Trends in RA patients’ adherence to subcutaneous anti-TNF therapies and costs

ABSTRACT

Objective: To examine adherence to adalimumab (ADA) and etanercept (ETA) and health care costs in rheumatoid arthritis (RA) patients, and to explore the association between adherence, utilization and costs.

Research design and methods: Using administrative claims data from a large managed health care plan, RA patients treated with etanercept or adalimumab during the period from 01/01/2005 through 12/31/2005 were identified. The first dispensing date was defined as the index date. Patient adherence and costs were assessed during the 1 year post-index period.

Main outcome measures: Nonadherence (medication possession ratio <80%) was modeled using logistic regression. Hazard ratios (HR) comparing time to discontinuation were estimated using Cox proportional hazard (PH) models. Propensity score matching with multivariate generalized linear modeling adjustment was done to assess cost difference between ADA and ETA.

Results: Of 3829 eligible RA patients, 1292 (765 existing, 527 naïve) and 2537 (1834 existing, 703 naïve) patients used ADA and ETA, respectively. Compared with ADA users, ETA users had longer average treatment duration (316 vs. 291 days; p?<?0.0001). Unadjusted adherence rates for naïve and existing users were 63% and 70% (ADA), and 65% and 73% (ETA). Logistic regression analysis indicated that compared with ETA users, ADA users were more likely to be nonadherent (OR, naïve 1.24; existing; 1.25). Cox PH models indicated that existing ADA users were more likely to discontinue (HR?=?1.11; p?=?0.06) their medication than existing ETA users. Compared with ADA users, ETA users had significantly lower RA-related pharmacy costs (naïve: $10,892 vs. $12,534, p?<?0.01; existing: $12,192 vs. $13,752, p?<?0.01) and RA-related total costs (naïve: $11,976.42 vs. $13,511.99, p?<?0.05; existing: $14,031 vs. $15,454, p?<?0.05).

Conclusions: ETA users had longer treatment duration, were more likely to adhere to their medication regimen and had lower RA-related pharmacy and RA-related total costs compared with ADA users. These findings must be considered within the limitations of this database analysis.     

The comparative effectiveness of biologics among older adults and disabled rheumatoid arthritis patients in the Medicare population

AimsOlder and disabled rheumatoid arthritis (RA) patients are often not present in large numbers in clinical trials or registries. A novel, claims‐based clinical effectiveness algorithm provides the potential to compare the effectiveness of different biologics among this population using large administrative databases.MethodUsing Medicare 2006–2010 data for 100% of patients with RA, we identified biologic naïve users of abatacept, adalimumab, etanercept and infliximab, defined as no biologic use during the 12 months before the biologic initiation. The effectiveness was evaluated at 365 days after biologic initiation, determined using a validated claims‐based algorithm. We compared the proportion meeting effectiveness criteria for each biologic using robust Poisson regression to compute risk ratios (RRs) adjusted for potential confounders. One year cost per effectively treated patient was calculated by different biologics.ResultsThe study included biologic naïve users of abatacept (n = 2129), adalimumab (n = 2944), etanercept (n = 3517) and infliximab (n = 5654). The algorithm classified the medications as 26% effective for abatacept, 24% for adalimumab, 28% for etanercept and 23% for infliximab, indicating comparable effectiveness. However, after adjustment and compared with infliximab, the RRs for effectiveness were 1.17 (95% CI 1.06, 1.30) for abatacept, 1.11 (95% CI 1.02, 1.23) for adalimumab and 1.27 (95% CI 1.17, 1.39) for etanercept. Older patients had a higher effectiveness than patients who were disabled (RR = 1.18, 95% CI 1.08, 1.28). Infliximab had highest cost per effectively treated patient.ConclusionAbatacept, adalimumab and etanercept are more effective than infliximab among RA patients initiating biologics. Effectiveness was significantly higher among older patients compared with disabled RA Medicare patients.     

