Celecoxib versus Non-COX-2 Selective Non-steroidal Anti … · Proton Pump Inhibitors: Clinical...

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TITLE: Celecoxib versus Non-selective Non-steroidal Anti-Inflammatory Drugs and Proton Pump Inhibitors: Clinical Effectiveness, Safety, and Cost-Effectiveness

DATE: 07 December 2011 CONTEXT AND POLICY ISSUES Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in controlling the symptoms of arthritis, including osteoarthritis (OA) and rheumatoid arthritis (RA), low back pain and soft tissue pain, by blocking cyclooxygenase (COX) enzymes.1-3 OA is a chronic condition that involves the degeneration of cartilage between the joints. It is the most common form of arthritis and is associated with pain, substantial disability and a poor quality of life.3 RA is a systemic auto-immune disorder that involves persistent joint inflammation.4 Two COX isoenzymes (COX-1 and COX-2) play important roles in the effects of NSAIDs. COX-1 mediates the mucosal protection of the gastrointestinal (GI) mucosa, while COX-2 is found throughout the body, including joint and muscle, and mediates effects on pain and inflammation. Generally, NSAIDs are classified into two categories. One is non-COX-2 selective NSAIDs (nsNSAIDs, or conventional NSAIDs, such as ibuprofen, naproxen and dichofenac), which blocks both COX-1 and COX-2 enzymes and can cause GI bleeding. The other is COX-2 selective NSAIDs (mainly celecoxib) that targets only the COX-2 enzyme, which are deemed safer with regard to GI bleeding than nsNSAIDs.3,5 Studies, however, found that they increase the risk of cardiovascular (CV) adverse events.6-8 Celecoxib has been approved in Canada since 19999 and is the main COX-2 inhibitor currently available in Canada. nsNSAIDs, such as naproxen, ibuprofen and diclofenac have been available in Canada since 1994.9 Proton pump inhibitors (PPIs, for example, omeprazole, esomeprazole and lansoprazole) have been available in Canada since 1989.10 In recent years, more patients with OA or RA who require anti-inflammatory treatment were taking celecoxib than nsNSAIDs.11 nsNSAIDs may cause serious gastric adverse events with continuous usage. PPIs are reported to reduce the risk of NSAID-induced gastric and duodenal ulcers.12 Celecoxib is associated with a lower GI side effect profile compared with nsNSAID, but it may be more costly.13 Currently, both celecoxib and co-therapy of nsNSAIDs and PPIs, such as omeprazole, esomeprazole and lansoprazole, are recommended for NSAIDs users with upper gastrointestinal (UGI) and CV risk factors.1,2,14,15

http://en.wikipedia.org/wiki/Non-steroidal_anti-inflammatory_drug

Celecoxib versus NSAIDs with PPIs 2

In the United States, there are an estimated 16,500 annual deaths due to NSAID-induced GI complications.8 Considering the higher cost for celecoxib versus the lower cost of PPIs to treat GI complications, there is an increasing need to understand the cost-effectiveness of celecoxib comparing with nsNSAIDs plus PPIs in the management of RA and OA. The purpose of this review is to evaluate the clinical effectiveness, safety and cost-effectiveness of celecoxib relative to combination therapy of nsNSAIDs and PPIs in adult patients with OA or RA, or other diseases that require pain management. This report is an upgrade of a previous summary of abstracts, “Celecoxib versus Non-selective Non-Steroidal Anti-Inflammatory Drugs and Proton Pump Inhibitors: Clinical Effectiveness, Safety, and Cost Effectiveness”. RESEARCH QUESTIONS 1. What is the comparative clinical effectiveness of celecoxib versus combination non-COX-2

selective non-steroidal anti-inflammatory drugs and proton pumps inhibitors for pain management in adult patients?

2. What is the evidence for the safety of celecoxib compared with combination non-COX-2


3. What is the cost-effectiveness of celecoxib compared with combination non-COX-2


KEY MESSAGE Limited evidence showed that celecoxib versus non-COX-2 selective non-steroidal anti-inflammatory drugs (nsNSAIDs) and proton pumps inhibitors (PPIs) had a similar clinical efficacy and safety profile. nsNSAIDs plus PPIs may be marginally more cost-effective versus celecoxib in the management of adult patients with rheumatoid arthritis or osteoarthritis. METHODS Literature Search Strategy This report makes use of a literature search conducted for a previous CADTH report. The original literature search was conducted in September 2011on key resources including PubMed, The Cochrane Library (2011, Issue 9), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit retrieval by study type. Where possible, retrieval was limited to the human population. The initial search was also limited to English language documents published between January 1, 2001 and September 6, 2011. For the current report, the PubMed database search was rerun on November 9 to capture any articles published since the initial search date. The search of major health technology agencies was also updated to include documents published since September 2011. Rapid Response reports are organized so that the evidence for each research question is presented separately.


Selection Criteria and Methods One reviewer screened the titles and abstracts of the retrieved publications, and evaluated the full-text publications for the final article selection, according to the selection criteria present in Table 1. Table 1: Selection Criteria

Population

Adult patients with osteoarthritis, rheumatoid arthritis or other conditions requiring pain management

Intervention

Celecoxib

Comparator

nsNSAIDs in combination with PPIs

Outcomes

Clinical benefit (for example, pain reduction) Adverse events (mainly interested in gastrointestinal events, but would like to include any adverse events) Economic evaluation

Study Designs

HTA/SR/MA, RCT for clinical efficacy, safety Non-RCT for safety only Economic evaluations

HTA=health technology assessment, SR=systematic review; RCT= randomized controlled trial; nsNSAIDs= non selective non-steroidal anti-inflammatory drugs; PPIs= proton pump inhibitors.

