibitor users (β ≥ 0.80, α = 0.05, 2-tailed). For all analyses, statistical significance was defined as a value of p <0.05. Statistical evaluation was performed using the SPSS system 11.1 (SPSS Inc., Chicago, Illinois) software.
Results
The EMMACE-2 database enrolled 2,484 consecutive patients with an ACS. Coronary angiography was performed in 1,602 patients (64.5%). More than 1 of 3 patients (either men or women) had angiograms without any obstructive lesion. As a result, we investigated 350 patients with nonobstructive CAD and 1,252 with obstructive CAD ( Table 1 ). Men were about 7 years younger than women in the obstructive and nonobstructive CAD groups (p <0.001). Briefly, patients with nonobstructive CAD compared with patients with obstructive CAD were approximately 10 years younger for both genders (p <0.001) and had less history of lipid disorders (34.6% vs 40.4%, p = 0.05), diabetes (11.7% vs 18.6%, p = 0.002), and hypertension (38.2% vs 44.0%, p = 0.05). Troponin level was increased in approximately 90% of patients with nonobstructive as well as obstructive CAD. ST-segment elevation myocardial infarction (as index event) occurred less frequently in those with nonobstructive CAD compare with those with obstructive CAD (8.6% vs 47.5%, p <0.001).
| Variable | All (n = 1,602) | Nonobstructive CAD (n = 350) | Obstructive CAD (n = 1,252) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Nonobstructive CAD (n = 350) | Obstructive CAD (n = 1,252) | p Value ∗ | Men (n = 236) | Women (n = 114) | p Value † | Men (n = 811) | Women (n = 441) | p Value † | |
| Age (yrs) | 60.5 ± 11.8 | 71.5 ± 12.1 | <0.001 | 58.4 ± 11.3 | 64.7 ± 11.9 | 0.001 | 68.7 ± 12.9 | 76.7 ± 10.8 | <0.001 |
| Lipid disorders | 121 (34.6) | 506 (40.4) | 0.05 | 74 (31.4) | 47 (41.2) | 0.07 | 330 (40.7) | 176 (39.9) | 0.81 |
| Diabetes mellitus | 41 (11.7) | 233 (18.6) | 0.002 | 31 (13.1) | 10 (8.8) | 0.29 | 136 (16.8) | 97 (22.0) | 0.02 |
| Hypertension | 134 (38.2) | 550 (44.0) | 0.05 | 84 (35.5) | 50 (43.9) | 0.12 | 333 (41.1) | 217 (49.2) | 0.006 |
| Current smoker | 135 (38.6) | 349 (27.9) | <0.001 | 95 (40.3) | 40 (35.1) | 0.34 | 256 (31.6) | 93 (21.1) | <0.001 |
| Former smoker | 113 (32.3) | 423 (33.8) | 0.59 | 83 (35.2) | 30 (26.3) | 0.11 | 301 (37.1) | 122 (27.7) | <0.001 |
| Previous angina pectoris | 91 (26.0) | 706 (56.4) | <0.001 | 52 (22.0) | 39 (34.2) | 0.09 | 440 (54.3) | 266 (60.3) | 0.04 |
| Peripheral arterial disease | 21 (6.0) | 117 (9.3) | 0.05 | 13 (5.5) | 8 (7.0) | 0.57 | 86 (10.6) | 31 (7.0) | 0.04 |
| Previous myocardial infarction | 2 (0.6) | 612 (48.9) | <0.001 | 2 (0.8) | 0 | 1.0 | 385 (47.5) | 227 (51.5) | 0.19 |
| Previous coronary artery bypass graft | 0 | 171 (13.7) | <0.001 | 0 | 0 | 1.0 | 129 (16.0) | 42 (9.6) | 0.002 |
| Previous percutaneous coronary intervention | 0 | 254 (20.3) | <0.001 | 0 | 0 | 1.0 | 187 (23.1) | 67 (15.2) | 0.001 |
| ST-segment depression | 87 (24.9) | 197 (15.7) | <0.001 | 60 (25.4) | 27 (23.7) | 0.79 | 124 (15.3) | 73 (16.6) | 0.57 |
| Positive troponin | 316 (90.3) | 1,128 (90.1) | 0.91 | 217 (91.9) | 99 (86.8) | 0.18 | 735 (90.6) | 393 (89.1) | 0.43 |
| Heart rate (beats/min) | 79.1 ± 19.6 | 81.8 ± 23.9 | 0.04 | 77.3 ± 19.7 | 82.8 ± 19.0 | 0.01 | 80.1 ± 22.5 | 84.9 ± 24.9 | 0.001 |
| Systolic blood pressure (mm Hg) | 149.2 ± 28.4 | 139.3 ± 30.9 | <0.001 | 149.2 ± 27.3 | 149.1 ± 28.7 | 0.99 | 138.1 ± 28.8 | 141.6 ± 31.1 | 0.04 |
| Index event | |||||||||
| STEMI | 30 (8.6) | 595 (47.5) | <0.001 | 19 (8.1) | 11 (9.6) | 0.68 | 412 (50.8) | 183 (41.5) | 0.002 |
| NSTEMI | 286 (81.7) | 533 (42.6) | <0.001 | 198 (83.9) | 88 (77.2) | 0.14 | 323 (39.8) | 210 (47.6) | 0.008 |
| Unstable angina pectoris | 34 (9.7) | 124 (9.9) | 0.91 | 19 (8.1) | 15 (13.2) | 0.18 | 76 (9.4) | 48 (10.9) | 0.43 |
∗ p Value derived from comparison between nonobstructive CAD and obstructive CAD.
