Who are we€¦ · Usage of standardized case causality assessment Algorithms and evaluation scales...
Transcript of Who are we€¦ · Usage of standardized case causality assessment Algorithms and evaluation scales...
WS SIG-MI Barcelona October 2012 1
Adverse Drug ReactionsApplying Theory to Clinical
Practice
Stephane Steurbaut, Brussels - BelgiumYolande Hanssens, Doha - Qatar
ESCP Barcelona30 October 2012
Who are we ?
WS SIG-MI Barcelona October 2012 2
3
Objectives
• To appreciate the importance of early recognition of possible ADRs and differentiate them from disease related events.
• To practice the causality scales to assist in a prompt identification of ADRs.
• To become familiar with information sources providing relevant details about ADRs.
WS SIG-MI Barcelona October 2012 3
Outline of this session• Introduction & definitions• Practical clinical guidance, sources of
information & causality assessment• Case studies in small groups
• Feedback from the groups• What is happening at the European level?• Current status & Conclusions
ADRs - Definition
“Any noxious, unintended, and undesired effect of a drug that occurs at doses used in man for prevention, diagnosis, or treatment of disease, or
modification of physiological function”
WHO, 1966
Any unwanted effect
WS SIG-MI Barcelona October 2012 4
ADRs - Terminology
Adverse effect/reaction: all unwanted effects
Side effect: beneficial or unwantedvia same or other mechanism dose-related or not
Adverse event: adverse outcome not necessarily related to drug
Toxic effect: “increase” of the desired therapeutic effect, dose-related
Medication error
ADRs - Terminology
I’m allergic
I don’t tolerate
I react
But Doctor, Pharmacist . . .
. . . .
WS SIG-MI Barcelona October 2012 5
ADRs - Classification
Type A reactions: pharmacological ADR
- related to the pharmacological actions of the drug
- predictable, dose-related
- low mortality
- usually identified before drug is marketed
• Examples: Toxicity or overdoseSecondary pharmacological effectDrug interaction
ADRs - Classification Predisposing factors to type A reactions
- drug formulation
- drug dose
- multiple drug therapy (drug-drug interactions)
- gender: females >> males
- age: altered pharmacokineticsaltered pharmacodynamic sensitivity
- underlying disease
- genetic polymorphism
WS SIG-MI Barcelona October 2012 6
ADRs - Classification Type B reactions:
- uncommon, unpredictable, non-dose-related, mostly NOT detected during clinical trials
- not related to the pharmacological actions of the drug
- high mortality
Idiosyncratic reactions
ADRs - Classification
Parameter Type A Reaction Type B ReactionPredictable Yes NoDose related Yes NoIncidence High LowFrequency Regular RareMorbidity High LowMortality Low HighTreatment Dose reduction Stop
Comparison Type A and Type B
WS SIG-MI Barcelona October 2012 7
Can I only buy the side effects of this cough syrup?
account for 2 - 6% of all hospital admissions
occur in 10 - 20% of hospital inpatients
cause death: in 0.1% medical inpatients in 0.01% surgical inpatients
ADRs - Importance
Manasse HR. Am J Health Sys Pharm 1989 Lazarou J. JAMA 1998
WS SIG-MI Barcelona October 2012 8
Terminology & overlap (1)
Nebeker J.R. et al. Ann Intern Med. 2004;140:795-801
Terminology & overlap (2)
Otero M.J. & Dominguez-Gil A. Farmacia Hospitalaria Med. 2000;24:258-66
WS SIG-MI Barcelona October 2012 9
Terminology & overlap (3)
Morimoto T. et al. Qual Saf Health Care. 2004;13:306-14
Importance
affect patient quality of life
cause patients to lose confidence in health care providers and may lead to medication non-adherence
may mimic disease (unnecessary investigations and delay in treatment)
increase cost of patient care
BURDEN ON HEALTH CARE BUDGET
ADVERSE DRUG REACTIONS
WS SIG-MI Barcelona October 2012 10
19
ADVERSE DRUG REACTIONSDiagnosis
dose-related reaction interacting drug
previous exposureTiming
WS SIG-MI Barcelona October 2012 11
pattern recognition
ADVERSE DRUG REACTIONSDiagnosis
background frequency
Diagnosis
3 key questions
1. Can the drug cause the ADR?2. Has the drug caused the ADR?3. Will the drug cause the ADR?Also – How likely is it that this drug is the
cause of this problem in this specific patient?
