Clinical Therapeutics/Volume 31, Number 4, 2009

April 2009 849

* Current aff iliation: Department of Drug Safety & Epidemiology, Novartis, Basel, Switzerland.

Accepted for publication February 26, 2009.doi: 10.1016/j.clinthera.2009.04.0120149-2918/$ - see front matter

© 2009 Excerpta Medica Inc. All rights reserved.

ABSTRACTBackground: In Australia, the prescribing of proton

pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H2RAs) for defined gastrointestinal dis-orders is approved for subsidy by the universal Australian Pharmaceutical Benefits Scheme. These agents also may be used with NSAIDs, but this prescribing is not approved for subsidy. PPI prescribing increased in Australia between 1997 and 2006, and some authori-ties are concerned that this increase may be due to prescriptions outside the approved indications.

Objectives: The aims of this study were to quantify gastroprotective drug consumption in Australia be-tween 1997 and 2006 and to investigate the relation-ship over time between this prescribing and NSAID prescribing.

Methods: Data from concession beneficiaries (se-niors and welfare recipients) were included. Data on PPIs, H2RAs, NSAIDs, and cyclooxygenase (COX)-2 inhibitors dispensed between 1997 and 2006 were gathered from Medicare Australia and are expressed as defined daily doses (DDDs) per 1000 concession beneficiaries per day (CBPDs). Gastroprotective drugs were defined using the World Health Organization Anatomical Therapeutic Chemical classification of 2006. Drug utilization 90% and expenditures in Aus- tralian dollars (AUD $, not normalized to an index year) were calculated.

Results: H2RA prescribing was stable between 1997 and 2001, at ~60 DDDs/1000 CBPDs. Dispensa- tion of H2RAs began to decrease in 2001 to 20 DDDs/ 1000 CBPDs in 2006. PPI consumption increased con-sistently, with a sharp change beginning in 2001 (from about 45 to 140 DDDs/1000 CBPDs between 2001 and 2006). The government expenditure for PPIs per con-cession beneficiary per year also increased from about AUD $26 in 1997 to almost AUD $74 in 2006, where-as the expenditure for H2RAs decreased from about AUD $24 to about AUD $5. Nonselective NSAID

prescribing decreased with the introduction of COX-2 inhibitors in 2000. COX-2 inhibitors increased the overall consumption of total NSAIDs in the first 4 years (2000–2003) after their introduction.

Conclusions: The prescribing of H2RAs decreased, whereas the prescribing of PPIs increased, between 1997 and 2006 in this population of concession bene-ficiaries in Australia. During the same period, nonse-lective NSAID prescribing decreased while COX-2 inhibitor prescribing increased. (Clin Ther. 2009;31: 849–861) © 2009 Excerpta Medica Inc.

Key words: proton pump inhibitors, H2 receptor antagonists, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, prescribing.

INTRODUCTIONProton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H2RAs) are recommended for the treatment of gastrointestinal (GI) disorders in pa-tients with documented duodenal or gastric ulcers, se-vere symptoms of gastroesophageal reflux disorder (GERD), and pathologic conditions such as Zollinger-Ellison syndrome, esophageal ulceration, or Barrett’s esophagitis.1–3 PPIs are indicated in combination with antibiotics for Helicobacter pylori eradication.2,3 PPIs are approved for subsidy by the Australian Pharma-ceutical Benefits Scheme (PBS) for these restricted indications.

Gastroprotective drugs are also recommended for the treatment of ulcers induced by nonselective (ns)-NSAIDs.3 GI damage is the most frequent adverse drug reaction associated with ns-NSAIDs.4 Therefore,

Gastroprotective Drugs in Australia: Utilization Patterns Between 1997 and 2006 in Relation to NSAID Prescribing

Nadia Barozzi, PhD1*; and Susan E. Tett, PhD, MPS2

1School of Pharmacy, University of Queensland, Brisbane, Australia; and 2Faculty of Health Sciences, University of Queensland, Brisbane, Australia

850 Volume 31 Number 4

Clinical Therapeutics

The aims of this study were to examine the pre-scribing patterns of H2RAs and PPIs in Australia be-tween 1997 and 2006 in seniors and those receiving welfare benefits, and to determine whether gastropro-tective drug prescribing could have been related to se-lective NSAID and ns-NSAID prescribing in Australia, perhaps changing with the advent of COX-2 inhibi-tors and the subsequent withdrawal of rofecoxib from the market in September 2004.

MATERIALS AND METHODSMedicare Australia is the agency responsible for pay-ment to community pharmacists for prescriptions subsidized by the PBS. All data on the dispensation of reimbursable prescribed drugs are recorded in a data-base, and aggregated, deidentified data are publicly accessible online (www.medicareaustralia.gov.au). The data are aggregated by item number (a code given to each formulation of each compound for medicines subsidized by the PBS).

The reimbursement system covers all permanent residents in Australia (PBS beneficiaries). There are 2 classes of PBS beneficiaries: general and concession. Concession beneficiaries consist of those Australian residents eligible for the Commonwealth Seniors Health Card, Health Care Card, and Pensioner Con-cession Card. These are people receiving senior or disability pensions, or are single parents, low-income families, or other patients eligible for a concession card, and they account for 80% of prescription medi-cation use.22 They contribute a low copayment (in 2007, AUD $4.90). General beneficiaries are all of the remaining Australian residents eligible for enrollment to Medicare Australia. General beneficiaries contrib-ute with higher copayments (in 2007, AUD $30.70).

