Several randomized trials and meta-analyses have shown that primary angioplasty is superior to thrombolytic therapy in the treatment of patients with ST-segment elevation myocardial infarction (STEMI) [1]. Stent implantation has further improved the outcome by reducing the occurrence of restenosis as compared to balloon angioplasty in selected STEMI patients [2, 3]. However, the outcome of bare metal stents seems to be worse in unselected patients with a rate of TVR up to 20% [4, 5], especially among diabetic patients [6–8]. Drug-eluting stents (DES) have been shown in several randomized trials to reduce restenosis and TVR in both elective [9–13] or STEMI patients [14–18] as compared to bare-metal stents (BMS). However, concerns have emerged on the potential higher risk of stent thrombosis and death with DES [19–22], that might be even more pronounced among STEMI patients, as suggested by a prospective registry [23]. In the PaclitAxel or Sirolimus-Eluting Stent vs Bare Metal Stent in primary angioplasty (PASEO) randomized trial 270 STEMI patients were randomized to SES, PES or BMS (1:1:1) [24, 25]. The aim of the current study was to evaluate the impact of diabetes on 5-year outcome in patients undergoing primary angioplasty with Glycoprotein IIb–IIIa inhibitors with or without DES.

Methods

Our population is represented by STEMI patients undergoing primary angioplasty and randomized to BMS (n = 90), SES (n = 90) or PES (n = 90). Details on study design have already been reported [24, 25]. Briefly, individuals eligible for enrolment were consecutive patients presenting with STEMI who fulfilled all the following inclusion criteria: (1) chest pain for more than 30 min; (2) ST-segment elevation of 1 mm or more in 2 or more contiguous electrocardiograph leads or with presumably new left bundle-branch block; (3) Hospital admission within 12 h from symptoms onset. Exclusion criteria included: (1) Active internal bleeding or a history of bleeding diathesis within the previous 30 days; (2) A history of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation or aneurysm; (3) Known allergy to sirolimus, paclitaxel, heparin, aspirin, or clopidogrel; (4) A history of stroke within 30 days or any history of hemorrhagic stroke; (5) Major surgical procedure or severe physical trauma within the previous month; (6) History, symptoms, or findings suggestive of aortic dissection; (7) Thrombolytic/fibrinolytic therapy within 24 h; (8) History of thrombocytopenia; (9) Hemorrhagic retinopathy; (10) Patients on warfarin or acenocoumarol with INR ≥ 2; 11) Pregnancy. A vessel size <2.25 mm was the only exclusion angiographic criteria.

The institutional review board of the Ospedale “S.G. Moscati” (Avellino, Italy) approved the protocol in 2003, and all patients gave written informed consent.

Medications

All patients received in the coronary care unit 70U/Kg i.v. bolus of unfractionated heparin (UFH) plus 1000U/h infusion (to maintain an activated clotting time of at least 200 s), aspirin intravenously (500 mg) and clopidogrel (300 mg loading dose). All patients received upstream Gp IIb–IIIa inhibitors administration as a routine adjunctive therapy before primary PCI. Postinterventional antiplatelet therapy for all patients included in the three study group, consisted of aspirin (100 mg) indefinitely and clopidogrel (75 mg for 6 months).

Angioplasty procedure

Stenting procedures were performed according to standard techniques. The number and length of stents, and the type of BMS to be implanted, were left to the operator’s discretion. The operator was allowed to implant DES to cover the entire length of the lesion with coverage of the entire stented segment and of 5 mm proximal and distal segments. The use of IVUS, adjunctive thrombectomy devices, distal protection devices and IABP were left to the operator’s discretion.

Angiographic analysis

Thrombolysis in Myocardial Infarction (TIMI) grade 3 coronary flow in the treated vessel and a residual stenosis less than 30% were the criteria used to define a successful PCI. Quantitative angiographic analyses (Integris Allura, Philips, The Netherlands) were performed on line and off line by two experienced technicians who were unaware of treatment assignment with the averaging scores if they were non in agreement.

Data collection and follow-up

As per protocol, patients were reviewed at our outpatient clinic or by telephone interview at 6, 12, 24, 36, and between 48 and 72 months. For patients who died during follow up, hospital records and necropsy data were reviewed, when possible. No patient was lost to follow up.

Study end points and definitions

End points of this study were: Death, reinfarction (reMI), combined death/reMI, target-vessel revascularization (TVR), in-stent thrombosis (IST) and Major Adverse Cardiac Events (MACE) at 5-year follow-up.

