Intravenous glycoprotein IIb/IIIa (GpIIb/IIIa) inhibitors have been proved to be a safe and effective treatment in patients undergoing percutaneous coronary intervention (PCI) by means of balloon-only percutaneous transluminal coronary angioplasty (PTCA) [1,2]. A number of seminal randomized controlled trials have also established the superior risk–benefit ratio of GpIIb/IIIa inhibitors in patients undergoing bare-metal stent (BMS) implantation [1,3,4]. As reported by Karvouni et al. , in a pooled analysis of more than 20 000 patients, GpIIb/IIIa inhibitors significantly reduce 30-day and 6-month mortality in the balloon-only and BMS era.
The benefit of GpIIb/IIIa inhibition in low-risk patients adequately pretreated with clopidogrel and aspirin has been recently challenged and are topic of ongoing research [5–10]. Indeed, the Intracoronary Stenting and Antithrombotic Regimen–Rapid Early Action for Coronary Treatment (ISAR-REACT) trials have shown that abciximab does not provide statistically significant benefits on top of optimal double antiplatelet therapy in stable patients and in low-risk unstable patients, whereas the opposite is true in higher risk unstable patients. However, the ISAR-REACT studies were all limited by an emphasis on risk-defining features based only on patient presentation, thus not giving any weight to coronary anatomical features. Moreover, all the large comparative placebo-controlled trials of GpIIb/IIIa inhibitors were conducted in the PTCA or BMS era and no randomized trials have tested their role with drug-eluting stents (DESs), except for one comparing two GpIIb/IIIa inhibitors without placebo arms .
These premises are the basis for the recent guidelines  that still recommend the use of GpIIb/IIIa inhibitors in stable patients with coronary artery disease (CAD) and complex lesions on a case-by-case basis and routinely in high-risk patients with non-ST-elevation acute coronary syndromes (NSTEACS). Yet, there is a lack of prospective clinical trial data available on the efficacy and risk–benefit profile of GpIIb/IIIa inhibitors in patients treated with DESs and high-loading clopidogrel .
All the three approved GpIIb/IIIa inhibitors appear effective , despite some differences, mainly due to pharmacokinetics and selectivity of GpIIb/IIIa receptor inhibition. Specifically, abciximab, the fragment of a chimeric monoclonal antibody against the GpIIb/IIIa receptor, was the first agent tested and proved effective. Tirofiban and eptifibatide are both reversible inhibitors of the GpIIb/IIIa receptor and, when given with an adequately dosed intravenous bolus followed by a 12–24 h infusion, appear noninferior to abciximab, at least in studies powered for surrogate clinical endpoints [2,11,13]. In addition, compared with abciximab and tirofiban, eptifibatide may inhibit platelet aggregation more consistently throughout both the early and late periods .
Since the introduction of DESs and high-dose clopidogrel preloading , there is uncertainty on the risk–benefit of additional treatment with GpIIb/IIIa inhibitors. Although clopidogrel loading might reduce the need for GpIIb/IIIa inhibition, DESs have made more common the treatment of patients and lesions at much higher risk of adverse periprocedural events. Specifically, consensus is building on the favorable results provided by GpIIb/IIIa inhibitors in high-risk patients , including those with multivessel coronary lesions or diffused single-vessel disease [16,17]. Yet, this approach is not supported by any controlled study that combines both high-dose clopidogrel pretreatment and GpIIb/IIIa inhibition in high-risk patients or complex coronary lesions.
Thus, this lack of data on the risk–benefit and cost–benefit profile of GpIIb/IIIa inhibitors in patients treated with DESs and high-loading clopidogrel provides sound ethical bases for a specific trial.
Design of the INtegrilin plus STenting to Avoid myocardial Necrosis Trial
Our hypothesis suggests that GpIIb/IIIa inhibition may provide significant benefits on top of high-dose clopidogrel pretreatment in high-risk patients undergoing PCI by means of implantation of greater than 33 mm of DESs (e.g. with two 23-mm DESs or one 32-mm and one 12-mm DES). The aim of the INtegrilin plus STenting to Avoid myocardial Necrosis Trial (INSTANT) is thus to prove, in a multicenter, randomized, single-blind controlled trial enrolling patients undergoing DES implantation for diffuse coronary artery disease, the efficacy and, secondarily, the effectiveness and safety of GpIIb/IIIa inhibition by means of eptifibatide vs. placebo.
