Administration of Eptifibatide during Transfer for Primary PCI in Patients with STEMI: Effect on Pre-PCI TIMI (full title below)

From the Department of Cardiology, S. Maria delle Croci Hospital, Ravenna, Italy. The authors report no conflicts of interest regarding the content herein. Manuscript submitted August 7, 2008, provisional acceptance given December 2, 2008, and final version accepted December 4, 2008. Address for correspondence: Matteo Aquilina, MD, Department of Cardiology, S. Maria delle Croci Hospital, Viale Randi 5, 48100 Ravenna, Italy. E-mail: ra.cardiologia@ausl.ra.it

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ABSTRACT: Background. Facilitation therapy in ST-elevation myocardial infarction (STEMI) is still controversial and no relationship between timing of treatment and efficacy has been reported to date. Methods. In order to evaluate the effect of pre-catheterization laboratory (cath lab) administration of eptifibatide on pre-percutaneous coronary intervention (PCI) thrombolysis in myocardial infarction (TIMI) flow and its correlation with ischemia duration, we studied all 438 STEMI patients treated with primary PCI from January 2006 to December 2007: 310 patients were pretreated with eptifibatide (Group P), while 128 patients received either no glycoprotein IIb/IIIa inhibitors or were only given them in the cath lab (Group C). All ischemia times (chest pain onset, diagnostic electrocardiogram, eptifibatide administration, cath lab arrival, first balloon inflation) were recorded. Group P was divided into early (E:159 patients with symptoms duration ≤ 90 minutes, and late (L: 151 patients) subgroups. Pre- and post-PCI TIMI grade flow, and 30-day outcomes were recorded. Results. At angiography, TIMI grade 2 or 3 flow was observed in 54% of cases in Group P vs. 34% in Group C (p p p Conclusions. In our experience, very early (J INVASIVE CARDIOL 2009;21:115–120

Key words: acute myocardial infarction, eptifibatide, primary angioplasty

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Primary percutaneous coronary intervention (PCI) achieves thrombolysis in myocardial infarction (TIMI) grade 2 or 3 flow in patients with ST-elevation myocardial infarction (STEMI) more often than systemic thrombolysis, and it is considered the treatment of choice for STEMI if performed by an experienced team within 90 minutes from initial medical contact.¹ Registry data² documented that less than half of patients will ever undergo primary PCI within the recommended 90 minutes. The administration of a prehospital pharmacologic regimen (facilitation) to initiate reperfusion prior to PCI is a logical strategy to improve baseline TIMI flow in the infarct-related artery. This last parameter has been shown to be associated with improved survival.³ The results of several pharmacologic strategies have been disappointing. Specifically, glycoprotein (GP) IIb/IIIa antagonists achieve TIMI grade 2 or 3 flow prior to PCI in 30–50% of patients, but their clinical benefit in primary PCI and optimal timing of their administration are still controversial.^4–7 The aim of this retrospective study was to evaluate the im-pact of pretreatment with eptifibatide on preprocedural TIMI flow in a population of patients referred to a “hub” center for primary PCI and to look specifically for a possible correlation between ischemia duration and efficacy of pretreatment with eptifibatide in restoring pre-PCI TIMI grade 2 or 3 flow.

