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Drugs Aging (2013) 30:2330

DOI 10.1007/s40266-012-0037-9

ORIGINAL RESEARCH ARTICLE

COX-2 Inhibitor and Non-Selective NSAID Use in Those


at Increased Risk of NSAID-Related Adverse Events
A Retrospective Database Study

Svetla Gadzhanova Jenni Ilomaki

Elizabeth E. Roughead

Published online: 23 November 2012


Springer International Publishing Switzerland 2012

Abstract at the end of the study period. Consistent with treatment


Background Adverse events related to analgesic use guidelines, in most of these cases, these drugs were
represent a challenge for optimizing treatment of pain in co-dispensed with proton pump inhibitors. COX-2 inhibitors
older people. were used at slightly higher rates than NS-NSAIDs in those
Objective The aim of this study was to determine with a prior history of MI or stroke, which is not consistent
whether non-selective non-steroidal anti-inflammatory with guidelines recommending NS-NSAID use.
drug (NS-NSAID) and cyclo-oxygenase (COX)-2 inhibitor
use is appropriately targeted in those with a prior history of
gastrointestinal (GI) events, myocardial infarction (MI) or 1 Introduction
stroke.
Methods A retrospective study of pharmacy claims data The recommendations for pharmacological management of
from the Australian Government Department of Veterans pain have evolved in recent years because of evidence of
Affairs was conducted, involving 288,912 veterans aged adverse events from cyclo-oxygenase (COX)-2 inhibitors
55 years and over. Analgesic utilization from 2007 to 2009 [14]. In the mid-2000s, mounting evidence of an
was assessed. Three risk cohorts (veterans with prior hos- increased risk of cardiovascular disease (CVD) related to
pitalization for GI bleed, MI or stroke) and a low-risk COX-2 inhibitor use [510] and, to a smaller extent, related
cohort were identified. Poisson regression was applied to to non-selective non-steroidal anti-inflammatory drug
test for a linear trend over the study period. (NS-NSAID) use caused changes in labelling in several
Results The prevalence of analgesics dispensed in the countries, including Australia [24]. A meta-analysis of
overall study population was approximately 34 % between observational studies reported a 35 % increased risk of
2007 and 2009. COX-2 inhibitors were more widely dis- cardiovascular ischaemia with the COX-2 inhibitor,
pensed than NS-NSAIDs in all those at risk of NSAID- rofecoxib [9]. There was also a 25 % increased risk reported
related adverse events. At the end of 2009, the ratio was for meloxicam and a 40 % increased risk for diclofenac.
5.1 % to 2.5 % in the GI cohort, 3.6 % to 3.2 % in the MI Meloxicam and diclofenac are traditionally classified as
cohort and 3.6 % to 2.6 % in the stroke cohort. NS-NSAIDs [11]; however, both have significant COX-2
Conclusions Although COX-2 inhibitors appeared to be inhibition [12]. A 30 % increased risk with indomethacin,
preferred over NS-NSAIDs in those with a prior history of an NS-NSAID, was also reported [9]. Although no increase
GI events, 2.5 % of patients were still using an NS-NSAID in risk was found with the use of the COX-2 inhibitor
celecoxib, another large cohort study found a dose-
dependent relationship between celecoxib and myocardial
S. Gadzhanova  J. Ilomaki (&)  E. E. Roughead infarction (MI), where a 61 % increase with doses greater
Quality Use of Medicines and Pharmacy Research Centre, than 200 mg was observed compared with non-users [13].
Sansom Institute, School of Pharmacy and Medical Sciences,
Evidence also suggests that individuals aged 65 years and
University of South Australia, GPO Box 2471,
Adelaide, SA, Australia older are at increased risk of serious cardiovascular-related
e-mail: jenni.ilomaki@unisa.edu.au events due to COX-2 inhibitor use [14].
24 S. Gadzhanova et al.

