- Email: [email protected]
Suboptimal inhibition of platelet aggregation following tirofiban bolus in patients undergoing percutaneous coronary intervention for unstable angina pectoris
acute infarct intervention. This may explain why lytic agents or glycoprotein IIb/IIIa inhibitors did not affect final cTFC in this cohort. In summary, cTFC after acute infarct intervention correlates with preprocedural lesion morphology as assessed by IVUS. 1. Gibson CM, Cannon CP, Daley WL, Daley WL, Dodge JT, Alexander B,
Marbe SJ, McCabe CH, Raymond L, Fortin T, Poole K, Brawnwald E, for the TIMI 4 Study Group. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996;93:879 –888. 2. Gibson CM, Cannon CP, Murphy SA, Marble SJ, Baron HV, Brawnwald EB, for the TIMI Study Group. Relationship of the TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention to long-term outcomes after thrombolytic administration in acute myocardial infarction. Circulation 2002;105:1909 –1913. 3. Hamada S, Nishiue T, Nakamura S, Sugiura T, Kamihata H, Miyoshi H, Imuro Y, Iwasaka T. TIMI frame count immediately after primary coronary angioplasty as a predictor of functional recovery in patients with TIMI 3 reperfused acute myocardial infarction. J Am Coll Cardiol 2001;38:666 –671. 4. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, Pinto FJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG. American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2001;37:1478 –1492. 5. Di Mario C, Gorge G, Peters R, Kearney P, Pinto F, Hausmann D, von Birgelen C, Colombo A, Mudra H, Roelandt J, Erbel R. Clinical application and image interpretation in intracoronary ultrasound. Study Group on Intracoronary Imaging of the Working Group of Coronary Circulation and of the Subgroup on Intravascular Ultrasound of the Working Group of Echocardiography of the European Society of Cardiology. Eur Heart J 1998;19:207–229.
6. Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K, Masuyama T, Kitabatake A, Minamino T. Lack of myocardial perfusion immediately after successful thrombolysis: a predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 1992;85:1699 –1705. 7. Maes A, Van de Werf F, Nuyts J, Bormans G, Desmet W, Mortelmans L. Impaired myocardial tissue perfusion early after successful thrombolysis. Impact on myocardial flow, metabolism, and function at late follow up. Circulation 1995;92:2072–2078. 8. Wu KC, Zerhouni EA, Judd RM, Lugo-Olivieri CH, Barouch LA, Schulman SP, Blumenthal RS, Lima JA. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation 1998;97:765–772. 9. Wakatsuki T, Nakamura M, Tsunoda T, Toma H, Degawa T, Oki T, Yamaguchi T. Coronary flow velocity immediately after primary coronary stenting as a predictor of ventricular wall motion recovery in acute myocardial infarction. J Am Coll Cardiol 2000;35:1835–1841. 10. Baim DS, Wahr D, George B, Leon MB, Greenberg J, Cutlip DE, Kaya U, Popma JJ, Ho KKL, Kuntz RE, on behalf of the Saphenous vein graft Angioplasty Free of Emboli Ramdomized (SAFER) Trial Investigators. Randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein aorto-coronary bypass grafts. Circulation 2002;105:1285–1290. 11. Grube E, Gerckens U, Yeung AC, Rowold S, Kirchhof N, Sedgewick J, Yadav JS, Stertzer S. Prevention of distal embolization during coronary angioplasty in saphenous vein grafts and native vessels using porous filter protection. Circulation 2001;104:2436 –2441. 12. Mintz GS, Pichard AD, Kent KM, Satler LF, Popma JJ, Leon MB. Axial plaque redistribution as a mechanism of percutaneous transluminal coronary angioplasty. Am J Cardiol 1996;77:427–430. 13. Potkin BN, Keren G, Mintz GS, Douek PC, Pichard AD, Satler LF, Kent KM, Leon MB. Arterial responses to balloon coronary angioplasty. An intravascular ultrasound study. J Am Coll Cardiol 1992;20:942–951. 14. Fitzgerald PJ, Ports TA, Yock PG. Contribution of localized calcium deposits to dissection after angioplasty. An observational study using intravascular ultrasound. Circulation 1992;86:64 –70. 15. Ahmed JM, Mintz GS, Weissman NJ, Lansky AJ, Pichard AD, Satler LF, Kent KM. Mechanism of lumen enlargement during intracoronary stent implantation: an intravascular ultrasound study. Circulation 2000;102:7–10.
