Acute Management Issues
What is the Role of Renal Replacement Therapy in the Setting of Dabigatran Toxicity? Marc Ghannoum* and Thomas D. Nolin† *Department of Nephrology, Verdun Hospital, University of Montreal, Montreal, Quebec, Canada, and †Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences and Department of Medicine, Renal-Electrolyte Division, Schools of Pharmacy and Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Dabigatran is a direct thrombin inhibitor approved in the United States for the prevention of stroke in patients with nonvalvular atrial fibrillation and in certain countries for the prevention of venous thromboembolism (1,2). In contrast to warfarin, dabigatran does not require laboratory monitoring (3), is more effective at preventing stroke, and is associated with a similar incidence of adverse effects (2,4). The FDA-approved dosing recommendation is 150 mg PO two times daily in patients with a creatinine clearance (CrCl) of >30 ml/minute and 75 mg PO two times daily in patients with a CrCl of 15–30 ml/minute (1). Unfortunately, because dabigatran is predominantly (80%) excreted unchanged by the kidneys, it can accumulate in patients with either acute kidney injury (AKI) or chronic kidney disease (CKD) (5). Dabigatran’s half-life increases from 12 to 17 hours in patients with normal kidney function to 27 hours in patients with a CrCl less than 30 ml/minute (6,7). If normal dosing is maintained in this setting, then higher serum concentrations and enhanced anticoagulant effects are likely. Hemorrhagic complications associated with dabigatran are increasingly being reported (8). Eight deaths associated with dabigatran were reported in the United States in 2012 (9). Although there is a correlation between serum dabigatran concentrations and routine coagulation tests, no precise methods to monitor dabigatran’s anticoagulant activity exist and dabigatran assays in most centers remain unavailable (3). This complicates the evaluation of patients with active bleeding where the contribution of dabigatran is uncertain. Another challenge is the lack of specific antidotes to reverse the drug’s anticoagulant effect (10). Because it
exhibits properties that are amenable to extracorporeal removal, i.e., it is a small molecule (free base = 627.8 Da) and exhibits low protein binding (35%) (1), methods to enhance the elimination of dabigatran using renal replacement therapy (RRT) and other extracorporeal treatment (ECTR) modalities have been investigated in limited studies. In this article, we briefly review these studies and explore the role of RRT in the setting of dabigatran toxicity. Dabigatran Kinetics During RRT The impact of RRT on the kinetics of dabigatran has been assessed in stable end-stage renal disease (ESRD) patients, as well as in patients with acute dabigatran toxicity. Two small prospective pharmacokinetic studies have been performed in chronic, stable, nonbleeding ESRD patients receiving a single (6) or three doses of dabigatran (11). The studies reported similar findings, including extraction ratios of 61–68%. In addition, dialytic clearance of about 180 ml/minute and reductions of serum dabigatran concentration up to 60% with 4 hours of high-flux hemodialysis [blood flow rate (QB) = 400 ml/minute, dialysate flow rate (QD) = 700 ml/minute] were reported (11). The manufacturer’s product label is consistent with this, reporting that approximately 57% of dabigatran can be cleared from plasma over 4 hours using a high-flux dialyzer with a QB = 300 ml/minute and QD = 700 ml/minute (1). Similar to other small molecules, clearance of dabigatran is dialysate and blood flow dependent (11). The maximal rebound in serum concentration after hemodialysis did not exceed 16% (11). These results suggest that hemodialysis may successfully remove systemic dabigatran during normal therapeutic use. Toxicokinetic data derived from patients requiring urgent extracorporeal treatment to reverse the effects of acute dabigatran toxicity are now available from several reports (Table 1) (5,12–23). In all cases, serum concentrations of dabigatran fell dramatically during RRT. The dabigatran half-life was
Address correspondence to: Thomas D. Nolin, PharmD, PhD, Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, 808 Salk Hall, 3501 Terrace Street, Pittsburgh, PA 15261, Tel.: 1 412 624 1290, or e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 3 (May–June) 2014 pp. 223–226 DOI: 10.1111/sdi.12230 © 2014 Wiley Periodicals, Inc. 223
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consistently shown (or calculated to be) considerably shorter during RRT than without it (5,13,14,17,18). Also, intermittent dialysis was generally more efficient than continuous techniques (5,17), likely because of higher attainable blood and dialysate flow rates during intermittent therapy. Saturation or efficiency loss of the dialyzer was noted in one study in which clearances progressively declined from 291 ml/minute to 51 ml/minute during dialysis (12). Two case reports in patients with hemorrhagic complications demonstrated a decrease in dabigatran concentrations of about 10 ng/ml per hour during hemodialysis (13,18). We recently reported the apparent half-life of dabigatran to be four to five times shorter during the intradialytic period than after dialysis in two patients (5). Moreover, in contrast to previous limited dosing studies performed in stable patients, in whom negligible rebound was observed (6,11,24), we and others have observed substantially larger rebound effects in patients with acute toxicity, with dabigatran concentrations increasing from 48% to >400% within 2 hours of completing hemodialysis (5,12,13). This rebound was associated with a parallel deterioration in the coagulation parameters, necessitating additional RRT (5). Rebound of this magnitude may be explained by continuous absorption of dabigatran following RRT, but this is unlikely considering dabigatran is absorbed quickly (25) and none of the published cases reported a massive ingestion. More probably, the rebound is explained by extensive redistribution from deeper compartments or by slow intercompartmental transfer between extravascular/ intracellular sites and plasma (5).