The risk of gastrointestinal (GI) events due to the use of administrative health claims database. These data include
NS-NSAIDs is well known. Pooled results from 18 obser- all veterans who have served in the Australian Defence
vational studies showed a fourfold overall increased risk of Force, their spouses and their dependants. According to the
GI bleeding or perforation among users of NS-NSAIDs DVAs most recent statistics, more than half of the veterans
compared with non-users [15]. The study also reported that served in the Second World War and the majority are aged
advanced age increased the risk of GI events. The risk of GI between 80 and 85 years [26]. Overall, 60 % of the DVA
bleeding was 4.5 times higher among those aged populations are men.
7080 years and 9.2 times higher among those aged over The pharmacy claims database provides de-identified
80 years than among those aged 2549 years. COX-2 patient-level information on all prescription medicines
inhibitors are reported to be safer in terms of GI events [16]. dispensed and subsidized to DVA clients under the Phar-
The CLASS (Celecoxib Long-term Arthritis Safety Study) maceutical Benefits Scheme or Repatriation Pharmaceuti-
trial showed that the risk of symptomatic ulcers and ulcer cal Benefits Scheme [27]. Dispensing data include the
complications among celecoxib users was 40 % lower than medicine dispensed, date of dispensing, quantity supplied,
among NS-NSAID users [17]. However, a meta-analysis of dosage form and strength. Client data include patient age,
clinical trials concluded that the risk of any GI event was gender, date of death and residential status. Hospitalization
20 % higher with celecoxib than with placebo [16]. data are also available and provide information on all
Current Australian guidelines recommend paracetamol hospital admissions of DVA clients to public and private
(acetaminophen) as the first-line pharmacological treatment hospitals. Diagnoses associated with the hospitalization are
for pain in osteoarthritis and rheumatoid arthritis [18, 19]. coded according to the International Classification of Dis-
NSAIDs are recommended if pain relief with paracetamol is ease 10th edition, Australian modification (ICD-10-AM)
inadequate, with recommendations to consider the patients [28]. Analgesic utilization from January 2007 to December
existing GI and CVD risk when selecting NSAIDs [1821]. 2009 was investigated in three risk cohorts (GI cohort, MI
In patients at high risk of GI events, COX-2 inhibitors are cohort and stroke cohort) and one low-risk cohort.
recommended over NS-NSAIDs. NS-NSAIDs can be used
if adequate GI protection with proton pump inhibitors
2.2 Definition of Cohort Populations
(PPIs) is added to the regimen. For those with CVD, NS-
NSAIDs are preferred to COX-2 inhibitors.
The study population included all veterans and their
Adverse events related to analgesic use present a chal-
dependants who were aged 55 years and older in January
lenge for optimizing the pharmacological treatment of
2006. They contributed to the following cohorts:
chronic pain, especially in older people, among whom
arthritis is one of the most common chronic conditions 1. GI cohortveterans who have had at least one
[22]. One in four Australians aged 6574 years reported hospitalization with a primary diagnosis of GI events
having osteoarthritis in 20072008, and this proportion (ICD-10-AM codes I21.0I22.9) between January
rose to 32 % amongst those aged 75 years and older [22]. 2006 and December 2009. Veterans entered the cohort
Older people are also most susceptible to NSAID-related and were considered to be at increased risk of NSAID-
adverse effects [23]. related adverse events from the date of their earliest
We have previously reported the rapid uptake of all (index) hospital admission for a GI event in the period.
NSAIDs after celecoxib was first subsidized in Australia in 2. MI cohortveterans who have had at least one hospital-
August 2000 and a subsequent overall decrease in NSAID ization with primary diagnosis of MI (ICD-10-AM codes
use after rofecoxib withdrawal in October 2004 [24]. K25.0K27.9) between January 2006 and December
Recognizing the new recommendations and knowledge 2009. They entered the MI cohort and were considered to
about adverse events, the aim of this study was to deter- be at increased risk of NSAID-related adverse events
mine whether NS-NSAID and COX-2 inhibitor use is from their index MI admission.
appropriately targeted in those with a prior history of GI 3. Stroke cohortveterans who have had at least one
events, MI or stroke. hospitalization with primary diagnosis of stroke
(ICD-10-AM codes I60.0I69.9) between January
2006 and December 2009. They entered the stroke
2 Methods cohort and were considered to be at increased risk of
NSAID-related adverse events from their index stroke
2.1 Data Source and Study Design admission.
4. Low-risk cohortincluded (a) veterans who had no
We conducted a retrospective study using the Australian hospitalizations for GI events, MI or stroke between
Government Department of Veterans Affairs (DVA) [25] January 2006 and December 2009 (they were
NSAID Use in Those at Risk of Adverse Events 25