Data were analyzed by gender to determine if there were any gender differences in disease therapies. According to this, the characteristics of the study population were sorted by gender ( Table 1 ). In the obstructive CAD group, men were younger than women (p <0.001) and they were less likely to have experienced previous angina pectoris (54.3% vs 60.3%, p = 0.04). Men, more often than women, had a previous coronary revascularization (either surgery or percutaneous intervention). Hypertension and diabetes were more prevalent in women and smoking in men. Myocardial infarction with ST-segment elevation (as index event) was more common in men (50.8% vs 41.5%, p = 0.002), whereas myocardial infarction without ST-segment elevation was more frequent in women (47.6% vs 39.8%, p = 0.008). In the nonobstructive CAD group, apart from age (men were younger than women, p <0.001), we did not find any significant difference between genders in the occurrence of cardiovascular risk factors, nor in the incidence of ST-segment elevation myocardial infarction, as index event.
Data from our registry revealed that 15% of patients with nonobstructive CAD and 25% of those with obstructive CAD did not receive aspirin at discharge (p <0.001). Patients with nonobstructive CAD had significantly higher unadjusted rates of β-blocker (77.8% vs 63.3%, p <0.001) and statin (91.4% vs 79.2%, p <0.001) but lower rates of ACE-inhibitor (57.7% vs 66.4%, p = 0.002) prescriptions at discharge compared with patients with obstructive CAD ( Table 2 ). Significant differences in the selection of medications between nonobstructive and obstructive CAD persisted independently by gender.
| Medications | All (n = 1,602) | Men (n = 1,047) | Women (n = 555) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Nonobstructive CAD (n = 350) | Obstructive CAD (n = 1,252) | p Value ∗ | Nonobstructive CAD (n = 236) | Obstructive CAD (n= 811) | p Value ∗ | Nonobstructive CAD (n = 114) | Obstructive CAD (n = 441) | p Value ∗ | |
| Aspirin | 303 (86.6) | 961 (76,6) | <0.001 | 208 (88.9) | 646 (81.3) | 0.006 | 95 (83.3) | 315 (73.1) | 0.02 |
| β Blockers | 272 (77.8) | 793 (63.3) | <0.001 | 188 (79.7) | 553 (68.2) | <0.001 | 84 (73.7) | 240 (54.4) | <0.001 |
| Statins | 320 (91.4) | 991 (79.2) | <0.001 | 217 (92.7) | 673 (84.8) | 0.001 | 103 (90.4) | 318 (74.1) | <0.001 |
| ACE inhibitors | 202 (57.7) | 831 (66.4) | 0.002 | 148 (63.2) | 560 (70.4) | 0.03 | 54 (47.8) | 271 (63.2) | 0.002 |
∗ p Value derived from comparison between nonobstructive CAD and obstructive CAD.
A total of 271 patients had a fatal adverse outcome in the first 6 months. Six-month cardiovascular mortality for patients with nonobstructive CAD was remarkably lower than that for patients with obstructive CAD (3.1% vs 20.7%, p <0.001). Men and women with nonobstructive CAD had similar risk of death (3.0% vs 3.5%, OR 0.99, 95% CI 0.95 to 1.04). Conversely, women with obstructive CAD had a higher unadjusted risk of death than men (26.2% vs 17.7%, OR 1.12, 95% CI 1.05 to 1.19).
Univariate and multivariate logistic regression analyses were performed to identify factors influencing cardiovascular mortality in the nonobstructive and obstructive groups of patients. Univariate associations were retained for multivariate analysis if p value was <0.05 ( Table 3 ). In patients with nonobstructive CAD, the use of ACE inhibitors was the only statistically independent variable having protective effect on death (OR 0.31, 95% CI 0.03 to 0.78, p = 0.004), whereas older age was the only independent variable predisposing to death at 6-month follow-up (OR 1.11, 95% CI 1.03 to 1.19, p = 0.007). In patients with obstructive CAD, all secondary prevention therapies (β blockers, statin, and ACE inhibitors) had an independent protective effect on outcome. Acute myocardial infarction with ST-segment elevation as index event was the strongest independent predictor of death (OR 1.92, 95% CI 1.33 to 2.77, p = 0.001). Older age and higher heart rate were all predictive of death independent of each other and the other variables listed.
