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Volume: 22 Issue: 4 April 2024

FULL TEXT

REVIEW
Direct Oral Anticoagulation in Lung Transplant Recipients

Objectives: Presently, the management of direct oral anticoagulants lacks specific guidelines for patients before and after transplant, particularly for lung transplant recipients. We aimed to consolidate the existing literature on direct oral anticoagulants and explore their implications in lung transplant recipients.
Materials and Methods: We conducted a comprehen-sive search in PubMed and Google Scholar databases for studies published between January 2000 and December 2022, using specific search terms. We only included studies involving lung transplant recipients and focusing on direct oral anticoagulants.
Results: Five relevant publications were identified, providing varied insights. None of the studies specifically addressed bleeding complications associ-ated with direct oral anticoagulants in lung transplant recipients. Limited details were available on the type of solid-organ transplant or the specific direct oral anticoagulant used in these studies.
Conclusions: Varied bleeding complications associated with direct oral anticoagulants in lung transplant recipients were reported, but studies lacked specificity on transplant type and direct oral anticoagulant variations. Notably, the incidence of venous throm-botic embolism in lung transplant recipients was comparatively higher than in other solid-organ transplant recipients, potentially linked to factors such as corticosteroid therapy, calcineurin inhibitors, and cytomegalovirus infections. Our synthesis on findings of use of direct oral anticoagulant in lung transplant recipients emphasized challenges of managing these medications in urgent transplant situations. Recom-mendations from experts suggested caution in initiation of direct oral anticoagulants posttransplant until stability in renal and hepatic function is achieved. The limited evidence on safety of direct oral anti-coagulants in lung transplant recipients underscores the need for further research and guidance in this specific patient population.


Key words : Bleeding complications, Calcineurin inhibitors, Corticosteroids, Direct oral anticoagulants, Solid-organ transplant

Introduction

There are several indications for anticoagulation in patients before and after lung transplant. For many years, the standard approach to long-term anticoagulation has involved the use of vitamin K antagonists, such as warfarin, phenprocoumon, and acenocoumarol. Nevertheless, these medications possess a narrow therapeutic window.1 They require regular laboratory monitoring, can interact significantly with food and other medications, and exhibit considerable interpatient and intrapatient variability.2 Furthermore, the use of warfarin in lung transplant recipients with maintenance oral corticos-teroid therapy has been linked to an elevated risk of osteoporosis.3 This is particularly concerning as osteoporosis is already an important risk factor in this population.4

Both sub- and supratherapeutic doses can result in morbidity or potentially even mortality.5 The therapeutic range is determined by the international normalized ratio (INR). In supratherapeutic doses, when INR >5, the relative risk of a major bleeding is 6.4 (95% CI, 3.1-6.6),6 which may necessitate hospitalization or even lead to fatalities. The risks associated with these complications are influenced by factors such as comedication, age, CHA2DS2-VASc score, prior history of major bleeding, and comorbidity.7

New oral anticoagulants, also known as direct oral anticoagulants (DOACs), are considered an appealing alternative to traditional long-term anticoagulation with warfarin, phenprocoumon, and acenocoumarol. They are generally safe and efficient for most patients, achieving full therapeutic effects within 1 to 3 hours of administration. In addition, DOACs do not require direct monitoring and have a fixed-dose regimen. The utilization of DOAC is not linked to an increased risk of osteoporosis.4 In clinical trials that compared DOACs, such as dabigatran, rivaroxaban, apixaban and edoxaban, with warfarin for stroke prevention in atrial fibrillation (AF), patients showed a lower incidence of major hemorrhages, particularly intracranial hemorrhages.8-11

Presently, there are 4 commercially available DOACs. Dabigatran functions as a synthetic thrombin inhibitor, targeting factor IIa. On the other hand, apixaban, edoxaban, and rivaroxaban directly inhibit factor Xa. Although these medications offer attractive options for anticoagulation in various patient populations, a significant question arises regarding their suitability for lung transplant recipients and individuals on wait lists for lung transplant.

Presently, there is a lack of specific guidelines regarding the management of DOACs in both pre- and posttransplant patients. To our knowledge, there have been no formal studies conducted to investigate the pharmacokinetics of DOAC therapy in lung transplant recipients.12 In this article, our objective was to consolidate the existing literature on DOACs and subsequently examine the implications of this therapy in the context of lung transplant recipients.

