Hepatotoxicity in association with acetaminophen poisonings in the U.S.

Transcription

1 Hepatotoxicity in association with acetaminophen poisonings in the U.S. Syed Rizwanuddin Ahmad, MD, MPH, FISPE, FCP Office of Surveillance and Epidemiology U.S. FDA/CDER ICPE August

2 Disclaimer These are my own views not necessarily shared by the FDA or the U.S. government No conflict of interest to declare. However, my employer receives money from the industry as part of user fee 2

3 Outline Objectives Background Methods Results Limitations Key Findings 3

4 Abstract Presentation Abstract - 3 years of data Presentation - New/updated analyses with 11 years of data Findings different from that presented in the abstract numerators vs. rates In the spirit of transparency we decided to present the full study results and focus on rates rather than numerator data 4

5 Abstract Numerator analysis - 1 In 3 yr study period ( ) 160,794 AP cases 88% adults vs 12% children <18 yrs Of all acetaminophen-associated poisonings (AP), accidental- 31%; intentional-54%, and unknown-15% Accidental AP, children - 6%; adults - 93% Intentional AP, children 15%; adults 84% Among AP cases, 69% of children s cases were intentional vs 52% of adult s cases Overall, intentional AP in adolescents was more common compared to adults 5

6 Abstract Numerator analysis - 2 In the 3 yr period ( ), there were 8% children (<18 yrs) vs 17% adults cases associated w/ accidental AP + hepatotoxicity In the intentional group, there were 4% children vs 8% adults Among children with AP + hepatotoxicity, 42% of cases with accidental poisoning had more severe hepatotoxicity compared 23% of those with intentional poisoning 6

7 Objectives To estimate the rate of hepatotoxicity associated with acetaminophen poisoning To estimate the rate of mortality in hospitalized patients with a discharge code of acetaminophen associated poisoning and with and without hepatotoxicity 7

8 Background -1 Acetaminophen is a very popular analgesic and antipyretic It is generally recognized as safe and effective when used as recommended Benefits millions of consumers every year Acetaminophen is the leading pharmaceutical product associated with acute liver failure (ALF) 8

9 Background-2 The Nationwide Inpatient Sample (NIS) is the largest national all-payer hospital inpatient care database in the US Nearly 8 million hospital stays/year from 1,000 hospitals Provides national estimates The sampling frame for NIS data comprises 95% of all U.S. discharges 9

10 Methods Analyzed data from Unit of analysis=hospital discharge (not patient) Acetaminophen-associated poisoning identified by any discharge diagnosis with these ICD-9-CM codes: : Poisoning by aromatic analgesics (AA) not elsewhere classified (NEC) --E850.4: Accidental poisoning by AA NEC 10

11 Hepatotoxicity (if coded in addition to Acetaminophen-associated poisoning code) DX (hepatorenal syndrome) DX (hepatic coma/hepatic encephalopathy) DX 570 (acute or subacute liver necrosis/acute hepatic failure) DX V42.7 (liver transplant) PR 50.5 (any encounter that listed liver transplant as a procedure code) DX (jaundice) DX (coagulopathy) DX 286.7(coagulation defect due to liver disease) DX (biliuria) (transaminsasemia) Methods---(2) (hepatitis, noninfectious toxic) 11

12 Methods---(3) In addition, the following codes were used to identify intent: E950.0: Suicide or self-inflicted poisoning by analgesics, antipyretics, and anti-rheumatics E962.0: Assault by poisoning with drugs and medicinal substances E980.0 Injury by analgesics, anti-pyretics, and anti-rheumatics, undetermined whether accidentally or purposely inflicted Cases were categorized into the following groups: and (E860.4 or E9635.4) = accidental poisoning by AA & E950.0 = intentional self-inflicted poisoning by AA and E962.0 = AA poisoning, assault and E980.0 = AA poisoning with undetermined intent Because of small numbers of cases, AA poisoning, assault and with undetermined intent were combined into one group (unknown/undetermined) for reporting purposes 12

13 Methods---(4) Rates per 100,000 U.S. population were estimated Numerator number of projected hospital discharges Denominator U.S. population in specified age groups, as reported in the U.S. census , in July of each year Trend analyses Statistical significance of changes over time in estimates was evaluated by comparing the 95% confidence interval around the estimate for period 1 ( ) to that for period 4 ( ) 13

14 Results 14

15 Rates of Acetaminophen-associated Poisoning Discharges with Hepatotoxicity, per 100,000 U.S. population, by Age All Acetaminophen poisoning All ages < 2 years old 2-12 years years 18+ years Rate Rate Rate Rate (95% CI) (95% CI) (95% CI) (95% CI) 1.33 ( ) 0.30 ( ) 0.04 ( ) 1.65 ( ) 1.61 ( ) 1.66 ( ) 0.10 ( ) 0.08 ( ) 2.15 ( ) 2.00 ( ) 1.90 ( ) 0.14 ( ) 0.09 ( ) 1.68 ( ) 2.35 ( ) 2.37 ( ) ( ) 0.03 ( ) 1.61 ( ) 2.98 ( ) Data Source: NIS

