Muhammad A Bukhari,Abdulrahman Al-Theaby,Mohammed Tawhari,Ali Al-Shaggag,Ryan Pyrke,Azim Gangji,Darin Treleaven,Christine Ribic

Abstract

Key words: Novel oral anticoagulants； Adult patients； Kidney transplantation； Renal outcomes； Efficacy

INTRODUCTION

Non-Vitamin K antagonists also known as novel oral anticoagulants (NOACs) were developed as alternatives to vitamin K antagonists,primarily warfarin,as they do not require routine monitoring and have limited drug-drug and drug-food interactions[1].NOACs are gaining popularity over the past few years as stroke-preventing agents for people with atrial fibrillation (AF)[1].NOACs have also been recommended for the treatment of systemic embolic events in patients with nonvalvular AF and for the treatment of venous thromboembolism (VTE)[1-3].They are recommended by the Canadian Cardiovascular Society guidelines for the management of AF with a class I recommendation[4].Four NOACs,(dabigatran,rivaroxaban,apixaban,and edoxaban)have received approval from the United States Food and Drug Administration for the prevention of AF.

Kidney transplantation is considered the treatment of choice for patients with endstage renal disease (ESRD) and has been shown to improve quality of life and survival rate for most patients compared to those maintained on dialysis[5,6].AF occurs in over 7% of kidney transplant recipients in the first 3years after transplantation and is associated with reduced graft and patient survival[7].NOACs represent a valuable anticoagulation therapy for kidney transplant recipients,which are at higher risk of bleeding and thrombotic complications.However,NOACs use in renal transplant patients is not yet recommended as they are excreted via kidney and there are concerns it may interact with immunosuppressive therapy[5,7].Indeed,as substrates of CYP3A4,apixaban and rivaroxaban,and p-glycoprotein,dabigatran； NOACs were suggested to interact with calcineurin inhibitors (CNIs) in a small retrospective study[8].In heart and lung transplant recipients,a recent study showed that NOACs were effective and safe but associated with high rate of drug interactions that require dose reduction (by 45%)[9].

Given the fact that NOACs don't require frequent monitoring and due to their low interactions and lower risk of spontaneous bleeding,these agents carry a great advantage over warfarin[1].However,the efficacy and safety of these agents in kidney transplantation are not well studied yet.In this study,we aimed to assess the safety of NOACs administration in patients after kidney transplantation,and to provide recommendations and guidelines on therapeutic strategies in these patients.

MATERIALS AND METHODS

This was a retrospective study carried out among adult patients who were actively on the following NOACs (apixaban,rivaroxaban or dabigatran) in our renal transplantation program from December 2015 to December 2016.The patients were identified primarily through the electronic medical record system (patient data linkage).We also included renal transplant recipients whose anticoagulation therapy with NOACs were stopped or changed but had at least one-year record of use of NOACs corresponding with our study period (i.e.,up to one year of use be December 1,2016).

1.3療效判定方法我們將患者的臨床治療分成了三個等級。顯效:患者的瘤體完全被切除,使用CT檢測,沒有發(fā)現(xiàn)殘留,病灶完全消失;有效:患者的瘤體縮小至少50%,存在部分殘留。無效:患者的瘤體縮小不足25%,有超過一半的病灶殘留。

Only records of adult patients (age ≥ 18 years) were included.Data of pediatric renal transplant recipients,adult patients with medication adherence issues,and those who stopped NOACs ＞12 mo prior to the study,were excluded from the analysis.The electronic records of the patients were retrieved from the electronic medical record system (Patient link).The data of patients with incomplete information were available in the electronic medical record system were extracted from the patients' paper charts.Data on the clinical and laboratory profile of the patients were extracted.

Statistical analysis

The study was approved by Hamilton Integrated Research Ethics Board (HiREB).Also,because this was a retrospective study of anonymized/deidentified electronic records,HiREB waived request for informed consent from patients.Data were analyzed with SPSS 22.0 (IBM Corp.,NY,United States).Continuous variables were expressed as means ± standard deviations and categorical variables were expressed as percentages.Chi-square tests were used for categorical variables and unpairedt-tests and one-way analyses of variance were used to compare continuous variables.Pvalues ＜ 0.05 were considered significant.The statistical methods of this study were reviewed by Dr.Mamta Gupta PhD (Public Health and Epidemiology/MPH Epidemiology and Biostatistics) from the Department of Epidemiology and Biostatistics,Alchemist Research and Data Analysis,Chandigarh,160 036,India.