considered at low risk for the whole period); and Analgesics were defined according to the World Health
(b) veterans who were considered to be at low risk prior Organizations (WHOs) Anatomical Therapeutic Chemical
to their first hospital admission due to a GI event, MI or (ATC) classification [11]. Paracetamol use was defined as
stroke between January 2006 and December 2009. ATC code N02BE01. All NS-NSAIDs and COX-2 inhibitors
Veterans were considered to be part of the relevant risk that were on the market in Australia and subsidized to vet-
cohort after their first hospital admission for any of these erans during the study period were included in the analyses.
events. How participants moved from the low-risk The NS-NSAIDs that were included were indomethacin
cohort to one of the risk cohorts is illustrated in Fig. 1. (M01AB01), diclofenac (M01AB05), sulindac (M01AB02),
piroxicam (M01AC01), ibuprofen (M01AE01), naproxen
Participants who had consecutive hospitalizations for
(M01AE02), ketoprofen (M01AE03), tiaprofenic acid
the same event in the period contributed person-months in
(M01AE11), mefenamic acid (M01AG01) and diflunisal
the corresponding risk cohort from the date of the earliest
(N02BA11). The COX-2 inhibitors that were included were
admission. Participants who had two or more hospital
celecoxib (M01AH01), lumiracoxib (M01AH06; until
admissions for different events contributed person-months
August 2007) and meloxicam (M01AC06). Although not
in each of the corresponding risk cohorts from the date of
classified a coxib by the WHO, meloxicam was included in
the earliest admission for the given event.
the COX-2 inhibitors because of its high COX-2 selectivity
[12]. The National Prescribing Service (NPS) [29] and
2.3 Definition of Analgesics Australian Therapeutic Goods Administration [30] both
classify meloxicam as a COX-2 inhibitor in their recom-
Analgesic use each month was assessed for each of the mendations for NSAIDs. The selected opioids included
following medicine classes: codeine and paracetamol combinations (N02AA59), oxy-
codone (N02AA05) and tramadol (N02AX02). We did not
1. Paracetamol only
include stronger opioids such as morphine, because they are
2. COX-2 inhibitors (including concurrent use with para-
mainly used for cancer pain and in palliative care, where pain
cetamol but excluding use with NS-NSAIDs or selected
management may differ from usual management of acute or
opioids)
chronic non-cancer pain [31].
3. NS-NSAIDs (including concurrent use with paraceta-
Monthly utilization was calculated as the proportion of
mol but excluding use with COX-2 inhibitors or
people dispensed the medicine of interest in each month
selected opioids)
among the cohort population in that month. To calculate
4. Selected opioids: tramadol, codeine with paracetamol,
the population using medicines each month, prescription
and oxycodone (including concurrent use with para-
durations were applied. The prescription duration was
cetamol, COX-2 inhibitors and NS-NSAIDs).
calculated from the data for each individual medicine and
The rationale for the definitions of the medicine classes reflected the time period within which 75 % of those who
was to take into account individuals who step up from first- were prescribed that medicine had a repeat prescription
line to second-line and stronger analgesia. Participants dispensed, thus most likely representing periods of actual
were excluded from the analyses if they were using COX-2 use. For example, 75 % of all prescriptions for meloxicam
inhibitors and NS-NSAIDs concomitantly. were dispensed every 43 days; therefore, for the purposes

First hospitalization Hospitalization for a different event

GI MI or stroke GI and MI/stroke


cohort cohorts
GI event

Veteran population No events Low-risk MI GI event or stroke MI and GI/stroke


MI
aged 55 years cohort cohort cohorts

Stroke
No hospitalizations Stroke GI event or MI Stroke and GI/MI
cohort cohorts

Low-risk
cohort

Fig. 1 Illustration of how participants of the veteran population could move from a low-risk cohort to a risk cohort after hospitalization for a
gastrointestinal (GI) event, myocardial infarction (MI) or stroke during the study period (20062009)
26 S. Gadzhanova et al.

