Economic analysis of treatments reducing coronary heart disease mortality in England and Wales, 2000-2010.

BACKGROUND: Coronary heart disease (CHD) in the UK affects approximately 3 million people, with >100,000 deaths annually. Mortality rates have halved since the 1980s, but annual NHS treatment costs for CHD exceed 2 billion pounds. AIM: To examine the cost-effectiveness of specific CHD treatments in England and Wales. METHODS: The IMPACT CHD model was used to calculate the number of life-years gained (LYG) from specific cardiological interventions from 2000 to 2010. Cost-effectiveness ratios (costs per LYG) were generated for each specific intervention, stratified by age and sex. The robustness of the results was tested using sensitivity analyses. RESULTS: In 2000, medical and surgical treatments together prevented or postponed approximately 25,888 deaths in CHD patients aged 25-84 years, thus generating approximately 194,929 extra life-years between 2000 and 2010 (range 143,131-260,167). Aspirin and beta-blockers for secondary prevention following myocardial infarction or revascularisation, for angina and heart failure were highly cost-effective (< 1000 pounds per LYG). Other secondary prevention therapies, including cardiac rehabilitation, ACE inhibitors and statins, were reasonably cost-effective (1957 pounds, 3398 pounds and 4246 pounds per LYG, respectively), as were CABG surgery (3239 pounds-4601 pounds per LYG) and angioplasty (3845 pounds-5889 pounds per LYG). Primary angioplasty for myocardial infarction was intermediate (6054 pounds-12,057 pounds per LYG, according to age), and statins in primary prevention were much less cost-effective (27,828 pounds per LYG, reaching 69,373 pounds per LYG in men aged 35-44). Results were relatively consistent across a wide range of sensitivity analyses. DISCUSSION: The cost-effectiveness ratios for standard CHD treatments varied by over 100-fold. Large amounts of NHS funding are being spent on relatively less cost-effective interventions, such as statins for primary prevention, angioplasty and CABG surgery. This merits debate.

Meta-analysis of trials comparing ximelagatran with low molecular weight heparin for prevention of venous thromboembolism after major orthopaedic surgery.

BACKGROUND: Use of low molecular weight heparin (LMWH) is standard practice for preventing postoperative venous thromboembolism (VTE). Ximelagatran is a new direct thrombin inhibitor for this indication. METHODS: A systematic review was conducted to compare the efficacy and safety of LMWH with ximelagatran in orthopaedic surgery. RESULTS: Six eligible, well conducted clinical trials (10 051 patients) were identified. Overall, the risk of VTE (OR (odds ratio) 1.22 (95 per cent confidence interval (c.i.) 0.89 to 1.67)) and serious bleeding (OR 0.70 (95 per cent c.i. 0.42 to 1.18)) was not significantly different for LMWH compared with ximelagatran. Exploratory analyses to investigate statistical heterogeneity found that results varied by surgical subtype and treatment regimen. Compared with postoperative ximelagatran, LMWH had a significantly lower rate of VTE (OR 0.68 (95 per cent c.i. 0.56 to 0.82); P < 0.001), with no significant difference in bleeding rate (OR 1.09 (95 per cent c.i. 0.62 to 1.94); P = 0.76), in hip surgery, and no significant differences in knee surgery. When ximelagatran was started immediately before surgery, LMWH had a significantly higher rate of VTE in both hip (OR 1.87 (95 per cent c.i. 1.20 to 2.92); P = 0.006) and knee (OR 1.49 (95 per cent c.i. 1.14 to 1.93); P = 0.003) surgery, but less bleeding: hip OR 0.30 (95 per cent c.i. 0.17 to 0.53; P < 0.001); knee OR 0.71 (95 per cent c.i. 0.30 to 1.67; P = 0.43). CONCLUSION: This review demonstrated no overall advantage for either LMWH or ximelagatran in thromboprophylaxis following orthopaedic surgery. Benefits in VTE prevention with ximelagatran were gained at the expense of an increased risk of serious bleeding.

Rofecoxib for rheumatoid arthritis.

