G. Makinson

Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis of information from company clinical trial reports

The objective was to improve understanding of adverse events occurring with celecoxib in the treatment of osteoarthritis and rheumatoid arthritis. Data were extracted from company clinical trial reports of randomised trials of celecoxib in osteoarthritis or rheumatoid arthritis lasting 2 weeks or more. Outcomes were discontinuations (all cause, lack of efficacy, adverse event, gastrointestinal adverse event), endoscopically detected ulcers, gastrointestinal or cardio-renal events, and major changes in haematological parameters. The main comparisons were celecoxib (all doses) versus placebo, paracetamol (acetaminophen) 4,000 mg daily, rofecoxib 25 mg daily, or nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen, diclofenac, ibuprofen, and loxoprofen). For NSAIDs, celecoxib was compared both at all doses and at licensed doses (200 to 400 mg daily). Thirty-one trials included 39,605 randomised patients. Most patients had osteoarthritis and were women of average age 60 years or above. Most trials lasted 12 weeks or more. Doses of celecoxib were 50 to 800 mg/day. Compared with placebo, celecoxib had fewer discontinuations for any cause or for lack of efficacy, fewer serious adverse events, and less nausea. It had more patients with dyspepsia, diarrhoea, oedema, more adverse events that were gastrointestinal or treatment related, and more patients experiencing an adverse event. There were no differences for hypertension, gastrointestinal tolerability, or discontinuations for adverse events. Compared with paracetamol, celecoxib had fewer discontinuations for any cause, for lack of efficacy, or diarrhoea, but no other differences. Compared with rofecoxib, celecoxib had fewer patients with abdominal pain and oedema, but no other differences. Compared with NSAIDs, celecoxib had fewer symptomatic ulcers and bleeds, endoscopically detected ulcers, and discontinuations for adverse events or gastrointestinal adverse events. Fewer patients had any, or a gastrointestinal, or a treatment-related adverse event, or vomiting, abdominal pain, dyspepsia, or reduced haemoglobin or haematocrit. Discontinuations for lack of efficacy were higher. No differences were found for all-cause discontinuations, serious adverse events, hypertension, diarrhoea, nausea, oedema, myocardial infarction, cardiac failure, or raised creatinine. Company clinical trial reports present much more information than published papers. Adverse event information is clearly presented in company clinical trial reports, which are an ideal source of information for systematic review and meta-analysis.

The burden of atopic dermatitis in US adults: results from the 2013 National Health and Wellness Survey

Abstract Objectives: To characterize comorbidities, health-related quality-of-life (HRQoL), productivity, and healthcare resource use in adults with atopic dermatitis (AD) relative to those without AD, and to evaluate the impact of patient-reported AD severity on these outcomes. Methods: Data were from the 2013 National Health and Wellness Survey (NHWS), which collected self-reported information on demographics, comorbidities, HRQoL (SF-36v2 Health Survey), productivity (Work Productivity and Impairment questionnaire [WPAI]), and healthcare utilization, which were weighted to the US general population. The AD cohort consisted of subjects who reported that they experienced AD within the past 12 months (n = 428), and the non-AD cohort included all subjects who did not report experiencing AD (n = 74,572); 366 AD subjects self-reported mild (n = 182) or moderate/severe (n = 184) disease. Univariable and multivariable analyses compared characteristics and outcomes between cohorts and between AD severity levels. Results: The AD cohort was younger than non-AD cohort (44.3 vs. 46.6 years; P = 0.0033), and had a higher proportion of females (64.4% vs. 51.8%; P < 0.0001). Relative to the non-AD cohort, the AD cohort had a significantly higher prevalence of atopic conditions including nasal allergies (46.4% vs. 19.8%) and asthma (22.4% vs. 7.9%), and neuropsychiatric conditions such as anxiety (42.5% vs. 21.3%) and depression (37.2% vs. 20.9%) (all P < 0.0001). Units of resource use (healthcare practitioner visits, emergency room, hospitalizations) were higher (all P < 0.05) and HRQoL was poorer (P < 0.0001) with AD. On the WPAI, AD employees reported almost twice as much lost work productivity as non-AD employees (30.0% vs. 16.3%; P < 0.0001). No clear differences in outcomes were observed among patient-reported AD severity categories, except greater impairment of work productivity and daily activities in those with moderate/severe AD relative to mild. Conclusions: The significant burden associated with AD relative to those without AD suggests an unmet need for more effective management strategies. There also appears to be a need for further characterization of disease severity and its impact on HRQoL.

