Increase in US medication-error deaths

CORRESPONDENCE

1600 1400 1200

Suicidal poisonings Undermined poisonings Adverse effects of drugs in therapeutic use

Medication errors Drug abuse Surgical and medical misadventures Homicide poisonings

Deaths

1000 800 600 400 200 0 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 Year of death Trends in deaths in England and Wales from medication errors and related causes 1983–1996 Causes plotted (with their ICD9 codes) are: medication errors (E850-858); homicidal poisoning (E962); suicidal poisoning (E950); poisonings undertermined whether accidental or purposeful (E980); dependent and non-dependent abuse of drugs (304-305); misadventures during medical care (E870-879); drugs causing adverse effects in therapeutic use (E930-949).

When we analysed deaths due to adverse drug events—ie, to adverse effects of drugs or to errors in the use of drugs—there were about four deaths from adverse effects for every death from error.4 An important prospective study of ADRs in a major teaching hospital in the USA showed a very similar relative incidence of the two causes.5 Codes E850-E858 include deaths from accidental overdose of drug, wrong drug given or taken in error, and drug taken inadvertently. Excluded are administration with suicidal (E950) or homicidal (E962) intent, or where investigation has failed to establish whether poisoning was accidental, suicidal, or homicidal (E980-E989). It seems at least plausible that only a small fraction of the deaths coded to E850-E858 do reflect medication errors in which mistakes in the prescription, dispensing, or (self) administration of medicines cause harm. With the uncertainties in the classification, and the difference of about 150-fold in the ratio of adverse effects to errors ascertained directly and through death-certification data, it is wrong to impute changes in them to altered medical practice. *R E Ferner, C Anton West Midlands Centre for Adverse Drug Reaction Reporting, City Hospital, Birmingham B18 7QH, UK

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Phillips DP, Christenfeld N, Glynn LM. Increase in US medication-error deaths between 1983 and 1993. Lancet 1998; 351: 643–44. Office for National Statistics. Mortality statistics: cause 1993 (revised) and 1994. Series DH2 no 21. London: HM Stationery Office, 1995: vi–viii. Smith CC, Bennett PM, Pearce HM, et al. Adverse drug reactions in a hospital general medical unit meriting notification to the Committee on Safety of Medicine. Br J Clin Pharmacol 1996; 42: 423–29. Ferner RE, Whittington RM. Coroner’s cases of death due to errors in prescribing or giving medicines or to adverse drug reactions: Birmingham 1986–1991. J R Soc Med 1994; 87: 145–48. Bates DW, Cullen D, Laird N, et al. Incidence of adverse drug events and potential adverse drug events: implications for prevention. JAMA 1995; 274: 29–34.

Sir—David Phillips and co-workers1 attribute the risk in deaths from medication errors in the USA to an increase in mistakes in taking or administration of prescribed drugs. They go on to say that this increase might be because of lack of medical supervision related to shorter hospital stays and increasing outpatient treatment. This explanation is a misinterpretation of death registration statistics. There is no such category as medication error in ICD-9. Phillips et al have assigned this definition to deaths certified as accidental poisoning with “drugs, medicaments and biologicals” (ICD-9 range E850-E858, APD). 80% of the 7391 APD deaths