Suboptimal Inhibition of Platelet Aggregation Following Tirofiban Bolus in Patients Undergoing Percutaneous Coronary Intervention for Unstable Angina Pectoris Daniel Soffer, MD, Issam Moussa, MD, Murat Karatepe, MD, Kishore J. Harjai, MD, Judith Boura, MS, Simon R. Dixon, MBChB, Cindy L. Grines, MD, William W. O’Neill, MD, Gary S. Roubin, MD, and Jeffrey W. Moses, MD he current dosing regimen for tirofiban during percutaneous coronary intervention is based on a T dose-ranging study that measured inhibition of platelet
aggregation (IPA) with 5-M adenosine diphosphate (ADP) as a platelet agonist.1 Based on this dosing regimen, a large randomized, double-blind, placebocontrolled trial of tirofiban, in high-risk patients with unstable angina who underwent coronary angioplasty, failed to demonstrate a significant reduction in ischemic complications at 30 days.2 In a recent, prospective head-to-head comparison of tirofiban and abciximab in patients scheduled for coronary stenting, tiroFrom the Division of Cardiology, William Beaumont Hospital, Royal Oak, Michigan; and the Lenox Hill Heart and Vascular Institute of New York, New York, New York. Dr. Soffer’s address is: Division of Cardiology, William Beaumont Hospital, 3601 W. 13 Mile Rd, Royal Oak, Michigan 48073. E-mail: [email protected]. Manuscript received July 31, 2002; revised manuscript received and accepted December 4, 2002.
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©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 April 1, 2003
fiban offered less protection from major ischemic events at 30 days than did abciximab.3 This study examines whether the current tirofiban bolus results in optimal IPA in patients undergoing coronary intervention, using 20-M ADP as a platelet agonist. Further, we explored the extent of variability and the impact of angina class on IPA after administration of tirofiban. •••
From March to September 1999, we measured IPA in 128 consecutive patients who underwent elective or urgent coronary intervention and received glycoprotein IIb/IIIa inhibitors. Seventeen patients who received abciximab and 9 patients who received eptifibitide were excluded from analysis. Thus, a total of 102 patients who received tirofiban (10 g/kg bolus followed by 0.15 g/kg/min infusion for 12 hours) were included in this analysis. All patients received aspirin 325 mg and were pretreated with clopidogrel before the procedure. Platelet aggregation studies were performed before and 15 min0002-9149/03/$–see front matter doi:10.1016/S0002-9149(03)00024-9
etry (LTA), the Ichor platelet analyzer, using 20-M ADP, has demGroup I Group II onstrated excellent correlation (r 2 ⫽ Variable (n ⫽ 61) (n ⫽ 41) p Value 0.81, p ⫽ 0.0001), and is currently approved by the Food and Drug AdAge (yrs) 62 ⫾ 10 62 ⫾ 9 0.87 Men 46 (75%) 34 (83%) 0.37 ministration for quantitative platelet Diabetes mellitus 23 (38%) 10 (24%) 0.21 aggregometry.5 As previously deCurrent smoker 11 (18%) 10 (24%) 0.72 scribed,5,6 platelet count is perSystemic hypertension (⬎160/90 mm Hg) 42 (69%) 26 (63%) 0.57 formed in a sample that passes Total cholesterol (serum)⬎240 mg/dl 44 (72%) 23 (56%) 0.10 Prior myocardial infarction 19 (31%) 16 (39%) 0.41 through an aperture, thereby interPrior coronary bypass 10 (16%) 8 (20%) 0.69 rupting a constant electrical current. Recent myocardial infarction (ⱕ5 d) 0 (0%) 14 (34%) ⬍0.0001 This results in an electrical pulse that Angiotensin-converting enzyme inhibitors 16 (26%) 11 (27%) 0.95 is amplified and sorted to provide the Antilipid drug(s) 36 (59%) 21 (51%) 0.44 final platelet count in platelets ⫻  blocker 40 (66%) 36 (88%) 0.012 Calcium antagonists 37 (61%) 31 (76%) 0.12 1,000/mm3. In the presence of ADP, Nitrates 27 (44%) 31 (76%) 0.002 platelets aggregate and therefore they exceed the threshold limitations for platelet size and are no longer counted as platelets. TABLE 2 Preprocedural Antiplatelet and Antithrombotic Therapy Baseline platelet function assay Group I Group II was performed before administration Medication (n ⫽ 61) (n ⫽ 41) p Value of tirofiban. An initial platelet count Aspirin 60 (98%) 40 (98%) 1.0 was obtained using ethylenediamiIV heparin 11 (18%) 38 (93%) ⬍0.0001 netetraacetic acid (control tube), and Clopidogrel loading dose (mg) 58 (95%) 41 (100%) 0.27 a second platelet count was taken 450 26 (43%) 19 (46%) 0.71 from the same blood sample, using 150 24 (39%) 20 (49%) 0.35 Mean loading dose (mg) 316 ⫾ 151 296 ⫾ 152 0.54 20-M ADP and 3.2% of sodium Clopidogrel therapy (ⱖ5 d) 11 (18%) 2 (5%) 0.051 citrate as an agonist and anticoaguDuration maintenance therapy (d) 11.5 ⫾ 8.4 5.5 ⫾ 0.7 0.04 lant, respectively (1 ml in each tube). The differential platelet count between the control tube and the ADPcontaining tube represents the functional (aggregable) platelets