Authors: Lilach Israeli-Shani, Avishag Tzur Dotan, Elad Guber, Ayal Romem, David Shitrit
Categories: Research Article, Aspirin, Clopidogrel, Cryobiopsy, Guidelines, Practice management
Source: Heliyon
Aspirin has been shown to be safe for patients undergoing certain diagnostic bronchoscopy procedures, such as transbronchial biopsies and endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration. However, there are no studies documenting the safety of aspirin in patients undergoing trans-bronchial lung cryobiopsy (TBLC).
To determine whether aspirin increases the risk of bleeding during or following TBLC.
172 consecutive patients undergoing TBLC were included in this retrospective cohort study. Data on demographic characteristics, comorbidities etc. were collected. Bleeding severity was defined by the intervention needed to stop the mild-cold saline injection, moderate-adrenalin/hexakarpon injection, or severe - Intensive Care Unit admission after bronchoscopy.
Fifty-one patients (29.6 %) were under aspirin treatment at the time of TBLC. Overall, there was no significant difference between the aspirin and the control groups regarding the incidence of moderate-severe bleeding (41.2 % vs. 33.1 %, respectively, p.0.31). the Clopidogrel was found as a risk factor for increased bleeding when taken together with aspirin (Odds ratio = 9.8 (1.1–86), p = 0.013). When taken alone, clopidogrel was also found as a risk factor to increased bleeding, yet these results didn't reach significance due to low number of patients (fig. 1, N = 5, Odds ratio = 2.8 (0.46–17.35), p = 0.245). No difference was observed between the groups regarding additional post-procedural complications, including pneumothorax, hospitalizations, and mortality.
To the best of our knowledge, this is the first study examining bleeding risk of cryobiopsy under aspirin treatment. Based on our results, it seems safe to perform TBLC under aspirin treatment, except for patients who are concurrently treated with clopidogrel. Further research should be conducted to substantiate this conclusion.
Keywords: Aspirin, Clopidogrel, Cryobiopsy, Guidelines, Practice management
Aspirin is effective for the treatment of pain, fever, and inflammation, with the main indication being secondary prevention in patients who sustained a myocardial infraction or cerebrovascular accident. It is estimated that over 25 % of patients are prescribed aspirin on a regular basis [1], although recent recommendations from the US Preventive Services Task Force (USPSTF) suggest otherwise [2]. Along with the benefit of reduced incidence of cerebrovascular accident due to increased thrombosis, comes the risk of increased bleeding. A recent meta-analysis estimated the risk of spontaneous bleeding from low dose aspirin treatment to be up to 3.6 % [3]. Moreover, as recently reviewed in a large meta-analysis by Wang et al. [4], the benefit of low-dose aspirin was equally balanced by major bleeding events, especially for patients over the age of 70.
Transbronchial lung cryobiopsy (TBLC) is used increasingly as an alternative to video-assisted thoracoscopic surgery (VATS) and transbronchial biopsy (TBB) procedures, as it allows larger tissue sampling [5,6]. In combination with clinical and radiological information, TBLC reaches a similar confidence level as surgical lung biopsy [7,8]. Although larger biopsy samples improve the diagnostic yield [[9], [10], [11], [12], [13]], there is an increased risk of bleeding, which may be further increased in subjects under aspirin treatment. Several studies tested the bleeding risk of patients undergoing TBB under aspirin therapy and concluded that there is no evidence to justify the cessation of aspirin therapy before the endoscopic procedure because bleeding severity was similar between the groups [1,14,15]. The CHEST guidelines emphasize the use of reduced-dose direct oral anticoagulants (DOACs) over aspirin or no therapy for deep vein thrombosis (DVT) and pulmonary embolism (PE) in non-cancer patients. In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, they suggest aspirin over no aspirin to prevent recurrent VTE [16].
Recent guidelines regarding the use of anti-platelet therapy during bronchoscopy procedures suggest that the decision should be individualized, although considered a low-risk procedure [17]. Since the chance of bleeding is higher in TBLC as compared to TBB [18], there is an unmet need to explore which procedures can be safely performed without discontinuing aspirin therapy.