Patient-level pooled analysis of adjudicated gastrointestinal outcomes in celecoxib clinical trials: meta-analysis of 51,000 patients enrolled in 52 randomized trials

IntroductionAlthough the safety of celecoxib has been investigated, limited data are available on complications affecting the entire (upper and lower) gastrointestinal (GI) tract, with no patient-level pooled analyses of upper and lower GI outcomes available. We therefore evaluated the upper and lower GI safety of celecoxib by using patient-level data from randomized controlled trials (RCTs).MethodsThis patient-level pooled analysis included 52 prospective, randomized, double-blind parallel-group studies from the Celecoxib Clinical Database. Each study had a planned duration of continuous treatment with celecoxib or a nonselective nonsteroidal antiinflammatory drug (nsNSAID), rofecoxib, or the placebo comparator arm for at least 4 weeks. All studies with final reports completed by 1 October 2007 were included. The primary end point was the combined incidence of clinically significant upper and lower GI events (CSULGIEs). An independent blinded committee reviewed and adjudicated all end points by using predefined criteria and all available reported adverse events, laboratory data, and case narratives. All doses of celecoxib and all doses of all nsNSAIDs were pooled for analysis.ResultsThe pooled analysis involved 51,048 patients; 28,614 were randomized to celecoxib; 15,278 to nsNSAIDs (including 3,248 patients taking naproxen, 2,640 taking ibuprofen, 8,066 taking diclofenac, 1,234 taking loxoprofen, and 90 taking ketoprofen); 5,827 to placebo and 1,329 to rofecoxib. The mean age was 60 years, and 65% were women. Data on 1,042 patients with potential GI events were reviewed for end-points adjudication; the adjudication committee confirmed 89 patients with CSULGIEs. The majority were in the celecoxib and nsNSAID groups (with raw incidence proportions of 37 (0.1%) and 40 (0.3%), respectively). The incidence rates were 0.3, 0.9 and 0.3 per 100 patient-years in the celecoxib, nsNSAID, and placebo groups, respectively. The time to incidence of CSULGIEs was significantly longer with celecoxib than with nsNSAIDs (P = 0.0004).ConclusionsWhen compared with nsNSAIDs, celecoxib is associated with a significantly lower risk of all clinically significant GI events throughout the entire GI tract. This pooled analysis of 52 RCTs significantly advances the understanding of the upper and lower GI safety profile of celecoxib and its potential benefits to patients.

Gastroprotection in patients prescribed non-selective NSAIDs, and the risk of related hospitalization

ABSTRACT Objective: To assess co-prescription of gastroprotective agents (GPAs) for non-selective NSAID (nsNSAID)-treated patients in UK primary care, and the rate of gastrointestinal (GI)-related hospitalizations occurring with varying levels of GPA use in patients at high Gl risk. Research design and methods: A retrospective, observational study was conducted using the DIN-LINK UK primary care database, on patients prescribed nsNSAIDs alone or concomitantly with GPAs between September 2003 and August 2005. Patients were stratified by GI risk, frequency of nsNSAID use and level of GPA use. Rates and odds ratios of GI-related hospitalizations were calculated for high GI–risk patients. Results: In August 2005, 26 371 patients with nsNSAID prescriptions were identified, of whom 55% were frequent users. In the overall and frequent nsNSAID-user populations, 74% and 71%, respectively, were co-prescribed none or few GPAs (0–19% level of use), and only 18% and 20%, respectively, received complete gastroprotection. GI risk factors were identified in 76% of all patients. Overall, 70% of patients with serious co-morbidity, 44% with GI event history, and 56% of aspirin users received little or no gastroprotection (0–19%). Data for previous months of the analysis period were similar. In patients with a GI-event history, based on data over the 2-year study period, hospitalization rates ranged from 2.4% (with full gastroprotection) to 8.0% (20–39% GPA use). Odds of a GI-related hospitalization were up to 3.5 times higher with low GPA use. Conclusion: This study revealed low levels of GPA co-prescription for nsNSAID users in UK primary care, even among high-risk patients. Lower levels of GPA co-therapy were associated with increasing rates of GI-related hospitalization.

Nurse practitioners, wake up and smell the smoke

Purpose: With the focus of modern health care on preventive care, and the well‐known benefits of smoking cessation on improving health and reducing healthcare costs, smoking cessation is a key focus of healthcare reform. To change the smoking habits of the U.S. population, two strategies are of particular importance to healthcare professionals: promoting tobacco‐free environments in healthcare systems and expanding affordable and effective treatments. Data sources: Recent policy literature. Conclusions: Barriers to providing smoking cessation counseling most frequently cited by healthcare professionals are lack of training and poor reimbursement; however, recent legislation, for example, the Patient Protection and Affordable Care Act (PPACA), should make preventive services more available and affordable. Nurse practitioners (NPs) have vast experience in addressing health promotion and disease prevention, and are therefore well placed to lead this reform. However, despite consistently higher referrals of tobacco‐dependent patients for smoking cessation interventions than any other group of healthcare provider, evidence suggests that NPs are not adequately trained to treat this addiction. Implications for practice: This article is a call to action for NPs to become familiar with the tobacco cessation policy changes affecting clinical practice, to become experts in tobacco treatment, and to take the lead in this healthcare reform initiative.