We will enroll consecutive patients with diffuse coronary artery disease involving a major epicardial coronary vessel (e.g. long lesions) who are undergoing percutaneous treatment of a native coronary vessel with planned implantation of greater than 33 mm DESs (e.g. Cypher, Cordis Corporation, Miami Lakes, Florida, USA; Taxus, Boston Scientific, Natick, Massachusetts, USA; Xience V, Abbott, Abbott Park, Illinois, USA; Promus, Boston Scientific; or Endeavor, Medtronic, Minneapolis, Minnesota, USA) with reference vessel diameter 2.25–4.0 mm and who agree and provide written informed consent and have no contraindications to a 6-month clinical follow-up. Candidates for this study should meet all of the following criteria: men or women who are able to understand and sign a witnessed informed consent, aged 18 years or older, patients with stable (Canadian Cardiovascular Society I–IV) or unstable angina pectoris [but with the most recent anginal episode occurring >48 h before the procedure (provided the most recent creatine kinase-MB mass levels are within the limits of normal)] or documented silent ischemia, stable hemodynamic conditions (systolic blood pressure >100 mmHg, heart rate >40 and <100 beats/min), and no clinical and ECG changes suggestive of ongoing acute or recent (<48 h) myocardial infarction. In addition, the following angiographic inclusion criterion will be enforced: angiographic evidence of a de-novo lesion greater than 50% requiring implantation of two DESs in overlapping with a total stent length greater than 33 mm and reference vessel diameter between 2.5 and 4.0 mm (by visual estimation) in one coronary vessel. Multiple lesions in the same vessels can be included but at least one lesion should require implantation of two DESs in overlapping with a total stent length greater than 33 mm. Conversely, the following exclusion criteria will apply: women with childbearing potential, aged less than 18 years, ongoing or recent episode (<48 h) of unstable coronary artery disease (including both ST elevation and non-ST elevation acute coronary syndromes) without normalization of creatine kinase-MB mass levels, administration of any GpIIb/IIIa inhibitors during the previous 2 weeks, serum creatinine greater than 2.5 mg/dl or greater than 350 μmol/l, ongoing serious bleeding or bleeding diathesis, previous stroke in the last 6 months, major surgery within the previous 6 weeks, platelet count higher than 100 000 per mm3, ejection fraction below 30%, known hypersensitivity or contraindication to aspirin, heparin, clopidogrel, or sensitivity to contrast that cannot be adequately premedicated, hemodynamic instability (systolic blood pressure <100 mmHg, heart rate <40 or >100 beats/min, complex ventricular arrhythmias, atrioventricular block) requiring balloon counterpulsation or inotropic support, simultaneous participation in another device or drug study (patient must have completed the follow-up phase of any previous study at least 30 days prior to enrollment in this study), positive clinical history for intracranial neoplasia, arteriovenous malformation, aneurysm, international normalized ratio (INR) at least 2.0 or prothrombin time 1.2 times upper limit of normality, clinically manifested reduced liver function, and programmed surgery within 1 month. In addition, the following angiographic exclusion criteria will be enforced: DES implantation in a chronic total occlusion, vessel size less than 2.25 mm or greater than 5 mm, and previous implantation of a BMS or a DES in the target lesion (Fig. 1).
All patients who meet all the eligibility criteria will be asked to participate. Once the patient's eligibility has been determined and the attending physician has agreed, a member of the research team will approach the patient to initiate the informed consent process. The patient must sign the informed consent form prior to enrolment. Failure to obtain a signed informed consent will render the patient ineligible for the study.
All patients will be implanted with a DES. Treatment assignment between eptifibatide and placebo will be determined by randomization in a ratio of 1: 1. Randomization will be performed by centrally provided sealed envelopes. To ensure that almost equal numbers of patients receive either treatment, randomization blocks will be used. Patients with and without diabetes and left anterior descending (LAD) vs. non-LAD treatment will be stratified in the two arms. In addition, for bailout GpIIb/IIIa usage, the envelopes will contain a scratch-away covering to allow both randomization and treatment assignment to be unblinded in case code break is needed.
