Increased risk of venous thromboembolic events with corticosteroid vs biologic therapy for inflammatory bowel disease.

BACKGROUND & AIMS: We investigated whether treatment of active inflammatory bowel disease with biologic agents is associated with a reduced risk of venous thromboembolic events (VTEs) compared with corticosteroid therapy. METHODS: We performed a retrospective analysis of 15,100 adults with inflammatory bowel disease who were identified from the Truven Health MarketScan databases. We analyzed data from patients who received 6 months of continuous medical and prescription coverage before and 12 months after their first diagnosis and had no VTE during the 6 months before they first received biologic or corticosteroid therapy. The outcome assessed was any VTE that occurred during the 12-month follow-up period. A multivariate logistic regression model was used to evaluate the effects of biologic, corticosteroid, and combination therapies (biologics and corticosteroids) on VTE risk. RESULTS: Three hundred twenty-five VTEs occurred during the study period (in 2.25% of patients receiving only corticosteroids, in 0.44% of patients receiving biologics, and in 2.49% of patients receiving combination therapy). Compared with patients receiving only corticosteroids, the odds ratio for VTE in patients receiving only biologics was 0.21 (95% confidence interval, 0.05-0.87) in the multivariate model, and the odds ratio for VTE in patients on combination therapy was 1.01. CONCLUSIONS: Compared with treatment with only a biologic agent, corticosteroid therapy is associated with a nearly 5-fold increase in risk for VTE. Combination therapy with corticosteroids and biologic agents was associated with the same risk for VTE as that of corticosteroids alone. Corticosteroids therefore appear to increase risk for VTE.

Adalimumab induces deep remission in patients with Crohn's disease.

BACKGROUND & AIMS: Patients with moderate to severe ileocolonic Crohn's disease (CD) who received adalimumab induction and maintenance therapy had greater rates of mucosal healing than patients who received placebo after adalimumab induction therapy in a 52-week trial (EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing). We investigated whether this treatment also induced deep remission-a composite clinical and endoscopic end point. METHODS: Rates of deep remission, defined as the absence of mucosal ulceration and CD Activity Index scores less than 150, were compared between patients given continuous adalimumab and those given only induction therapy followed by placebo. We assessed the relationships between deep remission and other outcomes among patients who received adalimumab. The outcomes of patients with deep remission were compared with those of patients with only the absence of mucosal ulceration or only clinical remission. RESULTS: Rates of deep remission were 16% in patients given adalimumab vs 10% in those given placebo (P = .34) at week 12, and 19% vs 0% (P < .001) at week 52. Rates of deep remission were greatest among patients who received adalimumab and had CD for 2 years or less (33% at weeks 12 and 52). At week 52, patients who achieved deep remission at week 12 required significantly fewer adalimumab treatment adjustments, hospitalizations, and CD-related surgeries; had significantly less activity impairment; and had better quality of life and physical function compared with patients not achieving deep remission. Deep remission generally was associated with better outcomes than only an absence of mucosal ulceration; outcomes of patients with deep remission vs only clinical remission were similar. Deep remission was associated with estimated total cost savings of $10,360 (from weeks 12 through 52) compared with lack of deep remission. CONCLUSIONS: In an exploratory study of patients with moderate to severe ileocolonic CD who received adalimumab induction and maintenance therapy, patients achieving deep remission appeared to have better 1-year outcomes than those not achieving deep remission. These findings should be validated in large, prospective trials. ClinicalTrials.gov number: NCT00348283.

The effects of adalimumab treatment and psoriasis severity on self-reported work productivity and activity impairment for patients with moderate to severe psoriasis.

BACKGROUND: Psoriasis significantly impairs work productivity and daily activities. OBJECTIVES: We sought to examine the effects of adalimumab on psoriasis-related work productivity and activity impairment and associations between the impairment and psoriasis severity in patients with moderate to severe psoriasis. METHODS: Data were from the first 16 weeks of the Randomized controlled EValuation of adalimumab Every other week dosing in moderate to severe psoriasis TriAL (REVEAL). Outcomes as measured by the Work Productivity and Activity Impairment Questionnaire for Psoriasis (WPAI-Psoriasis) included employment status, total work productivity impairment, and total activity impairment. Logistic regression and analyses of covariance were used to assess the effects of adalimumab and treatment response (≥ 75% improvement in Psoriasis Area and Severity Index responders) on WPAI-Psoriasis outcomes. Longitudinal generalized estimating equations and Pearson correlation coefficients were used to assess associations between WPAI outcomes and psoriasis severity. RESULTS: Greater improvements in total work productivity impairment and total activity impairment were observed with adalimumab treatment versus placebo (15.5 and 11.1 percentage points, respectively; P < .001). Unemployment rate, total work productivity impairment, and total activity impairment were significantly associated with greater baseline psoriasis severity. Changes in WPAI outcomes were significantly correlated with greater psoriasis severity. The Dermatology Life Quality Index had stronger associations with changes in WPAI outcomes compared with clinical severity measures (Psoriasis Area and Severity Index and Physician Global Assessment). LIMITATIONS: REVEAL only included WPAI data for 16 weeks. Therefore, long-term impact of adalimumab treatment on productivity outcomes could not be assessed. In addition, information on occupational job title or industry was not collected and data were not adjusted for psoriatic arthritis. CONCLUSIONS: Adalimumab reduced psoriasis-related work productivity and activity impairment in patients with moderate to severe psoriasis.

