Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive bronchoscopic procedure with an excellent safety profile and few contraindications. It is widely used to diagnose pulmonary diseases by allowing visualization and safe, highly accurate biopsies of intrathoracic structures.1–3 Because of comorbidities, some patients may be taking clopidogrel at the time of EBUS, and discontinuation of anticoagulation medication may put them at high risk for thrombosis.
Clopidogrel (Bristol-Myers Sqibb, New York, NY) is a thienopyridine compound that inhibits adenosine diphosphate–induced platelet aggregation.4 It has been shown to prevent thrombosis in patients with acute coronary syndrome, coronary artery stenting, and cardiovascular disease.5,6 Several studies have shown that withdrawing clopidogrel therapy in patients who have undergone placement of drug-eluting stent implantation can be associated with a marked increase in the risk of coronary thrombosis.7–9 The recent recommendation from the American Heart Association’s Science Advisory Committee is that patients who have undergone placement of a drug-eluting coronary artery stent should continue to receive dual antiplatelet therapy for at least 12 months.10,11 As a result, physicians are often faced with the challenge of performing the necessary procedure with a potential increased risk of bleeding versus holding clopidogrel for 5 to 7 days and increasing the risk of potentially fatal thrombosis with cardiac and neurological sequels. Our group has published on the safety of thoracentesis using an 8-french catheter in patients with pleural effusions receiving clopidogrel.12 Stather et al13 have also reported on a series of 15 patients undergoing EBUS-TBNA while on clopidogrel. In this manuscript, as a primary endpoint, we report a first prospective, multicenter (Cancer Treatment Centers of America, Southeastern Region, and Grady Memorial Hospital) study on the safety of EBUS-TBNA in the largest reported cohort of patients receiving clopidogrel.
PATIENTS AND METHODS
The study was approved by the Institutional Review Boards at both institutions and all patients provided written informed consent to the flexible bronchoscopy and EBUS-TBNA study. All patients undergoing EBUS-TBNA between June 2012 and August 2016 were evaluated. EBUS was performed for the purpose of evaluation of the mediastinum/hilum for staging or diagnosis. Patients eligible for inclusion in our study were older than 18 years, presenting with mediastinal and/or hilar adenopathy requiring sampling, taking a combination of clopidogrel (75 mg, to be take once a day orally) and aspirin (325 mg PO, once daily) until the day of the procedure, and had no known underlying coagulation problems as noted in their medical record (Table 1). After consultation with the primary prescriber, patients whose clopidogrel could be held safely for 5 to 7 days before the procedure were excluded, and their procedure was rescheduled. Others who were deemed, by their cardiologist and/or neurologist, high risk for holding clopidogrel (increased risk of thrombosis) were included in the trial. Patients included in our study were taking combination clopidogrel and aspirin for their cardiovascular disease which resulted in coronary stent placement. The mean age of the patients who underwent EBUS-TBNA while on clopidogrel was 68.5 years (range, 41 to 82 y); 75% were men. All patients in our study had platelets count >100,000 and an international normalized ratio <1.5 before the procedure. None of the patients were diagnosed with coagulation problems in their medical records, and after consultation with the primary physician (cardiologist or neurologist in this cohort). The baseline demographic data are presented in Table 1.
All procedures were performed by the interventional pulmonary attendings and interventional pulmonary fellows. All EBUS-TBNA were performed on an outpatient basis under total intravenous anesthesia and topical anesthesia.14 Following airway examination, EBUS was performed (BF-UC180F; Olympus Corporation of the Americas, Center Valley, PA) followed by TBNA of targeted lesions. First, 3 passes were performed with a 22-G needle (Olympus NA-201SX-4022-C). If no complications were encountered, we followed with additional 3 passes with a 21-G needle (Olympus NA-201SX-40 21-C). Rapid onsite evaluation was performed in all patients. Bleeding at the puncture site was considered significant if intervention was required to contain the bleeding. If the puncture site required cold saline, topical sympathomimetic, or balloon tamponade were applied to achieve and maintain homeostasis. Bleeding was considered nonsignificant if no interventions were required to achieve hemostasis. All patients were observed in the postoperative recovery unit for 60 minutes before discharge. All patients were contacted within 24 hours after discharge by phone. All patients were followed within 1 to 2 weeks after procedure. A complete blood count was obtained at the follow-up date, and compared with baseline preprocedure. Patients with benign diagnoses were followed by the referring pulmonary attending during management of the underlying disease. Patients with malignant diagnoses were followed by the specialized oncology team per treatment guidelines.
