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A risk stratification scheme for selection of a glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention based on clinical and angiographic criteria

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A risk stratification scheme for selection of a glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention based on clinical and angiographic criteria
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   A Risk Stratification Scheme for Selection of aGlycoprotein IIb/IIIa Inhibitor During PercutaneousCoronary Intervention Based on Clinical and Angiographic Criteria* Annapoorna S. Kini,  MD , David Reich,  MD , Cristina A. Mitre,  MD , andSamin K. Sharma,  MD I n randomized trials of glycoprotein (GP) IIb/IIIainhibitors during percutaneous coronary interven-tion (PCI), it appears that the trials involving abcix-imab have the greatest benefit, followed by trials withsmall molecules. 1–9 Despite a wide variety of clinicaland angiographic settings in which all GP IIb/IIIainhibitors have been studied, in some subgroups, suchas small vessels, restenotic vessels, and vein graftlesions, no clear-cut benefit has been shown. To date,there is only 1 randomized trial comparing abciximabwith tirofiban during PCI (do Tirofiban And ReoProGive similar Efficacy Trial [TARGET]) and no head-to-head randomized trial comparing the 3 availableGP IIb/IIIa inhibitors. Therefore, the decision to use 1agent over another is based on a case-by-case analysisof risk/benefit versus cost. Considering an averageincidence of periprocedural creatine kinase (CK)-MBelevation of 15%, a total of 1,500 patients (500 in eachgroup) will have 80% power to show a 15% relative(3% absolute) difference among the various groups.Based on our earlier observation and prior publishedreports of periprocedural CK-MB elevation and isch-emic procedural events, we formulated a risk stratifi-cation scheme for use of a particular GP IIb/IIIainhibitor during PCI: abciximab for the high-risk group, small molecules for the intermediate-risk group, and no GP IIb/IIIa inhibitor in low-risk group,with the provision of abciximab use as bailout forprocedural complications in intermediate and low-risk groups. In the present study, this risk stratificationscheme for selecting a particular GP IIb/IIIa inhibitorduring PCI was prospectively evaluated to assess theincidence of periprocedural CK-MB elevation, bailoutuse of abciximab, and 30-day major adverse cardiacevents.All patients (n    1,875) undergoing PCI at ourinstitution from January to December 1999 were an-alyzed based on the risk stratification protocol for useof GP IIb/IIIa inhibitors. Patients with acute myocar-dial infarction (MI) (  24 hours), elevated baselineCK-MB values, preprocedure GP IIb/IIIa inhibitoruse, serum creatinine  2.5 mg/dl, platelet count  150  10 9  /L, and contraindication to GP IIb/IIIa inhibitoruse were excluded. A risk stratification protocol wasdeveloped based on the clinical and angiographic cri-teria (Table 1). Abciximab was recommended forhigh-risk subsets, small molecules for intermediate-risk subjects, and no GP IIb/IIIa inhibitors for thelow-risk group. The choice of small molecules in theintermediate-risk group was left to the interventional-ist.The study population consisted of 1,655 consecu-tive patients undergoing PCI. GP IIb/IIIa inhibitorswere used in 75.1% of patients, abciximab in 48.2% (n   798), tirofiban in 13.3% (n    220), eptifibatide in13.6% (n    225), and no GP IIb/IIIa inhibitors in24.9% (n  412).An independent investigator verified the protocolcompliance from the case report forms. The compli-ance for the use of an individual agent as per protocolguideline was   98% in each risk group. Baselinecardiac enzymes, complete blood count with platelets,and chemistry were measured in all patients and re-peated at 4 to 8 hours and 16 to 24 hours after theprocedure, and thereafter if these measurements re-mained abnormal.All patients received aspirin 325 mg orally, clopi-dogrel 300 mg orally, and a 50 to 70 