The comparative safety of abciximab versus eptifibatide in patients on dialysis undergoing percutaneous coronary intervention: Insights from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2).

OBJECTIVES: We sought to evaluate the patterns of use and outcomes associated with eptifibatide and abciximab administration among dialysis patients who underwent percutaneous coronary intervention (PCI). BACKGROUND: Contraindicated medications are frequently administered to dialysis patients undergoing PCI often resulting in adverse outcomes. Eptifibatide is a glycoprotein IIb/IIIa inhibitor that is often used during PCI and is contraindicated in dialysis. METHODS: We included dialysis patients who underwent PCI from January 2010 to September 2015 at 47 hospitals in Michigan. We compared outcomes between patients who received eptifibatide compared with abciximab. Both groups required concurrent treatment with unfractionated heparin only. In-hospital outcomes included repeat PCI, bleeding, major bleeding, need for transfusion, and death. Optimal full matching was used to adjust for non-random drug administration. RESULTS: Of 177 963 patients who underwent PCI, 4303 (2.4%) were on dialysis. Among those, 384 (8.9%) received eptifibatide and 100 (2.3%) received abciximab. Prior to matching, patients who received eptifibatide had higher pre-procedural hemoglobin levels (11.3 g/dL vs. 10.7 g/dL; P < 0.001) and less frequently had a history of myocardial infarction (36.5% vs. 52.0%; P = 0.005). After matching, there were no significant differences in in-hospital outcomes between eptifibatide and abciximab including transfusion (aOR: 1.15; 95%CI: 0.55-2.40; P = 0.70), bleeding (1.47; 0.64-3.40; P = 0.36), major bleeding (4.68; 0.42-52.3; P = 0.21), repeat PCI (0.38; 0.03-4.23; P = 0.43), and death (1.53; 0.2-9.05; P = 0.64). CONCLUSIONS: Despite being contraindicated in dialysis, eptifibatide was used approximately 3.5 times more frequently than abciximab among dialysis patients undergoing PCI but was associated with similar in-hospital outcomes.

Digoxin Toxicity and Use of Digoxin Immune Fab: Insights From a National Hospital Database.

OBJECTIVES: This study was developed to determine contemporary management of digoxin toxicity and clinical outcomes. BACKGROUND: Although the use of digoxin in heart failure management has declined, toxicity remains a prevalent complication. METHODS: The Premier Perspective Comparative Hospital Database (Premier Inc., Charlotte, North Carolina) was used to retrospectively identify patients diagnosed with digoxin toxicity and/or who received digoxin immune fab (DIF) over a 5-year period (2007 to 2011). DIF was evaluated using treatment date, number of vials administered, and total cost. Clinical outcomes included length of stay (total hospitalization; days after DIF), cost of hospitalization, and in-hospital mortality. Exploratory multivariate analyses were conducted to determine predictors of DIF and effect on length of stay, adjusting for patient characteristics and selection bias. RESULTS: Digoxin toxicity diagnosis without DIF treatment accounted for 19,543 cases; 5,004 patients received DIF of whom 3086 had a diagnosis of toxicity. Most patients were >65 years old (88%). The predictors of DIF use were urgent/emergent admission, hyperkalemia, arrhythmia associated with digoxin toxicity, acute renal failure, or suicidal intent (odds ratios 1.7, 2.4, 3.6, 2.1, and 3.7, respectively; p < 0.0001 for all). The majority (78%) of DIF was administered on days 1 and 2 of the hospitalization; 10% received treatment after day 7. Digoxin was used after DIF administration in 14% of cases. Among patients who received DIF within 2 days of admission, there was no difference for in-hospital mortality or length of stay compared with patients not receiving DIF. CONCLUSIONS: Digoxin toxicity diagnoses are clustered in the elderly. One-fifth of cases receive treatment with DIF, most within 2 days of admission. Opportunities exist for improved diagnosis and post-DIF management. Prospective data may be required to assess the impact of DIF on length of stay.