Risks of developing psychiatric disorders in pediatric patients with psoriasis.

BACKGROUND: Symptoms of psoriasis can be embarrassing and distressing, and may increase risk of developing psychiatric disorders in young people. OBJECTIVE: We sought to compare incidences of psychiatric disorders between pediatric patients with psoriasis and psoriasis-free control subjects. METHODS: Patients (<18 years) with continuous health plan enrollment 6 months before and after first psoriasis diagnosis (index date) were selected (Thomson Reuters MarketScan database, 2000-2006 [Thomson Reuters, New York, NY]). Patients with psoriasis (N = 7404) were matched 1:5 on age and sex to psoriasis-free control subjects (N = 37,020). Patients were followed from index date to first diagnosis of a psychiatric disorder (ie, alcohol/drug abuse, depression, anxiety disorder, bipolar disorder, suicidal ideation, eating disorder), end of data availability, or disenrollment. Patients with psychiatric diagnoses or psychotropic medication use before the index date were excluded. Cox proportional hazard models controlling for age, sex, and comorbidities were used to estimate the effect of psoriasis on risks of developing psychiatric disorders. RESULTS: Patients with psoriasis were significantly more at risk of developing psychiatric disorders versus control subjects (5.13% vs 4.07%; P = .0001; hazard ratio = 1.25; P = .0001), especially depression (3.01% vs 2.42%; P = .0036; hazard ratio = 1.25; P = .0053) and anxiety (1.81% vs 1.35%; P = .0048; hazard ratio = 1.32; P = .0045). LIMITATIONS: Retrospective, observational studies of medical claims data are typically limited by overall quality and completeness of data and accuracy of coding for diagnoses and procedures. CONCLUSIONS: Pediatric patients with psoriasis had an increased risk of developing psychiatric disorders, including depression and anxiety, compared with psoriasis-free control subjects.

Increased risks of developing anxiety and depression in young patients with Crohn's disease.

OBJECTIVES: Crohn's disease (CD) is associated with substantial psychosocial burden and increased risks for mental health disorders. This retrospective cohort study compared the risks of developing anxiety disorders and depression and incidences of psychotropic medication use between young CD patients and matched CD-free controls. METHODS: Medical claims, prescription drug claims, enrollment, and demographic data for patients <18 years diagnosed with CD were obtained from the MarketScan database (1 January 2000-30 June 2006). Each CD patient was matched with five CD-free controls based on exact age, sex, and months of health plan enrollment. Incidence rates and risks of developing anxiety disorders and depression and psychotropic medication use in the 6 months after the index date were compared, as were risks of developing persistent anxiety or depression (receiving medical services related to a diagnosis of anxiety or depression or psychotropic therapy for >1 year). RESULTS: After adjustment for patient characteristics, the risks of developing anxiety disorders (hazard ratio (HR) [95% confidence interval (CI);[equals;2.28 [1.65-3.17]) and depression (HR [95% CI;[equals;1.74 [1.35-2.25]) after CD diagnosis were significantly greater for the CD cohort (N=2,144) than for CD-free controls (N=10,720). Patients with CD also had greater risks of developing persistent anxiety and persistent depression (HR [95% CI;[equals;4.35 [2.22-8.50] and 2.75 [1.73-4.38], respectively). CONCLUSIONS: Compared with matched CD-free controls, young patients with CD had significantly greater risks of developing anxiety disorders and depression, were more likely to receive psychotropic treatments, and had significantly greater risks of developing persistent anxiety and depression.

Effects of adalimumab versus placebo on risk of symptom worsening in psoriasis and subsequent impacts on health-related quality-of-life: analysis of pooled data from two randomized, double-blind, placebo-controlled, multicentre clinical trials.