No formal statistical hypotheses were assessed. Most of the analysis was descriptive in nature. The sample size was determined by the total number of patients undergoing EBUS-TBNA while receiving clopidogrel. The medians and ranges were reported for continues variables. All values are presented as means, numbers, or percentages in Tables 1 and 2.
In Table 1, we report the demographics of our study cohort. Averages are arrived at by examining the frequency of a particular event within our cohort compared with the total number of individuals in our cohort.
In Table 2, percentages were arrived at by considering a particular observed nodal element (ie, node location, type of cancer) to the total value expected (ie, 92 nodes in total biopsied).
Our study was approved by the Internal Review Boards of both Cancer Treatment Centers of America, Southeastern Regional Center, as well as Grady Memorial Hospital included 40 individuals all taking a combination of clopidogrel and aspirin in the trial (Table 1). A total of 92 lymph node stations were aspirated. A total of 6 passes were made per lymph node station [3 with 22 G, and additional 3 with 21-G needle if no bleeding occurred (0%), which did not occur]. Initially there was no bleeding seen in any of the patients using the 22-G needle, as a result all the patients received an additional 3 passes using a 21-G needle, as stated per protocol in this study. None of the passes using a 21-G needle resulted bleeding, a finding similar to the 22-G needle. A specific pathologic diagnosis was obtained in 38 of 40 patients (95%), with the remaining 2 showing benign nodal tissue. Of the patients with “benign nodal tissue,” one elected radiographic follow-up, and showed stability at 6 months, after which the interventional program referred to the general service for follow-up. The second patient underwent mediastinoscopy which confirmed his initial benign diagnosis. There was no bleeding seen in any of the cases at the time of bronchoscopy using either the 22 or 21-G needles. At the standard follow-up periods, postprocedure complete blood count values were similar to preoperative values. Further, none of the patients reported or presented with hemoptysis within 24-hour postprocedure. Our population in this study was thought to have been at higher risk for bleeding complications, given their course of antiplatelet therapy (clopidogrel and aspirin); however, our study has illustrated that there is no overt bleeding rate for those that are on this specific course of antiplatelet medications, a finding similar to the general population at large according to the standard of care for bronchoscopic procedures. This study further indicates that there was again no difference in this population between the 21 and 22-G needles used in the procedure; our results cannot be further extrapolated to make predictions regarding 19-G needles.
To our knowledge, this series of 40 consecutive prospective cases is the first multicenter report suggesting the safety of EBUS-TBNA in patients taking clopidogrel and aspirin in combination. Our large cohort did not show any significant bleeding complication with either the 21 or 22-G needles. Our current study is in parallel with what has been mentioned in the literature.10–13,15,16 Previously, we reported on the safety of thoracentesis in patients receiving clopidogrel alone.12 In addition, others reported on the safety of thoracotomy when performed on patients taking clopidogrel.12,16,17 Further, Stather et al13 in a retrospective single center review of 12 cases, reported no significant bleeding with similar gauge needles. In the latter study, patients were followed for 30 days postprocedure.13 In addition, Meena and colleagues, reported retrospectively on the safety of EBUS using a 22-G needle. Our results further supplement their findings by being prospective, and using a 21-G needle.18
The vast majority of patients receiving clopidogrel are usually on dual antiplatelet therapy (clopidogrel, 75 mg and aspirin, 325 mg) and this followed true in our study population. In a cohort from Riverside Methodist (Columbus, OH), none of the 20 patients on dual antiplatelet therapy bled during the procedure, but one (5%) had a hemoglobin drop of >2 g within 48 hours and another was readmitted to the hospital within 48 hours for procedure-related hemoptysis.19 Overall, the delayed bleeding event rate for patients using the dual antiplatelet therapy was 10%.19 In addition, 1 of the 13 patients (7.7%) on clopidogrel alone experienced a >2 g drop in hemoglobin.19 It is important to note that historically, EBUS-TBNA has been considered safe with low risk of bleeding complications.20 In the latter study, among the 300 patients not exposed to antiplatelet medication, the overall bleeding event rate was 2.6%, and the event rate for delayed bleeding was 1.3%.20 Although this study20,21 alludes to a 1.3% bleeding event rate, our study has no occurrence (0%) of bleeding, we believe, in part, as our team of physicians in interventional pulmonology are highly experienced and proficient in EBUS-TBNA procedures which can account for our improvement in the rate of bleeding both during and postprocedure.