Number needed to treat and costs per responder among biologic treatments for moderate-to-severe psoriasis: a network meta-analysis

Background: The clinical benefits of biologic therapies for moderate-to-severe psoriasis are well established, but wide variations exist in patient response.

Objectives: To determine the number needed to treat (NNT) to achieve a 75% and 90% reduction in the Psoriasis Area and Severity Index (PASI-75/90) with FDA-approved agents and evaluate the incremental cost per PASI-75 or PASI-90 responder.

Methods: The relative probabilities of achieving PASI-75 and PASI-90, as well as NNTs, were estimated using a network meta-analysis. Costs (2017 USD) included drug acquisition and administration. The incremental cost per PASI-75 or PASI-90 responder for each treatment was estimated for the clinical trial period, and annually.

Results: Compared with supportive care, the NNT to achieve PASI-75 was 1.18 for ixekizumab, 1.29 for secukinumab 300?mg, 1.37 for infliximab, 1.48 for adalimumab, 1.53 for secukinumab 150?mg, 1.58 for ustekinumab, 2.25 for etanercept, and 3.71 for apremilast. The one-year incremental cost per PASI-75 responder relative to supportive care was $59,830 for infliximab, $88,775 for secukinumab 300?mg, $91,837 for adalimumab, $95,898 for ixekizumab, $97,363 for ustekinumab, $105,131 for secukinumab 150?mg, $129,665 for apremilast, and $159,328 for etanercept. Results were similar for PASI-90.

Conclusion: The NNT and incremental cost per responder are meaningful ways to assess comparative effectiveness and cost effectiveness among psoriasis treatments.     

Clinical response to golimumab in rheumatoid arthritis patients who were receiving etanercept or adalimumab: results of a multicenter active treatment study

Objective: Evaluate the efficacy and safety of subcutaneous (SC) golimumab?+?methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite etanercept?+?MTX or adalimumab?+?MTX therapy and evaluate whether intravenous (IV) golimumab could rescue patients who were nonresponders to SC golimumab.

Methods: In this multicenter, assessor-blinded, active-switch study of patients with RA (n?=?433) with inadequate response to etanercept or adalimumab?+?MTX, patients continued MTX and received open-label SC golimumab 50?mg every 4 weeks through week 12. DAS28-ESR good responders at week 16 continued open-label SC golimumab through week 52 (Group 1); nonresponders were randomized to double-blind golimumab SC 50?mg (Group 2-SC) or IV 2?mg/kg (Group 2-IV). Week 14 ACR20 was the primary endpoint; assessments continued through week 52 and for patients in the voluntary long-term extension through week 76. A major secondary endpoint was the proportions of patients with ACR20 response at week 52 relative to week 16 in Group 2-SC and Group 2-IV.

Results: At week 14, 34.9% (p?n?=?75) achieved an ACR20 (62.7%). In Groups 2-SC (n?=?91) and 2-IV (n?=?184), 13.2% and 9.2% had an ACR20 at week 52 relative to week 16, with no significant difference between the randomized groups; 42.9% and 47.8% achieved DAS28-ESR response relative to week 0. Through week 16, 4.6% of patients had a serious adverse event. No differences in the rates or types of adverse events were observed between SC and IV golimumab from weeks 16 to 52. The trial limitations included a higher than expected discontinuation rate as a result of a programming error.

Conclusion: SC golimumab?+?MTX significantly suppressed disease activity in RA patients with inadequate response to etanercept and/or adalimumab + MTX. Patients randomized to Groups 2-SC and 2-IV had lower response rates than Group 1, with no difference between SC or IV mode of administration. The safety profile with IV golimumab was comparable to that established with SC golimumab.

Trial registration: NCT01004432, EudraCT 2009-010582-23.     