Making a differential diagnosis needs full access to all available data.
ADVERSE DRUG REACTIONS
WS SIG-MI Barcelona October 2012 12
Diagnosis- Causality
• Challenging• Discrepancies between evaluators Usage of standardized case causality assessment
Algorithms and evaluation scales WHO-UMC system & Naranjo scale
BUT – Limitations too
ADVERSE DRUG REACTIONS
ADVERSE DRUG REACTIONSAdvantages & limitations of
standardized case causality assessment
What it CAN do What it CANNOT doDecrease disagreement between assessors
Give accurate quantitative measurement of relationship likelihood
Classify relationship likelihood Distinguish valid from invalidcases
Mark individual case reports Prove the connection between drug and event
Improvement of scientific evaluations; educational
Quantify the contributions of a drug to the development of an ADRChange uncertainty into certainty
WS SIG-MI Barcelona October 2012 13
25
WHO – The Uppsala Monitoring Centre
26
WHO-UMC Causality
Categories
WHO-UMC 17.04.2012
WS SIG-MI Barcelona October 2012 14
Naranjo ADR
ProbabilityScale
To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score.
Yes No Do Not Know Score1. Are there previous conclusive reports on
this reaction?+1 0 0 ____
2. Did the adverse event appear after thesuspected drug was administered?
+2 -1 0 ____
3. Did the adverse reaction improve when thedrug was discontinued or a specificantagonist was administered?
+1 0 0 ____
4. Did the adverse reactions appear when thedrug was readministered?
+2 -1 0 ____
5. Are there alternative causes (other than thedrug) that could on their own have causedthe reaction?
-1 +2 0 ____
6. Did the reaction reappear when a placebowas given?
-1 +1 0 ____
7. Was the drug detected in the blood (orother fluids) in concentrations known to betoxic?
+1 0 0 ____
8. Was the reaction more severe when thedose was increased, or less severe when thedose was decreased?
+1 0 0 ____
9. Did the patient have a similar reaction tothe same or similar drugs in any previousexposure?
+1 0 0 ____
10. Was the adverse event confirmed by anyobjective evidence?
+1 0 0 ____
Total Score ____
Total Score ADR Probability Classification
9 Highly Probable5-8 Probable1-4 Possible0 Doubtful
Naranjo CA. Clin Pharmacol Ther 1981;30:239-45
ADVERSE DRUG REACTIONSDiagnosis
Use of AlgorithmThe Naranjo Algorithm
10 Questions with scoring system-1, 0, +1 and +2
Score of 9-10 “definitely” ADR5-8 “probable” ADR1-4 “possible” ADR< 1 “doubtful”
Naranjo CA. Clin Pharmacol Ther 1981
WS SIG-MI Barcelona October 2012 15
Outline of this session• Introduction & definitions• Practical clinical guidance, sources of
information & causality assessment• Case studies in small groups
• Feedback from the groups• What is happening at European level?• Current status & Conclusions
Causality AssessmentPractice in small groups
Causality assessment using1. Naranjo Scale2. WHO-UMC system Also consider for each case• Likely causes ?• Action to be taken ?• Investigations needed ?• Management ?• Further assessment?
WS SIG-MI Barcelona October 2012 16
Case 1- Male, 56 years, 92 kg, BMI 32- Medical conditions
• DM type 2• Dyslipidemia• Hypertension
Case 1Current home medication
– Metformin 500 mg TID– Atorvastatin 40 mg HS– Valsartan/Amlodipine 160/5
32
WS SIG-MI Barcelona October 2012 17
Case 1
- Admitted for minor elective surgery- Medication at Hospital
Home medication+
ranitidine 150 mg po BIDheparin 5000 units SubQ
33
Case 1
Platelet count (normal range 150 – 400 x109/L)
- Day 1 249 - Day 2 162 - Day 3 79
34
WS SIG-MI Barcelona October 2012 18
Case 1
Does ranitidine cause thrombocytopenia?