in the USA in 1993 were in people aged 25–49 years, only 8% were aged 60 or older, and three-quarters are in men. Deaths certified as due to poisoning by any substance that may be used as a drug are coded to E850-E858, unless the certifier indicates that the poisoning was intentional (suicide or homicide) or that investigation failed to determine the intent.2 Contrary to Phillips’ statement, no admission of error is required. We cannot tell from the code how the drug was prescribed or obtained. Deaths from unintentional poisoning that have any mention of drug addiction or dependence are assigned an underlying cause of 304 drug dependence in ICD-9.2–4 However, mention of drug abuse (305) does not affect the underlying cause assignment in the USA.3,4 Phillips and colleagues claim that the drugs showing the greatest rise in numbers of deaths are analgesics, particularly opiates, anaesthetics, and unspecified drugs. Opiates (E850.0) accounted for 1731 deaths in 1993, 23·4% of all APD. Anaesthetic poisoning would be largely cocaine, which is coded to E855.2 local anaesthetic poisoning, no matter why it was taken (1096 deaths, 14·8% of APD in 1993). E858, poisoning by other and unspecified drugs, includes combinations that would individually be coded to different E-codes (E858.8 1904 deaths, 25·8%), and vague terms such as drug poisoning or overdose of a mixture of drugs (E858.9 1318 deaths, 17·8%). Only about 1% are coded to poisoning with aromatic analgesics (acetaminophen or paracetamol). I have examined 1993 US multiple cause mortality data,5 which include ICD-9 codes for all conditions on the certificate up to 20 in total. I also searched all the cause fields of these 7391 deaths for the presence of any disease code, and then for conditions in each of the cause groups listed separately.* 45% had no codes other than those for poisoning. A further 24% had only codes for poisoning and for drug abuse (305). (Drug abuse was mentioned in almost 31% overall.) Only 31% had any condition mentioned other than poisoning, alcohol, or drug dependence or drug abuse, mainly terminal events, probably caused by poisoning. By contrast, only a few deaths had any serious disease mentioned (ischaemic heart disease 3·4%, respiratory disease 1·9%, neoplasms 1·5%, AIDS/HIV 0·5%) or diseases likely to lead to confusion (cerebrovascular disease 1·2%, mental 0·8%, neurological 0·6%).

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CORRESPONDENCE

There may be dangers associated with short hospitalisations and outpatient treatment, but these data provide no evidence for or against this theory. They do show that there are large numbers of deaths from accidental poisoning in young men, predominantly from drugs of abuse. *Table of results available from the author or The Lancet, on request.

Cleone Rooney UK WHO Collaborating Centre for the Classification of Diseases, Census, Population and Health Group, Office for National Statistics, London SW1V 2QQ, UK (e-mail: [email protected]) 1

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Phillips DN, Christenfeld N, Glynn LM. Increase in US medication-error deaths between 1983 and 1993. Lancet 1998; 351: 643–44. WHO. International classification of diseases, ninth revision. Geneva: WHO, 1977. National Centre for Health Statistics. Instruction manual part 2a: instructions for classifying the underlying cause of death. Hyattesville, MD: NCHS, 1992. National Centre for Health Statistics. Instruction manual part 2c; ICD-9 ACME decision tables for classifying the underlying cause of death. Hyattesville, MD: NCHS, 1992. National Centre for Health Statistics. 1993 Multiple cause of death file. CD-ROM series 20 No 11. Hyattesville, MD: US Department of Health and Human Services, 1997.

Authors’ reply Sir—In our report we documented a nearly three-fold increase in deaths classified as accidental poisoning by drugs, medicinal substances, and biologicals. This category (ICD-9 E850-E858) includes “accidental overdose of drug, wrong drug given or taken in error, and drug taken inadvertently”, as well as “accidents in the use of drugs and biologicals in medical and surgical procedures”.1 We referred to this category generally as medication errors. The increase in E850-E858 deaths was especially steep (8·48-fold) for outpatients. Henri Manasse’s suggestion is unlikely. First, in 1993, only 1·5% of E850-E858 decedents were under the age of 18 (109/7391). Second, deaths from anaesthetics showed an especially steep increase, but could not plausibly result from non-patients accidentally giving themselves anaesthetics. We agree that the precise cause of the increase in medication-error mortality is not yet known, but note that all Manasse’s suggestions are consistent with our point that the increase may be associated with recent trends in US medical care. R E Ferner and C Anton compare our data with death certificate counts from England and Wales. Their data

