Eptifibatide in Peripheral Vascular Interventions - Midwest ...

Original Contribution

Eptifibatide in Peripheral Vascular Interventions: Results of the Integrilin Reduces Inflammation in Peripheral Vascular Interventions (INFLAME) Trial Nicolas W. Shammas, MD1, Eric J. Dippel, MD1, Jon H. Lemke, MD2, Jon Robken, MD1 H. Lester Kirchner, MD3, Vickie Takes, RTR1, Matthew J. Kapalis, BS1, Theresa Palabrica, MD4 ABSTRACT: An acute inflammatory response occurs following percutaneous coronary and peripheral vascular interventions (PVI), partly mediated by platelet activation. Glycoprotein (GP) IIb/IIIa inhibitors might partially attenuate this inflammation rise in the coronary patient, but data in patients undergoing PVI are lacking. In the Integrilin Reduces Inflammation in Peripheral Vascular Interventions trial (INFLAME), we hypothesized that eptifibatide reduces the acute inflammatory responses following PVI. This is a single-center, randomized, open-label study of intravenous eptifibatide (180 µ/kg bolus x 2, 10 minutes apart, then 2 µ/kg/min infusion over 18 hours) and low-dose unfractionated heparin (60 Units per kg, target activated clotting time (ACT) 200–250 sec) [LDH+I group; n = 21] versus high-dose unfractionated heparin alone (100 Units per kg, target ACT 300–400 sec) [HDH group; n = 21] in patients undergoing iliac and infrainguinal interventions. The primary endpoints of the study were markers of inflammation (soluble CD-40L [sCD-40L], high-sensitivity C-reactive protein [hs-CRP] and interleukin-6 [IL-6]), thrombin generation (Fragment 1.2 [F1.2]), and fibrinogen measured at baseline and postrandomization. Markers were assayed at baseline, postdilatation at 30 minutes, 2 hours, 18 hours, 48 hours and 7 days. Mean platelet inhibition with eptifibatide was 98% (range 92–100%) using the Accumetrics Rapid Platelet Function Assay at 10 minutes after final bolus. After adjusting for baseline values, the mean ± SE difference in sCD-40L (loge scale), hs-CRP and F1.2 between the LDH+I group and the HDH was not significant. Fibrinogen had significantly higher mean levels at 7 days for the LDH+I group (541.19 mg/dL versus 472.26 mg/dL; p-value = 0.024). IL-6 was more detectable in the LDH+I group compared to the HDH following intervention. We conclude that LDH+I combination did not reduce acute inflammatory responses as compared to HDH in patients undergoing peripheral vascular interventions. J INVASIVE CARDIOL 2006;18:6–12

Balloon injury to the vessel wall triggers a reaction of thrombosis, inflammation and neointimal proliferation. The inflammatory process is mediated by a complex interaction between blood cells (platelets and leukocytes), coagulation factors (thrombin), and the endothelial/subendothelial layers, and is characterized by

a rise in plasma levels of acute-phase reactants,1–6 chemokines,7,8 cytokines3–6,9–11 and circulating cell adhesion molecules.12,13 E l evated baseline levels of inflammatory markers and their augmentation with vascular injury are individual-specific and correlate with poor procedural and late outcomes.1,14–19 Peripheral vascular patients are at high risk for cardiovascular events and demonstrate high baseline levels of circulating inflammatory markers.6,17,18,20–22 Furthermore, the augmentation in the levels of these markers during peripheral vascular interventions (PVI) appears to be more pronounced in the higher risk vascular bed for restenosis such as the femoropopliteal vessels compared to the iliac and carotid arteries, despite adjusting for the extent of vessel injury.2 Reduction of the inflammatory response during PVI might offer favorable short- and longterm results. Eptifibatide, a small molecule, is a selective inhibitor of the GP IIb/IIIa receptor and has been shown to bind the vitronectin receptor (αvB3)23 and lower levels of soluble CD40L,7 an early initiator of inflammation,11 after percutaneous coronary intervention. Eptifibatide might also exert its anti-inflammatory effect via inhibiting leukocyte-platelet interaction by blocking the GP IIb/IIIa receptor on platelets, and therefore inhibiting fibrinogen from crosslinking platelets and leukocytes and reducing their attachment to endothelial cells. It is unclear whether eptifibatide reduces inflammation in patients undergoing PVI. In the Integrilin Reduces Inflammation in Peripheral Vascular Interventions (INFLAME) trial, we evaluated the ability of the GP IIb/IIIa inhibitor, eptifibatide, to acutely reduce inflammation during peripheral vascular interventions of iliac and infrainguinal vessels.