Exclusion Criteria Studies were excluded if they did not meet the selection criteria, were duplicate publications, were abstracts or conference proceedings, or were published prior to 2001. Critical Appraisal of Individual Studies SIGN 50 check lists16,17 and Drummond’s checklist18,19 were used to assess the methodological quality for RCTs, non-randomized studies and economic evaluation reports, respectively. SUMMARY OF EVIDENCE: Quantity of Research Available The literature search from November 9, 2011, yielded 124 citations. Upon screening titles and abstracts, 103 citations were excluded, and 21 potentially relevant articles were retrieved for full-text review. Of the 21 potentially relevant reports, 10 did not meet the inclusion criteria. Six articles representing five RCTs, one non-RCT and four economic evaluations were included in this review.20-30 The study selection process is outlined in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart (Appendix 1).


Summary of Study Characteristics Comparative Clinical Effectiveness and Safety of Celecoxib versus Combination nsNSAIDS and PPIs The main characteristics of the included studies for clinical effectiveness and safety are summarized in Appendix 2. Five RCTs and one non-RCT were identified that reported clinical effectiveness and safety. The sample sizes of RCTs ranged from 242 to 4,484 patients, and the trial duration ranged from 12 weeks to six months. All RCTs compared celecoxib with nsNSAIDs plus PPIs in adult patients with OA or RA. The main outcomes of interest were pain reduction, recurrent GI events risk reduction and adverse events, such as dyspepsia.

Hochberg et al.21 reported the clinical efficacy of celecoxib and fixed dose combination of enteric-coated naproxen and esomeprazole for knee osteoarthritis from two 12-week RCTs. The two double-blind multi-centre phase III RCTs included patients with symptomatic knee osteoarthritis (aged 50 years or older). Following an OA flare up, patients received naproxen/esomeprazole or celecoxib for 12 weeks. In one trial (Study 307), 619 patients were randomized in either treatment arm and 614 were treated. In the other trial (Study 309), 615 patients were randomized and 610 were treated. In 2004, Lai et al.23 compared the efficacy of celecoxib with that of naproxen and lansoprazole co-therapy in the reduction of ulcer relapse in patients with a history of NSAID-related peptic ulcers. After healing of ulcers and eradication of Helicobacter pylori, patients were randomly assigned to celecoxib 200 mg daily (n = 120) or naproxen 750 mg daily and lansoprazole 30 mg daily (n = 122) for 24 weeks. Two publications by Chan et al.20,24 reported the findings from one RCT, which evaluated the ulcer incidence in patients on celecoxib or combination therapy of diclofenac plus omeprazole. Two-hundred and eighty-seven patients with NSAIDs-related ulcer bleeding were included. After ulcer healing, Helicobacter pylori negative patients were randomized to celecoxib 200 mg bid or combination therapy of diclofenac 75 mg bid plus omeprazole 20 mg once daily for 6 months. Endoscopy was performed if they developed recurrent bleeding or at the last follow-up visit for patients without recurrent events. In a 6-month, multi-nation, multi-centre and double-blinded RCT, Chan et al.22 compared the risk of GI events associated with celecoxib versus diclofenac plus omeprazole. The study included 4,484 patients with OA or RA with an increased GI risk, Helicobacter pylori negative, aged 60 years and older or 18 years or older with previous gastroduodenal ulceration. They were randomized to receive celecoxib 200 mg twice a day (n=2,238) or diclofenac 75 mg bid, plus omeprazole 20 mg qd (n= 2,246). The primary endpoint was clinically significant upper or lower GI events defined as GI bleeding, obstruction and perforation. Analysis was done by using intention to treat population. Targownik et al.26 performed a population-based matched case-control analysis based on Manitoba Population Health Research Data Repository. There were 1,382 nsNSAIDs or COX-2 inhibitor users with upper GI complications admitted to the hospital with a primary diagnosis for an upper GI complication. These patients were matched with 33,957 age- and sex-matched controls in the community. Conditional logistic regression analysis was used to determine the


relative efficacy of different gastroprotective strategies, such as PPIs, celecoxib, either alone or in combination and to adjust for multiple pertinent covariates.

Cost-Effectiveness of Celecoxib versus Combination nsNSAIDs and PPIs The detailed characteristics of the included economic evaluations are presented in Appendix 3. Four articles27-29,31 that reported seven economic evaluations 27-29,32-35 were identified. One study was conducted in Hungary in 2009,27 one in The Netherlands in 2008,29 and one in the UK in 2008.28 One HTA report31 presented four individual economic evaluations studies. Among these studies, one was published in Canada (2001),33 one in USA(2002),35 one in Switzerland (2001),32 and one in Hong Kong, China (2002).34 Time horizon ranged from six months32-34 to five years.28 These reports compared the cost effectiveness of celecoxib with nsNSAIDs plus PPIs, directly or indirectly.

Inotai et al.27 evaluated the cost-effectiveness of celecoxib and nsNSAIDs plus PPIs. A decision tree model was developed, with a one year time horizon, to simulate cohorts within celecoxib, nsNSAIDs and nsNSAIDs plus PPIs. The effectiveness of the different active agents of NSAIDs in therapeutically relevant doses was assumed to be the same. On the other hand, differences were observed in the side effect profile of the drugs, such as GI ulcers and bleeding. The direct medical costs and costs related to adverse events were calculated to measure the cost of an increase in health gain or quality-adjusted life-year (QALY), and the incremental cost-effectiveness ratio (ICER) was reported. In the 2008 HTA , Chen et al.28 reviewed the cost-effectiveness of celecoxib and nsNSAIDs (ibuprofen or diclofenac) plus PPI for OA and RA. Systematic reviews of RCTs and a model-based economic evaluation were undertaken. The model was designed to run in two forms: the ‘full Assessment Group Model (AGM)’, which included an initial drug switching cycle, and the ‘simpler AGM’, where an initial cycle and opportunities for the patient to switch NSAIDs were not included. In 2008, Al et al.29 assessed the costs and upper GI side effects of celecoxib and nsNSAIDs plus PPIs for patients with OR in The Netherlands. A model was used to convene data from various sources on the probability of GI side effects and resource use. The probabilities of GI side effects for celecoxib and NSAIDs alone were derived from trial data. The calculations were based on six months of treatment and were from a societal perspective. An extensive probabilistic sensitivity analysis was performed to address uncertainty. In a 2006 HTA, Brown et al.30 assessed the costs of celecoxib and nsNSAIDs plus PPIs for the prevention of NSAIDs-induced GI events. Four economic evaluations32-35 that examined the cost-effectiveness of celecoxib and nsNSAIDs plus PPIs were included. The data were reported individually. A probabilistic decision-analytic model was designed and populated with data to carry out incremental economic analysis. No ICER was reported. Summary of Critical Appraisal The strengths and limitations of all included studies in the report are summarized in Appendix 4.