Consistent with the observation of large rebound effects in the setting of toxicity is the discrepancy between extracorporeal clearance and corresponding removal of dabigatran. Specifically, despite high extracorporeal clearances during RRT, dabigatran recovery in effluent appears to be inconsequential; only 2.3 mg was removed during a single 4-hour treatment in one study (11), while less than 0.5% of the oral dose was recovered in another (6). This phenomenon is often seen with drugs, such as digoxin (26) and tricyclic antidepressants (27), that exhibit a large volume of distribution (VD) and are principally located outside of plasma at steady state. Dabigatran’s VD is normally fairly large at 50–70 l (1), approximating 1 l/kg for the average male patient. Importantly, however, considerably larger rebound effects observed in patients with acute toxicity suggest that the steady state VD in this setting may be greater than that reported in stable patients during normal therapeutic use. To accurately confirm any toxicokinetic advantage of RRT, studies measuring and quantifying dabigatran total body removal are needed. In addition to standard methods of RRT, other ECTR modalities have been investigated as possible approaches to enhance the elimination of dabigatran. An in vitro study evaluating the ability of an activated charcoal hemoperfusion cartridge to remove dabigatran from plasma reported an extraction ratio of 94% (28). An in vivo animal study also showed excellent clearances with charcoal hemoperfusion, as well as hemodialysis. Hemoperfusion provided better dabigatran clearance than hemodialysis (100% of blood flow compared to 65% of blood
TABLE 1. Summary of reports describing use of RRT in setting of dabigatran toxicity Author
Age, sex
AKI
GFR*
Cp (ng/ml)
RRT
% decrease in conc (duration)
Chang (13)
94, M
N
NA
312
HD
41% (2 hours)
Chen (12) Esnault (14)
80, M 62, F
Y N
NA 39
1100 123
HD HD
98% (4 hours) 78% (2 hours)
Lillo-Le Louet (15)
86, M
Y
58
2350
CVVHDF
Lowe (16)
79, M
Y
40
470
HD
Singh (5)
77, M 86, M 65, M
Y Y Y
81 68 NA
875 318 1200
HD HD HD, CVVHDF
81, F
Y
60
269
HD
77, F
Y
NA
149
HD
52% (5 hours)
Verma (17)
72, M
N
40
60
CVVH, HD
Warkentin (18)
79, M
N
36
95
HD
70% (18 hours CVVH) 14% (4 hours HD) 64% (6 hours)
61% (6 hours) 100% (85 hours) 47% (4 hours) 37% (4 hours) 56% (3 hours) 64% (4 hours) 65% (2 hours HD) 81% (30 hours CVVHDF) 77% (4 hours)
T1/2 (hour)
Rebound
4.1 during HD, 24.9 post HD 0.8 during HD 4.6 pre HD, 0.9 during HD 8.0 during CVVHDF
48% 456% NA
NA
NA
NA NA 1.3 during HD, 12.6 during CVVHDF 1.9 during HD, 12.3 postHD 4.7 during HD, 26.6 post HD 14 during CVVH, 2.3 during HD 14.1 pre HD, 4.3 during HD
41% 280% 49% after HD
NA
87% N Y during CVVH 7%
*ml/minute per 1.73 m2. AKI, acute kidney injury; GFR, glomerular filtration rate; Cp, peak plasma concentration; RRT, renal replacement therapy; T1/2, half-life; F, female; M, male; HD, intermittent hemodialysis; CVVHDF, continuous venovenous hemodiafiltration; CVVH, continous venovenous hemofiltration. 224
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RRT IN DABIGATRAN TOXICITY
flow), but was limited by early saturation of the cartridge when adsorption exceeded 30 mg (29). Currently, the precise role of hemoperfusion and other ECTR modalities in the treatment of dabigatran toxicity and their place in therapy relative to standard RRT methods require further study.
dialysis, multiple intermittent dialysis sessions, or a subsequent switch to a continuous modality. More studies are required to evaluate the dialyzability of dabigatran, and these should ideally quantify recovery in dialysate or effluent to determine total body removal. The precise role of RRT and other ECTR modalities in the treatment of dabigatran toxicity and particularly their impact on patient outcomes require further study. The decision to prescribe RRT needs to be individualized based on clinical data, coagulation parameters, and resources, and the risks associated with RRT should be weighed against its potential benefit.