This finding is important as it has been previously shown that clopidogrel significantly increases bleeding when performing other bronchoscopic procedures; Ernst et al15 showed that transbronchial biopsies performed in patients receiving clopidogrel is associated with high risk of bleeding. This high risk could be related to the technique of tearing pulmonary and peribronchial blood vessels during the biopsy.15,22 In contrast, EBUS-TBNA is performed with a 21 or 22-G needle with direct ultrasound visualization of the structures being biopsied, and neighboring structures. The latter makes vascular puncture avoidable and therefore less likely. Tissue-blood vessel differentiation is also made easier when using the Doppler option, especially when there is concern regarding indeterminate structures seen on the ultrasound image.23,24 It is imperative to note that our results may not be generally applied to non-EBUS-guided TBNA.
Why are these findings important? Our population is getting older due to novel therapeutic advances in the medical arena.25,26 As a result, the prevalence of individuals with many comorbidities is increasing, and many develop conditions necessitating antiplatelet therapy. Consequently, we frequently encounter these patients in our practice. Importantly, the risks associated with the discontinuation of clopidogrel even for short periods of time can be significant in patients with recently placed bare or drug-eluting coronary stents, or in patients with a history of recurrent cerebrovascular events.27 Several reports have shown that withdrawing clopidogrel therapy in patients who underwent placement of drug-eluting stent can be associated with a marked increase in the risk of coronary thrombosis (29%).7–9 In fact, withdrawal of clopidogrel has been shown to have a rebound effect, with an increase in the hypercoagulation and prothrombotic state.7,28 Unfortunately, no effective bridging regimen exists for these indications. As a result, patients will have to significantly delay diagnostic procedures, and consequently the time from diagnosis to treatment will increase as well. We do advocate though, delaying the procedure if the patient can tolerate withholding clopidogrel.
Our study has several limitations: first, our population was small: as stated in “the Patients and methods section,” both institutions were able to recruit 40 patients. Yet, despite this small number, it is the largest reported in the literature so far. Second, all procedures were carried out by highly trained, experienced operators. The attendings in both institutions were fellowship-trained interventional pulmonologists, and perform all diagnostic and therapeutic bronchoscopic procedures at their respective institutions. Similar diagnostic results, with low complication rates may not be extrapolated to less experienced operators. Finally, 19-G EBUS needles are now available on the market, and our results do not apply to them yet.
EBUS-TBNA can be performed safely in high-risk patients receiving clopidogrel and aspirin in combination, and presenting with mediastinal and hilar adenopathy. In this special category of patients, withholding clopidogrel and aspirin for 5 to 7 days is not necessary as the risk of bleeding is low. Further research and experience in larger studies is required to confirm the result of our study.
1. Chen C, Mu CY, Su MQ, et al. Endobronchial ultrasound-guided transbronchial needle aspiration increases the yield of transbronchial lung biopsy for the evaluation of peribronchial lesions. Chin Med J. 2017;130:11–14.
2. Herth FJ, Eberhardt R, Vilmann P, et al. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax. 2006;61:795–798.
3. Tremblay A, Stather DR, MacEachern P, et al. A randomized controlled trail of standard versus endobronchial ultrasonography
-guided transbronchial needle aspiration in patients with suspected sarcoidosis. Chest. 2009;136:340–346.
