The Headache Pipeline: Excitement and Uncertainty.

There are many new treatment options available for migraine and more are coming. Three calcitonin gene-related peptide (CGRP) antagonist monoclonal antibodies have been approved and a 4th is due in early 2020. Small molecule CGRP receptor-blocking oral compounds, both for acute care and prevention, are also coming. Four neurostimulators are available, with others on the way. New acute treatments coming soon include the 5HT1F agonist lasmiditan, a zolmitriptan intradermal micro-needle patch, and a nasal mist sumatriptan with a permeability enhancer. Farther out, three novel dihydroergotamine delivery systems, and a liquid-filled capsule of celecoxib show early promise. A new, safer form of methysergide is in the works, as is a longer-duration onabotulinumtoxinA. As always with new products, questions regarding safety, tolerability, cost, and insurance coverage will need to be addressed. Despite these concerns and uncertainties, a robust headache treatment pipeline is good for patients who are not satisfied with the results of their treatment and/or cannot tolerate existing treatments.

[Cost-effectiveness analysis of celecoxib versus non-selective non-steroidal anti-inflammatory drug therapy for the treatment of osteoarthritis in Spain: A current perspective]. / Análisis coste-efectividad de celecoxib frente a antiinflamatorios no esteroideos no selectivos en el tratamiento de la artrosis en España: una perspectiva actual.

OBJECTIVE: To assess the cost-effectiveness of celecoxib and non-selective non-steroidal anti-inflammatory drugs for the treatment of osteoarthritis in clinical practice in Spain. METHODS: A decision-tree model using distribution, doses, treatment duration and incidence of GI and CV events observed in the pragmatic PROBE-designed «GI-Reasons¼ trial was used for cost-effectiveness. Effectiveness was expressed in terms of event averted and quality-adjusted life-years (QALY) gained. QALY were calculated based on utility decrement in case of any adverse events reported in GI-Reasons trial. The National Health System perspective in Spain was applied; cost calculations included current prices of drugs plus cost of adverse events occurred. The analysis was expressed as an incremental cost-effectiveness ratio per QALY gained and per event averted. One-way and probabilistic analyses were performed. RESULTS: Compared with non-selective non-steroidal anti-inflammatory drugs, at current prices, celecoxib treatment had higher overall treatment costs €201 and €157, respectively. However, celecoxib was associated with a slight increase in QALY gain and significantly lower incidence of gastrointestinal events (p<.001), with mean incremental cost-effectiveness ratio of €13,286 per QALY gained and €4,471 per event averted. Sensitivity analyses were robust, and confirmed the results of the base case. CONCLUSION: Celecoxib at current price may be considered as a cost-effective alternative vs. non-selective non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis in daily practice in the Spanish NHS.

Actions following adverse drug events - how do these influence uptake and utilisation of newer and/or similar medications?

BACKGROUND: Over the last decade, actions following some adverse drug events received major publicity. This study investigated changes in usage patterns of medications in Australia following two examples - rofecoxib market withdrawal (2004) and warnings about jaw necrosis following bisphosphonates (2007). METHODS: Dispensing data for COX-2 inhibitors (2000-2008) and anti-osteoporosis medications (2003-2012) were obtained from the Australian Pharmaceutical Benefits Scheme database. For bisphosphonates, data on Australian marketing expenditures were purchased from Cegedim(R). RESULTS: For COX-2 inhibitors, celecoxib dispensing halved after rofecoxib withdrawal, but meloxicam dispensing increased by 60 %. When lumiracoxib was introduced (2006) there was uptake of prescribing at a faster rate than meloxicam in 2002, its first year of use. For bisphosphonates, alendronate had highest use at the time of the warnings (8.3 DDD/1000/day), dropping to 4.9 DDD/1000/day by 2012. In contrast, risedronate use rose 2007-2012 from 4.1 to 4.9 DDD/1000/day. There was 49 % increase in reported annual expenditure on detailing for risedronate from 2007 to 2008 (to AUD$7.3 million) and only 29 % increase for alendronate (to AUD$3.1 million). CONCLUSIONS: The rapid uptake of prescribing of lumiracoxib and increased use of meloxicam flagged a concern, especially after rofecoxib withdrawal due to safety issues. Bisphosphonates are useful drugs, however the dramatic rise in expenditure on detailing, followed by a rise in utilisation of risedronate could suggest that adverse publicity triggered a marketing response. These examples highlight the importance of tracking utilisation of medication classes in real time, using different data as needed, to ensure that due caution is exercised (and quick intervention provided if needed) for medications in the same class.