BACKGROUND: Editor's note: The anti-inflammatory drug rofecoxib (Vioxx) was withdrawn from the market at the end of September 2004 after it was shown that long-term use (greater than 18 months) could increase the risk of heart attack and stroke. Further information is available at www.vioxx.com. Rheumatoid arthritis (RA) is a systemic auto-immune disorder, in which the synovial lining of many joints and tendon sheaths are persistently inflamed. OBJECTIVES: To assess the efficacy and toxicity of rofecoxib for treating RA. SEARCH STRATEGY: We searched the following electronic databases up to December 2000: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Research Register, NHS Economic Evaluation Database, Health Technology Assessment database. The bibliographies of retrieved papers were scanned for additional references. The manufacturers of rofecoxib, MSD, were also approached by the UK National Institute for Clinical Excellence to submit additional evidence to inform it's appraisal on the use of cyclo-oxygenase inhibitors for arthritis. SELECTION CRITERIA: We included randomised controlled trials of parallel group design evaluating the efficacy and/or toxicity of rofecoxib in RA, both placebo based and comparative trials were eligible. Relevant outcome criteria had to be available to evaluate efficacy and/or toxicity, such as the OMERACT outcomes. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers and the results were compared for the degree of agreement. A validated tool (Jadad 1996) was used to score the quality of the randomised controlled trials. The planned analysis was to pool, where appropriate, continuous outcome measures using mean or standardized mean differences, and dichotomous outcome measures using relative risk ratios. MAIN RESULTS: Two randomised controlled trials evaluating rofecoxib for the treatment of RA were identified and met the inclusion criteria. One compared rofecoxib to placebo and was designed to assess the safety and efficacy of several doses of rofecoxib. The second trial compared rofecoxib to naproxen and was primarily designed to assess the safety of rofecoxib so did not include all the recommended RA efficacy measures. The overall number of ACR 20 responders who had received 25mg (82/ 171 = 48%) or 50mg (86/161 = 53%) was statistically significantly more than those receiving placebo (58/168 = 35% ) (RR 1.39 CI: 1.07, 1.80 and RR 1.55 CI: 1.20, 1.99 respectively) with no statistically significant differences between the 25 and 50 mg doses. The safety profile of rofecoxib was similar to that of placebo. In the comparative trial, rofecoxib at a dosage of 50 mg/day demonstrated similar efficacy to naproxen at a dosage of 500 mg twice daily. However, the combined rate of clinically significant complicated gastro-intestinal events (GI) (perforations, ulcers, bleeds, or obstructions) was lower with rofecoxib than with naproxen (RR 0.46, 95% CI, 0.34 to 0.63) due to a reduction in the number of ulcers and bleeds. Compared to patients taking naproxen, patients taking rofecoxib had a greater risk of having any cardiovascular event (45/4047 = 1.1% vs 19/4029 =0.47%) (RR 2.36 CI 1.38 to 4.02) and had greater risk of having a non-fatal myocardial infarction (MI) (18/4047 =0 .44% and 4/4029 =0.1%) (RR 4.48, 95% CI, 1.52 to 13.23). AUTHORS' CONCLUSIONS: In patients with RA, rofecoxib demonstrates a greater degree of efficacy than placebo, while having a comparable safety profile. Rofecoxib demonstrates a similar degree of efficacy as naproxen, but with a significantly lower rate of ulceration and gastrointestinal bleeding. Rofecoxib was associated with a greater risk for MI, but the exact significance and pathophysiology of this possible relationship is unclear. Rofecoxib was voluntarily withdrawn from global markets in October 2004. It cannot therefore be prescribed and therefore there are no implications for practice concerning its use. None the less when considering which NSAID to use, it must be borne in mind that the toxicity of NSAIDs is variable amongst patients and drugs and it tends to be dose related and associated with variation in the mode of action, absorption, distribution and metabolism. There remains a number of questions over both the benefits and risks associated with Cox II selective agents and further work is ongoing. It is likely that this issue will not be resolved until research has enabled a fuller understanding of the complex mechanism by which the Cox system operates.

Rofecoxib for osteoarthritis.

BACKGROUND: Editor's note: The anti-inflammatory drug rofecoxib (Vioxx) was withdrawn from the market at the end of September 2004 after it was shown that long-term use (greater than 18 months) could increase the risk of heart attack and stroke. Further information is available at www.vioxx.com. Osteoarthritis is a chronic disease of the joints, characterised by joint pain, stiffness and loss of physical function. Its onset is age-related and occurs usually between the ages of 50 and 60. It is the commonest cause of disability in those aged over 65, with OA of the knee and/or hip affecting over 20 per cent of the elderly population. OBJECTIVES: To establish the efficacy and safety of rofecoxib in the management of OA by systematic review of available evidence. SEARCH STRATEGY: We searched the following databases up to August 2004: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Research Register, NHS Economic Evaluation Database, Health Technology Assessment Database. The bibliographies of retrieved papers and content experts were consulted for additional references. SELECTION CRITERIA: All eligible randomised controlled trials (RCTs) were included. No unpublished RCTs were included in this edition of the review. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers. A validated checklist was used to score the quality of the RCTs. Comparable trials were pooled using fixed effects model. MAIN RESULTS: Twenty-six RCTs were included. The comparators were placebo, diclofenac, ibuprofen, naproxen, nimesulide, nabumetone, paracetamol, celecoxib and Arthrotec. The evidence reviewed indicated that rofecoxib was more effective than placebo (patient global response RR 1.75 95% CI: 1.35, 2.26) but was associated with more adverse events (RR 1.32 95% CI 1.11, 1.56). There were no consistent differences in efficacy between rofecoxib and any of the active comparators at equivalent doses. Endoscopic studies indicated that compared to ibuprofen 800 mg three times a day, rofecoxib caused fewer erosions and gastric ulcers at doses of 25mg and 50mg; the difference in duodenal ulcers was evident only at a dose of 25mg. Rofecoxib 50mg also caused more endoscopically observed ulcers greater than rofecoxib 25mg (RR 2.48 CI: 1.21, 5.11). Very few of the trials reported overall rates of GI adverse events although rofecoxib was found to cause fewer GI events than naproxen. Only one of the nine trials comparing rofecoxib to celecoxib reported on the overall rates of GI events and this was a comparison of the higher recommended dose of rofecoxib with the lower recommended dose of celecoxib. Similarly, the three trials in older hypertensive patients that examined the cardiovascular safety of rofecoxib and celecoxib used non-comparable doses; the results of these studies indicated that rofecoxib caused more patients to have oedema and a clinically significant increase in systolic blood pressure. This difference between rofecoxib and celecoxib was not evident in studies conducted in more general populations. AUTHORS' CONCLUSIONS: Rofecoxib was voluntarily withdrawn from global markets in October 2004 therefore there are no implications for practice concerning its use. There remains a number of questions over both the benefits and risks associated with Cox II selective agents and further work is ongoing.

