- Email: [email protected]
Association of eptifibatide and acute profound thrombocytopenia
pseudoaneurysms, may have been overlooked. The major limitations of this study were the small sample size and lack of randomization of beta WRIST patients. Coronary radiation therapy using 90Y and 192Ir for ISR demonstrated significant reductions in rates of clinical restenosis, with an acceptable safety profile at 2 years and with beta emitters as effective as gamma emitters. Radiation therapy remains the principal therapeutic strategy for instent restenosis. 1. Casterella PJ, Teirstein PS. Prevention of coronary restenosis. Cardiol Rev
1999;7:219 –231. 2. Hoffmann R, Mintz GS, Dussaillant GR, Popma JJ, Pichard AD, Satler LF,
Kent KM, Griffin J, Leon MB. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation 1996;94:1247–1254. 3. Reimers B, Moussa I, Akiyama T, Tucci G, Ferraro M, Martini G, Blengino S, Di Mario C, Colombo A. Long-term clinical follow-up after successful repeat percutaneous intervention for stent restenosis. J Am Coll Cardiol 1997;30:186 – 192. 4. Mehran R, Mintz GS, Satler LF, Pichard AD, Kent KM, Bucher TA, Popma JJ, Leon MB. Treatment of in-stent restenosis with excimer laser coronary angioplasty: mechanisms and results compared with PTCA alone. Circulation 1997;96:2183–2189. 5. Baim DS, Levine MJ, Leon MB, Levine S, Ellis SG, Schatz RA. Management of restenosis within the Palmaz-Schatz coronary stent (the U.S. multicenter experience). The U.S. Palmaz-Schatz Stent Investigators. Am J Cardiol 1993;71: 364 –366. 6. Gordon PC, Gibson CM, Cohen DJ, Carrozza JP, Kuntz RE, Baim DS. Mechanisms of restenosis and redilation within coronary stents-quantitative angiographic assessment. J Am Coll Cardiol 1993;21:1166 –1174.
7. Wiedermann JG, Marboe C, Amols H, Schwartz A, Weinberger J. Intracoro-
nary irradiation markedly reduces restenosis after balloon angioplasty in a porcine model. J Am Coll Cardiol 1994;23:1491–1498. 8. Waksman R, Robinson KA, Crocker IR, Gravanis MB, Cipolla GD, King SB III. Endovascular low-dose irradiation inhibits neointima formation after coronary artery balloon injury in swine. A possible role for radiation therapy in restenosis prevention. Circulation 1995;91:1533–1539. 9. Waksman R, Robinson KA, Crocker IR, Wang C, Gravanis MB, Cipolla GD, Hillstead RA, King SB III. Intracoronary low-dose -irradiation inhibits neointima formation after coronary artery balloon injury in the swine restenosis model. Circulation 1995;92:3025–3031. 10. Waksman R, Bhargava B, White L, Chan RC, Mehran R, Lansky AJ, Mintz GS, Satler LF, Pichard AD, Leon MB, Kent KM. Intracoronary -radiation therapy inhibits recurrence of in-stent restenosis. Circulation 2000;101:1895– 1898. 11. Teirstein PS, Massullo V, Jani S, Popma JJ, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Sirkin K, Cloutier DA, Leon MB, Tripuraneni P. Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation 2000;101:360 –365. 12. Waksman R, White RL, Chan RC, Bass BG, Geirlach L, Mintz GS, Satler LF, Mehran R, Serruys PW, Lansky AJ, Fitzgerald P, Bhargava B, Kent KM, Pichard AD, Leon MB. Intracoronary ␥-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165–2171. 13. Teirstein PS, Massullo V, Jani S, Popma JJ, Mintz GS, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Morris NB, Leon MB, Tripuraneni P. Catheterbased radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997;336:1697–703. 14. Liermann DD, Boettcher HD, Kollatch J, Schopol B, Strassman G, Strecker EP, Breddin KH. Prophlactic endovascular radiotherapy to prevent intimal hyperplasia after stent implantation in femoro-popliteal arteries. Cardiovasc Intervent Radiol 1994;17:12–16. 15. Waksman R, Bhargava B, Mintz GS, Mehran R, Lansky AJ, Satler LF, Pichard AD, Kent KM, Leon MB. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol 2000;36: 65– 68. 16. Waksman R, Bhargava B, Leon MB. Late thrombosis following intracoronary brachytherapy. Cathet Cardiovasc Interven 2000;49:344 –347.
Association of Eptifibatide and Acute Profound Thrombocytopenia Richard H. Hongo,
MD,
and Bruce N. Brent,
MD
bciximab use has been well associated with the development of thrombocytopenia at rates beA tween 2.5% and 5.6%, and with the potentially
single- to double-bolus eptifibatide use, we sought to evaluate the effect of bolus number on platelet counts.
