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* From the Division of Pulmonary and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; and Department of Pneumology and Critical Care Medicine, Thoraxklinik Heidelberg, Heidelberg, Germany.
Correspondence to: Armin Ernst, MD, Director, Interventional Pulmonology, Pulmonary and Critical Care Division, Beth Israel Deaconess Medical Center, Harvard Medical School, One Deaconess Rd, Boston, MA 02115; e-mail: aernst{at}bidmc.harvard.edu
Abstract
Study objectives: Clopidogrel is often prescribed for primary or secondary prevention of cardiovascular disease and has been associated with unwanted bleeding events. After having shown that transbronchial biopsy can safely be performed in pigs receiving clopidogrel, we sought to determine whether routine clopidogrel use increases the risk of bleeding after transbronchial lung biopsy in humans.
Design: Prospective cohort study.
Patients and interventions: Data were collected on 604 patients without underlying coagulation problems who underwent transbronchial lung biopsy over 13 months. Clopidogrel was not discontinued before biopsy in patients who were using it. Transbronchial biopsies were performed, and the incidence of bleeding and other complications among patients receiving clopidogrel was compared with that of other patients.
Results: The study was stopped early because the bleeding rate in the clopidogrel-only group (n = 18) was excessive (89% [16 of 18 patients] vs 3.4% [20 of 574 control subjects; p > 0.001] and also in the group receiving clopidogrel and aspirin (100% [12 of 12 patients] vs 3.4% among control subjects [p > 0.001]. Bleeding rates were significantly higher in the clopidogrel group for each degree of bleeding severity: mild (27% vs 1.5%), moderate (34% vs 1.5%), and severe (27% vs 0.3%; p > 0.001 for all comparisons). All 12 patients receiving both aspirin and clopidogrel had bleeding: moderate in 6 patients and severe in 6 patients. All bleeding was controlled by endoscopic means. There were no fatalities or need for blood transfusions in the patients enrolled in the trial.
Conclusions: Clopidogrel use greatly increases the risk of bleeding after transbronchial lung biopsy in humans and therefore should be discontinued before bronchoscopy with biopsies. Aspirin exacerbates the effect of clopidogrel on bleeding.
Key Words: aspirin • bleeding • bronchoscopy • clopidogrel • transbronchial biopsy
Clopidogrel is a thienopyridine compound that inhibits adenosine diphosphate-induced platelet aggregation.1 It can prevent thrombosis in patients with acute coronary syndrome, coronary artery stenting, and cerebrovascular disease.2345678
Patients are often advised to discontinue the use of clopidogrel several days before invasive procedures to reduce the presumed risk of bleeding. In fact, in a large, randomized, clinical trial2 of 12,562 patients presenting with acute coronary syndrome without ST-segment elevation, the rate of major bleeding complications (GI bleeding and bleeding at the sites of arterial punctures) associated with clopidogrel was higher than that with aspirin alone (relative risk, 1.38). However, there was no difference between the clopidogrel and aspirin groups in the incidence of life-threatening or fatal bleeding. Aspirin alone does not cause increased bleeding after transbronchial biopsy in humans9 Several other reports10111213 have indicated an increased risk of bleeding when clopidogrel was combined with other antiplatelet drugs.
Currently, no data address the effect of clopidogrel on the risk of bleeding during invasive pulmonary procedures such as transbronchial lung biopsy with flexible bronchoscopy in humans. However, in a recent survey,14 61% of 158 pulmonologists reported discontinuing clopidogrel in their patients for an average of 5 days before a planned transbronchial lung biopsy.
In a recent randomized study15 at our institution, we treated pigs with or without clopidogrel and found no difference in bleeding complications after transbronchial lung biopsies. Although these animal data were reassuring, we believed that the results needed to be validated in humans. Discontinuing clopidogrel before an invasive procedure does lead to the temporary discontinuation of a medication with proven benefits, and it can also delay the planned biopsy. Thus, we sought to determine whether clopidogrel increased the risk of bleeding after transbronchial biopsy in humans.
Materials and Methods
The study was approved by the Institutional Review Board, and all patients gave written informed consent to the bronchoscopy and biopsy procedures.
Study Population
All patients > 40 years old undergoing bronchoscopic transbronchial lung biopsy between January 2002 through January 2003 were evaluated. Patients were excluded for the following reasons: (1) use of either warfarin or heparin within 2 weeks of the endoscopic procedure, (2) history of a bleeding disorder, or (3) thrombocytopenia (platelet count < 80,000/µL). Patients receiving clopidogrel were compared to control subjects: patients meeting the enrollment criteria and who were not receiving clopidogrel. The study was conducted prospectively.
Use of Clopidogrel
During the study, patients were not discouraged from using clopidogrel or aspirin before the biopsy. Just before the biopsy, patients were questioned regarding the indications and frequency of their use of clopidogrel and aspirin. Bronchoscopy was then performed, and all necessary biopsies were performed. The operators were not aware of the patients’ clopidogrel use before the procedure.
