Alveolar Hemorrhage Associated with Periprocedural Eptifibatide Administration

Eptifibatide, a cyclic heptapeptide inhibitor of the platelet membrane glycoprotein (GP) IIb/IIIa receptor, reduces the incidence of ischemic complications when administered at the time of percutaneous coronary intervention (PC I).¹ Major bleeding (mostly at the vascular access site, but also including intracranial, gastrointestinal or retroperitoneal bleeding) is a recognized complication of aggressive periprocedural antiplatelet and anticoagulant therapy. This now typically includes aspirin, clopidogrel, procedural heparin and a GP IIb/IIIa inhibitor.¹ Pulmonary alveolar hemorrhage, although infrequent, has been reported as a complication of the platelet GP IIb/IIIa inhibitors abciximab and tirofiban.^2–7 To our knowledge, this is the first report of alveolar hemorrhage associated with the administration of eptifibatide. Case Report. A 77-year-old woman with a past medical history of coronary artery disease, coronary artery bypass graft surgery, hypertension, hyperlipidemia and chronic obstructive pulmonary disease presented to our hospital complaining of a prolonged episode of angina resistant to sublingual nitroglycerin administration. Her electrocardiogram revealed anterolateral ST-segment depression. Platelet count and coagulation profile [prothrombin time (PT), accelerated partial thromboplastin time (aPTT) and international normalized ratio (INR)] were all within normal limits. Her chest X-ray revealed bilateral interstitial fibrosis and bullous parenchymal changes (Figure 1). The patient was admitted to the coronary care unit and initially treated with aspirin, nitrates, intravenous unfractionated heparin and a beta-blocker. She experienced recurrent angina at rest approximately 24 hours after admission and underwent urgent diagnostic coronary angiography, which revealed a critical stenosis of a large-caliber distal left circumflex coronary artery that had not been bypassed. It was decided to proceed with immediate PCI. Her activated clotting time (ACT) was 200 seconds; an additional 1,500 units of intravenous unfractionated heparin, 300 mg of oral clopidogrel and an intravenous bolus of eptifibatide (180 µg/kg) were administered, followed by an intravenous infusion of eptifibatide (2.0 µg/kg/minute). An ACT of 258 seconds was documented prior to the first balloon dilatation. The distal circumflex stenosis was dilated, achieving an excellent angiographic result. Multiple attempts to deliver a stent to the treatment site were unsuccessful and no stent was deployed. However, during the final stages of this PCI, the patient started to cough uncontrollably and complained of severe shortness of breath. She became progressively hypoxic and hypotensive and required endotracheal intubation, mechanical ventilation, intravenous pressor support and insertion of an intra-aortic balloon pump. Following endotracheal intubation, large amounts of bright red blood were aspirated from her proximal airway. The second bolus of eptifibatide was not administered and the eptifibatide infusion was stopped, the effects of heparin were reversed with protamine sulphate, and blood products were administered, including two units of packed red blood cells and a single unit of donor platelets. The patient underwent emergency bronchoscopy in the cardiac catheterization laboratory. Large amounts of clotted blood that filled all lobes of both lungs was identified, but no endobronchial lesions or discrete bleeding sites. Several long, serpiginous blood clots were removed and the patient’s clinical condition immediately improved. Repeat coronary angiography revealed patency of the treated vessel and no new lesions were identified. The patient was transferred to the Intensive Care Unit, where she had an uneventful recovery. She was weaned off intravenous pressor support, the intra-aortic balloon pump was removed and she was extubated without complication. A repeat bronchoscopy identified minimal bloody secretions and, again, there was no evidence of an endobronchial lesion. Her platelet count remained normal and her coagulation profile promptly returned to normal following discontinuation of heparin and administration of protamine sulphate. She was discharged from the hospital on aspirin; clopidogrel was not administered because a stent had not been deployed. Clinical follow-up at 6 months was unremarkable and she has not experienced recurrent angina pectoris or required any further treatment for a cardiac or pulmonary condition. Discussion. Major and minor bleeding events complicate the periprocedural course of an important minority of patients who receive a GP IIb/IIIa inhibitor at the time of PCI.¹ We believe that this is the first published case report of diffuse alveolar hemorrhage associated with the synthetic small molecule platelet GP IIb/IIIa inhibitor eptifibatide. Alveolar hemorrhage has been reported as a complication of the platelet GP IIb/IIIa inhibitors abciximab, a chimeric monoclonal antibody Fab fragment, and tirofiban, a synthetic small molecule antagonist.