Pulmonary Hemorrhage During Glycoprotein IIb/IIIa Inhibitor Therapy: An Uncommon but Life-Threatening (and Under-Recognized) Com

The study presented by Ali et al. in this issue of the Journal reports an institutional experience with pulmonary hemorrhage in patients treated with platelet glycoprotein (GP) IIb/IIIa inhibitors. Use of these intravenous agents has been shown to lower the peri-procedural myonecrosis in patients who undergo coronary angioplasty and stent placement.^1–4 However, there are increased bleeding complications, most frequently at the vascular access site.^3–5 These complications are certainly in excess to those observed with heparin or bivalirudin when given alone, and appear to correlate with body mass and the intensity of concomitant anticoagulant therapy, especially heparin or direct antithrombins, but other antiplatelet drugs as well.^2,6,7 Another hematological complication of GP IIb/IIIa inhibitor therapy is thrombocytopenia, which typically does not lead to spontaneous bleeding (but can result in prolonged hospitalization for close observation if profound). Interestingly, both bleeding and thrombocytopenia appears to be somewhat greater than abciximab, which showed superior efficacy to a small molecule GP IIb/IIIa inhibitor (tirofiban) in a randomized trial.⁸ Also, a higher dose of eptifibatide in ESPRIT appeared to produce more such complications than earlier (and less effective clinically) dosage schemes.^9,10 Therefore, bleeding and thrombocytopenia appear to be a trade-off for greater clinical efficacy (preventing myonecrosis). A rather uncommon complication of the GP IIb/IIIa inhibitor use is pulmonary hemorrhage. Bleeding into the lung parenchyma may present as new radiologic infiltrates or acute respiratory distress symptoms, including hemoptysis. Such bleeding is less easily diagnosed than hemorrhage in other sites and can be unrecognized and possibly incorrectly diagnosed, most frequently as pulmonary edema or major pulmonary embolism. Anecdotal instances of pulmonary hemorrhage, have been reported sparsely for all three GP IIb/IIIa inhibitors.^11–15 In the present study, the incidence of pulmonary hemorrhage for abciximab, eptifibatide, and tirofiban was 0.7%, 0.5% and 0.9%, respectively. It is of note that in this report 5 of 7 patients had prolonged ACT > 250 seconds prior to pulmonary bleeding and all had elevated APTT at the time of the complication. This complication was reported somewhat more infrequently in the landmark clinical trials of abciximab (EPIC, EPILOG, EPISTENT, and CAPTURE);^3–5,16,17 only 10 of 5,382 patients (0.19%) who actually received abciximab had pulmonary blood loss according to the Thrombolysis in Myocardial Infarction criteria (7 major episodes and 3 minor episodes).¹⁸ The frequency of pulmonary hemorrhage appeared to be higher in early trials utilizing relatively high doses of heparin, but was reduced in later trials probably by the use of low-dose, weight-adjusted heparin. In the EPISTENT trial and EPILOG low-dose heparin group, one patient of 2,484 patients (0.04%) had TIMI-minor pulmonary bleeding compared to the standard-dose heparin used in EPIC, CAPTURE, and the EPILOG respective group that had 9 of 2,898 patients (0.31%) with pulmonary bleeding.¹⁹ Recently, alveolar hemorrhage was documented in 7 of 2,553 patients undergoing percutaneous coronary interventions (0.27%).16 The authors did not identify any similar events in 5,412 patients who did not receive abciximab. It would therefore appear that very potent antiplatelet therapy with abciximab combined with aspirin, ticlopidine or clopidogrel, and heparin, a combination in almost routine practice currently, may be linked with this serious complication.²⁰ Interestingly, Ali et al. report that the incidence of alveolar bleeding with tirofiban and eptifibatide was similar with abciximab use (p = NS). Pulmonary bleeding has only sparsely been reported with use of tirofiban and eptifibatide up to now.^{8–10,21–24} [See Ali et al. on pages 186–188] Six of 7 patients described by Ali et al. had an abnormal chest film at baseline and all had a history of congestive heart failure, elevated pulmonary wedge pressure, or left ventricular end-diastolic pressure at the time of the procedure. Even though any relation between the presence of pulmonary congestion and pulmonary hemorrhage or bleeding has not been supported previously, a possible mechanism could be the chronically elevated pressures endured by the alveolar membranes, which may have made them thinner with time and prone to bleeding with GP IIb/IIIa inhibitors. Based on this report, treating pulmonary hemorrhage should be sharp and intense: 1) supportive care including endotracheal intubation and mechanical ventilation is required; 2) a transfusion of packed red blood cells; 3) a reversal of all anticoagulation; and 4) a platelet transfusion, especially if abciximab was used. Another hint would be the avoidance of GP IIb/IIIa inhibitors as a “rescue” (in the middle of the procedure) therapy, at a time when the ACT value may be very high, especially in the patient subsets mentioned above. Despite these treatment measures, this potential complication of GP IIb/IIIa inhibitor therapy can still be life threatening and require physicians’ awareness to ensure early diagnosis.

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