Rofecoxib for the treatment of rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic auto-immune disorder, in which the synovial lining of many joints and tendon sheaths are persistently inflamed. OBJECTIVES: To assess the efficacy and toxicity of rofecoxib for treating RA. SEARCH STRATEGY: We searched the following electronic databases up to December 2000: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Research Register, NHS Economic Evaluation Database, Health Technology Assessment database. The bibliographies of retrieved papers were scanned for additional references. The manufacturers of rofecoxib, MSD, were also approached by the UK National Institute for Clinical Excellence to submit additional evidence to inform it's appraisal on the use of cyclo-oxygenase inhibitors for arthritis. SELECTION CRITERIA: We included randomised controlled trials of parallel group design evaluating the efficacy and/or toxicity of rofecoxib in RA, both placebo based and comparative trials were eligible. Relevant outcome criteria had to be available to evaluate efficacy and/or toxicity, such as the OMERACT outcomes. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers and the results were compared for the degree of agreement. A validated tool (Jadad 1996) was used to score the quality of the randomised controlled trials. The planned analysis was to pool, where appropriate, continuous outcome measures using mean or standardized mean differences, and dichotomous outcome measures using relative risk ratios. MAIN RESULTS: Two randomised controlled trials evaluating rofecoxib for the treatment of RA were identified and met the inclusion criteria. One compared rofecoxib to placebo and was designed to assess the safety and efficacy of several doses of rofecoxib. The second trial compared rofecoxib to naproxen and was primarily designed to assess the safety of rofecoxib so did not include all the recommended RA efficacy measures. The overall number of ACR 20 responders who had received 25mg (82/ 171 = 48%) or 50mg (86/161 = 53%) was statistically significantly more than those receiving placebo (58/168 = 35% ) (RR 1.39 CI: 1.07, 1.80 and RR 1.55 CI: 1.20, 1.99 respectively) with no statistically significant differences between the 25 and 50 mg doses. The safety profile of rofecoxib was similar to that of placebo. In the comparative trial, rofecoxib at a dosage of 50 mg/day demonstrated similar efficacy to naproxen at a dosage of 500 mg twice daily. However, the combined rate of clinically significant complicated gastro-intestinal events (GI) (perforations, ulcers, bleeds, or obstructions) was lower with rofecoxib than with naproxen (RR 0.46, 95% CI, 0.34 to 0.63) due to a reduction in the number of ulcers and bleeds. Compared to patients taking naproxen, patients taking rofecoxib had a greater risk of having any cardiovascular event (45/4047 = 1.1% vs 19/4029 =0.47%) (RR 2.36 CI 1.38 to 4.02) and had greater risk of having a non-fatal myocardial infarction (MI) (18/4047 =0.44% and 4/4029 =0.1%) (RR 4.48, 95% CI, 1.52 to 13.23). REVIEWER'S CONCLUSIONS: In patients with RA, rofecoxib demonstrates a greater degree of efficacy than placebo, while having a comparable safety profile. Rofecoxib demonstrates a similar degree of efficacy as naproxen, but with a significantly lower rate of ulceration and gastrointestinal bleeding. Rofecoxib was associated with a greater risk for MI, but the exact significance and pathophysiology of this possible relationship is unclear.