Overall, the research questions were adequately addressed in all RCTs. Randomization and double blind process, dropout and Intention to treat (ITT) analysis were well reported except one,23 in which the double blind was not reported. The non-RCT26 adjusted the results for potential confounding factors. The economic evaluations were also well conducted in terms of study design, data collection, data analysis and interpretation. The ICERs of nsNSAIDs plus PPIs compared with celecoxib, however, was not reported in the majority of included studies.29,32-

35

Summary of Findings Five RCTs published in six articles20-25 and one non-RCT26 study was identified evaluating the comparative clinical effectiveness and safety compared celecoxib with nsNSAIDs plus PPIs. The main findings were summarized below and in Appendix 5. Comparative Clinical Effectiveness of Celecoxib versus nsNSAIDs plus PPIs Pain Reduction In 2011, Hochberg et al.21 evaluated the efficacy of celecoxib in pain reduction compared with fixed dose combination of naproxen plus omeprazole. The primary outcomes measured were mean change from baseline to week 12 using Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain and function subscales, and Patient Global Assessment of osteoarthritis using a visual analog scale (PGA-VAS). It was reported that, after 12 weeks, both naproxen/esomeprazole and celecoxib were associated with improvements (least squares mean change from baseline to week 12) in WOMAC pain (Study 307: -42.0 and -41.8, respectively; Study 309: -44.2 and -42.9, respectively), WOMAC function (Study 307: -36.4 and -36.3, respectively; Study 309: -38.9 and -36.8, respectively), and PGA-VAS (Study 307: 21.2 and 21.6, respectively; Study 309: 29.0 and 25.6, respectively). A pre-specified non-inferiority margin of 10 mm between naproxen/esomeprazole and celecoxib was satisfied for each co-primary endpoint at week 12 in both studies. The authors concluded that naproxen/esomeprazole showed comparable efficacy to celecoxib for the management of pain associated with osteoarthritis of the knee over 12 weeks.

Prevention of GI Ulcer or Bleeding Relapse

In 2004, Lai et al.23 compared the efficacy of celecoxib with that of naproxen and lansoprazole combination therapy in the reduction of ulcer relapse in patients with a history of NSAID-related peptic ulcers. The primary endpoint was recurrent ulcer complications. During a median follow-up of 24 weeks, it was found that four patients [3.7%, (95% CI: 0.0% to 7.3%)] in the celecoxib group, compared with seven patients [6.3%, (95% CI 1.6% to 11.1%)] in the naproxen plus lansoprazole group, developed recurrent ulcer complications [absolute difference -2.6%; (95% CI: -9.1% to 3.7%)]. The margin for the non-inferiority was defined as less than 7% for the upper limit of the 95%CI for the difference between the two treatment groups. The results suggested that celecoxib was statistically non-inferior to naproxen-lansoprazole co-therapy in the prevention of recurrent ulcer complications. The author concluded that celecoxib was as effective as the naproxen-lansoprazole co-therapy in the prevention of recurrences of ulcer complications in patients with a history of NSAID-related complicated peptic ulcers.

Chan et al.20,24 reported the findings from one RCT, which evaluated the ulcer incidence in patients on celecoxib or combination therapy of diclofenac plus omeprazole. No statistically


significant difference was found in the rate of recurrent ulcers in six months [celecoxib: 18.7% and diclofenac plus omeprazole: 25.6%; difference between groups: -6.7%; (95% CI: -17.8% to 3.9%; P = 0.21)]. Recurrent ulcer bleeding occurred in seven patients [4.9 % (95% CI: 3.1 to 6.7) receiving celecoxib and in nine patients (6.4 % (95% CI, 4.3 to 8.4)) receiving diclofenac plus omeprazole [difference, 1.5 % (95 %CI: 6.8 to 3.8)]. The authors concluded that celecoxib was as effective as diclofenac plus omeprazole in terms of prevention of recurrent bleeding in patients with a recent history of ulcer bleeding.

In a 6-month, multi-nation, multi-centre and double-blind RCT, Chan et al.22 compared the risk of GI events associated with celecoxib versus diclofenac plus omeprazole. It was found that 20 patients (0.9%) receiving celecoxib and 81 patients (3.8%) receiving diclofenac plus omeprazole reported upper or lower GI events [hazard ratio 4.3, (95% CI: 2.6 to 7.0); p<0.0001)]. One-hundred and fourteen patients (6%) treated with celecoxib versus 167 patients (8%) receiving diclofenac plus omeprazole withdrew before the trial ended because of GI adverse events (p=0.0006). It was indicated that the risk of GI events was statistically significant lower in patients treated with celecoxib than in those receiving a diclofenac plus a PPI. In the case-control study, Targownik et al.26 found that, compared with nsNSAIDs alone, the adjusted odds ratio for overall upper GI complications was 0.67 (95% CI 0.48 to 0.95) (P<0.01) in nsNSAIDs plus PPIs group and 0.39 (0.32 to 0.48) P<0.01) in celecoxib group respectively. The findings suggested that celecoxib may be superior to the combination of nsNSAIDs with a PPI in the prevention of overall GI complications in patients with a history of GI bleeding, perforation or systematic ulcers. Comparative Safety of Celecoxib versus nsNSAIDs plus PPIs Dyspepsia and Other Adverse Events

Cryer et al.25 compared celecoxib with fixed dose combination of naproxen plus omeprazole in the treatment of patients with OR. It was found that, at the end of 12-week treatment, Modified Severity of Dyspepsia Assessment (mSODA) scores improved in each group, with no significant treatment differences between celecoxib and naproxen/esomeprazole. UGI AE incidence (Study 307: 17.3%; Study 309: 20.3%) was also similar between treatment groups. However, significantly more heartburn-free days was reported in naproxen/esomeprazole treated patients compared with celecoxib.