FabAV antivenin use after copperhead snakebite: clinically indicated or knee-jerk reaction?

Abstract Background Crotalidae Polyvalent Immune Fab (Ovine) (FabAV) antivenin is commonly recommended after pit viper snakebites. Because copperhead envenomations are usually self-limited, some physicians are reluctant to use this costly treatment routinely, while others follow a more liberal approach. We hypothesized that, in practice, only patients with evidence of significant (moderate or severe) copperhead envenomation [those with snakebite severity score (SSS) > 3] receive FabAV and examined a large cohort to determine the relationship between clinical findings and FabAV administration. Methods All data from patients evaluated for copperhead snakebite at a rural tertiary referral center from 5/2002 to 10/2013 were compiled. Demographics, transfer status, antivenin use, and clinical findings were collected; SSS was calculated. The relationships among FabAV use, clinical findings, and SSS were analyzed using t-test, chi-square, and Pearson’s coefficient (p < 0.05 was significant). Results During the study period, 318 patients were treated for copperhead snakebite; 44 (13.8 %) received antivenin. Median dose was four vials (range: 1–10; IQR: 4,6). There were no deaths. Most patients receiving FabAV (63.6 %) were admitted. With regard to demographics and symptoms, only the degree of swelling (moderate vs. none/mild; p < 0.01) and bite location (hand/arm vs. leg: p < 0.0001) were associated with FabAV use. A SSS > 3, indicating moderate or severe envenomation, was only very weakly correlated with antivenin use (r = 0.217;p < 0.0001). The majority of patients with SSS > 3 (65.8 %) did not receive antivenin while most patients who did receive antivenin (70.5 %) had SSS ≤ 3 (indicating mild envenomation). Conclusions Considerable variation occurs in antivenin administration after copperhead snakebite. Use of FabAV appears poorly correlated with patients’ symptoms. This practice may expose patients to the risks of antivenin and increasing costs of medical care without improving outcomes. Guidelines used for treating other pit viper strikes, such as rattlesnake or cottonmouth snakebite may be too liberal for copperhead envenomations. Our data suggests that most patients with mild or moderate envenomation appear to do well independent of FabAV use. We suggest, for patients with copperhead snakebite, that consideration be given to withholding FabAV for those without clinical evidence of severe envenomation until prospective randomized data are available.

MRI assessment of early response to certolizumab pegol in rheumatoid arthritis: a randomised, double-blind, placebo-controlled phase IIIb study applying MRI at weeks 0, 1, 2, 4, 8 and 16.

OBJECTIVES: To identify the first time point of an MRI-verified response to certolizumab pegol (CZP) therapy in patients with rheumatoid arthritis (RA). METHODS: Forty-one patients with active RA despite disease-modifying antirheumatic drug therapy were randomised 2:1 to CZP (CZP loading dose 400 mg every 2 weeks at weeks 0-4; CZP 200 mg every 2 weeks at weeks 6-16) or placebo→CZP (placebo at weeks 0-2; CZP loading dose at weeks 2-6; CZP 200 mg every 2 weeks at weeks 8-16). Contrast-enhanced MRI of one hand and wrist was acquired at baseline (week 0) and weeks 1, 2, 4, 8 and 16. All six time points were read simultaneously, blinded to time, using the Outcome Measures in Rheumatology Clinical Trials RA MRI scoring system. Primary outcome was change in synovitis score in the CZP group; secondary outcomes were change in bone oedema (osteitis) and erosion scores and clinical outcome measures. RESULTS: Forty patients were treated (27 CZP, 13 placebo→CZP), and 36 (24 CZP, 12 placebo→CZP) completed week 16. In the CZP group, there were significant reductions from baseline synovitis (Hodges-Lehmann estimate of median change, -1.5, p=0.049) and osteitis scores (-2.5, p=0.031) at week 16. Numerical, but statistically insignificant, MRI inflammation reductions were observed at weeks 1-2 in the CZP group. No significant change was seen in bone erosion score. Improvements across all clinical outcomes were seen in the CZP group. CONCLUSIONS: CZP reduced MRI synovitis and osteitis scores at week 16, despite small sample size and the technical challenge of reading six time points simultaneously. This study provides essential information on optimal MRI timing for subsequent trials. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT01235598.