4. Verstraete M, Zoldheyi P. Novel antithrombic drugs in development. Drugs. 1995;49:856–884.
5. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel
in addition to aspirin
in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494–502.
6. Moussa I, Oetgen M, Roubin G, et al. Effectiveness of clopidogrel
versus ticlopidine and aspirin
in preventing stent thrombosis after coronary stent implantation. Circulation. 1999;99:2364–2366.
7. Lakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug eluting stent. JAMA. 2005;293:2126–2130.
8. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel
use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007;297:159–168.
9. Park DW, Park SW, Park KH, et al. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up. Am J Cardiol. 2006;98:352–356.
10. Grines CL, Bonow RO, Casey DE Jr, et al. American Heart Association; American College of Cardiology; Society for Cardiovascular Angiography and Interventions; American College of Surgeons; American Dental Association; American College of Physicians. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation. 2007;115:813–818.
11. Kim DH, Daskalakis C, Ilvestry SC, et al. Aspirin
use in the early postoperative period following on-pump and off-pump coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2009;138:1377–1384.
12. Zalt M, Parks C, Bechara R. Thoracentesis in patients on clopidogrel
. J Bronchol Intervent Pulmonol. 2012;19:284–287.
13. Stather DR, MacEachern P, Chee A, et al. Safety of endobronchial ultrasound-guided transbronchial needle aspiration for patients taking clopidogrel
: a report of 12 consecutive cases. Respiration. 2012;83:330–334.
14. Dimov V, Altaqi B. Thoracentesis: a step-by-step procedure guide with photos. Clinical notes. 2004. Available at: http://note3.blogspot.com/2004/02/thoracentesis-procedure-guide.html
. Accessed May 11, 2005.
15. Ernst A, Eberhardt R, Wahidi M, et al. Effect of routine clopidogrel
use on bleeding complications after transbronchial biopsy in humans. Chest. 2006;129:734–737.
16. Certfolio RJ, Minnich DJ, Brayant AS, et al. General thoracic surgery is safe in patients taking clopidogrel
(plavix). J Thorac Cardiovasc Surg. 2012;140:970–976.
17. Swiatek K, Guthrie R, Elliott J. Antiplatelet therapy in patients undergoing EBUS-TBNA
: risk vs benefit. Chest. 2016;150:1123.
18. Meena N, Abouzgheib W, Patolia S, et al. EBUS-TBNA
and EUS-FNA: risk assessment for patients receiving clopidogrel
. J Bronchology Interv Pulmonol. 2016;23:303–307.
19. American College of Chest Physicians (ACCP). November, 2016.
20. Varela-Lema L, Fernandez-Villar A, Ruano-Ravina A. Effectiveness and safety of endobronchial ultrasound-transbronchial needle aspiration: a systematic review. Eur Respir J. 2009;33:1156–1164.
21. Hawes RH, Fockens P, Varadarajulu S. Endosonography. Amsterdam, The Netherlands: Elsevier Health Sciences; 2014:42.
22. Atul M, Prasoon J. Interventional bronchoscopy: a clinical guide. Respir Med. 2009;10:16–31.
23. Herth FJF, Eberhardt R, Vilmann P, et al. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax. 2006;61:795–798.
24. Chen CH, Liao WC, Wu BR, et al. Endobronchial ultrasound changed the world of lung cancer patients: an 11-year institutional experience. PLOS. 2015;10:e0142336.
25. World Health Organization. Global forum on innovations for aging populations. December 2013:1–62.
26. Innovations in healthcare and aging Harvard advanced leadership initiative. 2013:1–38.
27. Thim T, Johansen MB, Chrisholm G, et al. Clopidogrel
discontinuation within the first year after coronary drug-eluting stent implantation: an observational study. BMC Cardiovasc Disord. 2014;14:2261–2275.
28. Newsome LT, Weller RS, Gerancher JC, et al. Coronary artery stents. II: perioperative considerations and management. Anesth Analg. 2008;107:570–590.