in the blood sample. Percent platelet inhibition was calculated by dividing the platelet count following stimulation with ADP by the control platelet count ⫻ 100. An additional platelet function assay was performed 15 minutes after the tirofiban bolus. We defined optimal IPA as ⬎80% based on early studies that showed that ⬎80% IPA using LTA and 20 M ADP as platelet agonist is required to reduce thrombus formation and ischemic complications during coronary interventions.7,8 Quality control using normal and low quantitative solutions was performed on a daily basis. FIGURE 1. Percent IPA (mean ⴞ SD) at baseline and after the Categorical variables are presented as counts and tirofiban bolus between the 2 groups (group I: stable angina and percentages. Continuous variables are shown as the Braunwald class I unstable angina; group II: Braunwald class II means ⫾ SD. Differences in categorical variables or III unstable angina). p ⴝ 0.001 for the differences between between patient groups were examined using a chibaseline and after the bolus within each group. square test or Fisher’s 2-tailed exact test. Differences utes after the tirofiban bolus. Patients were classified into in continuous variables between groups were exam2 groups according to their Braunwald unstable angina ined using a Wilcoxon rank test. To determine the classification4: group I included 61 patients with stable independent association of angina class with optimal angina or Braunwald class I unstable angina pectoris, IPA, a logistic regression (stepdown) analysis was and group II included 41 patients with Braunwald class performed using IPA as a dichotomous outcome II or III unstable angina. Written, informed consent was (ⱕ80% vs ⬎80%). Variables that showed a significant or borderline (p ⬍0.10) association with angina class obtained from each patient before the procedure. Inhibition of ADP-mediated platelet aggregation were included in this model. Baseline characteristics of patients are listed in was measured with the Ichor point-of-care platelet analyzer (Helena Laboratories, Beaumont, Texas), us- Tables 1 and 2. Patients with Braunwald class II and ing 20-M ADP. In direct comparable studies with III unstable angina were more likely to have had a traditional platelet-rich light transmission aggregom- recent myocardial infarction (34% vs 0%, p ⬍0.0001) TABLE 1 Baseline Clinical Characteristics
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TABLE 3 Degree of Inhibition of Platelet Aggregation (IPA) at Baseline and After Tirofiban Bolus
Baseline IPA (%) After IPA bolus (%) Patients with ⬎80% IPA
All Patients (n ⫽ 102)
Group I (n ⫽ 61)
Group II (n ⫽ 41)
p Value
14 ⫾ 17 63 ⫾ 25 33 (32%)
17 ⫾ 19 72 ⫾ 20 27 (44%)
11 ⫾ 13 49 ⫾ 25 6 (15%)
0.15 ⬍0.0001 0.0017
Data are expressed as mean ⫾ SD.
extent of variability in the degree of IPA after the tirofiban bolus in each group is shown in Figure 2. In multivariate regression analysis, only Braunwald class II or III unstable angina was independently associated with ⱕ80% IPA (odds ratio 5.64, 95% confidence interval 1.12 to 28.4, p ⫽ 0.036, Figure 3). •••
Our study demonstrates that when using 20-M ADP as a platelet agonist, the current tirofiban bolus dose results in suboptimal IPA in all patients undergoing coronary intervention. Second, patients with Braunwald class II and III unstable angina in particular achieve a significantly lower IPA compared with patients who have stable angina or Braunwald class I unstable angina. Third, there is significant interpatient variability in the degree of IPA after the tirofiban bolus in patients undergoing coronary intervention. Only 15% of the patients with Braunwald class II or III unstable angina achieved ⬎80% IPA. This finding may reflect the higher degree of platelet activation FIGURE 2. Distribution and extent of variability in the degree of IPA following tirofiban bolus between the 2 groups (group I: staand aggregation in these patients, thus suggesting that ble angina and Braunwald class I unstable angina; group II: a higher bolus dose might be indicated. In multivariate Braunwald class II or III unstable angina). analysis, Braunwald class II or III unstable angina was the only predictor of ⱕ80% IPA after the tirofiban bolus. The mean inhibition of ADP-mediated platelet aggregation in the entire cohort was 63 ⫾ 25%. Only 32% of all patients and 44% of patients with stable angina achieved ⬎80% IPA. This further emphasizes that the current bolus dose may not be sufficient even in patients with stable angina. It may also indicate a need for a standardized point-of-care platelet function assay, which contains 20-M ADP, when monitoring IPA after administration of glycoprotein IIb/IIIa inhibitors. The wide range of variability in response to the tirofiban bolus that we found may suggest