life-threatening occurrence of acute profound thrombocytopenia5,6 at rates between 0.3% and 0.8%.1,2,5,6 Consequently, the monitoring of platelet counts with abciximab use has become routine. In contrast, eptifibatide has not been strongly associated with thrombocytopenia7 or acute profound thrombocytopenia,8 –10 and the role of routine platelet monitoring with its use remains unclear. In this study, we evaluated platelet counts in patients receiving eptifibatide during percutaneous coronary intervention, and sought to determine the effect of eptifibatide on platelet counts and on the incidence of thrombocytopenia and acute profound thrombocytopenia. In addition, because the study period spanned the transition from
We assessed 412 consecutive patients who received eptifibatide during percutaneous coronary intervention between September 1, 1999, and August 31, 2000. Patients were pretreated with aspirin and a 300-mg clopidogrel loading dose. After vascular access was established, a heparin bolus of 100 U/kg8 was given to patients receiving single-bolus, and 60 U/kg10 to those receiving double-bolus eptifibatide. Double-bolus dosing supplanted single-bolus dosing midway through the study (Figure 1) prompted by the results of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial.10 The bolus number was determined by the interventionalist, and the bolus (180 g/kg) was followed by a 16- to 20-hour infusion (2.0 g/kg/min). The pharmacy logged all cases of eptifibatide, recording bolus number, infusion dose, and indication. After platelet counts were collected from the institution’s computerized information system, the identities of the patients were hidden to ensure patient privacy. Three patients who received an adjusted eptifibatide
1– 4
From the Division of Cardiology, California Pacific Medical Center, San Francisco, California. Dr. Brent’s address is: Division of Cardiology, California Pacific Medical Center, 2333 Buchanan Street, San Francisco, California 94120. E-mail: [email protected]. Manuscript received February 1, 2001; revised manuscript received and accepted March 27, 2001.
428
©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 88 August 15, 2001
•••
0002-9149/01/$–see front matter PII S0002-9149(01)01695-2
TABLE 1 Platelet Counts and Thrombocytopenia in Singleand Double-Bolus Groups
Mean platelet counts (⫻ 109/L) Baseline Nadir Decrease Events (n) (%) Thrombocytopenia㛳 Acute profound thrombocytopenia¶
FIGURE 1. Eptifibatide use during percutaneous coronary intervention by month. Checkered columns, single bolus; white columns, double bolus.
dose for renal insufficiency, 2 patients with preexisting thrombocytopenia, and 5 patients without follow-up platelet counts were excluded from analysis. The study was approved by the institutional review board. The baseline and nadir platelet counts were defined as the most recent count within a week of eptifibatide use, and the lowest in-hospital follow-up count, respectively. Thrombocytopenia was defined as a nadir platelet count ⬍100 ⫻ 109/L. Acute profound thrombocytopenia was defined as a nadir platelet count ⬍20 ⫻ 109/L within 24 hours of eptifibatide bolus. The incidence of thrombocytopenia and acute profound thrombocytopenia were determined in cases with available nadir platelet counts (n ⫽ 402). The change in platelet count with eptifibatide use was determined in cases with baseline and nadir platelet counts (n ⫽ 347). Cases were grouped into those patients who received single- (n ⫽ 201) versus double-bolus (n ⫽ 201) eptifibatide. The platelet count change within each group and the mean platelet count change between the 2 groups were analyzed using unpaired and paired t tests, respectively. The incidence of thrombocytopenia in the 2 groups was assessed with chi-square analysis. A p value of ⬍0.05 was considered significant. Cases of acute profound thrombocytopenia were evaluated for platelet count trend, treatment strategy, and underlying etiology. Pseudothrombocytopenia11–13 was excluded by multiple blood smears. In 3 cases, heparin-induced platelet antibodies were assessed by aggregometry and platelet factor 4-heparin complex enzyme-linked immunosorbent assay methods.14,15 In 1 of the 3 cases, 14C-serotonin release assay was also performed. All tests were negative for heparin-induced antibodies, effectively excluding type II heparin-induced thrombocytopenia. Other possible causes for acute profound thrombocytopenia, including infection and other drugs, were absent. Thrombocytopenia occurred in 15 of 402 cases (3.7%). Profound thrombocytopenia occurred in 4 of 402 cases (1.0%). The differences between baseline and nadir platelet counts within the single- and dou-
Single Bolus
Double Bolus
(n ⫽ 161)†
(n ⫽ 186)†
212 ⫾ 53 182 ⫾ 52‡ 30 ⫾ 34 (n ⫽ 201) 5 (2.5%) 2 (1.0%)
211 ⫾ 62 177 ⫾ 55§ 34 ⫾ 35 (n ⫽ 201) 10 (5.0%) 2 (1.0%)
p Value*
0.21 0.29
*p ⬍0.05 was considered significant as assessed by t tests and chi-square analysis as appropriate. † Patients with both baseline and nadir platelet counts available. ‡ p ⬍0.0001 versus baseline (unpaired t test); §p ⬍0.0001 versus baseline (unpaired t test). 㛳 Defined as ⬍100 ⫻ 109/L; ¶defined as ⬍20 ⫻ 109/L within 24 hours of eptifibatide bolus.
FIGURE 2. Platelet count trends in cases with nonprofound thrombocytopenia (nadir platelet count <100 ⴛ 109/L and >20 ⴛ 109/L).
