High bolus tirofiban vs abciximab in acute STEMI patients undergoing primary PCI - The tamip study :Mohammed A Balghith, Heart Views

ORIGINAL ARTICLE
Year : 2012 | Volume : 13 | Issue : 3 | Page : 85--90

High bolus tirofiban vs abciximab in acute STEMI patients undergoing primary PCI - The tamip study

Mohammed A Balghith
King Abdulaziz Cardiac Center, King Saud Bin Abdulaziz University for Health Science, National Guard, Riyadh, Saudi Arabia

Correspondence Address:
Mohammed A Balghith
King Abdulaziz Cardiac Center, King Saud Bin Abdulaziz University for Health Science, P O BOX 22490, National Guard, Riyadh 11426
Saudi Arabia

Abstract

Background: Primary percutaneous coronary intervention (PCI) has been shown to be an effective therapy for patients with acute myocardial infarction (MI). Glycoprotein (GP) IIb/IIIa receptor blockers reduce thrombotic complications in patients undergoing PCI. Most available data relate to Reopro, which has been registered for this indication. GP IIb/IIIa reduce unfavorable outcome in U/A and non ST-elevation myocardial infarction (STEMI) patients. Only few studies focused on high dose Aggrastat for STEMI patients in the emergency department (ED) before PCI. The aim is to increase the patency during the time awaiting coronary angioplasty in patients with acute MI. Objectives: To study the effect of upfront high bolus dose (HDR) of tirofiban on the extent of residual ST segment deviation 1 hour after primary PCI and the incidence of TIMI 3 flow of the infarct-related artery (IRA). Materials and Methods: A randomized, open label, single center study in the ED. A total of 90 patients with acute ST-elevation MI, diagnosed clinically by ECG criteria (ST segment elevation of >2 mm in two adjacent ECG leads), and with an expectation that a patient will undergo primary PCI. Patients were aged 21-85 years and all received heparin 5000 u, aspirin 160 mg, and Plavix 600 mg. Patients were divided in two groups (group I: triofiban high bolus vs group II: Reopro) with 45 patients in each group. In group I, high bolus triofiban 25 mcg/kg over 3 min was started in the ED with maintenance infusion of 0.15 mcg/ kg/min continued for 12 hours and transferred to cath lab for PCI. Patients in group II were transferred to cath lab, where a standard dose of Reopro was given with a bolus of 0.25 mcg/kg and maintenance infusion of 0.125 mcg/kg/min over 12 hours. Results: ST segment resolution and TIMI flow were evaluated in both groups before and after PCI. Thirty-five patients (78%) enrolled in group I and 29 patients (64%) in group II had resolution of ST segment (P-value 0.24). Twenty-one patients (47% group I) vs 23 patients (51% group II) with P-value 0.83 achieved TIMI 0 flow. Twenty-four patients (53% group I) compared with 22 patients (49% group II) with P-value 0.83 had TIMI 1 to 3 flow before PCI. TIMI 3 flow was achieved in 40 patients (89% group I) compared with 38 patients (84% group II) with P-value 0.76. Conclusion: In this study there was a trend toward better ST segment resolution and patency of IRA (i.e., improved TIMI flow) in patients given high bolus dose Aggrastat in the ED. Larger studies are needed to confirm this finding.

How to cite this article:
Balghith MA. High bolus tirofiban vs abciximab in acute STEMI patients undergoing primary PCI - The tamip study.Heart Views 2012;13:85-90

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Balghith MA. High bolus tirofiban vs abciximab in acute STEMI patients undergoing primary PCI - The tamip study. Heart Views [serial online] 2012 [cited 2023 Jun 10 ];13:85-90
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Full Text

Introduction

Primary percutaneous coronary intervention (PPCI) has been shown to be an effective therapy in patients with an acute ST-elevation myocardial infarction (STEMI), not only at short-term but also at long-term follow-up. [1],[2] However, it can only be performed in centers with angioplasty facilities. Although patients with an acute myocardial infarction (MI) can safely be transported to a tertiary center, [3] delays in initiation of treatment due to transportation of high-risk infarct patients has been shown to increase infarct size and to reduce left ventricular function. [4]

Glycoprotein IIb/IIIa receptor blockers, which block the final common pathway leading to platelet aggregation, reduce thrombotic complications (MI or death) in patients undergoing percutaneous coronary intervention (PCI). This applies to both balloon angioplasty and stent implantation. [5],[6],[7],[8] Most data relate to abciximab, which has been registered for this indication. In addition, glycoprotein IIb/IIIa receptor blockers reduce unfavorable outcome in unstable angina patients receiving medical therapy. In particular, the risk of progression to MI or reinfarction is reduced. This is evident from previous trials like capture trial using abciximab in patients with acute coronary syndrome (ACS), [5] Eptifibatide was used in PURSUIT Trial [9] and tirofiban in PRISM and PRISM-PLUS in ACS patients. [10],[11],[12]

Few studies have focused on facilitated PCI, that is, the use of pharmacologic pretreatment before PCI. Facilitated PCI aims to increase patency during the time awaiting coronary angioplasty in patients with acute MI.