Naranjo Score ? WHO-UMC system ? Action plan ?
35
36
To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score.
Yes No Do Not Know Score1. Are there previous conclusive reports on
this reaction?+1 0 0 ____
2. Did the adverse event appear after thesuspected drug was administered?
+2 -1 0 ____
3. Did the adverse reaction improve when thedrug was discontinued or a specificantagonist was administered?
+1 0 0 ____
4. Did the adverse reactions appear when thedrug was readministered?
+2 -1 0 ____
5. Are there alternative causes (other than thedrug) that could on their own have causedthe reaction?
-1 +2 0 ____
6. Did the reaction reappear when a placebowas given?
-1 +1 0 ____
7. Was the drug detected in the blood (orother fluids) in concentrations known to betoxic?
+1 0 0 ____
8. Was the reaction more severe when thedose was increased, or less severe when thedose was decreased?
+1 0 0 ____
9. Did the patient have a similar reaction tothe same or similar drugs in any previousexposure?
+1 0 0 ____
10. Was the adverse event confirmed by anyobjective evidence?
+1 0 0 ____
Total Score ____
Total Score ADR Probability Classification
9 Highly Probable5-8 Probable1-4 Possible0 Doubtful
Ranitidine and thrombocytopenia
Score ?
WS SIG-MI Barcelona October 2012 19
37
WHO-UMC Causality
for ranitidine and
thrombocy-topenia
WHO-UMC 17.04.2012
Case 1
• Are there any other reasons for thrombocytopenia in this patient ?
38
WS SIG-MI Barcelona October 2012 20
39
To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score.
Yes No Do Not Know Score1. Are there previous conclusive reports on
this reaction?+1 0 0 ____
2. Did the adverse event appear after thesuspected drug was administered?
+2 -1 0 ____
3. Did the adverse reaction improve when thedrug was discontinued or a specificantagonist was administered?
+1 0 0 ____
4. Did the adverse reactions appear when thedrug was readministered?
+2 -1 0 ____
5. Are there alternative causes (other than thedrug) that could on their own have causedthe reaction?
-1 +2 0 ____
6. Did the reaction reappear when a placebowas given?
-1 +1 0 ____
7. Was the drug detected in the blood (orother fluids) in concentrations known to betoxic?
+1 0 0 ____
8. Was the reaction more severe when thedose was increased, or less severe when thedose was decreased?
+1 0 0 ____
9. Did the patient have a similar reaction tothe same or similar drugs in any previousexposure?
+1 0 0 ____
10. Was the adverse event confirmed by anyobjective evidence?
+1 0 0 ____
Total Score ____
Total Score ADR Probability Classification
9 Highly Probable5-8 Probable1-4 Possible0 Doubtful
Heparin and thrombocytopenia
Score ?
40
WHO-UMC Causality
for heparin and
thrombocy-topenia
WHO-UMC 17.04.2012
WS SIG-MI Barcelona October 2012 21
Case 2– ♀, 80 years, 65 kg– medical conditions:
• reflux • gastric ulcer• osteoporosis • hypertension • atrial fibrillation (paroxysmal)• depressed
Case 2Morning Breakfast Lunch Dinner Bedtime
spironolactone50 mg
bisoprolol5 mg
bisoprolol5 mg
Amlodipine5 mg
Aspirin80 mg
alendronate70 mg (weekly)
omeprazole20 mg
escitalopram10 mg
WS SIG-MI Barcelona October 2012 22
Case 2
• Hospitalisation for:– decrease of general health– confusion – agitation– sodium level: 116 mEq/L
Case 2 - Qs
• Likely causes ?• Action(s) to be taken ?• Investigations needed ?• Management ?• Further assessment ?
