Clinically stable patients with type 2 diabetes mellitus and coronary artery disease are not often thought to present with the symptom of typical angina. The aims of this study were to enumerate the proportion of patients presenting with typical angina or other cardiac symptoms and to elucidate what important clinical variables are associated with the presence of typical angina in patients with type 2 diabetes mellitus and angiographically documented coronary artery disease. Symptoms of angina, anginal equivalents, or an absence of symptoms were obtained using baseline data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial (n = 2,319). A bivariate analysis stratified by the presence or absence of previous revascularization and logistic regression modeling with a stepwise covariate selection was used. Eighty-two percent of patients had symptoms, while 18% presented asymptomatically. This was further divided approximately into typical angina (1/5), anginal equivalents (1/5), combination (2/5), and asymptomatic (1/5). A history of previous revascularization was a determinant of the type of symptom presentation with regard to the variables gender, age, current insulin use, myocardial jeopardy index score, and use of β blockers. In the multivariate logistic regression analysis, of the available candidate variables, only a history of β-blocker use (odds ratio 1.53, 95% confidence interval 1.24 to 1.94, p <0.0001) and previous percutaneous coronary intervention (odds ratio 1.55, 95% confidence interval 1.24 to 1.94, p <0.0001) had higher odds of an association with typical angina. In conclusion, a large proportion of patients with type 2 diabetes mellitus and coronary artery disease indeed have symptoms. Future studies of long-term outcomes associated with these symptoms are needed.
To gain an appreciation of symptom presentation in a select group of patients with type 2 diabetes mellitus (T2DM) and angiographically documented coronary artery disease (CAD), we sought to (1) enumerate the proportion of each symptom noted, (2) elucidate the important demographic and clinical variables independently associated with the presence of typical angina pectoris, and (3) assess the associations of the fibrinolytic variables plasminogen activator inhibitor–1 (PAI-1) antigen, PAI-1 activity, and tissue plasminogen activator (t-PA) to the symptom typical angina pectoris.
Methods
A cross-sectional analysis was designed using baseline data at the time of initial patient entry into the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. The study design, patient characteristics, and outcomes of the primary BARI 2D trial have been published. In brief, the BARI 2D study was a multicenter National Institutes of Health trial that tested 2 simultaneous hypotheses in a 2 × 2 factorial design (immediate vs delayed or no revascularization and insulin-sensitizing agents vs insulin-providing agents) in patients with T2DM and angiographically documented stable CAD who all received optimal intensive medical therapy to control risk factors.
To obtain entry into the trial, every patient had to have a coronary angiogram documenting ≥1 vessel with a ≥50% stenosis that was suitable for revascularization by either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) with either objective documentation of ischemia or subjective documentation of angina with a ≥70% stenosis. Major exclusion criteria included a definite need for revascularization as judged by the attending cardiologist, left main coronary artery stenosis, planned intervention on a bypass graft, advanced congestive heart failure, elevated creatinine, and poorly controlled T2DM (glycosylated hemoglobin >13%).
Patients were questioned regarding their symptoms at the time of their initial baseline visits. The symptoms that were reported occurred less than 6 weeks before this baseline visit. The symptoms reported were then categorized by clinical site staff members as typical angina pectoris, anginal equivalent (shortness of breath, dyspnea on exertion, exertional fatigue, nausea, unexplained diaphoresis, other), or asymptomatic (no angina or anginal equivalents). Typical angina pectoris was defined as a discomfort or pain located in the chest or upper epigastrium described as a pressure, heaviness, tightness, squeezing, burning, or choking sensation that suggested an ischemic heart disease diagnosis. Patients with symptoms of typical angina pectoris and anginal equivalents were categorized as having typical angina.
The fibrinolytic variables used were PAI-1 antigen, PAI-1 activity, and t-PA. The biologic basis for this addition was that elevated PAI-1 is likely to be associated with impaired fibrinolysis and promote a procoagulatory milieu that may contribute to the acceleration of CAD with precipitation of events including angina or anginal equivalents. Tissue plasminogen activator is known to track with PAI-1. This tracking reflects a complexing of t-PA with PAI-1 with a consequent diminished clearance of complexed t-PA that is biochemically inactive.