BACKGROUND: Rates and impacts of worsening symptoms in patients with psoriasis have not been well characterized. OBJECTIVES: To assess the risk of clinically relevant worsening of psoriasis symptoms in patients treated with adalimumab versus placebo and to determine the health-related quality-of-life (HRQOL) impacts of such worsening. METHODS: The cumulative incidence of worsening was compared for adalimumab (40 mg every other week following an 80 mg induction dose) versus placebo using data from two phase III randomized, placebo-controlled trials (CHAMPION and REVEAL). Clinically relevant worsening of psoriasis was defined as a follow-up visit with a ≥25% increase in the Psoriasis Area and Severity Index (PASI) from baseline or a ≥5-unit increase in the Dermatology Life Quality Index from baseline during the initial 16-week double-blind treatment periods. Patients with versus without worsening were compared in terms of pain, work productivity and activity impairment (WPAI) and the mental and physical component summary (MCS and PCS) scores of the Short-Form 36 Health Survey. A subgroup analysis was performed for patients with PASI 10-20 at baseline. RESULTS: The 17-week risk of clinically relevant worsening was 37.0% (95% CI 26.1, 46.3) for placebo (n = 445) and 4.2% (95% CI 2.0, 6.3) for adalimumab-treated patients (n = 914) [p < 0.0001]. Patients with versus without worsening experienced substantially increased pain, increased WPAI and greater impairment in MCS and PCS. Results were similar for patients with PASI 10-20 at baseline. LIMITATIONS: The short study duration may not reflect long-term outcomes. CONCLUSION: Clinically relevant worsening of psoriasis symptoms was associated with substantial worsening of HRQOL. Adalimumab treatment was associated with a substantially reduced risk of clinically relevant worsening.

Benefit-risk analysis of adalimumab versus methotrexate and placebo in the treatment of moderate to severe psoriasis: comparison of adverse event-free response days in the CHAMPION trial.

BACKGROUND: The Comparative Study of Humira versus Methotrexate (MTX) versus Placebo in Psoriasis Patients (CHAMPION) demonstrated superior efficacy of biologic over conventional systemic immunosuppressant therapy in psoriasis. OBJECTIVE: We sought to compare the risk-benefit profile of adalimumab (ADA), MTX, and placebo using data from CHAMPION. METHODS: Patients randomized to ADA (n = 107), MTX (n = 110), or placebo (n = 53) were followed up for 16 weeks. Response (≥75% improvement in Psoriasis Area and Severity Index), days free of adverse events (AEs), moderate to severe AEs, infection-related AEs, and study drug-related AEs were analyzed. RESULTS: ADA treatment was associated with substantially more days (SD) of AE-free response compared with MTX or placebo treatment, respectively: 36.9 (31.1) versus 8.3 (15.9) or 6.7 (18.1) days of response free of any AEs, 43.8 (31.9) versus 11.1 (19.9) or 7.9 (19.9) days of response free of moderate to severe AEs, 48.5 (29.2) versus 12.4 (21.7) or 9.2 (21.8) days of response free of infection-related AEs, and 44.6 (31.4) versus 11.8 (21.1) or 10.0 (24.0) days free of study drug-related AEs (all P < .0001 for ADA vs MTX or placebo). LIMITATIONS: This clinical trial-based analysis may not have captured the full spectrum of AEs in the actual clinical setting. The short (16-week) duration of the trial limited the ability to capture some important but uncommon AEs associated with long-term ADA or MTX use. CONCLUSION: With 4 times as many AE-free response days, ADA demonstrated a superior benefit-risk profile.

Impact of adalimumab on symptoms of psoriatic arthritis in patients with moderate to severe psoriasis: a pooled analysis of randomized clinical trials.

BACKGROUND: Psoriatic arthritis often affects patients with psoriasis. OBJECTIVE: To examine the effect of adalimumab on psoriatic arthritis in patients with moderate to severe psoriasis. METHODS: Data from patients with psoriasis and a reported history of comorbid psoriatic arthritis in 3 randomized, placebo-controlled psoriasis trials of adalimumab were analyzed. RESULTS: Adalimumab (n = 274) reduced the risk of psoriatic arthropathy adverse events by 75% versus placebo (1.1 vs. 4.8%; p = 0.025). Psoriasis/psoriatic arthritis-related pain was significantly reduced (-31.3 vs. -5.6 visual analog scale units; p < 0.0001). At week 16, adalimumab-treated patients were more likely to respond (56.9 vs. 4.5%; p < 0.001) and responded for a greater percentage of follow-up time (39.3 vs. 2.9%; p< 0.0001) than placebo-treated patients (regression model for PASI 75 and ACR 20 responses). CONCLUSION: Adalimumab treatment of moderate to severe psoriasis reduced symptoms of comorbid psoriatic arthritis.