The eptifibatide and placebo will be provided by GlaxoSmithKline (Verona, Italy). The vials will be identical in shape, color, and appearance but not in size. For the latter reason, an independent participant will administer the study drug to the patient, thus ensuring blinding of the patient but not of the investigator. Enrolled patients will be randomized in the catheterization laboratory, after the decision to perform PCI by means of planned implantation of DESs greater than 33 mm in length in the same coronary vessel, to intravenous placebo or intravenous eptifibatide [double bolus (180 μg/kg) followed by infusion (2 μg/kg/min) for 18–24 h after the procedure] .
All patients will be implanted with a DES (no BMS utilization is allowed) also for treating complications (such as proximal or distal dissection) during the index procedure. Only in case of stent implantation failure, other stent are permitted. Concomitantly to study drug administration, intravenous bolus of unfractionated heparin (60 IU/kg, according to the ESPRIT Trial protocol) will be administered in the catheterization laboratory . A clopidogrel loading dose of 600 mg will be recommended in all patients, even if pretreated . In addition, either the intravenous or oral route will provide aspirin to patients not previously treated. Following the procedure, patients with an angiographically successful procedure will continue to receive daily lifelong aspirin plus clopidogrel 75 mg a day for 12 months.
During the procedure, patients should receive intravenous boluses of heparin in sufficient doses to prolong the activated clotting time (ACT) (≥250 s). Procedural success will be defined as an angiographic residual diameter stenosis of less than 20% (visual estimation). Immediately following the procedure, no further heparin should be administered and the ACT should be monitored as per hospital standard and protocol prior to vascular sheath removal. Sheath removal should be managed as per hospital standard. Alternatively, the use of commercially available closure devices is left to the investigator's discretion. The hematocrit and status of the groin will be monitored on the next day. Patients will remain on bed rest until hemostasis has been adequately established (usually the day following the procedure), when they will be cautiously ambulated.
Clinical follow-up and endpoints
Patients will undergo preprocedural (6 ± 2 and 12 ± 2 h) blood draws to measure creatine kinase, creatine kinase-MB mass, and troponin measurement, and telephone-based interviews and office-based direct visits will be performed at 1 and 6 months, respectively, for endpoint adjudication. In case of abnormal postprocedural creatine kinase-MB mass levels, blood draws will be repeated at an interval of 6–8 h until the peak creatine kinase-MB mass has been identified.
The primary endpoint will be the rate of elevated postprocedural peak creatine kinase-MB mass ratio values [i.e. above the upper limit of normal (ULN), e.g. 1.01*ULN, according to each participating hospital laboratory]. Secondary endpoints will be the composite of cardiac death, nonfatal myocardial infarction (MI), urgent target vessel revascularization (TVR), and thrombotic bailout GpIIb/IIIa inhibitor therapy within 180 days, and in-hospital, 1 and 6-month major adverse cardiovascular events (MACE), defined as the composite of cardiac death, nonfatal MI, or urgent TVR. Myocardial infarction will be distinguished as new pathologic Q waves in at least two contiguous leads or non-Q wave MI (peak creatine kinase-MB mass more than times the ULN together with abnormal creatine kinase). As additional safety and efficacy tertiary endpoints, we will assess the rate of major and minor bleedings (defined according to the Thrombolysis In Myocardial Infarction criteria). Finally, as angiographic endpoints procedural changes in TIMI flow, corrected TIMI frame count, and TIMI myocardial perfusion grade will be assessed.
Specifically, target lesion revascularization (TLR) will be defined as a revascularization procedure (repeat angioplasty or coronary bypass surgery) performed because of angiographic restenosis at the site of the lesion treated (within the stent or 5 mm proximal or distal to it) associated with clinical (patient symptoms) or objective evidence (stress test, myocardial scintigraphy) of myocardial ischemia for lesions between 50 and 70%. Re-interventions will be considered appropriate for lesions over 70% even in absence of ischemia.
Owing to the presence of multivessel disease in the enrolled population, the need to revascularize a segment of the vessel not related at all to the baseline disease may occur. For this reason, we introduce the term remote TVR in order to identify a new procedure performed on the target vessel but in an area clearly far away from the target lesion. For example, a new procedure on the distal or mid LAD when the patient was treated for the left main and proximal LAD. Any remote TVR will not be considered an endpoint of the study.
Events will be adjudicated by an independent adjudication committee unaware of the treatment.
