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Effects of Tirofiban on Acute Systemic Inflammatory Response in Elective Percutaneous Coronary Interventions

Posted on: Friday, 7 January 2005, 03:00 CST

Key words: Acute systemic inflammatory response * Percutaneous coronary intervention * Tirofiban

SUMMARY

Objective: In this study the effect of a specific glycoprotein IIb/IIIa inhibitor, tirofiban [which also has antiplatelet activity on acute systemic inflammatory responses (IR) during elective percutaneous coronary intervention (PCI)] was evaluated.

Patients and methods: Patients with stable angina pectoris and similar baseline characteristics who angiographically had a single lesion in their coronary arteries with a PCI performed on that lesion were enrolled in the study. One group of patients (control group, n = 52) received 0.9% NaCl (15 mL/h for 24 h) and the other group (tirofiban group, n = 55) had tirofiban (10 g/kg bolus infusion in 3 min and 0.15 g/kg/min for 24 h) in addition to stenting without pre-dilatation. The effect of interventional procedure on levels of cardiac troponin T (cTnT) and several parameters of acute IR (leukocytes, fibrinogen, C-reactive protein, interleukin-1, interleukin-6, interleukin-8 and tumor necrotizing factor-α) was assessed on blood samples obtained from all patients before PCI and at pre-specified time points after PCI.

Results: During the follow-up after PCI, the number of patients becoming cTnT-positive (> 0.1 ng/mL) was greater in the control group [12 (23%) patients vs. 3 (5%) patients, p = 0.01]. However, both groups had changes (generally observed as elevations) in their levels of all inflammatory parameters during the study and C- reactive protein, interleukin-6 and tumor necrotizing factor-α levels were elevated significantly. Yet, no significant difference occurred between groups due to these changes in any phase of the study (p > 0.05).

Conclusions: Based on the findings of this study, it was concluded that although tirofiban limits development of myocardial necrosis during elective PCI, it does not directly affect the acute systemic inflammatory responses.

Introduction

During elective percutaneous coronary intervention (PCI), processes such as mechanical stretch, vascular injury, infections or homeostasis impairment may trigger acute local and systemic inflammatory responses over a period of time. Also, the interaction of factors contributing to acute inflammatory response are generally suggested to result in inflammation, cellular proliferation and apoptosis. The latter events may result in adverse outcomes by leading to stent thrombosis in early phase and stent occlusion in the later phases1"4. Some cardiologists have, therefore, suggested anti-inflammatory treatment to decrease the complications of interventions5,6.

Detection of clinical benefits of aspirin, antiplatelet agents like thienopyridines and GP IIb/IIIa inhibitors in PCIs and acute coronary syndrome (ACS) together with progressive additive effects7- 10 have focused attention on to these agents. Although at the beginning, only antithrombotic effects of combination treatments were considered, potential anti-inflammatory effects of these drugs were also reported in recent investigations". In this study, the effects of tirofiban, a specific GP Ilb/IIIa inhibitor (which has also been reported as achieving significant prevention of ischaemic events during PCIs12-14), on systemic inflammatory response in elective PCI's were investigated.

Patients and methods

Patients

Patients with stable angina pectoris and negative (< 0.1 ng/mL) baseline cardiac troponin T (cTnT) values, having a single haemodynamically significant lesion in their native coronary arteries as shown angiographically, who had successful stenting on that lesion without pre-dilation were enrolled in the study. However, all patients were subjected to clinical and angiographie exclusion criteria in order to achieve a certain degree of standardization. Clinically, patients with a recent history of any cardiovascular illness (myocardial infarction, stroke, heart failure etc.], diabetes mellitus, bleeding diatheses which can be contraindications for trombolysis, neoplasms, chronic organ failures (hepatic, renal), connective tissue disorders or systemic infectious diseases and patients whose angiograms showed bifurcations or calcifications of the coronary arteries or previous restenotic or graft lesions, were excluded.

Informed written consent was obtained from all patients who wished to participate in the study, on a voluntary basis, in accordance with our Institutional Ethics Committee and the Declaration of Helsinki for patient rights.