ble-bolus groups were significant (212 ⫾ 53 ⫻ 109/L vs 182 ⫾ 52 ⫻ 109/L, p ⫽ ⬍0.0001; 211 ⫾ 62 ⫻ 109/L vs 177 ⫾ 55 ⫻ 109/L, p ⫽ ⬍0.0001, respectively). There was no difference in the incidence of thrombocytopenia (2.5% vs 5.0%, p ⫽ 0.29), profound thrombocytopenia (1.0% vs 1.0%), or a decrease in mean platelet count (30 ⫾ 34 ⫻ 109/L vs 34 ⫾ 35 ⫻ 109/L, p ⫽ 0.21) between the single- and double-bolus groups (Table 1). The platelet count trends of those with nonprofound thrombocytopenia demonstrated a heterogenous group (Figure 2). The clinical information on the 4 cases of acute profound thrombocytopenia is listed in Table 2. Three cases had prior platelet glycoprotein IIb/IIIa inhibitor exposure, 2 to abciximab and 1 to eptifibatide. The platelet count trends in these 4 cases are illustrated in Figure 3. Profound thrombocytopenia occurred precipitously in 3 cases, within 3 hours of eptifibatide bolus. In case 2 the first platelet count was drawn 10 hours after bolus, at which time the platelet count had decrease to a near-profound level; time to nadir platelet count was 18 hours. In all cases, eptifiBRIEF REPORTS
429
than that seen in either the PURSUIT (0.1%) or ESPRIT (0.2%) trials,9,10 Nadir and may have been due to smaller Previous Baseline Platelet study size. This study did include Age (yrs)/ Bolus GP IIb/IIIa Creatinine Count patients who underwent urgent per9 Case Sex Presentation Number Inhibitor (mg/dl) (⫻ 10 /L) cutaneous coronary intervention, 1 86F Unstable angina 1 Abciximab 0.8 6 whereas the ESPRIT study10 did not, 2 68M Unstable angina 1 Abciximab 0.9 19 and 3 of the 4 cases of acute pro3 74M Silent ischemia 2 Eptifibatide 1.1 9 found thrombocytopenia occurred 4 62M Unstable angina 2 0 1.6 9 with nonelective percutaneous interAll cases underwent coronary stent implantation. vention in the setting of unstable anGP ⫽ glycoprotein. gina. Higher rates of acute profound thrombocytopenia have been reported with readministration of abciximab, which is believed to be related to a 6% to 7% human antichimeric antibody response seen with initial abciximab use.16 There is no evidence, however, of an immunogenic response with eptifibatide use or of cross-reactivity between abciximab and eptifibatide. Currently, there is no mechanistic reason that supports that prior exposure to glycoprotein IIb/IIIa inhibitors affects the incidence of eptifibatide-associated acute profound thrombocytopenia. Nevertheless, in this study, 3 cases of acute profound thrombocytopenia had prior exposure to glycoprotein IIb/IIIa inhibitors. The onset of profound thrombocytopenia was particularly rapid in 3 cases, with nadir platelet counts FIGURE 3. Platelet count trends in cases with acute profound within 3 hours of eptifibatide bolus, underscoring the thrombocytopenia (nadir platelet count <20 ⴛ109/L within 24 need for early platelet monitoring. Also notable was hours of eptifibatide bolus). the persistence of profound thrombocytopenia in cases 1 and 3, despite discontinuation of eptifibatide. Genbatide and other antithrombotic and antiplatelet agents erally, the effects of eptifibatide are readily reversible were promptly discontinued on recognition of pro- with a plasma half-life between 1 and 2.5 hours16,17; bleeding times return to baseline within 1 hour of found thrombocytopenia. Platelet monitoring strategies differed among the discontinuing eptifibatide,18 and significant recovery cases. In case 2, the first repeat platelet count was 8 of platelet aggregation is seen within 4 hours of terhours after discontinuation of eptifibatide with count minating infusion.18,19 Because the kidneys primarily improvement at this time. In the other 3 cases, platelet clear eptifibatide, renal function should play a major counts were initially drawn every 1 to 3 hours. In case role in platelet recovery in eptifibatide-associated 4, count improvement was seen at 90 minutes. In cases acute profound thrombocytopenia. Although the base1 and 3, count improvement occurred 8 hours after line creatinine was normal in both cases 1 and 3, renal discontinuation of eptifibatide. The only bleeding function was decreased by virtue of advanced age. Platelets were transfused in case 3 because of percomplication occurred in case 3 as epistaxis and pesistent profound thrombocytopenia in the setting of techiae, and 2 U of platelets were transfused initially. Three additional units were given over the next 3 clinical bleeding. The benefit of platelet transfusions hours because of persistent platelet counts ⬍20 ⫻ in eptifibatide-associated thrombocytopenia, however, 109/L. In all cases, once initial improvement was seen, may be limited.16 Because eptifibatide competitively platelet counts increased steadily. The time from dis- interacts with the glycoprotein IIb/IIIa receptor, the continuation of eptifibatide to platelet count ⬎100 ⫻ eptifibatide molecules will continue to associate with and disassociate from the platelet receptors of native 109/L was between 3 to 6 days. and transfused platelets until plasma levels are suffi••• In our study, thrombocytopenia and profound ciently low. thrombocytopenia occurred with an incidence of 3.7% In conclusion, despite the absence of an associand 1.0%, respectively. The incidence of thrombocytopenia approximates the 2.8% to 4.9% incidence of ation between eptifibatide and thrombocytopenia thrombocytopenia observed in the Integrilin to Mini- in population studies, we have described 4 cases of mize Platelet Aggregation and Coronary Thrombosis eptifibatide-associated acute profound thrombocy(IMPACT-II) and the Platelet Glycoprotein IIb/IIIa in topenia. Patients receiving eptifibatide during perUnstable Angina: Receptor Suppression Using Inte- cutaneous coronary intervention should have grilin Therapy (PURSUIT) trials.8,9 The incidence of platelet counts checked early, and if profound profound thrombocytopenia in this study was higher thrombocytopenia develops, eptifibatide discontinTABLE 2 Clinical Information in Cases With Acute Profound Thrombocytopenia
430 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 88
AUGUST 15, 2001
uation should be immediate and platelet monitoring frequent. There is no indication that the number of eptifibatide boluses influences the incidence of thrombocytopenia, the incidence of acute profound thrombocytopenia, or the degree of platelet count fall. Acknowledgment: We thank Gary Louie, PharmD, for help in data collection, and Stuart Dick, MPH, for statistical support. 1. Berkowitz SD, Sane DC, Sigmon KN, Shavender JH, Harrington RA, Tcheng
