In patients without a history of diabetes mellitus, increased levels of glycated hemoglobin (HbA1c) are associated with higher cardiovascular risk. The relation between undetected diabetes and clinical outcome after percutaneous coronary intervention is unknown. To investigate whether these patients may have an increased risk of periprocedural myocardial infarction (PMI), the most frequent adverse event after percutaneous coronary intervention, we assessed patients of the TWENTE trial (a randomized, controlled, second-generation drug-eluting stent trial) in whom HbA1c data were available. Patients were classified as known diabetics or patients without a history of diabetes who were subdivided into undetected diabetics (HbA1c ≥6.5%) and nondiabetics (HbA1c <6.5%). Systematic measurement of cardiac biomarkers and electrocardiographic assessment were performed. One-year clinical outcome was also compared. Of 626 patients, 44 (7%) were undetected diabetics, 181 (29%) were known diabetics, and 401 (64%) were nondiabetics. In undetected diabetics the PMI rate was higher than in nondiabetics (13.6% vs 3.7%, p = 0.01) and known diabetics (13.6% vs 6.1%, p = 0.11). Multivariate analysis adjusting for covariates confirmed a significantly higher PMI risk in undetected diabetics compared to nondiabetics (odds ratio 6.13, 95% confidence interval 2.07 to 18.13, p = 0.001) and known diabetics (odds ratio 3.73, 95% confidence interval 1.17 to 11.89, p = 0.03). After 1 year, target vessel MI rate was significantly higher in undetected diabetics (p = 0.02) than in nondiabetics, which was related mainly to differences in PMI. Target vessel failure was numerically larger in unknown diabetics than in nondiabetics, but this difference did not reach statistical significance (13.6% vs 8.0%, p = 0.25). In conclusion, undetected diabetics were shown to have an increased risk of PMI.
Periprocedural myocardial infarction (PMI) is the most frequent adverse event after percutaneous coronary interventions (PCI) outside the setting of ST-segment elevation MI. It has previously been shown that PMI is not necessarily a benign event and that patients with PMI may have a worse prognosis. Diabetic patients may be particularly prone to PMI because this disease is associated with dyslipidemia, hypercoagulability, increased atheroma burden, vessel wall inflammation, and development of vulnerable plaques. In patients with undetected diabetes, metabolic dysregulation and a long-term hyperglycemic state may result in a similar, perhaps even higher, PMI risk. The relation between increased glycated hemoglobin (HbA1c) and the occurrence of PMI has not yet been examined. We hypothesized that undetected diabetes and diabetes mellitus may be related to PMI. In the present study, we therefore assessed this hypothesis in patients of the The Real-World Endeavor Resolute Versus XIENCE V Drug-Eluting Stent Study (TWENTE)—a randomized controlled trial that compared 2 second-generation drug-eluting stents (DESs) in patients with various clinical presentations with the exception of ST-segment elevation MI.
Methods
The present study was performed in a subpopulation of patients enrolled in the TWENTE trial ( http://www.ClinicalTrials.gov , NCT01066650 ) in whom HbA1c levels were measured at the time of the index PCI procedure (±1 month). Details of the TWENTE study have previously been described. In brief, TWENTE is an investigator-initiated, patient-blinded, randomized noninferiority study with limited exclusion criteria in a “real-world” patient population treated at the Thoraxcentrum Twente in Enschede, the Netherlands. From June 2008 through August 2010, 1,391 patients with an indication for PCI with DES implantation were randomized for treatment with the second-generation Resolute stent (Medtronic, Inc., Santa Rosa, California) or Xience V stent (Abbott Vascular, Santa Clara, California). There were no angiographic exclusion criteria. The most important exclusion criterion was recent ST-segment elevation MI. The TWENTE trial was approved by the institutional ethics committee, complied with the Declaration of Helsinki, and all patients provided a written informed consent.
All patients were pretreated with acetylsalicylic acid and clopidogrel. At discharge we prescribed the combination of acetylsalicylic acid 100 mg 1 time/day indefinitely and clopidogrel 75 mg 1 time/day for 1 year. Predilation, direct stenting, stent postdilatation, and/or use of glycoprotein IIb/IIIa antagonists were permitted at the operators’ discretion.