For the purposes of this analysis, only concession beneficiaries were included in the population sample because of characteristics of the Australian admin- istrative database. The Medicare Australia database captures dispensation when the copayment has been paid in full; dispensations under the copayment fee are not recorded. Because general beneficiaries con-tribute with higher copayments, items below this co-payment amount (most H2RAs) are not captured by the dispensation reimbursement database. Concession beneficiaries in Australia represent the population subgroup responsible for the highest drug consump-tion.23 In Australia, concession beneficiaries are pre-dominantly those patients aged >65 years, and these

concurrent prescription of ns-NSAIDs with PPIs (or H2RAs, although these are not effective for the more common gastric ns-NSAID–induced ulcers5–7) is a com-mon practice of physicians treating patients at high risk for GI adverse events when ≥1 risk factors for GI adverse events are present.8 However, routine prophy-laxis or treatment of mild symptoms with PPIs is not well supported by the evidence and is not one of the restricted indications supported by the PBS subsidy.9 Nonetheless, PPIs have been available on the PBS with-out prior authorization since 2001, and there have been no administrative barriers to prescribing outside of the restricted indications.

Between 2000 and 2002, a newer generation of anti- inflammatory drugs, the cyclooxygenase (COX)-2 selec-tive inhibitors (celecoxib, rofecoxib, and meloxicam), became available in Australia as PBS-reimbursable prescribed medicines. In August 2006, an additional COX-2 inhibitor (lumiracoxib) became available in Australia. COX-2 inhibitors were introduced after a number of clinical trials10–13 found a better safety profile with regard to GI events with COX-2 inhibi-tors than with ns-NSAIDs.14 COX-2 inhibitors were introduced with the recommendation to limit their use only in patients at high risk for GI complications, in those refractory to ns-NSAIDs, in those concurrently using corticosteroids and anticoagulants, and in pa-tients >65 years of age.8,15 COX-2 inhibitors mark-edly influenced the overall NSAID prescribing in Australia.16 After the introduction of COX-2 inhibi-tors, prescribing of the newer-generation ns-NSAIDs decreased sharply.

Prescribing of gastroprotective drugs is a source of concern in Australia.17 Drugs for gastric acid- related disorders have been reported to contribute more to the cost of the PBS than almost any other group of drugs.18 PPIs are the second most expensive drug class for the Australian government.19 Prescrib-ing of PPIs has been increasing rapidly since they were listed for public subsidy in 1991.17 In 1997, ~7,726,600 prescriptions for gastroprotective drugs (World Health Organization [WHO] Anatomical Therapeutic Chemical [ATC] classification A02BA and A02BC20) were dispensed through community phar-macies in Australia, at the estimated cost of >252 mil-lion Australian dollars (AUD $, not normalized to an index year).21 In 2005, the number of prescriptions dispensed was ~14,557,800, at a cost of more than AUD $672 million.18

April 2009 851

N. Barozzi and S.E. Tett

Drug utilization 90% (DU90%)—drugs accounting for 90% of prescriptions within the group of medi-cines being studied, a variable that suggests prescrib-ing patterns of specific agents within a class over time— was calculated for gastroprotective drugs.27 DU90% has been used extensively in pharmacoepidemiology since its introduction by Bergman et al,27 who de-scribed it as an indicator of appropriateness in pre-scribing. Data are expressed as DDDs, and the drugs with the highest percentage are sequentially added together to reach 90% of the total consumption. DU90% is a tool that reveals changes in relative drug dispens-ing. Although it does not provide data on treatment adherence,28 DU90% can be used to identify changes in prescribing patterns.

H2RAs and PPIs subsidized in Australia from 1997 to 2006 included the H2RAs ranitidine, famotidine, nizatidine, and cimetidine and the PPIs omeprazole, pantoprazole, lansoprazole, esomeprazole, and rabep- razole. The NSAIDs subsidized during that period have been described elsewhere.16

DDDs, expenditure calculations, and statistical analyses were completed using Microsoft Excel 2003 (Microsoft Corporation, Redmond, Washington).

RESULTSData on H2RA and PPI dispensation for concession beneficiaries from 1997 to 2006 are shown in Figures 1 and 2, respectively. Prescribing of H2RAs was consis-tent from 1997 to 2001, at ~60 DDDs/1000 CBPDs, predominantly represented by ranitidine. Dispensa-tion of H2RAs began to decrease in 2001, to a low of 20 DDDs/1000 CBPDs in 2006 (DU90%). PPI prescrib-ing increased between 1997 and 2006, with a sharp change beginning in 2001. Between 2001 and 2006, total PPI prescribing changed from ~45 to 140 DDDs/ 1000 CBPDs. From 1997 to 2001, PPI prescribing was predominantly attributable to omeprazole (DU90%). However, prescribing of omeprazole did not change significantly between 2002 and 2006, and a slight decrease in omeprazole prescribing was observed in 2006. Pantoprazole, rabeprazole, and particularly eso- meprazole prescribing increased after 2002.

The costs of H2RAs and PPIs are shown in Table I.20 The cost of H2RAs to the government decreased over the time period, from about AUD $24 in 1997 to about AUD $5/CBPY in 2006. However, the cost of PPIs increased from about AUD $26 in 1997 to al-most AUD $74/CBPY in 2006. The PPI yearly expen-

beneficiaries are responsible for using up to 80% of dispensed medicines.24,25 The numbers of eligible con-cession beneficiaries from January 1997 to April 2006 were obtained by request from Centrelink, the govern-ment agency responsible for social services for the Australian community.

The numbers of PPIs, H2RAs, ns-NSAIDs, and COX-2 inhibitors dispensed to concession beneficia-ries in Australia from January 1997 to December 2006 were gathered from Medicare Australia.

The generic compounds were classified according to the WHO ATC 2006 classification system.20 The numbers of defined daily doses (DDDs, 2006 version) per 1000 concession beneficiaries per day (CBPDs) were calculated for all ns-NSAIDs, COX-2 inhibitors, PPIs, and H2RAs, as described elsewhere.16 The DDDs/1000 CBPDs (mean yearly data) were calcu-lated for each generic drug and plotted to investigate patterns in medication prescribing over time.