a role for monitoring IPA in the catheterization laboratory to assure opFIGURE 3. Multivariate analysis of predictors associated with suboptimal timal IPA at the time of balloon inflation and IPA (<80%). MI ⴝ myocardial infarction; NTG ⴝ nitroglycerin; UA ⴝ unstable angina. stent implantation. It may also help identify patients with a high degree of platelet activation and aggregation and may help risk stratand to have received intravenous heparin (93% vs ify them based upon their response to glycoprotein 18%, p ⬍0.0001),  blockers (88% vs 66%, p ⫽ IIb/IIIa inhibitors. This is analogous to monitoring 0.012), and nitrates (76% vs 44%, p ⫽ 0.0017). The 2 activated clotting time after a heparin bolus because groups were similar in other respects. The mean per- many factors are involved in the individual response cent IPA at baseline for all patients was 14 ⫾ 17% and to these agents. was similar between the 2 groups (17 ⫾ 19% vs 11 ⫾ Early studies have shown that ⬎80% IPA in LTA 13%, p ⫽ 0.15 in groups 1 and 2, respectively). using 20 M of ADP as the platelet agonist is required Following tirofiban bolus, however, group II patients to prevent thrombus formation and reduce the incihad significantly lower IPA than group I patients (72 dence of ischemic complications after percutaneous ⫾ 20% vs 49 ⫾ 25%, p ⬍0.0001; Figure 1). The mean coronary intervention.7,8 The dose of tirofiban used in IPA following tirofiban bolus for all patients was 63 ⫾ 2 large percutaneous coronary intervention trials2,3 25%. Only 32% of the entire cohort achieved IPA of was based on a small pharmacodynamic study that ⬎80% (44% in group I vs only 15% of patients in used LTA with 5 M of ADP as a platelet agonist and group II; p ⫽ 0.0017) (Table 3). The distribution and higher concentration of sodium citrate (3.8%) than 874 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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currently recommended (3.2%).1 This may have resulted in significant overestimation of IPA with tirofiban. In addition, in these 2 studies, there were no measurements of IPA in the time window between 5 minutes and 2 hours after the tirofiban bolus, which is the time window of coronary intervention. We previously measured IPA in patients who received tirofiban, eptifibatide (single bolus), or abciximab during coronary intervention using 3 different point-of-care assays. The following platelet agonists and anticoagulants were utilized: (1) 4-M thrombin receptor agonist peptide (iso-TRAP)/citrate, (2) 4-M iso-TRAP/PPACK, in the Ultegra system (Accumetrics, San Diego, California), and (3) 20-M ADP/ citrate in the Ichor platelet analyzer.9 Although mean IPA was 96 ⫾ 4% using iso-TRAP/citrate, and 88 ⫾ 7% using iso-TRAP/PPACK in the Ultegra system, it was 62.5 ⫾ 23% using 20-M ADP/citrate in the Ichorplatelet analyzer, (p ⬍0.0001 for all comparisons). The greater interpatient variability and the lower IPA, detected by the Ichorsystem with 20-M ADP, may enhance patient stratification based upon response to glycoprotein IIb/IIIa inhibitors. Kereiakes et al10 compared IPA in 30 patients with unstable angina who received abciximab, eptifibatide (single bolus), or tirofiban at the time of coronary intervention. When measured by LTA in response to 20-M ADP, ⬎80% median IPA was achieved only after 18 hours of intravenous tirofiban therapy compared with median levels that were ⬎80% at all time points during infusions of abciximab and eptifibatide. In a recent subgroup analysis from the DoTirofiban and Reo Pro Give Similar Efficacy (TARGET) trial, the difference between abciximab and tirofiban in the incidence of myocardial infarction was seen exclusively in the 3,025 patients who had unstable angina at both 30 days and 6 months (5.8% vs 8.5%, p ⫽ 0.004 and 7.2% vs 9.8%, p ⫽ 0.01, respectively).11 In summary, the current bolus dosing of tirofiban in patients undergoing coronary intervention for unstable angina is suboptimal. Our findings may explain the negative results of recent trials with tirofiban in such patients. Furthermore, there is significant interpatient variability in IPA following tirofiban bolus even among patients with stable angina. These findings raise concerns regarding
treating all patients undergoing coronary intervention with the same dose of glycoprotein IIb/IIIa inhibitors, irrespective of their angina class. In addition, our findings suggest a possible role for monitoring platelet aggregation during coronary intervention using 20-M ADP, when administering these agents. Prospective, randomized trials should determine whether a higher tirofiban bolus will improve clinical outcome in these patients. Acknowledgment: We thank Helena Laboratories (Beaumont, Texas) for supplying the Ichor platelet analyzer and platelet function assays.