Assessment of income growth in patients with rheumatoid arthritis treated with anti-tumor necrosis factor therapy.

OBJECTIVES: To compare income growth over time between employees with RA treated with anti-TNFs and those treated with methotrexate (MTX). METHODS: Privately insured employees (aged ≥18) with ≥1 RA diagnosis (ICD-9: 714.0) were identified from a large-scale US employer claims database (1998-2011). Patients were stratified into treatment groups (anti-TNF-treated patients and MTX-monotherapy patients) based on their treatment history. The anti-TNF-treated patients comprised patients who filled ≥1 prescription for anti-TNFs, with or without MTX (index date defined as the date of the first anti-TNF prescription). The MTX-treated patients comprised patients who filled ≥1 prescription for MTX-monotherapy (index date randomly selected). The primary study outcome was the annual income growth rate (US dollars). Patients were followed from their index date to health plan disenrollment or the end of data availability (maximum follow-up of 5 years). The effect of treatment type on income growth was assessed using a multivariable generalized estimating equation model, adjusting for key baseline characteristics. Income growth was compared to that of the general employed population using Social Security data (1998-2011). RESULTS: The regression-adjusted annual growth rate in income for anti-TNF-treated patients (n = 1848) was 2.8% (CI = 1.9-3.6%), significantly greater (p < 0.05) than the 0.6% (CI = -0.2-1.4%) for MTX-monotherapy patients (n = 1866). Compared to the general employed population, income growth was lower (p < 0.05) for MTX-monotherapy patients and comparable for anti-TNF-treated patients. CONCLUSIONS: Compared to MTX-monotherapy, anti-TNF treatment is associated with a higher income growth rate among employees with RA. Anti-TNF-treated patients experienced comparable income growth to the general employed population norm.

Health outcomes and cost-effectiveness of certolizumab pegol in the treatment of Crohn's disease.

Crohn's disease (CD) causes chronic inflammation of the gastrointestinal tract and leads to fluctuations between active disease and remission. Certolizumab pegol is one of the newer biological treatments for patients with moderate-to-severe CD. Certolizumab pegol was shown to be effective in CD patients achieving response and remission in both randomized and non-randomized studies, and is an alternative biological treatment for CD. The available data show that certolizumab pegol achieves similar therapeutic efficacy and health-related quality of life scores in CD patients as the other biological agents, but at a higher cost, if dose escalation of other biologics is not considered. Considering subcutaneous self-administration, and lower number and frequency of injections, patients may prefer certolizumab pegol over the other biological treatments.

Effect of certolizumab pegol on multiple facets of psoriatic arthritis as reported by patients: 24-week patient-reported outcome results of a phase III, multicenter study.