The costs of PPIs and H2RAs to the government and to consumers per concession beneficiary per year (CBPYs) were calculated. Cost to the government was calculated by obtaining the total expenditure for every relevant item available from Medicare Australia. The cost to patients was calculated by multiplying the number of services for every item by the relevant co-payment (1997, AUD $3.20; 1998, AUD $3.20; 1999, AUD $3.20; 2000, AUD $3.20; 2001, AUD $3.40; 2002, AUD $3.60; 2003, AUD $3.70; 2004, AUD $3.80; 2005, AUD $4.60; and 2006, AUD $4.70). Percentage changes over the previous year for PPIs and H2RA utilization data (DDDs per 1000 CBPDs) and expenditure data (AUD $ per CBPY) were calcu-lated. Costs were not adjusted for an index year.

The ns-NSAIDs were classified as being low, moderate, and high risk for GI adverse events accord-ing to the Gastroenterological Society of Australia classification.26 Ibuprofen and diclofenac have been classified as low risk; aspirin, sulindac, naproxen, and indomethacin, as moderate risk; and ketoprofen and piroxicam, as high risk for GI adverse events. These categories were used to calculate the percent-age of each classification (low, moderate, and high risk) over the total ns-NSAIDs prescribed. Because it might be anticipated that the prescribing of gas- troprotective agents changed as a higher or lower pro- portion of high-risk NSAIDs were dispensed, the ratio of low risk to high risk for GI adverse events was calculated.

852 Volume 31 Number 4

Clinical Therapeutics

30

15

60

90

120

0

DD

Ds/

1000

CB

PDs

20032002200120001999 20062005200419981997

Year

EsomeprazoleLansoprazoleOmeprazolePantoprazoleRabeprazoleTotal PPIs

150

45

75

105

135

x

xxxxx x

30

15

60

90

120

0

DD

Ds/

1000

CB

PDs

20032002200120001999 20062005200419981997

Year

CimetidineFamotidineNizatidineRanitidineTotal H2RAs

150

45

75

105

135

Figure 1. Prescribing of histamine type 2 receptor antagonists (H2RAs) among concession beneficiaries in Australia from 1997 to 2006. DDDs = defined daily doses; CBPDs = concession beneficiaries per day.

Figure 2. Prescribing of proton pump inhibitors (PPIs) among concession beneficiaries in Australia from 1997 to 2006. DDDs = defined daily doses; CBPDs = concession beneficiaries per day.

April 2009 853

N. Barozzi and S.E. Tett

overall total NSAID prescribing declined slightly (to ~75 DDDs/1000 CBPDs in 2006). However, ns-NSAID prescribing increased slightly in 2005. In 2005, celecoxib prescribing decreased slightly, while meloxi-cam prescribing increased (DU90%). Utilization pat-terns of selective NSAIDs and ns-NSAIDs from 1997 to 2006 have been described in detail elsewhere.16

Prescribing of ns-NSAIDs in relation to low, mod-erate, or high risk for GI adverse events is shown in Table II. Prescribing of NSAIDs associated with a high risk for GI adverse events decreased over the study period (from 26% to 18%). Prescribing of NSAIDs associated with a moderate and low risk for GI ad-verse events increased.

Analysis of PPIs and H2RA DU90%s found that PPIs almost completely replaced H2RAs from 2002 on-ward (Figure 5).

DISCUSSIONIn Australia, from 1997 to 2006, major changes were observed in gastroprotective drug and NSAID pre-scribing among concession beneficiaries. In particular, the prescribing of PPIs increased sharply, replacing

diture as copayments by the patient increased from ~AUD $1.50 to AUD $21.10/CBPY (Table I).

Changes in dispensing (DDDs/1000 CBPDs) and expenditures (AUD $/CBPY) over the previous year are shown in Figure 3. Prescribing increased every year. Very high percentage increases were observed for gastroprotective drugs between 2000 and 2001 (+30%) and between 2001 and 2002 (+40%), coinciding with the removal of the requirement for prior authoriza-tion for PPI subsidy. Yearly expenditure (cost to the government) increased between 1997 and 1999 and between 2000 and 2005. Decreases were observed between 1999 and 2000 (–12%) and between 2005 and 2006 (–7%). These data are not standardized to a specific year, but are given as reported by the govern-ment to show the relative expenditure increases.

Data on ns-NSAID and overall NSAIDs prescribing from 1997 to 2006 are shown in Figure 4. Prescribing of ns-NSAIDs decreased sharply with the introduction of COX-2 inhibitors. COX-2 inhibitors increased the overall consumption of total NSAIDs during the first 4 years after their introduction (2000–2003). After the withdrawal of rofecoxib from the market in 2004, the

Table I. Approximate expenditures per concession beneficiaries per year (CBPY) for histamine type 2 receptor antagonists and proton pump inhibitors as cost to the government and patients’ contribution be-tween 1997 and 2006 in Australia. Data are Australian dollars per CBPY, not normalized to an index year.

H2RAs* PPIs†

Government Patient’s Government Patient’s Total Australian Year Cost Contribution Cost Contribution Concession Beneficiaries

1997 24 4.30 26 1.50 4,595,7651998 17 3.90 30 1.80 4,689,7431999 15 4.10 34 2.20 4,783,7202000 15 4.10 30 2.50 4,879,0352001 13 3.70 37 3.40 4,983,7982002 9 3.40 52 7.60 5,024,6952003 7 2.80 64 9.60 5,035,7152004 7 2.60 74 11.40 4,976,0162005 6 2.70 79 15.10 4,934,4172006 5 3.20 74 21.10 4,934,417

H2RAs = histamine type 2 receptor antagonists; PPIs = proton pump inhibitors. * World Health Organization Anatomical Therapeutic Chemical classif ication A02BA.20 † World Health Organization Anatomical Therapeutic Chemical classif ication A02BC.20