Of the 2,368 patients enrolled in the BARI 2D study, 2,321 had 80% of their baseline data available for analysis. Of these, 2 patients did not report angina status <6 weeks before randomization. This report includes the data from 2,319 patients. Coronary revascularization was noted as the presence or absence of either PCI or CABG. An initial unadjusted and subsequent bivariate analysis stratified by revascularization method was performed. A p value of <0.05 was used to determine statistical significance. The p values in the baseline table refer to Cochran-Mantel-Haenszel tests of general association among the 3 symptom groups after controlling for cardiac revascularization status. Differences among the symptoms groups for continuous variables were tested using analysis of variance stratified by revascularization status. Multivariate stepwise logistic regression analysis was used to determine independent associations between baseline demographic, clinical, and angiographic variables and typical angina. The model was built using stepwise regression of the candidate variables with p values of 0.10 to enter the model and 0.05 to be included (stay) in the model. The candidate variables were age, gender, smoking status, exercise status, duration of T2DM, body mass index, systolic blood pressure, diastolic blood pressure, glycosylated hemoglobin level, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triglycerides, ankle-brachial index, history of lung disease, myocardial infarction, stroke, hypertension, non-coronary artery vascular disease, PCI, stent placement, CABG, myocardial jeopardy index score, coronary artery stenosis >70%, and current β-blocker, calcium channel blocker, statin, thiazolidinedione, and insulin use. The left ventricular ejection fraction was not placed in the regression model, because of the exclusion of patients with advanced congestive heart failure in the main trial. Myocardial jeopardy index was defined as the percentage of left ventricular myocardium jeopardized by ≥50% stenosis. Once the demographic and clinical variables having independent associations with typical angina were determined, baseline fibrinolysis measures of PAI-1 antigen, PAI-1 activity, and t-PA were added to the final typical angina model to determine if they added any more information to the model. Because PAI-1 antigen and activity measures were skewed, they were transformed using the natural logarithm. Two further similar logistic regression analyses were performed in patients with and without previous revascularization. SAS version 9.2 (SAS Institute Inc., Cary, North Carolina) was used for all statistical analysis.
Results
Symptoms reported were typical angina (n = 437 [19%]), anginal equivalents (n = 493 [21%]), combination of typical angina and anginal equivalents (n = 971 [42%]), and asymptomatic (n = 418 [18%]). The mean baseline left ventricular ejections fraction were 57.2 ± 10.9% in the entire cohort, 57.1 ± 11.0% in the PCI stratum, and 57.5 ± 10.8% in the CABG stratum. A history of previous coronary revascularization as well as the type of revascularization (PCI or CABG) was a determinant of symptom presentation ( Table 1 ). Regardless of previous revascularization status, men presented asymptomatically more often than women, women presented with typical angina more often, and older patients presented less often with typical angina. The variations across symptoms stratified by revascularization in the baseline characteristics are noted in Table 2 . As noted in Table 3 , all 3 fibrinolytic variables (PAI-1 activity, PAI-1 antigen, and t-PA) varied significantly across the groups (p = 0.0071, p = 0.0058, p = 0.0003, respectively) after adjustment for previous revascularization status.
