c ausality a ssessment of r eported a dverse d rug r eactions ana filipa macedo faculty of health...
TRANSCRIPT
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CAUSALITY ASSESSMENT OF
REPORTED ADVERSE DRUG REACTIONS
Ana Filipa Macedo Faculty of Health Sciences Portugal
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Safety is a relative concept
No drug which is pharmacologically effective is
entirely without hazard
Efficacy
Safety
Quality
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2000 b.C. – HAMMURABI CODE: “The Doctor who causes death
should loose his hands”
500 b.C. – HIPÓCRATES: “Primum non nocere”
HISTORICAL
PERSPECTIVE
200 – GALENO: “Drugs have a main
action and a secondary action ”
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PERSPECTIVA
HISTÓRICA…1937 – Sulfanilamide in Dietilenoglicol / Renal Impairment1961 – Thalidomide / Phocomelia - 10 000 Victims
1971 – Dietilstilbestrol / Vaginal Carcinoma in the daughters, 10 to 20 years after exposition
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INTERNATIONAL PHARMACOVIGILANCE
SYSTEMS
PREMARKETING INVESTIGATION
Long Latency ADR
Chronic ADR
Rare ADR
Interactions
Risk Groups
Limitations
POSTMARKETING INVESTIGATION
PH
AR
MA
CO
VIG
ILA
NC
E
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ADVERSE DRUG REACTION
“a response to a drug which is noxious and unintended, and which occurs at dose normally used in humans for the prophylaxis, diagnosis or therapy of disease, or for a modification of physiological function .”
W.H.O 1972
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EPIDEMIOLOGY OF ADVERSE DRUG REACTIONS• 4th to 6th cause of death in U.S.A. ,1994
• 5% of Hospital Admissions
• 11% of Hospital Patients
• Doubles costs, length of stay and mortality risk
• 50% are potentially preventable
• Less than 1% are reported
Medication Error
(Preventable)
Preventable ADRs
ADRs not Preventable
Quality Problems
Adverse Effects
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SAFETY MONITORIN
G
Identification of a Problem
Problem Characterizat
ion
Benefit – Risk
Evaluation
Risk Manageme
nt
Communication
Decision
PHARMACOVIGILANCE
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IMPUTATION
Drug Exposition
Reported Adverse Effect
“Drug Safety is a field where can be smoke without fire”
Waller, P.
Dynamic Process
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DIFFICULT...
•Complex Nature of Adverse
Events
•Individual Clinical Variability
•Retrospective Spontaneous
Report
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GLOBAL INTROSPECTION “ Clinical Judgement of Experts”
• Subjective
• Problems of reproducibility
• Not calibrated
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DECISIONAL ALGORITHMS
“Systematic Strategies of Decision in Uncertainty
Conditions”• Explicit
• Reproducible
• Simple
• Possible Automation
• Improve Reporting
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1. AD-ADRIAN
2. Aust-Australian
3. By-Bayesiano
4. B-Blanc
5. Ca-Castle
6. Co-Cornelli
7. CPMP- Syst. ABO
8. D-Dangoumau
9. Em-Emanueli
10. Ev-Evreux
11. HM-Hoskins & Maninno
12. HS-Hsu-Stoll
13. I-Irey
14. Ja-Jain
15. Jo-Jones
16. KL-Karch & Lasagna
17. Ki-Kitaguchi
18. Kr-Kramer
19. La-Lagier
20. Lu-Loupi
21. MV-V Maria
22. WHO
23. R-RUCAM
24. Ru-Ruskin
25. St-Stephens
26. Sk-Stricker
27. T-Taiwan
28. V-Venulet
29. W-Weber
30. Wi - Wiholm
DECISIONAL ALGORITHMS
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1.Challenge
2.Dechallenge
3.Rechallenge
4.Bibliographic
Description
• Etiologic Alternatives
CRITERIA
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Irey(1976)
Causal – Casos de overdose, Fármaco elegível. Período de latência consistente. Singularidade do fármaco (4). Resultados de autopsia ou exames clinico laboratoriais não revelam relação dadoença base ou estado mórbido com o acontecimento e níveis do fármaco dentrodos limites letais.
- Casos de testes específicos para identificação da relação fármaco-acontecimentoadverso (técnicas imunológicas, enzimáticas e/ou histoquimicas).
Provável – Casos essencialmente relacionados com o fármaco mas que diferem numaspecto critico,
Fármaco elegível.Período de latência consistente.Caracteristicas clinicas ou morfológicas do acontecimento, ou ambas,reconhecidas como ocorrendo com o fármaco por experiência prévia (5).Um ou mais dos seis factores devem apoiar a relação com o fármaco.Causas alternativas eliminadas com segurança razoável.
Possível – reacção adversa não confirmada nem negada. Factores anteriores verificadosmas,Padrão pode ser produzido por doença base, estado mórbido ou outras terapias,não excluídas como causa (causas alternativas).OU verificam-se alguns dos seis factores anteriores, mas os informação sobreos restantes não está disponível.OU critérios verificados, mas padrão não descrito na literatura com estefármaco (ex. reacção adversa nova).
Coincidente – doente exposto ao fármaco mas caracteristicas clinicas ou morfológicas doacontecimento, ou ambas (5), revelam causa alternativa para o acontecimento.
Negativo – fármaco não elegível OU estudos laboratoriais ou clinicopatológicos, ou ambos,excluem o fármaco como possibilidade.