A cost-effectiveness analysis of celecoxib compared with diclofenac in the treatment of pain in osteoarthritis (OA) within the Swedish health system using an adaptation of the NICE OA model.

OBJECTIVES: Celecoxib for the treatment of pain resulting from osteoarthritis (OA) was reviewed by the Tandvårds- och läkemedelsförmånsverket-Dental and Pharmaceutical Benefits Board (TLV) in Sweden in late 2010. This study aimed to evaluate the incremental cost-effectiveness ratio (ICER) of celecoxib plus a proton pump inhibitor (PPI) compared to diclofenac plus a PPI in a Swedish setting. METHODS: The National Institute for Health and Care Excellence (NICE) in the UK developed a health economic model as part of their 2008 assessment of treatments for OA. In this analysis, the model was reconstructed and adapted to a Swedish perspective. Drug costs were updated using the TLV database. Adverse event costs were calculated using the regional price list of Southern Sweden and the standard treatment guidelines from the county council of Stockholm. Costs for treating cardiovascular (CV) events were taken from the Swedish DRG codes and the literature. RESULTS: Over a patient's lifetime treatment with celecoxib plus a PPI was associated with a quality-adjusted life year (QALY) gain of 0.006 per patient when compared to diclofenac plus a PPI. There was an increase in discounted costs of 529 kr per patient, which resulted in an incremental cost-effectiveness ratio (ICER) of 82,313 kr ($12,141). Sensitivity analysis showed that treatment was more cost effective in patients with an increased risk of bleeding or gastrointestinal (GI) complications. CONCLUSIONS: The results suggest that celecoxib plus a PPI is a cost effective treatment for OA when compared to diclofenac plus a PPI. Treatment is shown to be more cost effective in Sweden for patients with a high risk of bleeding or GI complications. It was in this population that the TLV gave a positive recommendation. There are known limitations on efficacy in the original NICE model.

Gastroprotective strategies in chronic NSAID users: a cost-effectiveness analysis comparing single-tablet formulations with individual components.

OBJECTIVES: To evaluate the cost-effectiveness of competing gastroprotective strategies, including single-tablet formulations, in the prevention of gastrointestinal (GI) complications in patients with chronic arthritis taking nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: We performed a cost-utility analysis to compare eight gastroprotective strategies including NSAIDs, cyclooxygenase-2 inhibitors, proton pump inhibitors (PPIs), histamine-2 receptor antagonists, misoprostol, and single-tablet formulations. We derived estimates for outcomes and costs from medical literature. The primary outcome was incremental cost per quality-adjusted life-year gained. We performed sensitivity analyses to assess the effect of GI complications, compliance rates, and drug costs. RESULTS: For average-risk patients, NSAID + PPI cotherapy was most cost-effective. The NSAID/PPI single-tablet formulation became cost-effective only when its price decreased from €0.78 to €0.56 per tablet, or when PPI compliance fell below 51% in the NSAID + PPI strategy. All other strategies were more costly and less effective. The model was highly sensitive to the GI complication risk, costs of PPI and NSAID/PPI single-tablet formulation, and compliance to PPI. In patients with a threefold higher risk of GI complications, both NSAID + PPI cotherapy and single-tablet formulation were cost-effective. CONCLUSIONS: NSAID + PPI cotherapy is the most cost-effective strategy in all patients with chronic arthritis irrespective of their risk for GI complications. For patients with increased GI risk, the NSAID/PPI single-tablet formulation is also cost-effective.

A review of the efficacy, safety, and cost-effectiveness of COX-2 inhibitors for Africa and the Middle East region.