Statistical analysis and sample size calculation
Continuous variables will be reported as mean (SD) or median (interquartile range) and compared by means of unpaired t-test or Mann–Whitney tests, when appropriate. Categorical variables will be reported as raw numbers [n/N (%)] and compared by means of Pearson chi-square, Fisher exact, or log-rank tests, when appropriate. Survival analysis will be conducted by means of both Kaplan–Meier method and Cox proportional hazard analysis.
Regarding the primary endpoint sample size, given an expected rate of abnormal postprocedural peak creatine kinase-MB ratio of 10% for the experimental group vs. 25% for the control group [7,18], aiming for a 0.05 alpha and 0.90 power, a total of 292 patients will need to be enrolled (146 patients per group). This will be increased by 10% (leading to a total of 320 patients) in order to take into account potential losses to blood draw or follow-up.
An additional sample size computation for the secondary composite endpoint of cardiac death, nonfatal MI, urgent TVR, and thrombotic bailout GpIIb/IIIa inhibitor therapy within 180 days supports the previous sample size. Indeed, in light of previous and current large size studies of patients treated with BMS or DES [13,16,17,19], given a 30% rate of events at sixth months in the placebo group and an expected 40% reduction in the eptifibatide arm, considering an accrual time of 12 months and a follow-up time of 6 months, and aiming for a 5% alpha error and 90% power, 146 patients should be enrolled per group to establish by means of survival analysis the superiority of eptifibatide vs. placebo. Increasing the sample size by 10% to account for potential losses to follow-up would bring to a total of 320 patients (160 per group).
Thus, a total number of 320 patients would provide adequately powered sample sizes for both the primary efficacy endpoint and the secondary event-free survival analysis. Given their importance in determining the primary endpoint, sensitivity analyses will be carried out stratifying patients according to clinical diagnosis, diabetes status, left anterior descending, and bifurcation treatment.
Several pivotal randomized trials have shown the superior risk–benefit ratio of GpIIb/IIIa inhibitors in patients undergoing balloon-only angioplasty, BMS implantation, or other types of PCI, such as directional coronary atherectomy . However, data in the DES era are lacking, and though the benefits of GpIIb/IIIa inhibition are often implicitly inferred, the only studies reported to date suggest a paradoxical association between GpIIb/IIIa inhibitors and adverse clinical events . Although such occurrence may easily be explained by the nonrandomized design of such studies, and thus the greater likelihood of higher risk patients to be treated with bailout GpIIb/IIIa inhibitors, the time has definitely come for a modern randomized trial appraising the risk–benefit balance of these potent intravenous antiplatelet agents in the DES era, on top of optimal oral antiplatelet administration.
The multicenter randomized INSTANT trial will provide a more precise appraisal of the risk–benefit balance of routine GpIIb/IIIa inhibition on top of state of the art oral antiplatelet treatment in patients with high-risk coronary lesions but stable clinical conditions. As such, it will be a paradigm shift, in focusing not strictly on high-risk patients features, but more on the detailed anatomic and procedural appraisal available to the interventional cardiologist in the catheterization laboratory, after diagnostic angiography has been completed and before PCI has been initiated.
Despite its strengths, we should bear in mind that the primary endpoint of the study will be a surrogate one, and only achievement of statistical and clinical significance for the other secondary endpoints would provide enough evidence to shift current clinical practice.
Given its design as a single-blind multicenter randomized trial, the INSTANT study will likely maximize internal validity. However, given the moderate sample size and reliance on a clinically relevant yet clearly surrogate endpoint, its findings, if showing a beneficial effect of eptifibatide, will warrant further larger trials powered to clinically more relevant outcomes.
The study was supported by GlaxoSmithKline, Verona, Italy. Dr Biondi-Zoccai has consulted for Boston Scientific, Cordis and Mediolanum Cardio Research, and has lectured for Bristol Myers Squibb.
1 Karvouni E, Katritsis DG, Ioannidis JP. Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary interventions. J Am Coll Cardiol 2003; 41:26–32.
2 Brophy JM, Joseph L. Medical decision making with incomplete evidence: choosing a platelet glycoprotein IIbIIIa receptor inhibitor for percutaneous coronary interventions. Med Decis Making 2005; 25:222–228.
3 Topol EJ, Mark DB, Lincoff AM, Cohen E, Burton J, Kleiman N, et al
. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicenter randomised trial. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet 1999; 354:2019–2024.
4 O'Shea JC, Buller CE, Cantor WJ, Chandler AB, Cohen EA, Cohen DJ, et al
, ESPRIT Investigators. Long-term efficacy of platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention. JAMA 2002; 287:618–621.