Methods

2

Forty-two patients were enrolled in this single-center, randomized, open-label study of intravenous (IV) eptifibatide (180 µg/kg bolus x 2, 10 minutes apart, then 2 µg/kg/min infusion over 18 hours), and low-dose unfractionated heparin (LDH+I) (60 Units per kg, target ACT 200–250 sec) versus high-dose heparin (HDH) alone (100 Units per kg, target ACT 300–400 sec) in patients undergoing elective iliac and infrainguinal interventions. The Institutional Review Board of Genesis Health System approved the study, and all patients signed an informed consent. Patients were excluded if they met one of the following criteria: contraindication to the use of eptifibatide, inability to take oral antiplatelet drugs, thrombocytopenia, creatinine > 2.0, those who were undergoing renal interventions, or who had a recent

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The Journal of Invasive Cardiology

From the 1Midwest Cardiovascular Research Foundation, Davenport, Iowa, Genesis Health System, Davenport, Iowa, 3Case Western Reserve University, Cleveland, Ohio, and the 4Millennium Company. This trial was supported by a research grant from the Millennium Company and by the Midwest Cardiovascular Research Foundation. Manuscript received July 18, 2005, provisional acceptance given August 18, 2005, revised manuscript accepted October 19, 2005. Address for correspondence: Nicolas W. Shammas, MS, MD, Midwest Cardiovascular Research Foundation, Cardiovascular Medicine, PC, 1236 E. Rusholme, Suite 300, Davenport, IA 52803. E-mail: [email protected]

Results of the INFLAME Trial

cardiac or peripheral intervention within the past month of randomization. Patients needed to have a de novo iliac or infrainguinal lesion to be considered for randomization. Treatment of multiple lesions in more than one vascular bed was allowed in the same setting. The primary endpoint of the study was changes in markers of inflammation (sCD-40L, hs-CRP, IL-6), thrombin generation (F1.2), and fibrinogen. Baseline markers were obtained after achieving the minimum ACT target in each patient and immediately prior to balloon dilatation. Inflammation and thrombosis markers were then assayed postdilatation at 30 minutes, 2 hours, 18 hours, 48 hours and 7 days. Blood was drawn during the procedure from the arterial access sheath after discarding 10 cc of blood. Follow-up venous blood from the antecubital vein was used for marker assays. Assays were conducted at a central laboratory for F1.2, IL-6 and sCD-40L. Hs-CRP and fibrinogen were assayed at the Genesis Medical Center laboratory accredited by the American College of Pathology. All laboratory technicians were blinded to the treatment arms. Platelet inhibition was assayed using the Accumetrics rapid platelet function assay (RPFA) device at baseline and at 10 minutes after the final bolus. Sampling and assays of markers. The blood sample (10 cc) was drawn into precooled tubes containing specific anticoagulants. Blood samples were placed in melting ice and processed within 10 minutes of collection. For sCD-40L and IL-6, EDTA containing tubes were used. Platelet-poor plasma (PPP) was obtained by centrifuging the whole blood tube at 1,600 xg for 20 minutes at 40ºC. The PPP was then carefully removed with a plastic transfer pipette and aliquot into approximately 6 new microcentrifuge tubes. Samples were then stored at -80ºC and sent on dry ice by overnight courier to Cor Therapeutics central laboratory (San Francisco, California) for analysis. For F1.2, 0.105M NaCitrate containing tubes were used. A 5 cc blood sample was spun at 2,000 g for 15 minutes and plasma was pipetted into a microcentrifuge tube and stored at -80ºC. Samples were shipped on dry ice via overnight courier to the University of Rochester Medical Center Hematology Laboratory (Rochester, New York) for analysis. The ELISA technique was utilized for the markers’ assays. Hs-CRP and fibrinogen were assayed locally at the Genesis Medical Center laboratory. Major adverse event. A major adverse event (MAE) was considered to occur if any one of the following in-hospital endpoints occurred: death, limb loss, unplanned urgent revascularization, vascular complication (pseudoaneurysm, arterio-venous fistula or perforation), major bleeding (defined as a Hb drop of ≥ 3 gm/dL with a source of bleeding identified, transfusion with 2 units of packed red blood cells, intracranial hemorrhage, or a retroperitoneal bleed), embolic stroke, or distal embolization causing slow flow or visible filling defects. Statistical analysis. Baseline characteristics, conditions and adverse events are summarized using means and standard deviations for continuous variables, and frequencies and percentages for categorical variables. Comparisons between treatment groups were performed using exact Wilcoxon Rank Sum, Fisher’s exact, and exact permutation trend tests. Vol. 18, No. 1, January 2006