Materials and Methods

We searched original papers, observational studies, case reports, and meta-analyses published between January 2000 and December 2022 in English in the PubMed database and Google Scholar in adult patients (age >18 years old) with DOAC use after lung transplant. We used the search terms: DOAC OR “direct acting anticoagulant” OR “apixaban” OR “dabigatran” (MeSH) OR “edoxaban” OR “rivaroxaban” (MeSH) AND “Lung Transplantation” (MESH) OR “lung transplant”. We only included studies conducted in lung transplant recipients, excluding those studies conducted in other patients.

Results

Five publications were identified and included (Table 1). Bleeding complications associated with DOAC use in lung transplant recipients were not specifically addressed in any of these studies. In general, the studies did not provide specific information about the type of solid-organ transplant or the type of DOAC used.

Discussion

We found 5 studies on DOACs in lung transplant recipients. Although these studies reported various bleeding complications, they generally did not provide specific details regarding the type of solid-organ transplant and/or the specific DOAC utilized. Anticoagulation can be necessary for lung transplant recipients as a result of various reasons, with the most frequent posttransplant indications being AF, deep venous thrombosis (DVT), and pulmonary embolism (PE).

The overall incidence of DVT and PE is generally higher among solid-organ transplant recipients than among other patient populations. The higher inci-dence of DVT and PE among solid-organ transplant recipients may be attributed to the impaired fibrinolysis caused by long-term corticosteroid maintenance therapy. In addition, in vitro studies have indicated that calcineurin inhibitors (CNI) have procoagulant effects, further contributing to the pathophysiology of thrombotic events in these patients.13 Furthermore, cytomegalovirus infections exacerbate this risk by causing damage to the vascular endothelium.13

In lung transplant recipients, the incidence has been reported to be between 8% and 29%.14-19 In addition, compared with other solid-organ transplant recipients, the incidence of venous thrombotic embolism (VTE) after lung transplant is higher, with incidence of VTE shown to be around 3% to 5% for liver, 2% to 14% for renal, and 7% to 26% for heart transplant recipients.20

Pathophysiology of venous thromboembolic diseases
Venous thromboembolic diseases consist of 2 main conditions: DVT and PE; DVT can result in complications such as the postthrombotic syndrome, whereas PE has the potential to cause chronic thromboembolic pulmonary hypertension or, in severe cases, can even be fatal.21 Venous thrombi can form as a result of venous trauma, such as surgical procedures or indwelling venous catheters.22 Nontraumatic venous embolisms typically originate in the deep veins, mostly of the calf, where they originate in the valve cusps.

The endothelial cells, lining the valve cusps, start to express adhesion molecules on their surface. This process leads to entrapment of tissue factor-bearing leukocytes and microparticles, triggering coagulation.23 The trapped neutrophiles form struc-tures known as “neutrophil extracellular traps,” which can subsequently bind to platelets. This interaction promotes platelet aggregation, ultimately culminating in thrombus formation.24 The formation of a thrombus hampers blood flow, leading to decreased clearance of activated clotting factors, thereby facilitating thrombus formation. Fragments of the thrombus originating from the lower (or occasionally upper) extremities can travel (“embolize”) to the lungs, resulting in a PE.

Oral anticoagulation: pharmacological principles
The existing oral anticoagulant drugs include both vitamin K antagonists and DOACs. The traditional vitamin K antagonists encompass warfarin, phenprocoumon, and acenocoumarol, whereas the DOACs include dabigatran, rivaroxaban, apixaban, and edoxaban.

Vitamin K antagonists
Warfarin, originally developed as a rodenticide, was incidentally discovered in the 1920s in the United States when cattle experienced hemorrhagic disease.25 Investigations revealed that the hemorrhagic disease in cattle was caused by spoiled sweet clover, which led to the identification of a coumarin compound as the bleeding-inducing substance.25 Although it was initially introduced as a rodenticide under the name dicoumarol in 1941, further research and deve-lopment led to the synthesis of warfarin. It was subsequently approved for medical use in 1954.25

