Accepted Manuscript Editorial New oral anticoagulants (NOAC) and liver injury Nicholas Moore, Patrick Blin, Sinem-Ezgi Gulmez PII: DOI: Reference:
S0168-8278(14)00320-1 http://dx.doi.org/10.1016/j.jhep.2014.05.010 JHEPAT 5162
To appear in:
Journal of Hepatology
Received Date: Accepted Date:
28 April 2014 3 May 2014
Please cite this article as: Moore, N., Blin, P., Gulmez, S-E., New oral anticoagulants (NOAC) and liver injury, Journal of Hepatology (2014), doi: http://dx.doi.org/10.1016/j.jhep.2014.05.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
New oral anticoagulants (NOAC) and liver injury
Nicholas Moore, Patrick Blin, Sinem-Ezgi Gulmez
Université de Bordeaux, INSERM U657, INSERM CIC1401, Bordeaux, France
Russman et al describe spontaneous reports of drug-induced liver injury after rivaroxaban to the Swiss pharmacovigilance system. [1] They also found a similar signal in large spontaneous report databases (EMA, USFDA, WHO UMC monitoring centre)
The causality of rivaroxaban in these cases is plausible, and rivaroxaban may indeed be associated with liver injury, as most drugs are. However caution may be warranted in the interpretation of these findings, and especially before any firm conclusions are drawn or actions suggested.
Ten of the fourteen reported cases occurred after surgery, mostly total knee replacement, which involves anaesthetics and other drugs that may be hepatotoxic. Surgery itself may result in hepatic injury through transient low output syndrome in these often elderly patients. Most would also receive analgesics such as NSAIDs, even if this would be unlikely because of the use of anticoagulants, or paracetamol with or without opiates. Paracetamol may also be hepatotoxic even at "normal" doses. [2] This does not seem to have been mentioned in the case descriptions. In the cases that occurred in patients using the anticoagulant for atrial fibrillation (AF) there is no anaesthetic or analgesic risk but AF can cause episodes of low cardiac output that may also be injurious, and other hepatotoxic drugs such as amiodarone are often used. Therefore, considering the drug and the medical environment, one is not surprised at finding cases of hepatic injury in such patients. Causality may point to rivaroxaban as the more suspect drug, but causality assessment, even for hepatic-specific methods such as RUCAM, [3] is only as trustworthy as the data
used, and the lack of description of anaesthetic procedures, or analgesic or other drugs is a little worrisome. [4]
Looking at other reporting databases is useful to comfort a signal. However the WHO UMC database includes information from other databases, since it simply compiles data sent by individual countries. As such it is a secondary database, not a primary one. It would duplicate Eudravigilance data, and the FDA data. The FDA database itself includes cases occurring within the US, and industry-reported cases from outside the US: these may also be found in Eudravigilance, and in the WHO database. A very small number of cases may become an epidemic. These databases show that cases may exist, but the actual number of cases and their meaning are uncertain. Careful analysis of the individual cases might help identify duplicate reports in the different databases and give a clearer vision of real numbers of individual reports. However, it will certainly not provide actual event rates. [5]
Even if the cases were to demonstrate the existence of hepatic injury associated with rivaroxaban, is this drug worse than the alternatives?
There are reports of hepatic injury with warfarin and fluindione. [6] Ximelagatran was stopped because of hepatic injury during clinical trials. [7] There is as yet little or no post-marketing information on the other NOACs. A meta-analysis of clinical trials concerning NOACs and vitamin-K antagonists (VKA) found no difference between NOACs and VKA for hepatic problems. [8] Watkins et al did not find an increased risk of liver injury compared to enoxaparin in another meta-analysis of clinical trials. [9]
Several NOACs (rivaroxaban, apixaban, dabigatran, and others) have been recently or will be put on the market and are being carefully monitored for relative
effectiveness
and
bleeding
risk.
Carefully
designed
pharmacoepidemiological studies may also be able to give a reasonable answer for a possible hepatotoxicity, differential or not. If confirmed, it will obviously also have to be put in balance with the other risks of these drugs, especially of intracranial bleeding. Unless the liver toxicity leads to transplantation, [2] the liver usually recovers. The same can unfortunately not be said of the brain after
stroke. Proactive safety monitoring is certainly warranted before any firm conclusion is drawn or regulatory action is taken.