In 2004, Lai et al.23 reported that, during a median follow-up of 24 weeks, more patients in celecoxib group [15.0%, (95% CI 9.7 to 22.5)] experienced dyspepsia than those receiving naproxen- lansoprazole (5.7%, 95% CI 2.8 to11.4, P = .02).

Chan et al.20,24 also reported that more patients experienced dyspepsia in patients on celecoxib compared with diclofenac plus omeprazole [hazard ratio 5.3%, (95% CI: 2.6 to 10.8) ]. Cost-Effectiveness of Celecoxib versus nsNSAIDs plus PPIs Seven studies27-29,32-35 presented in four publications27-30 were found. The findings were summarized below and Appendix 6.


Inotai et al.27 evaluated the cost-effectiveness of Celecoxib and nsNSAIDs plus PPIs. It was reported that nsNSAIDs plus PPIs dominated celecoxib since celecoxib had higher costs and was less effective. In one 2008 HTA, Chen et al.28 reviewed the cost-effectiveness of celecoxib and nsNSAIDs (ibuprofen or diclofenac) plus PPIs for OA and RA. It was found that celecoxib was dominated by ibuprofen or diclofenac combined with PPIs in most cases. In other words, nsNSAIDs plus PPIs is more cost effective compared with celecoxib. This result applies both to ‘standard’ (defined as patients without previous history of GI events) and ‘high-risk’ arthritis patients (defined as patients with previous GI ulcers). The author concluded that the economic models showed a wide range of possible costs per QALY gained in patients with OA and RA. In 2008, Al et al.29 assessed the costs and upper GI side effects of celecoxib and nsNSAIDs plus PPIs for patients with OR in The Netherlands. It was found that the total cost per six months of therapy was: 255 Euros per patient for celecoxib and 243 Euros per patient for nsNSAIDs plus PPIs. Treatment with celecoxib was associated with the lowest number of GI side effects and related deaths. ICERs for celecoxib versus nsNSAIDs plus PPIs were not reported although the author reported that celecoxib is preferred treatment strategy in patients with more than 1.5% probability to have at least one serious GI event in one year. In a 2006 HTA, Brown et al.30 presented the data from four economic evaluations.32-35 ICERs were not presented in the HTA for any of the four economic evaluations. The authors of the HTA concluded that the economic models suggested that nsNSAIDs plus PPIs was more cost-effective compared with other treatment strategies, including celecoxib, to avoid endoscopic ulcers in patients, who required long-term NSAIDs therapy . Limitations Firstly, the clinical studies were conducted in different countries between 2001 and 2010. Over time, the clinic management of patients with RA and OA has changed.36,37 Secondly, the comparator (nsNSAIDs and PPIs) agents, dosage, and reporting outcomes varied from study to study, so it is difficult to compare their findings. Thirdly, the study durations in the primary clinical trials were less than or equal to six months. As a result, the lack of long-term clinical outcomes, such as mortality and serious GI and CV adverse events, may lead to an inaccurate estimation of the clinical benefits and harms. Finally, several economic evaluations32-35 included in the HTA by Brown30,39 were published in 2001 or 2002, Therefore, their study findings must be interpreted with caution. Moreover, the analyses were conducted in different countries using various economic models, so their findings may not be transferable to the Canadian setting. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: Limited evidence showed that celecoxib and nsNSAIDs plus PPIs provided a similar clinical effectiveness and safety profile. It also indicated that nsNSAIDs plus PPIs may be marginally more cost-effective compared with celecoxib in the management of adult patients with RA or OA. The findings must be interpreted with caution. An economic evaluation that compares the cost-effectiveness of celecoxib with nsNSAIDs plus PPIs in the management of OA or RA in the Canadian context is required to determine the cost-effectiveness in Canada.


PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca REFERENCES

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23. Lai KC, Chu KM, Hui WM, Wong BC, Hu WH, Wong WM, et al. Celecoxib compared with lansoprazole and naproxen to prevent gastrointestinal ulcer complications. Am J Med. 2005 Nov;118(11):1271-8.

24. Chan FK, Hung LC, Suen BY, Wong VW, Hui AJ, Wu JC, et al. Celecoxib versus diclofenac plus omeprazole in high-risk arthritis patients: results of a randomized double-blind trial. Gastroenterology. 2004 Oct;127(4):1038-43.

25. Cryer BL, Sostek MB, Fort JG, Svensson O, Hwang C, Hochberg MC. A fixed-dose combination of naproxen and esomeprazole magnesium has comparable upper gastrointestinal tolerability to celecoxib in patients with osteoarthritis of the knee: Results from two randomized, parallel-group, placebo-controlled trials. Ann Med. 2011 Dec;43(8):594-605.

26. Targownik LE, Metge CJ, Leung S, Chateau DG. The relative efficacies of gastroprotective strategies in chronic users of nonsteroidal anti-inflammatory drugs. Gastroenterology. 2008 Apr;134(4):937-44.