Warfarin is the preferred oral vitamin K antagonist in certain countries, notably the United States, where it is widely recognized as the primary vitamin K antagonist under the brand name Coumadin since 1954. In Europe, however, phenprocoumon (marketed as Marcoumar) or acenocoumarol (sold as Sintrom or Sintrom mitis) are more commonly utilized. Warfarin and phenprocoumon are more commonly used compared with acenocoumarol because of their longer half-life (36 hours and 10 hours, respectively). The longer half-life of these medications theoretically allows for more stable anticoagulation.26

Warfarin acts by blocking vitamin K epoxide reductase, which inhibits the conversion of oxidized vitamin K into its reduced form. Consequently, the functional levels of the clotting factors factor X and prothrombin are decreased. From a pharmacological standpoint, 2 distinct warfarin isomers can be identified, each following distinct metabolic pathways. Warfarin consists of R and S enantiomers, forming a racemic mixture. With oral intake, warfarin is absorbed from the gastrointestinal tract and enters the bloodstream, where over 97% to 99% of it binds to albumin. Only the remaining <3% of unbound warfarin retains its biological activity. Hypoalbuminemia can contribute to an increased risk of supratherapeutic blood concentrations of warfarin. This can be attributed to the reduced binding capacity of albumin, resulting in a higher proportion of unbound warfarin circulating in the bloodstream.27

Warfarin is primarily metabolized through the cytochrome P450 (CYP) 2C9 pathway.28 However, certain individuals, particularly around 25% of White populations, possess alternative variants such as CYP2C9*2 and CYP2C9*3. These variants result in reduced (*2) or missing (*3) activity of the CYP2C9 pathway, necessitating lower warfarin doses.29 Homozygosity for CYP2C9*2 or CYP2C9*3, as well as heterozygosity for the combination of CYP2C9*2 and CYP2C9*3 alleles (CYP2C9 *2/*2, *3/*3 and *2/*3 genotypes), may even require a significant reduction in warfarin dose, typically ranging from 50% to 70%.29

The response to warfarin can also be influenced by polymorphisms in the genetic variants of subunit 1 of the vitamin K epoxide reductase complex (VKORC1) alleles. These genetic variants contribute to a substantial portion of the variabilities observed in warfarin dose requirements.30 These polymor-phisms are more commonly found in Asian populations and are less prevalent in African American or Black populations.30 In addition to genetic factors, other elements that can potentially influence the anticoagulant effects of warfarin include diet,31 coadministration of other drugs (such as CNIs),26 and the presence of systemic inflammation.

The monitoring of warfarin therapy is typically conducted by calculating INR, which involves dividing the patient’s prothrombin time by the mean normal prothrombin time and multiplying the resulting ratio by the international sensitivity index. The recommended target INR for most indications is typically set between 2.5 and 3.5. In our setting, the target range is about 2.0 to 3.0 with the intention to reduce the risk of bleeding. Although bleeding complications can still occur within the therapeutic range of warfarin, an INR value above the therapeutic range substantially increases the risk of mild to severe and potentially life-threatening bleeding. Mild bleeding manifestations may include epistaxis, whereas more severe bleeding can manifest as gastrointestinal or intracranial bleeding. In case of bleeding, the management approach involves withholding warfarin, administering vitamin K to the patient, and, in severe bleeding situations, considering the use of 4-factor prothrombin complex concentrate. The specific treatment strategy depends on the severity of the bleeding event.

Direct oral anticoagulants
Direct oral anticoagulants offer a highly favorable benefit-to-risk profile compared with traditional vitamin K antagonists. In the realm of preventive therapy, DOACs serve as viable alternatives to vitamin K antagonists for stroke prevention in patients with nonvalvular AF. When it comes to treating acute VTE, DOACs not only demonstrate noninferiority to vitamin K antagonists but also result in substantially fewer bleeding complications. In the case of acute VTE treatment, DOACs can be initiated in an outpatient setting, except for patients with cancer. In addition, DOACs can be used as thromboprophylaxis, in comparison to enoxaparin, for elective hip or knee arthroplasty. In situations where immediate reversal of anticoagulation is necessary, vitamin K is ineffective for reversing the anticoagulant effects of DOACs. However, idarucizumab has been approved by the Food and Drug Administration for reversing the effects of the thrombin inhibitor dabigatran. Andexanet alfa can be used for reversing the effects of the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban (Table 2).