Figure 1. Scatterplot of maximum ACT observed versus total absolute heparin dose by treatment with jitter to distinguish duplicates.

Analysis of the marker values was accomplished using a mixed linear model. The mixed model was used to estimate and test relationships between treatment groups using restricted maximum likelihood estimation while controlled for the baseline inflammation marker. Plots of mean changes from baseline for each marker obtained from the models are provided to demonstrate changes in inflammation markers over time. The IL-6 outcome marker was excluded from these analyses due to the infrequent detectable values. For all other markers, undetectable values were replaced with half the detection limit and values above the detection limits were replaced with the largest detectable value. For IL-6, exact stratified Poisson distributions compared the number of detectable values stratifying by the number of blood draws. The natural logarithm transformation was used for the outcome markers sCD-40L, hs-CRP, IL-6 and F1.2. The transformation corrected skewness of the distributions, heterogeneity of variances, and confirms that change is proportional. Fibrinogen was analyzed on the original scale. Analyses were performed using StatXact, MINITAB, and SAS Version 9 (SAS Statistical Inc., Cary, North Carolina).

Results Baseline analysis of clinical, angiographic and inflammatory marker variables in the HDH and the LDH+I groups. Forty-two patients were randomized to LDH+I (n = 21) and HDH (n = 21). The baseline demographic or behavioral variables (Table 1), baseline medical conditions (Table 2), clinical markers (Table 3), preprocedure medications (Table 4), angiographic disease (Table 5) and procedural contrasts (Table 6) did not vary significantly across treatment groups. The relationship between heparin and ACT is shown in Figure 1. Of the HDH participants, 61.9% reached an ACT > 400 versus 38.1% of the LDH+I participants. Furthermore, mean platelet inhibition with eptifibatide was 98% (range 92–100%) at 10 minutes after final bolus. Descriptive statistics at the baseline measurement are presented in Table 7. There was no statistically significant difference 7

SHAMMAS, et al. Table 1. Summary of baseline demographic variables and smoking behavior. Variable

HDH

LDH+I

(n = 21)

(n = 21)

Mean age (years) 65.6 (11.2) Mean BMI (kg/ m2) 27.6 (4.2) Percent male 66.7% Smoking: Current (%) 42.9% Previous (%) 23.8% Never (%) 33.3%

Signficance

All (n = 42)

69.5 (11.2) 28.4 (5.2) 57.1%

NS NS NS

67.5 (11.2) 28.0 (4.7) 61.9%

42.9% 33.3% 23.8%

NS NS NS

42.9% 28.6% 28.5%

Standard deviations follow means in ( )s. NS = not significant. Significance is defined as a p-value < 0.05.

Table 2. Prevalence of baseline medical conditions. Medical Condition

HDH

Hypercholesterolemia Hypertension Angina History of coronary angioplasty Diabetes Myocardial infarction Family history of premature CAD Congestive heart failure Cerebrovascular disease Recent infection Rheumatoid arthritis NYHC (Class II–III) Claudication 1 2a 2b 3 4

LDH+I S i g n i f i c a n c e

All

(n = 21)

(n = 21)

(n = 42)

95.2% 61.9% 71.4%

71.4% 66.7% 52.4%

NS NS NS

83.3% 64.3% 61.9%

66.7% 38.1% 19.0%

47.6% 57.1% 38.1%

NS NS NS

57.1% 47.6% 28.6%

28.6% 9.5% 9.5% 4.8% 0.0% 4.8%

23.8% 9.5% 9.5% 4.8% 9.5% 9.5%

NS NS NS NS NS NS NS

26.2% 9.5% 9.5% 4.8% 4.8% 7.1%

14.3% 14.3% 61.9% 0.0% 9.5%

9.5% 0.0% 61.9% 14.3% 14.3%

11.9% 7.1% 61.9% 7.1% 11.9%

CAD = coronary artery disease; NS = not significant. Significance is defined as a p-value < 0.05.