OBJECTIVE: To examine the effect of certolizumab pegol (CZP) on patient-reported outcomes (PROs) in psoriatic arthritis (PsA) patients with and without prior tumor necrosis factor (TNF) inhibitor exposure. METHODS: The ongoing phase III RAPID-PsA trial was double blind and placebo controlled to week 24. Patients were randomized 1:1:1 to placebo every 2 weeks or CZP 400 mg at weeks 0, 2, and 4, followed by either CZP 200 mg every 2 weeks or CZP 400 mg every 4 weeks. PRO measures evaluated were the Health Assessment Questionnaire (HAQ) disability index (DI), health status (measured by the Short Form 36 [SF-36] health survey), Psoriatic Arthritis Quality of Life (PsAQOL), Fatigue Assessment Scale, patient assessment of pain (visual analog scale), and Dermatology Life Quality Index (DLQI). Post hoc analyses of PROs in patients with and without prior TNF inhibitor exposure were conducted. Change from baseline for all PROs was analyzed for the randomized population using analysis of covariance with last observation carried forward imputation. RESULTS: A total of 409 patients were randomized. Twenty percent had received a prior TNF inhibitor. Baseline demographics were similar between the treatment groups. At week 24, clinically meaningful differences in HAQ DI, SF-36, PsAQOL, fatigue, pain, and DLQI were observed in both CZP arms versus placebo (P < 0.001), irrespective of prior TNF inhibitor exposure. More CZP-treated patients reached SF-36 general population norms than placebo-treated patients. CONCLUSION: Both CZP dosing schedules provided rapid improvements in PROs across multiple disease aspects in patients with PsA. The benefits of CZP treatment for health-related quality of life were seen across generic, PsA-specific, and dermatology-specific measures and were observed in patients regardless of prior TNF inhibitor exposure.

Evaluation of four sensitive troponin assays for risk assessment in acute coronary syndromes using a new clinically oriented approach for comparison of assays.

BACKGROUND: Measurement of cardiac troponin T or I (cTnT; cTnI) is useful for risk prediction in acute coronary syndromes. The objective of the present study was to compare the prognostic capacity of four sensitive cardiac troponin assays using a new method for comparison. METHODS: Cardiac troponin was analyzed in serum samples from 1335 patients with acute coronary syndrome using the Elecsys high sensitivity TnT (hs-cTnT), ARCHITECT STAT high sensitivity TnI (hs-cTnI), Access AccuTnI (Acc-cTnI) and Architect cTnI (Arc-cTnI) assays. All patients were followed for 30 days regarding death and acute myocardial infarction (AMI), and for 1 year regarding mortality. RESULTS: By receiver operating characteristic (ROC) curve analyses, there were only minor differences in the area under the curves (AUC) between the assays. At a given sensitivity of 85% the hs-cTnT, Arc-cTnI and Acc-cTnI assays showed comparable specificities, while 90% or higher sensitivity was only possible to achieve with the hs-cTnT, hs-cTnI and Acc-cTnI assays. The highest odds ratios for death/AMI at 30 days and death at 1 year, respectively, were reached by cut-off levels yielding 95% sensitivity; these cut-off levels were below the respective 99th percentile levels. CONCLUSIONS: By the adoption of a new method for the comparison of cardiac troponin assays we showed that the hs-cTnT, hs-cTnI and Acc-cTnI assays had comparable prognostic properties, while the Arc-cTnI assay had inferior prognostic sensitivity.

Gender differences in long-term outcome after primary percutaneous intervention for ST-segment elevation myocardial infarction.

BACKGROUND: Previous studies on gender differences in outcome in patients with ST segment elevation myocardial infarction (STEMI) have been performed, but most of those are from before the current era of PCI technique and medical therapy and have a short duration of follow-up. The objective of our study is to assess the influence of gender on long-term outcome in patients with STEMI who underwent primary percutaneous intervention (PCI) between January 2006 and May 2008. METHODS: Two-year follow-up data from 202 female and 668 male patients undergoing primary PCI for STEMI were available from the DEBATER (A Comparison of Drug Eluting and Bare Metal Stents for Primary Percutaneous Coronary Intervention with or without Abciximab in ST-segment elevation Myocardial Infarction: The Eindhoven Reperfusion Study) trial database. The primary endpoint was major adverse cardiac events (MACE), defined as the composite of death, myocardial infarction, and target vessel revascularization. RESULTS: Women were older (64.7 ± 11.7 vs. 59.0 ± 10.7; P < 0.001), and had more often diabetes mellitus (15% vs. 9%; P = 0.01) and hypertension (44% vs. 25%; P < 0.001). At two years, the rate of MACE was significantly higher in women (21% vs. 14%; P = 0.02). The mortality rate in women was 8% versus 2.6% in men (P < 0.001). However, multivariate analysis after adjustment for age and the baseline characteristics hypertension, smoking, diabetes mellitus, stent diameter, and time between onset of symptoms and arrival of the ambulance showed similar MACE and mortality rates in men and women. CONCLUSION: Women have higher rates of both MACE and mortality after primary PCI for STEMI compared to men because of higher age with higher baseline risk profiles.