Pretransplant and posttransplant complications that necessitate systemic anticoagulation
a) Atrialfibrillation
In a group of 224 individuals who underwent lung transplant, 65 (29%) experienced postoperative AF.32 Factors such as pneumonia, mediastinitis, and bronchial dehiscence were identified as risk factors, although AF itself did not independently contribute to mortality.32 Although AF is frequently observed after lung transplant, it is not always benign. In fact, a study indicated a notable mortality rate, with rate of 9% in patients treated with antiarrhythmic medications and rate of 5.8% in patients receiving rate-control therapy.33 Interestingly, postoperative AF as a complication of lung transplant tends to occur relatively late, with an average onset of 7 days and a median onset of 5 days posttransplant.32

Various risk factors have been identified for postoperative AF in lung transplant, including having bilateral lung transplant versus single lung transplant and having a history of coronary artery disease, hypertension, and a higher preoperative risk of AF.32 Of note, the same study found the incidence of postoperative AF to be independent of the indication for lung transplant.32 In contrast to some studies, the posttransplant period for patients with lung fibrosis has been suggested to lead to a higher risk of AF postoperatively, similar to the pret-ransplant period.

The high incidence of AF can generally be attributed to multiple factors in the posttransplant period. These factors include surgical trauma (such as atrial dissection), local inflammation, myocardial injury, adrenergic stimulation leading to catecholamine surge, postoperative autonomic imbalance, and interstitial fluid mobilization. These factors collectively affect the “aged atriums” and contribute to the development of AF.32,33 In our experience, use of perioperative (centrally cannulated) extracorporeal membrane oxygenation (ECMO) also increases the risk of AF. In a comprehensive study of 382 lung transplant patients, the overall incidence of atrial arrhythmias was 25%, with AF occurring in 17.8% of cases and other types of atrial arrhythmias (such as atrial flutter or supraventricular tachycardia) in 7.6% of cases.33

b) Venous thromboembolism
The incidence of VTE in lung transplant recipients varies considerably in the literature, ranging from 9% to 64%.15,16,19,34-37 There is speculation that the increased use of ECMO may contribute to a rise in VTE incidence among these patients.37 Neto and colleagues reported a posttransplant VTE incidence of 73.8% in patients receiving ECMO therapy.37 Of note, VTE has been identified as an independent risk factor for mortality and time to death following lung transplant.37

Risk of direct oral anticoagulant use in patients on lung transplant wait lists
Considering the half-lives of DOACs, their use is contraindicated for patients who are waiting for lung transplant. These patients do not have sufficient time to cease DOAC therapy upon receiving the call for transplant. Like any urgent major emergency surgery, the usual recommendations of postponing the procedure, if feasible, or allowing 1 to 2 elimination half-lives (approximately 13-24 hours) are often impractical for most patients scheduled for urgent lung transplant.38

An additional challenge arises from the fact that the extent of anticoagulation cannot be accurately measured for DOACs, unlike with phenprocoumon and acenocoumarol where the INR can be used. Although the activated partial thromboplastin time for dabigatran and the prothrombin time for rivaroxaban, apixaban, and edoxaban offer some indication of coagulation status, these parameters are unreliable and poorly correlated with plasma drug levels.

For rivaroxaban, apixaban, and edoxaban, which are factor Xa inhibitors, measuring anti-Xa activity with a substance-specific assay can serve as an alternative, as the activity has demonstrated a linear relationship with DOAC concentration. Nevertheless, the interpretation remains difficult; because of the nature of DOACs, target values of anti-Xa activity are not clearly defined. In emergencies involving dabigatran, the administration of idarucizumab can be considered. Idarucizumab is a monoclonal antibody fragment specifically designed to reverse the anticoagulant effects of dabigatran. However, it is not effective for reversing the anticoagulation caused by other DOACs. Clinical experience with idarucizumab in the field of transplant medicine is limited. There have been successful cases of its use in heart-lung transplant patients who were previously on dabigatran therapy.39

Another study reported successful lung trans-plants in 6 patients on dabigatran, with four of them receiving idarucizumab.40 Idarucizumab rapidly reverses the anticoagulant effect within 3 minutes. Alternatively, hemodialysis can remove approximately 60% of the plasma concentration of dabigatran within 2 to 3 hours.38 However, it is important to note that a rebound effect of the drug has been observed, leading to the redistribution of dabigatran from the extravascular to the intravascular space within a few hours after hemodialysis. This necessitates repeat hemodialysis to further minimize the risk of bleeding.38 Of note, the other 3 DOACs are not dialyzable and do not respond to hemodialysis as a reversible option.