854 Volume 31 Number 4

Clinical Therapeutics

may be their prescription to patients who are receiv-ing low-dose aspirin for primary or secondary preven-tion of acute coronary syndrome or together with clopidogrel in patients undergoing coronary artery stenting with drug-eluting stents (first used in mid-2002 in Australia).29 PPIs initially became available in Australia as “authority required” benefits (ie, requir-ing prior approval from the relevant government agency) when first listed on the PBS in 1992. In 2001, the prior-authorization restriction was changed to “restricted benefits” (ie, no prior authorization re-quired, but supposedly limited to specific therapeutic uses), and a marked increase in PPI prescribing was observed. At the same time, a sharp decrease in H2RA prescribing was observed. Before 2000, H2RAs repre-sented the main class of gastroprotective drugs, accounting for up to 67% of the total prescribing. However, beginning in 2001, only ranitidine and famo-

H2RAs almost completely from 2002 onward. Simi-larly, ns-NSAID prescribing decreased while COX-2 inhibitor prescribing increased. However, there were no obvious patterns to suggest a relationship between prescribing of these 2 groups in this population. For example, no association was evident between pre-scribing of high-risk ns-NSAIDs and gastroprotective drugs, or any related changes in prescribing of gastro-protective drugs after the withdrawal of rofecoxib from the market.

The rapid increase in PPI prescribing since 2001 strongly suggests that these medications are being prescribed on the PBS for indications that are not ap-proved for subsidy, because it is highly unlikely that such large increases in the prevalence of the approved subsidy indications (peptic ulcer disease or GERD) occurred. Another possible reason for the increased prescribing of PPIs outside of approved indications

10

–10

–20

20

30

40

0

20042003200220012000 2006200519991998

Year

% C

hang

e

Over the previous year AUD $Over the previous year DDD

50

Figure 3. Defined daily doses (DDDs) and Australian dollars (AUD $, not normalized to an index year) per con-cession beneficiary per year for gastroprotective drugs (histamine type 2 receptor antagonists and proton pump inhibitors): percentage change over the previous calendar year from 1997 to 2006.

April 2009 855

N. Barozzi and S.E. Tett

30

15

60

90

120

0

DD

Ds/

1000

CB

PDs

20032002200120001999 20062005200419981997

Year

150

45

75

105

135

xx x

x

All NSAIDsns-NSAIDsCOX-2 inhibitorsCelecoxibRofecoxibMeloxicamLumiracoxib

x

Figure 4. Prescribing of NSAIDs, nonselective (ns)-NSAIDs, and cyclooxygenase (COX)-2 inhibitors among concession beneficiaries in Australia from 1997 to 2006. DDDs = defined daily doses; CBPDs = concession beneficiaries per day.

Table II. Utilization of nonselective NSAIDs by risk for gastrointestinal adverse effects and low- to high-risk ratio among concession beneficiaries between 1997 and 2006 in Australia.

High Risk, Moderate Risk, Low Risk, Total, Low/High Year % % % % Ratio

1997 26 36 26 88 1.0

1998 26 36 28 90 1.1

1999 26 35 31 92 1.2

2000 24 38 30 92 1.3

2001 21 36 34 91 1.6

2002 20 36 36 92 1.8

2003 18 36 39 93 2.2

2004 18 39 36 93 2.0

2005 18 41 38 97 2.1

2006 18 40 37 95 2.1

856 V

olume 31 N

umber 4

Clinical T

herapeutics

Ranitidine45

Famotidine22

Omeprazole21

1997

Famotidine15

Lansoprazole5

Ranitidine46

Omeprazole24

1998

Famotidine12

Lansoprazole5

Ranitidine46

Omeprazole26

1999

Famotidine10

Lansoprazole6

Ranitidine46

Omeprazole28

2000

Pantoprazole11

Famotidine7

Ranitidine40

Omeprazole31

2001

Pantoprazole17

Esomeprazole12

Lansoprazole7

Ranitidine19

Omeprazole36

2003

Ranitidine15

Pantoprazole18

Esomeprazole17

Rabeprazole7

Omeprazole33

2004

Ranitidine12

Esomeprazole20

Pantoprazole19

Rabeprazole9

Omeprazole31

2005

Ranitidine10

Esomeprazole24

Pantoprazole19

Rabeprazole10

Omeprazole28

2006

Pantoprazole17

Lansoprazole7

Ranitidine25

2002

Omeprazole40

Figure 5. Drug utilization 90% for histamine type 2 receptor antagonists (white) and proton pump inhibitors (all other shades) among concession beneficiaries in Australia from 1997 to 2006. Numbers indicate the percentage of the total prescribing in each year.

April 2009 857

N. Barozzi and S.E. Tett

untreated, such as gastroesophageal reflux or mild GI symptoms. However, the administrative database does not permit further person-specific analyses to deter-mine whether H2RA prescriptions were replaced with PPI prescriptions. The public-hospitalization rate for GERD has been reported as ~9 per 10,000 people (2001).41 Other sources have suggested that GI dis- orders and GERD-related symptoms may occur inter-mittently in up to 40% of the population (2000–2003).13–15 Even if similar proportions were estimated for the entire concession population considered in this study, only 1 to 2 million Australian concession bene- ficiaries would be experiencing GERD, and this num-ber still does not account for the high rate of PPI prescribing observed.

The number of concession beneficiaries in Australia increased by 7% over the study period, while PPI pre-scribing increased 7-fold during the same period. The increased rate of PPI prescribing might have been re-lated to an increase in the number of people receiving the drug, an increase in the dose each person was re-ceiving, or both. Prescribing guidelines recommend that after 4 to 8 weeks of treatment with a standard dose of PPI, step-down therapy should be consid-ered.42 However, step-down therapy often does not occur, and patients may continue receiving unneces-sarily high dosages.43 In Australia, electronically gen-erated prescriptions may be set to default to the maxi-mum number of refills; as a consequence, patients may initially receive a prescription for a full 6-month supply rather than a lesser, appropriate quantity.17 This practice may explain some of the apparent overprescribing.

