The CHIPS12 (Management of Hyperglycaemia and Platelet Activity in Patients With Acute Coronary Syndrome) study is a randomized, single-center trial that evaluated the impact of allocation to an intensive protocol with intravenous insulin for blood glucose control on platelet reactivity in ACS patients with hyperglycemia. The details and results of the first randomization phase of this trial were recently published.12,13

For the present long-term study, at the time of hospital discharge patients were again randomized 1:1 to an optimized treatment protocol for glucose control (target glucose value, 80-120 mg/dL) or to conventional treatment (target glucose value, <180 mg/dL). The optimized management consisted of follow-up in the hospital diabetes mellitus unit by endocrinologists with expertise in diabetes mellitus. Patients in this group received ultra-slow insulin by protocol, together with rapid-acting insulin with meals. Conventional management consisted of follow-up by primary care physicians, who sent patients to a general endocrinologist or not, at their discretion. Glucose levels were measured with the capillary blood glucose test (Accu-Chek Sensor®; Roche, Mannheim, Germany).

As to the management of ACS, all participants received the treatment currently recommended in clinical practice guidelines, except when there were contraindications.20,22,23 The study was carried out in accordance with the Declaration of Helsinki and was approved by the ethics committee of our hospital. All patients gave written consent for participation in the study.

The primary endpoint of the study was defined as the reduction in platelet aggregation following stimulation with 20 μM adenosine diphosphate (ADP), evaluated at 12 months after ACS. Secondary endpoints were the reductions in platelet function occurring with other parameters of aggregation and activation, and the incidence of cardiovascular events.

For the study of platelet function, blood samples were collected by forearm venipuncture. A total blood volume of approximately 30mL was extracted at baseline (at the time of hospital discharge and before randomization) and at 12 months after treatment. The first 3 mL of sample was discarded to avoid spontaneous platelet activation. All samples were analyzed within 1 h after collection by investigators blinded to the assigned intervention group.

Normal distribution of the variables was confirmed with the Kolmogorov-Smirnov test. Quantitative variables that met the condition of normality are expressed as the mean (standard deviation), and non-normal variables as the median [interquartile range]. Categorical variables are expressed as frequencies and percentages. In all cases, we tested the distribution of the variable against theoretical models and tested the assumption of homogeneity of variances. Associations between categorical variables were determined with the chi-square test or the Fisher exact test when at least 25% of the values showed an expected frequency<5. The Student t test was used to compare quantitative variables with 2 categories. The nonparametric Mann-Whitney U test was used for variables with non-normal distribution. Associations between quantitative variables were examined with the Pearson correlation coefficient. Differences with a probability error≤5% (P≤.05) were considered significant. Data analysis was performed with SPSS, version 15.0 (SPSS Inc.; Chicago, Illinois, United States).

Management of hyperglycemia during the one-year follow-up, treatment administered, and adverse events recorded are summarized in Table 3. Patients assigned to optimized treatment had a larger number of daily capillary blood glucose tests and were more thoroughly monitored (P<.001). Optimized treatment resulted in better glucose control at 12 months than did conventional treatment (104 vs 119 mg/dL; P<.001), and better metabolic control, as assessed by HbA1c values (6.4 [0.7] vs 6.8 [1.3] mg/dL; P<.001). Furthermore, with optimized management, there was a smaller decline in renal function than with conventional management. This was best seen with cystatin C measurements (0.8 [0.2] vs 1.1 [0.6]; P=.03).

There were no differences between the groups with regard to antiplatelet treatment, but hyperglycemia management did differ. A larger percentage of patients were treated with insulin instead of oral antidiabetic agents in the group receiving optimized treatment. As to adverse events, a larger number of patients with optimized management presented with episodes of hypoglycemia (glucose level<60mg/dL), but there were no significant differences between the groups in the percentage of episodes of severe hypoglycemia (9.4% vs 2.0%; P=.10).

The results of platelet function analysis at 12 months of treatment are shown in the Figure. There were no significant differences between optimized and conventional treatment regarding the primary endpoint of the study: percentage (standard deviation) of platelet aggregation following stimulation with 20 μM of ADP (54.2% [14.3%] vs 55.1% [18.3%]; P=.81). Nor were there differences for the remaining parameters analyzed: ADP 5 μM (34.0% [15.6%] vs 33.4% [15.8%]; P=.87), collagen 6 μg/mL (29.1% [23.1%] vs 37.2% [22.9%]; P=.17), epinephrin 20 μM (32.9% [15.0%] vs 30.1% [16.1%]; P=.46), thrombin receptor-activating peptide 25 μM (67.6% [12.5%] vs 65.8% [14.3%]; P=.56), platelet reactivity index (59.3% [22.1%] vs 64.2 [22.6%]; P=.44), GPIIb/IIIa expression (60.1% [16.7%] vs 65.5% [19.2%]; P=.21), and P-selectin expression (61.0% [23.7%] vs 63.5% [23.4%]; P=.65).

Figure.

Analysis of platelet function after 12 months of treatment. ADP, adenosine diphosphate; GPIIb/IIIa, glucoprotein IIb/IIIa; PRI, platelet reactivity index; TRAP, thrombin receptor activating peptide.

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Although this is a randomized trial, it was conducted in a single center. The study lacks power to detect possible differences in adverse events, mainly severe episodes of hypoglycemia. Nonetheless, despite these limitations, the robustness of the methods and statistical analysis lends support to the results obtained.