Impaired glycemic control (GC) is a troubling clinical condition with an unclear prognostic value that is frequent in diabetics, especially in the setting of acute coronary syndrome. Residual platelet reactivity can be also affected by GC. We evaluated the relation between response to dual antiplatelet therapy and GC in diabetics with STEMI treated with primary coronary angioplasty (PCI). Sixty diabetic patients were prospectively enrolled in the study. All patients were treated with clopidogrel and aspirin. Platelet reactivity (whole blood aggregation and phosphorylation of vasodilator-stimulated phosphoprotein, VASP) were assessed serially before and 24 hours, 7 days, and 30 days after the PCI. Blood glucose >8.5 mmol/L on admission was an independent predictor of a impaired clopidogrel response measured with platelet reactivity index (PRI) >50% on admission (OR 7.8, 95% CI 1.4-17.7, p<0.02) and 24 hours after PCI (OR 13.1, 95% CI 3.4-28.1, p<0.01). In conclusion, diabetic patients with STEMI and glycemia >8.5 mmol/L on admission is related to a poorer response to clopidogrel. There were no interaction between glycated hemoglobin level or glycemia on admission and platelet reactivity measured with collagen, arachidonic acid or thrombin receptor agonist peptide-induced aggregation. Further clinical studies of the role of GC in the efficacy of antiplatelet agents are warranted.
Dual antiplatelet therapy is the cornerstone of preventive treatment in patients with acute coronary syndromes, especially after coronary stent implantation However, the success of current antiplatelet strategies is not overwhelming. One of the main causes of the “resistance” phenomenon is thought to be impaired metabolism of clopidogrel into its active form because of the polymorphism of cytochrome P450 genes encoding enzymes. Up to 70% of the variable response to clopidogrel is attributable to genetic factors. In addition, an incomplete response to clopidogrel has been observed in obese patients and, importantly, in diabetics. In fact, patients with type 2 diabetes mellitus exhibit a consistently poorer prognosis after acute coronary syndrome compared to nondiabetics. Therefore, the potential link of diabetes severity, especially in patients with uncontrolled impaired glycemic control (GC), to response to antiplatelet agents is valuable but unclear. Among the potential causes of such adverse association are increased baseline blood platelet reactivity, endothelial dysfunction, inflammatory burst, oxidative stress, increased platelet turnover, and increased P2Y12 receptor activity owing to insulin resistance. The association between GC and the effects of antiplatelet therapy is still unclear. Although hyperglycemia has been known to activate platelets, increased glycated hemoglobin (HbA1c) levels have not been shown to affect the response to antiplatelet drugs. The aim of this study was to assess the relation between GC and response to antiplatelet therapy in diabetic patients with ST-segment elevation myocardial infarction (STEMI) treated with primary coronary angioplasty.
The study was approved by the bioethics committee of the Medical University of Silesia. All patients were required to sign an informed consent for study participation. Inclusion criteria were STEMI treated with primary coronary angioplasty with stent implantation, final postoperative coronary Thrombolysis In Myocardial Infarction flow grade 3, and diabetes mellitus diagnosed and treated before index hospital admission. Exclusion criteria were cardiogenic shock, repeat MI, platelet count <100,000 or >450,000/mm 3 in peripheral blood, allergy to salicylates or thienopyridine derivatives, intraoperative administration of intravenous platelet glycoprotein IIb/IIIa receptor blocker, or previous dual antiplatelet therapy. Patients included in the study were treated with primary coronary angioplasty according to standards of the European Society of Cardiology. Before the procedure, in the ambulance, all patients were administered a loading dose of clopidogrel 600 mg and acetylsalicylic acid 300 mg. Medications were continued with clopidogrel 75 mg and acetylsalicylic acid 75 mg starting from the day after hospitalization. On discharge, clopidogrel was recommended for 12 months and acetylsalicylic acid for life. Before angioplasty, coronarography was carried out in the catheterization laboratory to evaluate coronary anatomy; intravenous heparin was administered according to current standards, and bare metal stents were implanted.