of these analyses, it was assumed that the person was using Table 1 Cohort characteristics
the medicine from the date of dispensing until 43 days Cohort No. of participants Age Sex
later. In Australia, subsidized medicines can be dispensed [years; mean [women (%)]
only for the equivalent of a 1-month supply. Jan Dec (SD)] (Jan 2007)
2007 2009 (Jan 2007)
2.4 Statistical Analysis GI cohorta 514 1,277 82.0 (7.78) 43
a
MI cohort 2,025 4,969 83.2 (7.48) 35
Participants were followed up until death or the end of the Stroke 2,481 5,356 84.1 (6.38) 41
study period. They were excluded from a cohort when they cohorta
entered palliative care (defined as the date 3 months before Low-risk 279,361 199,534 79.7 (9.85) 41
the first claim for palliative care item) or when they were cohort
dispensed a medicine for neuropathic pain (if any). This GI gastrointestinal, MI myocardial infarction, SD standard deviation
was done because pain management among these groups a
3.6 % of participants in the risk cohorts were included in more than
differs from that for those with acute or chronic non-cancer one risk cohort
pain [31, 32].
Cohort characteristics are presented as means and pro- COX-2 inhibitor use was more prevalent than NS-
portions. Medicine utilization rates were age-standardized NSAID use in all cohorts (Table 2). At the end of 2009, the
using the veteran population in January 2007 as the stan- use of COX-2 inhibitors was twice as high as the use of
dard population in 5-year categories. Poisson regression NS-NSAIDs in the GI and low-risk cohorts (5.1 % vs.
models were used to calculate age-standardized rate ratios 2.5 % and 5.6 % vs. 3.3 %, respectively). In December
(SRRs), and the rate in 1 year was compared with that for 2009, COX-2 inhibitors were used at slightly higher rates
the previous year to test for linear trends over the period than NS-NSAIDs in the MI cohort (3.6 % vs. 3.2 %), and
20072009. All analyses were done for all analgesic groups the rates were 3.6 % vs. 2.6 % in the stroke cohort.
in each cohort. Analyses were performed using an SAS 9.3 The use of both COX-2 inhibitors and NS-NSAIDs
statistical package (SAS Institute, Cary, NC, USA). declined significantly throughout the study years in the
DVA Ethics Committee and the Human Research Ethics stroke and the low-risk cohorts (Table 2). The rates of
Committee of the University of South Australia approved COX-2 inhibitor and NS-NSAID use also declined in the
this study. GI cohort, but the decrease was not statistically significant
for NS-NSAIDs. A significant decline was observed in NS-
NSAID use in the MI cohort.
3 Results

The study included 288,912 subjects. The mean (SD) age 4 Discussion
was 79.8 (9.82) years and 40 % were women. Between
2006 and 2009, 19,544 subjects had at least one hospital- We found that one-third of the overall study population
ization for a GI event, MI or stroke, which accounted for used analgesics. There was a significant decline in COX-2
6.8 % of all subjects. Of the 19,544 hospitalized subjects, inhibitor use among the GI and stroke cohorts, and a
3.6 % experienced hospitalization for more than one type decline in NS-NSAID use among the MI and stroke
of event. Characteristics of the cohorts are presented in cohorts.
Table 1. The age-standardized prevalence of overall anal- Paracetamol was the most commonly dispensed anal-
gesic use was approximately 34 % among the overall study gesic in all our cohorts, accounting for half of all analgesic
population (Table 2). Analgesic use was higher in the risk use. This supports guideline recommendations to use par-
cohorts than in the low-risk cohort. In December 2009, the acetamol as a first-line therapy [18, 19]. Our results also
prevalence of analgesic use was 47 % in the GI cohort, demonstrated practice consistent with guidelines for the GI
40 % in the MI and stroke cohorts and 34 % in the low-risk cohort, where COX-2 inhibitors were the preferred NSAID.
cohort. There was a low prevalence of NS-NSAID use among
Paracetamol was the most commonly used analgesic those with a prior history of a GI event, with only 2.5 %
within each cohort, accounting for more than half of any using NS-NSAIDs at the end of the study period. Further
analgesic use (Table 2; Fig. 2). The prevalence of para- analysis showed that 82 % of NS-NSAID users in the GI
cetamol use was higher in the risk cohorts, ranging from cohort were using PPIs concomitantly, consistent with the
21 % to 23 %, compared with 16 % in the low-risk cohort. guidelines [18, 21]. A positive finding was also seen in the
Selected opioids were the next most widely used analgesic decrease in COX-2 inhibitor use among those with a prior
after paracetamol.
NSAID Use in Those at Risk of Adverse Events 27