Impact of RRT on Outcome While it appears that RRT can enhance systemic clearance of dabigatran in patients with normal and impaired kidney function, it remains unclear if this translates to a favorable outcome in patients with active bleeding. To date, prospective randomized controlled trials or observational studies comparing the effect of RRT to control have not been performed in patients with dabigatran toxicity. Virtually all currently available literature consists of case reports and case series, which require cautious interpretation due to a lack of control, treatment confounders, and possible publication bias. Nevertheless, it is interesting to note that in most cases, RRT accelerated correction of an abnormal coagulation profile, proportional to the reduction in dabigatran plasma concentration (5,11–23). The best surrogate of dabigatran’s anticoagulation effect remains unclear. However, both aPTT and TT usually decrease during RRT and appear to correlate with dabigatran plasma concentrations (5,11). Obviously, RRT will not reverse a bleeding focus, but based on available published cases, it could prevent extension of a life-threatening bleed and help in reversing dabigatran-induced anticoagulation. Another potential application of RRT is to reverse dabigatran’s anticoagulant effect prior to emergent surgery (14,15,22). However, as the drug’s apparent half-life during hemodialysis is up to 5 hours, a 4-hour high-flux hemodialysis session, even if in the absence of relevant rebound, will likely not be long enough to reduce dabigatran serum concentrations below the therapeutic range. If RRT is performed prior to elective or urgent surgery, then a longer treatment may be necessary to significantly minimize the risk of bleeding. The potential beneficial effect of RRT in the setting of acute dabigatran toxicity should be weighed against the inherent risks of RRT, including insertion of a central line. Although the risk of severe bleeding can be minimized by ultrasonographic placement of the catheter, the risk is not null (30). Furthermore, RRT, hemodialysis in particular, may itself increase intracranial pressure, which is a concern in patients who present with intracerebral bleeding (31). In summary, RRT appears to have a role in treating dabigatran toxicity by enhancing dabigatran clearance, even in patients with normal kidney function. Dabigatran’s large steady state volume of distribution leads to a corresponding rebound effect following RRT, but this may be addressed by performing a prolonged duration of intermittent
Financial Disclosure The authors declare no financial conflicts of interest. References 1. Pradaxa (dabigatran etexilate mesylate) prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT: December 2013. Available at http://www.pradaxa.com, Accessed January 30, 2014 2. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151, 2009 3. Van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A: Dabigatran etexilate - A novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 103:1116–1127, 2010 4. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L: Newly identified events in the RE-LY trial. N Engl J Med 363:1875–1876, 2010 5. Singh T, Maw TT, Henry BL, Pastor-Soler NM, Unruh ML, Hallows KR, Nolin TD: Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephrol 8:1533–1539, 2013 6. Stangier J, Rathgen K, Stahle H, Mazur D: Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 49:259–268, 2010 7. Stangier J: Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 47:285–295, 2008 8. Chen BC, Viny AD, Garlich FM, Basciano P, Howland MA, Smith SW, Hoffman RS, Nelson LS: Hemorrhagic complications associated with dabigatran use. Clin Toxicol (Phila) 50:854–857, 2012 9. Mowry JB, Spyker DA, Cantilena LR Jr, Bailey JE, Ford M: 2012 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 30th Annual Report. Clin Toxicol (Phila) 51:949–1229, 2013 10. Weitz JI, Quinlan DJ, Eikelboom JW: Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation 126:2428–2432, 2012 11. Khadzhynov D, Wagner F, Formella S, Wiegert E, Moschetti V, Slowinski T, Neumayer HH, Liesenfeld KH, Lehr T, Hartter S, Friedman J, Peters H, Clemens A: Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 109:596–605, 2013 12. Chen BC, Sheth NR, Dadzie KA, Smith SW, Nelson LS, Hoffman RS, Winchester JF: Hemodialysis for the treatment of pulmonary hemorrhage from dabigatran overdose. Am J Kidney Dis 62:591–594, 2013 13. Chang DN, Dager WE, Chin AI: Removal of dabigatran by hemodialysis. Am J Kidney Dis 61:487–489, 2013 14. Esnault P, Gaillard PE, Cotte J, Cungi PJ, Beaume J, Prunet B: Haemodialysis before emergency surgery in a patient treated with dabigatran. Br J Anaesth 111:776–777, 2013 15. Lillo-Le Louet A, Wolf M, Soufir L, Galbois A, Dumenil AS, Offenstadt G, Samama MM: Life-threatening bleeding in four patients with an unusual excessive response to dabigatran: implications for emergency surgery and resuscitation. Thromb Haemost 108:583–585, 2012 16. Lowe MP, Collins J, Yehia M, Eaddy N: Reversal of dabigatran with haemodialysis in a patient requiring decompression for cord
225
226 17.
18.
19.
20. 21. 22.
23.
24.