WS SIG-MI Barcelona October 2012 23
Case 2 - Aws• Likely causes
– Hyponatremia• Drug induced ?
– escitalopram + spironolactone
• Other ?– SIADH
Case 2 - Aws• Action(s) to be taken
– Dechallenge• escitalopram• (temporally) stop spironolactone ?
– Rechallenge ?
WS SIG-MI Barcelona October 2012 24
Case 2 - Aws• Investigations needed
– Lab values• electrolytes: Na, K, …
– Blood pressure
– Mini-mental state
Case 2 - Aws• Management
– Infusion: • 0.9% NaCl
– SLOWLY !
• 40 mEq/L KCl (lab result: 3.2 mEq/L)
– Liquid restriction
WS SIG-MI Barcelona October 2012 25
Case 2 - Aws• Further assessment & follow-up
– Electrolyte balance– Blood pressure control– Assess need for antidepressive medication
• no (S)SRI/(S)NRI
Case 4– ♀, 24 years, 85 kg, 164 cm– Medical conditions:
• chronic:– diabetes type 1– obesity– hypertension
• acute– pelvic inflammatory disease
• penicillin allergy
WS SIG-MI Barcelona October 2012 26
Case 4
• Medication taken at home– NovoRapid® (insulin aspart):
• 8h: 30E / 12h: 30E / 18h: 40E
– Lantus® (insulin glargine):• 23h: 42E NovoRapid®
– ramipril• 8h: 5 mg
Case 4• Medication received in the hospital
– ciprofloxacin IV 400 mg/200 ml• 8h: 30E / 12h: 30E / 18h: 40E
– paracetamol IV 1 g
• Complaints– burning sensation– erythema multiforme
WS SIG-MI Barcelona October 2012 27
Case 4 - Qs
• Likely causes ?• Action(s) to be taken ?• Investigations needed ?• Management ?• Further assessment ?
Case 4 - Aws• Likely causes
– ADR on ciprofloxacin
– Preventable?• penicillin allergy?• infusion time:
– advised: 60 min– here: 30 min
medication error
WS SIG-MI Barcelona October 2012 28
Case 4 - Aws• Action(s) to be taken
– Dechallenge• stop ciprofloxacin IV
– Rechallenge ?• possible with correct infusion rate• nevertheless, chosen to give ciprofloxacin
orally
Case 4 - Aws• Investigations needed
– None
• Management– Oral antihistaminic
WS SIG-MI Barcelona October 2012 29
Case 4 - Aws• Further assessment & follow-up
– Erythema vanished after 45 minutes – Patient recovered completely followed by
hospital discharge few days later
Outline of this session• Introduction & definitions• Practical clinical guidance, sources of
information & causality assessment• Case studies in small groups
• Feedback from the groups• What is happening at the European
level?• Conclusions & take home messages
WS SIG-MI Barcelona October 2012 30
ADVERSE DRUG REACTIONS
www.adrreports.eu
ADVERSE DRUG REACTIONS
WS SIG-MI Barcelona October 2012 31
ADVERSE DRUG REACTIONS
ADVERSE DRUG REACTIONS
WS SIG-MI Barcelona October 2012 32
ADVERSE DRUG REACTIONS
WS SIG-MI Barcelona October 2012 33
Outline of this session• Introduction & definitions• Practical clinical guidance, sources of
information & causality assessment• Case studies in small groups
• Feedback from the groups• What is happening at European level?• Current status & Conclusions
ADRs - Definition
“Any noxious, unintended, and undesired effect of a drug that occurs at doses used in man for prevention, diagnosis, or treatment of disease, or
modification of physiological function”
WHO, 1966
Any unwanted effect
WS SIG-MI Barcelona October 2012 34
67
What triggered the WHO in 1966 ?