There may be a signal, and there may even be an alert. But is it really an alarm?
References
[1] Russmann S, Niedrig DF, Budmiger M, Schmidt C, Stieger B, Hurlimann S, et al. Rivaroxaban Postmarketing Risk of Liver Injury. Journal of hepatology 2014. [2] Gulmez SE, Larrey D, Pageaux GP, Lignot S, Lassalle R, Jove J, et al. Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study. Drug safety : an international journal of medical toxicology and drug experience 2013;36:135-144. [3] Lewis JH, Larrey D, Olsson R, Lee WM, Frison L, Keisu M. Utility of the Roussel Uclaf Causality Assessment Method (RUCAM) to analyze the hepatic findings in a clinical trial program: evaluation of the direct thrombin inhibitor ximelagatran. International journal of clinical pharmacology and therapeutics 2008;46:327-339. [4] Gulmez SE, Moore N, Pageaux GP, Lignot S, Horsmans Y, Stricker B, et al. Causality of Drugs Involved in Acute Liver Failure Leading to Transplantation: Results from the Study of Acute Liver Transplant (SALT). Drug safety : an international journal of medical toxicology and drug experience 2013. [5] Moore N, Gulmez SE, Larrey D, Pageaux GP, Lignot S, Lassalle R, et al. Choice of the denominator in case population studies: event rates for registration for liver transplantation after exposure to NSAIDs in the SALT study in France. Pharmacoepidemiology and drug safety 2013;22:160-167. [6] Ehrenforth S, Schenk JF, Scharrer I. Liver damage induced by coumarin anticoagulants. Seminars in thrombosis and hemostasis 1999;25:79-83. [7] Keisu M, Andersson TB. Drug-induced liver injury in humans: the case of ximelagatran. Handbook of experimental pharmacology 2010:407-418. [8] Caldeira D, Barra M, Santos AT, de Abreu D, Pinto FJ, Ferreira JJ, et al. Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and metaanalysis. Heart 2014;100:550-556. [9] Watkins PB, Desai M, Berkowitz SD, Peters G, Horsmans Y, Larrey D, et al. Evaluation of drug-induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery. Drug safety : an international journal of medical toxicology and drug experience 2011;34:243-252.
S0168-8278(14)00320-1 http://dx.doi.org/10.1016/j.jhep.2014.05.010 JHEPAT 5162
To appear in:
Journal of Hepatology
Received Date: Accepted Date:
28 April 2014 3 May 2014
Please cite this article as: Moore, N., Blin, P., Gulmez, S-E., New oral anticoagulants (NOAC) and liver injury, Journal of Hepatology (2014), doi: http://dx.doi.org/10.1016/j.jhep.2014.05.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
New oral anticoagulants (NOAC) and liver injury
Nicholas Moore, Patrick Blin, Sinem-Ezgi Gulmez
Université de Bordeaux, INSERM U657, INSERM CIC1401, Bordeaux, France
Russman et al describe spontaneous reports of drug-induced liver injury after rivaroxaban to the Swiss pharmacovigilance system. [1] They also found a similar signal in large spontaneous report databases (EMA, USFDA, WHO UMC monitoring centre)
The causality of rivaroxaban in these cases is plausible, and rivaroxaban may indeed be associated with liver injury, as most drugs are. However caution may be warranted in the interpretation of these findings, and especially before any firm conclusions are drawn or actions suggested.