Kumar and Shirali 25. Stangier J, Rathgen K, Stahle H, Gansser D, Roth W: The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 64:292–303, 2007 26. Gundert-Remy U, Gotz R, Seitz H, Cygan P: Effectivity of hemoperfusion in patients with digoxin overdosage [abstract]. Naunyn-Schmiedeberg’s Arch Pharmacol 316:R81, 1981 27. Heath A, Wickstrom I, Martensson E, Ahlmen J: Treatment of antidepressant poisoning with resin hemoperfusion. Hum Toxicol 1:361– 371, 1982 28. Van Ryn J, Neubauer M, Flieg R, Krause B, Storr M, Hauel N, Priepke H, Clemens A: Successful removal of dabigatran in flowing blood with an activated charcoal hemoperfusion column in an in vitro test system. Haematologica 95:293, 2010 29. Lange J, Thiel C, Thiel K, Klingert W, Klingert K, Konigsrainer A, Formella S, Clemens A, van Ryn J, Schenk M: Acceleration of dabigatran elimination by activated charcoal perfusion and hemodialysis in a pig model [abstract]. Blood 120:2272, 2012 30. Rabindranath KS, Kumar E, Shail R, Vaux EC: Ultrasound use for the placement of haemodialysis catheters. Cochrane Database Syst Rev 11:CD005279, 2011 31. Lin CM, Lin JW, Tsai JT, Ko CP, Hung KS, Hung CC, Su YK, Wei L, Chiu WT, Lee LM: Intracranial pressure fluctuation during hemodialysis in renal failure patients with intracranial hemorrhage. Acta Neurochir Suppl 101:141–144, 2008
compression from an epidural abscess. Nephrology (Carlton) 18:580– 582, 2013 Verma A, Nathan R, Abramov K, Trainor MJ, Stoff JS: Role of dialysis in dabigatran related bleeding [abstract]. J Am Soc Nephrol 23:363A, 2012 Warkentin TE, Margetts P, Connolly SJ, Lamy A, Ricci C, Eikelboom JW: Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 119:2172–2174, 2012 Cano EL, Miyares MA: Clinical challenges in a patient with dabigatran-induced fatal hemorrhage. Am J Geriatr Pharmacother 10:160– 163, 2012 Dy EA, Shiltz DL: Hemopericardium and cardiac tamponade associated with dabigatran use. Ann Pharmacother 46:e18, 2012 Kulik A, Saltzman MB, Morris JJ: Dabigatran after cardiac surgery: caution advised. J Thorac Cardiovasc Surg 142:1288, 2011 Wanek MR, Horn ET, Elapavaluru S, Baroody SC, Sokos G: Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother 46:e21, 2012 Wychowski MK, Kouides PA: Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment. Ann Pharmacother 46:e10, 2012 Liesenfeld KH, Staab A, Hartter S, Formella S, Clemens A, Lehr T: Pharmacometric characterization of dabigatran hemodialysis. Clin Pharmacokinet 52:453–462, 2013
What is the Best Therapy for Toxicity in the Setting of Methotrexate-Associated Acute Kidney Injury: High-Flux Hemodialysis or Carboxypeptidase G2? Neelja Kumar and Anushree C. Shirali Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut
Methotrexate (MTX) is an antifolate therapeutic agent that possesses potent anticancer activity against both solid tumors and leukemias. MTX enters cells via the reduced folate carrier and affects intracellular enzymes (1). Specifically, MTX inhibits dihydrofolate reductase and prevents generation of tetrahydrofolate, the active form of folate, which is necessary for pyrimidine synthesis (2). Thus, as chemotherapy, MTX antagonizes active division of tumor cells by inhibiting DNA and RNA synthesis. However, this tumoricidal effect often comes at the expense of systemic and kidney-specific toxicity. Methotrexate is associated with dose-dependent nephrotoxicity because the kidneys excrete 85– 100% of the parent drug. At the conventional doses (~20 mg/m2) employed against rheumatological diseases and most solid tumors, kidney function is not usually affected. In contrast, nephrotoxicity is generally seen following high-dose MTX (1000–33,000 mg/m2), which is reserved for
treatment of aggressive malignancies, including osteosarcoma, breast cancer, and acute lymphoblastic leukemia. Serum levels of MTX are predictive of kidney injury, with levels >5–10 lM/l at 24 hours, or >1 lM/l at 48 hours or >0.1 lM/l at 72 hours conferring greater risk of nephrotoxicity and increased morbidity and mortality (2). Kidney injury occurs via intratubular crystal deposition, which is a consequence of the low solubility of MTX in normally acidic solution such as urine, and clinically manifests as a prolonged episode of acute kidney injury (AKI). This tendency for MTX to crystallize is exacerbated by volume depletion and ameliorated by urinary alkalinization. In addition to these parent drug characteristics, metabolites including 7-hydroxy-MTX (7-OHMTX) and 2,4-diamino-N10-methylpteroic acid (DAMPA) are even less soluble. While unproven, 7-OH-MTX may also contribute to crystal-associated toxicity. MTX can also cause direct tubular injury by production of reactive oxygen species (3). Both types of MTX-associated kidney injury can lead to elevated serum MTX levels and systemic toxicity, including myelosuppression, mucositis, hepatitis, and dermatitis. The risk of toxicity increases when drugs that compete with its tubular excretion are concurrently administered (4), such as probenecid and salicylates. In addition, genomic studies in
Address correspondence to: Anushree C. Shirali, MD, Section of Nephrology, Yale University School of Medicine, P.O. Box 208029, New Haven, CT 06520-8029, or e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 3 (May–June) 2014 pp. 226–228 DOI: 10.1111/sdi.12220 © 2014 Wiley Periodicals, Inc. 226