U/kg intravenousbolus of heparin. Subsequently, periodic intravenousheparin boluses were given to maintain the activatedclotting time between 225 and 300 seconds, with atrend toward lower values in the abciximab group.The GP IIb/IIIa inhibitors were administered in thefollowing doses: abciximab (Evaluation of IIb/IIIaPlatelet Inhibitor for STENTing [EPISTENT] trialdose), 0.25 mg/kg bolus with infusion of 0.125   g/ kg/min (maximum 10   g/min) for 12 hours; tirofiban(Randomized Efficacy Study of Tirofiban for Out-comes and REstenosis [RESTORE] trial dose), 10  g/kg bolus with infusion of 0.15   g/kg/min for 16 to24 hours; eptifibatide (Platelet glycoprotein IIb/IIIa inUnstable angina: Receptor Suppression Using Integri-lin Therapy [PURSUIT] trial dose), 180   g/kg boluswith infusion of 2.0   g/kg/min for 16 to 24 hours. Allinterventions were performed using conventionaltechniques, and the choice of the interventional devicewas left to the operator (stents were used in 88.6% of cases). Complete angiographic vessel and lesion char-acteristics and procedural results were recorded aftereach coronary intervention.  Angiographic success:  residual stenosis   30% From the Cardiac Catheterization Laboratory, Cardiovascular Institute,Mount Sinai Hospital, New York, New York. Dr. Sharma’s address is:Mount Sinai Hospital, Cardiac Catheterization Laboratory, Cardiovas-cular Institute, Cardiology-Box 1030, One Gustave Levy Place, NewYork, New York 10029-6574. E-mail: samin.sharma@mssm.edu.Manuscript received June 13, 2001; revised manuscript received andaccepted July 24, 2001.*There is no conflict of interest among any authors involved in thisstudy. 1287 ©2001 by Excerpta Medica, Inc. All rights reserved. 0002-9149/01/$–see front matterThe American Journal of Cardiology Vol. 88 December 1, 2001 PII S0002-9149(01)02089-6  with at least Thrombolysis In Myocardial Infarctiongrade 2 flow in the distal vessel. Clinical success:  angiographic success of at least 1lesion in the absence of any major complications.  Major complications:  Q-wave MI, non–Q-waveMI with CK-MB elevation   8    normal, emergentcoronary artery bypass surgery, and death.  Non–Q-wave MI:  elevated CK-MB  3  normal.  American College of Cardiology/American Heart  Association classification of lesions:  type A, B, and Clesions. Small vessels:  vessel size  2.5 mm.  Minor procedural events: 10 transient vessel clo-sure, slow flow/no flow, spasm, thrombus, thrombo-embolism, minor intimal dissections, side-branch clo-sure, and persistent chest pain.  Mild-moderate thrombocytopenia:  platelet countbetween 50 and 100  10 9  /L or  50% decrease frombaseline. Severe thrombocytopenia:  platelet count   50   10 9  /L. Vascular complications:  major bleeding (  5 gdrop in hemoglobin or intracranial bleeding) or needfor vascular surgery.  Major adverse cardiac events:  death, Q-wave MI,stent thrombosis, or urgent revascularization.All patients were monitored in the hospital formajor complications and various ischemic and non-ischemic events. Patients with normal CK-MB valueswho were clinically stable were discharged the fol-lowing day, with instructions to take aspirin (325mg/day) in the absence of stent implantation, or aspi-rin (325 mg/day) plus clopidogrel (loading dose 300and 75 mg once daily for 4 weeks) if a stent wasimplanted.All patients discharged from the hospital were fol-lowed for major adverse cardiac events at 30 days bytelephone contact to the patient or private physician.Planned staged interventions of non-target vesselswere not included in the major adverse cardiac eventsanalysis.Data were entered in a Microsoft Excel (Seattle,Washington) database and transferred to the statisticalprogram StatView 4.1 (Cary, North Carolina) for anal-ysis. Results are presented as mean  SD or number(%). Comparison between the 2 groups was doneusing chi-square analysis or Fisher’s exact test forcategorical variables and 2-tailed Student’s  t   test forcontinuous variables.The PCI procedural success of 96.7% and clinicalsuccess of 97.2% for the entire group were similar