Burden of smoking on quality of life in patients with chronic obstructive pulmonary disease

The objective of this study was to assess the impact of smoking on health-related quality of life, Work Productivity and Activity Impairment (WPAI) in chronic obstructive pulmonary disease (COPD) patients. Respondents of the 2009/2010 US National Health and Wellness Survey (NHWS), aged ≥40 years, with COPD, chronic bronchitis or emphysema, were included in the study. Current and former (had not smoked for ≥11 years) smokers were compared. Physical component summary (PCS) and mental component summary (MCS) scores from the Short Form-12 version 2 (SF-12v2), health utilities (SF-6D) and WPAI were evaluated. Differences between current (n = 1685) and former (n = 1932) smokers were revealed: MCS (44.80, 46.73; p < 0.01); PCS (35.12, 35.79; p < 0.1); SF-6D (0.63, 0.65; p < 0.05). WPAI: presenteeism (23%, 18%; p < 0.05); work impairment (25%, 21%; p < 0.05); activity impairment (52%, 49%; p < 0.01). In conclusion, COPD patients who smoke have poorer health-related quality of life, impaired productivity and higher healthcare costs than former smokers.

Impact of access restrictions on varenicline utilization

Aim: To assess the impact of access restrictions on varenicline utilization. Methods: Employer-sponsored health plans contributing to the MarketScan Commercial Claims and Encounters Database were categorized according to 2009 varenicline access restrictions: no coverage; prior authorization; smoking cessation program requirement; no restrictions. The cohort comprised all adults continuously enrolled in plans during 2009. Each restriction cohort was compared with the no restrictions cohort using descriptive analyses. Data were assessed using logistic regression; demographic and clinical characteristics were covariates. Results: In this study (no coverage, n = 454,419; prior authorization, n = 171,530; smoking cessation program, n = 108,181; no restrictions, n = 607,389), compared with the no restrictions cohort, the odds of treatment were 71% lower (odds ratio: 0.29; 95% CI: 0.26, 0.31) in the smoking cessation program cohort (p < 0.001) and 80% lower (odds ratio: 0.20; 95% CI: 0.19, 0.22) in the prior authorization cohort (p < 0.001). Conclusions: Access restrictions were associated with significantly lower odds for varenicline utilization.

FRI0324 Does High Serum URIC Acid Increase the Risk of Renal Disease in Patients with Gout? Results from a Retrospective Analysis of Electronic Health Record Data

Background Understanding the relationship between hyperuricemia and renal disease may help improve renal outcomes in patients with gout. Objectives To evaluate the association between SrUA levels and risk of renal disease in patients with gout using electronic health records (EHR) data. Methods Data for this retrospective analysis were derived from de-identified EHR data in the Humedica database from 2010 through 2013. Patients were adults (≥18 years) with ≥2 ICD-9-CM diagnoses for gout ≥30 days apart (the first ICD-9 diagnosis was the index date), with ≥1 SrUA assessments on or after the index date, and ≥6 months pre- and ≥12 months post-index activity. Renal disease was identified by ICD-9 codes, and included a variety of conditions including acute renal failure, hypertensive chronic kidney disease, renovascular hypertension, nephritis, nephritic syndrome, and nephrosis. Patients were stratified by four defined, clinically relevant SrUA ranges based on their SrUA assessment closest to the renal diagnosis, or their last assessment during the study period for those without a renal diagnosis: Group 1, 0.01-4.0mg/dL (n=5784); Group 2, 4.1-6.0mg/dL (n=9939); Group 3, 6.1-8.0mg/dL (n=12,572); and Group 4, ≥8.1mg/dL (n=9514). Survival curves for each group were generated using Kaplan-Meier (KM) estimates and compared using the log-rank test; patients with any ICD-9 diagnosis of renal disease during the 6-month pre-index period were excluded. A Cox proportional hazards time to renal event analysis was also performed to explore additional potential risk factors among demographic and clinical variables. Results Gout patients were mostly male (72.4%), white (80.9%), with a mean ± SD age of 62.8±13.3 years and a mean ± SD Charlson Comorbidity Index (CCI) of 0.69±1.14. Overall, 14.9% of patients were diagnosed with renal disease during the 12-month post-index period, with 3.4% diagnosed concurrently at the index date. KM curves (Figure) showed significant differences in number of patients diagnosed with renal disease across the groups during the post-index period (P<0.0001). In particular, pairwise comparison showed that renal disease was diagnosed in a significantly higher proportion of patients in Group 4 (>8.1mg/dL), 21.7%, relative to each of the other groups (all P<0.0001) (Figure). Group 1 was significantly greater relative to Group 2, 13.6% vs 11.7% (P<0.001), but was similar to Group 3 (12.7%); Group 3 was also significantly greater than Group 2 (P<0.05). Median time from first SrUA assessment to renal disease diagnosis was shortest in Group 4, 20 days, followed by Group 3, 27 days; the longest median time to renal disease diagnosis, 38 days, was in Group 2. Gender was the only potential risk factor not significant in the model; the largest Hazard Ratios were associated with race (African American vs Caucasian, 1.64) and CCI score (1.34 per unit increase). Conclusions High SrUA appeared to be associated with increased risk of renal disease, and very low SrUA may also increase the risk. Further evaluation of the relationship and mechanisms underlying SrUA and renal disease is warranted. Disclosure of Interest M. Essex Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Hopps Employee of: Pfizer Inc, M. Udall Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Fu Consultant for: Pfizer Inc, E. Bienen Consultant for: Pfizer Inc, J. Mardekian Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, G. Makinson Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