Study Design

Eligible patients attended the catheterization laboratory without any premedication. At the catheterization laboratory, simultaneous cannulations were performed at the right antecubital vein for maintaining venous patency, left antecubital vein for assessment of laboratory parameters and right femoral artery for the interventional coronary procedure. During the period following cannulations, blood samples were obtained for measuring baseline (Hour O] values of inflammatory parameters; soon after, diagnostic coronary angiographies were performed via the femoral artery. During the angiographie analyses performed at the same time, patients with a haemodynamically significant lesion in only one coronary artery were given 300 mg aspirin (maintenance 150 mg/day), 450 mg clopidogrel (maintenance 75 mg/day), 100 IU/kg iv bolus standard heparin (maintenance enoxaparin 1 mg/kg/24 h) and either 0.9 % sodium chloride for 24 h (control group) or tirofiban 10 g/kg bolus infusion in 3 min and 0.15 g/kg/min for 24 h (tirofiban group) during stent implementation with single-balloon inflation without pre-dilatation. Patients with a proven procedural success (achievement of TIMI grade 3 coronary blood flow, adequate patency after stenting or residual stenosis < 20%) at follow-up angiographie evaluations were included in a follow-up period for an additional 48 h in order to determine possible changes in cTnT and acute inflammatory response parameters.

Blood Samples

Blood samples for assessment of acute inflammatory response parameters [leukocytes (L), fibrinogen (F), C-reactive protein (CRP) and cytokines such as interleukin-1 (IL-1β), interleukin-6 (IL- 6), interleukin 8 (IL-8), tumor necrotizing factor-α (TNF- β)] and myocardial necrosis parameters (cTnT) were obtained before PCI (Hour 0) and at 30 min, 2 h, 4 h, 6 h, 12 h, 24 h and 48 h after PCI. The blood samples were centrifuged at 2000 g for 10 min and immediately frozen at -70C to be analyzed later. Parameters for L and F were analyzed by using Bayer Advia 120 Cell Counter Hematologia autoanalyzer (Bayer Advia 120 CBC Counter, USA) and cytokines by the ELISA method (Endogen Inc. Ma., USA); CRP concentrations were measured by using the immunoturbidimetric method (Roche Unimate 3CP, Milan Italy).

Coronary Angiography and Percutaneous Coronary Intervention (PCI)

Coronary angiographies were performed immediately after baseline and stent implementation using the same angiographie projections as the standard Judskins method15. Nevertheless, all patients were given 100 g-200 g intracoronary nitroglycerine in order to achieve optimal vasodilation before angiographic imaging or to prevent possible vasospasms. Angiographic data obtained by coronary angiography were analyzed by blinded cardiologists at the same instance using the Coronary Measurement System (Coronary Measurement Sistem, MEDIS, Leiden, The Netherlands). For all patients presenting angiographically with a single lesion in a single native coronary artery (luminal diameter reduction > 50% and < 100% by quantitative coronary angiography) after adequate (70IU/kg-100IU/kg) infusion of iv heparin, a 6 French (Fr) guiding catheter (Cordis Corparation, Miami, Florida) was inserted in the target coronary artery. A 0.014 in coronary guide wire (Boston Scientific/Scimed, Maple Grove, Minnesota) was then passed through this guiding catheter. Finally, a stent (Crossflex LC, Cordis Corporation, Miami, Florida) was placed at the target coronary artery with single-balloon inflation without pre-dilatation (patients who could not achieve sufficient stent patency with single-balloon inflation, who developed dissection at the stent edges or who required additional stenting were excluded from the study).

Statistical Analysis

A general linear model was used for changes in levels of acute inflammatory response parameters occurring in time and for repetitive differences between groups. Study data were expressed as mean value SD or percentages. The chi-square test was used for categorical variables between groups and the t-test for continuous variables. Results with a p value less than 0.05 were considered statistically significant.

Table 1. Baseline characteristics of patients

Results

The study enrolled a total of 114 patients well-matched for baseline clinical characteristics (control group, n = 55, tirofiban group, n = 59). In the control group, three patients were excluded from the study: two patients due to failure of stenting without pre- dilatation, one patient due to acute stent thrombosis; in the tirofiban group two patients were excluded due to failure of stenting without pre-dilatation, one patient due to development of haematoma the in femoral access site and one patient due to acute thrombocytopenia. Thus, the study was conduct\ed with 107 patients (control group, n = 52, tirofiban group, n = 55) (see Tables 1 and 2).

