The Usage Of Vicodin And Percocet et. al. Is Questioned

July 6, 2009

Acetaminophen Leading Culprit in Drug-Induced Liver Injury

Acetaminophen leads the list of drugs implicated in liver damage requiring transplantation, although antiepileptics are more lethal, according to a new study.
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Analysis of records from a transplant database found that patients with acetaminophen-induced injury were also more likely to be on life support than patients with liver failure caused by the next most common culprits, antituberculosis drugs, antiepileptics, and antibiotics (82%, versus 44% to 70%, P <0.0001), according to Ayse L. Mindikoglu, MD, of the University of Maryland in Baltimore and colleagues.

Patients whose liver failure was caused by acetaminophen also had a higher mean serum creatinine (3.21 mg/dL versus 1.31 to 1.86 mg/dL, P<0.0001), and a greater requirement for dialysis prior to transplantation (27% versus 3% to 10%, P<0.0001), the investigators reported in the July issue of Liver Transplantation.

Their report was issued just days after an FDA advisory panel recommended a “black box” warning for prescription combination drugs that contain acetaminophen. The panel also recommended that the maximum single adult dose be reduced from 1,000 mg to 650 mg, and that the maximum daily dose be reduced from its current level of 4,000 mg. (See FDA Panel Backs ‘Black Box’ Warning for Acetaminophen Prescription Combos)

As potentially hazardous to the liver as acetaminophen may be, the risk of death following liver transplantation was highest among patients whose liver injury was caused by antiepileptics, Dr. Mindikoglu found. In fact, the risk attributable to antiepileptics increased by a factor of 4.13 for patients under 18 and 1.03 for older patients.

The findings emerged from a retrospective cohort study of the United Network for Organ Sharing database, which includes almost all liver transplants in the U.S.

The records show that between October 1987 and December 2006, there were 661 liver transplantations for drug-induced injury.

A total of 567 were adults. The median age was 36, and the majority were female and white.

The implicated agents were:

* Acetaminophen in 265 (40%)
* Antituberculosis drugs in 50 (8%)
* Antiepileptics in 46 (7%)
* Antibiotics in 39 (6%)

Median survival for the whole cohort was 14.4 years, and one-year estimated survival probabilities were:

* Acetaminophen 76%
* Antituberculosis drugs 82%
* Antiepileptics 52%
* Antibiotics 82%
* Other drugs 79%

Comparison of outcomes according to age showed no overall significant differences in survival rates between pediatric and adult patients (P=0.56).

Two-year survival probabilities were 0.06 for children and .074 for adults.

But a marked difference was seen in survival following acute liver failure resulting from the use of antiepileptics, with a one-year survival of only 27% for children, compared with 75% for adults.

The high rate of death among pediatric patients with antiepileptic-induced liver failure may relate to valproic acid-induced hyperammonemic encephalopathy and carnitine depletion, the investigators suggested.

Patients whose liver failure related to antiepileptic use also had a greater frequency of retransplantation than the other groups (24% versus 4% to 9%).

Males were 1.4 times more likely to die than females, while a doubling of the serum creatinine increased mortality risk by 1.19. Patients on life support were 2.08 times more likely to die, the researchers reported.

Cox stepwise regression analysis found that independent pretransplant predictors of death were a requirement for life support, liver failure from antiepileptic drugs before age 18, and elevated serum creatinine.

The researchers proposed that those independent predictors could be used in a prognostic model for predicting post-transplant outcomes.

In an accompanying editorial, Paul H. Hayashi and Paul Watkins of the University of North Carolina wrote that this is the first study to propose a mathematical model to predict survival after transplantation for acute liver failure.

“Their attempt at modeling falls short of immediate usefulness, but the identification of poorer outcomes for children with antiepileptic [drug-induced acute liver failure] is intriguing and points out the need for more focused research,” the editorialists wrote.

They also observed that drug-induced liver failure, while a rare event, “has wide implications for all of us who take and prescribe medications,” and that in coming years significant advances can be expected in understanding of factors such as genetic predisposition.

The investigators noted that their study had limitations, “as expected from any retrospective database analysis,” such as the fact that they were unable to estimate numbers of patients who died before transplantation or spontaneously recovered.

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