JE, Topol EJ, Califf RM, for the EPIC Study Group. Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous revascularization. J Am Coll Cardiol 1998;32:311–319. 2. The CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997;349:1429 –1435. 3. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689 –1696. 4. The EPISTENT Investigators. Randomised 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. 5. Kereiakes DJ, Essell JH, Abbottsmith CW, Broderick TM, Runyon JP. Abciximab-associated profound thrombocytopenia: therapy with immunoglobulin and platelet transfusion. Am J Cardiol 1996;78:1161–1163. 6. Berkowitz SD, Harrington RA, Rund MM, Tcheng JE. Acute profound thrombocytopenia after c7E3 Fab (abciximab) therapy. Circulation 1997;95:809 – 813. 7. Giugliano RP, Hyatt RR. Thrombocytopenia with GP IIb/IIIa inhibitors: a meta-analysis (abstr). J Am Coll Cardiol 1998;31(suppl A):185A. 8. The IMPACT-II Investigators. Randomized placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet 1997;349:1422–1428. 9. McClure MW, Berkowitz SD, Sparapani R, Tuttle R, Kleiman NS, Berdan LG,
Lincoff AM, Deckers J, Diaz R, Karsch KR, et al, for the PURSUIT Investigators. Clinical significance of thrombocytopenia during a non-ST-elevation acute coronary syndrome: the platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using Integrilin therapy (PURSUIT) trial experience. Circulation 1999;99:2892–2900. 10. The ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet 2000;356:2037–2044. 11. Christopoulos CG, Machin SJ. A new type of pseudothrombocytopenia: EDTA-mediated agglutination of platelets bearing Fab fragments of a chimaeric antibody. Br J Haematol 1994;87:650 – 652. 12. Sane DC, Damaraju LV, Topol EJ, Cabot CF, Mascelli MA, Harrington RA, Simoons ML, Califf RM. Occurrence and clinical significance of pseudothrombocytopenia during abciximab therapy. J Am Coll Cardiol 2000;36:75– 83. 13. Moll S. Eptifibatide in acute coronary syndromes (lett). N Engl J Med 1999;340:60 – 61. 14. Amiral J, Bridey F, Dreyfus M, Vissac AM, Fressinaud E, Wolf M, Meyer D. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992;68:95–96. 15. Arepally G, Reynolds C, Tomaski A, Amiral J, Jawad A, Poncz M, Cines DB. Comparison of PF4/heparin ELISA assay with the 14C-serotonin release assay in the diagnosis of heparin-induced thrombocytopenia. Am J Clin Pathol 1995;104: 648 – 654. 16. Tcheng JE. Clinical challenges of platelet glycoprotein IIb/IIIa receptor inhibitor therapy: bleeding, reversal, thrombocytopenia, and retreatment. Am Heart J 2000;139(suppl):S38-S45. 17. Charo IF, Scarborough RM, du Me´e CP, Wolf D, Phillips DR, Swift RL. Pharmacodynamics of the GPIIb-IIIa antagonist Integrilin: phase I clinical studies in normal healthy volunteers (abstr). Circulation 1992;86(suppl I):I-260. 18. Harrington RA, Kleiman NS, Kottke-Marchant K, Lincoff AM, Tcheng JE, Sigmon KN, Joseph D, Rios G, Trainor K, Rose D, et al. Immediate and reversible platelet inhibition after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention. Am J Cardiol 1995;76:1222–1227. 19. Tcheng JE, Harrington RA, Kottke-Marchant K, Kleiman NS, Ellis SG, Kereiakes DJ, Mick MJ, Navetta FI, Smith JE, Worley SJ, et al. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker Integrilin in elective coronary intervention. Circulation 1995;91:2151–2157.
Statin Therapy and the Acute Inflammatory Response After Coronary Artery Bypass Grafting David J. Brull, MRCP, Julie Sanders, BSc, Ann Rumley, PhD, Gordon D.O. Lowe, Steve E. Humphries, PhD, and Hugh E. Montgomery, MD reoperative statin therapy improves cardiovascular outcome after coronary artery bypass grafting P (CABG); however, the clinical gain is in excess of the reduction in lipids. We hypothesized that statin therapy exerts an anti-inflammatory effect mediated through reduced interleukin-6 (IL-6) production. Administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (“statins”) is of proved benefit in the prevention of acute coronary events1,2 and reduces mortality after acute myocardial infarction.3 However, such benefits exceed those attributable to From the Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Department of Medicine, Royal Free and University College London Medical School, London, United Kingdom; and Department of Medicine, Glasgow Royal Infirmary, Glasgow, Scotland. Drs. Brull, Rumley, Lowe, Montgomery, and Humphries were supported by the British Heart Foundation, London, United Kingdom. Dr. Brull’s address is: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Department of Medicine, Royal Free and University College London Medical School, Rayne Building, 5 University St., London WC1E 6 J J, United Kingdom. E-mail: [email protected]. Manuscript received January 30, 2001; revised manuscript received and accepted March 13, 2001. ©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 88 August 15, 2001
MD,
associated alterations in lipid profile or coronary luminal diameter.4 – 6 In a recent report, Dotani et al7 demonstrated that preoperative statin administration is also associated with improved outcome after CABG. An anti-inflammatory role for statin therapy might offer one explanation for these observations. Acute inflammatory processes, particularly the local expression of IL-6, are strongly implicated in the genesis of plaque instability and rupture.8 Given that statins suppress plaque inflammation and IL-6 production,9 we postulated that suppression of the systemic inflammatory response might underlie these perioperative benefits. •••
To examine the relations of baseline and postoperative plasma IL-6 to CABG, a prospective cohort study was performed between October 1999 and September 2000 at the Middlesex Hospital, London, United Kingdom. The study had hospital ethics committee approval, and all patients gave written informed consent. The study cohort comprised consecutive patients who underwent elective first-time 0002-9149/01/$–see front matter PII S0002-9149(01)01696-4
431
1999;7:219 –231. 2. Hoffmann R, Mintz GS, Dussaillant GR, Popma JJ, Pichard AD, Satler LF,
Kent KM, Griffin J, Leon MB. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation 1996;94:1247–1254. 3. Reimers B, Moussa I, Akiyama T, Tucci G, Ferraro M, Martini G, Blengino S, Di Mario C, Colombo A. Long-term clinical follow-up after successful repeat percutaneous intervention for stent restenosis. J Am Coll Cardiol 1997;30:186 – 192. 4. Mehran R, Mintz GS, Satler LF, Pichard AD, Kent KM, Bucher TA, Popma JJ, Leon MB. Treatment of in-stent restenosis with excimer laser coronary angioplasty: mechanisms and results compared with PTCA alone. Circulation 1997;96:2183–2189. 5. Baim DS, Levine MJ, Leon MB, Levine S, Ellis SG, Schatz RA. Management of restenosis within the Palmaz-Schatz coronary stent (the U.S. multicenter experience). The U.S. Palmaz-Schatz Stent Investigators. Am J Cardiol 1993;71: 364 –366. 6. Gordon PC, Gibson CM, Cohen DJ, Carrozza JP, Kuntz RE, Baim DS. Mechanisms of restenosis and redilation within coronary stents-quantitative angiographic assessment. J Am Coll Cardiol 1993;21:1166 –1174.