Cardiac Troponin T (cTnT)

Although all patients in both groups had negative baseline cTnT values (< 0.1 ng/mL), 23% of patients in the control group (n = 12) and 5% of patients in the tirofiban group (n = 3) had become cTnT positive (> 0.1 ng/mL) during the follow-up period after PCI. Thus, an apparent difference occurred between groups at the end of the follow-up period (p = 0.01).

Leukocyte (L) Counts

L counts of patients in control and tirofiban groups were similar before PCI (control group: 7426 2617 mm^sup 3^, tirofiban group: 7347 2455mm^sup 3^; p = 0.86). However, slight increases were observed in both groups beginning from about 24 h after PCI until the end of the follow-up period (control group from 7426 2617 mm^sup 3^ to 8331 2415 mm^sup 3^, p = 0.56; tirofiban group from 7347 2455 mm^sup 3^ to 7928 2231 mm^sup 3^, p = 0.66). Nonetheless, no difference occurred in L counts between groups at the end of the follow-up period (control group: 8331 2415 mm^sup 3^, tirofiban group: 7928 2231 mm^sup 3^, p = 0.72).

Table 2. Angiographic findings of patients

Fibrinogen (F) Levels

There was no difference between groups in F levels before PCI (control group: 311 155 mg/dL, tirofiban group: 323 161 mg/dL; p = 0.68). However, a slight increase in F levels of control group patients and a slight decrease in F levels of tirofiban group patients were seen during the follow-up period after PCI (control group from 311 155 mg/dL to 333 176 mg/dL, p = 0.24; tirofiban group: 323 161 mg/dL to 314 144 mg/dL, p = 0.55). Despite all these differences no significant difference occurred in F levels between groups at the end of the follow-up period (control group: 333 176 mg/dL, tirofiban group: 314 144 mg/dL; p = 0.33).

C-reactive Protein (CRP) Levels

CRP levels of patients in control and tirofiban groups were similar before PCI (control group: 1.3 0.4 mg/dL, tirofiban group: 1.3 0.1 mg/dL; p = 0.98). However, CRP levels increased gradually in both groups beginning from Hour 6 during the follow-up period after PCI although the control group had slightly greater increases (control group from 1.3 0.4 mg/dL to maximum 4.1 2.2 mg/dL, p = 0.02; tirofiban group from 1.3 0.1 mg/dL to maximum 3.5 1.3mg/dL, p = 0.03). Nonetheless, there was no significant difference between groups in CRP levels at the end of the follow-up period (control group: 4.1 2.2 mg/dL, tirofiban group: 3.5 1.3mg/dl; p = 0.07) (Figure 1).

Cytokine Levels

Interleukin-1β (IL-1β)

IL-1β levels of patients in control and tirofiban groups were similar before PCI (control group: 0.50 0.04pg/mL, tirofiban group: 0.48 0.01 pg/mL; p = 0.33). However, both groups had changes in their IL-1β levels that were observed as slight occasional increases and decreases during the follow-up period after PCI although the control group had slightly greater changes. Nevertheless, changes in IL-1β levels that occurred during and at the end of the follow-up period did not result in any statistical difference between groups (p > 0.05) (Figure 2).

Interleukin-6 (IL-6)

Although IL-6 levels were similar in both groups before PCI (control group: 4.7 2.6 pg/mL, tirofiban group: 4.3 2.3 pg/mL; p = 0.7), an apparent increase was observed in IL-6 levels beginning from about 6 h after the interventional procedure until Hour 12 in both groups (control group: 4.7 + 2.6pg/mL to maximum 7.8 2.3 pg/ mL, p = 0.001, tirofiban group: 4.3 2.3 pg/mL to maximum 7.3 2.2 pg/mL; p = 0.01). However, after Hour 12, IL-6 levels slightly decreased in both groups until the end of the follow-up period. Yet, there was no significant difference in IL-6 levels between groups at the end of the follow-up period (control group: 6.0 3.1 pg/mL, tirofiban group: 5.3 2.4 pg/mL; p = 0.37) (Figure 3).