What is the Role of Renal Replacement Therapy in the Setting of Dabigatran Toxicity? Marc Ghannoum* and Thomas D. Nolin† *Department of Nephrology, Verdun Hospital, University of Montreal, Montreal, Quebec, Canada, and †Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences and Department of Medicine, Renal-Electrolyte Division, Schools of Pharmacy and Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Dabigatran is a direct thrombin inhibitor approved in the United States for the prevention of stroke in patients with nonvalvular atrial fibrillation and in certain countries for the prevention of venous thromboembolism (1,2). In contrast to warfarin, dabigatran does not require laboratory monitoring (3), is more effective at preventing stroke, and is associated with a similar incidence of adverse effects (2,4). The FDA-approved dosing recommendation is 150 mg PO two times daily in patients with a creatinine clearance (CrCl) of >30 ml/minute and 75 mg PO two times daily in patients with a CrCl of 15–30 ml/minute (1). Unfortunately, because dabigatran is predominantly (80%) excreted unchanged by the kidneys, it can accumulate in patients with either acute kidney injury (AKI) or chronic kidney disease (CKD) (5). Dabigatran’s half-life increases from 12 to 17 hours in patients with normal kidney function to 27 hours in patients with a CrCl less than 30 ml/minute (6,7). If normal dosing is maintained in this setting, then higher serum concentrations and enhanced anticoagulant effects are likely. Hemorrhagic complications associated with dabigatran are increasingly being reported (8). Eight deaths associated with dabigatran were reported in the United States in 2012 (9). Although there is a correlation between serum dabigatran concentrations and routine coagulation tests, no precise methods to monitor dabigatran’s anticoagulant activity exist and dabigatran assays in most centers remain unavailable (3). This complicates the evaluation of patients with active bleeding where the contribution of dabigatran is uncertain. Another challenge is the lack of specific antidotes to reverse the drug’s anticoagulant effect (10). Because it
exhibits properties that are amenable to extracorporeal removal, i.e., it is a small molecule (free base = 627.8 Da) and exhibits low protein binding (35%) (1), methods to enhance the elimination of dabigatran using renal replacement therapy (RRT) and other extracorporeal treatment (ECTR) modalities have been investigated in limited studies. In this article, we briefly review these studies and explore the role of RRT in the setting of dabigatran toxicity. Dabigatran Kinetics During RRT The impact of RRT on the kinetics of dabigatran has been assessed in stable end-stage renal disease (ESRD) patients, as well as in patients with acute dabigatran toxicity. Two small prospective pharmacokinetic studies have been performed in chronic, stable, nonbleeding ESRD patients receiving a single (6) or three doses of dabigatran (11). The studies reported similar findings, including extraction ratios of 61–68%. In addition, dialytic clearance of about 180 ml/minute and reductions of serum dabigatran concentration up to 60% with 4 hours of high-flux hemodialysis [blood flow rate (QB) = 400 ml/minute, dialysate flow rate (QD) = 700 ml/minute] were reported (11). The manufacturer’s product label is consistent with this, reporting that approximately 57% of dabigatran can be cleared from plasma over 4 hours using a high-flux dialyzer with a QB = 300 ml/minute and QD = 700 ml/minute (1). Similar to other small molecules, clearance of dabigatran is dialysate and blood flow dependent (11). The maximal rebound in serum concentration after hemodialysis did not exceed 16% (11). These results suggest that hemodialysis may successfully remove systemic dabigatran during normal therapeutic use. Toxicokinetic data derived from patients requiring urgent extracorporeal treatment to reverse the effects of acute dabigatran toxicity are now available from several reports (Table 1) (5,12–23). In all cases, serum concentrations of dabigatran fell dramatically during RRT. The dabigatran half-life was
Address correspondence to: Thomas D. Nolin, PharmD, PhD, Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, 808 Salk Hall, 3501 Terrace Street, Pittsburgh, PA 15261, Tel.: 1 412 624 1290, or e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 3 (May–June) 2014 pp. 223–226 DOI: 10.1111/sdi.12230 © 2014 Wiley Periodicals, Inc. 223
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consistently shown (or calculated to be) considerably shorter during RRT than without it (5,13,14,17,18). Also, intermittent dialysis was generally more efficient than continuous techniques (5,17), likely because of higher attainable blood and dialysate flow rates during intermittent therapy. Saturation or efficiency loss of the dialyzer was noted in one study in which clearances progressively declined from 291 ml/minute to 51 ml/minute during dialysis (12). Two case reports in patients with hemorrhagic complications demonstrated a decrease in dabigatran concentrations of about 10 ng/ml per hour during hemodialysis (13,18). We recently reported the apparent half-life of dabigatran to be four to five times shorter during the intradialytic period than after dialysis in two patients (5). Moreover, in contrast to previous limited dosing studies performed in stable patients, in whom negligible rebound was observed (6,11,24), we and others have observed substantially larger rebound effects in patients with acute toxicity, with dabigatran concentrations increasing from 48% to >400% within 2 hours of completing hemodialysis (5,12,13). This rebound was associated with a parallel deterioration in the coagulation parameters, necessitating additional RRT (5). Rebound of this magnitude may be explained by continuous absorption of dabigatran following RRT, but this is unlikely considering dabigatran is absorbed quickly (25) and none of the published cases reported a massive ingestion. More probably, the rebound is explained by extensive redistribution from deeper compartments or by slow intercompartmental transfer between extravascular/ intracellular sites and plasma (5).