Would tirofiban have been shown non-inferior to abciximab had the TENACITY trial not been terminated for financial reasons?

OBJECTIVES: To investigate whether tirofiban would have been non-inferior to abciximab had the trial completed enrollment and place the termination of this trial in a broader research ethics context. BACKGROUND: TENACITY was terminated by the sponsor for financial reasons. At the time, event rates for the 2 treatment arms were unknown. METHODS: TENACITY was designed to compare tirofiban with abciximab in approximately 8,000 patients; however, enrollment was terminated after 383 (4.8%) patients. The primary end-point was a composite of 30-day death, myocardial infarction, and urgent target vessel revascularization. Non-inferiority was defined as the likelihood that tirofiban would preserve at least 50% of the ability of abciximab to reduce the primary end-point at 30 days, based on abciximab's demonstrated ability to reduce such events by 43% (relative risk, 0.573; 95% confidence interval [CI], 0.507-0.648; P < 0.001). To determine the probability of non-inferiority given the patients already enrolled, a Bayesian approach was used. RESULTS: The primary composite end-point occurred in 8.8% of patients randomized to abciximab versus 6.9% receiving high-bolus-dose tirofiban (odds ratio, 0.77; 95% CI, 0.37-1.64). The estimated conditional power for the test that tirofiban would be non-inferior to abciximab if all patients been enrolled is 93.7%. Using the estimated predictive power method, the likelihood was 84.8%. CONCLUSIONS: TENACITY was well powered to identify non-inferiority with tirofiban versus abciximab, and the patients enrolled strengthened the probability that this would have been the outcome had the trial been completed. When a clinical trial is terminated solely for financial reasons, it is incumbent upon the sponsor to provide proper patient follow-up and publication of the findings.

European viper envenomings: Assessment of Viperfav™ and other symptomatic treatments.

UNLABELLED: The treatment of European viper envenomings is based on IV antivenom infusions. Viperfav™ contains purified F(ab')(2) fragments of equine antibodies, and a 4 ml vial can neutralize 500-1000 mouse LD50 of Vipera aspis, V. ammodytes and V. berus venoms and is known to be safe and efficient. Assessments of Viperfav™ (dosage and timing of infusions) and of symptomatic treatments such as low-molecular-weight heparin (LWHM), corticosteroids and the routine use of antibiotic therapy have not as yet been reported. OBJECTIVES: The objective was to compare the efficacy and safety of Viperfav™ as a function of the time to infusion and to assess other symptomatic treatments given for European viper bites such as antibiotics, corticosteroids and LWMH. METHODS: A prospective case review study of viper envenomings treated with Viperfav™ was compiled by the Angers Poisons Centre. The endpoints chosen were as follows: duration of hospital stay, complications (haematoma, infection) and persistent functional discomfort on day 15. Statistical studies were based on multivariate data analysis (MVA). RESULTS: 268 moderate or severe envenomings (Grades II and III) recorded in adults and children between 1999 and 2009 were included in the study. A time to the Viperfav™ infusion < 10 h after the bite (179 patients vs. 72) significantly reduced the incidence of haematomas (OR 2.3; p < 0.006), functional discomfort (OR 3.7; p < 10 - 4) and length of hospital stay (OR 2.1; p < 0.03). Multiple doses of Viperfav™ (2 or 3 vials in 22 patients vs. 246 treated with 1 vial) did not improve the selected endpoints. Routine antibiotic therapy was prescribed in 102 patients (vs. 166 patients without) and no significant difference was seen with respect to the endpoints. Moreover, no local or systemic infections were recorded in the non-antibiotic group. Corticosteroids were prescribed in 36 patients (vs. 232 without) but they did not significantly improve the endpoints or oedema. LMWH in 32 patients (vs. 236 without) increased the length of hospital stay (OR 3.2; p < 0.009 and the level of significantly persistent functional discomfort at day 15 (OR 3.7; p < 0.003). CONCLUSIONS: A single infusion of Viperfav™ (one vial) was effective whatever the grade of envenomation, and multiple doses did not improve the outcome. Viperfav™ was most effective when given soon (< 10 h) after envenoming. The routine use of antibiotic therapy was not necessary. Corticosteroids did not improve the endpoints selected, and we do not recommend the use of LMWH as this increased persistent functional discomfort and the length of hospital stay.