Concurrent prescription of NSAIDs and gastropro-tective drugs is a common practice in the prevention of peptic ulcers induced by NSAIDs.42 Alternatively, COX-2 inhibitors may be recommended in therapeu-tic guidelines.44 COX-2 inhibitors were introduced and marketed in Australia as better tolerated with re-spect to GI adverse events. As a consequence of their rapid increase in prescribing rate (particularly be-tween 2000 and 2004), a decrease in PPI prescribing could have been anticipated because there was no need for gastroprotective drug coprescription. In addi-tion, when rofecoxib was withdrawn, increases in PPI utilization and prescribing of low-risk ns-NSAIDs could have been anticipated. However, PPI prescrip-tions continued to increase independently, with no evi-dent sign of influence from the introduction of COX-2

tidine were included in the DU90%. H2RA prescribing continued to decrease, and by the end of 2006, raniti-dine accounted for only 10% of the total gastropro-tective drug prescribing.

Of all of the PPIs, omeprazole had the highest pre-scribing rate throughout the study period, and its prescribing increased consistently between 1997 and 2002. However, in 2002, omeprazole prescribing be-came stable, while pantoprazole, rabeprazole, and particularly esomeprazole prescribing progressively increased between 2001 and 2006. Esomeprazole was launched on the market in 2000.30 With the patent of omeprazole about to expire in 2002, the manufac- turer spent US $500 million in marketing and adver-tising in the United States in the year after the intro-duction of esomeprazole.31 In Australia in 2003, esomeprazole was registered as having had the highest-volume prescribing change over the previous year among all drugs listed on the PBS.32 However, eso- meprazole (single enantiomer) and omeprazole (race-mate) have the same pharmacologic activity.33 Studies that compared efficacy between esomeprazole and other PPIs found that esomeprazole was associated with only small improvements.34–36 This change from omeprazole to esomeprazole seems to have been the result of marketing rather than any therapeutic need.

The high prescribing rates of drugs introduced more recently (eg, rabeprazole and esomeprazole) seem ir-rational considering their contribution to the increase in expenditures and little variation in efficacy across the different PPIs in randomized trials.37 PPIs and H2RAs have been found to have similar effectiveness in treating GERD symptoms, peptic ulcer disease (duo- denal), esophagitis, and dyspepsia.38,39 However, H2RAs are a much less expensive option.38–40 The PBS subsidies for 30 days of continuous therapy with eso- meprazole were AUD $59.58 for initial therapy (40 mg) and AUD $37.15 for maintenance therapy (20 mg); prices of omeprazole were AUD $34.38 (20 mg) and AUD $29.75 to AUD $37.15 (10–20 mg).40 Dispensa-tion of ranitidine in the same period would cost AUD $20.05 for initial therapy.40

Removal of the preauthorization requirement might also have encouraged physicians to prescribe PPIs to patients who were previously receiving H2RAs or those who were receiving drugs associated with a risk for adverse events that included GI damage. Alterna-tively, the increase in prescribing could have been due to prescribing for indications that were previously

858 Volume 31 Number 4

Clinical Therapeutics

A number of strategies have been attempted in dif-ferent settings to limit the enormous increase in costs and the unreasonable prescribing of these classes of drugs.49 In Italy, for example, even though the reim-bursement system covers all residents, certain PPIs are not subsidized when prescribed together with COX-2 inhibitors.50 In British Columbia, Canada, since the introduction of a restriction policy in 2003, only 1 PPI (rabeprazole) has been approved for subsidy by the local health care system.51 Similarly, in Nova Scotia, Canada, a patient beginning PPI therapy first receives rabeprazole and must complete a trial of at least 4 to 8 weeks before any of the other PPIs can be considered for coverage.52 In Australia, the National Prescribing Service has issued several recommendations about PPI prescribing to promote more rational use.17,53,54

The 12% decrease in expenditures observed from 1999 to 2000 was most likely due to replacement of the capsule formulation with omeprazole tablets, which were listed on the PBS at a lower price (14% dif- ference).55,56 In 2002, omeprazole tablets were already ranked as the second most prescribed item, and they ranked first the following year.57 Between 2000 and 2002, pantoprazole prescribing increased remarkably, and because it was less expensive than omeprazole, it might also have contributed to the expenditure de-crease. The decline observed between 2005 and 2006 (7%) was most likely related to the price-reduction policy implemented in Australia.58 Since August 2005, a generic medicine newly listed on the PBS has to be priced 12.5% lower than the existing product, and then, because of competition, the cost of most for- mulations of that generic drug is decreased to that price.

This study had some limitations. In Australia, pre-scription data are not linked to other data sources (eg, medical services or hospitalizations). Consequently, it was not possible to establish from the present study whether prescription of any of the drugs was appro-priate, whether the drugs were prescribed for the cor-rect indications (eg, correct dosage and duration), or whether the prescriptions came from general practi-tioners or specialists. In addition, it was not possible to complete any analysis of comorbidity or concurrent prescription or to further identify the cohorts of pa-tients treated with gastroprotective agents, ns-NSAIDs, and COX-2 inhibitors. Moreover, we could not estab-lish whether the PPI prescription data indicated as-needed use or continuous use.

inhibitors, and no significant changes in the relative rates of prescription of low-, moderate-, and high-risk ns-NSAIDs were observed between 2004 and 2006. The introduction of COX-2 inhibitors and the change in authorization requirements for PPIs occurred dur-ing the same period, and prescribing of both classes of drugs were sharply increasing at the time. Unfortu-nately, data on concurrently prescribed drugs could not be obtained. Prescription data for this analysis were downloaded from the Medicare Australia Web site, and no linked data from the PBS database were accessible. Obtaining linked PBS data is a complicated and lengthy process and has become available only recently.