Consistent with the observation of large rebound effects in the setting of toxicity is the discrepancy between extracorporeal clearance and corresponding removal of dabigatran. Specifically, despite high extracorporeal clearances during RRT, dabigatran recovery in effluent appears to be inconsequential; only 2.3 mg was removed during a single 4-hour treatment in one study (11), while less than 0.5% of the oral dose was recovered in another (6). This phenomenon is often seen with drugs, such as digoxin (26) and tricyclic antidepressants (27), that exhibit a large volume of distribution (VD) and are principally located outside of plasma at steady state. Dabigatran’s VD is normally fairly large at 50–70 l (1), approximating 1 l/kg for the average male patient. Importantly, however, considerably larger rebound effects observed in patients with acute toxicity suggest that the steady state VD in this setting may be greater than that reported in stable patients during normal therapeutic use. To accurately confirm any toxicokinetic advantage of RRT, studies measuring and quantifying dabigatran total body removal are needed. In addition to standard methods of RRT, other ECTR modalities have been investigated as possible approaches to enhance the elimination of dabigatran. An in vitro study evaluating the ability of an activated charcoal hemoperfusion cartridge to remove dabigatran from plasma reported an extraction ratio of 94% (28). An in vivo animal study also showed excellent clearances with charcoal hemoperfusion, as well as hemodialysis. Hemoperfusion provided better dabigatran clearance than hemodialysis (100% of blood flow compared to 65% of blood
TABLE 1. Summary of reports describing use of RRT in setting of dabigatran toxicity Author
Age, sex
AKI
GFR*
Cp (ng/ml)
RRT
% decrease in conc (duration)
Chang (13)
94, M
N
NA
312
HD
41% (2 hours)
Chen (12) Esnault (14)
80, M 62, F
Y N
NA 39
1100 123
HD HD
98% (4 hours) 78% (2 hours)
Lillo-Le Louet (15)
86, M
Y
58
2350
CVVHDF
Lowe (16)
79, M
Y
40
470
HD
Singh (5)
77, M 86, M 65, M
Y Y Y
81 68 NA
875 318 1200
HD HD HD, CVVHDF
81, F
Y
60
269
HD
77, F
Y
NA
149
HD
52% (5 hours)
Verma (17)
72, M
N
40
60
CVVH, HD
Warkentin (18)
79, M
N
36
95
HD
70% (18 hours CVVH) 14% (4 hours HD) 64% (6 hours)
61% (6 hours) 100% (85 hours) 47% (4 hours) 37% (4 hours) 56% (3 hours) 64% (4 hours) 65% (2 hours HD) 81% (30 hours CVVHDF) 77% (4 hours)
T1/2 (hour)
Rebound
4.1 during HD, 24.9 post HD 0.8 during HD 4.6 pre HD, 0.9 during HD 8.0 during CVVHDF
48% 456% NA
NA
NA
NA NA 1.3 during HD, 12.6 during CVVHDF 1.9 during HD, 12.3 postHD 4.7 during HD, 26.6 post HD 14 during CVVH, 2.3 during HD 14.1 pre HD, 4.3 during HD
41% 280% 49% after HD
NA
87% N Y during CVVH 7%
*ml/minute per 1.73 m2. AKI, acute kidney injury; GFR, glomerular filtration rate; Cp, peak plasma concentration; RRT, renal replacement therapy; T1/2, half-life; F, female; M, male; HD, intermittent hemodialysis; CVVHDF, continuous venovenous hemodiafiltration; CVVH, continous venovenous hemofiltration. 224
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flow), but was limited by early saturation of the cartridge when adsorption exceeded 30 mg (29). Currently, the precise role of hemoperfusion and other ECTR modalities in the treatment of dabigatran toxicity and their place in therapy relative to standard RRT methods require further study.
dialysis, multiple intermittent dialysis sessions, or a subsequent switch to a continuous modality. More studies are required to evaluate the dialyzability of dabigatran, and these should ideally quantify recovery in dialysate or effluent to determine total body removal. The precise role of RRT and other ECTR modalities in the treatment of dabigatran toxicity and particularly their impact on patient outcomes require further study. The decision to prescribe RRT needs to be individualized based on clinical data, coagulation parameters, and resources, and the risks associated with RRT should be weighed against its potential benefit.