All deaths were considered cardiac unless an unequivocal noncardiac cause could be identified. Recurrent MI was defined as recurrence on anginal symptoms with typical ECG changes and increase above upper limit of normal of CKMB or troponin. The indication for a second intervention had to be substantiated by symptoms or by ECG or scintigraphic evidence of ischaemia at rest or during exercise. Subsequent revascularisation of other coronary arteries did not constitute an end point.

Statistical analysis

Continuous data were expressed as median (25–75th percentiles) and categorical data as percentages. The analysis of variance was appropriately used for continuous variables. The χ2 test or the Fisher’s exact test was used for categorical variables. The difference in event rates between groups during the follow up period was assessed by the Kaplan–Meier method with the log rank test. A probability value of P < 0.05 was considered significant. Statistical analysis was performed using SPSS 15.0.

Results

Patient population

Our population is represented by 270 patients with STEMI. Diabetes was observed in 69 patients (34.1%). As shown in Table 1, no difference in demographic and clinical characteristics was observed between the two groups. As shown in Table 2, no difference was observed in terms of angiographic and procedural characteristics. Almost 50% of patients underwent PCI of left anterior descending artery. All patients received upstream glycoprotein IIb–IIIa inhibitors. Procedural success was obtained in 93–95% of patients. A direct stenting strategy was adopted in 24–29% of patients. As reported in Table 3, no difference was observed in terms of clopidogrel prescription between the two groups, with almost all patients stopping clopidogrel therapy at 6 months follow-up.

Table 1 Baseline demographic and clinical characteristics according to diabetes
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Table 2 Angiographic and procedural characteristics according to diabetes
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Table 3 Medical therapy of the three groups of patients
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Diabetes and long-term outcome

Follow-up data were available in all patients at 1510 ± 406 days. As reported in Table 4, at long-term follow-up diabetes was associated with a significantly higher rate of death (29.5 vs. 5.1%, HR [95% CI] = 9.75 [4.11–23.1], P < 0.0001) (Fig. 1), reinfarction (24.1 vs. 9.1% HR [95% CI] = 3.42 [1.66–7.01], P < 0.0001) (Fig. 2), death/reMI (44.8 vs. 13.7%, HR [95% CI] = 5.17 [2.98–8.98], P < 0.001) (Fig. 3), IST (17.2 vs. 6.8%, HR [95% CI] = 6.3 [2.33–17.1], P < 0.001) (Fig. 4) and MACE (51.9 vs. 25.1%, HR [95% CI] = 3.24 [2.06–5.08], P < 0.001) (Fig. 6). These results were confirmed in both patients receiving BMS or DES, except for TVR, where no difference was observed between diabetes and non-diabetic patients. In the analysis restricted to diabetic patients, DES, as compared to BMS, were associated with a significant reduction in TVR (14.3 vs. 27.3%, HR [95% CI] = 0.13 [0.034–0.46], P = 0.002) (Fig. 5) and MACE (38.4 vs. 88.3%, HR [95% CI] = 0.34 [0.17–0.66], P = 0.002) (Fig. 6), and slightly benefits in terms of death (25.1 vs. 39.1%, HR [95% CI] = 0.54 [0.22–1.31], P = 0.17) (Fig. 1), reinfarction (17.8 vs. 38.3%, HR [95% CI] = 0.43 [0.15–1.24], P = 0.12) (Fig. 2) and in-stent thrombosis (27.7 vs. 14.3%, HR [95% CI] = 0.55 [0.17–1.8], P = 0.32) (Fig. 4).

Table 4 Clinical outcome at long-term follow-up
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Fig. 1
figure 1

Kaplan–Meier survival curves showing the impact of diabetes on survival in overall population (a), BMS (b), DES (c). Graph D shows the impact of DES on survival among diabetic patients, as compared to BMS

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Fig. 2
figure 2

Kaplan–Meier survival curves showing the impact of diabetes on event-free survival from reinfarction (reMI) in overall population (a), BMS (b), DES (c). Graph D shows the impact of DES on reMI among diabetic patients, as compared to BMS

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Fig. 3
figure 3

Kaplan–Meier survival curves showing the impact of diabetes on event-free survival from combined death/reinfarction (reMI) in overall population (a), BMS (b), DES (c). Graph D shows the impact of DES on combined death/reMI among diabetic patients, as compared to BMS