16 Rates of Acetaminophen-associated Poisoning Discharges with Hepatotoxicity, per 100,000 U.S. population, by Age/Intentionality - 1 Accidental Poisoning Rate Rate Rate Rate (95% CI) (95% CI) (95% CI) (95% CI) All ages 0.29 ( ) 0.36 ( ) 0.45 ( ) 0.60 ( ) < 2 years 0.26 ( ) 0.10 ( ) 0.12 ( ) 0.11 ( ) 2-12 years 0.02 ( ) 0.03 ( ) 0.05 ( ) 0.01 ( ) years 0.29 ( ) 0.29 ( ) 0.24 ( ) 0.26 ( ) 18+ years 0.35 ( ) 0.45 ( ) 0.57 ( ) 0.77 ( ) Data Source: NIS

17 Rates of Acetaminophen-associated Poisoning Discharges with Hepatotoxicity, per 100,000 U.S. population, by Age/Intentionality Rate Rate Rate Rate (95% CI) (95% CI) (95% CI) (95% CI) Intentional Poisoning All ages 0.77 ( ) 0.92 ( ) 1.07 ( ) 1.26 ( ) < 2 years* 2-12 years 0.01 ( ) 0.04 ( ) 0.04 ( ) 0.01 ( ) years 1.14 ( ) 1.53 ( ) 1.17 ( ) 1.11 ( ) 18+ years 0.93 ( ) 1.08 ( ) 1.30 ( ) 1.57 ( ) Data Source: NIS

18 In-hospital mortality among Inpatients with Acetaminophen-associated Poisoning, All Ages & by Intentionality, with or without Hepatotoxicity, All ages Accidental poisoning Intentional poisoning Number of AP inpatients N 59, ,526 Hepatotoxicity 59,753 No hepatotoxicity 343,526 Number of deaths Percent died in the hospital In-hospital mortality rate per 1,000,000 population N % Rate (95% CI) (95% CI) (95% CI) 1,418 ( 1,221-1,615 ) 1,734 ( 1,512-1,956 ) 3,226 ( 2,844-3,608 ) 1,550 ( 1,366-1,733 ) 2.39 ( ) 0.64 ( ) 5.40 ( ) 0.45 ( ) 0.44 ( ) ( ) 1.01 ( ) 0.48 ( ) Data Source: NIS AP = Acetaminophen-associated poisoning 18

19 In-hospital mortality among Pediatric inpatients with Acetaminophenassociated Poisonings, by Intentionality with or without Hepatotoxicity, Ages 0-17 years Accidental poisoning Intentional poisoning Hepatotoxicity No hepatotoxicity Number of AP inpatients N 9,608 55,728 4,549 72,260 Number of deaths Percent died in the hospital In-hospital mortality rate per 1,000,000 population N % Rate (95% CI) (95% CI) (95% CI) 23 ( ) 31 ( ) 28 ( ) 35 ( ) 0.24 ( ) 0.06 ( ) 0.61 ( ) 0.05 ( ) ( ) 0.04 ( ) 0.03 ( ) ( ) Data Source: NIS AP = Acetaminophen-associated poisoning 19

20 In-hospital mortality among Adult inpatients with Acetaminophenassociated Poisonings, by Intentionality with or without Hepatotoxicity, Ages 18+ years Accidental poisoning Intentional poisoning Number of AP inpatients N 49, ,798 Hepatotoxicity 55,204 No hepatotoxicity 271,266 Number of deaths Percent died in the hospital In-hospital mortality rate per 1,000,000 population N % Rate (95% CI) (95% CI) (95% CI) 1,395 ( 1,200-1,591 ) 1,703 ( 1,482-1,924 ) 3,199 ( 2,818-3,579 ) 1,514 ( 1,334-1,695 ) 2.80 ( ) 0.79 ( ) 5.79 ( ) 0.56 ( ) 0.58 ( ) 0.71 ( ) 1.34 ( ) 0.63 ( ) Data Source: NIS AP = Acetaminophen-associated poisoning 20

21 Limitations Unit of analysis is hospital discharge (not patient); patients with multiple hospitalizations could be counted multiple times Underestimation of total discharges excludes poisonings treated in federal hospitals and outpatient settings Medical records are not available to validate diagnoses Data are based on administrative records that are used for billing purposes and clinical details are limited Poisonings from other drugs and other relevant medical conditions were not excluded Inpatient mortality is based on discharge status of death 21

22 Key Findings --1 Rate of hospitalizations in association with acetaminophen poisonings and hepatotoxicity across all ages were very low, but increased from 1.33 per 100,000 in to 2.37 per 100,000 in Rates of AP hospitalizations with hepatotoxicity and accidental and intentional AP hospitalizations, increased between and With few exceptions, rates of AP hospitalizations with hepatotoxicity did not change among children Hospitalization w/ hepatotoxicity rates fell for children <2 yrs old: from 0.300/100,000 in to 0.146/100,000 in Rate of AP hospitalizations with hepatotoxicity increased in adult 18+ years of age from 1.6/100,000 in to about 3/100,000 in

23 Key Findings--2 As expected, the in-hospital mortality rate was significantly higher for hospitalized cases with hepatotoxicity across all ages 1.0 per 1,000,000 for hospitalizations in association with acetaminophen poisonings with hepatotoxicity vs per 1,000,000 for those without hepatotoxicity 23

24 Acknowledgements Anne Elixhauser, PhD Senior Research Scientist AHRQ, Rockville, MD Janet Pagan-Sutton, PhD Senior Research Scientist Social & Scientific Systems, Inc. Silver Spring, MD 24