Table 3. Preprocedure medications. HDH Aspirin Lipid-lowering agent Beta blocker Ace inhibitor Clopidogrel Calcium channel blocker Cilostazol Nitrates Angiotensin receptor blocker Antiarryhthmic Participants with diabetes Insulin (%) Oral medications (%) Diabetes medication (%)

LDH+I S i g n f i c a n c e

(n = 21)

(n = 21)

85.7% 81.0% 67.1% 42.9% 42.9% 28.6% 14.3% 14.3% 9.5% 4.8% (n = 8) 25.0% 75.0% 87.5%

95.2% 61.9% 42.9% 42.9% 33.3% 14.3% 9.5% 0.0% 4.8% 0.0% (n = 12) 50.0% 58.3% 83.3%

All (n = 42)

NS NS NS NS NS NS NS NS NS NS NS

90.5% 71.4% 50.0% 42.9% 38.1% 21.4% 11.9% 7.1% 7.1% 2.4% (n = 20) 40.0% 65.0% 85.0%

Figure 2. Detectable Interleukin-6 at follow-up by treatment. Note all of the HDH participants returned to undetectable levels (< 12.5 pg/mL) by 48 hours. Seven (33.3%) of the LDH+I group had IL-6 draws that were detectable at 48 hours and three still had detectable levels at 7 days.

Figure 3. Change from Baseline in Ln(CD-40 ng/mL). Points represent group- and time-specific change from baseline means with standard error bars, adjusting for baseline.

between the treatment groups. Spearman correlation coefficients were estimated between each pair of inflammation markers. Only hs-CRP and fibrinogen yielded a significant correlation (r = 0.5918, p < 0.0001). Changes of markers with time in both HDH and LDH+I groups. IL-6 (pg/mL): From 2 hours through 7 days, 20 of 80 (25%) draws for the LDH+I group were detectable and 6 of 71 (8.5%) draws were detectable for the HDH group (relative risk = 2.73; p-value = 0.0296). All of the HDH participants returned to undetectable levels (< 12.5 pg/mL) by 48 hours. Seven (33.3%) of the LDH+I group had IL-6 draws that were detectable at 48 hours and 3 still had detectable levels at 7 days (Figure 2). sCD-40L (ng/mL): None of the values were below or above detection limits. The estimated adjusted means at each post-baseline blood draw are presented in Table 8. After adjusting for a single outlier, there were no differences in sCD40L between the LDH+I and the

NS = not significant. Significance is defined as a p-value < 0.05.

