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Drug-related morbidity and mortality: Pharmacoepidemiological aspects
Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adverse drug reactions (ADRs) constitute a significant health problem with consequences for the patient as well as for society. Suspected ADRs have been reported to occur in about 2-14% of hospitalised patients. In about 5% of deceased hospitalised patients suspected ADRs may have caused or contributed to the fatal outcome. When a pharmaceutical drug is approved for marketing, the drug has been tested only on a limited number of patients (often <6000) for a limited time period in a controlled environment. Hence mostly common ADRs are detected in these trials. Moreover, certain patient groups, for example patients with co-morbidities, elderly patients, children and pregnant women are often not included in these studies. Thus, it is important to closely monitor the use of drugs after marketing to observe new effects and detect new ADRs.

The aim of this thesis is to describe the pattern of pharmaceutical substance use related to morbidity and mortality and to investigate two serious ADRs. We have studied the incidence of fatal ADRs, fatal intoxications, cerebral haemorrhage related to warfarin treatment and venous thromboembolism (VTE) related to treatment with antipsychotic drugs.

Observational studies form the basis for this thesis. Data from the Swedish Cause of Death Register, medical case records, the Swedish database on ADRs, the forensic pathology and forensic toxicology databases, and Swedish and Danish hospital discharge registers, Danish prescription registers, and civil registry systems were used.

In Paper I we found that 3% of all fatalities in a Swedish population were related to a suspected ADR. Of the deceased hospitalised patients, 6% were related to a suspected ADR. Haemorrhage was the most commonly observed fatal suspected ADR, accounting for almost two-thirds of the events and anticoagulantia was the most common drug group associated with fatal suspected ADRs (almost 50%). A suspected intoxication could have contributed to the fatal outcome in 0.6% of the deceased. Among the fatal intoxications in Swedish medico-legal autopsies studied in Paper II, on average four substances were detected per case. The five most commonly detected substances in individuals with a fatal intoxication were ethanol, propoxyphene, paracetamol, diazepam and flunitrazepam. Among patients diagnosed with cerebral haemorrhage, 10% (59 cases) were treated with warfarin at onset of symptoms (Paper III). Of these, 7 cases (12%) were considered to have been possibly avoidable since the patients were treated with concomitant drugs that have the potential to enhance warfarin effects. The results from Paper IV and Paper V in combination with the published literature suggest that patients treated with antipsychotic drugs have an increased risk for VTE. Compared with non-users, an adjusted odds ratio for VTE of 2.0 was found for users of any antipsychotic drugs in a Danish population. In a medico-legal autopsy series, an adjusted odds ratio for fatal pulmonary embolism of 2.4 and 6.9 was found for users of first-generation low-potency antipsychotics and second-generation antipsychotics, respectively.

In summary, drug-related morbidity and mortality is a significant problem and suspected ADRs contribute to a substantial number of deaths. Fatal intoxications are relatively common and it is important to observe changes in patterns of substances associated with fatal intoxications to be able to discover new trends and monitor effects of preventive work. A significant proportion of warfarin-related cerebral haemorrhage was caused by drug-drug interactions and was considered possible to avoid. Users of antipsychotic drugs may increase the risk of VTE.

Abstract [sv]

Idag finns det säkra och effektiva behandlingar mot många sjukdomar. Läkemedel är den vanligaste behandlingsformen i sjukvården och under 2006 hämtade sex miljoner svenskar (68%) ut ett eller fler recept på ett apotek i Sverige. Även om läkemedelsbehandling har många positiva effekter kan även oönskade och skadliga effekter vid läkemedelsbehandling uppkomma, dvs. läkemedelsbiverkningar. Innan ett läkemedel kommer ut för försäljning har man studerat effekter och biverkningar på ett begränsat antal individer (ofta <6000) under en begränsad tidsperiod där patienterna övervakas noga. Dessutom är det i regel enbart patienter med få andra sjukdomar och läkemedel som ingår i dessa studier. Därför är oftast enbart de vanligaste biverkningarna kända när ett läkemedel börjar säljas till allmänheten. När ett läkemedel blir tillgängligt för ett stort antal patienter är det därför viktigt att man med olika metoder fortsätter att följa läkemedlets effekter och biverkningar. Tidigare har man visat att ungefär 2-14% av inläggningar på sjukhus beror på läkemedelsbiverkningar. Dessutom kan biverkningar ha bidragit eller orsakat dödsfallet i ungefär 5% av de som avlider på sjukhus. Biverkningar orsakar mycket lidande för patienten och kostar samhället både tid och pengar. Om det skulle vara möjligt att förhindra några av dessa sjukhusinläggningar eller dödsfall skulle man vinna mycket. Det är svårt att uppskatta hur många biverkningar som kan förhindras. Genom att studera faktorer som kan öka risken för en oönskad effekt kan man bättre anpassa behandlingen till den enskilde patienten och därmed förhindra biverkningar.