Response to biologic therapy in Crohn's disease is improved with early treatment: an analysis of health claims data.

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy is an important treatment option for management of active Crohn's disease (CD) and is labeled for use after failure of conventional therapy (step-up). However, there is debate on the introduction of anti-TNF agents earlier in the treatment strategy (top-down) to potentially improve clinical outcomes. The aim of this study was to determine if a top-down approach with anti-TNF therapy is associated with improved outcomes for patients with active CD. METHODS: Claims data were from adult patients with CD with continuous enrollment in the same health plan for ≥ 6 months prior to the initial diagnostic claim for CD, ≥ 12 months after their initial anti-TNF claim, and with ≥ 1 anti-TNF claims after their initial diagnosis for CD. RESULTS: Three patient groups were identified: The Step-Up group used 5-aminosalicylates and/or corticosteroids prior to anti-TNF; the immunosuppression (IS)-to-TNF inhibitor group used IS prior to anti-TNF therapy; the Early-TNF group initiated anti-TNF therapy within 30 days of the first prescription for CD. Response to anti-TNF therapy was determined up to 24 months following anti-TNF initiation by concomitant corticosteroid use, CD surgery, anti-TNF dose escalation, and anti-TNF discontinuation/switch. A top-down approach to anti-TNF therapy was associated with a lower risk of concomitant corticosteroid use, anti-TNF dose escalation, discontinuation/switch of anti-TNF, and CD-related surgery compared with the step-up and IS-to-TNF therapy approaches. CONCLUSIONS: These "real-world" data show that a top-down approach to anti-TNF therapy in CD is associated with reductions in loss of response and fewer surgeries than conventional step-wise management.

Certolizumab pegol compared to natalizumab in patients with moderate to severe Crohn's disease: results of a decision analysis.

INTRODUCTION: A significant proportion of patients with Crohn's disease (CD) lose response to antibodies directed against tumor necrosis factor α (TNF). Prior TNF-antagonist failure is associated with lower rates of response to subsequent TNF-antagonist therapy. In patients failing two anti-TNF agents, a choice exists between using a third-anti-TNF therapy or natalizumab (NAT), an α-4 integrin inhibitor. A cost-effectiveness analysis comparing these competing strategies has not been performed. METHODS: A decision analytic model was constructed to compare the performance of certolizumab pegol (CZP) versus NAT in patients with moderate to severe CD. Previously published estimates of efficacy of third-line anti-TNF therapy and NAT were used to inform the model. Costs were expressed in 2010 US dollars. A 1-year time frame was used for the analysis. RESULTS: In the base case estimate, use of NAT was only marginally more effective [0.71 vs. 0.70 quality adjusted life-years (QALYs)] than CZP but was expensive with an incremental cost-effectiveness ratio (ICER) of $381,678 per QALY gained. For CZP 2 months response rate of at least 24%, NAT had an ICER above the willingness-to-pay (WTP) threshold. The model was sensitive to the costs of both therapies; for all CZP costs below $2,300 per dose, NAT had higher ICER than the WTP threshold. Substituting adalimumab for CZP resulted in similar ICER estimates and thresholds for NAT use. CONCLUSIONS: In patients with moderate to severe CD failing two TNF-antagonists, using a third TNF-antagonist therapy appears to be a cost-effective strategy without significantly compromising treatment efficacy.