1. Kereiakes DJ, Kleiman NS, Ambrose J, Cohen M, Rodriguez S, Palabrica T,
Herrmann HC, Sutton JM, Weaver WD, McKee DB, Fitzpatrick V, Sax FL. Randomized, double-blind, placebo-controlled dose ranging study of tirofiban (MK-383) platelet IIb/IIIa blockade in high risk patients undergoing coronary angioplasty. J Am Coll Cardiol 1996;27:536 –542. 2. The RESTORE Investigators. Effect of platelet glycoprotein IIb/IIIa blockade with tirofiban on advers cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997;96: 1445–1453. 3. Topol EJ, Moliterno DJ, Herrmann HC, Powers ER, Grines CL, Cohen DJ, Cohen EA, Bertrand M, Neumann FJ, Stone GW, DiBattiste PM, Demopoulos L. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization, for the TARGET investigators. N Engl J Med 2001;344:1888 –1894. 4. Braunwald E. Unstable angina: a classification. Circulation 1989;80:410 –414. 5. Carville DGM, Schleckser PA, Guyer KE, Corsello M, Walsh MM. Whole blood platelet function assay on the ICHOR™ point-of-care hematology analyzer. J Extracorporeal Technol 1998;30:171–176. 6. Lakkis NM, George S, Thomas E, Ali M, Guyer K, Carville D. Use of ICHOR-platelet works to assess platelet function in patients treated with GPIIb/ IIIa inhibitors. Cathet Cardiovasc Intervent 2001;53:346 –351. 7. Tcheng JE, Ellis SG, George BS, Kereiakes DJ, Kleiman NS, Talley JD, Wang AL, Weisman HF, Califf RM, Topol EJ. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody fab 7E3 in high-risk coronary angioplasty. Circulation 1994;90:1757–1764. 8. Simoons ML, Jan de Boer M, van den Brand MJBM, van Miltenburg AJM, Hoorntje JCA, Heyndrickx GR, van der Wieken LR, De Bono D, Rutsch W, Schaible TF, et al, and the European Cooperative Study Group. Randomized trial of a GPIIb/IIIa platelet receptor blocker in refractory unstable angina. Circulation 1994;89:596 –603. 9. Soffer D, O’Neill WW, Harjai KJ, Dixon SR, Boura JA, Safian RD, Grines CL, Moussa I, Roubin GS, Moses JW. Inter-assay variability in the degree of platelet inhibition following GPIIb/IIIa receptor blockade in patients undergoing coronary intervention: a comparison of three different point-of-care assays (abstr). J Am Coll Cardiol 2002;39(suppl A):72A. 10. Kereiakis DJ, Broderick TM, Roth EM, Whang D, Shimshak T, Runyon JP, Hattemer C, Schneider J, Lacock P, Mueller M, Abbottsmith CW. Time course, magnitude, and consistency of platelet inhibition by abciximab, tirofiban, or eptifibatide in patients with unstable angina pectoris undergoing percutaneous coronary intervention. Am J Cardiol 1999;84:391–395. 11. Stone GW, Moliterno DJ, Bertrand M, Neumann FJ, Hermann HC, Powers ER, Grines CL, Cohen DJ, Cohen EA, Cohen M, Piedmonte M, DiBattiste PM. Impact of clinical syndrome acuity on the differential response to two glycoprotein IIb/IIIa inhibitors in patients undergoing coronary stenting: the TARGET trial. Circulation 2002;105:2347–2354.
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875
Marbe SJ, McCabe CH, Raymond L, Fortin T, Poole K, Brawnwald E, for the TIMI 4 Study Group. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996;93:879 –888. 2. Gibson CM, Cannon CP, Murphy SA, Marble SJ, Baron HV, Brawnwald EB, for the TIMI Study Group. Relationship of the TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention to long-term outcomes after thrombolytic administration in acute myocardial infarction. Circulation 2002;105:1909 –1913. 3. Hamada S, Nishiue T, Nakamura S, Sugiura T, Kamihata H, Miyoshi H, Imuro Y, Iwasaka T. TIMI frame count immediately after primary coronary angioplasty as a predictor of functional recovery in patients with TIMI 3 reperfused acute myocardial infarction. J Am Coll Cardiol 2001;38:666 –671. 4. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, Pinto FJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG. American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2001;37:1478 –1492. 5. Di Mario C, Gorge G, Peters R, Kearney P, Pinto F, Hausmann D, von Birgelen C, Colombo A, Mudra H, Roelandt J, Erbel R. Clinical application and image interpretation in intracoronary ultrasound. Study Group on Intracoronary Imaging of the Working Group of Coronary Circulation and of the Subgroup on Intravascular Ultrasound of the Working Group of Echocardiography of the European Society of Cardiology. Eur Heart J 1998;19:207–229.
6. Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K, Masuyama T, Kitabatake A, Minamino T. Lack of myocardial perfusion immediately after successful thrombolysis: a predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 1992;85:1699 –1705. 7. Maes A, Van de Werf F, Nuyts J, Bormans G, Desmet W, Mortelmans L. Impaired myocardial tissue perfusion early after successful thrombolysis. Impact on myocardial flow, metabolism, and function at late follow up. Circulation 1995;92:2072–2078. 8. Wu KC, Zerhouni EA, Judd RM, Lugo-Olivieri CH, Barouch LA, Schulman SP, Blumenthal RS, Lima JA. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation 1998;97:765–772. 9. Wakatsuki T, Nakamura M, Tsunoda T, Toma H, Degawa T, Oki T, Yamaguchi T. Coronary flow velocity immediately after primary coronary stenting as a predictor of ventricular wall motion recovery in acute myocardial infarction. J Am Coll Cardiol 2000;35:1835–1841. 10. Baim DS, Wahr D, George B, Leon MB, Greenberg J, Cutlip DE, Kaya U, Popma JJ, Ho KKL, Kuntz RE, on behalf of the Saphenous vein graft Angioplasty Free of Emboli Ramdomized (SAFER) Trial Investigators. Randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein aorto-coronary bypass grafts. Circulation 2002;105:1285–1290. 11. Grube E, Gerckens U, Yeung AC, Rowold S, Kirchhof N, Sedgewick J, Yadav JS, Stertzer S. Prevention of distal embolization during coronary angioplasty in saphenous vein grafts and native vessels using porous filter protection. Circulation 2001;104:2436 –2441. 12. Mintz GS, Pichard AD, Kent KM, Satler LF, Popma JJ, Leon MB. Axial plaque redistribution as a mechanism of percutaneous transluminal coronary angioplasty. Am J Cardiol 1996;77:427–430. 13. Potkin BN, Keren G, Mintz GS, Douek PC, Pichard AD, Satler LF, Kent KM, Leon MB. Arterial responses to balloon coronary angioplasty. An intravascular ultrasound study. J Am Coll Cardiol 1992;20:942–951. 14. Fitzgerald PJ, Ports TA, Yock PG. Contribution of localized calcium deposits to dissection after angioplasty. An observational study using intravascular ultrasound. Circulation 1992;86:64 –70. 15. Ahmed JM, Mintz GS, Weissman NJ, Lansky AJ, Pichard AD, Satler LF, Kent KM. Mechanism of lumen enlargement during intracoronary stent implantation: an intravascular ultrasound study. Circulation 2000;102:7–10.