Despite an increasingly sophisticated understanding of pain mechanisms, acute and chronic pain remain undertreated throughout the world. This situation reflects the large gap that exists between evidence and practice in pain management and is typified by inappropriate use of nonsteroidal anti-inflammatory drugs (NSAIDs). The scientific evidence around these drugs continues to expand at a high rate, yet physicians are often unaware of best practice. To address this gap among physicians in Africa and the Middle East, an Expert Panel meeting was convened with representatives from the region. The principal objective of the meeting was to review the latest guidelines on the management of acute and chronic pain and to review the efficacy, safety, and cost-effectiveness of cyclooxygenase-2 (COX-2) inhibitors in these settings. The main outcome of this review process was a number of consensus statements concerning the definitions of acute and chronic pain, and the efficacy, safety and cost-effectiveness of traditional nonselective NSAIDs (nsNSAIDs) and selective COX-2 inhibitors (coxibs). The panel agreed that nsNSAIDs and coxibs are effective analgesics with similar efficacy for acute pain; for chronic musculoskeletal pain, NSAIDs are significantly more effective than either placebo or paracetamol. Coxibs offer important safety advantages over nsNSAIDs, including gastrointestinal safety and preservation of platelet function; notably, the cardiovascular safety of coxibs has been the subject of much recent debate. Furthermore, the panel agreed there is substantial evidence to indicate that cost savings can be achieved by using celecoxib in patients at moderate to high risk of gastrointestinal adverse events, even in countries with moderate healthcare expenditures.

Economic outcomes for celecoxib: a systematic review of pharmacoeconomic studies.

Osteoarthritis and rheumatoid arthritis are conditions that are associated with significant clinical burden, and impact on patients' functional status and quality of life. Medical costs related to treating these common and disabling conditions place an economic strain on healthcare systems. This systematic review was conducted to investigate the impact of celecoxib on healthcare costs for patients with rheumatoid arthritis and osteoarthritis. In total, 24 studies examined economic outcomes associated with celecoxib in patients with these conditions. Six of these studies evaluated economic outcomes in developing regions, including Mexico, Asia and Turkey. Across all geographies, most studies were cost-effectiveness analyses comparing celecoxib with nonselective NSAIDs alone or in combination with gastroprotective agents. Overall, based on local standards, economic models indicated favorable cost-effectiveness profiles for celecoxib compared with nonselective NSAIDs and other active-treatment options. Cost analyses indicated that the use of celecoxib resulted in lower direct medical costs.

The cost-effectiveness of celecoxib vs diclofenac in the treatment of osteoarthritis in the UK; an update to the NICE model using data from the CONDOR trial.

OBJECTIVES: The National Institute for Health and Clinical Excellence (NICE) health economic model for assessing the cost-effectiveness of celecoxib plus a proton pump inhibitor (PPI) compared to diclofenac plus PPI in the treatment of osteoarthritis has been updated using new adverse event (AE) risks from the CONDOR trial. In light of this new information, this study aimed to evaluate the incremental cost-effectiveness ratio (ICER) of celecoxib plus PPI compared to diclofenac plus PPI. METHODS: NICE developed a health economic model as part of their 2008 multiple technology assessment of treatments for osteoarthritis. The model was adapted for this study to update the relative risks of adverse events, using data from the CONDOR trial. RESULTS: Using the AE data from the CLASS trial alone, celecoxib plus PPI has an ICER of £9538 per QALY when compared to diclofenac plus PPI. When the AE data from CONDOR alone is used, this ICER decreases to £4773 per QALY. Using the pooled data from both trials, celecoxib plus PPI has an ICER of £9377 per QALY compared to diclofenac plus PPI. DISCUSSION: The results suggest that when new AE risks are used, celecoxib plus PPI remains a cost-effective treatment for OA when compared to diclofenac plus PPI. However, this analysis is limited by the short time horizon, and additional AEs that have not been considered.

Cost-utility analysis and economic burden of knee osteoarthritis treatment: the analysis from the real clinical practice.