27 . Inotai A, Mészáros A. Economic evaluation of nonsteroidal anti-inflammatory drug strategies in rheumatoid arthritis. Int J Technol Assess Health Care. 2009 Apr;25(2):190-5.

28. Chen YF, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, et al. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation [Internet]. Health Technol Assess. 2008 Apr [cited 2011 Nov 10];12(11):1-278, iii. Available from: http://www.hta.ac.uk/fullmono/mon1211.pdf

29. Al MJ, Maniadakis N, Grijseels EW, Janssen M. Costs and effects of various analgesic treatments for patients with rheumatoid arthritis and osteoarthritis in the Netherlands. Value Health. 2008 Jul;11(4):589-99.

30. Brown TJ, Hooper L, Elliott RA, Payne K, Webb R, Roberts C, et al. A comparison of the cost-effectiveness of five strategies for the prevention of non-steroidal anti-inflammatory

http://www.hta.ac.uk/fullmono/mon1211.pdf


drug-induced gastrointestinal toxicity: a systematic review with economic modelling. Health Technol Assess. 2006 Oct;10(38):iii-iv, xi-xiii, 1-183.

31. Engström A, Jacob J, Lundin D. Sharp drop in prices after the introduction of generic substitution [Internet]. Solna (SE): LFN: Pharmaceutical Benefits Board; 2006 Jun. [cited 2011 Dec 2]. Available from: http://ppri.oebig.at/Downloads/Sweden_EffectsGenericSubstitution.pdf

32. Chancellor JV, Hunsche E, de Cruz E, Sarasin FP. Economic evaluation of celecoxib, a new cyclo-oxygenase 2 specific inhibitor, in Switzerland. Pharmacoeconomics. 2001;19(Suppl 1):59-75.

33 . Zabinski RA, Burke TA, Johnson J, Lavoie F, Fitzsimon C, Tretiak R, et al. An economic model for determining the costs and consequences of using various treatment alternatives for the management of arthritis in Canada. Pharmacoeconomics. 2001;19(Suppl 1):49-58.

34. You JH, Lee KK, Chan TY, Lau WH, Chan FK. Arthritis treatment in Hong Kong--cost analysis of celecoxib versus conventional NSAIDS, with or without gastroprotective agents. Aliment Pharmacol Ther. 2002 Dec;16(12):2089-96.

35. El-Serag HB, Graham DY, Richardson P, Inadomi JM. Prevention of complicated ulcer disease among chronic users of nonsteroidal anti-inflammatory drugs: the use of a nomogram in cost-effectiveness analysis. Arch Intern Med. 2002 Oct 14;162(18):2105-10.

36. Kanis JA, Burlet N, Cooper C, Delmas PD, Reginster JY, Borgstrom F, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int [Internet]. 2008 Apr [cited 2011 Dec 2];19(4):399-428. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613968

37. Doan QV, Chiou CF, Dubois RW. Review of eight pharmacoeconomic studies of the value of biologic DMARDs (adalimumab, etanercept, and infliximab) in the management of rheumatoid arthritis. J Manag Care Pharm. 2006 Sep;12(7):555-69.

38. Maetzel A, Krahn M, Naglie G. The cost effectiveness of rofecoxib and celecoxib in patients with osteoarthritis or rheumatoid arthritis. Arthritis Rheum. 2003;49(3):283-92.

39. Brown TJ, Hooper L, Elliott RA, Payne K, Webb R, Roberts C, et al. A comparison of the cost-effectiveness of five strategies for the prevention of non-steroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling [appendices]. Health Technol Assess [Internet]. 2006 [cited 2011 Nov 28];10(38):184-401. Available from: http://www.hta.ac.uk/fullmono/mon1038a.pdf

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613968

http://www.hta.ac.uk/fullmono/mon1038a.pdf


APPENDIX 1: Selection of Included Studies

103 citations excluded

21 potentially relevant articles retrieved for scrutiny (full text, if

available)

0 potentially relevant reports retrieved from other sources (grey

literature, hand search)

21 potentially relevant reports

10 reports excluded: -irrelevant population (1) -irrelevant intervention (1) -irrelevant comparator (1) -duplicate publications (3) -other (e.g., review articles, editorials, etc.)(4)

11 reports included in review

124 citations identified from electronic literature search and

screened


Appendix 2: Characteristics of Included Studies on Clinical Effectiveness and Safety

First Author, Publication Year, Country

Study Design, Length of Follow-up

Patient Characteristics, Sample Size

Intervention Comparators Main Outcomes

Hochberg, 2011

21

USA

Two RCTs (Study 307 and Study 309) reported in this article 12 weeks

Patients with knee osteoarthritis (Study 307: n=619 Study 309: n=615)

Celecoxib (200mg qd)

Naproxen plus esomeprazole (fixed dose combination 500m/20mg, bid

Primary efficacy endpoints (mean change from baseline at end ) WOMAC pain and function subscales; PGA-VAS).

Cryer, 201125

USA

From the same RCT as Hochberg, 2011

21

Patients with knee osteoarthritis (Study 307: n=619 Study 309: n=615)

Celecoxib Naproxen plus esomeprazole (fixed dose combination)

Tolerability end-points mSODA); heartburn severity; UGI adverse events (AEs).