Figure 1. Changes in serum CRP levels of patients with or without concomitant tirofiban during PCI in time

Figure 2. Changes in IL-1β levels of patients with or without concomitant tirojiban during PCl in time

Figure 3. Changes in IL-6 levels of patients with or without concomitant tirofiban during PCI in time

Figure 4. Changes in IL-8 levels of patients with or without concomitant tirofiban during PCl in time

Interleukin-8 (IL-8)

IL-8 levels of patients in control and tirofiban groups were similar before PCI (control group: 110 84 pg/mL, tirofiban group: 122 91; p = 0.33]. However, both groups had slight occasional increases or decreases in IL-8 levels during the follow-up period after PCI. Yet, changes in IL-8 levels that occurred during and at the end of the follow-up period did not result in any statistical difference between groups (p > 0.05) (Figure 4).

Figure 5. Changes in TNF-α levels of patients with or without concomitant tirofiban during PCI in time

Tumor Necrotising Factor-α (TNF-α)

TNF-α levels of patients in control and tirofiban groups were similar before PCI (control group: 4.2 0.32pg/mL, tirofiban group: 4.14 0.27pg/mL; p = 0.52). However, TNF-α levels increased substantially compared to levels before PCI and reached a maximum in both groups about 30 min after the interventional procedure (control group from 4.2 0.32 pg/mL to 5.8 0.28 pg/mL, p = 0.02; tirofiban group from 4.14 0.27 pg/mL to 5.5 0.33pg/mL, p = 0.05). Also after these peak points, TNF-α levels of patients in both groups tended to decrease until Hour 12 and slightly increase after Hour 12. But, there was no significant difference in TNF-α levels between groups at the end of the follow-up period (control group: 4.4 30 pg/mL, tirofiban group: 4.0 24pg/mL; p = 0.24) (Figure 5).

Discussion

In this study it was found that tirofiban applied during elective PCI decreased cTnT positivity in the post procedural period, but could not entirely prevent the activation of an acute systemic inflammatory response. The decreased positivity rate of cTnT in the tirofiban group may be important in respect to the infrequent development of myocardial injury16,17. However, we think that peri- procedural problems go further than this because of the continuation of inflammation processes.

It is known that mechanical stretching, vascular injury and hypoxic events in peri- and post-procedural periods cause unwanted events during PCI18-24. Myocardial injury and inflammatory response caused by these events determine these unwanted effects3,4,22-29. Recently it was reported that with the use of GP IIb/IIIa inhibitors, the rate of these unwanted events in peri-and post- procedural periods decreased8-12,16,30-32. The reason for this is not known exactly. On the other hand, Januzzi et al. reported that, compared to heparin alone, a tirofiban and heparin combination treatment resulted in lower Troponin I levels and so, lesser myocardial injury31. Additionally, cTnT positivity was significantly lower in the tirofiban group in the TOPSTAR trial during elective PCI16. Lincoff et al. reported that systemic inflammatory markers increased within 24 h-48 h of PCI and they suggested that these increments may be decreased by the administration of peri- procedural abciximab. They also suggested that long term beneficial effects arose from anti-inflammatory effects of this drug11. But, we think that this anti-inflammatory effect cannot be generalized to all GP IIb/IIIa inhibitors. Although the results of these two studies16,31 seem to support our findings, with the use of tirofiban we could not obtain such an anti-inflammatory effect that Lincoff et al. obtained with abciximab. Our results are more in keeping with the findings of recent studies by Bronz et al.33. They suggested that tirofiban did not have a direct effect on inflammatory parameters during elective PCI and the change in inflammatory parameters was just related to troponin T positivity or negativity33.

The reason for lower cTnT positivity levels in the tirofiban group may be the result of the capability of this agent to decrease the microembolization that is seen frequently in PCIs16,18,34. The recent RESTORE12, EPISTENT13 and TACTICS-TIMI 1814 studies suggest that the key mechanism in the improvement of patient results might be the effect of integrin GP Ilb/IIIa inhibitors to decrease micro and macroembolizations, which would seem to support our contention.

