Use of Platelet Glycoprotein IIb/IIIa Inhibitors and Spontaneous Pulmonary Hemorrhage

Key words: percutaneous coronary intervention, platelet glycoprotein IIb/IIIa inhibitors, pulmonary hemorrhage In 1983, the description of an antibody that blocked the platelet glycoprotein (GP) IIb/IIIa receptor led to the development of a chimeric monoclonal antibody called abciximab for treatment of patients undergoing high-risk percutaneous coronary intervention (PCI).^1,2 The EPIC trial clearly demonstrated the clinical benefits of abciximab in these patients.³ Since then, multiple peptide and nonpeptide antagonists of the IIb/IIIa receptor have been developed.^4,5 Large clinical trials have evaluated the efficacy of these agents for the treatment of unstable angina, acute myocardial infarction (AMI) and PCI indications.^6–8 It is well accepted that the addition of these novel antiplatelet drugs to the standard armamentarium of heparin and aspirin may result in an increased risk of bleeding complications. Pulmonary hemorrhage is a rare but potentially lethal complication of antithrombotic and antiplatelet therapy. The true incidence of this serious complication is not known. The purpose of this study was to determine the incidence of pulmonary hemorrhage in patients who received platelet GP IIb/IIIa inhibitors during PCI. Methods The medical records of 1,020 consecutive patients who received GP IIb/IIIa inhibitors and underwent PCI at our institution between August 1997 and December 1999 were reviewed. Data were collected for the type of GP IIb/IIIa antagonist used, indication for the procedure, previous use of GP IIb/IIIa antagonist, previous history of pulmonary disease, peak activated clotting time (ACT) measured in the cardiac catheterization laboratory, activated partial thromboplastin time (aPTT) and platelet count measured at the time of onset of pulmonary hemorrhage, concomitant use of other antiplatelet and antithrombotic agents, incidence of pulmonary hemorrhage, and time of onset of bleeding following administration of GP IIb/IIIa antagonists. We defined pulmonary hemorrhage as an episode of spontaneous hemoptysis associated with new infiltrates on chest x-ray. Patients with episodes of epistaxis without radiographic evidence of pulmonary involvement (n = 3) or with bleeding following traumatic endotracheal intubation (n = l) were excluded. Results Abciximab, eptifibatide and tirofiban were used in 398 (39%), 408 (40%), and 214 (21 %) patients, respectively. Diffuse pulmonary hemorrhage developed in 7 patients (0.68%). The incidence of pulmonary hemorrhage for abciximab, eptifibatide and tirofiban was 0.7%, 0.5% and 0.9%, respectively (p = NS among the groups). Three of these patients have been previously reported.¹⁴ Patient characteristics, platelet count, aPTT at the time of pulmonary hemorrhage, and time of onset of bleeding following administration of GP IIb/IIIa antagonists are summarized in Table 1. None of these patients had previously received GP IIb/IIIa antagonists. Pulmonary hemorrhage was associated with a high mortality rate (2/7 patients). Both patients died of multi-organ failure. All 7 patients had elevated filling pressures as measured by left ventricular end-diastolic pressure and/or pulmonary capillary wedge pressure. Six of the 7 patients also had baseline radiographic abnormalities. Five of 7 patients with pulmonary hemorrhage had ACT > 250 seconds during the procedure. aPTT measured at the time of pulmonary hemorrhage was elevated in all patients (mean, 85 seconds; range, 69–95 seconds). Discussion Pulmonary hemorrhage associated with GP IIb/IIIa inhibitor use is rare, but potentially life-threatening. It may be unrecognized due to a striking resemblance between the radiographic features of diffuse alveolar hemorrhage and cardiogenic pulmonary edema.⁹ The overall incidence of pulmonary blood loss in large published trials of abciximab was 0.19% (10 of 5,382 patients).¹⁰ No similar data are available regarding eptifibatide or tirofiban. There has been a series of case reports of pulmonary hemorrhage with the use of abciximab and 1 report of this complication with tirofiban.^11–14 Patients in these reports demonstrated evidence of elevated filling pressures and/or evidence of pulmonary congestion on chest x-ray. All 7 of our patients had history of congestive heart failure (CHF) and had elevated pulmonary capillary wedge pressure (PCWP) and/or left ventricular end-diastolic pressure (LV-EDP) at the time of index procedure. Six patients also had evidence of baseline radiographic abnormalities. Based on the previous reports and our data, an elevated filling LV-EDP or PCWP and/or evidence of pulmonary congestion on chest x-ray, particularly in patients with a previous history of CHF, should alert the physician about the potential development of pulmonary hemorrhage following administration of GP IIb/IIIa inhibitors. Acute respiratory distress associated with radiographic alveolar shadowing — with or without profuse hemoptysis and/or unexplained drop in hematocrit — following administration of GP IIb/IIIa inhibitors should also prompt consideration of diffuse pulmonary hemorrhage. Higher heparin dosage was responsible for an increased risk of bleeding in the EPIC trial.³ Use of weight-adjusted heparin to maintain an ACT of 200–250 seconds during coronary intervention has been shown to reduce the incidence of major bleeding complications.^1–5 Another important point is that 5 of 7 patients in our series had higher ACTs prior to development of pulmonary hemorrhage, and all had elevated aPTT at the time of pulmonary hemorrhage. Careful attention to heparin dosing during the administration of these agents in an attempt to keep the ACT 16 but our report is a first attempt to determine the risk of this complication with eptifibatide and tirofiban also. Conclusion In summary, diffuse pulmonary hemorrhage is a potentially disastrous complication of GP IIb/IIIa antagonists. The true incidence of this complication is unknown, but may be higher than reported in earlier trials. No specific predictors can be identified, but evidence of pulmonary congestion, baseline pulmonary abnormalities and use of higher heparin dosages may predispose patients to this serious complication. Development of chest x-ray lung opacification following administration of GP IIb/IIIa antagonists, specifically in the setting of hemoptysis, should not be dismissed as CHF and diagnosis of alveolar hemorrhage should be considered.

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