Correspondence
Abciximab and Alveolar Hemorrhage
N Engl J Med 1998; 339:1861-1863December 17, 1998
- Article
To the Editor:
Abciximab (ReoPro, Eli Lilly, Indianapolis, and Centocor, Malvern, Pa.), a new antiplatelet agent, is used during high-risk percutaneous transluminal coronary angioplasty (PTCA). In the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial, the use of an abciximab bolus was associated with major bleeding complications in 11 percent of patients.1 No significant differences in the risk of major bleeding were observed among the three treatment groups in the Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG) study.2 The incidence of major bleeding (3.8 percent) was lower in the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial than in the EPIC trial.3 Since our initial report of fatal alveolar hemorrhage and abciximab therapy,4 four additional cases of alveolar hemorrhage have been diagnosed at our institution (for a total of six patients). We describe our experience with these patients.
The mean age of these six patients was 65 years. Four were male. Five patients were smokers and had chronic obstructive pulmonary disease. One patient had had an episode of noncardiogenic pulmonary edema several years earlier. None had a history of bleeding. The coagulation profile was abnormal in only one (international normalized ratio, 1.7). All six presented with acute myocardial infarction and had an abnormal chest x-ray film on admission that was characterized by interstitial infiltrates. The patients were treated with a weight-adjusted dose of heparin, ticlopidine (250 mg), and aspirin (325 mg). Evaluation of the right heart values before PTCA and stent placement revealed elevated pulmonary-capillary wedge pressures (mean, 24 mm Hg; range, 13 to 45) as well as elevated pulmonary arterial pressures (mean systolic, 44 mm Hg [range, 20 to 60]; mean diastolic, 28 mm Hg [range, 15 to 34]). Abciximab was given as a bolus dose of 0.25 mg per kilogram of body weight followed by a 12-hour infusion at a rate of 10 μg per minute. The mean activated coagulation time during the procedure was 245 seconds (range, 150 to 297). Alveolar hemorrhage was manifested by the acute onset of dyspnea after the initiation of abciximab, the development of moderate-to-severe hemoptysis, a decrease in hemoglobin, and an increase in pulmonary infiltrates on the chest films. Three of the six patients received red-cell and platelet transfusions and required mechanical ventilation, and all three died. The others eventually recovered.
The use of low-dose, weight-adjusted heparin decreases the incidence of bleeding complications and enhances the safety of abciximab therapy.2 In an elegant review of the results of the EPIC trial, Aguirre et al.5 demonstrated that an increased risk of bleeding complications was associated with acute myocardial infarction, low body weight, older age, and a long and unsuccessful or complicated PTCA. In addition, we think that the presence of underlying lung conditions, such as chronic obstructive pulmonary disease, pulmonary hypertension, and a high pulmonary-capillary wedge pressure, may be associated with an increased risk of alveolar hemorrhage, a potentially life-threatening complication. Further investigations are warranted to increase the safety of abciximab therapy.
5 ReferencesHomayoun Khanlou, M.D.
Glenn Eiger, M.D.
Shahriar Yazdanfar, M.D.
Albert Einstein Medical Center, Philadelphia, PA 191411
The EPIC Investigators
Full Text | Web of Science | Medline2
The EPILOG Investigators
Full Text | Web of Science | Medline3
Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study
CrossRef | Web of Science | Medline4
Khanlou H ,Tsiodras S ,Eiger G , et al. Fatal alveolar hemorrhage and abciximab (ReoPro) therapy for acute myocardial infarction. Cathet Cardiovasc Diagn 1998;44:313-316
CrossRef | Medline5
Aguirre FV ,Topol EJ ,Ferguson JJ , et al. Bleeding complications with the chimeric antibody to platelet glycoprotein IIb/IIIa integrin in patients undergoing percutaneous coronary intervention. Circulation 1995;91:2882-2890
Web of Science | Medline
Author/Editor Response
Spokespersons for Centocor and Lilly Research Laboratories reply:
To the Editor: Khanlou et al. report their institution's experience with pulmonary hemorrhage in patients who received abciximab. We appreciate the opportunity to provide additional information.
Pulmonary bleeding has consistently been an uncommon complication during clinical trials of abciximab: the EPIC, CAPTURE, EPILOG, and Evaluation of GP IIb/IIIa Platelet Inhibitor for Stenting (EPISTENT) trials.1-4 Only 10 of 5382 patients (0.19 percent) who actually received abciximab had pulmonary blood loss according to the Thrombolysis in Myocardial Infarction criteria (7 major episodes and 3 minor episodes).5 The frequency of all bleeding events, including pulmonary hemorrhage, was higher in early trials (in the EPIC and CAPTURE trials1,3 and the EPILOG group given standard-dose heparin,2 9 of 2898 patients [0.31 percent] had pulmonary bleeding) but was reduced in later trials (in the EPILOG group given low-dose heparin2 and the EPISTENT trial,4 1 of 2484 patients [0.04 percent] had minor pulmonary bleeding) by the use of low-dose, weight-adjusted heparin.
Since the introduction of abciximab into clinical practice in 1995, we have received 109 reports of pulmonary bleeding of any severity through MEDWatch. We estimate that over 445,000 patients have received abciximab. This rate of pulmonary bleeding is significantly below that reported in our large clinical trials, but we recognize that this difference may reflect underreporting. Nevertheless, the general rate does not appear to be any greater than the rate we have seen in clinical trials.