High prevalence of potential drug-drug interactions for psoriasis patients prescribed methotrexate or cyclosporine for psoriasis: associated clinical and economic outcomes in real-world practice.

BACKGROUND: Methotrexate (MTX) and cyclosporine (CYC) may adversely interact with common medications in patients with psoriasis. OBJECTIVE: Our purpose was to investigate the prevalence and outcomes of MTX/CYC polypharmacy. METHODS: We evaluated rates of events that may be associated with drug-related toxicity, health care resource utilization and costs for patients with psoriasis in the Ingenix(R) Impact National Managed Care Database (1999-2007) who were exposed or not exposed to potential drug-drug interactions. RESULTS: Among 4,583 (57.6%) exposed and 3,372 (42.4%) nonexposed patients, nonsteroidal anti-inflammatory drugs and antibiotics were the most common drugs with potential interactions. The exposed patients had significantly greater risks of developing renal [adjusted odds ratio (OR): 2.58; p = 0.0145], gastrointestinal (OR: 1.36; p = 0.0197) and pulmonary events (OR: 1.20; p = 0.0470), and significantly greater health care resource utilization (e.g. OR for inpatient and emergency department visits: 1.47; p < 0.0001) and costs (adjusted incremental cost: USD 1,722; p < 0.0001). CONCLUSIONS: MTX/CYC polypharmacy is prevalent in patients with psoriasis and associated with significant risks.

Comparison of two adalimumab treatment schedule strategies for moderate-to-severe Crohn's disease: results from the CHARM trial.

OBJECTIVES: To compare outcomes of induction dosing followed by continuous adalimumab treatment with those of induction dosing with reinitiation of adalimumab (in the event of clinical deterioration) for patients with moderate-to-severe Crohn's disease (CD) who participated in the Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM). METHODS: In the CHARM trial, all patients received open-label induction therapy with adalimumab 80 mg and 40 mg at weeks 0 and 2, respectively. In total, 778 patients were randomized at week 4 to one of three groups: (1) placebo after initial induction doses (followed by reinitiation of adalimumab therapy); (2) continuous maintenance treatment with adalimumab 40 mg every other week (e.o.w.); and (3) continuous maintenance treatment with adalimumab 40 mg every week. At/after week 12, patients receiving placebo with flare or non-response could reinitiate open-label adalimumab 40 mg e.o.w., and patients receiving continuous blinded adalimumab therapy could switch to open-label 40 mg e.o.w. Patients in all groups could switch to weekly therapy with continued flare/non-response. In the previously published primary analysis, results for only those patients who had responded at week 4 (decrease in Crohn's Disease Activity Index (CDAI) of > or = 70 points, referred to as "randomized responders") and remained on blinded therapy were analyzed. In this analysis, data from all randomized patients were analyzed based on original randomized treatment using an intention-to-treat analysis, regardless of whether they subsequently switched to open-label therapy. Disease activity, clinical remission, number of flares, Inflammatory Bowel Disease Questionnaire (IBDQ) score, number of CD-related surgeries, and hospitalization incidence were compared between the continuous and induction only/reinitiation adalimumab groups. RESULTS: Results for all outcome measures were superior for both continuous groups compared with the induction only/reinitiation group. On the basis of median CDAI and IBDQ results, patients in both continuous treatment groups achieved statistically significantly greater improvements vs. the induction only/reinitiation group (P < 0.05). At week 56, a significantly greater percentage of patients who had received continuous adalimumab (51% for e.o.w. and 49% for weekly) were in clinical remission vs. the induction only/reinitiation group (38%, P < 0.05). Continuous adalimumab therapy was also associated with fewer flares and fewer CD-related surgeries (P < 0.05). Patients in both continuous adalimumab groups had significantly lower risks of CD-related and all-cause hospitalizations than did patients in the induction only/reinitiation group (P < 0.05). CONCLUSIONS: For patients with active CD, continuous treatment with adalimumab was more effective than a strategy of induction dosing followed by reinitiation of adalimumab with clinical deterioration for maintenance of clinical remission, improved quality-of life outcomes, reduced flares, and a decrease in number of surgeries and risk of hospitalization.

Cost utility of adalimumab versus infliximab maintenance therapies in the United States for moderately to severely active Crohn's disease.