Impact of RRT on Outcome While it appears that RRT can enhance systemic clearance of dabigatran in patients with normal and impaired kidney function, it remains unclear if this translates to a favorable outcome in patients with active bleeding. To date, prospective randomized controlled trials or observational studies comparing the effect of RRT to control have not been performed in patients with dabigatran toxicity. Virtually all currently available literature consists of case reports and case series, which require cautious interpretation due to a lack of control, treatment confounders, and possible publication bias. Nevertheless, it is interesting to note that in most cases, RRT accelerated correction of an abnormal coagulation profile, proportional to the reduction in dabigatran plasma concentration (5,11–23). The best surrogate of dabigatran’s anticoagulation effect remains unclear. However, both aPTT and TT usually decrease during RRT and appear to correlate with dabigatran plasma concentrations (5,11). Obviously, RRT will not reverse a bleeding focus, but based on available published cases, it could prevent extension of a life-threatening bleed and help in reversing dabigatran-induced anticoagulation. Another potential application of RRT is to reverse dabigatran’s anticoagulant effect prior to emergent surgery (14,15,22). However, as the drug’s apparent half-life during hemodialysis is up to 5 hours, a 4-hour high-flux hemodialysis session, even if in the absence of relevant rebound, will likely not be long enough to reduce dabigatran serum concentrations below the therapeutic range. If RRT is performed prior to elective or urgent surgery, then a longer treatment may be necessary to significantly minimize the risk of bleeding. The potential beneficial effect of RRT in the setting of acute dabigatran toxicity should be weighed against the inherent risks of RRT, including insertion of a central line. Although the risk of severe bleeding can be minimized by ultrasonographic placement of the catheter, the risk is not null (30). Furthermore, RRT, hemodialysis in particular, may itself increase intracranial pressure, which is a concern in patients who present with intracerebral bleeding (31). In summary, RRT appears to have a role in treating dabigatran toxicity by enhancing dabigatran clearance, even in patients with normal kidney function. Dabigatran’s large steady state volume of distribution leads to a corresponding rebound effect following RRT, but this may be addressed by performing a prolonged duration of intermittent
Financial Disclosure The authors declare no financial conflicts of interest. References 1. Pradaxa (dabigatran etexilate mesylate) prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT: December 2013. Available at http://www.pradaxa.com, Accessed January 30, 2014 2. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151, 2009 3. Van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A: Dabigatran etexilate - A novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 103:1116–1127, 2010 4. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L: Newly identified events in the RE-LY trial. N Engl J Med 363:1875–1876, 2010 5. Singh T, Maw TT, Henry BL, Pastor-Soler NM, Unruh ML, Hallows KR, Nolin TD: Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephrol 8:1533–1539, 2013 6. Stangier J, Rathgen K, Stahle H, Mazur D: Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 49:259–268, 2010 7. Stangier J: Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 47:285–295, 2008 8. Chen BC, Viny AD, Garlich FM, Basciano P, Howland MA, Smith SW, Hoffman RS, Nelson LS: Hemorrhagic complications associated with dabigatran use. Clin Toxicol (Phila) 50:854–857, 2012 9. Mowry JB, Spyker DA, Cantilena LR Jr, Bailey JE, Ford M: 2012 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 30th Annual Report. Clin Toxicol (Phila) 51:949–1229, 2013 10. Weitz JI, Quinlan DJ, Eikelboom JW: Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation 126:2428–2432, 2012 11. Khadzhynov D, Wagner F, Formella S, Wiegert E, Moschetti V, Slowinski T, Neumayer HH, Liesenfeld KH, Lehr T, Hartter S, Friedman J, Peters H, Clemens A: Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 109:596–605, 2013 12. Chen BC, Sheth NR, Dadzie KA, Smith SW, Nelson LS, Hoffman RS, Winchester JF: Hemodialysis for the treatment of pulmonary hemorrhage from dabigatran overdose. Am J Kidney Dis 62:591–594, 2013 13. Chang DN, Dager WE, Chin AI: Removal of dabigatran by hemodialysis. Am J Kidney Dis 61:487–489, 2013 14. Esnault P, Gaillard PE, Cotte J, Cungi PJ, Beaume J, Prunet B: Haemodialysis before emergency surgery in a patient treated with dabigatran. Br J Anaesth 111:776–777, 2013 15. Lillo-Le Louet A, Wolf M, Soufir L, Galbois A, Dumenil AS, Offenstadt G, Samama MM: Life-threatening bleeding in four patients with an unusual excessive response to dabigatran: implications for emergency surgery and resuscitation. Thromb Haemost 108:583–585, 2012 16. Lowe MP, Collins J, Yehia M, Eaddy N: Reversal of dabigatran with haemodialysis in a patient requiring decompression for cord
225
226 17.
18.
19.
20. 21. 22.
23.
24.