The patterns of prescribing PPIs found in the pres-ent analysis are consistent with findings from previ-ously published studies. In a study in Northern Ire-land, Girvin et al45 found that the total number of DDDs for PPIs prescribed in 2002 was 2.5-fold higher than in 1997, and that PPI prescribing increased at rates similar to those seen before the introduction of rofecoxib and celecoxib.45 Similarly, in Finland, PPI prescribing increased by 30% between 2003 and 2006.46 However, the absolute PPI utilization ob-served in the present study was much higher because the present study analyzed drug utilization among concession beneficiaries only, whereas the other stud-ies considered the total population.45,46 The elderly population has often been found to account for the highest drug consumption.23,47 In Australia, it was estimated that concession beneficiaries (25% of the population) receive ~80% of all PBS-subsidized medi-cations.22 Hence, the present study measured drug utilization in the small proportion of the population that consumes the most medication. The concession population (seniors and welfare recipients) was also chosen because they are a similar population group for future international comparisons; many other countries (eg, some provinces in Canada and some states in the United States) subsidize prescription medicines only in these populations.

This study found that a large segment of the concession-beneficiary population seemed to have re-ceived PPI prescriptions for a number of different clinical conditions not necessarily related to NSAID prescribing or to the conditions approved by the PBS. In 1998, McManus et al48 found in a cohort study that PPIs were largely prescribed outside of recom-mended indications.

April 2009 859

N. Barozzi and S.E. Tett

4. Laine L. The gastrointestinal effects of nonselective NSAIDs and COX-2-selective inhibitors. Semin Arthritis Rheum. 2002;32(Suppl 1):25–32.

5. Ehsanullah RS, Page MC, Tildesley G, Wood JR. Preven-tion of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: Controlled trial of ranitidine. BMJ. 1988;297:1017–1021.

6. Hudson N, Taha AS, Russell RI, et al. Famotidine for heal-ing and maintenance in nonsteroidal anti-inflammatory drug-associated gastroduodenal ulceration. Gastroenter- ology. 1997;112:1817–1822.

7. Yeomans ND, Tulassay Z, Juhász L, et al, for the Acid Sup-pression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med. 1998;338:719–726.

8. National Institute for Clinical Excellence. Guidance on the use of cyclo-oxygenase (COX) II selective inhibitors, cele-coxib, rofecoxib, meloxicam and etodolac for osteoarthri-tis and rheumatoid arthritis. http://www.nice.org.uk/nicemedia/pdf/coxiifullguidance.pdf. Accessed January 1, 2009.

9. Rostom A, Dube C, Wells G, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev. 2002;CD002296.

10. Furst DE. Meloxicam: Selective COX-2 inhibition in clini-cal practice. Semin Arthritis Rheum. 1997;26(Suppl 1):21–27.

11. Hawkey C, Kahan A, Steinbrück K, et al, for the Interna-tional MELISSA Study Group. Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. Meloxicam Large-scale International Study Safe-ty Assessment [published correction appears in Br J Rheu-matol. 1998;37:1142]. Br J Rheumatol. 1998;37:937–945.

12. Scheiman JM. Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors. Cleve Clin J Med. 2001;69(Suppl 1):SI40–SI46.

13. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000;284: 1247–1255.

14. Barclay L. Vioxx withdrawal prompts reevaluation of COX-2 inhibitor safety. Medscape Medical News. 2004. http:// www.medscape.com/viewarticle/490979?src=mp. Accessed March 12, 2009.

15. Lanas A. Review article: Recommendations for the clini- cal management of patients taking non-steroidal anti- inflammatory drugs—a gastroenterologist’s prospective. Aliment Pharmacol Ther. 2005;1:16–19.

16. Barozzi N, Tett SE. What happened to the prescribing of other COX-2 inhibitors, paracetamol and non-steroidal

Another limitation was related to the population sample considered. In Australia, concession beneficia-ries account for ~25% of the population. The advan-tage in this selection is that all claims processed would have been captured because the costs of all medica-tions are higher than copayment level, and also, as men-tioned earlier, this population (seniors and welfare re-cipients) is comparable to those in other countries that subsidize prescription medicines for a limited popula-tion. A disadvantage of including general beneficiaries from the Australian population is that one cannot capture those prescriptions (eg, for H2RAs) that fall under the copayment level (currently, AUD $30.70).

The data gathered for this study described a group of people (ecologic study) rather than individuals, with the assumption that all members of the popula-tion studied shared the same potential for exposure to gastroprotective drugs, NSAIDs, and COX-2 inhibi-tors. However, there may be differences within the population group.59,60 An ecologic approach was per-tinent in this case to analyze the exposures of interest because Australian concession beneficiaries have been studied previously and compared with other interna-tional groups in pharmacoepidemiologic studies.16,61 Ecologic approaches avoid the problem of response bias because all individuals aggregated as the popula-tion sample are available for analysis.62

CONCLUSIONSPrescribing of H2RAs decreased while the prescribing of PPIs increased between 1997 and 2006 in this population of concession beneficiaries in Australia. During the same period, ns-NSAID prescribing de-creased while COX-2 inhibitor prescribing increased.

REFERENCES 1. North of England Dyspepsia Guideline Development

Group. Dyspepsia: Managing dyspepsia in adults in pri-mary care 2004. http://www.nice.org.uk/nicemedia/pdf/CG017fullguideline.pdf. Accessed January 1, 2009.

2. The Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, The Pharmaceutical Society of Australia, The Royal Australian College of General Practitioners. Australian Medicines Handbook 2007. http://amh.hcn.net.au/. Accessed October 25, 2007.

3. Therapeutic Guidelines: Gastrointestinal Expert Group. Therapeutic Guidelines Gastrointestinal Version 4, 2006. Mel-bourne, Australia: Therapeutic Guidelines Ltd; 2006. http://www.tg.org.au/index.php?sectionid=45. Accessed March 12, 2009.