This study evaluated whether aspirin increases the risk of bleeding during or right after TBLC.
This retrospective cohort study included all consecutive eligible patients who underwent TBLC between November 2019 and August 2022 at Meir Medical Center. The incidence of complications between patient continuing aspirin treatment vs. those who did not (control) was compared. Intake of clopidogrel was also recorded.
Inclusion criteria: All patients over the age of 18 undergoing cryobiopsy for parenchymal findings with or without aspirin and/or clopidogrel treatment. Available data regarding bleeding and outcomes of the procedure in the electronic records.
Patients who were treated with anti-coagulation or anti-aggregation therapy other than aspirin, which could not be stopped prior to the procedure, patients undergoing cryobiopsy for endoluminal lesions, laboratory results of INR >1.5 or platelets <100 before the procedure. Patients treated with clopidogrel were allowed to continue the medication. Patients were considered as ‘on aspirin’ during TBLC if they had consumed aspirin within the preceding 48 h.
The following data was collected from electronic records for each age, sex, comorbidities, anti-aggregation or anti-coagulation, medication before and during the procedure, lab tests (hemoglobin, platelets, INR, systolic pulmonary arterial pressure estimated by cardiac echo), indication for the procedure, complications (bleeding, pneumothorax, hospitalization, 30-day and total mortality rates of a 1-year follow-up), and histological diagnosis.
All TBCB procedures were performed by two interventional bronchoscopists under general anesthesia/deep sedation with spontaneous breathing. An endotracheal tube was used to secure the airway. The TBCB was performed using two bronchoscopes (Olympus TH 190; Olympus, Tokyo, Japanese), as previously described (17). An Erbe (Tübingen, Germany) 1.9 (reusable)-cryoprobe or 1.7 mm (single use) cryoprobe was advanced through the working channel of the first bronchoscope to the distal lung parenchyma under fluoroscopic guidance. The probe was withdrawn approximately 1 cm from the point of resistance, and cryofreezing was activated with freeze times of 3–8 s. The bronchoscope and cryoprobe were then withdrawn en-bloc and handed to an assistant. Immediately, the second bronchoscope was advanced into the airway and wedged at the target bronchus to control bleeding. Once thawing was adequate, the specimen was removed from the probe and preserved in a formalin solution. All patients underwent a chest x-ray following the procedure and were monitored for an additional 2 h before discharge.
It was estimated (based on our prior observations) that bleeding rate would not change significantly due to Aspirin use. Thus, a specified time period was set, and all patients within the 3 year period were included. The primary outcome was bleeding severity, which was defined according to the intervention needed to stop the Mild - cold saline injection treatment, Moderate - adrenalin/hexakarpon injection, or Severe - Intensive Care Unit admission after bronchoscopy. Secondary outcomes included incidence of pneumothorax, hospitalizations and 30-day mortality. Pneumothorax was evaluated by chest X-ray following the procedure.
Continuous variables are presented as mean or median with standard deviation (SD), or as numbers and percentage for nominal parameters. The study groups were compared using t-test, Mann-Whitney test, Fisher's exact test or Pearson chi-square test according to the scale of the measured variables. Multivariate binary logistic regression was done to account for covariates. The difference between the groups was considered statistically significant at a two-sided p-value of <0.05. All data were analyzed using SPSS-25 software (IBM Corp., Armonk, NY, USA).
All patients who underwent bronchoscopy with TBLC from November 2019 to August 2022 were eligible. Of the 172 patients included, 60 (34.9 %) were taking aspirin daily before the TBLC, and 112 (65.1 %) were not (Fig. 1). Table 1 shows the patient characteristics of the aspirin and no aspirin groups. As expected, it was found that the group taking aspirin is overall older, includes more males, and a higher percentage of individuals with IHD, hypertension and diabetes (Table 1).
Fig. 1 Flow chart of study design.
