Transcript Australasian Society of Clinical Immunology

Australasian Society of Clinical
Immunology and Allergy
Adverse Reactions to NSAIDs
David Henry
Faculty of Medicine and Health Sciences
The University of Newcastle
NSW Australia
Aims of this presentation
• To show how epidemiological methods can
be used to investigate adverse drug effects
• To review the main ‘predictable’ adverse
effects of NSAIDs on the GI tract kidneys
and cardiovascular system
• To discuss how such data can be used in
health services research to influence
practice and policy
Background
• Non steroidal anti-inflammatory drugs
(NSAIDs) are widely used for management of a
range of painful disorders
• NSAIDs are the commonest reported cause of
serious adverse reactions to drugs
• NSAIDs can cause serious ADRs in any body
system, but those involving the upper GIT the
CVS and the kidneys are the most common
• The outcomes of these ADRs are hemorrhage,
ulcer perforation, renal failure, heart failure
Questions that need to be
addressed
• How frequently are these drugs used?
• What are the levels of risk of
development of serious GIH, functional
renal impairment, congestive heart
failure?
– To what extent are these risks
dependent on factors such as drug
dose, half-life, COX selectivity?
Questions that need to be
addressed (cont)
• What are the associated public heath
burdens?
• What are the practice and policy
implications?
How commonly are these drugs
used?
• Prescription survey : In 1988 12 million
prescriptions were written for NSAIDs in
Australia
• Prevalence survey: In 1987/88 23% of women
and 20% of men aged >65 years in Newcastle
had taken NSAIDs in the previous 4 days (not
including aspirin). This figure dropped to
around 15% by 1994
What are the levels of risk for
development of serious
gastrointestinal hemorrhage and
ulcer perforation, and what
factors modify this risk?
Principal Methodology:
Case-control Study
• Major advantages over traditional case
series
• Involves definition and careful selection of
– subjects with the disease (cases)
– subjects without the disease (controls)
• Unbiased measurement of prior use of the
drugs of interest
Principal Methodology:
Case-control Study
• The Odds Ratio (adjusted for
confounders ) provides an estimate of the
Relative Risk of the outcome in exposed
compared with non-exposed individuals
• The Odds Ratio is an accurate estimate of
the Relative Risk when the condition
under study is uncommon
Relative Risk
•
•
•
•
Background Risk 1/1000
Relative Risk 4.0
Risk in exposed group 4/1000
Excess risk 3/1000
Major gastrointestinal
complications
• Case-control study to determine the risk of
development of GI complications
• Case-control study to determine the risk of
dying of GI complications
• Collaborative meta-analysis to determine
the variation in risk with individual
compounds
Major gastrointestinal
complications (cont)
• Information on 644 cases of GIH or ulcer
perforation and 1268 community and hospital
controls (matched for age and sex)
• Overall Relative Risk 3.0 (2.3, 3.5)
– Dose response relationship obvious
– Apparent differences in risk between
individual drugs
Death from major GI complications
• Information on 80 cases who died of peptic ulcer
complications and 160 controls who survived
hospitalisation with peptic ulcer complications
– Controls were matched on age, sex, site and
nature of complication and analyses were
adjusted for co-morbidity
• Adjusted RR of dying of peptic ulcer
complications with use of NSAIDs or aspirin
were 1.1 (0.6, 2.1) and 1.2 (0.5, 1.9) respectively
Collaborative Meta-analysis
• Investigators from six countries pooled data
from 12 epidemiological studies with data
from 10,000 cases and 30,000 controls
• The main aim was to investigate the range of
risks with individual agents and the extent to
which this could be explained by dosage
• Results were combined by ranking as different
combinations of drugs had been included in
different studies
Estimated relative risks of major gastrointestinal
complications with individual drugs
50
Estimated relative risk
5
0.5
Aza Pirox Keto Indo Nap Asp Sulin Difl
Dicl Ibup
.
Estimated
Estimated relative
relative risks
risks of
of major
major gastrointestinal
gastrointestinal
complications
complications with
with individual
individual drugs
drugs
Summary
Summary ranking
ranking method
method
Ibup n=11
Dicl n=9
Difl n=2
Fenop n=2
Asp n=6
Sulin n=5
Nap n=12
Indo n=12
Pirox n=11
Ketop n=7
Tolm n=2
Aza n=2
0
2
4
6
8
10
12
14
Rank from low risk to high risk: avge of 12 top scores
Major gastrointestinal complications :
Conclusions
• Overall RR around 3.0. Higher for
perforation
• Case-fatality rate unaffected by NSAIDs
• 34% of elderly bleeds due to NSAIDs
• Significant differences between individual
drugs: ibuprofen and diclofenac have the
lowest risks and piroxicam and ketoprofen
the highest
Cardiac and Renal Complications
• Vasodilator PGs are important in maintaining
renal blood flow, and (possibly) modulating
systemic vascular resistance in times of stress
• NSAIDs have been shown to reduce GFR and
increase systemic vascular resistance in
selected individuals
• There have been very few epidemiological
studies and these have been confined to endstage renal failure
Cardiac and Renal Complications
• Case-control study of 365 cases of CHF and 658
matched controls
• Case-control study of 110 cases of functional renal
impairment (FRI) and 189 matched controls
• The estimated RR for hospitalisation with first
episode of CHF with NSAIDs was 2.8 (1.5, 5.1).