Syftet med den här avhandlingen är att beskriva mönster av läkemedelsrelaterade sjukdomar och dödsfall, och att undersöka risken för två allvarliga läkemedelsbiverkningar. Förekomsten av misstänkta läkemedelsbiverkningar, vilka faktorer som kan öka risken för att få en läkemedelsbiverkan, samt vilka läkemedel och biverkningar som förekommer har studerats. Detta gjordes utifrån uppgifter hämtade från dödsorsaksregistret, svenska biverkningsregistret, journaler, rättsmedicinska register, slutenvårdsregister och receptregister. Genom att utnyttja sådan information har vi i närmare detalj studerat förekomsten av dödsfall där ett eller flera läkemedel kan ha haft betydelse för dödsfallet, förgiftningsdödsfall, blödningar i samband med blodförtunnande medicinering och blodproppar i samband med antipsykotisk medicinering.

I de arbeten som ingår i avhandlingen har vi funnit att en läkemedelsbiverkan misstänks ha bidragit eller orsakat dödsfallet i ungefär 3% av de som avlidit i en svensk population (Arbete I). Blödningar står för nästan två tredjedelar av dessa biverkningar och blodförtunnande medel misstänks vara inblandade i nästan hälften av de misstänkta läkemedelsbiverkningarna. I den här svenska populationen avled 0,6% till följd av misstänkt läkemedelsförgiftning. Bland rättsmedicinskt undersökta förgiftningsdödsfall påvisades i genomsnitt fyra substanser per fall (Arbete II). De fem vanligaste påvisade substanserna i studien var alkohol, dextropropoxifen, paracetamol, diazepam och flunitrazepam. Bland patienter som får hjärnblödning behandlades 10% vid blödningstillfället med ett blodförtunnande medel, warfarin (Arbete III). I 7 fall (12%) skulle hjärnblödningen möjligen kunna ha förhindrats då patienterna samtidigt behandlades med andra läkemedel som kan ha ökat blödningsrisken. Den sammantagna bilden av den litteratur som finns publicerad och resultatet av Arbete IV och Arbete V, tyder på att patienter som behandlas med antipsykotiska preparat har en ökad risk för att få blodpropp. Flera faktorer har föreslagits som kan förklara den ökade risken för blodpropp bland patienter som behandlas med antipsykotika som har med sjukdomen att göra och/eller behandlingen med antipsykotiska läkemedel.

Sammanfattningsvis visar detta avhandlingsprojekt att läkemedelsbiverkningar är ett väsentligt sjukvårdsproblem som bidrar till ett betydande antal dödsfall. Förgiftningsdödsfall med läkemedel är också relativt vanliga och det är viktigt att bevaka effekter av preventiva åtgärder och se om de substanser som används ändras över tid. En del läkemedelsrelaterade biverkningar skulle kunna förhindras då t.ex. en betydande andel av warfarinrelaterade hjärnblödningar beror på läkemedelsinteraktioner. Förekomsten av venösa blodproppar verkar vara förhöjd bland patienter som behandlas med antipsykotiska läkemedel, men fler studier behövs för att avgöra detta och vad det i så fall beror på.

Place, publisher, year, edition, pages
Institutionen för medicin och hälsa , 2007.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1030
Keyword [en]
Adverse drug reactions, pharmacoepidemiology, antipsychotics, venous, thromboembolism, warfarin, haemorrhage, intoxication, medico-legal autopsies, mortality
Keyword [sv]
Läkemedelsbiverkningar, farmakoepidemiologi, antipsykotika, venös tromboembolism, warfarin, blödning, intoxikation, rättsmedicinska obduktioner, fatal
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:liu:diva-10460ISBN: 978-91-85895-33-5 (print)OAI: oai:DiVA.org:liu-10460DiVA: diva2:17207
Public defence
2007-12-14, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2007-12-19 Created: 2007-12-19 Last updated: 2009-08-22
List of papers
1. Incidence of fatal adverse drug reactions: A population based study
Open this publication in new window or tab >>Incidence of fatal adverse drug reactions: A population based study
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2008 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 65, no 4, 573-579 p.Article in journal (Refereed) Published
Abstract [en]

What is already known about this subject

• Although drugs generally are safe and effective therapies for numerous diseases, adverse drug reactions do occur and may even be fatal.