The study population was grouped into patients with a known history of diabetes mellitus versus patients without a history of diabetes. Patients without a history of diabetes were then subdivided based on a cut-off HbA1c value of 6.5%; patients with an HbA1c level ≥6.5% were classified as undetected diabetics and patients with an HbA1c level <6.5% as nondiabetics. Assessment of HbA1c was performed with a COBAS Integra 800 analysis system (Roche Diagnostics, Basel, Switzerland) at the department of clinical chemistry of our center.
In all patients cardiac biomarkers and electrocardiograms were systematically assessed and analyzed before and after PCI to identify PMI. Cardiac biomarker measurements were scheduled before PCI and 6 to 18 hours after PCI, with subsequent serial measurements for relevant biomarker increases or complaints until peak increase was established. We used the PMI definition of the Academic Research Consortium: creatine kinase (CK) >2 times upper limit of normal with increase of CK-MB and/or troponin. If baseline cardiac biomarkers were above the upper limit of normal or MI was in progress, PMI was established when (1) there was recurrent chest pain or new electrocardiographic changes consistent with MI with an increase of CK >2 times upper limit of normal or (2) if increased CK after the index MI peaked and the CK level returned below the upper limit of normal when there was an increase of CK >2 times upper limit of normal or (3) if increased CK after the index MI peaked and the CK level did not return below the upper limit of normal, an increase in CK ≥50% above the previous level, and >2 times upper limit of normal confirmed by an increase of CK-MB and/or troponin. Clinical end points included target vessel failure within 1 year (composite end point consisting of cardiac death, target-vessel related MI [or not attributable to a nontarget vessel], or clinically driven target vessel revascularization), individual components of target vessel failure, stent thrombosis and a patient-oriented composite end point consisting of all-cause mortality, any MI, and any repeat revascularization. All clinical end points including stent thrombosis were defined according to the Academic Research Consortium.
Clinical follow-up data were obtained at visits at outpatient clinics or, if not feasible, by telephone follow-up and/or medical questionnaire. Follow-up data were available in all patients; 2 patients withdrew informed consent before follow-up at 1 year and thus are not included in the follow-up analysis. Processing of clinical data and adjudication of all adverse clinical events were performed by an independent external contract research organization (Cardialysis, Rotterdam, the Netherlands).
All statistical analyses were performed with SPSS 15.0 (SPSS, Inc., Chicago, Illinois).
When comparing undetected diabetics to nondiabetics and undetected diabetics to known diabetics, differences in categorical variables were assessed with chi-square or Fisher’s exact tests, as appropriate, whereas continuous variables were assessed with the Wilcoxon rank-sum test or Student’s t test, as appropriate. Unless otherwise specified, p values and confidence intervals (CIs) were 2-sided and a p value <0.05 was considered statistically significant. Univariate and multivariate logistic regression analyses were performed to evaluate diabetic status as an independent predictor of PMI in the subpopulation of undetected diabetics and nondiabetics and in the subpopulation of undetected diabetics and known diabetics. All variables were evaluated as possible predictors, and only those with significance at a p value ≤0.15 for PMI were considered candidate variables for multivariate logistic regression analysis and were assessed for their relation with diabetes. If this relation was also present with significance at a p value ≤0.15, they were included in the model. To obtain a parsimonious model, we started with all candidate variables. Subsequently, we eliminated the variables with the highest p value step by step until the estimate for diabetes changed by ≥10% or only significant predictors remained.
Results
Of all patients enrolled in the TWENTE trial, 626 had HbA1c measurements within the predefined time frame and formed the study population of the present analysis. Patients in the study population had more diabetes mellitus (29% vs 16%, p <0.001), chronic renal failure (3.8% vs 1.8%, p = 0.02), hypertension (61% vs 51%, p <0.001), hypercholesterolemia (66% vs 54%, p <0.001), and family history of coronary artery disease (57% vs 50%, p = 0.01) than TWENTE trial patients without HbA1c measurements.
Of the study population 181 (29%) had a history of diabetes mellitus. In addition, 445 patients of the study population (71%) had no history of diabetes mellitus; according to HbA1c levels, 44 patients of the study population were classified as undetected diabetics (7.0%) and 401 as nondiabetic patients (64%).