Real-world utilization of methotrexate or prednisone co-therapy with etanercept among Canadian patients with rheumatoid arthritis: a retrospective cohort study

Objective: To evaluate whether initiation of etanercept therapy among patients with rheumatoid arthritis (RA) impacts use of co-therapy with methotrexate or prednisone, and to describe etanercept dosing dynamics compared to product monograph in the Canadian real-world setting.

Methods: A retrospective cohort study was conducted using claims-level data from IQVIA Private Drug Plan database, Ontario Public Drug Plan database and Régie de l’assurance maladie du Québec database. Bio-naïve RA patients initiating etanercept between July 2014 and June 2015 were identified and their claims for methotrexate or prednisone were analyzed. Utilization of methotrexate or prednisone was calculated as average weekly dose in milligrams, and compared in the 6?months pre-initiation versus 12?months post-initiation of etanercept. Weekly etanercept dosing of each patient was calculated and analyzed to determine whether patients had at least 20% higher or lower average dose than monograph recommended dose (50?mg/week), and were then flagged as above-monograph or below-monograph, respectively.

Results: A total of 2876 patients with RA (66% female, 76% aged 18–65) were included; 62% (n?=?1,140) used methotrexate and 27% used prednisone (n?=?498) both pre- and post-initiation of etanercept. In methotrexate patients, the average weekly dose dispensed was 25.4?mg in the 6?months pre-etanercept, and 25.0?mg in the 12?months post-etanercept initiation (p?=?.5282). In prednisone patients, the average weekly dose dispensed reduced from 122.6?mg pre-etanercept to 107.1?mg post-etanercept initiation (p?=?.2173). Among patients who were already on methotrexate or prednisone, after initiating on etanercept 16% (n?=?213) and 34% (n?=?254) of patients stopped methotrexate and prednisone, respectively. When compared to the recommended dose, 12% (n?=?168) of patients were below-monograph and 7.1% of patients were above-monograph during their first year of etanercept therapy. Average etanercept dosing was consistently lower than product monograph during the follow-up year.

Conclusions: Patients had a modest but not statistically significant decrease in prescribed doses of co-therapy with methotrexate and prednisone when etanercept was added to patients’ therapy. In addition, 12–14% of patients stopped their co-therapy with methotrexate or prednisone. Further study is needed to understand the impact on patient outcomes and safety.     

Healthcare costs among adults with type 2 diabetes initiating saxagliptin or linagliptin: a US-based claims analysis

Objective: To compare healthcare costs of adults with type 2 diabetes (T2D) after initiation of saxagliptin or linagliptin, two antidiabetic medications in the dipeptidyl peptidase-4 inhibitor medication class.

Methods: Patients with T2D who were at least 18 years old and initiated saxagliptin or linagliptin (index date) between 1 June 2011 and 30 June 2014 were identified in the MarketScan Commercial and Medicare Supplemental Databases. All-cause healthcare costs and diabetes-related costs (T2D diagnosis on a medical claim and/or an antidiabetic medication claim) were measured in the 1 year follow-up period. Saxagliptin and linagliptin initiators were matched using propensity score methods. Cost ratios (CRs) and predicted costs were estimated from generalized linear models and recycled predictions.

Results: There were 34,560 saxagliptin initiators and 18,175 linagliptin initiators identified (mean ages 57 and 59; 55% and 56% male, respectively). Before matching, saxagliptin initiators had significantly lower all-cause total healthcare costs than linagliptin initiators (mean?=?$15,335 [SD $28,923] vs. mean =?$20,069 [SD $48,541], p?p?n?=?16,069 per cohort), saxagliptin initiators had lower all-cause follow-up costs than linagliptin initiators (CR?=?0.953, 95% CI?=?0.932–0.974, p?p?=?0.017; predicted costs?=?$3989 vs. $4159).

Conclusions: Adult patients with T2D initiating treatment with saxagliptin had lower total all-cause healthcare costs and diabetes-related medical costs over 1 year compared with patients initiating treatment with linagliptin.     