Chan, 201022

Hong Kong, China

RCT 6 months

Patients with OA or RA at increased GI event risk (n=4484)

Celecoxib (200mg bid)

Diclofenac plus omeprazole (75 mg bid plus omeprazole 20 mg qd)

Risk of GI events

Lai, 2005

23

RCT 24 weeks

Patients with OA or RA and a history of NSAID-related peptic ulcers (n=242)

Celecoxib 200mg qd

Naproxen plus lansoprazole (750mg/30mg qd)

Ulcer relapse

Chan, 2004

24

Hong Kong, China

RCT 6 months

Patients with arthritis and NSAIDs-associated ulcer bleeding. Randomized after healing of ulcers and eradication of Helicobacter pylori (N=287)

Celecoxib (200mg bid)

Diclofenac plus omeprazole (75 mg bid / 20 mg qd)

Ulcer relapse

Chan, 2002

20

Hong Kong, China

From the same RCT as Chan, 2004

24

Patients with arthritis and NSAIDs-associated ulcer bleeding; Randomized after healing of ulcers and eradication of Helicobacter pylori (n=290)

Celecox 200mg bid

Diclofenac plus omeprazole (75mg bid/20mg qd)

Recurrent ulcer bleeding

Targownik, 2008

26

Canada

Population-based matched case-control analysis

NSAID users admitted to the hospital for an upper GI complication (N=1382) matched to NSAID-using controls in the community( n=33,957)

Celecoxib nsNSAIDs plus PPIs Upper GI complications

AE=adverse events; bid=twice a day; qd.=once daily; GI=gastrointestinal; NSAID=non-steroidal anti-inflammatory drug; nsNSAIDs= non-COX-2-selective non-steroidal anti-inflammatory drugs; OA=osteoarthritis; PGA-VAS=patient global assessment-visual analogue scale; PPIs=proton pump inhibitors ; mSODA= Modified Severity of Dyspepsia Assessment; RA=rheumatoid arthritis; RCT=randomized controlled trials; WDAE=withdraw due to adverse events; WOMAC=Western Ontario and McMaster Osteoarthritis Index; UGI=upper gastrointestinal.


APPENDIX 3: Characteristics of Included Economic Evaluations First Author, Publication Year, Country

Study Design, Time horizon

Patient Characteristics, Sample Size

Intervention

Comparators

Assumptions

Inotai, 2009

27

Hungary

Economic evaluations, One year

RA patients; drug costs (euros) based on the average costs formulary named Pharmindex; All costs were originally calculated in HUFs (Hungarian forint), then converted to euro (2007)

Celecoxib nsNSAIDs plus PPIs

●Adopted a QALY value ●Utility values to be similar to QALY values for a 3-month period from Maetzel et al.(2003)

38

●The efficacy of the different active agents of NSAIDs in therapeutically relevant dose was assumed to be the same. ●Mortality rate for serious GI outcomes: 0.08 AMI mortality rate (dying because of AMI in 30 days): 0.192

Chen, 2008

28

UK

HTA, Economic evaluations, 5 years

OA or RA patients Celecoxib nsNSAIDs plus PPIs

●nsNSAIDs do not protect against the risk of MI ●Dyspepsia requiring medical consultation (base case value: 10.2%) ●Hospitalized if complicated UGI event (base case value: 62.7%) ●Symptomatic ulcer (3 months) – diclofenac (0.137%)

Al, 2008

29

The Netherlands

Economic evaluations, 6 months

OA or RA patients Celecoxib nsNSAIDs plus PPIs

●Serious GI events : probability: 0.0029, Relative risk: 0.5 Anemia: Probability: 0.0036 RR: 0.33

Brown, 2006

30,39

UK

HTA, Economic evaluations, 6 months to one year

4 reports were included

32-35

Celecoxib nsNSAIDs plus PPIs

●All NSAIDs (excluding aspirin) have greater efficacy than simple analgesics (such as paracetamol and codeine) in reducing pain and improving physical function. ●All NSAIDs (excluding aspirin and simple analgesics) are of equal efficacy based on equivalent dose.

AE=adverse events; AMI=acute myocardial infarction; GI=gastrointestinal; MI=myocardial infarction; mSODA= Modified Severity of Dyspepsia Assessment; NSAIDs=non-steroidal anti-inflammatory drugs; nsNSAIDs= non-COX-2 selective non-steroidal anti-inflammatory drugs; OA=osteoarthritis; PGA-VAS=patient global assessment-visual analogue scale; PPI=proton pump inhibitor; QALY=quality adjusted life year; RA=rheumatoid arthritis; WOMAC=Western Ontario and McMaster Osteoarthritis Index; UGI=upper gastrointestinal.


APPENDIX 4: Critical Appraisal of Included Studies

First Author, Publication Year

Strengths Limitations

Randomized Controlled Trials

Hochberg, 2011

21

●Research questions, randomization, allocation concealment, double blinding process, ITT were reported; ●Baseline characteristics were reported and were comparable between groups; ●Treatment under investigation is the only difference between groups; ●Dropout rate was approximately 9.5% and comparable between groups;

●Pain reduction scale was based on visual analogue scale; ●Whether the results for all sites were comparable: not reported;

Cryer, 2011

25

●Research questions, randomization, allocation concealment, double blinding process, ITT were reported; ●Baseline characteristics were reported and comparable; between groups; ●Treatment under investigation is the only difference between groups; ●Dropout rate was approximately 9.5% and comparable between groups;

●Pain reduction scale was based on visual analogue scale; ●Whether the results for all sites were comparable: not reported;

Chan, 2010

22

●Research questions, randomization, allocation concealment, double blinding process, ITT were reported; ●Baseline characteristics were reported and comparable between groups; ●Treatment under investigation is the only difference between groups; ●Main outcomes were assessed using validated measurements, such as GI bleeding and endoscopic ulcers;

●Dropout rate greater than 20% in both groups; ●Whether the results for all sites were comparable: not reported;

Lai, 2005

23

●Research questions, randomization, allocation concealment, ITT were reported; ●Baseline characteristics were reported and comparable between groups; ●Treatment under investigation is

●Open label




the only difference between groups; ●Dropout was approximately 2% and comparable between groups; ●Main outcomes were assessed using validated measurements, such as GI bleeding and endoscopic ulcers;

Chan, 2004

24

●Research questions, randomization, allocation concealment, double blinding process, ITT were reported ●Baseline characteristics were reported and comparable between groups; ●Dropout was approximately 6% and comparable between groups ●Main outcomes were assessed using validated measurements, such as GI bleeding and endoscopic ulcers