Recently in MULTISTRATEGY trial patients with STEMI undergoing PCI, compared with abciximab, tirofiban therapy was associated with noninferior resolution of ST-segment elevation at 90 min following coronary intervention. [13]

In the most recent analysis of On-TIME 2 Trial showed that early, prehospital treatment with high bolus dose (HBD) tirofiban and high-dose clopidogrel improved clinical outcome after primary PCI in patients with STEMI. [14]

Materials and Methods

A randomized, open label, single center study was conducted in the emergency department (ED). A total of 90 patients with acute ST-elevation MI, diagnosed clinically by ECG criteria (ST-segment elevation of >2 mm in two adjacent ECG leads), and with expectation that the patient will undergo primary PCI. Patients were aged 21-85 years and all received heparin 5000 u, aspirin 160 mg, and Plavix 600 mg. Patients were divided in two groups (group I: tirofiban high bolus vs group II: Reopro) with 45 patients in each group. In group I, high bolus tirofiban 25 mcg/kg over 3 min was started in ED with maintenance infusion of 0.15 mcg/kg/min continued for 12 hours and transfer to cath lab for PCI. Patients in group II were transferred to cath lab, where a standard dose of Reopro was given with a bolus of 0.25 mcg/kg and maintenance infusion of 0.125 mcg/kg/min over 12 hours.

Study protocol is shown in [Figure 1]. Demographic and clinical characteristics were recorded on admission [Table 1]. For all patients, clinical data were collected 30 days after the acute event and/or until the moment of death. The coronary angiographies were evaluated by two cardiologists blinded to group or clinical information. The patency of the infarct-related artery (IRA) was evaluated according to the TIMI classification. TIMI flow grade 3 is defined as rapid and complete filling of the IRA, compared with the coronary arteries which are not involved in the MI; TIMI flow grade 2 is defined as complete but slower filling of the IRA, compared with the coronary arteries not involved in the MI. Before primary angioplasty, TIMI flow grades 2 and 3 were considered a (partially) patent IRA. After primary angioplasty, successful reperfusion of the IRA was defined as TIMI flow grade 3 in combination with a residual stenosis of less than 50%.{Figure 1}{Table 1}

Statistical analysis

Differences between group means were assessed with the two-tailed Student's t-test. Chi-square analysis or Fisher's exact test were used to evaluate differences between proportions. Statistical significance was defined by a P-value of less than 0.05.

Patient follow-up

Patients were seen in the outpatient clinic at 30 days and contacted by telephone at 1 year after the PCI and as frequently as considered necessary by the investigator.

Recurrent MI

Recurrent MI within 30 days after completion of PCI is defined as a new increase in Troponin I and CK-MB (>3 times the upper limit of normal), whether or not accompanied by chest pain and/or ECG changes. Elevation of cardiac enzymes needed to be present in two separate blood samples.

Urgent target vessel revascularization

Urgent target vessel revascularization (TVR) is defined as re-PCI of the IRA within 30 days after the index PCI.

Primary endpoint

To investigate the effect of pretreatment with high bolus (25 μg/kg) and maintenance infusion tirofiban on the amount of residual cumulative ST deviation 1 hour after primary PCI for acute STEMI, compared with Reopro bolus in cath lab during PCI and maintenance with similar pretreatment (aspirin, heparin, and 600 mg of clopidogrel).

Residual cumulative ST deviation (ST res ) one Hour after PPCI

ECGs done 1 hour after PCI. Patients with right bundle branch block who clearly have ST segment-elevations are included in the analysis. All ECGs were analyzed by an independent cardiologist. The sum of ST segment deviation was measured 20 microseconds after the end of the QRS complex with a caliper. The sum of residual ST-segment deviation is classified into four groups. [15] - 0 mm: normalized ST segment, defined as no residual ST segment deviation; 1-3 mm: defined as residual ST segment deviation between 1 and 3 mm; 4-6 mm: defined as residual ST segment deviation between 4 and 6 mm; and >7 mm: defined as a residual ST segment deviation more than 7 mm.