Baseline characteristics of the study population and subgroups are presented in Table 1 . Compared to known diabetic patients and nondiabetic patients, undetected diabetics showed many similarities in baseline characteristics but less often tended to have a family history of coronary artery disease (p = 0.02 for the 2 groups). As may be expected, mean HbA1c levels differed across groups and undetected diabetics had higher HbA1c levels compared to nondiabetic patients (6.95 vs 5.77, p <0.001).
| Study Population (n = 626) | Undetected DM (n = 44) | No DM (n = 401) | Known DM (n = 181) | p Value | ||
|---|---|---|---|---|---|---|
| Undetected vs No DM | Undetected vs Known DM | |||||
| Age (years) | 64.7 ± 9.9 | 66.8 ± 9.7 | 64.1 ± 9.8 | 65.5 ± 0.3 | 0.09 | 0.46 |
| Glycated hemoglobin (%) | 6.25 ± 0.94 | 6.95 ± 0.74 | 5.77 ± 0.31 | 7.13 ± 1.15 | <0.001 | 0.32 |
| Men | 450 (72%) | 32 (73%) | 295 (74%) | 123 (68%) | 0.91 | 0.54 |
| Body mass index (kg/m 2 ) | 28.0 ± 4.1 | 27.7 ± 2.8 | 27.5 ± 3.8 | 29.2 ± 4.6 | 0.75 | 0.10 |
| Insulin treatment | 67 (11%) | — | — | 67 (37%) | ||
| Insulin treatment and oral glucose-lowering medication | 43 (7%) | — | — | 43 (24%) | ||
| Chronic renal failure ⁎ | 24 (4%) | 2 (5%) | 11 (3%) | 11 (6%) | 0.50 | 0.70 |
| Arterial hypertension | 382 (61%) | 30 (68%) | 227 (57%) | 125 (69%) | 0.28 | 0.91 |
| Hypercholesterolemia | 402/610 (66%) | 24/39 (62%) | 246/392 (63%) | 132/179 (74%) | 0.88 | 0.25 |
| Current smoker | 135 (22%) | 11 (25%) | 90 (22%) | 34 (19%) | 0.70 | 0.36 |
| Family history of coronary artery disease | 358 (57%) | 16 (36%) | 235 (59%) | 107 (59%) | 0.02 | 0.02 |
| Myocardial infarction (any) | 186 (30%) | 15 (34%) | 118 (29%) | 53 (29%) | 0.52 | 0.53 |
| Previous percutaneous coronary intervention | 139 (22%) | 6 (14%) | 84 (21%) | 49 (27%) | 0.25 | 0.06 |
| Previous coronary artery bypass grafting | 70 (11%) | 4 (9%) | 43 (11%) | 23 (13%) | 0.74 | 0.51 |
| Clinical indication | 0.69 | 0.51 | ||||
| Stable angina pectoris | 426 (68%) | 30 (68%) | 282 (70%) | 114 (63%) | ||
| Unstable angina | 120 (19%) | 10 (23%) | 72 (18%) | 38 (21%) | ||
| Non–ST-segment elevation myocardial infarction | 80 (13%) | 4 (9%) | 47 (12%) | 29 (16%) | ||
| Clinical indication: acute coronary syndrome | 200 (32%) | 14 (32%) | 119 (30%) | 67 (37%) | 0.77 | 0.52 |
| Left ventricular ejection fraction <30% † | 15/473 (3%) | 1/35 (3%) | 6/294 (2%) | 8/144 (6%) | 0.75 | 0.51 |
⁎ Chronic renal failure defined by serum creatinine level ≥130 μmol/L.
† Left ventricular ejection fraction assessed with ultrasound, magnetic resonance imaging, or left ventricular angiography.
Angiographic and procedural characteristics are presented in Table 2 . Undetected diabetics were less frequently treated for left anterior descending coronary artery lesions (36% vs 53%, p = 0.04) and type B2/C lesions (43.2% vs 60.3%, p = 0.03) compared to nondiabetic patients. Diabetic patients were treated more frequently for long lesions (>27 mm) than nondiabetic patients (25% vs 22%, p = 0.05). Side branch occlusion was observed in 2.6% of patients and distal embolization in 0.5%, with no significant difference between groups. Medication at discharge did not differ between groups except for higher rates of angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker prescription in undetected diabetics compared to nondiabetics (p = 0.04; Table 3 ).