OBJECTIVE: To determine and compare the cost utilities of the tumour necrosis factor (TNF) antagonists adalimumab and infliximab as maintenance therapies for patients in the US with moderately to severely active Crohn's disease. METHODS: Maintenance regimens of adalimumab (40 mg every other week) and infliximab (5 mg/kg) were compared using primary data from the CHARM and published data from the ACCENT I clinical trials. Differences in study samples were minimized by matching and weighting baseline characteristics (Crohn's Disease Activity Index score, age and sex) between the patient groups using the primary clinical trial data. Utilization data were estimated from trial data. Unit costs of TNF antagonists (year 2007 values), hospitalizations (year 2006 values), and other medical costs (year 2006 values) were derived from a systematic literature search. Standard gamble-calculated primary data were used to derive health-utility estimates. Data were analysed in a cost-utility framework from a private payer perspective over a 56-week time horizon. Univariate and probabilistic sensitivity analyses were used to explore uncertainty related to the base-case cost-utility analysis. Given the time horizon, costs and effects were not discounted. RESULTS: Adalimumab- and infliximab-treated patients were in remission for 47.2% and 37.1% of the 56-week period, respectively. Hospital admissions were 34-40% lower for adalimumab than for infliximab, based on the model and observed data, respectively. Patients treated with adalimumab accrued greater expected QALYs (0.014; 95% CI 0.000, 0.022) and lower costs (-$US4852; 95% CI -6758, 491) in the first year of therapy than patients treated with infliximab. Compared with infliximab maintenance therapy, adalimumab had lower drug and administration costs, less drug waste, and lower hospitalization rates. Univariate and multivariate probabilistic sensitivity analyses suggested that these results were robust. CONCLUSIONS: This analysis suggests that adalimumab maintenance therapy is a dominant strategy versus infliximab maintenance therapy for patients with moderate to severe Crohn's disease. Adalimumab appeared more effective and less costly than infliximab.

Loss of treatment response to infliximab maintenance therapy in Crohn's disease: a payor perspective.

OBJECTIVES: To assess the incidence and economic implications of loss of treatment response among patients with Crohn's disease (CD) treated with infliximab maintenance therapy. METHODS: This was a retrospective observational study of infliximab response and costs among patients with CD using a large health-care claims database. Patients with CD receiving infliximab maintenance therapy with an initial response were selected from the Integrated Healthcare Information Services claims database (1999-2005). Patients' claim histories were used to identify patterns of response to infliximab treatment. Incidence of loss of response was estimated using Kaplan-Meier method. Annual total health-care and CD-related costs were estimated and adjusted for inflation to 2005 US dollars. Generalized linear model was used to assess the impact of loss of response on treatment costs. RESULTS: The study sample included 262 patients with CD with an initial response to infliximab therapy. Within 24 months of therapy initiation, 77% of patients lost treatment response. Upward dose adjustment, a new drug therapy for CD, and CD-related emergency room or inpatient visits were the three most common indicators of loss of response. Both annual total and CD-related health-care costs for patients who lost treatment response during the first year were found to be approximately one-third higher than for those who did not lose response. CONCLUSIONS: The majority of patients who had initial responses to infliximab maintenance treatment subsequently lost response within 2 years. Loss of response was associated with a significant increase in total health-care and CD-related costs.

Adalimumab improves patient-reported outcomes and reduces indirect costs in patients with moderate to severe Crohn's disease: results from the CARE trial.

BACKGROUND AND AIMS: Crohn's disease negatively affects patients' quality of life and ability to work. We investigated the impact of adalimumab on work productivity, daily activities, and quality of life in an open-label trial (N=945). The population comprised both infliximab-naïve and -exposed patients, including infliximab primary non-responders. METHODS: Patients received adalimumab induction therapy (160 mg/80 mg at Weeks 0/2), followed by adalimumab 40 mg every other week for up to 20 weeks (patients with flares/non-response could receive 40 mg weekly at/after Week 12). The Work Productivity and Activity Impairment Questionnaire and Short Inflammatory Bowel Disease Questionnaire were assessed. Indirect cost savings were estimated based on the average work productivity improvements at Week 20. RESULTS: Mean baseline scores indicated severe productivity impairment and poor quality of life. At Week 20, 60% of infliximab-naïve and 47% of infliximab primary non-responders achieved clinically important improvements (≥9 points) on the Short Inflammatory Bowel Disease Questionnaire, and 51% and 43%, respectively, achieved the minimum clinically important difference (improvement ≥7 percentage points) for total work productivity impairment (non-responder imputation). At Week 20, 64% of infliximab-naïve and 55% of infliximab primary non-responders achieved clinically important improvements in total activity impairment. Estimated 20-week total indirect productivity-related cost savings were €3070 per infliximab-naïve patient and €2059 per infliximab-exposed patient. CONCLUSIONS: Adalimumab therapy significantly improved work productivity and disease-specific quality of life for patients with moderate to severe Crohn's disease. Patients who failed prior infliximab therapy and patients naïve to infliximab benefited from adalimumab, with potentially greater benefits for infliximab-naïve patients (NCT00409617).