• The incidence of fatal adverse drug reactions in hospitalized patients has been estimated to be approximately 5%.

• In previous studies the incidence of fatal adverse drug reactions in hospitalized patients has been reported, but the incidence of fatal adverse drug reactions in the general population is largely unknown.

What this study adds

• Fatal adverse drug reactions account for approximately 3% of all deaths in the general population.

• Haemorrhages amount to almost two-thirds of the fatal adverse drug reactions and antithrombotic agents are implicated in more than half of the suspected fatal adverse drug reactions.

• Fatal adverse drug reactions are estimated to be the seventh most common cause of death in Sweden.

 

Aims: To determine the incidence of fatal adverse drug reactions (FADRs) in a Swedish population.

 

Methods: Every seventh randomly selected deceased in three counties in South-east Sweden during 1 January 2001–31 December 2001 was identified in the Cause of Death Register. Relevant case records (hospitals and/or primary care centres and medicolegal files) were reviewed to identify suspected drug-related fatalities.

 

Results: Of 1574 deceased study subjects, 49 (3.1%; 95% CI 2.2%, 4.0%) were suspected to have died from FADRs. The most common suspected FADRs were gastrointestinal haemorrhages (n = 18; 37%), central nervous system haemorrhages (n = 14; 29%), cardiovascular disorders (n = 5; 10%), other haemorrhages (n = 4; 8%) and renal dysfunction (n = 3; 6%). The drugs most commonly implicated in FADRs were antithrombotic drugs (n = 31; 63%), followed by nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 9; 18%), antidepressants (n = 7; 14%) and cardiovascular drugs (n = 4; 8%). Of all the 639 fatalities in hospital 41 (6.4%; 95% CI 4.5%, 8.3%) were suspected to be due to FADRs.

 

Conclusions: The medical burden of FADRs is significant. Haemorrhages were seen in a majority of the FADRs; antithrombotic agents or NSAIDs were implicated in most of these events. These results suggest that preventive measures should be taken to reduce the number of deaths caused by drugs.

Place, publisher, year, edition, pages
Chichester, West Sussex United Kingdom: Wiley-Blackwell, 2008
Keyword
adverse drug reactions, epidemiology, mortality, population based study
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12847 (URN)10.1111/j.1365-2125.2007.03064.x (DOI)000253883800017 ()
Available from: 2007-12-19 Created: 2007-12-19 Last updated: 2014-01-13Bibliographically approved
2. Fatal intoxications in a Swedish forensic autopsy material during 1992-2002
Open this publication in new window or tab >>Fatal intoxications in a Swedish forensic autopsy material during 1992-2002
2004 (English)In: Forensic Science International, ISSN 0379-0738, Vol. 143, no 1, 53-59 p.Article in journal (Refereed) Published
Abstract [en]

Compilations of substances detected in fatal intoxications are important in order to observe changes in intoxication patterns, to monitor effects of preventive work and to discover new trends in drug usage. The aim of the present study was to describe the current pattern of substances detected in fatal intoxications in Sweden. Fatal intoxications investigated at the Department of Forensic Chemistry, Linköping, Sweden, during 1992–2002, were analysed. All suicides, uncertain cases and accidents where the cause of death were fatal intoxications (ICD-9: E950, E980 and E859) were included and substances detected in more than 50 fatal intoxications (in femoral blood) were listed. For each substance, a cut off value was set, above which concentrations were considered toxic. Fatal intoxications were detected by forensic-chemical analyses in 12% (6998/60,314) of the forensic autopsies during the study period. Among the suicides, an average of 3.8 substances were detected per case, the corresponding figure for uncertain cases and accidents were 3.5 and 4.1 substances, respectively. Ethanol was by far the most frequently detected substance, detected in 43% (3039) of the fatal intoxications, of which 32% (960) had toxic concentrations, followed by propoxyphene, detected in 27% (1863) of the fatal intoxications of which 74% (1370) had toxic concentrations. The number of cases where ethanol and propoxyphene were detected decreased during the study period. Moreover, other CNS-active drugs such as antidepressants, analgesics and anxiolytics were also frequently detected. The drugs with high proportions of cases with toxic concentrations detected were propoxyphene, amitriptyline, zolpidem, carisoprodol, alprazolam, thioridazine, methadone and ketobemidone. Selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) were detected in 12% (833) and 10% (665), respectively. A significantly (P<0.001) higher proportion of cases where TCA were detected had toxic concentrations when compared with cases where SSRI were detected (64% versus 31%).