Table 2 Prevalence and changes in analgesics use from 2007 to 2009


Cohort Drug class January 2007 December 2009 Average SRR 95 % CI p valuea
annual
n CR SR n CR SR change
(%) (%) (%) (%) (%)

GI event Any analgesic 251 48.83 47.57 604 47.30 47.10 -0.5 0.995 0.985, 1.004 0.2500
groupb
Paracetamolc 115 22.37 21.31 326 25.53 23.11 ?0.3 1.003 0.985, 1.021 0.7695
COX-2 40 7.78 7.89 64 5.01 5.06 -6.0 0.940 0.904, 0.978 0.0021
inhibitord
NS-NSAIDe 18 3.50 3.76 29 2.27 2.47 -4.7 0.953 0.895, 1.016 0.1400
Selected opioidsf 77 14.98 14.20 184 14.41 16.36 ?1.9 1.019 0.984, 1.055 0.2835
MI Any analgesic 777 38.37 37.20 1,953 39.30 39.66 ?0.0 1.000 0.991, 1.010 0.9750
groupb
Paracetamolc 418 20.64 19.03 1,113 22.40 20.51 ?1.6 1.016 0.998, 1.034 0.0790
COX-2 70 3.46 3.79 154 3.10 3.57 ?0.6 1.006 0.977, 1.037 0.6851
inhibitord
NS-NSAIDe 53 2.62 2.64 134 2.70 3.21 -5.8 0.942 0.910, 0.975 0.0007
Selected opioidsf 234 11.56 11.65 547 11.01 12.27 -1.3 0.987 0.973, 1.000 0.0573
Stroke Any analgesic 1,007 40.59 39.81 2,161 40.35 40.31 -1.6 0.984 0.977, 0.992 0.0001
groupb
Paracetamolc 580 23.38 19.93 1,343 25.07 22.26 ?0.6 1.006 0.993, 1.018 0.3745
COX-2 101 4.07 4.09 176 3.29 3.57 -3.4 0.966 0.949, 0.983 \0.0001
inhibitord
NS-NSAIDe 65 2.62 2.92 110 2.05 2.59 -11.5 0.885 0.854, 0.917 \0.0001
Selected opioidsf 258 10.40 12.75 531 9.91 11.87 -1.6 0.984 0.967, 1.001 0.0692
Low risk Any analgesic 95,425 34.16 34.18 67,744 33.95 34.14 -1.0 0.990 0.984, 0.997 0.0067
groupb
Paracetamolc 40,240 14.40 14.44 32,346 16.21 16.29 ?2.5 1.025 1.009, 1.041 0.0022
COX-2 18,281 6.54 6.54 11,051 5.54 5.61 -4.8 0.952 0.944, 0.961 \0.0001
inhibitord
NS-NSAIDe 10,836 3.88 3.87 6,675 3.35 3.32 -4.9 0.951 0.940, 0.962 \0.0001
Selected opioidsf 25,526 9.14 9.13 17,377 8.71 8.76 -2.1 0.979 0.973, 0.985 \0.0001
Whole study Analgesicsg 97,429 34.27 34.27 72,273 34.31 34.44 -0.8 0.992 0.985, 0.999 0.0276
population
CI confidence interval, COX-2 cyclo-oxygenase-2, CR crude rate, GI gastrointestinal, MI myocardial infarction NS-NSAID non-selective non-
steroidal anti-inflammatory drug, SR age-standardized rate, SRR age-standardized rate ratio
a
p values for the ratio of the rate in 1 year to the rate in the previous year were calculated using a Poisson regression model accounting for over-/
under-dispersion in the data when necessary
b
Any analgesic group includes the use of paracetamol, NS-NSAIDs, COX-2 inhibitors, tramadol, oxycodone, and paracetamolcodeine
combination products, including concurrent use
c
Paracetamol includes paracetamol-only use without any other analgesics
d
COX-2 inhibitor includes COX-2 use with or without paracetamol, but excluding concomitant use with NS-NSAIDs or selected opioids
e
NS-NSAID includes NS-NSAID use with or without paracetamol, but excluding concomitant use with COX-2s or selected opioids
f
Selected opioids include tramadol, codeine with paracetamol, and oxycodone (including concurrent use with paracetamol, COX-2 inhibitors
and NS-NSAIDs)
g
Analgesics includes all analgesics in the individual drug classes, including concurrent use