實時跟蹤系統(tǒng)就是跟蹤、記錄學(xué)生的學(xué)習(xí)過程和教師的教學(xué)過程，得到大量的學(xué)習(xí)數(shù)據(jù)和教學(xué)數(shù)據(jù)，并智能化分析這些數(shù)據(jù)，得出有建設(shè)性的結(jié)論和建議，為改進教學(xué)和學(xué)習(xí)提供強有力的指導(dǎo)。這一功能模塊與銅職院的質(zhì)量管理辦公室所做的工作切合，質(zhì)量管理辦公室的主要任務(wù)就是對學(xué)校教學(xué)質(zhì)量進行診斷改進分析研判。實時跟蹤系統(tǒng)不僅對單個教師的教學(xué)提供幫助，更是對整個學(xué)校的教學(xué)改革和教學(xué)研究提供大數(shù)據(jù)支持。因此這是學(xué)校應(yīng)該重點建設(shè)的第二個模塊，此方面可能涉及到人臉識別、智能跟蹤定位、數(shù)據(jù)存儲等相關(guān)的技術(shù)。

RESULTS

Our cohort included a total of 47 patients； only 42 patients were retained for further analysis after excluding 5 patients due to incomplete data.The clinical characteristics of patients are presented in Table 1.Most patients were males 25 (59.5%) and the vast majority 28 (66.7%) were older than 60 years old with 11 (26.2%) being ≥ 75 years old.The mean age in our cohort was 64.7 ± 13.88 years.The mean duration since renal transplantation of the patients was 8.8 ± 7.4 years (range 1 to 30 years).The average estimated glomerular filtration rate (eGFR) was 62.90 ± 18.98 mL/min/1.73 m2.No significant difference in eGFR among age groups was noticed.A total of 38 patients were white (90.5%)； only 2 were Asian,1 Indian and 1 Hispanic.The Most common causes of ESRD in our cohort were hypertension and polycystic kidney disease,occurring in 8 patients (19.0%) each,followed by 7 patients with diabetic nephropathy and chronic glomerulonephritis (16.7%) (Table 2).

A total 29 patients (69%) were treated with apixaban,10 patients (23.8%) with rivaroxaban and 3 patients (7.14%) with dabigatran (Table 2).Among those that were on apixaban,58.6% were on low dose of 2.5 mg bid and 41.3% were on full dose of 5 mg bid.Similarly,of the 10 patients on rivaroxaban,5 were on a full daily dose of 20 mg and 5 were on reduced daily dose of 15 mg.In our cohort,25 patients (59.5%)were on NOACs due to AF,10 patients (23.8%) due to VTE and 5 patients (11.9%) due to both AF and VTE.Most patients were on tacrolimus-based anti-rejection(immunosuppressive) therapy (31； 76.8%) and 5 patients (11.9%) were on a cyclosporine-based regimen,and only 4 patients (9.6%) were on sirolimus-based regimen.In addition,all the 42 patients (100%) received oral prednisolone and mycophenolate mofetil.Table 3 shows the profile of the immunosuppressive agents received according the type of NOAC agent.NOACs were used without a concomitant antiplatelets therapy in 37 of the patients (88.1%).

Overall,we observed 3 bleeding events (7.1%) in our cohort consisting of 1 patient treated with rivaroxaban 15 mg daily and 2 patients who received apixaban 2.5 mg twice daily (Table 4).One of these was a major bleeding event which occurred while rivaroxaban was on hold for over a month in preparation for a cataract surgery.The patient had a background of severe retinopathy and had intraocular bleeding one day after the surgery.This bleeding event was assumed to be unrelated to the medication,and rivaroxaban was resumed a few months later.This patient didn't experience any further bleeding events after rivaroxaban resumption.The other two bleeding events were bleeding per-rectum events that occurred in two ladies on low-dose apixaban.There were no significant reduction in the patients creatinine,eGFR or CNI levels at the time of the events.The bleeding events in both cases were minor,didn't cause hemodynamic instability,and didn't require surgical intervention or complete cessation of NOACs.