Ten of the fourteen reported cases occurred after surgery, mostly total knee replacement, which involves anaesthetics and other drugs that may be hepatotoxic. Surgery itself may result in hepatic injury through transient low output syndrome in these often elderly patients. Most would also receive analgesics such as NSAIDs, even if this would be unlikely because of the use of anticoagulants, or paracetamol with or without opiates. Paracetamol may also be hepatotoxic even at "normal" doses. [2] This does not seem to have been mentioned in the case descriptions. In the cases that occurred in patients using the anticoagulant for atrial fibrillation (AF) there is no anaesthetic or analgesic risk but AF can cause episodes of low cardiac output that may also be injurious, and other hepatotoxic drugs such as amiodarone are often used. Therefore, considering the drug and the medical environment, one is not surprised at finding cases of hepatic injury in such patients. Causality may point to rivaroxaban as the more suspect drug, but causality assessment, even for hepatic-specific methods such as RUCAM, [3] is only as trustworthy as the data
used, and the lack of description of anaesthetic procedures, or analgesic or other drugs is a little worrisome. [4]
Looking at other reporting databases is useful to comfort a signal. However the WHO UMC database includes information from other databases, since it simply compiles data sent by individual countries. As such it is a secondary database, not a primary one. It would duplicate Eudravigilance data, and the FDA data. The FDA database itself includes cases occurring within the US, and industry-reported cases from outside the US: these may also be found in Eudravigilance, and in the WHO database. A very small number of cases may become an epidemic. These databases show that cases may exist, but the actual number of cases and their meaning are uncertain. Careful analysis of the individual cases might help identify duplicate reports in the different databases and give a clearer vision of real numbers of individual reports. However, it will certainly not provide actual event rates. [5]
Even if the cases were to demonstrate the existence of hepatic injury associated with rivaroxaban, is this drug worse than the alternatives?
There are reports of hepatic injury with warfarin and fluindione. [6] Ximelagatran was stopped because of hepatic injury during clinical trials. [7] There is as yet little or no post-marketing information on the other NOACs. A meta-analysis of clinical trials concerning NOACs and vitamin-K antagonists (VKA) found no difference between NOACs and VKA for hepatic problems. [8] Watkins et al did not find an increased risk of liver injury compared to enoxaparin in another meta-analysis of clinical trials. [9]
Several NOACs (rivaroxaban, apixaban, dabigatran, and others) have been recently or will be put on the market and are being carefully monitored for relative
effectiveness
and
bleeding
risk.
Carefully
designed
pharmacoepidemiological studies may also be able to give a reasonable answer for a possible hepatotoxicity, differential or not. If confirmed, it will obviously also have to be put in balance with the other risks of these drugs, especially of intracranial bleeding. Unless the liver toxicity leads to transplantation, [2] the liver usually recovers. The same can unfortunately not be said of the brain after
stroke. Proactive safety monitoring is certainly warranted before any firm conclusion is drawn or regulatory action is taken.
There may be a signal, and there may even be an alert. But is it really an alarm?
References
[1] Russmann S, Niedrig DF, Budmiger M, Schmidt C, Stieger B, Hurlimann S, et al. Rivaroxaban Postmarketing Risk of Liver Injury. Journal of hepatology 2014. [2] Gulmez SE, Larrey D, Pageaux GP, Lignot S, Lassalle R, Jove J, et al. Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study. Drug safety : an international journal of medical toxicology and drug experience 2013;36:135-144. [3] Lewis JH, Larrey D, Olsson R, Lee WM, Frison L, Keisu M. Utility of the Roussel Uclaf Causality Assessment Method (RUCAM) to analyze the hepatic findings in a clinical trial program: evaluation of the direct thrombin inhibitor ximelagatran. International journal of clinical pharmacology and therapeutics 2008;46:327-339. [4] Gulmez SE, Moore N, Pageaux GP, Lignot S, Horsmans Y, Stricker B, et al. Causality of Drugs Involved in Acute Liver Failure Leading to Transplantation: Results from the Study of Acute Liver Transplant (SALT). Drug safety : an international journal of medical toxicology and drug experience 2013. [5] Moore N, Gulmez SE, Larrey D, Pageaux GP, Lignot S, Lassalle R, et al. Choice of the denominator in case population studies: event rates for registration for liver transplantation after exposure to NSAIDs in the SALT study in France. Pharmacoepidemiology and drug safety 2013;22:160-167. [6] Ehrenforth S, Schenk JF, Scharrer I. Liver damage induced by coumarin anticoagulants. Seminars in thrombosis and hemostasis 1999;25:79-83. [7] Keisu M, Andersson TB. Drug-induced liver injury in humans: the case of ximelagatran. Handbook of experimental pharmacology 2010:407-418. [8] Caldeira D, Barra M, Santos AT, de Abreu D, Pinto FJ, Ferreira JJ, et al. Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and metaanalysis. Heart 2014;100:550-556. [9] Watkins PB, Desai M, Berkowitz SD, Peters G, Horsmans Y, Larrey D, et al. Evaluation of drug-induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery. Drug safety : an international journal of medical toxicology and drug experience 2011;34:243-252.
