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 ?

[email protected] [email protected] [email protected]


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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.


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


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 . . .

. . . .


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


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


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


Terminology & overlap (1)

Nebeker J.R. et al. Ann Intern Med. 2004;140:795-801


Otero M.J. & Dominguez-Gil A. Farmacia Hospitalaria Med. 2000;24:258-66



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


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ADVERSE DRUG REACTIONSDiagnosis

dose-related reaction interacting drug

previous exposureTiming


pattern recognition


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.



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 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


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WHO – The Uppsala Monitoring Centre

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WHO-UMC Causality

Categories

WHO-UMC 17.04.2012


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


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




• 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?


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

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Case 1

- Admitted for minor elective surgery- Medication at Hospital

Home medication+

ranitidine 150 mg po BIDheparin 5000 units SubQ

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Case 1

Platelet count (normal range 150 – 400 x109/L)

- Day 1 249 - Day 2 162 - Day 3 79

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Case 1

Does ranitidine cause thrombocytopenia?

Naranjo Score ? WHO-UMC system ? Action plan ?

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+2 -1 0 ____


+1 0 0 ____


+2 -1 0 ____


-1 +2 0 ____


-1 +1 0 ____


+1 0 0 ____


+1 0 0 ____


+1 0 0 ____


+1 0 0 ____

Total Score ____



Ranitidine and thrombocytopenia

Score ?


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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 ?

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+2 -1 0 ____


+1 0 0 ____


+2 -1 0 ____


-1 +2 0 ____


-1 +1 0 ____


+1 0 0 ____


+1 0 0 ____


+1 0 0 ____


+1 0 0 ____

Total Score ____



Heparin and thrombocytopenia

Score ?

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WHO-UMC Causality

for heparin and

thrombocy-topenia

WHO-UMC 17.04.2012


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


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 ?


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 ?


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


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


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


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


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


Case 4 - Aws• Further assessment & follow-up

– Erythema vanished after 45 minutes – Patient recovered completely followed by

hospital discharge few days later



• Feedback from the groups• What is happening at the European

level?• Conclusions & take home messages



www.adrreports.eu





• 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


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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)

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Softenon® tragedy


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 …

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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 …


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


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.


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.


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


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