Thalidomide (Contergan®, Softenon®) launched by Grünenthal in 1957 &
marketed in 47 countries (not in US) used as samples on 20,000 US patients sold until 1961 for insomnolence &
morning sickness during pregnancy 10 to 20,000 babies with deformities
(phocomelia)
68
Softenon® tragedy
WS SIG-MI Barcelona October 2012 35
Softenon® tragedy1 SEP 2012 – apologies from Grünenthal
for not trying to reach out to victims for over 50 years 5000 to 6000 sufferers are still aliveVictims criticize the company for not
compensating them and for ignoring the red flags
Too little too late …
69
Adverse Drug ReactionsApplying Theory to Clinical
Practice• Do causality scales solve all problems?• Remember … What it CAN do What it CANNOT do
Decrease disagreement between assessors
Give accurate quantitative measurement of relationship likelihood
Classify relationship likelihood
Distinguish valid from invalid cases
Mark individual case reports
Prove the connection between drug and event
Improvement of scientific evaluations; educational
Quantify the contributions of a drug to the development of an ADR
Change uncertainty into certainty
limitations too …
WS SIG-MI Barcelona October 2012 36
Method: 6 assessors 2 pharmacists2 physicians 2 nurses
- Assessed 200 ADR reports for causality using Naranjo ADR Probability ScaleVenulet algorithm WHO causality term assessment criteria
- Assessment of agreement between1. assessors using the same algorithms2. algorithms for the same assessor
WS SIG-MI Barcelona October 2012 37
Results:
Majority of the causality assessments resulted in ‘probable’ or ‘possible’ Physician and pharmacist assessment was more likely to result in ‘definite’ or ‘certain’ causality assessments than nurse assessment, when using the Naranjo and WHO algorithms. Use of the Venulet algorithm resulted in a higher number of ‘unlikely’ or ‘unrelated’ assessments than the other two methods.
Results: cont’d The inter-assessor agreement measured was no greater
than ‘fair’ (weighted kappa = 0.31) for any comparison between raters, and for three comparisons, inter-assessor agreement was less than that expected by chance.
Conversely, the weighted observed proportion of agreement, Po (w), was good (>0.6) for all assessments.
Intra-assessor agreement between scales was highest for the Naranjo algorithm versus the WHO algorithm, with ‘substantial’ (weighted kappa = 0.61) agreement between assessments made by pharmacist 1.
The mean Po (w) for intra-assessor agreement was 0.81.
WS SIG-MI Barcelona October 2012 38
Conclusions:
1. Comparability between assessors was found to be ‘fair’ or less for the ADR causality assessment methods examined.
2. The most consistent results were produced by the application of the Naranjo algorithm and the least consistent was theVenulet algorithm.
3. It is likely that the clinical experience of the assessor influences how the assessment methods are applied.
4. The high level of disagreement in the results produced using the assessment scales in this study question the robustness of causality assessments.
Adverse Drug ReactionsApplying Theory to Clinical Practice Problems with different scales Problems of reproducibility and validity No single method is universally accepted Different causality categories are adopted in each
method Categories are assessed using different criteria Assessment methods are also not entirely devoid of
individual judgments, therefore inter-rater reliability can be low
In conclusion, there is still no method universally accepted for causality assessment of ADRs
Agbabiaka TB, Drug Saf. 2008;31(1):21-37.
WS SIG-MI Barcelona October 2012 39
Adverse Drug ReactionsApplying Theory to Clinical Practice
So, what did we do this afternoon …?
BUT …
with the growing rate of new pharmaceuticals
Early recognition of potential ADRs is critical
Reporting of ADRs is an essential part of healthcare practice
We cannot allow another Softenon® tragedy
ADRs Useful Websites & References
http://www.fip.org/www2/uploads/database_file.php?id=273&table_id
http://en.wikipedia.org/wiki/Pharmacovigilance
http://www.medicinesauthority.gov.mt/phvigilance.htm
http://www.arizonacert.org/consumers/logicModel/logicModel.htm
http://www.ahrq.gov/qual/aderia/aderia.htm
http://www.who-umc.org
http://www.medscape.com
http://www.medscape.com/pharmacists
http://www.adrreports.eu
WS SIG-MI Barcelona October 2012 40
79