Of the 60 patients taking aspirin, 51 (85 %) continued the treatment despite having the TBLC (Fig. 1). Among all patients, bleeding was classified as mild in 47 patients (27.3 %), moderate in 53 patients (30.8 %), and severe in 8 patients (4.7 %). The aspirin group included a higher percentage of males and the average age was older than in the no aspirin group (median age 69.9 vs. 61.8 years; p = 0.001). As expected, more patients taking aspirin had ischemic heart disease (IHD), hypertension and diabetes.
There was no significant difference in the total bleeding rate, including mild bleeding, between aspirin users (60.8 %) and those not using aspirin (63.6 %, p = 0.724, Table 2).
In total, 11 patients also received Clopidogrel (Plavix), which was continued until the TBLC procedure. Of the 11 patients, six continued Aspirin and five did not. After extracting the patients treated with Clopidogrel in addition to Aspirin (n = 6), no difference was observed between the Aspirin group and the control group, even in the moderate-severity bleeding. Notably, the Clopidogrel was found as a risk factor for increased bleeding when taken together with aspirin (Fig. 2A, Odds ratio = 9.8 (1.1–86), p = 0.013).
Fig. 2 (A) The combination of clopidogrel and aspirin increased the rate of moderate-severe bleeding during TBLC. Patients in the control group were not taking aspirin nor clopidogrel. (B) Survival analysis for mortality from any cause for patients taking aspirin (n = 51, black line) vs. those that did not (n = 107, grey line). ** indicates p = 0.01. TBLC, trans-bronchial lung cryobiopsy.
Moreover, following a multivariate binary linear regression that took into account the significant differences found above (i.e. factors found significant in Table 1, as well as smoking and clopidogrel), the significance of Aspirin intake on any bleeding event was 0.97 (Table 2). An additional analysis, testing only the moderate-severe bleeding events as the outcome, with the same confounding factors as above, showed that the odds ratio of Aspirin treatment was 1.24 (p = 0.93).
Cancer is known to be a risk factor for beeding during bronchoscopy. Thus, a separate analysis was done for all patients diagnosed with NSCLC retrospectively. In fact, a small difference in bleeding incidence was observed between the aspirin and no aspirin groups (excluding clopidogrel) among subjects with cancer, with the non-cancer group experiencing more bleeding events (2/7 (28.5 %) vs. 24/38 (63 %), p = 0.09, respectively).
A total of 11 patients also received clopidogrel (Plavix), which was continued until the TBLC procedure (Fig. 1). When taken alone, clopidogrel was also found as a risk factor to increased bleeding, yet these results didn't reach significance due to low number of patients (Fig. 2A, N = 5, Odds ratio = 2.8 (0.46–17.35), p = 0.245).
The secondary outcomes, which included pneumothorax, hospitalization and 30-day mortality are shown in Table 3. Since it was found Plavix was a significant confounder of the results, we analyzed complication rate with and without clopidogrel. Although significant impact was observed on bleeding rates, extraction of the patients receiving clopidogrel did not change AE rate, suggesting complications were not associated with clopidogrel use (Table 3). In total, 8 patients (4.7 %) developed pneumothorax after undergoing TBLC, of them 7 needed hospitalization. Thus, pneumothorax was added to the regression calculation of hospitalization (OR = 431 for hospitalization, p < 0.001). Sixteen (9.3 %) subjects needed hospitalization following the procedure, among which none died within the following 30 days. A total of 24 cases were performed during hospitalization. Among them, 2 patients (7.7 %) died within 30 days, from their baseline fibrotic lung disease. Overall survival (total mortality from any cause) during a 1-year follow-up was similar between the groups (82.4 % and 81 %, aspirin vs. control, Kaplan-Meier analysis, Log Rank p = 0.92, Fig. 2B)
Bleeding is a worrisome complication of TBLC [8,19,20]. Due to lack of formal guidelines and scarce evidence in the literature regarding continuing aspirin before TBLC procedures, this treatment is frequently discontinued even in high-risk patients with cardiovascular disease. Our study aimed to evaluate the risk of bleeding among patients undergoing TBLC while under aspirin treatment. Overall, we found no difference in bleeding frequency between study groups. However, clopidogrel (Plavix) was found to increase bleeding severity.