Comparison of medical costs among patients using adalimumab and infliximab: a retrospective study (COMPAIRS).

BACKGROUND: Anti-tumor necrosis factor (TNF) medications have similar efficacy in Crohn's disease (CD), but have not been compared in the real world. This study compared health costs and utilization for patients with CD newly initiating anti-TNF therapy with adalimumab (ADA) or infliximab (IFX) by using insurance data. METHODS: CD patients initiating ADA or IFX therapy were identified from the MarketScan database. ADA and IFX groups were matched using a propensity score. The primary endpoint was direct costs of healthcare for the 6 months following initiation. The secondary endpoints compared healthcare utilization between groups. RESULTS: After propensity matching, characteristics were similar between the ADA (n = 623) and IFX (n = 623) groups. During the 6-month interval following anti-TNF initiation, healthcare costs were significantly lower for ADA compared with IFX. Total healthcare cost was $18,885 for ADA and $24,355 for IFX, a difference in cost of $5,470 (P < 0.0001). CD-related costs made up the majority of the costs: $16,454 for ADA and $22,316 for IFX (P < 0.0001). The largest difference in cost was seen in outpatient visits: $2,082 difference between the two groups (P < 0.0001). Both all-cause and CD-related hospitalization decreased for both ADA and IFX groups. Emergency room and hospitalization use in the 6-month follow-up period was not statistically different between groups, although numerically slightly higher in the IFX group. CONCLUSIONS: Patients with CD using ADA had lower healthcare costs than patients using IFX; this difference was partly driven by outpatient medical costs.

Risk-benefit analysis of adalimumab versus traditional non-biologic therapies for patients with Crohn's disease.

BACKGROUND: Adalimumab is indicated for the treatment of moderately to severely active Crohn's disease (CD). A systematic analysis of risks and benefits of adalimumab versus traditional non-biologic therapies for patients refractory to non-biologic therapy is lacking. METHODS: A base-case analysis compared expected benefits of adalimumab therapy with a 12-week stopping rule for non-responders versus non-biologic therapies using data from clinical trials (CHARM, CLASSIC I). Adverse events (AEs) recorded in clinical trials (CHARM, CLASSIC I, CLASSIC II, GAIN, open-label extensions) were compiled. Sensitivity analyses incorporated all observed benefits of adalimumab and placebo (CHARM, CLASSIC I, GAIN) and observed AEs from a systematic literature review of non-biologic therapies (MEDLINE search of randomized trials 1990-2007). Distributional information from maintenance clinical trial observations and benefit model predictions were used in a probabilistic simulation. Incremental net benefits were estimated based on utility estimates from the literature. RESULTS: Average time in remission (i.e., CDAI <150) over 1 year of therapy was 39.9% for adalimumab versus 6.6% for traditional non-biologic therapies. Adalimumab was associated with fewer expected hospitalizations, better fistula closure rates, and lower AE rates. These findings were robust in sensitivity analyses. In the probabilistic simulation, with serious AEs as a composite of risks, adalimumab provided greater benefits with fewer AEs versus non-biologic therapies (P < 0.01). Adalimumab demonstrated greater incremental net quality-adjusted life-years (0.12) versus non-biologic therapies. CONCLUSIONS: Adalimumab demonstrated greater benefits and lower rates of AEs versus traditional non-biologic therapies for patients with moderately to severely active CD who were refractory to non-biologic therapies.

Efficacy and safety of adalimumab among patients with moderate to severe psoriasis with co-morbidities: Subanalysis of results from a randomized, double-blind, placebo-controlled, phase III trial.