| Study Population (n = 626) | Undetected DM (n = 44) | No DM (n = 401) | Known DM (n = 181) | p Value | ||
|---|---|---|---|---|---|---|
| Undetected vs No DM | Undetected vs Known DM | |||||
| Target lesion coronary artery | ||||||
| Left anterior descending | 316 (51%) | 16 (36%) | 213 (53%) | 100 (55%) | 0.04 | 0.16 |
| Left circumflex | 216 (35%) | 17 (39%) | 140 (35%) | 59 (33%) | 0.62 | 0.45 |
| Right | 222 (36%) | 15 (34%) | 137 (34%) | 70 (39%) | 0.99 | 0.57 |
| Left main | 24 (96%) | 2 (5%) | 13 (3%) | 9 (5%) | 0.65 | 0.91 |
| Bypass graft | 19 (3%) | 1 (2%) | 12 (3%) | 6 (3%) | 0.79 | 0.72 |
| Multivessel treatment | 156 (25%) | 6 (14%) | 106 (26%) | 44 (24%) | 0.06 | 0.13 |
| Total lesions treated per patient | 0.13 | 0.21 | ||||
| 1 | 384 (61%) | 29 (66%) | 241 (60%) | 114 (63%) | ||
| 2 | 172 (28%) | 14 (32%) | 110 (27%) | 48 (27%) | ||
| ≥3 | 70 (11%) | 1 (2%) | 50 (13%) | 19 (11%) | ||
| Number of stents placed | 2.08 ± 1.29 | 1.75 ± 0.99 | 2.10 ± 1.29 | 2.11 ± 1.34 | 0.08 | 0.10 |
| American College of Cardiology/American Heart Association class B2 or C lesion treated | 361 (58%) | 19 (43%) | 242 (60%) | 100 (55%) | 0.03 | 0.15 |
| De novo coronary lesions only ⁎ | 582 (93%) | 42 (96%) | 374 (93%) | 166 (92%) | 0.58 | 0.40 |
| ≥1 chronic total occlusion | 57 (9%) | 3 (7%) | 41 (10%) | 13 (7%) | 0.47 | 0.93 |
| ≥1 bifurcation | 152 (24%) | 15 (34%) | 92 (23%) | 45 (25%) | 0.10 | 0.21 |
| ≥1 bifurcation with side branch treatment | 96 (15%) | 9 (21%) | 59 (15%) | 28 (16%) | 0.32 | 0.42 |
| ≥1 in-stent restenosis | 28 (5%) | 1 (2%) | 17 (4%) | 10 (6%) | 0.53 | 0.37 |
| ≥1 small vessel (reference vessel diameter <2.75 mm) | 419 (67%) | 28 (64%) | 275 (69%) | 116 (64%) | 0.50 | 0.96 |
| ≥1 lesion length >27 mm | 141 (23%) | 5 (11%) | 90 (22%) | 46 (25%) | 0.09 | 0.05 |
| Preprocedural Thrombolysis In Myocardial Infarction flow (grades 0–1) | 43 (7%) | 2 (5%) | 29 (7%) | 12 (7%) | 0.51 | 0.61 |
| Aggressive stent postdilatation of >18 atm | 476 (88%) | 30 (81%) | 300 (88%) | 146 (90%) | 0.28 | 0.12 |
| Side branch occlusion | 16 (2.6%) | 1 (2.3%) | 13 (3.2%) | 2 (1.1%) | 0.73 | 0.55 |
| Distal embolization | 3 (0.5%) | 0 (0%) | 1 (0.2%) | 2 (1.1%) | 0.74 | 0.48 |
⁎ Including chronic total occlusion but not grafts and in-stent restenosis.
| Study Population (n = 626) | Undetected DM (n = 44) | No DM (n = 401) | Known DM (n = 181) | p Value | ||
|---|---|---|---|---|---|---|
| Undetected vs No DM | Undetected vs Known DM | |||||
| Antiplatelet therapy | ||||||
| Acetylsalicylic acid | 619 (99%) | 44 (100%) | 397 (99%) | 178 (98%) | 0.51 | 0.39 |
| Clopidogrel | 625 (100%) | 44 (100%) | 400 (100%) | 181 (100%) | 1.00 | 1.00 |
| Other medication | ||||||
| Statin | 536 (86%) | 35 (80%) | 345 (86%) | 156 (86%) | 0.25 | 0.27 |
| β Blocker | 518 (83%) | 34 (77%) | 331 (83%) | 153 (85%) | 0.39 | 0.25 |
| Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker | 321 (51%) | 27 (61%) | 180 (45%) | 114 (63%) | 0.04 | 0.84 |
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