history of stroke. However, COX-2 inhibitor use was still 16.5 % [33]. The difference may be attributed to the fact
higher than NS-NSAID use in the stroke and MI cohorts. that the survey included both prescription and over-the-
We found a lower use of paracetamol and NSAIDs when counter medicines. We could locate no comparable inter-
compared with data from an Australian survey of medicine national studies that reported trends in analgesic use in the
use among those aged 50 years and over, which reported same time period. Based on sales data, a European study
past-month paracetamol use of 42.9 % and NSAID use of reported paracetamol as the most commonly used analgesic
28 S. Gadzhanova et al.

Paracetamol
Selected opioids
COX-2 inhibitors
NS-NSAIDs
GI cohort MI cohort
24 24

Percentage of participants
Percentage of participants

20 20

16 16

12 12

8 8

4 4

0 0

M -08

N -08

M -09

N -09
Ja 08

9
M -08

Se 8

M 09

Se 9
Ju 8

Ju 9
M -07

N -07
M -08

N -08

M -09

N -09

Ja 07
Ja 08

M -07

Se 7
M -08

Se 8

M 09

Se 9

Ju 7
Ju 8

Ju 9
M -07

N -07
Ja 07
M -07

Se 7
Ju 7

-0
l-0

l-0
-0

-0
-0

l-0
l-0

l-0

-0
-0

-0
l-0
-0

-
n-
-
-
n-
-

ar

ar

p
ov

ov
n

ay

ay
ar

p
ar

ar

ov
ov

ov

n
n

ay
ay

ay
ar

p
ov
n

ay

Ja
Ja

Stroke cohort Low-risk cohort


24 24
Percentage of participants

Percentage of participants
20 20

16 16

12 12

8 8

4 4

0 0

M -08

N -08

M -09

N -09
Ja 08

9
M -08

Se 8

M 09

Se 9
Ju 8

Ju 9
M -07

N -07
Ja 07
M -07

Se 7
Ju 7
M -08

N -08

M -09

N -09
Ja 08

9
M -08

Se 8

M 09

Se 9
Ju 8

Ju 9
M -07

N -07
Ja 07
M -07

Se 7
Ju 7

-0
l-0

l-0
-0

-0
l-0
-0
-0
l-0

l-0
-0

-0
l-0
-0

-
n-
-
-
n-
-

ar

ar

p
ov

ov
n

ay

ay
ar

p
ov
n

ay
ar

ar

p
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ov
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ay

ay
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ay

Ja
Ja

Fig. 2 Age-standardized analgesics use in the risk (GI, MI, and participants dispensed NS-NSAIDs does not include those also
stroke) and low-risk cohorts during 20072009. The group of dispensed COX-2 inhibitors or selected opioids. Selected opioids are
participants dispensed paracetamol does not include those also defined as tramadol, codeine with paracetamol, and oxycodone. COX-
dispensed NS-NSAIDs, COX-2 inhibitors or selected opioids. The 2 cyclo-oxygenase-2, GI gastrointestinal, MI myocardial infarction,
group of participants dispensed COX-2 inhibitors does not include NS-NSAID non-selective non-steroidal anti-inflammatory drug
those also dispensed NS-NSAIDs or selected opioids. The group of