Suboptimal Inhibition of Platelet Aggregation Following Tirofiban Bolus in Patients Undergoing Percutaneous Coronary Intervention for Unstable Angina Pectoris Daniel Soffer, MD, Issam Moussa, MD, Murat Karatepe, MD, Kishore J. Harjai, MD, Judith Boura, MS, Simon R. Dixon, MBChB, Cindy L. Grines, MD, William W. O’Neill, MD, Gary S. Roubin, MD, and Jeffrey W. Moses, MD he current dosing regimen for tirofiban during percutaneous coronary intervention is based on a T dose-ranging study that measured inhibition of platelet
aggregation (IPA) with 5-M adenosine diphosphate (ADP) as a platelet agonist.1 Based on this dosing regimen, a large randomized, double-blind, placebocontrolled trial of tirofiban, in high-risk patients with unstable angina who underwent coronary angioplasty, failed to demonstrate a significant reduction in ischemic complications at 30 days.2 In a recent, prospective head-to-head comparison of tirofiban and abciximab in patients scheduled for coronary stenting, tiroFrom the Division of Cardiology, William Beaumont Hospital, Royal Oak, Michigan; and the Lenox Hill Heart and Vascular Institute of New York, New York, New York. Dr. Soffer’s address is: Division of Cardiology, William Beaumont Hospital, 3601 W. 13 Mile Rd, Royal Oak, Michigan 48073. E-mail: [email protected]. Manuscript received July 31, 2002; revised manuscript received and accepted December 4, 2002.
872
©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 April 1, 2003
fiban offered less protection from major ischemic events at 30 days than did abciximab.3 This study examines whether the current tirofiban bolus results in optimal IPA in patients undergoing coronary intervention, using 20-M ADP as a platelet agonist. Further, we explored the extent of variability and the impact of angina class on IPA after administration of tirofiban. •••
From March to September 1999, we measured IPA in 128 consecutive patients who underwent elective or urgent coronary intervention and received glycoprotein IIb/IIIa inhibitors. Seventeen patients who received abciximab and 9 patients who received eptifibitide were excluded from analysis. Thus, a total of 102 patients who received tirofiban (10 g/kg bolus followed by 0.15 g/kg/min infusion for 12 hours) were included in this analysis. All patients received aspirin 325 mg and were pretreated with clopidogrel before the procedure. Platelet aggregation studies were performed before and 15 min0002-9149/03/$–see front matter doi:10.1016/S0002-9149(03)00024-9
etry (LTA), the Ichor platelet analyzer, using 20-M ADP, has demGroup I Group II onstrated excellent correlation (r 2 ⫽ Variable (n ⫽ 61) (n ⫽ 41) p Value 0.81, p ⫽ 0.0001), and is currently approved by the Food and Drug AdAge (yrs) 62 ⫾ 10 62 ⫾ 9 0.87 Men 46 (75%) 34 (83%) 0.37 ministration for quantitative platelet Diabetes mellitus 23 (38%) 10 (24%) 0.21 aggregometry.5 As previously deCurrent smoker 11 (18%) 10 (24%) 0.72 scribed,5,6 platelet count is perSystemic hypertension (⬎160/90 mm Hg) 42 (69%) 26 (63%) 0.57 formed in a sample that passes Total cholesterol (serum)⬎240 mg/dl 44 (72%) 23 (56%) 0.10 Prior myocardial infarction 19 (31%) 16 (39%) 0.41 through an aperture, thereby interPrior coronary bypass 10 (16%) 8 (20%) 0.69 rupting a constant electrical current. Recent myocardial infarction (ⱕ5 d) 0 (0%) 14 (34%) ⬍0.0001 This results in an electrical pulse that Angiotensin-converting enzyme inhibitors 16 (26%) 11 (27%) 0.95 is amplified and sorted to provide the Antilipid drug(s) 36 (59%) 21 (51%) 0.44 final platelet count in platelets ⫻  blocker 40 (66%) 36 (88%) 0.012 Calcium antagonists 37 (61%) 31 (76%) 0.12 1,000/mm3. In the presence of ADP, Nitrates 27 (44%) 31 (76%) 0.002 platelets aggregate and therefore they exceed the threshold limitations for