BACKGROUND: Psoriasis is associated with a variety of major physical and mental co-morbidities. OBJECTIVE: To assess the incremental burden of co-morbidities on patient-reported outcomes and evaluate the efficacy and safety of adalimumab in psoriasis patients with co-morbidities. STUDY DESIGN: Data were obtained from the initial 16-week, double-blind treatment period of REVEAL (Randomized controlled EValuation of adalimumab Every other week dosing in moderate to severe psoriasis triAL), a randomized, multicenter, phase III clinical trial. INTERVENTION: Patients with moderate to severe psoriasis were randomized in a 2 : 1 ratio to receive adalimumab 80 mg (two 40 mg injections administered subcutaneously) at baseline followed by one 40 mg injection every other week from week 1 to week 15 or placebo. MAIN OUTCOME MEASURES: Clinical severity (Psoriasis Area and Severity Index [PASI]) and patient-reported outcomes (Dermatology Life Quality Index [DLQI], Short Form 36 [SF-36] health survey, Work Productivity and Activity Impairment [WPAI] questionnaire) were assessed during the trial. The effect of selected co-morbidities (i.e. hypertension, psoriatic arthritis, hyperlipidemia, obesity, depression, other forms of arthritis, diabetes mellitus, and other cardiovascular diseases) on patient-reported outcomes was evaluated using multivariate analysis of covariance models. Subgroup analyses were performed by co-morbidity type to statistically compare the clinical efficacy, patient-reported outcome benefits, and safety of adalimumab with placebo in the presence of these conditions. RESULTS: Study co-morbidities were each independently associated with significantly greater impairment on at least one general patient-reported outcome measured at baseline (all p < 0.05), with the exception of hyperlipidemia. During the 16-week study, adalimumab patients demonstrated significantly greater PASI 75 response rates (defined as a reduction of at least 75% in PASI scores from baseline) compared with placebo patients for all co-morbidity subgroups. Adalimumab provided consistent improvements in DLQI, SF-36 Physical Component Summary and Mental Component Summary scores, and WPAI total scores from baseline to week 16 within co-morbidity subgroups. Rates of serious adverse events (AEs), serious infectious AEs, and AEs leading to discontinuation were comparable between adalimumab and placebo for patients with co-morbidities. CONCLUSIONS: Co-morbidities were associated with additionally impaired health-related quality of life and work productivity in patients with psoriasis. Adalimumab significantly improved efficacy and patient-reported outcomes and was well tolerated in patients with co-morbidities.

Greater refill adherence to adalimumab therapy for patients using specialty versus retail pharmacies.

INTRODUCTION: Retail pharmacies provide regular prescription drugs and some specialty prescription drugs, whereas specialty pharmacies focus on distributing specialty prescription drugs, including tumor necrosis factor (TNF) antagonists. It is unknown whether pharmacy type impacts patients' adherence to anti-TNF therapy. The relationship between pharmacy type (specialty vs. retail) and refill adherence to therapy with the TNF antagonist adalimumab was examined. METHODS: This was a retrospective analysis of dispensing records of patients in the United States who were prescribed a TNF antagonist (adalimumab 40 mg per 0.8-mL injection) during a dispensation period from January 2003 to August 2009. Patients treated with adalimumab were included in the analysis regardless of diagnosis. For each patient, medication refill adherence (MRA) was calculated as total days of supply divided by total number of days evaluated, multiplied by 100. A regression analysis was conducted in which the dependent variable was MRA and the independent variables included pharmacy type (specialty vs. retail pharmacy), reimbursement/payment type, copayment/payment amount per prescription, age, sex, ethnicity, and annual income. RESULTS: Of the 86,079 patients included, 70% obtained the medication from a specialty pharmacy, 92% were members of Blue Cross and Blue Shield plans, 67% were women, and 81% were white. The average MRA was 84, and the average age was 52 years. Significant predictors (P<0.05) of MRA included pharmacy type, reimbursement/payment type, copayment/payment amount per prescription, age, sex, and ethnicity; and pharmacy type was the strongest predictor. When other independent variables were controlled for, MRA was 16% less for patients who used a retail pharmacy vs. patients who used a specialty pharmacy. CONCLUSION: Patients who used a specialty pharmacy to fulfill prescriptions for a TNF antagonist had a greater refill adherence than did patients who used a retail pharmacy.

Comparative effectiveness without head-to-head trials: a method for matching-adjusted indirect comparisons applied to psoriasis treatment with adalimumab or etanercept.