in Norway and Denmark in 2009, while in Finland, Esto- Our data also show seasonal effects in analgesic use.
nia, Czech Republic and Slovakia, ibuprofen was the most The seasonal variation is due to the Australian Safety Net
commonly used analgesic [34]. where, once annual threshold costs are exceeded, medi-
A Danish study reported a rapid decrease in the number cines become less expensive or free for the rest of the
of COX-2 inhibitors used among the whole Danish popu- calendar year. This causes the safety net effect where
lation between 2002 and 2005, to almost 0 % in 2005 [35]. more medicines are collected from pharmacies late in the
Similarly, a previous study on NSAID use in our study calendar year while at the beginning of the year the dis-
population showed a decrease until July 2007 [24]. The pensing rate declines [36].
current results demonstrate that, between 2007 and 2009, Our study was based on a large nationwide dataset of
the decline continued in all our cohorts, albeit at more almost 300,000 Australian veterans and their dependants.
modest rates. COX-2 inhibitors continued to decrease in all We had a long follow-up period with monthly data on
cohorts except the MI cohort, in which COX-2 inhibitor medicine dispensing. DVA subsidises all prescribed med-
use was already low at the beginning of our study. These icines to their clients, which means that we captured all
findings are encouraging and it seems that the majority of prescribed analgesic use for the study population.
pharmacological pain management is consistent with The veteran population have slightly more visits to
guideline recommendations. general practitioners (GPs) [relative risk (RR) 1.17;
NSAID Use in Those at Risk of Adverse Events 29

p \ 0.05] and hospitalizations (RR 1.21; p \ 0.05) annu- 3. European Medicines Agency. Scientific conclusions for the
ally than the general Australian population aged C40 years amendment of the marketing authorisationCOX-2 inhibitors.
European Medicines Agency. 2005. http://www.ema.europa.eu/
[25]. Due to the higher rate of GP visits, veterans receive docs/en_GB/document_library/Referrals_document/Celecoxib_31/
slightly more prescriptions per year than the general pop- WC500012417.pdf. Accessed 24 Jan 2012.
ulation (RR 1.13; p \ 0.05), suggesting that our study 4. Food and Drug Administration. COX-2 selective (includes Bex-
results may slightly overestimate the prescribing rates over tra, Celebrex, and Vioxx) and Non-Selective Non-Steroidal Anti-
Inflammatory Drugs (NSAIDs). Food and Drug Administration.
those for the general population. However, because of our 2005. http://www.fda.gov/drugs/drugsafety/postmarketdrugsafety
inability to include over-the-counter medicine use, our informationforpatientsandproviders/ucm103420.htm. Accessed
study may slightly underestimate overall rates of use. 24 Jan 2011.
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basis of hospitalization data for GI events, MI and stroke. associated with rofecoxib in a colorectal adenoma chemopre-
We have no information on events that may have occurred vention trial. N Engl J Med. 2005;352(11):1092102.
8. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular
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Thus, our results reflect use in those with more severe adenoma prevention. N Engl J Med. 2005;352(11):107180.
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Acknowledgments Svetla Gadzhanova and Elizabeth E. Roughead Qual Outcomes. 2009;2(3):15563.
were responsible for study design. Svetla Gadzhanova, Jenni Ilomaki 14. Motsko SP, Rascati KL, Busti AJ, et al. Temporal relationship
and Elizabeth E. Roughead were responsible for the analyses, inter- between use of NSAIDs, including selective COX-2 inhibitors,
pretation of the results and preparation of the manuscript. This study and cardiovascular risk. Drug Saf. 2006;29(7):62132.
was funded by NPS Better choices Better health. The authors wish to 15. Hernandez-Daz S, Rodrguez LA. Association between nonste-
thank Mark Bartlett from NPS for his comments on the manuscript. roidal anti-inflammatory drugs and upper gastrointestinal tract
We acknowledge the support of the Australian Government Depart- bleeding/perforation: an overview of epidemiologic studies pub-
ment of Veterans Affairs, which provided data for the conduct of lished in the 1990s. Arch Intern Med. 2000;160(14):20939.
these analyses. The authors have no conflicts of interest. 16. Moore RA, Derry S, Makinson GT, et al. Tolerability and adverse
events in clinical trials of celecoxib in osteoarthritis and rheu-
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