5 Kastrati A, Mehilli J, Schuhlen H, Dirschinger J, Dotzer F, ten Berg JM, et al
, Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment Study Investigators. A clinical trial of abciximab in elective percutaneous coronary intervention
after pretreatment with clopidogrel. N Engl J Med 2004; 350:232–238.
6 Mehilli J, Kastrati A, Schuhlen H, Dibra A, Dotzer F, von Beckerath N, et al
, Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) Study Investigators. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation 2004; 110:3627–3635.
7 Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) Study. Circulation 2005; 111:2099–2106.
8 Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the clopidogrel loading with eptifibatide to arrest the reactivity of platelets (CLEAR PLATELETS) study. Circulation 2005; 111:1153–1159.
9 Lotrionte M, Biondi-Zoccai G, Agostoni P, Abbate A, Angiolillo DJ, Valgimigli M, et al
. Metaanalysis appraising high clopidogrel loading in patients undergoing percutaneous coronary intervention
. Am J Cardiol 2007; 100:1199–1206.
10 Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein H, et al
, Intracoronary Stenting and Antithrombotic: Regimen Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) Trial Investigators. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention
after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 2006; 295:1531–1538.
11 Valgimigli M, Percoco G, Malagutti P, Campo G, Ferrari F, Barbieri D, et al
, STRATEGY Investigators. Tirofiban and sirolimus-eluting stent vs abciximab and bare-metal stent for acute myocardial infarction: a randomized trial. JAMA 2005; 293:2109–2117.
12 Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C, et al
, For the Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 2005; 26:804–847.
13 Valgimigli M, Percoco G, Barbieri D, Ferrari F, Guardigli G, Parrinello G, et al
. The additive value of tirofiban administered with the high-dose bolus in the prevention of ischemic complications during high-risk coronary angioplasty: the ADVANCE Trial. J Am Coll Cardiol 2004; 44:14–19.
14 Batchelor WB, Tolleson TR, Huang Y, Larsen RL, Mantell RM, Dillard P, et al
. Randomized comparison of platelet inhibition with abciximab, tiRofiban and eptifibatide during percutaneous coronary intervention
in acute coronary syndromes: the COMPARE trial. Comparison of measurements of platelet aggregation with Aggrastat, Reopro, and Eptifibatide. Circulation 2002; 106:1470–1476.
15 Biondi-Zoccai GGL, Sangiorgi GM, Chieffo A, Vittori G, Falchetti E, Margheri M, et al
, RECIPE (Real-world Eluting-stent Comparative Italian retrosPective Evaluation) Study Investigators. Validation of predictors of intraprocedural stent thrombosis in the drug-eluting stent
era. Am J Cardiol 2005; 95:1466–1468.
16 Orlic D, Bonizzoni E, Stankovic G, Airoldi F, Chieffo A, Corvaja N, et al
. Treatment of multivessel coronary artery disease with sirolimus-eluting stent implantation: immediate and mid-term results. J Am Coll Cardiol 2004; 43:1154–1160.
17 Tsagalou E, Chieffo A, Iakovou I, Ge L, Sangiorgi GM, Corvaja N, et al
. Multiple overlapping drug-eluting stents to treat diffuse disease of the left anterior descending coronary artery. J Am Coll Cardiol 2005; 45:1570–1573.
18 Cavallini C, Savonitto S, Violini R, Arraiz G, Plebani M, Olivari Z, et al
, On behalf of the Italian ‘Atherosclerosis, Thrombosis, and Vascular Biology’ and ‘Society for Invasive Cardiology: GISE’ Investigators. Impact of the elevation of biochemical markers of myocardial damage on long-term mortality after percutaneous coronary intervention
: results of the CK-MB and PCI study. Eur Heart J 2005; 26:789–794.
19 Pasceri V, Patti G, Nusca A, Pristipino C, Richichi G, Di Sciascio G, ARMYDA Investigators. Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2004; 110:674–678.
20 Teirstein PS, Kao J, Watkins M, Tannenbaum MA, Laufer N, Chang M, et al
. Impact of platelet glycoprotein IIb/IIIa Inhibition on the paclitaxel-eluting stent in patients with stable or unstable angina pectoris or provocable myocardial ischemia (a TAXUS IV substudy). Am J Cardiol 2005; 96:500–505.