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SIM NÃONÃO SEI
PONTOS
1. Existem outras notificações conclusivas sobre esta reacção? +1 0 0
2. O acontecimento adverso manifestou-se depois da administração do fármaco suspeito?
+2 -1 0
3. A reacção adversa melhorou com suspensão do fármaco ou administração de um antagonista específico?
+1 0 0
4. A reacção adversa reapareceu com readministração do fármaco? +2 -1 0
5. Existem causas alternativas (diferentes do fármaco) capazes de provocar a reacção por si mesmas?
-1 +2 0
6. A reacção adversa reapareceu com administração dum placebo? -1 +1 0
7. Foi detectado fármaco no sangue (ou outros fluidos) em concentrações tóxicas?
+1 0 0
8. A reacção foi mais severa com aumento da dose e menos com a diminuição?
+1 0 0
9. O doente apresentou uma reacção semelhante ao fármaco ou outros semelhantes em qualquer exposição anterior?
+1 0 0
10.O acontecimento adverso foi confirmado por qualquer tipo de evidência objectiva?
+1 0 0
PONTUAÇÃO TOTAL
Naranjo et al(1981)
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Dangoumau e colaboradores(versão revista do método Francês em 1985)
I – Critérios cronológicos Tempo de manifestação Muito sugestivo compatívelReadministração R(+) R(0) R(-) R(+) R(0) R(-) incompatível
Suspensão do tratamentoSugestiva (regressão C3 C3 C1 C3 C2 C1 C0 com suspensão)
Inconclusiva (regressão espontânea ou provocada por tratamento sintomático, não C3 C2 C1 C3 C1 C1 C0 efectuada, desconhecida ou irreversível)
não sugestiva (ausência
de regressão dum acontecimento C1 C1 C1 C1 C1 C1 C0 reversível ou regressão sem suspensão)
classificação cronológica de 4 possibilidades: C3 – sugestiva; C2 – possível; C1- duvidosa; C0 – incompatível.
II- Critérios Semiológicos Semiologia Sugestiva de relação com o Outras Fármaco e/ou factores favorecedores Causas Testes específicos L(+) L(0) L(-) L(+) L(0) L(-)
Causa alternativasNão medicamentosasAusentes (após busca apropriada) S3 S3 S1 S3 S2 S1
Possível (presente ou não procurada) S3 S2 S1 S3 S1 S1
classificação semiológica de 3 possibilidades: S3 – sugestiva; S2 – possível; S1 – duvidosa.
Os resultados destas duas tabelas de conduzem a uma tabela de decisão final quedetermina a imputabilidade intrínseca, agora dada por 5 níveis para facilitarcomparações internacionais .
SemiologiaCronologia
S1 S2 S3
C0 I0 I0 I0
C1 I1 I1 I2
C2 I1 I2 I3
C3 I3 I3 I4
A combinação permite graus de imputação global de EXCLUIDA (I0),DUVIDOSA (I1), POSSIVEL (I2), PROVAVEL (I3) e MUITO PROVAVEL (I4).
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Judith K. Jones(1982)
Começar aqui*
Não
Sim
Não
Sim
Não
Sim
Não Não
Não
Sim
O acontecimento temuma associaçãotemporal razoável, como uso do fármaco?
Relação causalconsiderada Remota.
Houve suspensão dofármaco?
O acontecimentoobservado regrediu coma suspensão?
Houve readministração?
A reacção ouacontecimento reapareceucom a readministração?
Relação causal consideradaMuito Provável
Relação causalconsiderada Possível
Relação causalconsiderada Possível
O acontecimentopode ser explicadopor uma condiçãoclinica existente
Relação causalconsiderada Provável
Relação causalconsiderada Possível
SimSim
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LIMITATIONS
• Fixed Scoring
• Arbitrary Scoring
• Disagreement between algorithms
None universally accepted as gold standard
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CAUSALITY ASSESSMENT
GLOBAL INTROSPECTION
SELECTED ALGORITHMS
1. Aust-
Australian
2. B-Blanc
3. Co-Cornelli
4. D-Dangoumau
5. Em-Emanueli
6. HS-Hsu-Stoll
7. I-Irey
8. Jo-Jones
9. KL-Karch &
Lasagna
10. Ki-Kitaguchi
11. Kr-Kramer
12. N -Naranjo
13. St-Stephens
14. V-Venulet
15. W-Weber
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RESULTS
Agreement between algorithms and GI was 43% in average
100% agreement was not found for any algorithm
None of the adverse events was equally imputed by all the algorithms
Sensitivity 93% and Specificity 7% in average
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A reference method was not identified
Decisional algorithms are not definite alternatives in the
individual causality assessment of adverse drug reactions.
CONCLUSIONS
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DECISIONAL ALGORITHMS AND
QUANTITATIVE METHODS OF SIGNAL
DETECTIONBayesian Confidence Propagation Neural Network (BCPNN)
Signal
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REFERENCES
[1] MACEDO, A.F. [et al.] - Causality assessment of adverse drug reactions: comparison of the results obtained from published decisional algorithms and from the evaluations of an expert panel, according to different levels of imputability. J Clin Pharm Ther.2003. 28: 137-143.
[2] STAHL, M. [et al.] – Introducing triage logic as a new strategy for the detection of signals in the WHO Drug Monitoring Database. Pharmacoepidemiol Drug Safe. 2004; 13: 355-363.