Materials and Methods

The area of Ravenna province is 1,858 km² and has approximately 350,000 inhabitants. The Ravenna Department of Cardiology is the “hub” center (cardiac catheterization laboratory with PCI available 24 hours/day) of the local STEMI treatment network, with the cardiology units (ICUs) of two peripheral hospitals located within 20–25 km as the “spoke” centers. The network includes hospital emergency departments (EDs) and the 118 area emergency medical services (EMS), which provide electrocardiographic (ECG) transmission from the patient’s home via mobile phone to the referral ICU and direct transportation to the hub center. Since January 2006, a protocol of STEMI treatment approved by the network of ICUs, EDs and EMS calls for pretreatment with eptifibatide of all patients referred for primary PCI, if not contraindicated (recent trauma or surgical intervention, active bleeding, chronic anticoagulant therapy, previous cerebral hemorrhage, uncontrolled hypertension). Eptifibatide was administered intravenously (IV) with 2 boluses of 180 µg/kg 10 minutes apart and an infusion of 2 µg/kg/minute starting after the first bolus for at least 12 hours, as recommended in the ESPRIT trial.8 Patients also received aspirin (250 mg IV) and unfractionated heparin (60 U/kg IV). A clopidogrel loading dose of 300 mg was given after the procedure and a 75 mg daily dose was continued for 1 month in cases of bare-metal stent (BMS) implantation or for 12 months in cases of drug-eluting stent (DES) implantation. A STEMI was defined as chest pain of (Invatec, Brescia, Italy) was performed at the operator’s discretion. Stent deployment was systematically performed in patients with favorable anatomic characteristics. Assessment of left ventricular function was performed by left ventriculography at the completion of the PCI in hemodynamically stable patients or by echocardiography within 48 hours post PCI. After PCI, an Angioseal™ device (St. Jude Medical, St. Paul, Minnesota) was used to achieve hemostasis at the puncture site, if not contraindicated. The study population is comprised of patients with STEMI occurring within ≤ 12 hours who were treated with eptifibatide before primary PCI (in a spoke center, in the ambulance, or in the ICU of the hub center in cases of delayed admission to the catheterization laboratory) (Group P), while the control group (Group C) is comprised of patients with STEMI within ≤ 12 hours who did not receive a GP IIb/IIIa inhibitor prior to primary PCI, or who ­­were treated with a GP IIb/IIIa inhibitor in the catheterization laboratory at the first operator’s discretion. The time of pain onset, diagnostic ECG, initiation of eptfibatide therapy, admission to the catheterization laboratory and first balloon dilatation were all recorded in a dedicated database. We were then able to determine the time intervals of pain-to-therapy (from pain onset to administration of eptifibatide in Group P) or pain-to-cath lab (from pain onset to catheterization laboratory arrival in Group C), therapy-to-cath lab (pretreatment duration in Group P), ECG-to-balloon, and pain-to-balloon for each patient. All data relative to clinical outcomes (in-hospital death, major vascular complications including surgical vascular complications and need for transfusion, reinfarction, target vessel revascularization) were recorded in the dedicated database of the catheterization laboratory at the hub center. Hemoglobin values and platelet count were checked every 8 hours for the first 24 hours. Data relative to 30-day mortality were derived from analysis of the Ravenna province anagraphic database (ANARA) or by telephone contact for patients living outside the province. Recurrent myocardial infarction was defined as fulfilling at least two of the following criteria: prolonged chest pain, new ST-segment modification and an increase in creatine kinase-MB fraction > 2 times the upper limit of normal. Bleeding was assessed using the TIMI criteria.