inall 4 groups (p  NS). There was no difference in theincidence of postprocedure CK-MB elevation betweenvarious groups (p    0.4), except for significantlylower (  3  normal) CK-MB elevation in the no-GPIIb/IIIa inhibitor versus GP IIb/IIIa groups (p  0.01;Figure 1). There were no differences among variousgroups with regard to in-hospital major ischemic andvascular complications or the incidence of 30-daymajor adverse cardiac events (p    NS for all vari-ables) (Table 2). There was a nonstatistically higherincidence of 30-day major adverse cardiac events inthe tirofiban group (3.2% vs 1.5% in other groups) dueto 3 cases of subacute stent thrombosis; 2 of thesepatients had intervention of thrombotic lesions afterMI (protocol deviation). The incidence of 30-day ma- jor adverse cardiac events including non–Q-wave MIwas not significantly different between the 3 GP IIb/ IIIa inhibitors (abciximab 5.4%, tirofiban 6.8%, andeptifibatide 5.3%; p    0.2), but was 2.4% in theno-GP IIb/IIIa group (p    0.02 vs groups with GPIIb/IIIa). The incidence of minor procedural eventsshowed an increasing trend from the no-GP IIb/IIIagroup to the small-molecule and abciximab groups (p  0.007), reflecting the increasing lesion complexity.The incidence of thrombocytopenia was statisticallyhigher in the abciximab group. The bailout use of abciximab for periprocedural events was relativelylow (  4%) and was not different in various non-abciximab groups. Despite significant differences inthe clinical and lesion characteristics, there was nodifference in the postprocedure length of stay betweenall groups (  2 days).Our prospective, nonrandomized study revealedthat a risk stratification protocol based on clinical andangiographic criteria is safe and is associated withsimilar procedural and 30-day results after use of various GP IIb/IIIa inhibitors. Studies of GP IIb/IIIainhibitors during PCI have the 30-day end point of death, MI, or urgent revascularization from   11% TABLE 1  Risk Stratification Scheme Based on Clinical andAngiographic Criteria Criteria RecommendedHigh RiskClinical type: rest angina, post-MI,diabetes mellitusAbciximabLesion type: ACC/AHA type C andsome type B: complex, bifurcation,chronic total occlusion, ostial,thrombotic, moderate to heavilycalcifiedRotational atherectomy, multivesselinterventionIntermediate RiskClinical type: new-onset or crescendoanginaTirofiban or eptifibatide;abciximab as bailoutLesion type: ACC/AHA type A andmost type B: moderate angulation ortortuosity, mild calcification,nonostial, vein graftPrior abciximab useLow RiskClinical type: stable angina orasymptomaticNo GP IIb/IIIa inhibitor;abciximab as bailoutLesion type: simple lesions, in-stentrestenosis, restenosis, small vessels,moderate stenosis (50%70%)Inability to cross the lesion ACC/AHA    American College of Cardiology/American Heart Associa-tion. 1288  THE AMERICAN JOURNAL OF CARDIOLOGY   VOL. 88 DECEMBER 1, 2001  (range 10.6% to 12.8%) in the placebo group to  6%(range 5.4% to 8.6%) in the treatment group. 1–9 De-spite the marked differences in the patient populationsstudied in various GP IIb/IIIa inhibitor trials, absolutebenefit appears to be greater in the abciximab versussmall-molecules trials (4% to 6% vs 2% to4.5%). 1,4,5,8,9 In the absence of head-to-head compar-ison trials of the 3 available GP IIb/IIIa inhibitors, thedecision to use one over another is usually based oncase-by-case analysis of risk/benefit versus cost andanecdotal experience.The similar important clinical outcome observed inthe present study across all groups is a provocativefinding for several reasons. First, because the 3 treat-ment arms (no GP IIb/IIIa inhibitor, small molecules,abciximab) deliver a platelet-inhibiting effect of in-creasing potency (  50% to 70% to   90%) and thelesions treated are also grouped in subsets of increas-ing complexity, the major finding of this study may beits confirmation of the central role of platelets indetermining the clinical outcome after PCI. 11–15 Sec-ond, the equivalent outcome across the 3 groups leadsto the conclusion that one can duplicate “ReoPro-like”results in intermediate clinical/lesion subsets using thecheaper small molecules without an increase in isch-emic complications. More importantly, this interme-diate level of complexity/risk can be prospectivelydetermined. In the EPISTENT trial, the largest trial todate of abciximab versus placebo, which included awide variety of lesions, the 30-day major adversecardiac events in the stent plus abciximab group was5.3%. 