BACKGROUND: Non-steroidal anti-inflammatory drug (tNSAIDs) or selective COX-II inhibitor (COXIBs) are generally used as the first-line intervention of knee osteoarthritis (OA). Total knee arthroplasty (TKA) is suggested for those who dissatisfy from non-surgical treatment. However the long-term usage of tNSAIDs may lead to articular cartilage and resulted in higher rate of TKA. The evaluation of real clinical practice needs to be scrutinized as the inappropriate treatment will be socially burden. OBJECTIVE: To evaluate cost-utility of selective COX-II inhibitors (COXIBs) compared to traditional NSAIDs in patients with knee osteoarthritis (OA) and to estimate health and economic burden of disease of knee OA. MATERIAL AND METHOD: The present study is an economic evaluation alongside a prospective observational study. The data of cost and treatment outcomes were collected from real clinical practice. EQ-5D questionnaire was employed to calculate utility values at baseline and 6 months after treatment. RESULTS: Total 939 patients were prescribed tNSAIDs and 380 patients received celecoxib. Eleven cases (1.17%) of all tNSAIDs usages and 3 cases (0.79%); p = 0.56 of celecoxib usages were detected GI complication. Two cases of tNSAIDs group were dead from severe GI bleeding. TKA was markedly reported with 12.99% of tNSAIDs and 9.80% of celecoxib; p = 0.06. QALYs gained from 6 months was 0.34 (+/- 0.11) for tNSAIDs and 0.36 (+/- 0.11) for celecoxib; p = 0.004. Average direct medical expenses per patient were comparable with 17,468.97 THB for tNSAIDs and 17,495.07 THB for celecoxib. Cost of TKA was a key element in both groups with 90% and 67% of total expenses in tNSAIDs and celecoxib groups, respectively. Incremental cost-effectiveness ratio (ICER) per Quality-adjusted life years (QALY) gained comparing celecoxib and tNSAIDs was 1,382.70 THB. CONCLUSION: The finding from our study can be a concrete evidence to support the appropriate future decision of clinical judgment and health care provider.

Value of information in the osteoarthritis setting: cost effectiveness of COX-2 selective inhibitors, traditional NSAIDs and proton pump inhibitors.

BACKGROUND: Recent National Institute for Health and Clinical Excellence (NICE) guidance recommended that when traditional NSAIDs or cyclo-oxygenase (COX)-2 selective inhibitors are used by people with osteoarthritis (OA), they should be prescribed along with a proton pump inhibitor (PPI). However, specific recommendations about the type of NSAID or COX-2 could not be made due to high levels of uncertainty in the economic evaluation. OBJECTIVE: To investigate the value of obtaining further evidence to inform the economic evaluation of NSAIDs, COX-2s and PPIs for people with OA. METHODS: An economic evaluation with an expected value of perfect information (EVPI) analysis was conducted, using a Markov model with data identified from a systematic review. The base-case model used adverse event data from the three largest randomized trials of COX-2 inhibitors, and we repeated the analysis using observational adverse event data. The model was run for a hypothetical population of people with OA, and subgroup analyses were conducted for people with raised gastrointestinal (GI) and cardiovascular (CV) risk. The EVPI was based upon the OA population in England - approximately 2.8 million people. Of these, 50% were assumed to use NSAIDs or COX-2 selective inhibitors for 3 months per year and 56% of these were assumed to be patients with raised GI and CV risk. RESULTS: The value of further information for this decision problem was very high. Population-level EVPI was £85.1 million in the low-risk group and £179.5 million in the high-risk group (2007-8 values). Expected value of partial perfect information (EVPPI) analysis showed that the groups of parameters for which further evidence was likely to be of most value were CV adverse event risks and all adverse event rates associated with the specific drugs celecoxib and ibuprofen. The value of perfect information remained high even when observational adverse event data were used. CONCLUSIONS: There is a very high value associated with obtaining further information on uncertain parameters for the economic evaluation of NSAIDs, COX-2 selective inhibitors and PPIs for people with OA. Obtaining further randomized or observational information on CV risks is likely to be particularly cost effective.

National estimates and predictors of prescription medication sample use in the United States, 1999-2005.