¹⁰ We defined major bleeding as clinically overt signs of hemorrhage associated with a drop in hemoglobin > 50 g/l. Statistical analysis. Statistical analysis was performed using the SAS statistical package (SAS Institute SRL, Milan, Italy). All continuous variables were expressed as mean ± standard deviation (SD) and categorical variables as percentages. Comparison between groups was performed using the chi-square test for categorical variables and the unpaired Student’s t-test for continuous data. The Wilcoxon nonparametric test was applied for median comparison. A two-sided p-value Results From January 2006 to December 2007, 438 consecutive patients with STEMI within ≤ 12 hours were treated with primary PCI at our catheterization laboratory. Of these, 310 (71%) received eptifibatide facilitation before arrival to the catheterization laboratory (Group P). One hundred twenty-eight patients did not receive pretreatment with eptifibatide (Group C); in this group, 35 patients (27%) received a GP IIb/IIIa inhibitor (abciximab) and 65 (51%) received eptifibatide in the catheterization laboratory, while 28 (22%) were not given a GP IIb/IIIa inhibitor due to contraindications (oral anticoagulants, previous cerebral hemorrhage, active bleeding, recent trauma or major surgical intervention). Since the median pain-to-therapy time was 90 minutes, Group P was divided into two subgroups: the early (E) group, where pretreatment with eptifibatide started ≤ 90 minutes from the onset of chest pain, and the late (L) group, where pretreatment started ≥ 90 minutes after chest pain onset. Clinical, angiographic and procedural characteristics for patients in groups C and P, and subgroups E and L are listed in Table 1. Baseline clinical characteristics were similar with the exception of referral from the spoke centers and incidence of stent implantation, both of which were more frequent in Group P. In the two subgroups of pretreated patients, anterior location, left anterior descending (LAD) artery involvement and DES implantation were all more frequent in patients in the E Subgroup, while thromboaspiration devices were used more frequently in the L Subgroup. Time intervals from pain onset-to-balloon dilatation and the results of pre- and post-PCI TIMI flow are summarized in Table 2. The incidence of pre- and post-procedure TIMI flow ≥ 2 was greater in patients who received eptifibatide pretreatment compared with the control group (pre-PCI TIMI flow ≥ 2, p p = 0.008). Due to the larger number of patients transferred to the hub center in Group P, the ECG-to-balloon times were longer for that group than those of Group C, while the pain-to-cath lab times were similar between the two groups. In Group P, the duration of eptifibatide pretreatment was at least 20 minutes, with a median value of 47 minutes (mean value of 50 minutes). In the eptifibatide-pretreated patients, early administration of the drug (≤ 90 minutes from the onset of chest pain) resulted in better pre-PCI TIMI flow (TIMI ≥ 2 for 64% in Group E vs. 44% in Group L; p p = 0.516). The strong correlation between ischemia time and pre-PCI TIMI flow in patients pretreated with eptifibatide was more evident after dividing the patients of Group P into quartiles on the basis of pain-to-therapy time: the rate of TIMI flow ≥ 2 decreased from 70.5% to 38% from the first to the fourth quartile (p p = 0.20). As for the duration of eptifibatide infusion, no differences were observed in pre-PCI TIMI flow ≥ 2 in the 4 quartiles of patients based on therapy-to-cath lab time ( 62 minutes: 59%; p = 0.383). Multivariable analysis showed pretreatment with eptifibatide (Group P) (OR 2.20, 95% CI 1.19–4.08; p p = 0.003) to be independent predictors of pre-PCI TIMI flow ≥ 2. Thirty-day follow up was available for 427 patients (97.5%). A higher mortality rate was observed in Group C compared to Group P (9.5% and 1.9%, respectively; p p = 0.13). No cases of reinfarction were observed during patients’ hospital stay and no difference between groups was noted with regard to major and minor bleeding events (Table 3).