| Variable | Total | Typical Angina | Anginal Equivalent | Asymptomatic | p Value |
|---|---|---|---|---|---|
| (n = 2,319) | (n = 1,408) | (n = 493) | (n = 418) | ||
| Any previous coronary revascularization | 23.5% | 26.2% | 22.1% | 16.0% | <0.0001 |
| Previous PCI | 19.6% | 22.2% | 17.2% | 13.4% | <0.0001 |
| Previous CABG | 6.4% | 7.0% | 6.9% | 4.1% | 0.09 |
| Variable | No History of Revascularization | History of Revascularization | p Value | ||||
|---|---|---|---|---|---|---|---|
| Typical Angina (n = 1,039) | Anginal Equivalent (n = 384) | Asymptomatic (n = 351) | Typical Angina (n = 369) | Anginal Equivalent (n = 109) | Asymptomatic (n = 67) | ||
| Men | 66.6% | 71.1% | 78.6% | 71.0% | 71.6% | 79.1% | <0.0001 |
| Age at study entry (years) | 61.6 ± 8.9 | 63.1 ± 8.7 | 63.1 ± 8.9 | 61.8 ± 8.8 | 64.6 ± 9.6 | 65.5 ± 7.3 | <0.0001 |
| Current smokers | 11.9% | 14.9% | 11.7% | 14.1% | 7.3% | 6.0% | 0.49 |
| Regular exercise | 22.9% | 24.0% | 34.2% | 25.0% | 23.9% | 43.3% | <0.0001 |
| Age at T2DM diagnosis (years) | 51.0 ± 10.9 | 51.7 ± 10.9 | 52.7 ± 11.3 | 50.6 ± 10.9 | 52.1 ± 11.3 | 54.6 ± 8.6 | 0.094 |
| Duration of T2DM (years) | 10.2 ± 8.4 | 10.9 ± 9.1 | 9.8 ± 8.6 | 10.8 ± 9.2 | 11.8 ± 8.3 | 10.4 ± 7.6 | 0.2036 |
| Currently taking insulin | 26.9% | 30.7% | 21.1% | 33.1% | 31.2% | 25.4% | 0.0092 |
| Currently taking thiazolidinedione | 15.0% | 21.6% | 21.4% | 18.2% | 28.4% | 34.3% | <0.0001 |
| Glycosylated hemoglobin (%) | 7.68 ± 1.61 | 7.65 ± 1.61 | 7.57 ± 1.68 | 7.71 ± 1.62 | 7.74 ± 1.62 | 7.54 ± 1.38 | 0.19 |
| History of lung disease ⁎ | 10.6% | 11.2% | 5.1% | 13.6% | 12.0% | 9.0% | 0.0043 |
| Sitting systolic blood pressure (mm Hg) | 132.2 ± 20.7 | 132.9 ± 20.6 | 131.9 ± 19.6 | 129.2 ± 19.2 | 129.8 ± 16.3 | 134.2 ± 17.8 | 0.74 |
| Myocardial jeopardy score (%) | 46.9 ± 24.2 | 42.9 ± 25.1 | 48.2 ± 24.1 | 38.3 ± 22.1 | 36.8 ± 24.5 | 44.4 ± 23.7 | 0.0015 |
| Coronary stenosis >70% | 62.6% | 59.6% | 66.9% | 64.0% | 73.1% | 67.2% | 0.25 |
| Low-density lipoprotein cholesterol (mg/dl) | 92.0 (72.0–116.0) | 96.0 (77.0–118.0) | 90.5 (74.0–111.0) | 89.0 (72.0–109.0) | 92.0 (69.0–115.0) | 93.6 (80.0–113.0) | 0.45 |
| β blockers | 74.7% | 64.8% | 64.4% | 82.3% | 74.3% | 80.6% | <0.0001 |
| Calcium channel blockers | 30.3% | 30.5% | 28.2% | 37.0% | 35.8% | 32.8% | 0.63 |
| Any nitrates | 55.3% | 25.8% | 27.1% | 63.6% | 45.9% | 32.8% | <0.0001 |
| Statins | 71.8% | 71.0% | 68.9% | 85.9% | 86.2% | 92.5% | 0.88 |
| Variable | No History of Revascularization | History of Revascularization | p Value | ||||
|---|---|---|---|---|---|---|---|
| Typical Angina (n = 1,039) | Anginal Equivalent (n = 384) | Asymptomatic (n = 351) | Typical Angina (n = 369) | Anginal Equivalent (n = 109) | Asymptomatic (n = 67) | ||
| PAI-1 activity (AU/ml) | 16 (10.0–26.0) | 18 (11.0–28.0) | 15 (9.3–25.0) | 17 (9.9–28.0) | 13 (9.0–23.0) | 17 (9.0–27.0) | 0.007 |
| PAI-1 antigen (ng/ml) | 23 (16.0–35.0) | 24 (16.0–36.0) | 22 (14.0–33.0) | 24 (15.0–36.0) | 21.5 (13.0–33.0) | 23 (14.0–35.0) | 0.006 |
| t-PA(ng/ml) | 10.36 ± 4.05 | 10.49 ± 3.97 | 9.69 ± 3.71 | 10.29 ± 4.52 | 9.59 ± 3.88 | 9.56 ± 3.47 | 0.0003 |
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