Transbronchial Lung Biopsy
Fluoroscopy was used for all transbronchial biopsies. At least three specimens were obtained with a standard forceps (FB-20C; Olympus; Tokyo, Japan). The endoscopist documented the intensity of bleeding on the basis of the need for clinical intervention. No bleeding was defined as the presence of only traces of blood after finishing the biopsies, with no need for continued suctioning. Mild bleeding was defined as the need for continued suctioning of blood from the airways after the procedure, and moderate bleeding required intubation of the biopsied segment with the flexible bronchoscope into the wedge position. Severe bleeding was defined as the need for additional interventions, such as placing a temporary bronchus blocker, applying a fibrin sealant, admission to a critical care unit, or infusing blood products.
Statistical Methods
All values are presented as means and SDs, numbers, or percentages. Statistically significant differences between patient groups were determined using a 
2 test; 
was set at 0.05. Statistical software (SPSS 11.0; SPSS; Chicago, IL) was used for the analysis. An interim analysis was planned for 6 months after the study was begun. Data were reviewed by a safety monitor, who determined whether to stop or to continue the study. There were no formal stopping rules.
Results
The study was stopped after 6 months because the bleeding rates in the clopidogrel group were excessive. Until the time of the planned interim analysis, 604 eligible patients had agreed to participate in the study. Of these, 30 patients (5%) had used clopidogrel within 24 h of the bronchoscopy; all were using it daily and continued to do so after the biopsy. The most common reason for using clopidogrel was primary or secondary prevention of coronary heart disease and prevention of graft occlusion after coronary artery bypass surgery. In addition, 111 patients (18%) regularly used aspirin; 12 patients (2%) used both aspirin and clopidogrel.
The mean age of the patients was 57.8 years (range 44 to 78 years), 68% were men, and 407 patients (67%) were smokers. The groups did not differ significantly at baseline (Table 1 ).
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Of 48 patients (7.9%) who had procedure-related bleeding, bleeding was mild in 12 patients, moderate in 21 patients, and severe in 15 patients (Table 2 ). Patients receiving clopidogrel or clopidogrel and aspirin had significantly more bleeding events than control subjects: 88% and 100% vs 3.4%, respectively (20 of 574 patients; p < 0.001; Table 2). Bleeding was not statistically different among groups with different indications for biopsy. Every patient receiving aspirin and clopidogrel (n = 12) had bleeding; bleeding was moderate in 6 patients and severe in 6 patients.
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No other important complications occurred during or after biopsy; there were no deaths. Bleeding responded to topical endoscopic treatment, and no patients required intubation or admission to critical care areas. No patients required blood transfusion.
Discussion
Pulmonologists frequently encounter patients who require transbronchial lung biopsy with flexible bronchoscopy and who are receiving antiplatelet drugs. We previously found that aspirin alone is not associated with an increase in bleeding complications from transbronchial lung biopsy and therefore does not need to be stopped before this procedure.
These data cannot be generalized to clopidogrel use because its mechanism of action differs from that of aspirin. The results in this trial were not subtle: marked bleeding was observed in most patients receiving clopidogrel and all patients receiving clopidogrel combined with aspirin. Fortunately, all bleeding could be controlled endoscopically and no serious events such as death or the need for blood transfusions occurred.
On the basis of these results, we recommend stopping clopidogrel use 5 to 7 days before transbronchial biopsy to ensure patient safety. The indications for transbronchial biopsies need to be clearly defined, as it means stopping a beneficial medication for patients with cardiovascular diseases.
Our results also question the validity of the assumption that results of animal experiments in this area can be extrapolated to humans. For example, a study by Brickey and Lawlor16 is frequently quoted as evidence that warfarin-induced international normalized ratio prolongation is not associated with bleeding complications during transbronchial biopsies done in pigs. This trial was also performed in animals, and its validity has never been tested in humans. Our current trial reminds us that animal testing cannot always substitute for examining and establishing the effects of diagnostic and therapeutic interventions in humans.
Limitations of the Study
We relied on patient self-report to determine whether patients were using aspirin or clopidogrel at the time of the biopsy. This reliance is a limitation in studying the underlying biological relationship between medication use and bleeding, but it is a strength in ascertaining the practical risk of clopidogrel use under typical conditions of health-care delivery.
Conclusions
Routine clopidogrel use greatly increases the risk of bleeding after transbronchial lung biopsy and therefore should be discontinued before this procedure.
Received for publication July 29, 2005. Accepted for publication September 24, 2005.
References
This article has been cited by other articles:
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  P. Albaladejo, E. Marret, V. Piriou, and C.-M. Samama Perioperative management of antiplatelet agents in patients with coronary stents: recommendations of a French Task Force. Br. J. Anaesth., October 1, 2006; 97(4): 580 - 582. [Full Text] [PDF]
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