All the patients described by Khanlou et al. had an abnormal chest film at base line and presented with myocardial infarction with a Killip class of at least 3 (which is associated with a mortality rate of 30 to 40 percent that is independent of abciximab therapy6), and at least five of the six patients had chronic obstructive pulmonary disease. Examination of our large trials of abciximab failed to demonstrate any relation between the presence of chronic obstructive pulmonary disease and pulmonary hemorrhage or bleeding, but we cannot comment on a relation between abnormal chest films and pulmonary bleeding, since these data were not collected in the studies. Pulmonary edema increases pulmonary blood loss, which may have been aggravated by treatment with abciximab and other anticoagulant agents in these patients.
In summary, pulmonary bleeding from abciximab use is an uncommon event in both clinical trials and reported clinical experience. In addition to the usual supportive care, discontinuation of the agents affecting hemostasis, and reversal of their effects, platelet transfusion may restore adequate platelet aggregation in abciximab-treated patients. However, this potential risk can be serious, and we are collecting and analyzing additional data to elucidate further this or other potential risk factors for bleeding.
6 ReferencesSidney A. Cohen, M.D., Ph.D.
Centocor, Malvern, PA 19355Mark B. Effron, M.D.
Lilly Research Laboratories, Indianapolis, IN 462851
The EPIC Investigators
Full Text | Web of Science | Medline2
The EPILOG Investigators
Full Text | Web of Science | Medline3
Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study
CrossRef | Web of Science | Medline4
Topol EJ. EPISTENT. Presented at the 47th Annual Scientific Session of the American College of Cardiology, Atlanta, March 31, 1998.
5
Rao AK ,Pratt C ,Berke A , et al. Thrombolysis in Myocardial Infarction (TIMI) Trial -- phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11:1-11
CrossRef | Web of Science | Medline6
Topol EJ. Textbook of cardiovascular medicine. Philadelphia: Lippincott–Raven, 1998:459.
- Citing Articles (11)
Citing Articles
1
Eugenia Nikolsky, Gregg W. Stone, Ajay J. Kirtane, George D. Dangas, Alexandra J. Lansky, Brent McLaurin, A. Michael Lincoff, Frederick Feit, Jeffrey W. Moses, Martin Fahy, Steven V. Manoukian, Harvey D. White, E. Magnus Ohman, Michel E. Bertrand, David A. Cox, Roxana Mehran. (2009) Gastrointestinal Bleeding in Patients With Acute Coronary Syndromes: Incidence, Predictors, and Clinical Implications. Journal of the American College of Cardiology 54:14, 1293-1302
CrossRef2
Enrico Vizzardi, Antonio D’Aloia, Gregoriana Zanini, Elena Antonioli, Claudio Pedrinazzi, Riccardo Raddino, Livio Dei Cas. (2008) A case report of alveolar haemorrhage associated with severe thrombocytopenia induced by abciximab infusion in a patient with an acute coronary syndrome. Internal and Emergency Medicine 3:4, 345-347
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Robert J. Applegate, Matthew T. Sacrinty, Michael A. Kutcher, Frederic R. Kahl, Sanjay K. Gandhi, Renato M. Santos, William C. Little. (2008) Trends in Vascular Complications After Diagnostic Cardiac Catheterization and Percutaneous Coronary Intervention Via the Femoral Artery, 1998 to 2007. JACC: Cardiovascular Interventions 1:3, 317-326
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Capt Maria Conley, Maj Gilberto Patino, Maj Benjamin Romick, Maj Michael Almaleh, Charles Campbell, Maj Karin Hawkins, Lt Col Scott Moore, Maj Patrick Allan. (2008) Abciximab-induced alveolar hemorrhage after percutaneous coronary intervention. Canadian Journal of Cardiology 24:2, 149-151
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Eugenia Nikolsky, Gregg W Stone. (2007) Antithrombotic strategies in non-ST elevation acute coronary syndromes: focus on bivalirudin. Future Cardiology 3:4, 345-364
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SAID B. ISKANDAR, EHAB S. KASASBEH, BASSAM K. MECHLEB, ISRAEL GARCIA, ANN JACKSON, STEPHEN FAHRIG, KAISS ALBALBISSI, PHILLIP D. HENRY. (2006) Alveolar Hemorrhage: An Underdiagnosed Complication of Treatment with Glycoprotein IIb/IIIa Inhibitors. Journal of Interventional Cardiology 19:4, 356-363
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Nilesh I. Gupta, Panayotis Fasseas, Ralph M. Schapira. (2006) Pulmonary Hemorrhage and Antithrombotic Therapy. Clinical Pulmonary Medicine 13:4, 251-254
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T S Lin, S L Penza, B R Avalos, M R Lucarelli, S S Farag, J C Byrd, E A Copelan. (2005) Diffuse alveolar hemorrhage following gemtuzumab ozogamicin. Bone Marrow Transplantation 35:8, 823-824
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Francisco J. Rodríguez-Gómez, Ángel Sánchez, Francisco J. Martínez, Juan Andreu, Alejandra Álvarez, Emilio Pujol. (2005) Hemorragia pulmonar por abciximab. Factores de riesgo y papel de la protamina. Revista Española de Cardiología 58:4, 453-455
CrossRef10
Arshad Ali, Sandish Patil, Kevin J. Grady, Theodore L. Schreiber. (2000) Diffuse alveolar hemorrhage following administration of tirofiban or abciximab: A nemesis of platelet glycoprotein IIb/iIIa inhibitors. Catheterization and Cardiovascular Interventions 49:2, 181-184
CrossRef11
&NA;. (1999) Abciximab. Reactions Weekly &NA;:733, 7
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