8



HDH groups. A graphical representation of the model, expressed as a change from baseline is shown in Figure 3. For both treatVariable HDH LDH+I Signficance All ment groups, the mean sCD-40L values Ejection fraction (n = 18) (n = 15) (n = 33) were significantly lower than baseline at 18 52.9 (12.8) 52.5 (16.5) NS 52.7 (14.4) hours (p-values < 0.01). Blood pressure (n = 21) (n = 21) (n = 42) Hs-CRP (mg/L): Mean baseline hs-CRP Systolic 143.3 (24.5) 148.4 (29.6) NS 145.9 (26.9) values in the HDH and LDH+I group were Diastolic 77.2 (10.9) 76.1 (17.3) NS 76.6 (14.3) 4.21 ± 5.79 mg/L and 6.80 ± 8.64 mg/L ABI at rest NS respectively (p = 0.34). Controlling for baseRight rest 0.73 (0.27) 0.74 (0.24) 0.73 (0.26) Left rest 0.78 (0.22) 0.77 (0.32) 0.78 (0.27) line, no differences were found between the ABI under exercise NS groups. For both treatment groups, the hsRight exercise 0.46 (0.18) 0.80 (0.33) 0.61 (0.30) CRP values were significantly greater than Left exercise 0.47 (0.25) 0.62 (0.20) 0.54 (0.23) baseline at 18, 48 hours and 7 days (p-values Lipids (n = 14) (n = 9) NS (n = 23) < 0.01, Figure 4). LDL cholesterol 94.6 (34.5) 94.1 (33.6) 94.4 (33.4) Fibrinogen (mg/dL): After controlling HDL cholesterol 44.9 (12.3) 39.3 (10.8) 42.7 (11.8) Triglycerides 180.1 (119.0) 197.0 (97.4) 186.7 (109.0) for baseline, only at 7 days post-baseline are Total cholesterol 173.6 (45.7) 173.2 (38.4) 173.5 (42.06) the groups significantly different (p = ABI = ankle-brachial index , LDL = low density lipoprotein, HDL = high density lipoprotein, NS = not 0.0241). For both treatment groups, the mean fibrinogen values were significantly significant. Significance is defined as a p-value < 0.05. greater than baseline at 48 hours and 7 days Table 5. Angiography disease contrasts. (p-values < 0.01; Figure 5). F1.2 (nmol/L): Controlling for baseline, no significant Variables (percent) HDH LDH+I Signficance differences were found between the 2 groups. For the Iliacs - right 52.4 23.8 NS LDH+I and HDH groups, the F1.2 values were significantly SFA - right 52.4 61.9 NS greater than baseline at 18 hours, and for the HDH group, Popliteal - right 9.5 23.8 NS the F1.2 values were significantly greater than baseline at 7 Tibials - right 61.9 52.4 NS Iliacs - left 47.6 33.3 NS days (p-values < 0.01; Figure 6). SFA - left 52.4 61.9 NS Major Adverse Events (MAE): At 30-day follow-up, in the Popliteal - left 14.3 33.3 NS LDH+I group there were 3 major events, all of which were major Tibials - left 61.9 57.1 NS bleeds [incidence rate = 14.29% with a 95% C.I. (3.05%, Access site R/L NS 36.34%)]. The HDH treatment group had 1 MAE, which was a Left 28.6 19.0 death within 48 hours of discharge [incidence rate = 4.76% with Right 47.6 71.4 a 95% CI (0.12%, 23.82%)] related to acute renal failure. The Both 23.8 9.5 incidence rates for all other MAEs were observed to be 0.0% with SFA = superficial femoral artery; R/L = right/left; NS = not significant. Signifi95% confidence intervals (0.0%, 13.30%). There was no expeccance = a p-value < 0.05. tation that there would be sufficient power and high enough inciTable 6. Procedure contrasts. dence rates to compare them across treatment groups. One LDH+I participant with a major bleed later developed Variables (mean) HDH LDH+I Signficance a vascular complication confirmed by duplex ultrasound Length of procedure (mins) 100.9 107.5 NS (pseudoaneurysm). One patient from each treatment group had Closure device NS a revascularization of the same vessel within 6 months (day 140 None 9.5 9.5 for LDH+I participant, day 119 for HDH participant). Six Angio-Seal 9.5 23.8 patients (28.6%) in each treatment group returned within 6 VasoSeal 0.0 0.0 months for a revascularization in a different vessel. Perclose 81.0 61.9 Table 4. Means (with standard deviations) for ejection fractions, blood pressure, ABIs, and lipids by treatment group.

Other Sheath Removed in lab Removed on floor Removed more than 6 hrs Direction Contralateral Ipsilateral

Other

0.0

4.8

90.5 9.5 0.0

95.2 4.8 0.0

57.1 (n = 12) 9.5 (n = 2)

81.0 (n = 17) 4.8 (n = 1)

33.3 (n = 7)

14.3 (n = 3)

NS

NS

NS = not significant. Significance is defined as a p-value < 0.05.