Kumar and Shirali 25. Stangier J, Rathgen K, Stahle H, Gansser D, Roth W: The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 64:292–303, 2007 26. Gundert-Remy U, Gotz R, Seitz H, Cygan P: Effectivity of hemoperfusion in patients with digoxin overdosage [abstract]. Naunyn-Schmiedeberg’s Arch Pharmacol 316:R81, 1981 27. Heath A, Wickstrom I, Martensson E, Ahlmen J: Treatment of antidepressant poisoning with resin hemoperfusion. Hum Toxicol 1:361– 371, 1982 28. Van Ryn J, Neubauer M, Flieg R, Krause B, Storr M, Hauel N, Priepke H, Clemens A: Successful removal of dabigatran in flowing blood with an activated charcoal hemoperfusion column in an in vitro test system. Haematologica 95:293, 2010 29. Lange J, Thiel C, Thiel K, Klingert W, Klingert K, Konigsrainer A, Formella S, Clemens A, van Ryn J, Schenk M: Acceleration of dabigatran elimination by activated charcoal perfusion and hemodialysis in a pig model [abstract]. Blood 120:2272, 2012 30. Rabindranath KS, Kumar E, Shail R, Vaux EC: Ultrasound use for the placement of haemodialysis catheters. Cochrane Database Syst Rev 11:CD005279, 2011 31. Lin CM, Lin JW, Tsai JT, Ko CP, Hung KS, Hung CC, Su YK, Wei L, Chiu WT, Lee LM: Intracranial pressure fluctuation during hemodialysis in renal failure patients with intracranial hemorrhage. Acta Neurochir Suppl 101:141–144, 2008
compression from an epidural abscess. Nephrology (Carlton) 18:580– 582, 2013 Verma A, Nathan R, Abramov K, Trainor MJ, Stoff JS: Role of dialysis in dabigatran related bleeding [abstract]. J Am Soc Nephrol 23:363A, 2012 Warkentin TE, Margetts P, Connolly SJ, Lamy A, Ricci C, Eikelboom JW: Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 119:2172–2174, 2012 Cano EL, Miyares MA: Clinical challenges in a patient with dabigatran-induced fatal hemorrhage. Am J Geriatr Pharmacother 10:160– 163, 2012 Dy EA, Shiltz DL: Hemopericardium and cardiac tamponade associated with dabigatran use. Ann Pharmacother 46:e18, 2012 Kulik A, Saltzman MB, Morris JJ: Dabigatran after cardiac surgery: caution advised. J Thorac Cardiovasc Surg 142:1288, 2011 Wanek MR, Horn ET, Elapavaluru S, Baroody SC, Sokos G: Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother 46:e21, 2012 Wychowski MK, Kouides PA: Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment. Ann Pharmacother 46:e10, 2012 Liesenfeld KH, Staab A, Hartter S, Formella S, Clemens A, Lehr T: Pharmacometric characterization of dabigatran hemodialysis. Clin Pharmacokinet 52:453–462, 2013
What is the Best Therapy for Toxicity in the Setting of Methotrexate-Associated Acute Kidney Injury: High-Flux Hemodialysis or Carboxypeptidase G2? Neelja Kumar and Anushree C. Shirali Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut
Methotrexate (MTX) is an antifolate therapeutic agent that possesses potent anticancer activity against both solid tumors and leukemias. MTX enters cells via the reduced folate carrier and affects intracellular enzymes (1). Specifically, MTX inhibits dihydrofolate reductase and prevents generation of tetrahydrofolate, the active form of folate, which is necessary for pyrimidine synthesis (2). Thus, as chemotherapy, MTX antagonizes active division of tumor cells by inhibiting DNA and RNA synthesis. However, this tumoricidal effect often comes at the expense of systemic and kidney-specific toxicity. Methotrexate is associated with dose-dependent nephrotoxicity because the kidneys excrete 85– 100% of the parent drug. At the conventional doses (~20 mg/m2) employed against rheumatological diseases and most solid tumors, kidney function is not usually affected. In contrast, nephrotoxicity is generally seen following high-dose MTX (1000–33,000 mg/m2), which is reserved for
treatment of aggressive malignancies, including osteosarcoma, breast cancer, and acute lymphoblastic leukemia. Serum levels of MTX are predictive of kidney injury, with levels >5–10 lM/l at 24 hours, or >1 lM/l at 48 hours or >0.1 lM/l at 72 hours conferring greater risk of nephrotoxicity and increased morbidity and mortality (2). Kidney injury occurs via intratubular crystal deposition, which is a consequence of the low solubility of MTX in normally acidic solution such as urine, and clinically manifests as a prolonged episode of acute kidney injury (AKI). This tendency for MTX to crystallize is exacerbated by volume depletion and ameliorated by urinary alkalinization. In addition to these parent drug characteristics, metabolites including 7-hydroxy-MTX (7-OHMTX) and 2,4-diamino-N10-methylpteroic acid (DAMPA) are even less soluble. While unproven, 7-OH-MTX may also contribute to crystal-associated toxicity. MTX can also cause direct tubular injury by production of reactive oxygen species (3). Both types of MTX-associated kidney injury can lead to elevated serum MTX levels and systemic toxicity, including myelosuppression, mucositis, hepatitis, and dermatitis. The risk of toxicity increases when drugs that compete with its tubular excretion are concurrently administered (4), such as probenecid and salicylates. In addition, genomic studies in
Address correspondence to: Anushree C. Shirali, MD, Section of Nephrology, Yale University School of Medicine, P.O. Box 208029, New Haven, CT 06520-8029, or e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 3 (May–June) 2014 pp. 226–228 DOI: 10.1111/sdi.12220 © 2014 Wiley Periodicals, Inc. 226