●Numeric imbalance in the number of patients receiving concomitant aspirin (5.2% in celecoxib arm and 12.3% in diclofenac plus omeprazole)

Chan, 2002

20

●Research questions, randomization, allocation concealment, double blinding process, ITT were reported ●Baseline characteristics were reported and comparable between groups; ●Dropout was approximately 6% and comparable between groups ●Main outcomes were assessed using validated measurements, such as GI bleeding and endoscopic ulcers

●Numeric imbalance in the number of patients receiving concomitant aspirin (5.2% in celecoxib arm and 12.3% in diclofenac plus omeprazole)

Non-randomized Study

Economic Evaluations

Inotai, 2009

27

●Research questions and selection criteria were reported; ●Sources of effectiveness estimates used were stated; ●Choice of model used and the key parameters on which it was based were justified;

●Decision tree models cannot handle the long-term effect of chronic diseases, such as RA; ●It was also unable to consider the increased risk after the recrudescence of peptic ulcer and acute ●The same hospitalization rate was used for peptic ulcer for all treatments arms, which may differ in the different therapeutic strategies; ●Conflict of interests declared;

Chen, 2008

28

●Research questions and selection criteria were reported; ●Sources of effectiveness

●Lack of consistency in the reporting safety events; ● The choice and dose of nsNSAIDs




estimates used were stated; ●Choice of model used and the key parameters on which it was based were justified; ● Conflict of interests declared;

varies from country to country; age restrictions and other exclusion criteria also limit generalizability and potential publication bias;

Al, 2008

29

●Research questions and selection criteria were reported; ●Sources of effectiveness estimates used were stated ●Choice of model used and the key parameters on which it was based were justified. ● Conflict of interests declared;

●Unrealistic 100% patient compliance was assumed, though it might be expected that the number of GI events would increase when adherence decreases; ●ICER not reported for the interested comparison;

Brown, 2006

30,39

●Research questions and selection criteria were reported; ●Sources of effectiveness estimates used were stated; ●Choice of model used and the key parameters on which it was based were justified; ●Conflict of interests declared;

● Drug cost data from four included studies based on the source of 2001-2002; Therefore, the conclusion from each individual study must be interpreted with caution. ●Very little information on the relative effectiveness between strategies owing to lack of head-to-head studies; ●Direct healthcare costs were available only as reported estimates from clinicians. There is little or no patient-based information about the resource use consequences of NSAID-related GI events;

AMI= myocardial infarction; GI=gastrointestinal; ICER=incremental cost effectiveness ratio; ITT=intention to treat analysis; NSAID=non-steroidal anti-inflammatory drug; nsNSAIDs= non-COX-2 selective non-steroidal anti-inflammatory drugs; PPIs=proton pump inhibitors.


Appendix 5: Main Study Findings and Authors’ Conclusions – Clinical Effectiveness and Safety


Main results Author’s Conclusions Celecoxib nsNSAID plus PPI

Hochberg, 2011

21

WOMAC pain score change from baseline: Study 307: -41.8; Study 309: -42.9; WOMAC function change from baseline Study 307: -36.3; Study 309: -36.8; PGA-VAS change from baseline Study 307: 21.6, Study 309: 25.6,

WOMAC pain score: change from baseline Study 307: -42.0 Study 309: -44.2 WOMAC function change from baseline Study 307: -36.4 Study 309: -38.9; PGA-VAS change from baseline Study 307: 21.2 Study 309: 29.0

Naproxen/esomeprazole has comparable efficacy to celecoxib in the management of pain associated with osteoarthritis of the knee over 12 weeks

Cryer, 2011

25

(Companion publication of Hochberg 2011

21)

(data expressed as mean change from baseline) mSODA Study 307: -4.8 Study 309: -3.3 Heartburn free days Study 307: 75.8% Study 309: 72.1% UGI AE Study 307: 16.9% Study 309: 21.6% Discontinuation due to UGI Study 307: 1.6% Study 309: 3.7% Discontinuation due to any AE Study 307: 6.6% Study 309: 9.0%

(data expressed as mean change from baseline) mSODA Study 307: -3.5 Study 309: -4.5 Heartburn free days Study 307: 83.9% Study 309: 78.4% UGI AE Study 307: 16.6% Study 309: 18.9% Discontinuation due to UGI Study 307: 1.2% Study 309: 0.8% Discontinuation due to any AE Study 307: 7.3% Study 309: 6.6%

mSODA: (Celecoxib vs. naproxen/esomeprazole) difference of change from baseline) were not significant; UGI AE incidence was also similar between treatment groups; Significantly more heartburn-free days was reported in naproxen/esomeprazole treated patients compared with celecoxib.

Chan, 2010

22

GI risk: # of patients (%) 20 (0.9%) (hazard ratio 4.3, 95% CI 2.6 to 7.0; p<0.0001 vs. nsNSAID plus PPIs) Withdrawal due to GI AE: 114 (6%) (p=0.0006 vs. nsNSAIDs plus PPI)

GI risk: # of patients (%) 81 (3.8%) Withdrawal due to GI AE: 167 (8%)

GI risk was lower with celecoxib than a diclofenac plus a PPI

Targownik, UGI complications UGI complications In terms of UGI



Main results Author’s Conclusions Celecoxib nsNSAID plus PPI

200826

(adjusted odds ratio (OR, 95%CI) compared with nsNSAIDs alone): 0.39 (0.32 to 0.48) P<0.01)

(adjusted odds ratio (OR, 95%CI) compared with nsNSAIDs alone): 0.67 (0.48 to 0.95) (P<0.01)

complication risk reduction, Celecoxib may be superior to nonselective NSAIDs plus a PPI.