Vol. 18, No. 1, January 2006

Discussion In this study, patients with peripheral vascular disease had a baseline-heightened inflammatory state, predicting a high risk for future cardiovascular events.24–26 Inflammatory markers were shown to increase in patients after angioplasty of the renal,6 femoropopliteal, iliac, carotid2,21,27 and tibial arteries.17 In our study, both hs-CRP and fibrinogen significantly increased with percutaneous intervention. Hs-CRP peaked at about 48 to 72 hours in both HDH and LDH+I groups. Neither hs-CRP nor fibrinogen returned to baseline after 7 days in either group. 9

SHAMMAS, et al.

Figure 4. Change from baseline in ln(hs-CRP mg/L). Points represent group- and time-specific change from baseline means with standard error bars, adjusting for baseline.

Figure 5. Change from baseline in fibrinogen. Points represent groupand time-specific change from baseline means with standard error bars, adjusting for baseline.

Table 7. Baseline descriptive statistics of inflammation marker measurements by treatment group. Marker

Heparin Only Mean Median ± SD (Range)

N CD-40 ng/mL

21

2.41 ± 4.11

0.80

N 19

Heparin + Integrilin Mean Median ± SD (Range) 1.24 ± 1.66

0.37

(0.07, 17.60)

hs-CRP mg/L

21

4.21 ± 5.79

2.90

F1.2 nmol/L

21

336.52

337.0

± 102.37

(187.0, 644.0)

1.02 ± 0.49

1.01

0.38

(0.12, 6.68)

21 6.80 ± 8.64

3.70

(0.10, 27.80)

Fibrinogen mg/dL 21

p-Value

0.34

(0.48, 30.10)

21

20

342.33

322.0

± 70.55

(236.0, 467.0)

1.20 ± 0.84

0.97

(0.42, 2.67)

0.60

0.89

(0.41, 3.65)

Table 8. Baseline adjusted loge CD-40 means and difference between groups.1 HDH

LDH+I

Difference2

p-Value

Mean ± SE

Mean ± SE

Mean ± SE

95% CI

30 mins

-0.112 ± 0.182

-0.740 ± 0.202

-0.628 ± 0.273

-1.182, -0.074

0.0274

2 hrs

-0.380 ± 0.222

-0.657 ± 0.237

-0.277 ± 0.326

-0.937, 0.383

0.4007

18 hrs

-1.138 ± 0.2904

-1.129 ± 0.2924

0.009 ± 0.412

-0.828, 0.846

0.9830

48 hrs

-0.158 ± 0.247

-0.469 ± 0.259

-0.311 ± 0.359

-1.041, 0.418

0.3920

7 days

-0.089 ± 0.300

-0.196 ± 0.304

-0.108 ± 0.429

-0.986, 0.771

0.8236

Average3

-0.375 ±0.161

-0.638 ± 0.167

-0.263 ± 0.233

-0.735, 0.209

0.2658

1 Controlled for baseline ln(CD-40) 2 Difference = LDH+I mean – HDH mean 3 Average = average of all post-baseline measurements from model 4 Significantly different than baseline (p-value < 0.01).

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Measures that reduce the inflammatory process following PVI might improve the procedural outcome of these patients. In this study, we hypothesized that the GP IIb/IIIa inhibitor eptifibatide might reduce inflammation post-PVI. Eptifibatide, has been shown to bind the αvβ3 (vitronectin) receptor 2 3 and inhibit sCD40L release in patients undergoing coronary angioplasty,7 but its inflammatory effects are more likely mediated via indirect effects due to inhibition of platelet binding to leukocytes and the endothelium. Our findings, however, suggest that there might be a discordance between the antiaggregatory and anti-inflammatory effects of eptifibatide in patients undergoing PVI. Although platelet inhibition by eptifibatide reached 98% in our patients, sCD40L and hs-CRP were not reduced. I t should be noted that neither LDH nor HDH was sufficient to inhibit thrombin generation at 18 hours above baseline, a finding recently reported during percutaneous coronary intervention. 36 It is unclear whether this thrombin generation led to an increase in inflammation markers counteracting some potential anti-inflammatory properties of eptifibatide. Further studies are needed to clarify this potential confounding factor. Clinically, however, LDH is the current adjunctive therapy approved The Journal of Invasive Cardiology


Figure 6. Change from baseline in F1.2. Points represent group- and time-specific change from baseline means with standard error bars, adjusting for baseline.