All patients had their glucose level (millimoles per liter) and percent HbA1c in peripheral blood measured on admission. Fasting glycemia at <5.5 mmol/L and HbA1c <6.5% were considered normal. Whole blood for tests was collected in test tubes containing hirudin (25 μg/ml) as an anticoagulant. Samples for aggregation studies were taken before angioplasty and then at 24 hours, 7 days, and 30 days postoperatively. Platelet aggregation was assessed with the Multiplate impedance aggregometer (Dynabyte, Munich, Germany). The aggregation agonists used were arachidonic acid at a target concentration of 0.5 mmol/L, adenosine diphosphate at a target concentration of 6.4 μmol/L, collagen at a target concentration of 3.2 μg/ml, and thrombin receptor agonist peptide at a target concentration of 32 μmol/L. Reagents were provided by the manufacturer of the aggregometer. Aggregation was assessed within 2 hours after blood sampling and included the area under aggregation curve (AUC) expressed in arbitrary units in minutes (AU*min). Each aggregation measurement was performed 2 times, and the mean value was calculated. For a 10% difference between measurements, the result was rejected and aggregation tests were repeated. Phosphorylation of vasodilator-stimulated phosphoprotein (VASP) assessment was conducted in peripheral blood before the procedure and then 24 hours, 7 days, and 30 days after the procedure using VASP/P2Y12 kits (BioCytex, Marseille, France). Platelet reactivity index (PRI; percentage) was calculated based on mean fluorescence intensity of blood samples incubated with prostaglandin E1 and prostaglandin E1 plus adenosine diphosphate. Two assessments were made for each sample; a difference >5% necessitated a new assessment. Laboratory personnel evaluating aggregation and VASP phosphorylation were not aware of patients’ clinical data.
Response to acetylsalicylic acid was assessed by arachidonic acid-induced aggregation, and response to clopidogrel was assessed with adenosine diphosphate–induced aggregation. The obtained values were seen as continuous data and were divided into quartiles in further analysis. Based on available data, the cut-off point for incomplete response to clopidogrel was determined for cases with AUC>416 (AU*min). Response to clopidogrel was also assessed by VASP phosphorylation; the obtained results were treated as continuous variables and divided into quartiles, with PRI >50% being the cut-off point for incomplete response. To evaluate platelet reactivity in relation to GC, collagen-induced and thrombin receptor agonist peptide–induced aggregations were assessed.
Statistical analysis was conducted using STATISTICA 9.0 (StatSoft, Chicago, Illinois). For all patients, mean ± SD was calculated, and the distribution of analyzed parameters was evaluated with normality tests, i.e., Kolmogorov–Smirnov test, Lillefors test, and Shapiro–Wilk test. Significance of differences between groups was determined using Student’s t test for nonassociated variables with normal distribution and Mann–Whitney U test for variables without normal distribution. For dichotomous variables, statistical significance of differences between groups was assessed using chi-square, chi-square with Yates correction, or Fisher’s exact test, depending on the size of the analyzed group of patients. Multifactor analysis and receiver operator characteristic curve analysis were also conducted.
Results
The study included 60 patients and their detailed clinical characteristics are presented in Table 1 . Statistically significantly higher VASP test values (continuous variables) and more frequent incomplete response to clopidogrel (cut-off point for incomplete response to clopidogrel with PRI >50%) were observed in patients with impaired GC. This association was consistent and observed on admission and 24 hours and 7 days after the procedure. The effect ceased 30 days postoperatively ( Table 2 , Figure 1 ) . Blood glucose >8.5 mmol/L on admission was a predictor of PRI >50% on admission (area under receiver operator characteristic curve 0.74, 95% confidence interval [CI] 0.60 to 0.85, p = 0.045) with 80.0% sensitivity and 83.3% specificity. Glycemic level >10.2 mmol/L on admission predicted PRI >50% 24 hours postoperatively (area under receiver operator characteristic curve 0.88, 95% CI 0.76 to 0.95, p <0.0001; Figure 2 ) with 76.2% sensitivity and 100% specificity. Glucose >9.7 mmol/L on admission was a predictor of PRI >50% 7 days after the procedure (area under receiver operator characteristic curve 0.67, 95% CI 0.53 to 0.80, p = 0.038) with 81.2% sensitivity and 65% specificity.