Sensitivity analysis for causal inference using inverse probability weighting.

Evaluation of impact of potential uncontrolled confounding is an important component for causal inference based on observational studies. In this article, we introduce a general framework of sensitivity analysis that is based on inverse probability weighting. We propose a general methodology that allows both non-parametric and parametric analyses, which are driven by two parameters that govern the magnitude of the variation of the multiplicative errors of the propensity score and their correlations with the potential outcomes. We also introduce a specific parametric model that offers a mechanistic view on how the uncontrolled confounding may bias the inference through these parameters. Our method can be readily applied to both binary and continuous outcomes and depends on the covariates only through the propensity score that can be estimated by any parametric or non-parametric method. We illustrate our method with two medical data sets.

RAPID3 (Routine Assessment of Patient Index Data 3) severity categories and response criteria: Similar results to DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index) in the RAPID 1 (Rheumatoid Arthritis Prevention of Structural Damage) clinical trial of certolizumab pegol.

OBJECTIVE: To compare categories for activity/severity according to the Disease Activity Score 28-joint count (DAS28), the Clinical Disease Activity Index (CDAI), and the Routine Assessment of Patient Index Data 3 (RAPID3), an index without formal joint counts calculated in 5 versus >100 seconds, as well as the European League Against Rheumatism (EULAR)- DAS28 and the RAPID3 response criteria, in the Rheumatoid Arthritis Prevention of Structural Damage (RAPID 1) clinical trial of certolizumab pegol (CZP). METHODS: Post hoc analyses were performed using correlations, cross-tabulations, and kappa statistics. Patients (treated with CZP plus methotrexate [MTX] or placebo plus MTX) were classified at baseline and at 52 weeks as high, moderate, low activity/severity or remission, according to the DAS28 (>5.1, >3.2 to ≤5.1, 2.6 to ≤3.2, <2.6 [total range 0-10]), the CDAI (>22, >10 to ≤22, >2.8 to ≤10, ≤2.8 [total range 0-76]), and RAPID3 (>12, >6 to ≤12, >3 to ≤6, ≤3 [total range 0-30]), as well as for good, moderate, and poor EULAR-DAS28 and proposed RAPID3 response criteria. RESULTS: All measures were correlated significantly: RAPID3 with DAS28 and CDAI (rho > 0.7), higher than erythrocyte sedimentation rate with C-reactive protein level (rho = 0.47). At 52 weeks, DAS28, CDAI, and RAPID3 low activity/remission was seen in 30%, 44%, and 42% of CZP-treated patients versus 3%, 7%, and 10% of control patients. Good, moderate, and poor EULAR-DAS28 responses were seen in 30%, 51%, and 19% of CZP-treated patients versus 3%, 28%, and 70% of control patients, and for RAPID3 in 39%, 30%, and 32% of CZP-treated patients versus 8%, 16%, and 76% of control patients. Kappa and weighted kappa values ranged from 0.36-0.53, indicating fair to moderate agreement. CONCLUSION: RAPID3, DAS28, and CDAI give similar results to distinguish CZP patients from controls in the RAPID 1 clinical trial. DAS28 is specific for clinical trials; RAPID3 appears pragmatically useful for usual care.

Evaluation of a daily practice composite score for the assessment of Crohn's disease: the treatment impact of certolizumab pegol.