8,16 Therefore, if this number is viewed as thecurrent gold standard for PCI plus adjunctive pharma-cotherapy, then small molecules can be expected toachieve comparable results if used judiciously in pro-spectively determined intermediate-risk groups, as ob-served in the present study. 9 Thus, in the intermediate-risk subset, whether abciximab is more effective thansmall molecules in lowering the ischemic risk is ques-tionable, and whether it is more cost-effective ishighly unlikely. Furthermore, because the present al-gorithm was able to define a low-risk group in whichthe procedural and 30-day events were relatively low,there is obviously a group of patients in whom GPIIb/IIIa inhibitors will not substantially reduce the risk further.TherecentlyreportedTARGETtrial,involving4,812patients with various clinical syndromes undergoing cor-onary stenting, revealed that abciximab was associatedwith a lower incidence of the triple composite end points FIGURE 1. Incidence and magnitudeof CK-MB elevation in all 4 groups(n  1,655).TABLE 2  Use of GP IIb/IIIa Inhibitors and Complications ResultsAbciximab(n  798)Tirofiban(n  220)Eptifibatide(n  225)No GP IIb/IIIa(n  412) p ValueMajor complications 0.7% 1.4% 0.4% 0.7% NSMinor procedural events 11.3% 9.8% 9.6% 5.8%   0.01*Vascular complications 1.4% 1.4% 1.3% 1.0% NSACT (s) 232  48 260  32 258  28 290  22 0.01ThrombocytopeniaMild-moderate 5.6% 1.4% 0.9% 0   0.01Severe 2.1% 0 0 0   0.01Bailout use of abciximab - 4.1% 3.1% 2.2% NSPostprocedure LOS (d) 2.1  0.8 2.2  1.1 2.1  0.9 1.9  0.9 NS30-day MACE 1.4% 3.2% 1.3% 1.6% NSDeath/MI 0.4%/0.9% 0.4%/2.2% 0.4%/0.8% 0.2%/0.5% NS30-day MACE with nonQ-wave MI 5.4% 6.8% 5.3% 2.4% 0.02* *p  NS among various GP IIb/IIIa inhibitors.ACT  activated clotting time; LOS  length of stay; MACE  major adverse cardiac events. BRIEF REPORTS  1289  of death/MI/urgent revascularization than tirofiban(6.0% vs 7.5%; p  0.038). Subgroup analysis revealedthat high-risk patients with acute coronary syndromederived the maximum benefit (6.3% vs 9.3% in favor of abciximab; p  0.02), whereas in stable patients (38% of the population) tirofiban was equal to abciximab (4.5%vs5.5%;p  NS).Therefore,theresultsoftheTARGETtrial confirm our risk stratification scheme of the use of abciximab in acute coronary syndrome high-risk pa-tients, and the use of tirofiban (or eptifibatide based onthe Enhanced Suppression of the Platelet IIb/IIIa Recep-tor with Integrilin Therapy [ESPRIT] trial) in intermedi-ate-risk patients. 17 Thus, in the absence of a head-to-head comparison,the decision to use a particular GP IIb/IIIa inhibitorduring PCI based on a clinical and angiographic al-gorithm can be expected to result in a similar outcomeand may be justified from the cost-effectiveness pointof view. The impact of this strategy on long-termoutcome needs to be determined.The present study is not a randomized trial, but aprospective one involving a large cohort of patients.Therefore, investigators’ bias cannot be excluded.Also, only 30-day major adverse cardiac events arereported, and it may be that cardiac events in thesegroups may differ in  1 years. Some protocol devia-tion was observed in each group, but it was  2% andtherefore unlikely to significantly affect results. Thesynergistic effect of low molecular weight heparinwith an individual GP IIb/IIIa inhibitor was not stud-ied because it was not in the formulary at our institu-tion during the study period. Our data demonstrate that a risk stratificationscheme based on clinical and angiographic vari-ables for selection of the most appropriate GPIIb/IIIa inhibitor during PCI—abciximab for high-risk subjects, small molecules for intermediate-risksubjects, and no GP IIb/IIIa inhibitor for low-riskpatients—can be justified without compromisingpatients’ safety and short-term outcome and canresult in significant cost savings. 