Etiologic fraction 19%
• The estimated RR for hospitalisation with evidence
of FRI with NSAIDs was 1.5 (0.80, 2.9).
How do we study factors such
as drug dose, half-life and COX
selectivity in epidemiological
studies of NSAID toxicity?
Effects of Dose on Relative Risk of GI Complications
with Individual NSAIDs: meta-analysis
10
RR, 95% CI
8
6
4
2
0
Low
High
Ibuprofen
Low
High
Naproxen
Low
High
Indomethacin
Effects of Dose on Relative Risk of CHF
1000
100
10
1
0.1
0
0.01-0.35
0.36-1.0
>1.0
Mean daily dose of NSAID (standard dose units) in the previous week
The Relationship between GI Risk and
Drug Half-life
• Relative risks were ordered by the
summary ranking procedure (metaanalysis)
• Published values for T1/2 were ranked
• Non parametric correlation:
– Kendall’s Tau 0.504, P = 0.023
The Relationship between Half-life
and risk of CHF
• Relationship between T1/2 and RR for first
admission with CHF (multivariate):
– <4 hrs
2.0 (0.56, 7.4)
– 5 - 11 hrs 4.3 (0.66, 27.4)
– > 12 hrs 10.6 (1.1, 103.7)
– P (for trend) = 0.016
The Relationship between Half-life
and risk of Renal Impairment
• Relationship between T1/2 and RR for
functional renal impairment (multivariate):
– <4 hrs
1.3 (0.48, 3.6)
– 5 - 11 hrs 2.8 (0.66, 12.0)
– > 12 hrs 3.8 (0.68, 21.0)
– P (for trend) = 0.012
COX selectivity
• Cyclo-oxygenase exists in two isoforms, COX1 and COX-2
• COX-1 is responsible for the ‘constitutional’
effects of PGs
• COX-2 is responsible for the inflammatory
effects
COX selectivity
• Drugs were ranked by COX-1, COX-2
activities and COX-1/COX-2 ratio
• Relative risks were ordered by the
summary ranking procedure (metaanalysis)
• Significant correlation with COX-1
activity, but not with the other variables
Public Health Issues
• GI complications: 4000 - 5000 admissions in
elderly subjects annually, and 300 - 400 deaths
• Approximately 1500 admissions and 100 deaths
are attributable to use of NSAIDs
• Cardiac Failure: 50,000+ admissions annually,
with 5000 deaths in hospital and many more in
the next year
• Approximately 8000 admissions and up to 800
deaths could be attributable to use of NSAIDs
What is happening to use of
NSAIDs in Australia ?
Recent Trends in Use of NSAIDs
1994
1993
1992
1991
• Overall use of NSAIDs
fell from 50.1
DDD/1000/day in 1990
to 34.6 DDD/1000/day
in 1994 (31% fall)
• In subjects over 60
years prescription use
fell by 44%
50
45
40
35
30
25
20
15
10
5
0
1990
McManus et al MJA 1996; 164: 589-592
Recent Trends in Use of NSAIDs
McManus et al MJA 1996; 164: 589-592
1994
'Low'
Risk
'High'
Risk
1992
18
16
14
12
10
8
6
4
2
0
1990
• The fall in the use of
‘low risk’ drugs
(ibuprofen, diclofenac
and diflunisal) was
greater than the fall in
‘high risk’ drugs
(piroxicam and
ketoprofen)
High
Medium
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Low
Selection of NSAIDs by GPs
• Analysis of NSAID
prescribing by 2 GP
Divisions with similar
overall rates (per 100 MC
services)
• Feedback of data may
result in an overall
reduction in prescribing
and a shift to the left
Conclusions
• The high use of NSAIDs constitutes a problem of
public health dimensions
• The cardiovascular effects are little recognised
and in community terms may be more important
than the GI effects
• There are significant differences in risk between
the drugs. Both dose and drug half-life seem
important
• COX-selectivity potentially is an important factor
but assessment with current data difficult due to
confounding