| Variable | Admission Blood Glucose (mmol/L) | |
|---|---|---|
| >8.5 | <8.5 | |
| (n = 45) | (n = 15) | |
| Age (years), mean ± SD | 62.1 ± 6.8 | 61.7 ± 4.4 |
| Men/women | 30/15 | 6/9 |
| Arterial hypertension | 35 (77%) | 11 (73%) |
| Hypercholesterolemia | 39 (86%) | 11 (73%) |
| Total cholesterol (mmol/L) | 5.3 ± 1.1 | 4.9 ± 1.8 |
| High-density lipoprotein cholesterol (mmol/L) | 1.2 ± 0.3 | 1.1 ± 0.5 |
| Low-density lipoprotein cholesterol (mmol/L) | 3.4 ± 1.0 | 3.7 ± 0.7 |
| Triglycerides (mmol/L) | 1.6 ± 1.0 | 1.2 ± 0.8 |
| Pantoprazole | 45 (100%) | 15 (100%) |
| Statins | 45 (100%) | 15 (100%) |
| Atorvastatin | 35 (78%) | 12 (80%) |
| Atorvastatin dose (mg), minimum–maximum (median) | 20–80 (40) | 20–80 (40) |
| Simvastatin | 10 (22%) | 3 (20%) |
| Simvastatin dose (mg), minimum–maximum (median) | 20–40 (40) | 20–40 (40) |
| Insulin | 25 (55%) | 7 (46%) |
| Insulin dose/day (IU), minimum–maximum (median) | 10–86 (33) | 12–94 (41) |
| Metformin | 20 (44%) | 4 (46%) |
| Metformin dose/day (mg), minimum–maximum (median) | 850–2,000 (1,700) | 850–2,000 (1,700) |
| Sulfonylurea derivatives | 13 (28%) | 6 (40%) |
| Gliclazide | 5 (11%) | 3 (20%) |
| Gliclazide dose/day (mg), minimum–maximum (median) | 80–320 (160) | 80–320 (160) |
| Glimepiride | 8 (17%) | 3 (20%) |
| Glimepiride dose/day (mg), minimum–maximum (median) | 1–6 (4) | 1–6 (4) |
| Glucose serum level (mmol/L), mean ± SD | ||
| Before percutaneous coronary intervention (not fasting) | 13.2 ± 4.2 | 7.01 ± 1.5 |
| 24 hours after percutaneous coronary intervention (fasting) | 6.2 ± 1.1 | 5.8 ± 1.0 |
| 7 days after percutaneous coronary intervention (fasting) | 5.2 ± 0.9 | 5.4 ± 1.0 |
| 30 days after percutaneous coronary intervention (fasting) | 5.8 ± 0.7 | 4.3 ± 0.5 |
| Hypercholesterolemia | 39 (86%) | 11 (73%) |
| Current cigarette smoking | 25 (55%) | 5 (33%) |
| Infarct-related coronary artery | ||
| Left anterior descending | 18 (40%) | 6 (40%) |
| Left circumflex | 11 (24%) | 4 (27%) |
| Right | 16 (36%) | 5 (33%) |
| Stents used, mean (median) | 1.3 (1) | 1.2 (1) |
| Stents length (mm), mean (median) | 21 (18) | 18 (18) |
| Stent diameter (mm), mean (median) | 3.0 (3.0) | 3.2 (3.0) |
| Baseline Thrombolysis In Myocardial Infarction flow grade 0/1/2/3 | 20/19/6/0 | 7/4/3/1 |
| Time from aspirin and clopidogrel loading dose to percutaneous coronary intervention (minutes), mean ± SD | 85 ± 35 | 91 ± 21 |
| Maximum troponin I level (ng/ml), mean ± SD | 27.1 ± 6.9 | 25.7 ± 4.5 |
| Admission glycated hemoglobin (%), mean ± SD | 7.1 ± 1.5 | 6.8 ± 2.1 |
| Left ventricular ejection fraction at discharge (%), mean ± SD | 42.1 ± 4.6 | 44.1 ± 5.2 |
| Statin therapy | 45 (100%) | 15 (100%) |
| β-Blocker therapy | 42 (93%) | 14 (93%) |
| Angiotensin-converting enzyme inhibitor | 45 (100%) | 15 (100%) |
| Aspirin (75 mg 1 time/day) | 45 (100%) | 15 (100%) |
| Clopidogrel (75 mg 1 time/day) | 45 (100%) | 15 (100%) |
| Platelet reactivity | Blood Glucose on Admission (mmol/L) | p Value | HbA1c on Admission | ||
|---|---|---|---|---|---|
| <8.5 | >8.5 | <6.5% | >6.5% | ||
| (n = 15) | (n = 45) | (n = 14) | (n = 46) | ||
| Adenosine diphosphate-induced aggregation (AUC) (AU*min), mean ± SD | |||||
| Before percutaneous coronary intervention | 851 ± 460 | 748 ± 361 | NS | 787 ± 377 | 835 ± 477 ⁎ |
| 24 hours after percutaneous coronary intervention | 261 ± 213 | 306 ± 198 | NS | 322 ± 221 | 200 ± 136 |
| 7 days after percutaneous coronary intervention | 358 ± 216 | 346 ± 212 | NS | 359 ± 217 | 379 ± 231 |
| 30 days after percutaneous coronary intervention | 382 ± 231 | 396 ± 234 | NS | 417 ± 254 | 299 ± 178 |
| Vasodilator-stimulated phosphoprotein–platelet reactivity index (%), mean ± SD | |||||
| Before percutaneous coronary intervention | 58.0 ± 26.5 | 73.4 ± 9.6 | <0.01 | 70.2 ± 15.7 | 64.9 ± 23.5 |
| 24 hours after percutaneous coronary intervention | 44.9 ± 20.6 | 63.1 ± 11.6 | <0.001 | 58.2 ± 14.7 | 56.8 ± 23.2 |
| 7 days after percutaneous coronary intervention | 42.5 ± 16.0 | 57.1 ± 13.6 | <0.01 | 53.0 ± 13.7 | 52.0 ± 23.2 |
| 30 days after percutaneous coronary intervention | 49.4 ± 19.1 | 50.6 ± 17.5 | NS | 51.5 ± 17.8 | 37.6 ± 17.5 |
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