with GP IIb/IIIa inhibitors and our data are relevant to current clinical practice. These findings are in contrast to published data in patients with acute coronary syndromes undergoing percutaneous interventions where GP IIb/IIIa inhibition reduced inflammatory markers.10,13,28 This discrepancy could be related to differences in the various GP IIb/IIIa inhibitors and their ability to reduce inflammation. Several studies have shown that tirofiban, a GP IIb/IIIa inhibitor, does not reduce inflammatory markers postintervention in stable angina patients undergoing coronary angioplasty.29,30 In contrast, abciximab, a large antibody, has significant anti-inflammatory properties due to its ability to block non-GP IIb/IIIa receptors such as the MAC-1 and vitronectin receptors. Thrombus is the hallmark of acute coronary syndromes and is also prevalent with acute and subacute peripheral vascular patients. 31 Thrombosis and inflammation are strongly l i n k e d .32 GP IIb/IIIa inhibitors may mediate some antiinflammatory properties via reduction of the global thrombus burden33 and reducing platelet-leukocyte aggregates.34,35 Our patients included mostly stable outpatient claudicant (80.9% of patients) with a low prevalence of thrombus, which could have influenced our results. In our study, the LDH+I group showed a delayed and more persistent elevation of IL-6 and fibrinogen when compared to HDH. It is possible that this was due to chance, given the small number of patients in the study. Also, it is possible that eptifibatide promotes secretion of inflammatory markers, despite its strong antiplatelet effects, as previously reported with other GP IIb/IIIa inhibitors.37–41 In INFLAME, there was a trend toward more bleeds in the LDH+I group than the HDH group. Although the bleeding was not statistically significant, it might be clinically important. In the coronary, bleeding with eptifibatide was more apparent in patients with an ACT > 250 seconds.42 In our patients, the Vol. 18, No. 1, January 2006

ACT was > 250 seconds in the majority of patients who received eptifibatide, despite the use of a “low” dose of heparin (60 Units/kg) (Figure 1), which could explain the increase in major bleeds in this group. Heparin dosing was selected based on common practice in coronary interventions. Our data emphasize the difficulty in dosing heparin to an appropriate ACT response. 31 Reducing heparin dose, however, in the LDH+I group to minimize major bleeding might increase thrombin production and enhance the inflammatory response. In conclusion, eptifibatide as an adjunctive therapy with low-dose heparin does not reduce inflammatory markers in outpatient elective patients undergoing peripheral vascular interventions. Further studies are needed to understand the role of various GP IIb/IIIa inhibitors with various adjunctive therapies in reducing inflammation and improving outcome in the acute or subacute peripheral vascular patients. Study limitations. This study included a relatively small number of patients and was not designed to assess differences in clinical outcomes among treatment groups. It is not uncommon for the prevalence of the clinical conditions to vary by greater than 15%, and this might have an impact on the baseline values and course of the inflammation markers. These differences, however, did not reach statistical significance. Furthermore, the two arms of this study had a different heparin dose, which could confound the results of our analysis as different doses of heparin suppress thrombin generation differently. A small dose of heparin is, however, the current standard in coronary interventions when GP IIb/IIIa inhibitors are used as adjunctive therapy to minimize the risk of major bleeding. Therefore, INFLAME reflects on the change of inflammatory markers with currently accepted dosing of heparin and GP IIb/IIIa inhibitors in coronary interventions. In this study, anticoagulants were administered prior to obtaining baseline markers. Therefore, we cannot conclude the impact of LDH+I or HDH on markers of inflammation prior to angioplasty. In this study, markers of inflammation were assayed before and after angioplasty and therefore our conclusions are limited to patients receiving angioplasty and have been pretreated with anticoagulants. In INFLAME, the study design was an open-label and was not blinded to the operator. The primary outcome of the study is, however, a measured outcome of blood markers conducted by a central laboratory with technicians blinded to the source of the blood samples. We cannot, however, exclude the possibility that the open design could have altered the approach to the treatment of the patient by the investigator. This seems to be unlikely, however, as procedural characteristics were matched in both groups. Finally, a larger study is needed to understand what patient characteristics influence the direction of inflammatory markers such as the role of gender, body mass index, age, diabetes, smoking and acute or subacute limb ischemia.

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