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indicate that, with the exception of a shift in tabulation policy in 1993, British deaths classified as E850-E858 do not increase greatly between 1983 and 1993. Such a finding does not undermine our explanation for the US increase, because England and Wales did not shift to managed care during that period. They also appear to be arguing that ADRs are under-reported on certificates, and thus think it plausible that not all E850-E858 deaths result from medication errors. However, especially in a medical climate as litigious as that in the USA, it is likely that medication errors would be under-reported rather than overreported as a cause of death. Cleone Rooney argues that our category of medication errors includes numerous deaths from street drugs, especially cocaine. There are two reasons to think that the deaths we examined were not mainly due to street cocaine. First, deaths from street cocaine should include on the certificate, not only accidental poisoning by local anaesthetics, but also dependent (304.2) or nondependent (305.6) abuse of cocaine. Only 4% (44/1096) of local anaesthetic deaths in 1993 co-listed cocainerelated drug abuse (304.2 and 305.6). Second, one can use the Nature of Injury codes to help distinguish street cocaine from medicinal cocaine. One such code, N968.5, “poisoning by surface and infiltration anaesthetics”, explicitly excludes deaths due to “drug dependence (304.0–304.9) and nondependent abuse (305.0–305·9)”.1 99% of local anaesthetic deaths in 1993 co-listed N968.5, which suggests that nearly all local anaesthetic deaths were from medicinal rather than street cocaine. Why then are medication errors associated with non-dependent abuse of drugs (305)? The frequent co-listing of E850-E858 and ICD-9 305 may result, not from abuse of street cocaine, but from abuse of alcohol, which is a far more frequent cause of death in ICD 305. Many drugs interact dangerously with alcohol, and physicians, who are decreasingly likely to know their patients well, may miss signs of alcohol abuse or intoxication.2 To test the hypothesis that alcohol might be a risk factor for medicationerror deaths, we examined death certificates co-listing E850-E858 and those ICD-9 305 certificates explicitly mentioning alcohol (either ICD-9 305.0 or ICD-9 305 with ICD-9 571.0–571.3 [cirrhosis of the liver with mention of alcohol], ICD-9 303 [alcohol dependence syndrome]), ICD-9 357.5, 425.5, 790.3, 535.3,

291, E860, N980, N977.3, or E947.3).3 Death certificates co-listing medication errors and alcohol abuse increased 45-fold, from seven in 1983 to 315 in 1993. Drug abuse is indeed associated with the increase in medication errors, but the drug appears to be alcohol, not cocaine. *D P Phillips, N Christenfeld, L M Glynn Department of Sociology, UCSD, La Jolla, CA 92093, USA 1

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US Department of Health and Human Services. International Classification of Diseases, 9th Revision. Washington, DC: Government Printing Office, 1994. O’Connor PG, Schottenfeld RS. Patients with alcohol problems. N Engl J Med 1998; 338: 592–602. National Center for Health Statistics. 1993 Multiple cause of death file, series 20, No 11. Hyattsville, USA: Department of Health and Human Services, 1997.

Lack of efficacy of neutral endopeptidase inhibitor ecadotril in heart failure Sir—Heart failure is associated with the activation of several vasoconstrictor and vasodilator neuroendocrine systems. Although activation of vasoconstrictor systems seems harmful and agents that interrupt some of these systems are of clinical benefit, enhancing the action of vasodilator systems has not yet been shown to be beneficial. Inhibitors of neutral endopeptidase (NEP) inhibit the degradation of natriuretic peptides. The resulting increase in plasma concentration of natriuretic peptides is slight, but NEP inhibitors do cause acute natriuresis and diuresis1 and reduce cardiac filling pressures, with negligible acute effects on resting vascular resistance or cardiac output at rest.2 Placebo-controlled studies of NEP inhibitors reported so far suggest that these agents are safe for use in heart failure and that during medium-term therapy moderate increases in exercise capacity can be seen. However, none of these studies has shown an improvement in symptoms. In a recently completed multinational study, 279 patients with chronic heart failure were randomised into five equal groups to receive placebo or one of four doses (50 mg, 100 mg, 200 mg, or 400 mg twice daily) of the NEP inhibitor ecadotril (sinorphan, the s-enantiomer of the racemate acetorphan). All patients enrolled were receiving inhibitors of angiotensinconverting enzyme and conventional diuretic therapy and had echocardiographic left ventricular

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