860 Volume 31 Number 4

Clinical Therapeutics

health.gov.au/internet/main/ publishing.nsf/Content/health-pbs-general-pricing-pbparpt.htm. Accessed March 12, 2009.

33. Lindberg P, Keeling D, Fryklund J, et al. Review article: Esomeprazole—enhanced bioavailability, specificity for the proton pump and inhibition of acid secretion. Aliment Pharmacol Ther. 2003;17:481–488.

34. Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole (40 mg) com-pared with lansoprazole (30 mg) in the treatment of erosive esophagi-tis. Am J Gastroenterol. 2002;97:575– 583.

35. Richter JE, Kahrilas PJ, Johanson J, et al, for the Esomeprazole Study Investigators. Efficacy and safety of esomeprazole compared with ome- prazole in GERD patients with ero-sive esophagitis: A randomized con-trolled trial. Am J Gastroenterol. 2001;96:656–665.

36. Kahrilas PJ, Falk GW, Johnson DA, et al, for the Esomeprazole Study Investigators. Esomeprazole improves healing and symptom resolution as compared with omeprazole in re-flux oesophagitis patients: A ran-domized controlled trial. Aliment Pharmacol Ther. 2000;14:1249–1258.

37. McDonagh MS, Carson S. Drug class review on proton pump inhibitors. Updated final report. Portland, Ore: Oregon Evidence-Based Practice Center; 2004.

38. Soga T, Matsuura M, Kodama Y, et al. Is a proton pump inhibitor nec-essary for the treatment of lower-grade reflux esophagitis? J Gastro- enterol. 1999;34:435–440.

39. Rackoff A, Agrawal A, Hila A, et al. Histamine-2 receptor antagonists at night improve gastroesophageal re-flux disease symptoms for patients on proton pump inhibitor therapy. Dis Esophagus. 2005;18:370–373.

40. Australian Government, Depart-ment of Health and Ageing. Phar-maceutical Benefits Scheme. 2007.

41. Australian Government, Australian Institute of Health and Welfare.

Modelling Our Future: Population Age-ing, Health, and Aged Care. Boston, Mass: Elsevier; 2003:169–196.

23. Nair B. Older people and medica-tions: What is the right prescrip-tion? Australian Prescriber. 1999;22: 130–131.

24. The University of Adelaide. Disci-pline of General Practice. Medic-GP: Overview 2007. http://www.adelaide.edu.au/health/gp/units/medic-gp/overview/. Accessed De-cember 27, 2007.

25. Australian General Practice Statistics and Classification Centre (AGPSCC). The BEACH project. Bettering the Evaluation and Care of Health [AGPSCC Web site]. http://www.fmrc.org.au/beach.htm. Accessed December 27, 2007.

26. Gastroenterological Society of Aus-tralia. NSAID therapy—maximizing the benefit, minimizing the risk. GESA; 2004. http://www.gesa.org.au/members_booklets/nsaid/NSAIDTherapy.pdf. Accessed May 12, 2007.

27. Bergman U, Popa C, Tomson Y, et al. Drug utilization 90%—a simple method for assessing the quality of drug prescribing. Eur J Clin Pharma-col. 1998;54:113–118.

28. WHO Collaborating Centre for Drug Statistics Methodology (WHOCC). Use and misuse. http://www.whocc.no/atcddd/use_misuse. html. Accessed March 12, 2009.

29. National Prescribing Centre. Pre-scribing antiplatelet drugs in pri-mary care. MeReC Bulletin. 2004;15: 21–24.

30. Creutzfeldt W. Chiral switch, a suc-cessful way to drug development: Ex-ample of esomeprazole [in German]. Z Gastroenterol. 2000;38:893–897.

31. Angell M. The Truth About the Drug Companies: How They Deceive Us and What To Do About It. Melbourne, Australia: Scribe Publications; 2006.

32. Australian Government, Depart-ment of Health and Ageing. Phar-maceutical Benefits Pricing Authori- ty. Annual Reports. http://www.

anti-inflammatory drugs when rofe-coxib was withdrawn in Australia? Pharmacoepidemiol Drug Saf. 2007;16: 1184–1191.

17. National Prescribing Service. Pro-ton pump inhibitors: Too much of a good thing? NPS News 2004:33. Sydney, Australia: National Prescrib-ing Service Limited; 2004. http://www.nps.org.au/__data/assets/pdf_file/0016/15820/news33.pdf. Accessed March 12, 2009.

18. Australian Government, Depart-ment of Health and Ageing. Phar-maceutical Pricing Section Pharma-ceutical Benefits Branch. Expenditure and prescriptions: Twelve months to 31 December 2005. http://www.health.gov.au/internet/wcms/publishing. nsf/Content/1CF96D8028AE509ECA2570BA001AC076/$File/complete. pdf. Accessed October 9, 2007.

19. Australian Department of Health and Aged Care. Australian Statistic on Medicines 1997. http://www.health.gov.au/internet/wcms/ publishing.nsf/Content/health-pbs-general-pubs-asm.htm/$FILE/asm97.pdf. Accessed October 25,

2007.20. World Health Organization. ATC

index with DDDs. Oslo, Norway: Collaborating Centre for Drug Sta-tistics Methodology; 2006. Phar-maceutical consumption by DDDs. http://www.ecosante.org/OCDEENG/ 720020.html. Accessed March 12, 2009.

21. Commonwealth Department of Health and Family Services. Austra-lian Statistics on Medicines 1997. http://www.health.gov.au/internet/ main/Publishing.nsf/Content/health-pbs-general-pubs-asm.htm/$FILE/asm97.pdf. Accessed March 12, 2009.

22. Brown L, Abello A, Phillips B, Hard-ing A. The Australian Pharmaceuti-cals Benefit Scheme and Older Aus-tralians: Changes in Government Outlays and Consumer Costs from the 2002–03 Federal Budget Mea-sures. In: Gupta A, Harding A, eds.