Discussion

Our experience represents the first registry study of early eptifibatide administration before transfer of STEMI patients to a hub center for primary PCI, and is one of the few studies evaluating the effect of pretreatment on pre-PCI TIMI flow in relation to ischemia time. Early administration of GP IIb/IIIa inhibitors for acute MI patients was studied in several controlled trials, but the results were not always concordant. In the ADMIRAL study,⁴ early (in-ambulance) administration of abciximab resulted in greater efficacy than did late administration (catheterization laboratory) of the drug. However, the ERAMI study⁶ showed no difference between these two strategies, and recently, the FINESSE trial⁷ confirmed these negative results. It is worth noting that the time which elapsed from symptom onset to abciximab bolus administration was rather long in these two studies (4 hours for ERAMI; 2 hours 45 minutes as the median time for FINESSE); this could have led to stabilization of thrombus with fibrin formation less prone to respond to the antiplatelet action of the drug. Recently, the ON-TIME 2 trial showed a better mean ST-segment resolution both before and 1 hour post PCI in patients pretreated with a high bolus dose of tirofiban with respect to placebo. The median time from onset of chest pain-to-diagnosis was 76 minutes, and in this setting, prehospital administration of GP IIb/IIIa inhibitors seems to significantly enhance reperfusion. This study also showed a trend toward better pre-PCI TIMI flow in patients pretreated with tirofiban.¹⁶ The TITAN-TIMI 34 study5 compared early (ED) to late (catheterization laboratory) eptifibatide treatment in patients with STEMI, with better pre-PCI TIMI flow ≥ 2 in the early strategy arm. In our registry, the administration of eptifibatide before primary PCI was associated with better pre-PCI TIMI flow compared to the control group. In addition, we found a strong correlation between pain-to-therapy time and the effect on pre-PCI TIMI flow, as shown by the difference between the E and L subgroups and by quartile analysis. Patients with symptom duration > 2 hours 50 minutes had pre-PCI TIMI grade 2–3 flow similar to that of the control group (Figure 1 and Table 3). This observation concords with the experience reported more recently by Rakowsky et al11 who showed a favorable incidence of pre-PCI TIMI grade 2–3 flow (48%), similar to that observed in our study in the subgroup of patients who received early treatment with abciximab. Therefore, ischemia time should be a fundamental parameter to consider when evaluating the effect of pharmacologic facilitation during a STEMI. Probably many, if not every, pharmacologic facilitation strategy will be of limited efficacy in longer ischemia times while maintaining undesirable hemorrhagic side effects and its effects in patients presenting with more than 2–3 hours of symptom duration are still to be ascertained. Even if ECG-to-balloon and pain-to-balloon times are slightly longer in the pretreatment group, results in terms of TIMI flow, procedural success and 30-day mortality are significantly better than those in the control group, thus reinforcing the role of eptifibatide pretreatment. In our practice, the efficiency of the network for STEMI treatment has led to optimization of all temporal parameters. The median ECG-to-balloon time is 82 minutes for Group P patients who frequently need transportation to the hub center from the surrounding area or from spoke centers, and the pain-to-therapy or pain-to-cath lab time is p p = 0.008). This finding can explain the higher 30-day mortality rate in Group C compared to Group P, although multivariable analysis cannot be applied due to the small size of our population and the low number of clinical events. Moreover, patients who were not treated with GP IIb/IIIa inhibitors due to contraindications may represent a higher-risk subgroup, as suggested by the higher 30-day mortality rate. Patients pretreated with eptifibatide in the Early subgroup had a greater rate of anterior MI, which could be explained by the more severe symptoms that led them to seek medical attention earlier. Consequently, the prevalence of a culprit lesion location in the LAD, with a more frequent initial TIMI grade 3 flow, may explain the greater use of DES in this subgroup, even if low in absolute terms (18%). The main finding of this study is that patients who received early treatment with eptifibatide (within 90 minutes from the onset of chest pain) showed a substantial increase in pre-PCI TIMI flow grade ≥ 2 with respect to those treated later (64% vs. 43%), and that the group treated later had pre-PCI TIMI flow similar to patients in the control group (34% of pre-PCI TIMI grade 2–3 flow), thus reinforcing the hypothesis that GP IIb/IIIa administration in a phase when the clot is fresh and not organized confers a significant reperfusion benefit. The safety of eptifibatide has been confirmed based on a low incidence of major complications and a similar rate of minor hemorrhages, though quite frequent (16%), in both groups. Likewise, a loss of hemoglobin > 2 g/dl is commonly observed in patients with acute coronary syndrome who undergo early intervention. In our series, the routine use of the femoral approach and 7 Fr sheaths may have influenced the relatively high incidence of minor bleeding complications. The safety profile of the drug, together with its ease of preparation, favorable pharmacokinetics¹² (rapid onset of action, brief half-life in the event of complications or necessity of a bypass graft operation) and lower cost, all compare favorably with the more extensively studied abciximab. Even if the STEMI guidelines¹ relegate small-molecule GP IIb/IIIa antagonists to a level of evidence of benefit that is lower than abciximab due to the limited number of randomized clinical trials in STEMI patients,^5,13 several adequately-sized registries from the United States, where eptifibatide utilization in primary PCI is common, showed similar efficacy and an even better safety profile compared to abciximab.^14,15Study limitations. The main limitation of this study is the relatively small population size, which precludes translating the finding of culprit artery patency after eptifibatide administration into a definite clinical benefit, even if the mortality rate observed in the pretreated group was lower. However, TIMI flow ≥ 2 is widely used as a surrogate clinical endpoint in such types of studies. Furthermore, this is a registry study and not a randomized clinical trial, and confounders in the groups are possible. We did not evaluate TIMI frame counts or myocardial blush in our study population, nor did we perform routine echocardiographic evaluation of ejection fraction at 6 months to determine the possibility of better outcomes in the pretreated group. However, the systematic data collection in a well-organized STEMI network and the concordance with the results from all the analyses strengthen the association between the timing of administration and the efficacy of eptifibatide facilitation for STEMI patients.

Conclusion

In conclusion, our study showed that pretreatment with eptifibatide in STEMI patients prior to primary PCI improved pre-PCI TIMI flow compared to patients who were not treated or who received GP IIb/IIIa inhibitors during the procedure, with lower 30-day mortality and no increase in bleeding complications. The greater efficacy found in the pretreated patients should reinforce the choice of facilitation therapy for STEMI patients with shorter ischemia duration, especially when transportation to a hub center for primary PCI is needed.

References

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