The use of prothrombin complex concentrates may be used as a reversal agent in rivaroxaban (and apixaban). In vitro findings suggest that 4-factor prothrombin complex concentrates at the dose of 25 U/kg might suffice to reverse the anticoagulant effects of rivaroxaban.41 Nevertheless, the application of prothrombin complex concentrates could poten-tially heighten the occurrence of thrombotic events by skewing the hemostatic equilibrium toward hypercoagulability.41

Expert recommendations and safety of direct oral anticoagulants in lung transplant recipients
Expert recommendations advise against the use of DOACs in the immediate postoperative period for lung transplant recipients. Direct oral anticoagulant therapy should only be considered once there is stability in renal and hepatic function and when the bleeding risk has been stabilized.12

However, a small study involving thoracic transplant recipients, including 32 lung transplant recipients, suggested that the study population tolerated DOAC therapy relatively well. Bleeding occurred in 21.6% of the study population, with 1 lung transplant recipient on rivaroxaban who experienced a major gastrointestinal bleeding that required transfusion.14 Another small study observed major bleeding complications in 13 of 74 lung transplant recipients receiving anticoagulation therapy, but only 3 recipients were on DOACs.42

Drug-drug interactions
Rivaroxaban and apixaban are both relevant substrates of CYP3A4. All DOACs are substrates of P-glycoprotein (P-gp) with different affinities, ranging from minor pathway for rivaroxaban, relevant pathway for apixaban, and major pathway for edoxaban and dabigatran.43,44

Calcineurin inhibitors, such as tacrolimus and cyclosporine, play a crucial role in the long-term immunosuppressive therapy to prevent organ rejection in transplant medicine. These CNIs share certain metabolic pathways, as they are substrates of the cytochrome P450 isoenzymes CYP3A4 (major pathway for both tacrolimus and cyclosporine) and CYP3A5 (relevant pathway for tacrolimus, minor pathway for cyclosporine), which are part of the CYP3A metabolic pathway. Another common metabolic pathway shared by CNIs and DOACs is the P-gp pathway. Inhibitors of the CYP3A and/or P-gp pathway can lead to increased blood concentrations of CNIs.

A generally nonclinical and substantial alteration of CNI levels can be induced by DOACs, particularly with cyclosporine, although the precise mechanism of this interaction remains unknown. However, the typical drug-drug interaction studies involving CYP3A4 and P-gp substrates for regulatory approval have clearly demonstrated that DOACs do not affect these enzymes.45,46

The potential drug-drug interactions between apixaban and cyclosporine or tacrolimus have been studied in healthy volunteers.47 In a small study involving 12 healthy male volunteers, no dose adjustments were necessary when using cyclosporine alone or in combination with tacrolimus during treatment with apixaban.47

Another study indicated that apixaban and rivaroxaban might lead to a slight increase (<20%) in CNI concentrations, but this effect is unlikely to warrant an adjustment in dosage.45 The authors recommended monitoring the CNI levels within 5 to 7 days after initiation of a DOAC.45 It is worth noting that cyclosporine may have a higher likelihood of inhibiting drug-metabolizing enzymes and transporters compared with tacrolimus.12

The benefit-to-risk ratio of DOACs, particularly rivaroxaban, may be negatively affected by antimycotic drug treatment, especially itraconazole. Combining DOACs with itraconazole, which inhibits both CYP3A4 strongly and P-gp moderately, can lead to abnormally high levels of DOACs.

However, the combination of rivaroxaban, apixaban, and edoxaban with itraconazole or other azoles inhibiting CYP3A4 and P-gp simultaneously has been well studied: The Swiss medicinal product information of Xarelto (rivaroxaban) describes an increase of the concentration of rivaroxaban of an average of 2.6 times if administrated together with azoles such as itraconazole,48 which can lead to potential strong bleedings.