7. Wiedermann JG, Marboe C, Amols H, Schwartz A, Weinberger J. Intracoro-
nary irradiation markedly reduces restenosis after balloon angioplasty in a porcine model. J Am Coll Cardiol 1994;23:1491–1498. 8. Waksman R, Robinson KA, Crocker IR, Gravanis MB, Cipolla GD, King SB III. Endovascular low-dose irradiation inhibits neointima formation after coronary artery balloon injury in swine. A possible role for radiation therapy in restenosis prevention. Circulation 1995;91:1533–1539. 9. Waksman R, Robinson KA, Crocker IR, Wang C, Gravanis MB, Cipolla GD, Hillstead RA, King SB III. Intracoronary low-dose -irradiation inhibits neointima formation after coronary artery balloon injury in the swine restenosis model. Circulation 1995;92:3025–3031. 10. Waksman R, Bhargava B, White L, Chan RC, Mehran R, Lansky AJ, Mintz GS, Satler LF, Pichard AD, Leon MB, Kent KM. Intracoronary -radiation therapy inhibits recurrence of in-stent restenosis. Circulation 2000;101:1895– 1898. 11. Teirstein PS, Massullo V, Jani S, Popma JJ, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Sirkin K, Cloutier DA, Leon MB, Tripuraneni P. Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation 2000;101:360 –365. 12. Waksman R, White RL, Chan RC, Bass BG, Geirlach L, Mintz GS, Satler LF, Mehran R, Serruys PW, Lansky AJ, Fitzgerald P, Bhargava B, Kent KM, Pichard AD, Leon MB. Intracoronary ␥-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165–2171. 13. Teirstein PS, Massullo V, Jani S, Popma JJ, Mintz GS, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Morris NB, Leon MB, Tripuraneni P. Catheterbased radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997;336:1697–703. 14. Liermann DD, Boettcher HD, Kollatch J, Schopol B, Strassman G, Strecker EP, Breddin KH. Prophlactic endovascular radiotherapy to prevent intimal hyperplasia after stent implantation in femoro-popliteal arteries. Cardiovasc Intervent Radiol 1994;17:12–16. 15. Waksman R, Bhargava B, Mintz GS, Mehran R, Lansky AJ, Satler LF, Pichard AD, Kent KM, Leon MB. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol 2000;36: 65– 68. 16. Waksman R, Bhargava B, Leon MB. Late thrombosis following intracoronary brachytherapy. Cathet Cardiovasc Interven 2000;49:344 –347.
Association of Eptifibatide and Acute Profound Thrombocytopenia Richard H. Hongo,
MD,
and Bruce N. Brent,
MD
bciximab use has been well associated with the development of thrombocytopenia at rates beA tween 2.5% and 5.6%, and with the potentially
single- to double-bolus eptifibatide use, we sought to evaluate the effect of bolus number on platelet counts.
life-threatening occurrence of acute profound thrombocytopenia5,6 at rates between 0.3% and 0.8%.1,2,5,6 Consequently, the monitoring of platelet counts with abciximab use has become routine. In contrast, eptifibatide has not been strongly associated with thrombocytopenia7 or acute profound thrombocytopenia,8 –10 and the role of routine platelet monitoring with its use remains unclear. In this study, we evaluated platelet counts in patients receiving eptifibatide during percutaneous coronary intervention, and sought to determine the effect of eptifibatide on platelet counts and on the incidence of thrombocytopenia and acute profound thrombocytopenia. In addition, because the study period spanned the transition from
We assessed 412 consecutive patients who received eptifibatide during percutaneous coronary intervention between September 1, 1999, and August 31, 2000. Patients were pretreated with aspirin and a 300-mg clopidogrel loading dose. After vascular access was established, a heparin bolus of 100 U/kg8 was given to patients receiving single-bolus, and 60 U/kg10 to those receiving double-bolus eptifibatide. Double-bolus dosing supplanted single-bolus dosing midway through the study (Figure 1) prompted by the results of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial.10 The bolus number was determined by the interventionalist, and the bolus (180 g/kg) was followed by a 16- to 20-hour infusion (2.0 g/kg/min). The pharmacy logged all cases of eptifibatide, recording bolus number, infusion dose, and indication. After platelet counts were collected from the institution’s computerized information system, the identities of the patients were hidden to ensure patient privacy. Three patients who received an adjusted eptifibatide
1– 4
From the Division of Cardiology, California Pacific Medical Center, San Francisco, California. Dr. Brent’s address is: Division of Cardiology, California Pacific Medical Center, 2333 Buchanan Street, San Francisco, California 94120. E-mail: [email protected]. Manuscript received February 1, 2001; revised manuscript received and accepted March 27, 2001.