The patency of the IRA was evaluated according to the TIMI classification.

Results

ST-segment resolution (STR) after PCI and TIMI flow before and after PCI was evaluated in both groups before and 1 hour after PCI. STR after PCI was seen in 64% of Reopro group and 78% of Aggrastat group with P-value of 0.24 [Figure 2]. TIMI 0 flow before PCI was 51% in Reopro group and 47% in Aggrastat group with P-value 0.83 [Figure 3]. TIMI 1-3 before PCI was 49% in Reopro group and 53% in Aggrastat group with P-value 0.83 [Figure 4]. TIMI 3 flow after PCI was 84% in Reopro group and 89% in Aggrastat with P-value 0.76 [Figure 5].{Figure 2}{Figure 3}{Figure 4}{Figure 5}

Repeated revascularization was done during 1 year in three patients in Reopro group and in two patients in Aggrastat group. Death occurred in two patients in Reopro group (one patient due to cardiac and one noncardiac cause during hospitalization) and one patient in the Aggrastat group due to cardiac cause (VSD).

Discussion

GP IIb/IIIa inhibition in AMI improves myocardial perfusion and downstream microvascular function. New angiographic techniques (e.g., TIMI myocardial blush score) and noninvasive diagnostic tests (e.g., continuous ST-segment monitoring and contrast echocardiography) have been used to show that epicardial TIMI flow grade 3 may be an incomplete measure of reperfusion success. [16]

Although many events can be identified by angiography (e.g., side branch occlusion or the no-reflow phenomenon), a substantial number of "angiographically silent" events occur at the level of myocardial perfusion. Persistent ST-segment elevation following primary PCI, for example, is associated with reduced left ventricular function and increased mortality. [17] Despite epicardial vessel patency, disrupted microvascular function and inadequate myocardial perfusion are often the result of thromboembolic debris. [18]

To date, a number of studies examining the potential benefit of myocardial perfusion with GP IIb/IIIa antagonists have demonstrated improvements in distal microcirculatory flow. In the TIMI 14 study, patients treated with combined abciximab and fibrinolytic therapy experienced more rapid and complete restoration of epicardial flow as well as angiographically evident thrombus. [19] However, when comparing all patients with 60-min TIMI 3 flow, combination therapy also resulted in more complete STR. Since these findings were independent of the fibrinolytic agent used, an additional mechanism by which abciximab improved myocardial perfusion was proposed. By preventing microvascular obstruction from platelet thromboemboli and the proaggregatory effects of fibrinolysis, abciximab may improve myocardial and microvascular perfusion in addition to epicardial flow. [20]

In the single-center, open label, randomized STOP-AMI trial, the combination of stenting plus abciximab was shown to enhance myocardial salvage and markedly improve event-free survival at 30 days and 1 year compared with accelerated t-PA. [21] Similarly, among 162 AMI patients randomized to primary PCI with abciximab or a pharmacologic strategy of reduced-dose alteplase with full-dose abciximab, coronary stenting plus abciximab resulted in significantly greater myocardial salvage and infarct size measured by nuclear imaging at 11 days postinfarction.

Although 6-month survival tended to favor patients randomized to the invasive strategy, overall survival did not significantly differ in this modest-sized study. [22] Neumann et al. [23] also explored the effects of abciximab on myocardial recovery and coronary flow following stenting in AMI patients. In that study, 200 patients within 48 hours of onset of AMI in whom a primary or rescue stent strategy was planned were randomized to a bolus plus 12-hour infusion abciximab regimen or control. Patients treated with abciximab had a lower composite rate of in-hospital death, reinfarction, or urgent TVR (9.2% vs 2.0%; P < 0.05).

Regional wall motion, global left ventricular function, and peak coronary blood flow velocity by Doppler were greater in abciximab-treated patients, consistent with improved distal microcirculatory function, presumably due to reduced distal thromboemboli and/or capillary plugging. However, no significant differences in clinical events or angiographic restenosis were present at 6 months. In summary, adjunctive treatment with GP IIb/IIIa inhibition not only increases epicardial patency but, unlike fibrinolytic therapy, may also enhance myocardial perfusion that results in improved ventricular function and decreased infarct size. [24]