Cardiovascular disease is the major cause of mortality globally [20], accounting for more than 1 in 4 deaths in the US [2]. The benefits of aspirin in lowering mortality, myocardial infarction, and stroke vs. the risk of bleeding and other side-effects is a subject of controversy [[21], [22], [23]]. While the European Society of Cardiology clinical guidelines provide definitive recommendations for low-dose aspirin in patients with stable cardiovascular disease, the American College of Cardiology–American Heart Association guidelines are not definitive [21,24,25]. Furthermore, the USPSTF recently recommended against initiating low-dose aspirin use for primary prevention of cardiovascular disease in adults 60 years or older [2]. A recent real-world clinical practice study that evaluated major bleeding risks and mortality among individuals receiving antiplatelet drugs, found that the incidence of major bleeding and mortality was low, overall. In monotherapy, low-dose aspirin was the safest therapeutic option, whatever the indication [26]. However, for treatment of DVT or PE, the overall recommendation is the use of reduced-dose DOACs over aspirin or no therapy in non-cancer patients [16].
The risk of bleeding related to diagnostic bronchoscopy procedures while taking aspirin has been studied and reported in the literature [1,14,15]. In a large prospective study by Herth and colleagues, continuation of aspirin before transbronchial biopsy did not increase the risk of bleeding [1]. A total of 1217 patients were prospectively enrolled, of whom 285 (23 %) were prescribed aspirin. Less than 1 % of the patients experienced severe bleeding. Moreover, all episodes of bleeding were controlled bronchoscopically [1]. Based on these results, aspirin use is considered to be well-tolerated during TBB. Moreover, small series have confirmed the safety of EBUS-guided transbronchial needle aspiration (TBNA), while on dual antiplatelet therapy consisting of aspirin and clopidogrel [27]. Our findings, showing no increased rates of bleeding following TBLC support these results.
TBLC itself may be considered a relatively risky procedure. However, this highly depends on the experience of the performing centers [6]. In a meta-analysis of 13 studies investigating the yield and safety of cryoprobe for performing 764 TBLC lung biopsies in subjects with diffuse pulmonary parenchymal diseases; overall, there were 55 (7.2 %) major complications. Pneumothorax occurred in 52 (6.8 %), severe bleeding in 2 (0.3 %), and one death (0.1 %) [28]. Kassem et al. demonstrated that aspirin use was not associated with increased risk of bleeding or therapeutic bronchoscopy-related complications [14]. In another meta-analysis by Ravaglia et al. [29], no episodes of severe bleeding were reported. The overall pooled probability of developing a moderate bleeding, as derived from 12 studies, including 383 patients, was 0.12 (95 % CI 0.02–0.25). The rate of moderate to high bleeding in our study was about 35 %. These results agree with recent reports that showed an average rate of 38.9 % for moderate bleeding in patients during/following cryobiopsy [30].
Dual antiplatelet therapy (DAPT) combines aspirin and a P2Y12 inhibitor (Clopidogrel). Active metabolites of clopidogrel irreversibly bind to the platelet P2Y12 receptor, thereby inhibiting ADP-induced platelet activation and aggregation. Maximum platelet inhibition takes 5–10 days with a maintenance dose of 75 mg·day−1, as compared to 12–15 h after a loading dose of 300–600 mg [17,31]. Clopidogrel maintenance therapy is considered clinically effective for preventing cardiac death, myocardial infarction, stroke, and acute ischemic events. However, especially in comparison to aspirin, it has been investigated less often and the guidelines are even less clear. The decision to stop clopidogrel prior to the bronchoscopic procedure can be challenging, especially when there is an increased risk for thromboembolic events such as in-stent thrombosis [17].