OBJECTIVES: To determine the prevalence of free medication sample use in the United States and analyze the effects of socioeconomic status and drug safety actions. DESIGN: Cross-sectional study. SETTING: United States from 1999 to 2005. PARTICIPANTS: Survey respondents representative of the civilian noninstitutionalized population. INTERVENTION: Analysis of data from the Medical Expenditure Panel Survey, a nationally representative longitudinal household survey. MAIN OUTCOME MEASURES: Identification of a medication as being provided as a sample at least once during a study year. RESULTS: An annual average of 5.1% (range 4.4% in 2005 to 5.8% in 2002) of all prescription medications were provided as a sample at least once during a year, with 18.3% of all Americans who received at least one prescription drug receiving at least one drug as a sample. On multivariate analysis, sample use was greater among young (18-30 years) non-Hispanic whites and the uninsured but had minimal independent association with income. The proportion of sample use among users of hormone replacement therapy and cyclooxygenase-2 inhibitors remained relatively constant even as total use of these drugs declined after Food and Drug Administration regulatory action. CONCLUSION: Use of medication samples is common in the U.S. population. After adjusting for health insurance, sample use was not associated with income and samples were less frequently provided to racial/ethnic minorities and to the elderly. The putative economic benefits of free samples do not appear to go to patients with the greatest financial need. Drug regulatory actions did not have a disproportionate effect on provision of drugs as samples.

Identifying early prescribers of cycloxygenase-2 inhibitors (COX-2s) in Nova Scotia, Canada: Considerations for targeted academic detailing.

BACKGROUND: Expenditures on prescribed drugs in Canada are now well past those for all services provided by outpatient physicians ($26.9 billion vs. $21.5 billion in 2007). Government has the opportunity to dedicate resources to continuing medical education of physicians, and effective profiling would assist in the allocation of these educational resources. OBJECTIVE: The purpose of this study was to evaluate physician prescribing patterns and establish criteria by which various prescribing profiles may be segmented and identified, so as to better target detailing and continuing medical education resources. METHODS: A sample of 925 physicians practicing in Nova Scotia (NS) was characterized by age, sex, rural/urban nature of their practice and specialty. They were subsequently evaluated relative to all prescriptions filled by their patients who were beneficiaries of the NS Department of Health's senior's Pharmacare drug insurance program. The adoption of COX-2 inhibitors (eg, Vioxx) and Celebrex) and their substitution for NS-NSAIDs (non-specific non-steroidal anti-inflammatory drugs, eg, Motrin) from 1999 to 2003 were examined. RESULTS: This analysis established the profiles of 2 key groups of physicians. The first consisted of those most likely to comprise the early, high volume COX-2-prescribing universe (profiles based on the absolute number of prescriptions written over a given period). These individuals were likely to be older, more experienced, male general practitioners operating in a rural practice. The second group consisted of those most likely to comprise the early, high-relative, COX-2-prescribing universe (prescribing of COX-2s relative to non-selective, non-steroidal anti-inflammatory drugs (NS-NSAIDs)). These individuals were likely to be younger, less experienced female general practitioners, operating in an urban practice. CONCLUSION: This research moves us closer to identifying unique physician segments that account for either the largest volume of prescriptions for new drugs, or the largest relative volume of prescriptions. Use of these physician groups can help continuing medical education providers target specific prescribers with information to assist them in examining and improving their prescribing.

Are COX-2 inhibitors preferable to combined NSAID and PPI in countries with moderate health service expenditures?

RATIONALE: In developed countries, cyclooxygenase 2 (COX-2) inhibitors were shown to be less costly than the combination of non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) in treatment of patients with high risk of serious gastrointestinal (GI) adverse effects. It is questionable if such results apply to developing countries where health service costs are lower and there is high discrepancy between generic and patent protected drug prices. We analysed the direct cost of treatment with generic NSAIDs in combination with PPIs versus branded COX-2 inhibitors in patients with high risk of serious GI adverse effects from the perspective of the public health service in Serbia. METHODS: Total cost of treatment of serious GI complications and the use of NSAID+PPI versus COX-2 inhibitors were calculated. A model for estimation of cost of treatment of NSAID+PPI versus COX-2 inhibitors which included the probability of developing serious GI adverse effects was developed. RESULTS: Total cost of treatment of serious GI adverse effects resulted in an average of $814/patient. Considering the relative risk of such adverse effects for patients with four or more risk factors, the least costly treatment over 6 months was the use of celecoxib ($487). Compared with diclofenac+omeprazole, cost savings were estimated at $59 and $22 per patient with celecoxib and etoricoxib, respectively. CONCLUSION: Cost savings may be achieved by using COX-2 inhibitors in patients at high risk of GI adverse effects even in countries with moderate health care service expenditures. Such possibility requires further investigation.