BACKGROUND: Successful treatment of systemic inflammatory symptoms is essential for improving health-related quality of life in patients with active Crohn's disease. Patient-reported outcomes provide unique perspectives on the impact of chronic disease. It is unknown whether a combination of different instruments might improve sensitivity to clinically relevant changes in health status. AIM: To develop a composite score based upon Crohn's Disease Activity Index (CDAI) and Inflammatory Bowel Disease Questionnaire (IBDQ) items. METHODS: Patients from the PRECiSE 2 trial who responded at week 6 to certolizumab pegol (CZP) were randomised to receive treatment with CZP 400 mg or placebo for up to 26 weeks. IBDQ and CDAI scores were assessed at weeks 0, 6, 16 and 26. A 'daily practice' composite score (DP-6) containing two items from the CDAI and four items from IBDQ was constructed. RESULTS: Correlation coefficients between the CDAI score and IBDQ total score at baseline and at week 26 were -0.344 and -0.603, respectively (P<0.05). All IBDQ items were improved following CZP treatment. The DP-6 had the highest responsiveness at assessing response to treatment, relative to CDAI total score, when compared with other scores. CONCLUSIONS: The DP-6 composite score could be used to optimise the use of existing instruments by serving as an index of symptoms due to systemic inflammation. Additional studies are needed to determine if the DP-6 composite score differentiates the impact of different treatments on patient-reported outcomes, and to determine if the use of the DP-6 improves the care of patients in clinical practice.

Certolizumab pegol (CIMZIA®) for the treatment of rheumatoid arthritis.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of certolizumab pegol (CZP) for adults with active rheumatoid arthritis (RA) that have not responded adequately to treatment with conventional disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX), in accordance with the licensed indication, based upon the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcome measures included American College of Rheumatology (ACR) 20, 50 and 70 response rates and quality of life measures after 3 months and 6 months of treatment. The ERG examined the submission's search strategies and considered they appeared comprehensive and that it was unlikely that relevant studies would have been missed. Only English language studies were considered in the submission and non-English language studies relevant to the decision problem may possibly have been ignored. The ERG analysed the first submitted economic model so as to itemise in detail clarification points that were brought to the attention of the manufacturer. In response the manufacturer submitted a modified cost-effectiveness analysis. The ERG undertook further analysis of this second model and other additional submitted evidence. The clinical evidence was derived from two multicentre blinded randomised controlled trials (RCTs) comparing CZP + MTX to placebo + MTX (the RAPID 1 and RAPID 2 trials). RAPID 1 lasted 52 weeks with 982 patients and RAPID 2 24 weeks with 619 patients. Evidence for clinical effectiveness of CZP in mono-therapy came from the 24-week FAST4WARD trial with 220 patients that compared CZP (400 mg every 4 weeks) versus placebo. The three key RCTs demonstrated statistically significant superiority of CZP + MTX versus placebo + MTX and of CZP versus placebo with respect to a variety of outcomes including ACR 20, ACR 50 and ACR 70 measures and quality of life measures at 3 and 6 months. On the basis of results from the indirect comparison meta-analyses, the manufacturer suggested that CZP may be at least as effective as other 'biological' DMARD (bDMARD) comparators and, in a few ACR measures at 3 and 6 months, more effective. CZP is an effective therapy for adult RA patients whose disease has failed to respond adequately to cDMARDs including MTX or who are intolerant of MTX. The cost-effectiveness of CZP relative to other bDMARDs is unclear because the economic modelling undertaken may have ignored relevant effectiveness data and potential differences between trial populations, and so may have included effectiveness results that were biased in favour of CZP; underestimated uncertainty in the relative effectiveness of compared DMARDs; and ignored the potential influence of differences between bDMARDs with regard to adverse events and their related costs and health impacts. The NICE guidance issued in October 2009 states that: the Committee is minded not to recommend certolizumab pegol as a treatment option for people with RA; and the Committee recommends that NICE asks the manufacturer of CZP for more information on the clinical effectiveness and cost-effectiveness of CZP for the treatment of people with RA. On receipt of this information and details of a patient access scheme NICE issued final guidance recommending CZP, under certain criteria, as a treatment option for people with RA.