428
©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 88 August 15, 2001
•••
0002-9149/01/$–see front matter PII S0002-9149(01)01695-2
TABLE 1 Platelet Counts and Thrombocytopenia in Singleand Double-Bolus Groups
Mean platelet counts (⫻ 109/L) Baseline Nadir Decrease Events (n) (%) Thrombocytopenia㛳 Acute profound thrombocytopenia¶
FIGURE 1. Eptifibatide use during percutaneous coronary intervention by month. Checkered columns, single bolus; white columns, double bolus.
dose for renal insufficiency, 2 patients with preexisting thrombocytopenia, and 5 patients without follow-up platelet counts were excluded from analysis. The study was approved by the institutional review board. The baseline and nadir platelet counts were defined as the most recent count within a week of eptifibatide use, and the lowest in-hospital follow-up count, respectively. Thrombocytopenia was defined as a nadir platelet count ⬍100 ⫻ 109/L. Acute profound thrombocytopenia was defined as a nadir platelet count ⬍20 ⫻ 109/L within 24 hours of eptifibatide bolus. The incidence of thrombocytopenia and acute profound thrombocytopenia were determined in cases with available nadir platelet counts (n ⫽ 402). The change in platelet count with eptifibatide use was determined in cases with baseline and nadir platelet counts (n ⫽ 347). Cases were grouped into those patients who received single- (n ⫽ 201) versus double-bolus (n ⫽ 201) eptifibatide. The platelet count change within each group and the mean platelet count change between the 2 groups were analyzed using unpaired and paired t tests, respectively. The incidence of thrombocytopenia in the 2 groups was assessed with chi-square analysis. A p value of ⬍0.05 was considered significant. Cases of acute profound thrombocytopenia were evaluated for platelet count trend, treatment strategy, and underlying etiology. Pseudothrombocytopenia11–13 was excluded by multiple blood smears. In 3 cases, heparin-induced platelet antibodies were assessed by aggregometry and platelet factor 4-heparin complex enzyme-linked immunosorbent assay methods.14,15 In 1 of the 3 cases, 14C-serotonin release assay was also performed. All tests were negative for heparin-induced antibodies, effectively excluding type II heparin-induced thrombocytopenia. Other possible causes for acute profound thrombocytopenia, including infection and other drugs, were absent. Thrombocytopenia occurred in 15 of 402 cases (3.7%). Profound thrombocytopenia occurred in 4 of 402 cases (1.0%). The differences between baseline and nadir platelet counts within the single- and dou-
Single Bolus
Double Bolus
(n ⫽ 161)†
(n ⫽ 186)†
212 ⫾ 53 182 ⫾ 52‡ 30 ⫾ 34 (n ⫽ 201) 5 (2.5%) 2 (1.0%)
211 ⫾ 62 177 ⫾ 55§ 34 ⫾ 35 (n ⫽ 201) 10 (5.0%) 2 (1.0%)
p Value*
0.21 0.29
*p ⬍0.05 was considered significant as assessed by t tests and chi-square analysis as appropriate. † Patients with both baseline and nadir platelet counts available. ‡ p ⬍0.0001 versus baseline (unpaired t test); §p ⬍0.0001 versus baseline (unpaired t test). 㛳 Defined as ⬍100 ⫻ 109/L; ¶defined as ⬍20 ⫻ 109/L within 24 hours of eptifibatide bolus.
FIGURE 2. Platelet count trends in cases with nonprofound thrombocytopenia (nadir platelet count <100 ⴛ 109/L and >20 ⴛ 109/L).