On the other hand,no thromboembolic events (0%) were observed.In addition,no significant change in serum tacrolimus level was observed three days after the initiation of NOACs among patients treated with tacrolimus (pre- and post-NOACs serum tacrolimus level was 7.25 and 7.89 ng/mL,P= 0.55).Similarly,after one year of treatment with NOACs there was no significant change in the pre- and post-NOACs serum creatinine level with mean levels of 107.6 μmol/L and 113.11 μmol/L (P=0.772) respectively,(median 107.5vs108.5 μmol/L,respectively).This is summarized in Figure 1.Besides,as shown in Figure 2,pre- and post-NOACs eGFR levels after one-year of treatment with NOACs did not significantly change with respective mean levels of 72.2 mL/min/1.73 m2and 65.9 mL/min/1.73 m2(P= 0.232； median: 68.2vs60.4 mL/min/1.73 m2,respectively).

Table 1 Demographic characteristics of the patients

DISCUSSION

Dabigatran was the first NOAC agent released into the European market for VTE prophylaxis post joint replacement surgeries in 2008[1].It was the first NOAC agent to get Food and Drug Administration approval for AF in 2010,and VTE in 2014.International recommendations suggested the need to change NOACs name from novel oral anticoagulation drugs to non-vitamin K antagonist agents keeping the same acronym； NOACs[10].

To our knowledge,this is the first study that addresses the efficacy and safety of NOACs in kidney transplantation recipients.Our results show that NOACs treatment has no effect on kidney function.Indeed,none of the NOACs used in our study induced changes in creatinine or eGFR levels after treatment.A previous study on lungs and heart transplantation suggested that NOACs can interact with CNIs[9].Moreover,Wannhoffet al[11]suggested that cyclosporine has a higher rate of drug interaction with rivaroxaban in another liver transplantation study.On the other hand,Vanhoveet al[12]reported similar,but clinically insignificant (＜ 20% change),interaction that didn't warrant CNI dose adjustments in transplant recipients.

In our study,we didn't report any thromboembolic event in any of the patients after CNI initiation.This might suggest NOACs are as effective in kidney transplantation population as the general population.Also,we had a few bleeding events with low doses (2.5 mg twice daily) of apixaban and a moderate dose (15 mg daily) of rivaroxaban,which may suggest a good safety profile.However,there is a need to further assess the mechanisms of bleeding in patients exposed to NOACs.Although our study indicates that NOACs may be safe and effective for the prevention and treatment of thromboembolic events in renal transplant recipients,there is a need to highlight some of its important advantages and disadvantages compared to other vitamin K antagonists.Its major advantages include absence of food interactions,few strong drug interactions,predictable pharmacokinetic and pharmacodynamic properties,a rapid onset and offset of action,a short half-life,and the absence of the need for laboratory monitoring[13].

Table 2 Clinical characteristics of the patient groups,n (%)

However,pharmacokinetic and pharmacodynamic studies show that NOACs elimination is dependent on renal clearance to varying extents； but compared with vitamin K antagonists,the efficacy and safety of the NOACs is preserved in patients with moderate renal impairment[14,15].There is a need to administer NOACs with caution in individuals with severe kidney or hepatic damage particularly the elderly.This is because up to 25%,33% and 80% of apixaban,rivaroxaban and dabigatran,respectively are eliminated through the kidneys as an active drug[13-15].In severe renal or hepatic damage,the elimination of the drug may be affected requiring adjustments in the dosing of the NOAC agent.

Our analysis only included renal transplant recipients with an eGFR of ＞ 54 mL/min/1.73 m2.Therefore,dosage adaptation of the NOACs should ideally not be necessary.However,considering the very limited or no prior experience in the use of NOACs in kidney transplant recipients (with/without renal impairment),doses of NOACs were administered to the patients in this study using the Health Canada dosing algorithm for each of the NOACs according to renal function and clinical status of the patients[14,16].Thus,the effectiveness of NOACs observed in our data can only be interpreted in the context of kidney transplant recipients with sufficiently preserved renal function.Several clinical trials such as the EINSTEIN,ARISTOTLE,and RE-LY trials have previously demonstrated the safety and efficacy of these NOACs in individuals with varying levels of renal impairment[17-19].