Cost effectiveness of etoricoxib versus celecoxib and non-selective NSAIDS in the treatment of ankylosing spondylitis.

To evaluate the cost effectiveness of etoricoxib (90 mg/day) relative to celecoxib (200 or 400 mg/day), and the non-selective NSAIDs naproxen (1000 mg/day) and diclofenac (150 mg/day) in the initial treatment of ankylosing spondylitis (AS) from the UK NHS perspective. A Bayesian cost-effectiveness model was developed to estimate the costs and benefits associated with initiating AS treatment with etoricoxib, celecoxib, diclofenac or naproxen. Efficacy, safety and medical resource and cost data were obtained from the literature. The obtained efficacy estimates were synthesized with a mixed treatment comparison meta-analysis. Treatment benefit and degree of disease activity, as reflected with Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores, were related to QALYs and AS-specific costs (related to BASDAI). Other cost outcomes related to drug acquisition, and gastrointestinal and cardiovascular safety. Uncertainty in the source data was translated into uncertainty in cost-effectiveness estimates and therefore decision uncertainty. Costs and outcomes were discounted at 3.5% per annum. There was a >98% probability that treatment with etoricoxib results in greater QALYs than the other interventions. Over a 30-year time horizon, starting AS treatment with etoricoxib was associated with about 0.4 more QALYs than the other interventions. At 2 years there was a 77% probability that etoricoxib had the lowest cost. This increased to >99% at 30 years. Etoricoxib is expected to save 13 620 UK pounds (year 2007 values) relative to celecoxib (200/400 mg), 9957 UK pounds relative to diclofenac and 9863 UK pounds relative to naproxen. For a willingness-to-pay ceiling ratio of 20 000 UK pounds per QALY, there was a >97% probability that etoricoxib was the most cost-effective treatment. Additional analysis with different assumptions, including celecoxib 200 mg, and ignoring cost-offsets associated with improvements in disease activity, supported these findings. This economic evaluation suggests that, from the UK NHS perspective, etoricoxib is the most cost-effective initial NSAID treatment for AS patients.

Trends in the non-steroidal anti-inflammatory drug market in six Central-Eastern European countries based on retail information.

PURPOSE: The objective of this study was to evaluate the non-steroidal anti-inflammatory drug market of six Central and Eastern European countries. Trends and similarities were compared across the examined countries. METHODS: The Intercontinental Marketing Service Health database was used to determine consumption data between the years 2000 and 2007. We applied the anatomical therapeutical chemical-defined daily dose method, focussing on three major non-steroidal anti-inflammatory drug groups: conventional non-steroidal anti-inflammatory drugs, 'stronger cyclooxygenase 2 inhibitors' (all together as: non-cyclooxygenase 2 selective non-steroidal anti-inflammatory drugs) and selective cyclooxygenase 2 inhibitors. The main outcome measure was defined daily dose/1000 inhabitants/day. Different active agents have been distinguished between the three major groups. RESULTS: In total the non-steroidal anti-inflammatory drug group reached a 42.82-74.17 defined daily dose/1000 inhabitants/day volume in 2007, with an average total increase of 25.1% between 2002 and 2007. In the conventional non-steroidal anti-inflammatory drug group, diclofenac and ibuprofen have attained the highest consumption. Our results show a notable increase (325%, 2002-2007) of the 'stronger cyclooxygenase 2 inhibitor group' (nimesulide and meloxicam). Trends of selective cyclooxygenase 2 inhibitor volumes differ within the observed countries. CONCLUSION: Differences in the six countries concerning their NSAID consumption and market trends could not be explained with the inequalities in patient characteristics. The conventional NSAID retail gave the majority of the total NSAID market. The consumption of selective COX2 inhibitors in all of the six countries were much lower than in the US or Australia. The NSAID risk profile in the region is comparable to previous studies in other countries.