^2–6 Kalra et al. identified 7 cases of severe alveolar hemorrhage after retrospective analysis of 2,553 patients who received abciximab at the time of PCI, yielding an incidence of 0.27% (95% confidence interval, 0.14–0.56); no cases of alveolar hemorrhage were identified among a control group of 5,412 patients who underwent coronary procedures without abciximab infusion (p=0.0003).⁵ All 7 patients received standard antiplatelet therapy (aspirin and a thienopyridine), a standard dose of abciximab (bolus of 0.25 mg/kg, infusion of 1.25 µg/kg/min for 12 hours) and weight-adjusted heparin to achieve an ACT of 200–300 seconds, although many were over-anticoagulated (mean, 323 seconds; range, 246–457 seconds). The critical role of heparin in influencing bleeding among patients on a GP IIb/IIIa inhibitor cannot be overemphasized. However, the patient in the current report and the majority of patients described in the medical literature had appropriate target ACT measurements at the time of the episode of alveolar hemorrhage.^2–6 Importantly, all 7 patients described by Kalra et al. were ex-smokers, and 4 of the 7 patients had a prior diagnosis of chronic obstructive pulmonary disease. In fact, the presence of chronic lung disease, cardiogenic pulmonary edema or elevated pulmonary capillary wedge pressure appears to be common to all the published reports of alveolar hemorrhage in patients treated with a GP IIb/IIIa inhibitor, although due to the very low incidence of this complication, it has not been possible to confirm a statistical association. Similarly, a number of cases of pulmonary hemorrhage have been reported to the Food and Drug Administration MedWatch program. MedWatch receives spontaneous reports of suspected side effects associated with FDA-licensed products; events observed after a product exposure are not necessarily due to that exposure and the clinical details may be incomplete. Nevertheless, Bell et al. identified 183 recipients of a GP IIb/IIIa inhibitor (abciximab, eptifibatide or tirofiban) who developed pulmonary hemorrhage (128, 32 and 23 cases were reported, respectively).⁷ The majority of these patients were receiving multiple anticoagulant and/or antiplatelet agents at the time of the bleeding episode, and 41% received 3 or more concurrent anticoagulants. Further clinical details describing the clinical presentation, comorbid conditions, diagnostic tests and treatment strategy were not presented. The differential diagnosis for hemoptysis, new radiographic infiltrates and hypoxemia in a patient with coronary artery disease undergoing PCI is broad and includes pulmonary infection, pulmonary edema, aspiration pneumonia, endobronchial malignancy and pulmonary thromboembolism; all should be considered. In the setting of the catheterization laboratory, it is also important to consider traumatic intubation and direct pulmonary artery trauma due to placement of a pulmonary artery or Swan-Ganz catheter. We believe that the management of a patient with hemoptysis should include reversal of heparin anticoagulation with protamine, discontinuation of the GP IIb/IIIa inhibitor, and administration of donor platelets if the monoclonal antibody fragment abciximab has been administered. Similarly, there is in vitro evidence that administration of donor platelets may also benefit patients with major bleeding who have received a small molecule competitive GP IIb/IIIa inhibitor if accompanied by fibrinogen supplementation (fresh frozen plasma or cryoprecipitate).⁸ Endotracheal intubation and mechanical ventilation are necessary in the majority of patients who develop pulmonary hemorrhage, both for maintenance of oxygenation and to facilitate appropriate airway management. Rapid diagnosis of alveolar hemorrhage and exclusion of an endobronchial lesion or other discrete bleeding site are best achieved by emergency bronchoscopy. It may also have therapeutic value, and balloon tamponade of a localized affected area or local administration of a hemostatic agent, such as thrombin, is possible. Conclusion. Alveolar hemorrhage is a rare but potentially fatal complication of platelet GP IIb/IIIa inhibitor administration at the time of PCI and may be associated with any of the 3 commonly available intravenous agents (abciximab, tirofiban and eptifibatide). Alveolar hemorrhage may be more common in patients who have underlying lung disease, but no reliable prediction model has been developed since it is such an infrequent occurrence. A broad differential diagnosis should be considered and immediate steps should be taken to confirm the diagnosis and provide potentially life-saving treatment, including bronchoscopy, endotracheal intubation and mechanical ventilation, and administration of protamine and donor platelets.