Table 3 Profile of the cases that developed bleeding

In the present study,3 of the subjects received dabigatran with tacrolimus-based CNIs.Previous studies have called for caution in the use of NOACs and immunosuppressive agents due to the potential for drug-drug interactions[8,20,21].A study suggested that dabigatran should not be administered to patients receiving CNIs because CNIs are known substrates of both CYP 450 3A4 and P-gp,and can lead to increased exposure to dabigatran[8,20].Because of the limited evidence of NOACs usage with CNIs in the setting of solid organ transplantation,this clinical recommendation was made based on an underpowered analysis of nine heart transplant recipients immunosuppressed with CNIs and treated with dabigatran for AF,VTE,or atrial thrombus[8].In the study,patients who received tacrolimus with dabigatran were more likely to require a decrease in tacrolimus dose during therapy and numerically had more major bleeding events[8].However,observations from the RE-LY trial indicate that concomitant use of dabigatran with P-gp inhibitors (like amiodarone or verapamil) increased dabigatran exposure but was not associated with significant differences in the event rate or bleeding[22,23].A recent review indicates that in patients receiving dabigatran etexilate for the treatment and prevention of VTE,there is no need for dose adjustments and no contraindication to its co-administration with P-gp inhibitors so long as the patients have a creatinine clearance greater than 50 mL/min[24].All the patients in our study had creatinine clearance greater than 50 mL/min and none of those who received dabigatran had a bleeding event.Recent expert opinion conclude that provided adequate attention is given to renal function,the co-administration of NOACs and CNIs in solid organ transplantation is safe and effective[24].

This study has some limitations.First,this was a retrospective observational study,therefore any reported association does not imply causation.Second,all the patients in this study had sufficiently preserved renal function (creatinine clearance ＞ 50 mL/min),therefore we cannot report on the safety or efficacy of the NOACs in kidney transplant recipients with substantial renal impairment.Third,more than half of the patients received low doses of the NOAC agent.Therefore,our finding may not reflect the outcomes in renal transplant recipients treated with higher doses of NOAC agent.

In conclusion,our study suggests that NOACs may be safe and effective for the prevention and treatment of thromboembolic events in renal transplant recipients with limited complications.Further studies need to be conducted to assess the effectiveness and safety profile of NOACs compared to other vitamin K antagonists(e.g.,warfarin) in kidney transplant population.

Table 4 Profile of the immunosuppressive agents received according the type of Novel oral anticoagulants agent

Figure 1 Creatinine levels before and after treatments with novel oral anticoagulants.

Figure 2 Estimated glomerular filtration rate before and after treatments with novel oral anticoagulants.

ARTICLE HIGHLIGHTS

Research background

Novel oral anticoagulants are increasingly being used in recent times for preventing stroke in individuals with atrial fibrillation and for the management of systemic embolic events and venous thromboembolism.With the increased risk of atrial fibrillation and thrombotic events observed in kidney transplant recipients,whether novel oral anticoagulants have clinical significance in this group of patients remains unclear.

Research motivation

Novel oral anticoagulants are being used as an oral anticoagulation agent for the prevention of embolic events in individuals with atrial fibrillation and for the treatment of venous thromboembolism.They also have the advantage of not requiring frequent monitoring and having a lower adverse effects profile.There are concerns regarding the clinical use of novel oral anticoagulants in renal transplant recipients because of its renal excretion and the likelihood of its interaction with immunosuppressive agents.Although,novel oral anticoagulants have successfully been used for anticoagulation in heart-lung transplant recipients,its use for this role in kidney transplant recipients is unknown.

Research objectives

We performed this retrospective study to assess the efficacy and safety of novel oral anticoagulants administration in patients after kidney transplantation,and to provide recommendations and guidelines on therapeutic strategies in these patients.

Research methods

This was a retrospective study carried out among adult patients who were actively on the following novel oral anticoagulants (apixaban,rivaroxaban or dabigatran) in our renal transplantation program from December 2015 to December 2016.The outcomes of interest include the profile of the patients,thromboembolic and bleeding events,and kidney dysfunction.

Research results

The authors observed 3 (7.1%) bleeding events in the cohort.Also,no (0%) thromboembolic events were observed.In addition,no significant changes in pre- and post- novel oral anticoagulants tacrolimus level,creatinine level,and estimated glomerular filtration rates were observed.

Research conclusions

Novel oral anticoagulants appear to be as effective in the renal transplantation population as in the general population.Also,we had a few bleeding events and no changes in renal function after the initiation of novel oral anticoagulants which suggests a good safety profile.

Research perspectives

This study demonstrated that novel oral anticoagulants are safe and effective in renal transplant recipients.There is a need for further clinical studies to assess the mechanisms of bleeding in patients exposed to novel oral anticoagulants.Randomised controlled trials are needed to compare the effectiveness and safety of novel oral anticoagulants compared to other vitamin K antagonists (e.g.,warfarin) in kidney transplant population.