Keyword
Forensic science, Forensic chemistry, Fatal intoxications, Postmortem, Toxicology
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12848 (URN)10.1016/j.forsciint.2004.02.010 (DOI)
Available from: 2007-12-19 Created: 2007-12-19 Last updated: 2009-08-19
3. Cerebral haemorrhage induced by warfarin - the influence of drug-drug interactions
Open this publication in new window or tab >>Cerebral haemorrhage induced by warfarin - the influence of drug-drug interactions
2007 (English)In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, ISSN 1, Vol. 16, no 3, 309-315 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: To evaluate the frequency, severity and preventability of warfarin-induced cerebral haemorrhages due to warfarin and warfarin-drug interactions in patients living in the county of Östergötland, Sweden.

Methods: All patients with a diagnosed cerebral haemorrhage at three hospitals during the period 2000-2002 were identified. Medical records were studied retrospectively to evaluate whether warfarin and warfarin-drug interactions could have caused the cerebral haemorrhage. The proportion of possibly avoidable cases due to drug interactions was estimated.

Results: Among 593 patients with cerebral haemorrhage, 59 (10%) were assessed as related to warfarin treatment. This imply an incidence of 1.7/100 000 treatment years. Of the 59 cases, 26 (44%) had a fatal outcome, compared to 136 (25%) among the non-warfarin patients (p < 0.01). A warfarin-drug interaction could have contributed to the haemorrhage in 24 (41%) of the warfarin patients and in 7 of these (12%) the bleeding complication was considered being possible to avoid.

Conclusions: Warfarin-induced cerebral haemorrhages are a major clinical problem with a high fatality rate. Almost half of the cases was related to a warfarin-drug interaction. A significant proportion of warfarin-related cerebral haemorrhages might have been prevented if greater caution had been taken when prescribing drugs known to interact with warfarin.

Keyword
warfarin, cerebral haemorrhage, drug interactions, prevention
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12849 (URN)10.1002/pds.1291 (DOI)
Available from: 2007-12-19 Created: 2007-12-19 Last updated: 2014-01-13
4. Antipsychotics and risk for venous thromboembolism: A population based case-control study
Open this publication in new window or tab >>Antipsychotics and risk for venous thromboembolism: A population based case-control study
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2009 (English)In: Clinical Epidemiology, ISSN 1179-1349, Vol. 1, 19-26 p.Article in journal (Refereed) Published
Abstract [en]

During the last decade, the risk of venous thromboembolism (VTE) has been reported in users of antipsychotic drugs. However, the reports have been inconclusive. This study aimed to determine the relative risk of VTE in antipsychotic drug users. Using data from medical databases in North Jutland and Aarhus Counties, Denmark, and the Danish Civil Registration System, we identified 5,999 cases with a first-time diagnosis of VTE and, based on risk set sampling, 59,990 sex- and age-matched population controls during 1997–2005. Users of antipsychotic drugs were identified from population-based prescription databases and categorized based on filled prescriptions prior to admission date for VTE or index date for controls as current (at least one prescription within 90 days), recent (at least one prescription within 91–180 days), former (at least one prescription within 181–365 days) or nonusers (no recorded prescription within 365 days). Compared with nonusers, current users of any antipsychotic drugs had an increased risk of VTE (adjusted relative risk [ARR]: 1.99, 95% confidence interval [CI]: 1.69–2.34). Former users of any antipsychotic drugs had a nonsignificant elevated risk of VTE compared with nonusers (ARR: 1.54, 95% CI: 0.99–2.40, p-value: 0.056). In conclusion, users of antipsychotic drugs have an increased risk of VTE, compared with nonusers, which might be due to the treatment itself, to lifestyle factors, to the underlying disease, or to residual confounding.

Keyword
antipsychotic agents, venous thromboembolism, adverse effects, case-control study
Identifiers
urn:nbn:se:liu:diva-12850 (URN)
Note
Original Publication: Anna K. Jönsson, Erzsebet Horváth-Puhó, Staffan Hägg, Lars Pedersen and Henrik T Sörensen, Antipsychotics and risk for venous thromboembolism: A population based case-control study, 2009, Clinical Epidemiology, (1), 19-26. http://www.dovepress.com/antipsychotics-and-risk-of-venous-thromboembolism-a-population-based-c-peer-reviewed-article-CLEP Licensee: Dove Medical Press http://www.dovepress.com/index.php Available from: 2007-12-19 Created: 2007-12-19 Last updated: 2010-01-29
5. Antipsychotics associated with pulmonary embolism in a Swedish medico-legal autopsy series
Open this publication in new window or tab >>Antipsychotics associated with pulmonary embolism in a Swedish medico-legal autopsy series
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Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-12851 (URN)
Available from: 2007-12-19 Created: 2007-12-19 Last updated: 2010-01-13

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