ble-bolus groups were significant (212 ⫾ 53 ⫻ 109/L vs 182 ⫾ 52 ⫻ 109/L, p ⫽ ⬍0.0001; 211 ⫾ 62 ⫻ 109/L vs 177 ⫾ 55 ⫻ 109/L, p ⫽ ⬍0.0001, respectively). There was no difference in the incidence of thrombocytopenia (2.5% vs 5.0%, p ⫽ 0.29), profound thrombocytopenia (1.0% vs 1.0%), or a decrease in mean platelet count (30 ⫾ 34 ⫻ 109/L vs 34 ⫾ 35 ⫻ 109/L, p ⫽ 0.21) between the single- and double-bolus groups (Table 1). The platelet count trends of those with nonprofound thrombocytopenia demonstrated a heterogenous group (Figure 2). The clinical information on the 4 cases of acute profound thrombocytopenia is listed in Table 2. Three cases had prior platelet glycoprotein IIb/IIIa inhibitor exposure, 2 to abciximab and 1 to eptifibatide. The platelet count trends in these 4 cases are illustrated in Figure 3. Profound thrombocytopenia occurred precipitously in 3 cases, within 3 hours of eptifibatide bolus. In case 2 the first platelet count was drawn 10 hours after bolus, at which time the platelet count had decrease to a near-profound level; time to nadir platelet count was 18 hours. In all cases, eptifiBRIEF REPORTS
429
than that seen in either the PURSUIT (0.1%) or ESPRIT (0.2%) trials,9,10 Nadir and may have been due to smaller Previous Baseline Platelet study size. This study did include Age (yrs)/ Bolus GP IIb/IIIa Creatinine Count patients who underwent urgent per9 Case Sex Presentation Number Inhibitor (mg/dl) (⫻ 10 /L) cutaneous coronary intervention, 1 86F Unstable angina 1 Abciximab 0.8 6 whereas the ESPRIT study10 did not, 2 68M Unstable angina 1 Abciximab 0.9 19 and 3 of the 4 cases of acute pro3 74M Silent ischemia 2 Eptifibatide 1.1 9 found thrombocytopenia occurred 4 62M Unstable angina 2 0 1.6 9 with nonelective percutaneous interAll cases underwent coronary stent implantation. vention in the setting of unstable anGP ⫽ glycoprotein. gina. Higher rates of acute profound thrombocytopenia have been reported with readministration of abciximab, which is believed to be related to a 6% to 7% human antichimeric antibody response seen with initial abciximab use.16 There is no evidence, however, of an immunogenic response with eptifibatide use or of cross-reactivity between abciximab and eptifibatide. Currently, there is no mechanistic reason that supports that prior exposure to glycoprotein IIb/IIIa inhibitors affects the incidence of eptifibatide-associated acute profound thrombocytopenia. Nevertheless, in this study, 3 cases of acute profound thrombocytopenia had prior exposure to glycoprotein IIb/IIIa inhibitors. The onset of profound thrombocytopenia was particularly rapid in 3 cases, with nadir platelet counts FIGURE 3. Platelet count trends in cases with acute profound within 3 hours of eptifibatide bolus, underscoring the thrombocytopenia (nadir platelet count <20 ⴛ109/L within 24 need for early platelet monitoring. Also notable was hours of eptifibatide bolus). the persistence of profound thrombocytopenia in cases 1 and 3, despite discontinuation of eptifibatide. Genbatide and other antithrombotic and antiplatelet agents erally, the effects of eptifibatide are readily reversible were promptly discontinued on recognition of pro- with a plasma half-life between 1 and 2.5 hours16,17; bleeding times return to baseline within 1 hour of found thrombocytopenia. Platelet monitoring strategies differed among the discontinuing eptifibatide,18 and significant recovery cases. In case 2, the first repeat platelet count was 8 of platelet aggregation is seen within 4 hours of terhours after discontinuation of eptifibatide with count minating infusion.18,19 Because the kidneys primarily improvement at this time. In the other 3 cases, platelet clear eptifibatide, renal function should play a major counts were initially drawn every 1 to 3 hours. In case role in platelet recovery in eptifibatide-associated 4, count improvement was seen at 90 minutes. In cases acute profound thrombocytopenia. Although the base1 and 3, count improvement occurred 8 hours after line creatinine was normal in both cases 1 and 3, renal discontinuation of eptifibatide. The only bleeding function was decreased by virtue of advanced age. Platelets were transfused in case 3 because of percomplication occurred in case 3 as epistaxis and pesistent profound thrombocytopenia in the setting of techiae, and 2 U of platelets were transfused initially. Three additional units were given over the next 3 clinical bleeding. The benefit of platelet transfusions hours because of persistent platelet counts ⬍20 ⫻ in eptifibatide-associated thrombocytopenia, however, 109/L. In all cases, once initial improvement was seen, may be limited.16 Because eptifibatide competitively platelet counts increased steadily. The time from dis- interacts with the glycoprotein IIb/IIIa receptor, the continuation of eptifibatide to platelet count ⬎100 ⫻ eptifibatide molecules will continue to associate with and disassociate from the platelet receptors of native 109/L was between 3 to 6 days. and transfused platelets until plasma levels are suffi••• In our study, thrombocytopenia and profound ciently low. thrombocytopenia occurred with an incidence of 3.7% In conclusion, despite the absence of an associand 1.0%, respectively. The incidence of thrombocytopenia approximates the 2.8% to 4.9% incidence of ation between eptifibatide and thrombocytopenia thrombocytopenia observed in the Integrilin to Mini- in population studies, we have described 4 cases of mize Platelet Aggregation and Coronary Thrombosis eptifibatide-associated acute profound thrombocy(IMPACT-II) and the Platelet Glycoprotein IIb/IIIa in topenia. Patients receiving eptifibatide during perUnstable Angina: Receptor Suppression Using Inte- cutaneous coronary intervention should have grilin Therapy (PURSUIT) trials.8,9 The incidence of platelet counts checked early, and if profound profound thrombocytopenia in this study was higher thrombocytopenia develops, eptifibatide discontinTABLE 2 Clinical Information in Cases With Acute Profound Thrombocytopenia
430 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 88
AUGUST 15, 2001