We found that a subset of subjects receiving clopidogrel had significantly increased bleeding rates. The safety of performing transbronchial biopsy in patients receiving clopidogrel was evaluated by Ernst et al. that showed showed a 100 % bleeding rate in the group receiving a combination of clopidogrel and aspirin (p < 0.001) [32]. These results were contradicted by Stather et al. [27] that showed no significant bleeding in all 12 consecutive cases that received clopidogrel and underwent EBUS-TBNA, and hence suggested that the procedure can be safely performed. However, they recommended continuing clopidogrel through the procedure only if the risk of short-term thrombosis outweighed the risk of bleeding. In a large meta-analysis, Nguyen et al. concluded that dual antiplatelet therapy, extended clopidogrel therapy, and high maintenance dose (150 mg/day) of clopidogrel were definite risk-factors for any bleeding [33]. In patients with atrial fibrillation, all combinations of warfarin, aspirin, and clopidogrel were found to be associated with increased risk of nonfatal and fatal bleeding. Dual warfarin and clopidogrel therapy and triple therapy carried a more than 3-fold higher risk compared to warfarin monotherapy [34]. These findings warrant further evaluation and suggest discontinuing clopidogrel treatment before TBLC procedures, when possible.
Of note, is an interesting observation by Goh et al. [35], while prospectively examining patients undergoing neuro-interventional procedures. They found that hyper-response to clopidogrel is associated with increased risk of major hemorrhage. P2Y12 receptor–mediated platelet inhibition was tested by using the VerifyNow device. Measured response to clopidogrel varied from 0 % to 99 % (median, 30 %; IQR, 12%–61 %). Moreover, genetic polymorphism of the CYP2C19 allele, crucial to metabolism of clopidogrel into its active metabolite, has been implicated as a mechanism of both hyper- and hypo-response [36]. Therefore, adding these tests prior to the procedure may also present with an effective strategy for anti-coagulation management for this subset of patients.
This study had several limitations, many of which are inherent in the retrospective nature of the study. This was a single-center experience, and the sample size was relatively small, which made it difficult to generalize the results. Patients in the aspirin group were slightly older, which is likely due to increased use of aspirin in older patients with IHD and comorbid diseases. However, bleeding was similar between the groups, despite the increased rate of comorbidities. Moreover, all these confounding factors were accounted for in a multivariate analysis, which actually strengthened the observation that aspirin use does not have an effect on bleeding events during the procedure. Due to the small number of patients in the severe bleeding group, moderate and severe groups were combined. Similar results were obtained for this group, showing again no significant impact of aspirin and bleeding events. One important critique of the study could be that the exact amount of blood loss during procedures was not quantified. Alternatively, we used selected interventions to manage bleeding to categorize it as mild, moderate or severe, which may have caused inter-observer bias [32]. Despite its limitations, this is still the first study to suggest that patients undergoing TBLC may be able to continue taking aspirin without excessive risk of bleeding.
We conclude that patients treated with both aspirin and clopidogrel, but not aspirin alone, are at higher risk for moderate to severe bleeding during TBLC. Prospective randomized multicenter studies are warranted to corroborate these findings and to further develop the standards for clinical practice in this area.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments. The study protocol was reviewed and approved by the Meir Medical Center IRB, approval number MMC- 20–0073.
For this type of study, no formal consent was required.
No funding was received for this study.
All data generated or analyzed during this study are included in this article. The data that has been used is confidential as per IRB regulations. Further enquiries can be directed to the corresponding author.
Has data associated with your study been deposited into a publicly available repository? No, as the data that has been used is confidential.
This study was not funded.
Lilach Israeli-Shani: Writing – original draft, Validation, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. Avishag Tzur Dotan: Writing – original draft, Validation, Project administration, Methodology, Investigation, Formal analysis, Data curation. Elad Guber: Writing – original draft, Validation, Resources, Investigation, Data curation, Conceptualization. Ayal Romem: Writing – review & editing, Supervision, Resources, Methodology, Investigation, Formal analysis, Conceptualization. David Shitrit: Writing – review & editing, Validation, Resources, Investigation, Funding acquisition, Conceptualization.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
We thank Navah Jelin, MS for assisting with the statistical analysis. She is an employee of Meir Medical Center.
The following is the Supplementary data to this article.
All data generated or analyzed during this study are included in this article. The data that has been used is confidential as per IRB regulations. Further enquiries can be directed to the corresponding author.
Has data associated with your study been deposited into a publicly available repository? No, as the data that has been used is confidential.