1.  The EPIC Investigators. Use of a monoclonal antibody directed against theplatelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty.  N Engl J Med   1994;330:956–961. 2.  The IMPACT-II Investigators. Randomized placebo-controlled trial of effectof eptifibatide on complications of percutaneous coronary intervention: IM-PACT-II.  Lancet   1997;349:1422–1428. 3.  The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockadewith tirofiban on adverse cardiac events in patients with unstable angina or acutemyocardial infarction undergoing coronary angioplasty.  Circulation  1997;96:1445–1453. 4.  The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIawith eptifibatide in patients with acute coronary syndromes.  N Engl J Med  1998;339:436–443. 5.  The PRISM-PLUS Study Investigators. Inhibition of the platelet glycoproteinIIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardialinfarction.  N Engl J Med   1998;338:1488–1497. 6.  The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade andlow-dose heparin during percutaneous coronary revascularization.  N Engl J Med  1997;336:1689–1697. 7.  The CAPTURE Investigators. Randomized placebo-controlled trial of abcix-imab before and during intervention in refractory unstable angina: CAPTUREstudy.  Lancet   1997;349:1429–1435. 8.  The EPISTENT Investigators. Randomized placebo-controlled and balloonangioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade.  Lancet   1998;352:87–92. 9.  The ESPRIT Investigators. Novel dosing regimen of eptifibatide in plannedcoronary stent implantation (ESPRIT): a randomized placebo-controlled trial.  Lancet   2000;356:2037–2044. 10.  Kini A, Marmur JD, Kini S, Dangas G, Cocke T, Wallenstein S, Brown E,Ambrose J, Sharma SK. Creatine kinase-MB elevation after coronary interven-tion correlates with diffuse atherosclerosis, and low-to-medium level elevationhas a benign clinical course.  J Am Coll Cardiol  1999;34:663–671. 11.  Simoons M, van der Brand M, Lincoff M, Harrington R, van der Wieken R,Vahanian A, Rutsch W, Kootstra J, Boersma E, Califf R, Topol E. Minimalmyocardial damage during coronary intervention is associated with impairedoutcome.  Eur Heart J   1999;20:1112–1119. 12.  Neumann FJ, Blasini R, Schmitt C, Alt E, Dirschinger J, Gawaz M, KastratiA, Schomig A. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after placement of coronary arterystents in acute myocardial infarction.  Circulation  1998;98:2695–2701. 13.  Sharma SK, Kini A, Marmur JD, Fuster V. Cardioprotective effect of prior  -blocker therapy in reducing creatine kinase-MB elevation after coronary inter-vention: Benefit is extended to improvement in intermediate-term survival.  Cir-culation  2000;102:166–172. 14.  Ellis S, Vandormael M, Cowley M, DiSciascio G, Deligonul U, Topol E,Bulle TM. Coronary morphologic and clinical determinants of procedural out-come with angioplasty for multivessel coronary disease: implications for patientselection.  Circulation  1990;82:1193–1202. 15.  Bhatt D, Topol E. Current role of platelet glycoprotein IIb/IIIa inhibitors inacute coronary syndromes.  JAMA  2000;284:1549–1558. 16.  Topol E, Mark D, Lincoff M, Cohen E, Burton J, Kleiman N, Talley D, SappS, Booth J, Cabot C, Anderson K, Califf R, for the EPISTENT Investigators.Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIablockade in patients undergoing coronary stenting: results from a multicenterrandomized trial.  Lancet   1999;354:2019–2024. 17.  The TARGET Investigators. Comparison of two platelet glycoprotein IIb/IIIainhibitors tirofiban and abciximab for the prevention of ischemic events withpercutaneous coronary revascularization.  N Engl J Med   2001;344:1888–1894. 1290  THE AMERICAN JOURNAL OF CARDIOLOGY   VOL. 88 DECEMBER 1, 2001
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