In our study, the reason for the absence of an anti-inflammatory response with tirofiban (in contrast to the findings of Lincoff et al.11 with abciximab) might be attributable to differences in specificity of these agents at the receptor level35,36. It has been observed that although GP Ilb/IIIa inhibitors with a lower specificity but greater effect such as abciximab block mainly Mac1 receptors in leukocytes and vitronectin (&946;^sub 3^) receptors in smooth muscle cells, GP IIb/IIIa inhibitors with a greater specificity such as tirofiban inhibit only integrin receptors35,36. Receptor specificity differences may also be the reason for the lower peri-procedural event rate with abciximab than tirofiban in the TARGET study32,37. However, because the TARGET study did not measure inflammatory marker levels, this explanation may not be entirely accurate32,37.

In contrast to this, the inflammatory marker levels of the tirofiban group remained at lower levels than the control group during the follow-up period which is not significant statistically. We think that this may be due to the effect of tirofiban in decreasing myocardial micronecrosis developed due to microembolization during PCI16,18,34. In recent studies it has been observed that the most important sources of local inflammation seen after PCI are vascular damage in endothelial and smooth muscle cells and myocardial micronecroses which develop following microembolizations19-21,38-43 and specifically these microembolizations may be reduced by integ\rin GP Ilb/IIIa inhibitors12-14.

Limitations of the Study

The primary limitation of our study is the small sample size. The second, and may be the most important limitation, is the collection of blood samples for inflammatory response parameters from the peripheral vein. If the blood samples could be obtained from a site close to the target site such as coronary sinus; inflammatory responses initiated by peripheric manipulations (arterial and venous cannulation) could be eliminated and just local inflammatory response dependent upon PCI19-21,38-43 could be evaluated. The third limitation of our study is the lack of sufficient knowledge about morphology and pathologic structure of plaque material. We think that PCI for unstable vulnerable plaques may cause a more severe inflammatory response, because these plaques have more intense macrophage content which are responsible for IL-I, IL-6, TNF-α and CRP synthesis and release44-45. The fourth limitation of our study is the use of tirofiban in a fixed dose. If we were able to give it in higher doses, a better appreciation of the inflammatory effect would be obtained. Merino et al.46 reported that eptifibatide, a specific GP IIb/IIIa inhibitor, may attenuate the increase in CRP levels after angioplasty in high doses. Finally, in our opinion, homogeneous distribution of patient populations in groups and minimized use of mechanical manipulations during interventional procedure (stent placement without predilation) could confer important advantages.

Conclusion

The number of patients becoming cTnT positive (> 1 ng/mL) was less in the group receiving tirofiban during elective PCI. However, both groups had changes (generally observed as elevations) in their levels of all inflammatory parameters during the study and CRP, IL6 and TNF-α levels elevated significantly. Yet, no significant difference occurred between groups due to these changes in any phase of the study (p > 0.05). As a result, it was concluded that although tirofiban limits development of myocardial necrosis during elective PCI, it does not directly affect the acute systemic inflammatory response.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2636_4, Accepted for publication: 12 August 2004

Published Online: 27 September 2004

doi: 10.1185/030079904X4400

Mehmet Akbulut1, Yilmaz Ozbay1, Ozlem Gundogdu2, Necati Dagli2, Polat Durukan3, Erdogan Ilkay4 and Nadi Arslan4

1 Assistant Professor of Cardiology, Firat University Medical School, Elazig, Turkey

2 Resident in Cardiology, Firat University Medical School, Elazig, Turkey

3 Specialist in Emergency Medicine, Firat University Medical School, Elazig, Turkey

4 Professor of Cardiology, Firat University Medical School, Elazig, Turkey

Address for correspondence: Dr Mehmet Akbulut, Firat University Faculty of Medicine, Department of Cardiology, 23100 Elazig, Turkey. Tel.: +90-424-238-80-80; Fax: +90-424-233-50-38; email: drakbulut@yahoo.co.uk

Copyright Librapharm Nov 2004

Source: Current Medical Research and Opinion

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