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Fig. 4
figure 4

Kaplan–Meier survival curves showing the impact of diabetes on event-free survival from In-stent thrombosis (IST) in overall population (a), BMS (b), DES (c). Graph D shows the impact of DES on IST among diabetic patients, as compared to BMS

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Fig. 5
figure 5

Kaplan–Meier survival curves showing the impact of diabetes on event-free survival from target-vessel revascularization (TVR) in overall population (a), BMS (b), DES (c). Graph D shows the impact of DES on TVR among diabetic patients, as compared to BMS

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Discussion

The main finding of the present study is that diabetes was associated with a significantly higher mortality, reinfarction, TVR and IST. These results were similarly observed among patients treated with BMS or DES, except for TVR, where no difference was observed among patients treated with DES. Among diabetic patients, the use of DES was safe, with a non significant reduction in death and reinfarction and IST but a significant reduction in TVR and overall MACE, as compared to BMS.

Several studies have demonstrated that hyperglycemia at admission is associated with larger infarct size and higher mortality in patients with STEMI [26–31]. In fact, several in vitro and in vivo experiments have shown that hyperglycemia may be involved in the reperfusion injury. Acute hyperglycemia increases intercellular adhesion molecule-1 levels [32], which would augment plugging of leukocytes in the capillaries [33]. Furthermore, leukocytes trapped in the coronary capillaries and venules early after coronary reperfusion are much more frequently observed in the diabetic rat heart than in the nondiabetic heart [34]. Plugging of enhanced leukocytes in the microcirculation may further contribute to the impaired myocardial perfusion [35]. Hyperglycaemia may also augment thrombus formation. Blood glucose has been demonstrated to be an independent predictor of platelet-dependent thrombosis, even in the normal range [36]. A recent study suggested that a microthrombus in the capillaries play a crucial role in the no-reflow phenomenon after STEMI [37]. Finally, diabetes has also been associated with abnormal coronary endothelial function, diminished coronary flow reserve, and impaired ischemic preconditioning [38–40], all of which may result in abnormal myocardial perfusion.

Fig. 6
figure 6

Kaplan–Meier survival curves showing the impact of diabetes on event-free survival from Major Adverse Cardiac Events (MACE) in overall population (a), BMS (b), DES (c). Graph D shows the impact of DES on MACE among diabetic patients, as compared to BMS

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In a recent report, De Luca et al. [41] found among patients treated with Gp IIb–IIIa inhibitors that diabetes was associated with higher occurrence of distal embolization, impaired myocardial reperfusion, and higher mortality.

However, diabetes is associated with a significantly higher rates of restenosis [6–8]. In a previous report, De Luca et al. [42], found that BMS did not provide significant benefits in outcome as compared to balloon angioplasty in unselected diabetic patients undergoing primary angioplasty. The recent introduction of DES, has certainly reduced the risk of restenosis, that may be counterbalanced by an higher rate of late in-stent thrombosis, especially among STEMI. A recent individual patients’ data meta-analysis showed that, among STEMI diabetic patients undergoing primary angioplasty, the use of DES was safe, and associated with a significant reduction in TVR at 1-year follow-up. However, it has been described a late catch-up phenomenon in terms of restenosis, with a potential risk of late in-stent thrombosis.

Our study is the first one evaluating the impact of diabetes on 5-year outcome among STEMI patients undergoing primary angioplasty in the era of DES. Diabetes was associated with a significantly higher mortality, reinfarction, TVR and IST, irrespective of DES or BMS, except than for TVR. In fact, among patients treated with DES, no difference was observed between diabetic and non-diabetic patients. Furthermore, among diabetic patients, the use of DES was safe, with a non significant reduction in death and reinfarction, similar rates of IST but a significant reduction in TVR and overall MACE, as compared to BMS.

Limitations

Despite long-term follow-up data, due to the relatively small sample size, this study can not provide definite conclusions on DES safety in terms of death and reinfarction in diabetic patients, that will hopefully be provided by large randomized trials.

The relatively high rate of cardiogenic shock observed in our study may be due to the fact that in peripheral hospitals of our province lysis still represents, if not contraindicated, the initial preferred strategy, whereas primary angioplasty is preferred in patients with haemodynamic compromise that are therefore transferred to our hospital to undergo mechanical reperfusion.

Conclusions

This study shows that among STEMI patients undergoing primary angioplasty with Gp IIb–IIIa inhibitors, diabetes is associated with worse long-term mortality, reinfarction, and IST, even with DES implantation, that, however, were able to equalize the outcome in terms of TVR as compared to non diabetic patients.