Clinical trials demonstrating improved outcomes among acute MI patients with a patent IRA before percutaneous revascularization have provided further support for facilitated PCI. Percutaneous intervention following initial pharmacologic reperfusion therapy may not only identify those patients with incomplete reperfusion but also provide added benefit with mechanical revascularization. For example, among patients receiving GP IIb/IIIa inhibition and/or fibrinolytic therapy in the TIMI 10B and 14 trials, those with TIMI 0 or 1 flow who underwent "rescue" PCI tended to have lower 30-day mortality than patients treated medically (6% vs 17%; P = 0.28). However, even among patients with TIMI 2 or 3 flow, performance of adjunctive PCI was associated with significantly lower 30-day mortality and/or reinfarction compared with a strategy of delayed revascularization (odds ratio 0.46, 95% confidence interval 0.24-0.57; P = 0.02). [25]

The ideal combination of fibrinolytic, antithrombin, and GP IIb/IIIa inhibitor is also uncertain. Clinical results from forthcoming trials should therefore further clarify the safety and efficacy of combined therapy in addition to its potential as a cost-effective measure.

Integration of most effective pharmacology with percutaneous revascularization strategies also remains an unresolved issue. The improvements in ventricular function, early recurrent ischemia, and both early and intermediate survival with GP IIb/IIIa inhibition in primary PCI support the use of these agents as adjunctive therapy to mechanical revascularization, particularly with timely administration before arrival in the catheterization laboratory. Whether the early performance of angiography and catheter-based intervention following combination therapy for ST- elevation MI will yield favorable outcomes similar to the experience in non-ST-elevation ACS (TIMI 18-TACTICS) is less definitive.

However, considering the importance of prompt restoration of flow in the IRA, the collective experience with fibrinolysis and primary PCI has fostered the concept of "facilitated PCI", and randomized trials evaluating the safety and efficacy of this strategy are underway. [26] Analysis from the On-TIME 2 trial evaluated the efficacy of triple antiplatelet therapy on initial patency and STR in relation to time from symptom onset to first medical contact. Patients were randomized to dual (500 mg aspirin and 600 mg clopidogrel) or triple antiplatelet (500 mg aspirin, 600 mg clopidogrel, and tirofiban 25 μg/kg bolus and 0.15 μg/kg/min maintenance infusion for 18 hours) pretreatment in the ambulance.

Primary outcome of this sub-analysis was initial patency of the infarct-related vessel and STR before PCI according to time from symptom onset to first medical contact in quartiles. Initial patency, STR before PCI, and the incidence of aborted MI gradually increased with shorter time from symptom onset to first medical contact. Initial thrombolysis in MI flow was present in 21.2% in the total population and 26.2%, 21.5%, 18.1%, and 18.8% in the time quartiles, respectively (P for trend = 0.01). The incidence of complete STR pre-angiography was 16.6% in the total population and 23.4%, 18.2%, 14.7%, and 9.9% in the four quartiles, respectively (P for trend < 0.001). This was largely driven by the effect of triple antiplatelet therapy, which further improved initial patency and STR and led to a significantly higher incidence of aborted MI (13.2% vs 8.7%, P = 0.011), especially in the patients with short duration of symptoms. Antiplatelet pretreatment before primary PCI, including a glycoprotein IIb/IIIa blocker, seems to be most effective when given shortly after symptom onset. [27]

In our small trial of 90 patients, there was a trend for better STR and more patency of IRA and improved TIMI flow in patients who were given high bolus dose of Aggrrastat, which was started early in the ED in comparison with patient who were given abciximab standard dose in the cath lab during their PCI. Regardless of the treatment strategy, effective platelet inhibition appears to be a critical element in rising above the "ceiling of reperfusion" and past the limitations of current therapies. While the available data should facilitate the use of adjunctive GP IIb/IIIa inhibitors as part of initial antithrombotic therapy for primary PCI, results from future trials should further refine the role of these agents as part of treatment algorithm for the initial pharmacologic management of patients with acute MI.

Conclusion

Most current trials with GP IIb/IIIa inhibitor in ST elevation MI have been conducted with abciximab. There is some data with high dose bolus (HDR) tirofiban plus high-dose clopidogrel in STEMI. This study demonstrates a minor trend toward better STR and TIMI flow in IRA in the aggrastat group. These findings are consistent with On-TIME 2 study result. Larger studies are needed to clarify if this strategy and dose regimen have a clinical impact.

Limitation of the study

The patient number is small; the research center has limited the number for a period of only 1 year. Immediately tirofiban was started in the ED, whereas the abciximab was started during the PCI in catheterization laboratory.

Acknowledgment

To the ED including the ED doctors and nurses who helped us to recruit those patients who fit the criteria of the study. Also, very special thanks to catheterization laboratory staff including the consultants, residents, nurses, and technicians at KACC.

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