Lai, 2005

23

Ulcer relapse at 24 weeks follow up: # of patients (%) 4 (3.7%, 95% CI: 0.0% to 7.3% Absolute difference betwee groups: -2.6%; 95% CI for the difference: -9.1% to 3.7%); GI events 22.5%

Dyspepsia

15.0%, 95% CI 9.7to 22.5)

(P = .02 vs. nsNSAID plus PPI

CV AE:

0.8%

Withdrawal:

5%

Ulcer relapse at 24 weeks follow up: # of patients (%) 7 (6.3%, 95% CI 1.6% to 11.1%)

GI events 15.6%

Dyspepsia

(5.7%, 95% CI 2.8 to11.4)

CV AE:

0.8%

Withdrawal:

4.1%

Efficacy was comparable in the prevention of ulcer relapse;

AE: more patients experienced dyspepsia in celecoxib arm

Chan, 2004

24

Rate of ulcers relapse in 6 months 18.7%(95CI: 11.3 to 26.1) Difference between groups: -6.7%; 95% CI: -17.8% to 3.9%) (P = 0.21). Dyspepsia (celecoxib vs. nsNSAIDs plus PPI) Hazard ratio: 5.3 95%CI 2.6 to 10.8 (P<0.001) Overall withdrawal rate 5.1% WDAE 3.4%

Rate of ulcers relapse in 6 months 25.6% (95%CI) 17.1-34.1) Overall withdrawal rate Similar to celecoxib group WDAE 6.6%

Efficacy: similar Dyspepsia: more in celecoxib arm

Chan, 2002

20

Recurrent ulcer bleeding 7 patients (4.9 %, 95% CI: 3.1 to 6.7) (difference between groups: 1.5 %( 95 %CI 6.8% to 3.8%). Dyspepsia 15.3% CV events 1.4% Renal adverse events 24.3 % WDAE 10.4%

Recurrent ulcer bleeding 9 patients (6.4 % , 95% CI, 4.3 to 8.4) Dyspepsia 8.4% CV events 1.4% Renal adverse events: 30.8% WDAE 9.8%

Efficacy: comparable: AE: similar

AE=adverse events; CV=cardiovascular; GI=gastrointestinal; UGI=upper gastrointestinal; nsNSAIDs= non-selective non-steroidal anti-inflammatory drugs; PPIs=proton pump inhibitors; WDAE=withdraw due to adverse events; WOMAC=Western Ontario and


McMaster Osteoarthritis Index; PGA-VAS=patient global assessment-visual analogue scale; mSODA= Modified Severity of Dyspepsia Assessment; QALY=quality adjusted life year;


Appendix 6 Main Findings of Economic Evaluations


Treatment Strategies

Cost per patientper time period

Incremental cost (nsNSAID +PPI – celecoxib)

Effectiveness

(QALYs)

Incremental

Effectiveness

(QALYs) nsNSAID +PPI – celecoxib)

ICER ( PER QALY

Inotai, 2009

27

Celecoxib 557.2 (Euro per patient per year)

0.6785 D*

nsNSAIDs plus PPIs

242.2 -315* 0.6808 0.0095*

Al, 2008

29

Celecoxib 255 (Euro per patient per six months)

NR NR NR

nsNSAIDs plus PPIs

243 -12 (euro)* NR NR NR

Four individual studies presented in Brown et al 2006 30,39

Chancellor, 2001

32

Celecoxib 435 (SwF per patient per six months)

NR NR NR NR

nsNSAIDs plus PPIs

1414.72 (SwF per patient per six months)

976.66* NR NR NR

Zabinski, 2001

33

Celecoxib 273 (CDN $ per patient per six months)

NR NR NR NR

nsNSAIDs plus PPIs

731 (CDN per patient per six months)

458* NR NR NR

You, 2002

34

Celecoxib 1545 (HK dollar per/patient per six months)

NR NR NR NR

nsNSAIDs plus PPIs

2,857 (HK $ per/patient per six months)

1321* NR NR NR

El-Serag, 2002

35

Celecoxib 1,029 (US $ per patient per year)

- NR NR NR

NsNSAIDs plus PPIs

1,632 (US $ per patient per year)

603* NR NR NR

Chen, 2008

28

For standard patients (without previous history of GI events)

Diclofenac + PPIs

970.56 (£/patient/year)

- 3.21803 - -

Celecoxib (LD)

1,455.04 (£/patient/year)

484.48 3.20100 –0.01703 D

Celecoxib 2,564.55 1,593.99 3.20100 –0.01703 D



Treatment Strategies

Cost per patientper time period

Incremental cost (nsNSAID +PPI – celecoxib)

Effectiveness

(QALYs)

Incremental

Effectiveness

(QALYs) nsNSAID +PPI – celecoxib)

ICER ( PER QALY

(HD)

Ibuprofen + PPI

950.38 3.22032

Celecoxib (LD)

1,455.04 504.66 3.20100 0.01932 D

Celecoxib (HD)

2,564.55 1,614.17 3.20100 –0.01932 D

For patients with previous history of GI events

Diclofenac + PPI

982.26 - 3.21537 - -

Celecoxib (LD)

1,455.79 473.53 3.19393 –0.02144 D

Celecoxib (HD)

2,540.73 1,558.47 3.19393 –0.02144 D

Ibuprofen + PPI

980.56 3.21380

Celecoxib (LD)

1,455.79 475.23 3.19393 –0.01987 D

Celecoxib (HD)

2,540.73 1,560.17 3.19393 –0.01987 D

D=celecoxib is dominated by nsNSAIDs plus PPIs. It indicates that compared with nsNSAIDs plus PPIs, Celecoxib is more expensive and less effective. LD=low dose; HD= high dose; NR=not reported; nsNSAIDs= non selective non-steroidal anti-inflammatory drugs; PPIs=proton pump inhibitors; QALY=quality adjusted life year; SwF= Swiss francs; HK =Hong Kong; CDN=Canadian; US=United States of American *Data were calculated based on reported data;

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