platelet size and are no longer counted as platelets. TABLE 2 Preprocedural Antiplatelet and Antithrombotic Therapy Baseline platelet function assay Group I Group II was performed before administration Medication (n ⫽ 61) (n ⫽ 41) p Value of tirofiban. An initial platelet count Aspirin 60 (98%) 40 (98%) 1.0 was obtained using ethylenediamiIV heparin 11 (18%) 38 (93%) ⬍0.0001 netetraacetic acid (control tube), and Clopidogrel loading dose (mg) 58 (95%) 41 (100%) 0.27 a second platelet count was taken 450 26 (43%) 19 (46%) 0.71 from the same blood sample, using 150 24 (39%) 20 (49%) 0.35 Mean loading dose (mg) 316 ⫾ 151 296 ⫾ 152 0.54 20-M ADP and 3.2% of sodium Clopidogrel therapy (ⱖ5 d) 11 (18%) 2 (5%) 0.051 citrate as an agonist and anticoaguDuration maintenance therapy (d) 11.5 ⫾ 8.4 5.5 ⫾ 0.7 0.04 lant, respectively (1 ml in each tube). The differential platelet count between the control tube and the ADPcontaining tube represents the functional (aggregable) platelets in the blood sample. Percent platelet inhibition was calculated by dividing the platelet count following stimulation with ADP by the control platelet count ⫻ 100. An additional platelet function assay was performed 15 minutes after the tirofiban bolus. We defined optimal IPA as ⬎80% based on early studies that showed that ⬎80% IPA using LTA and 20 M ADP as platelet agonist is required to reduce thrombus formation and ischemic complications during coronary interventions.7,8 Quality control using normal and low quantitative solutions was performed on a daily basis. FIGURE 1. Percent IPA (mean ⴞ SD) at baseline and after the Categorical variables are presented as counts and tirofiban bolus between the 2 groups (group I: stable angina and percentages. Continuous variables are shown as the Braunwald class I unstable angina; group II: Braunwald class II means ⫾ SD. Differences in categorical variables or III unstable angina). p ⴝ 0.001 for the differences between between patient groups were examined using a chibaseline and after the bolus within each group. square test or Fisher’s 2-tailed exact test. Differences utes after the tirofiban bolus. Patients were classified into in continuous variables between groups were exam2 groups according to their Braunwald unstable angina ined using a Wilcoxon rank test. To determine the classification4: group I included 61 patients with stable independent association of angina class with optimal angina or Braunwald class I unstable angina pectoris, IPA, a logistic regression (stepdown) analysis was and group II included 41 patients with Braunwald class performed using IPA as a dichotomous outcome II or III unstable angina. Written, informed consent was (ⱕ80% vs ⬎80%). Variables that showed a significant or borderline (p ⬍0.10) association with angina class obtained from each patient before the procedure. Inhibition of ADP-mediated platelet aggregation were included in this model. Baseline characteristics of patients are listed in was measured with the Ichor point-of-care platelet analyzer (Helena Laboratories, Beaumont, Texas), us- Tables 1 and 2. Patients with Braunwald class II and ing 20-M ADP. In direct comparable studies with III unstable angina were more likely to have had a traditional platelet-rich light transmission aggregom- recent myocardial infarction (34% vs 0%, p ⬍0.0001) TABLE 1 Baseline Clinical Characteristics
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TABLE 3 Degree of Inhibition of Platelet Aggregation (IPA) at Baseline and After Tirofiban Bolus
Baseline IPA (%) After IPA bolus (%) Patients with ⬎80% IPA
All Patients (n ⫽ 102)
Group I (n ⫽ 61)
Group II (n ⫽ 41)
p Value
14 ⫾ 17 63 ⫾ 25 33 (32%)
17 ⫾ 19 72 ⫾ 20 27 (44%)
11 ⫾ 13 49 ⫾ 25 6 (15%)
0.15 ⬍0.0001 0.0017
Data are expressed as mean ⫾ SD.