April 2009 861

N. Barozzi and S.E. Tett

57. Australian Government, Depart-ment of Health and Ageing, Phar-maceutical Pricing Section Pharma-ceutical Benefits Branch. Expenditure and prescriptions: Twelve months to 31 December 2003. http://www.health. gov.au/internet/main/Publishing.nsf/Content/3CC2D4DF821FE5ADCA2570F40005B9B1/$File/pb-dec03.pdf. Accessed March 12, 2009.

58. Australian Government, Department of Health and Ageing. PBS pricing. Administrative guideline on the scope of the 12.5% price reduction policy (Updated July 2005). http://www.health.gov.au/internet/main/ publishing.nsf/Content/health-pbs-pricing-adminguide. Accessed March 12, 2009.

59. Cooke C, Nissen L, Sketris I, Tett SE. Quantifying the use of the statin antilipemic drugs: Comparisons and contrasts between Nova Scotia, Canada, and Queensland, Australia. Clin Ther. 2005;27:497–508.

60. Tett SE, Smith AJ, Sketris I, et al. A comparison of benzodiazepine and related drug use in Nova Scotia, Can-ada and Australia. Abstract 108. Pre-sented at: 4th Canadian Therapeutics Congress; Halifax, Nova Scotia; May 27–30, 2007. http://www.cjcp.ca/pdf/4thcongress_F_may11correct.pdf. Accessed March 12, 2009.

61. McManus P, Primrose JG, Henry DA, et al. Pattern of non-steroidal anti-inflammatory drug use in Aus-tralia 1990–1994. A report from the Drug Utilization Sub-Committee of the Pharmaceutical Benefits Advi-sory Committee. Med J Aust. 1996; 164:589–592.

62. Strom B. Pharmacoepidemiology. 4th ed. Bognor Regis, United Kingdom: John Wiley & Sons; 2005.

2005. http://www.agenziafarmaco.it/ATTIVITA_EDITORIALE/section 8bd4.html?target=&area_tematica= ATTIVITA_EDITORIALE%C2%A7ion_ code=AIFA_PUB_PFN&entity_id=111.19977.1133834662520. Accessed March 12, 2009.

51. PharmaCare. BC PharmaCare News-letter. 2005;05:1–3.

52. Nova Scotia Department of Com-munity Services. Proton pump inhibitors—policy changes. May Bulletin 2003.

53. National Prescribing Service. GORD and non-ulcer dyspepsia—symptoms and risk factors. NPS News 2001:14. Sydney: National Prescribing Ser-vice Limited; 2001. http://www.nps.org.au/__data/assets/pdf_file/0005/15782/news14.pdf. Ac-cessed March 12, 2009.

54. National Prescribing Service Limited (NPS). NPS News 46: Proton pump inhibitors [NPS Web site]. http://w w w . n p s . o r g . a u / h e a l t h _ professionals/publications/nps_new s/cur r ent/nps_new s_46/ proton_pump_inhibitors. Accessed March 12, 2009.

55. Australian Government, Depart-ment of Health and Ageing. Aus- tralian Statistics on Medicines 2003. http://www.health.gov.au/internet/ main/Publishing.nsf/Content/872454 E0BDD67CA5CA257110000A95FD/ $File/Stats%20on%20Medicines.pdf. Accessed March 12, 2009.

56. Australian Government, Depart-ment of Health and Ageing. Aus- tralian Statistics on Medicines 2001– 2002. http://www.health.gov.au/internet/main/Publishing.nsf/ Content/hea l th-pbs-genera l - pubs-asm.htm/$FILE/asm01.pdf. Accessed March 12, 2009.

Australian Hospital Statistics 2001–02. http://www.aihw.gov.au/publications/index.cfm/title/8881. Accessed March 12, 2009.

42. Therapeutic Guidelines: Gastroin-testinal Writing Group. Therapeutic Guidelines: Gastrointestinal. 3rd ed. Melbourne, Australia: Therapeutic Guidelines Ltd; 2002.

43. Inadomi JM, McIntyre L, Bernard L, Fendrick AM. Step-down from multiple- to single-dose proton pump inhibitors (PPIs): A prospective study of patients with heartburn or acid regurgitation completely relieved with PPIs. Am J Gastroenterol. 2003; 98:1940–1944.

44. Therapeutic Guidelines: Analgesic Writing Group. Therapeutic Guide-lines: Analgesic. 4th ed. Melbourne, Australia: Therapeutic Guidelines Ltd; 2002.

45. Girvin B, Rafferty T, Stevenson M, Johnston GD. Uptake of COX-2 se-lective inhibitors and influence on NSAID prescribing in Northern Ire-land. Pharmacoepidemiol Drug Saf. 2004;13:153–157.

46. National Agency for Medicines [Fin-land]. Drug consumption statistics. 2007. http://www.nam.fi/english/medicines/drug_consumption/ index.html. Accessed October 24, 2007.

47. Jackson SH, Mangoni AA, Batty GM. Optimization of drug prescrib-ing. Br J Clin Pharmacol. 2004;57: 231–236.

48. McManus P, Marley J, Birkett DJ, Lindner J. Compliance with restric-tions on the subsidized use of pro-ton pump inhibitors in Australia. Br J Clin Pharmacol. 1998;46:409–411.

49. Parliament of Australia, Parliamen-tary Library. Rickard M. The phar-maceutical benefits scheme: Op-tions for cost control. Current Issues Brief no. 12, 2001–02. http://www.aph.gov.au/library/Pubs/CIB/ 2001-02/02cib12.htm. Accessed March 12, 2009.

50. Agenzia Italiana del Farmaco. Pron-tuario Farmaceutico Nazionale

Address correspondence to: Nadia Barozzi, PhD, School of Pharmacy, University of Queensland, Steele Building, Brisbane QLD 4072, Australia. E-mail: nbarozzi@gmail.com