The maximal concentration and area under the curve of apixaban were shown to increase by 62% and 99%, respectively, when given together with ketoconazole.49 This finding correlates with the recommendation of the US label of Eliquis (apixaban) to give only half of the dose (5 mg or 2.5 mg twice daily instead of 10 mg or 5 mg twice daily), respectively, to avoid apixaban if the accurate dose is 2.5 mg twice daily if combined with an inhibitor of CYP3A4 and P-gp.

For edoxaban, the area under the curve was increased to mean of about 2.3-fold if given together with ketoconazole, because of the inhibition of P-gp, as edoxaban is not a substrate of CYP3A4.50 This finding also correlated with the recommendation of the US label to prescribe 30 mg daily instead of 60 mg daily if given along with an inhibitor of P-gp. In the pharmacovigilance database VigiBase from the World Health Organization (WHO), a search for the combination of itraconazole with either rivaroxaban or apixaban showed 16 and 3 individual case safety reports, respectively, whereas the combination of itraconazole and edoxaban showed 0 individual safety reports.51,52 This could be partially explained by the less important potential for drug-drug interaction of edoxaban compared with rivaroxaban and apixaban. However, of note, case reports from the WHO database do not necessarily indicate an actual causal relationship between adverse events with medication intake because of the nature of the spontaneous reporting system.

Other antimycotics, like voriconazole and fluconazole, can increase rivaroxaban and apixaban levels. However, voriconazole and fluconazole, being CYP3A4 inhibitors but not P-gp inhibitors, have a lesser effect on rivaroxaban and apixaban levels and no effect on edoxaban levels. Because of the less important potential for a drug-drug interaction, edoxaban seems us to be the substance of choice if a DOAC is necessary after lung transplant. Although measurement of maximal concentration and trough concentrations can help prevent overdosing, these procedures are not helpful to monitor the efficacy of the therapy, as there are no clinically validated target levels.

Direct oral anticoagulants and the risk of lung allograft dysfunction
To date, few studies or trials have specifically assessed the safety of DOACs in relation to lung allograft dysfunction. However, in other solid-organ transplant recipients, DOACs have been investigated in limited case series. In the WHO pharmacovigilance database VigiBase, a search for the preferred term “lung transplant rejection” using standardized MedDRA queries showed 0 cases with rivaroxaban, apixaban, edoxaban, or dabigatran as suspected or concomitant drug.51,52 However, lack of data in the WHO database does not necessarily indicate an actual inexistant relationship between adverse events with medication intake because of the nature of the spontaneous reporting system.

Evaluation of the use of direct oral anticoagulants in routine biopsies after lung transplant
During the first year after lung transplant, routine bronchoscopy procedures including bronchoalveolar lavage and transbronchial or cryo-biopsies are commonly conducted to assess for rejection in surveillance bronchoscopies.

However, when patients are on DOACs, these medications must be temporarily discontinued before the endobronchial intervention. In contrast, patients on vitamin K antagonists who may have forgotten to discontinue their medication can be treated with vitamin K and do not necessarily need to postpone the bronchoscopy. The absence of readily available reversal agents for DOACs in this context necessitates rescheduling the intervention, resulting in increased costs and potential strain on health care resources.

Impact of nephrotoxic medication on the dosage of direct oral anticoagulants in lung transplant recipients
Renal function in lung transplant recipients can often be variable due to the administration of nephrotoxic medications. This variability poses a challenge in determining the appropriate dosage of DOACs for these patients. Direct oral anticoagulants are generally considered safe in patients with creatinine clearance of above 30 mL/minute without concomitant use of an inhibitor of CYP3A4 and/or P-gp.

Conclusions

In lung transplant recipients, specific complications can necessitate systemic anticoagulation, such as postoperative AF and VTE. The use of DOACs in patients on lung transplant wait lists can have challenges, but potential options may be available for reversal in urgent transplant situations. As we have shown here, recommendations from experts suggested caution in initiation of direct oral anticoagulants posttransplant until stability in renal and hepatic function is achieved. The limited evidence on safety of direct oral anticoagulants in lung transplant recipients underscores the need for further research and guidance in this specific patient population.


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Volume : 22
Issue : 4
Pages : 249 - 257
DOI : 10.6002/ect.2023.0338


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From the 1Division of Pulmonology, University Hospital Zurich; the 2Faculty of Medicine, University of Zurich; and the 3Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: René Hage, Division of Pulmonology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
Phone: +41 44 255 9111
E-mail: rene.hage@usz.ch