The absence of head-to-head trials is a common challenge in comparative effectiveness research and health technology assessment. Indirect cross-trial treatment comparisons are possible, but can be biased by cross-trial differences in patient characteristics. Using only published aggregate data, adjustment for such biases may be impossible. Although individual patient data (IPD) would permit adjustment, they are rarely available for all trials. However, many researchers have the opportunity to access IPD for trials of one treatment, a new drug for example, but only aggregate data for trials of comparator treatments. We propose a method that leverages all available data in this setting by adjusting average patient characteristics in trials with IPD to match those reported for trials without IPD. Treatment outcomes, including continuous, categorical and censored time-to-event outcomes, can then be compared across balanced trial populations. The proposed method is illustrated by a comparison of adalimumab and etanercept for the treatment of psoriasis. IPD from trials of adalimumab versus placebo (n = 1025) were re-weighted to match the average baseline characteristics reported for a trial of etanercept versus placebo (n = 330). Re-weighting was based on the estimated propensity of enrolment in the adalimumab versus etanercept trials. Before matching, patients in the adalimumab trials had lower mean age, greater prevalence of psoriatic arthritis, less prior use of systemic treatment or phototherapy, and a smaller mean percentage of body surface area affected than patients in the etanercept trial. After matching, these and all other available baseline characteristics were well balanced across trials. Symptom improvements of ≥75% and ≥90% (as measured by the Psoriasis Area and Severity Index [PASI] score at week 12) were experienced by an additional 17.2% and 14.8% of adalimumab-treated patients compared with the matched etanercept-treated patients (respectively, both p < 0.001). Mean percentage PASI score improvements from baseline were also greater for adalimumab than for etanercept at weeks 4, 8 and 12 (all p < 0.05). Matching adjustment ensured that this indirect comparison was not biased by differences in mean baseline characteristics across trials, supporting the conclusion that adalimumab was associated with significantly greater symptom reduction than etanercept for the treatment of moderate to severe psoriasis.

Adherence to infliximab maintenance therapy and health care utilization and costs by Crohn's disease patients.

INTRODUCTION: Studies suggest infliximab decreases hospitalization and surgery rates in Crohn'fs disease (CD). The aim of this analysis was to evaluate adherence to infliximab maintenance therapy and the impact of medication adherence on health care utilization and costs by patients with CD. METHODS: Patients with CD who had at least four infliximab infusions (with the time between consecutive infusions < or =12 weeks for the first four infusions) during the first year following infliximab initiation (index date) were identified from the Integrated Health Care Information Service claims database (2002-2006). Nonadherence was defined as fewer than seven infliximab infusions in the first year. One-year health care resource utilization and costs (excluding infliximab drug and administration costs) were compared between adherent and nonadherent patients, with adjustment for baseline characteristics. RESULTS: A total of 571 patients with CD who were receiving infliximab maintenance therapy were identified. The infusion-based nonadherence rate was 34.3% during the first year of therapy. The multivariate analysis demonstrated that compared with adherent patients, nonadherent patients were more likely to have been hospitalized (odds ratio [OR]=2.7 [all-cause] and OR=2.5 [CD-related]; both P<0.001). Compared with infliximab-adherent patients, adjusted medical costs by nonadherent patients were 73% ($6,692) and 90% ($4,961) greater for all-cause and CD-related medical costs, respectively (both P<0.001), and adjusted hospitalization costs were 115% ($11,450) and 115% ($9,570) greater for all-cause and CD-related hospitalization costs, respectively (both P<0.001). CONCLUSION: More than one-third of patients on infliximab maintenance therapy were nonadherent to recommended maintenance. Further, nonadherence was associated with increased medical costs and a greater rate of hospitalization.

Cost-effectiveness of adalimumab for the maintenance of remission in patients with Crohn's disease.

OBJECTIVE: Adalimumab is a fully human, monoclonal antibody clinically effective for the treatment of active Crohn's disease. The cost-effectiveness of adalimumab versus conventional, nonbiologic pharmacotherapies is unknown. This study evaluated the cost-effectiveness of adalimumab versus conventional, nonbiologic pharmacotherapies in the maintenance of Crohn's disease. METHODS: Trial data from two randomized controlled studies [Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM) and CLinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn's Disease (CLASSIC I)] were analyzed within a cost-utility framework using a 1-year horizon from the perspective of the National Health Service (UK). The treatment efficacy and use for the adalimumab arm were based on observations from CHARM. A regression model used data from CLASSIC I to predict efficacy in patients who received nonbiologic pharmacotherapy. Unit costs of drugs, hospitalization, and other medical resources were derived from the literature. Primary standard gamble-calculated data were used to derive health-utility estimates. RESULTS: Compared with conventional, nonbiologic pharmacotherapy, adalimumab seemed to be cost-effective for the treatment of patients with severe disease and moderate-to-severe disease. The 56-week incremental cost-effectiveness ratio was 16 064 UK pounds/quality-adjusted life-year and 33 731 UK pounds/quality-adjusted life-year for severe and moderate-to-severe groups, respectively. Sensitivity analyses showed that the findings were robust. In the treatment of patients over their lifetimes, the incremental cost-effectiveness ratio was 6550 UK pounds/quality-adjusted life-year and 17 873 UK pounds/quality-adjusted life-year for patients with severe Crohn's disease and those with moderate-to-severe Crohn's disease, respectively. CONCLUSION: Adalimumab maintenance therapy seems to be cost-effective versus conventional, nonbiologic therapies for the maintenance of remission in patients with active Crohn's disease.