SAT0327 Relationship of Serum Uric Acid Levels with Cardiovascular Disease in Patients with Gout: A Retrospective Analysis of Electronic Health Record Data

Background Hyperuricemia is an established risk factor for gout, but there is less certainty regarding the effect of serum uric acid (SrUA) levels on cardiovascular (CV) disease. Objectives To use electronic health records (EHR) data to evaluate the relationship between SrUA levels and risk of CV disease in patients with gout. Methods This retrospective study used de-identified EHR data from the Humedica database from 2010 through 2013. Patients were adults (≥18 years) with ≥2 ICD-9-CM diagnoses for gout ≥30 days apart (the first diagnosis was the index date), with ≥1 SrUA assessments on or after the index date, and ≥6 months pre- and ≥12 months post-index activity. ICD-9 codes were used to identify CV diseases including myocardial infarction (MI), congestive heart failure (CHF), and coronary artery disease (CAD). Patients were stratified by four defined, clinically relevant SrUA ranges based on their SrUA assessment closest to the CV diagnosis (those with CV diagnoses), or their last assessment during the study period (those without a CV diagnosis): Group 1, 0.01-4.0mg/dL (n=5594); Group 2, 4.1-6.0mg/dL (n=9267); Group 3, 6.1-8.0mg/dL (n=12,548); and Group 4, ≥8.1mg/dL (n=9267). Survival curves for each group were generated using Kaplan-Meier (KM) estimates and compared using the log-rank test; patients with each of the CV diagnoses during the 6-month pre-index period were excluded from that particular analysis. Results Patients were mostly male (71.6%), white (79.4%) with a mean ± SD age of 62.4±13.3 years and a mean ± SD Charlson Comorbidity Index of 0.81±1.31. KM curves for diagnosis of any CV event during the 12-month post-index period (Figure) showed significant differences across the groups (P<0.0001). In pairwise comparisons, Group 4 (≥8.1mg/dL) had a significantly higher incidence of any CV diagnosis, 17.4% (P<0.05 vs all other groups), and Group 1 (0.01-4.0mg/dL) was significantly greater relative to Group 2 (14.4% vs 10.5%; P<0.05) but similar to Group 3 (13.4%). In analyses of individual CV diagnoses, although the incidence of MI was low in all groups, significant differences were observed only for Group 4 (1.8%) relative to Group 2 (1.2%; P<0.0001) and Group 3 (1.5%; P<0.05). However, Group 4 also had significantly higher incidence of CHF (8.2%) and CAD (13.4%) diagnoses relative to all other groups (P<0.0001 for all pairwise comparisons). Group 1 (0.01-4.0mg/dL) had a significantly higher incidence of CHF (5.9%) relative to Group 2 (4.3%; P<0.0001) and Group 3 (4.8%; P<0.001). Similarly for CAD, the incidence in Group 1, 11.6%, was higher than for Groups 2 and 3, 10.2% and 11.1%, respectively, but the difference was only significant relative to the former (P<0.05). Median times to all CV diagnoses were consistently shorter in Group 4. Conclusions High SrUA appears to be associated with increased risk of CV disease, which was primarily driven by CAD and CHF, and very low SrUA may also increase the CV risk. However, neither the effects of pharmacologic therapy for hyperuricemia on these outcomes nor the longitudinal changes in SrUA were determined. Further research is warranted. Disclosure of Interest M. Essex Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Hopps Employee of: Pfizer Inc, M. Udall Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Fu Consultant for: Pfizer Inc, E. Bienen Consultant for: Pfizer Inc, J. Mardekian Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, G. Makinson Shareholder of: Pfizer Inc, Employee of: Pfizer Inc