extent of variability in the degree of IPA after the tirofiban bolus in each group is shown in Figure 2. In multivariate regression analysis, only Braunwald class II or III unstable angina was independently associated with ⱕ80% IPA (odds ratio 5.64, 95% confidence interval 1.12 to 28.4, p ⫽ 0.036, Figure 3). •••
Our study demonstrates that when using 20-M ADP as a platelet agonist, the current tirofiban bolus dose results in suboptimal IPA in all patients undergoing coronary intervention. Second, patients with Braunwald class II and III unstable angina in particular achieve a significantly lower IPA compared with patients who have stable angina or Braunwald class I unstable angina. Third, there is significant interpatient variability in the degree of IPA after the tirofiban bolus in patients undergoing coronary intervention. Only 15% of the patients with Braunwald class II or III unstable angina achieved ⬎80% IPA. This finding may reflect the higher degree of platelet activation FIGURE 2. Distribution and extent of variability in the degree of IPA following tirofiban bolus between the 2 groups (group I: staand aggregation in these patients, thus suggesting that ble angina and Braunwald class I unstable angina; group II: a higher bolus dose might be indicated. In multivariate Braunwald class II or III unstable angina). analysis, Braunwald class II or III unstable angina was the only predictor of ⱕ80% IPA after the tirofiban bolus. The mean inhibition of ADP-mediated platelet aggregation in the entire cohort was 63 ⫾ 25%. Only 32% of all patients and 44% of patients with stable angina achieved ⬎80% IPA. This further emphasizes that the current bolus dose may not be sufficient even in patients with stable angina. It may also indicate a need for a standardized point-of-care platelet function assay, which contains 20-M ADP, when monitoring IPA after administration of glycoprotein IIb/IIIa inhibitors. The wide range of variability in response to the tirofiban bolus that we found may suggest a role for monitoring IPA in the catheterization laboratory to assure opFIGURE 3. Multivariate analysis of predictors associated with suboptimal timal IPA at the time of balloon inflation and IPA (<80%). MI ⴝ myocardial infarction; NTG ⴝ nitroglycerin; UA ⴝ unstable angina. stent implantation. It may also help identify patients with a high degree of platelet activation and aggregation and may help risk stratand to have received intravenous heparin (93% vs ify them based upon their response to glycoprotein 18%, p ⬍0.0001),  blockers (88% vs 66%, p ⫽ IIb/IIIa inhibitors. This is analogous to monitoring 0.012), and nitrates (76% vs 44%, p ⫽ 0.0017). The 2 activated clotting time after a heparin bolus because groups were similar in other respects. The mean per- many factors are involved in the individual response cent IPA at baseline for all patients was 14 ⫾ 17% and to these agents. was similar between the 2 groups (17 ⫾ 19% vs 11 ⫾ Early studies have shown that ⬎80% IPA in LTA 13%, p ⫽ 0.15 in groups 1 and 2, respectively). using 20 M of ADP as the platelet agonist is required Following tirofiban bolus, however, group II patients to prevent thrombus formation and reduce the incihad significantly lower IPA than group I patients (72 dence of ischemic complications after percutaneous ⫾ 20% vs 49 ⫾ 25%, p ⬍0.0001; Figure 1). The mean coronary intervention.7,8 The dose of tirofiban used in IPA following tirofiban bolus for all patients was 63 ⫾ 2 large percutaneous coronary intervention trials2,3 25%. Only 32% of the entire cohort achieved IPA of was based on a small pharmacodynamic study that ⬎80% (44% in group I vs only 15% of patients in used LTA with 5 M of ADP as a platelet agonist and group II; p ⫽ 0.0017) (Table 3). The distribution and higher concentration of sodium citrate (3.8%) than 874 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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currently recommended (3.2%).1 This may have resulted in significant overestimation of IPA with tirofiban. In addition, in these 2 studies, there were no measurements of IPA in the time window between 5 minutes and 2 hours after the tirofiban bolus, which is the time window of coronary intervention. We previously measured IPA in patients who received tirofiban, eptifibatide (single bolus), or abciximab during coronary intervention using 3 different point-of-care assays. The following platelet agonists and anticoagulants were utilized: (1) 4-M thrombin receptor agonist peptide (iso-TRAP)/citrate, (2) 4-M iso-TRAP/PPACK, in the Ultegra system (Accumetrics, San Diego, California), and (3) 20-M ADP/ citrate in the Ichor platelet analyzer.9 Although mean IPA was 96 ⫾ 4% using iso-TRAP/citrate, and 88 ⫾ 7% using iso-TRAP/PPACK in the Ultegra system, it was 62.5 ⫾ 23% using 20-M ADP/citrate in the Ichorplatelet analyzer, (p ⬍0.0001 for all comparisons). The greater interpatient variability and the lower IPA, detected by the Ichorsystem with 20-M ADP, may enhance patient stratification based upon response to glycoprotein IIb/IIIa inhibitors. Kereiakes et al10 compared IPA in 30 patients with unstable angina who received abciximab, eptifibatide (single bolus), or tirofiban at the time of coronary intervention. When measured by LTA in response to 20-M ADP, ⬎80% median IPA was achieved only after 18 hours of intravenous tirofiban therapy compared with median levels that were ⬎80% at all time points during infusions of abciximab and eptifibatide. In a recent subgroup analysis from the DoTirofiban and Reo Pro Give Similar Efficacy (TARGET) trial, the difference between abciximab and tirofiban in the incidence of myocardial infarction was seen exclusively in the 3,025 patients who had unstable angina at both 30 days and 6 months (5.8% vs 8.5%, p ⫽ 0.004 and 7.2% vs 9.8%, p ⫽ 0.01, respectively).11 In summary, the current bolus dosing of tirofiban in patients undergoing coronary intervention for unstable angina is suboptimal. Our findings may explain the negative results of recent trials with tirofiban in such patients. Furthermore, there is significant interpatient variability in IPA following tirofiban bolus even among patients with stable angina. These findings raise concerns regarding
treating all patients undergoing coronary intervention with the same dose of glycoprotein IIb/IIIa inhibitors, irrespective of their angina class. In addition, our findings suggest a possible role for monitoring platelet aggregation during coronary intervention using 20-M ADP, when administering these agents. Prospective, randomized trials should determine whether a higher tirofiban bolus will improve clinical outcome in these patients. Acknowledgment: We thank Helena Laboratories (Beaumont, Texas) for supplying the Ichor platelet analyzer and platelet function assays.
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