uation should be immediate and platelet monitoring frequent. There is no indication that the number of eptifibatide boluses influences the incidence of thrombocytopenia, the incidence of acute profound thrombocytopenia, or the degree of platelet count fall. Acknowledgment: We thank Gary Louie, PharmD, for help in data collection, and Stuart Dick, MPH, for statistical support. 1. Berkowitz SD, Sane DC, Sigmon KN, Shavender JH, Harrington RA, Tcheng
JE, Topol EJ, Califf RM, for the EPIC Study Group. Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous revascularization. J Am Coll Cardiol 1998;32:311–319. 2. The CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997;349:1429 –1435. 3. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689 –1696. 4. The EPISTENT Investigators. Randomised 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. 5. Kereiakes DJ, Essell JH, Abbottsmith CW, Broderick TM, Runyon JP. Abciximab-associated profound thrombocytopenia: therapy with immunoglobulin and platelet transfusion. Am J Cardiol 1996;78:1161–1163. 6. Berkowitz SD, Harrington RA, Rund MM, Tcheng JE. Acute profound thrombocytopenia after c7E3 Fab (abciximab) therapy. Circulation 1997;95:809 – 813. 7. Giugliano RP, Hyatt RR. Thrombocytopenia with GP IIb/IIIa inhibitors: a meta-analysis (abstr). J Am Coll Cardiol 1998;31(suppl A):185A. 8. The IMPACT-II Investigators. Randomized placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet 1997;349:1422–1428. 9. McClure MW, Berkowitz SD, Sparapani R, Tuttle R, Kleiman NS, Berdan LG,
Lincoff AM, Deckers J, Diaz R, Karsch KR, et al, for the PURSUIT Investigators. Clinical significance of thrombocytopenia during a non-ST-elevation acute coronary syndrome: the platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using Integrilin therapy (PURSUIT) trial experience. Circulation 1999;99:2892–2900. 10. The ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet 2000;356:2037–2044. 11. Christopoulos CG, Machin SJ. A new type of pseudothrombocytopenia: EDTA-mediated agglutination of platelets bearing Fab fragments of a chimaeric antibody. Br J Haematol 1994;87:650 – 652. 12. Sane DC, Damaraju LV, Topol EJ, Cabot CF, Mascelli MA, Harrington RA, Simoons ML, Califf RM. Occurrence and clinical significance of pseudothrombocytopenia during abciximab therapy. J Am Coll Cardiol 2000;36:75– 83. 13. Moll S. Eptifibatide in acute coronary syndromes (lett). N Engl J Med 1999;340:60 – 61. 14. Amiral J, Bridey F, Dreyfus M, Vissac AM, Fressinaud E, Wolf M, Meyer D. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992;68:95–96. 15. Arepally G, Reynolds C, Tomaski A, Amiral J, Jawad A, Poncz M, Cines DB. Comparison of PF4/heparin ELISA assay with the 14C-serotonin release assay in the diagnosis of heparin-induced thrombocytopenia. Am J Clin Pathol 1995;104: 648 – 654. 16. Tcheng JE. Clinical challenges of platelet glycoprotein IIb/IIIa receptor inhibitor therapy: bleeding, reversal, thrombocytopenia, and retreatment. Am Heart J 2000;139(suppl):S38-S45. 17. Charo IF, Scarborough RM, du Me´e CP, Wolf D, Phillips DR, Swift RL. Pharmacodynamics of the GPIIb-IIIa antagonist Integrilin: phase I clinical studies in normal healthy volunteers (abstr). Circulation 1992;86(suppl I):I-260. 18. Harrington RA, Kleiman NS, Kottke-Marchant K, Lincoff AM, Tcheng JE, Sigmon KN, Joseph D, Rios G, Trainor K, Rose D, et al. Immediate and reversible platelet inhibition after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention. Am J Cardiol 1995;76:1222–1227. 19. Tcheng JE, Harrington RA, Kottke-Marchant K, Kleiman NS, Ellis SG, Kereiakes DJ, Mick MJ, Navetta FI, Smith JE, Worley SJ, et al. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker Integrilin in elective coronary intervention. Circulation 1995;91:2151–2157.
Statin Therapy and the Acute Inflammatory Response After Coronary Artery Bypass Grafting David J. Brull, MRCP, Julie Sanders, BSc, Ann Rumley, PhD, Gordon D.O. Lowe, Steve E. Humphries, PhD, and Hugh E. Montgomery, MD reoperative statin therapy improves cardiovascular outcome after coronary artery bypass grafting P (CABG); however, the clinical gain is in excess of the reduction in lipids. We hypothesized that statin therapy exerts an anti-inflammatory effect mediated through reduced interleukin-6 (IL-6) production. Administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (“statins”) is of proved benefit in the prevention of acute coronary events1,2 and reduces mortality after acute myocardial infarction.3 However, such benefits exceed those attributable to From the Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Department of Medicine, Royal Free and University College London Medical School, London, United Kingdom; and Department of Medicine, Glasgow Royal Infirmary, Glasgow, Scotland. Drs. Brull, Rumley, Lowe, Montgomery, and Humphries were supported by the British Heart Foundation, London, United Kingdom. Dr. Brull’s address is: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Department of Medicine, Royal Free and University College London Medical School, Rayne Building, 5 University St., London WC1E 6 J J, United Kingdom. E-mail: [email protected]. Manuscript received January 30, 2001; revised manuscript received and accepted March 13, 2001. ©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 88 August 15, 2001
MD,
associated alterations in lipid profile or coronary luminal diameter.4 – 6 In a recent report, Dotani et al7 demonstrated that preoperative statin administration is also associated with improved outcome after CABG. An anti-inflammatory role for statin therapy might offer one explanation for these observations. Acute inflammatory processes, particularly the local expression of IL-6, are strongly implicated in the genesis of plaque instability and rupture.8 Given that statins suppress plaque inflammation and IL-6 production,9 we postulated that suppression of the systemic inflammatory response might underlie these perioperative benefits. •••
To examine the relations of baseline and postoperative plasma IL-6 to CABG, a prospective cohort study was performed between October 1999 and September 2000 at the Middlesex Hospital, London, United Kingdom. The study had hospital ethics committee approval, and all patients gave written informed consent. The study cohort comprised consecutive patients who underwent elective first-time 0002-9149/01/$–see front matter PII S0002-9149(01)01696-4
431