Rofecoxib for the treatment of rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic auto-immune disorder, in which the synovial lining of many joints and tendon sheaths are persistently inflamed. OBJECTIVES: To assess the efficacy and toxicity of rofecoxib for treating RA. SEARCH STRATEGY: We searched the following databases up to December 2000: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Research Register, NHS Economic Evaluation Database, Health Technology Assessment database. The bibliographies of retrieved papers were scanned for additional references. The manufacturers of rofecoxib, MSD, were also approached by the UK National Institue for Clincal Excellence to submit additional evidence to inform it's appraisal on the use of cyclo-oxygenase inibitors for arthritis. SELECTION CRITERIA: Relevant studies were randomised controlled trials of parallel group design evaluating the efficacy and/or toxicity of rofecoxib in RA, both placebo based and comparative trials were eligible. Relevant outcome criteria had to be available to evaluate efficacy and/or toxicity, such as the OMERACT outcomes. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers and the results were compared for the degree of agreement. A validated tool (Jadad 1995) was used to score the quality of the randomised controlled trials. The planned analysis was to pool, where appropriate, continuous outcome measures using mean or standardized mean differences, and dichotomous outcome measures using relative risk ratios. MAIN RESULTS: Two randomised controlled trials evaluating the efficacy and toxicity of rofecoxib in RA were identified and met the criteria. One compared rofecoxib to placebo and the other compared rofecoxib to naproxen. The overall number of ACR 20 responders who had received 25mg (82/ 171 = 48%) or 50mg (86/161 = 53%) was statistically significantly more than those receiving placebo (58/168 = 35% ) (RR 1.39 CI: 1.07, 1.80 and RR 1.55 CI: 1.20, 1.99 respectively) with no statistically significant differences between the 25 and 50 mg doses. The safety profile of rofecoxib was similar to that of placebo. In the comparative trial, rofecoxib at a dosage of 50 mg/day demonstrated similar efficacy to naproxen at a dosage of 500 mg twice daily. However, the combined rate of clinically significant complicated gastro-intestinal events (GI) (perforations, ulcers, bleeds, or obstructions) was lower with rofecoxib than with naproxen (RR 0.46, 95% CI, 0.34 to 0.63) due to a reduction in the number of ulcers and bleeds. Patients taking rofecoxib had a greater risk of having a myocardial infarction (MI) than patients taking naproxen (RR 4.03, 95% CI, 2.86 to 5.68). REVIEWER'S CONCLUSIONS: In patients with RA, rofecoxib demonstrates a greater degree of efficacy than placebo, while having a comparable safety profile. Rofecoxib demonstrates a similar degree of efficacy as naproxen, but with a significantly lower rate of ulceration and gastrointestinal bleeding. Rofecoxib was associated with a greater risk for MI, but the exact significance and pathophysiology of this possible relationship is unclear.

Celecoxib for rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic auto-immune disorder, involving persistent joint inflammation. NSAIDs are used to control the symptoms of RA, but are associated with significant gastro-intestinal toxicity, including a risk of potentially life threatening gastroduodenal perforations, ulcers and bleeds. The NSAIDs known as the selective Cox II inhibitors, of which celecoxib is a member, were developed in order to reduce the GI toxicity, but are more expensive. OBJECTIVES: To establish the efficacy and safety of celecoxib in the management of RA by systematic review of available evidence. SEARCH STRATEGY: We searched the following databases up to August 2002: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Research Register, NHS Economic Evaluation Database, Health Technology Assessment Database. The bibliographies of retrieved papers and content experts were consulted for additional references. SELECTION CRITERIA: All eligible randomised controlled trials (RCTs) were included. No unpublished RCTs were included in this edition of the review. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers. Data was analysed using a fixed effects model. A validated checklist was used to score the quality of the RCTs. The planned analysis was to pool, where appropriate continuous outcomes using mean differences and dichotomous outcomes using relative risk ratios. This was not however possible due to the lack of data. MAIN RESULTS: Five RCTs were included (4465 participants); three of the studies also enrolled individuals with OA. The comparators were placebo, naproxen, diclofenac and ibuprofen. The evidence reviewed suggests that celecoxib controls the symptoms of RA to a similar degree to that of the active comparators examined (naproxen, diclofenac and ibuprofen). When compared to placebo, the percentage of patients showing improvement according to ACR 20 criteria at week 4 were 42/82 (51%) in the twice daily celecoxib 200mg group and 43/82 (52%) in the twice daily celecoxib 400mg group; these were significantly different from the placebo group in which 25/85 (29%) improved. The six month data reviewed support a reduced rate of UGI complications with celecoxib but there is also evidence to suggest that these benefits may not be evident in the long-term and that celecoxib offers no additional benefit in patients who are also receiving cardio-prophylactic low dose aspirin. REVIEWER'S CONCLUSIONS: For an individual with RA the potential benefits of celecoxib need to be balanced against the uncertainty that the short-term reduced incidence of upper GI complications are maintained in the long-term and its increased cost in comparison to traditional NSAIDs.