The effect of adjunctive mood stabilizers on antipsychotic utilization pattern and health resource utilization for Medicaid enrollees with schizophrenia

ABSTRACT

Background: Prescribing adjunctive mood stabilizers to manage schizophrenia is prevalent, despite the lack of substantial evidence to support the long-term use of this treatment regimen.

Objective: The objective of this study was to assess the impact of using adjunctive mood stabilizers on antipsychotic utilization, total health expenditures, inpatient hospital­izations, long-term care stays, and emergency room (ER) visits for patients with schizophrenia.

Methods: Georgia Medicaid claims from 1999 through 2001 were analyzed to identify recipients diagnosed with schizophrenia (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD?9?CM]: 295.XX). The treatment groups consisted of subjects who received combination therapy of mood stabilizers and anti­psychotics (including both atypical and typical medica­tions), while the comparison group consisted of subjects who were on antipsychotic medications without exposure to the mood stabilizers under investigation. Four treatment groups (valproate, lithium, carbamazepine, and combina­tion mood stabilizer therapy) were formed based on the mood stabilizers patient received. Differences in annual health care use and expenditures were estimated between propensity score matched treatment and comparison groups controlling for comorbidity, prior utilization, demographic, and health provider specialty.

Results: During the 1?year observation period, subjects in treatment groups filled an average of 200-days supply of adjunctive mood stabilizers. These adjunctive mood stabilizer recipients had significantly longer antipsychotic treatment durations than the subjects who did not have exposure to mood stabilizers (valproate + antipsychotic vs. antipsychotic only, net difference: 56.47 days, p < 0.0001; lithium + antipsychotic vs. antipsychotic only, net difference: 90.25 days, p < 0.0001; carbamazepine + antipsychotic vs. antipsychotic only, net difference: 41.27 days, p = 0.0439; multiple mood stabilizers + anti­psychotic vs. antipsychotic only, net difference: 83.14 days, p < 0.0001). The intensive pharmacotherapy associated with treatment groups resulted in $900–$1300 higher pharmacy costs than the comparison groups (valproate + antipsychotic vs. antipsychotic only, net difference: $1218.43, p < 0.0001; lithium + antipsychotic vs. antipsychotic only, net difference: $985.79, p = 0.0015; carbamazepine + antipsychotic vs. anti­psychotic only, net difference: $911.63, p = 0.0497; multiple mood stabilizers + antipsychotic vs. antipsychotic only, net difference: $1281.91, p < 0.0047). However, there were no statistically significant differences for total health expenditures, hospitalizations, emergency room visits, and nursing home admissions between propensity-matched treatment and control groups.

Conclusions: There were no differences in health care costs or utilization of ER, long-term care, and inpatient services between schizophrenia patients who did and did not receive adjunctive mood stabilizer; however, longer anti­psychotic treatment durations were observed in patients receiving adjunctive mood stabilizers. Interpretation of these results is limited by the unknown selection bias between the treatment and the comparison groups and the relatively small number of patients in some treatment groups. The development of a better-controlled study to further evaluate this treatment regimen is warranted.     

Healthcare expenditures and patient satisfaction: cost and quality from the consumer's perspective in the US*

ABSTRACT

Background: Both cost and quality of healthcare are major concerns in the United States. Using patient satisfaction as a quality indicator, we seek to identify the relationship between healthcare cost and quality from the perspective of the community-dwelling population in the United States.

Methods: We examined a nationally representative sample of 13?980 adults (age?≥?18 years) in the 2003 Medical Expenditure Panel Survey (MEPS). Given the idiosyncrasies of the cost data distribution, a recently developed extended estimating equation (EEE) model was employed to identify the relationship between patient satisfaction and healthcare expenditure, after controlling for individual demographic covariates, co-morbidity profile, and functional and activity limitations. A series of sensitivity analyses were conducted, in addition, to verify the identified relationship. All statistics were adjusted using the proper sampling weight from the MEPS data.

Results: Average annual healthcare expenditures for 2003 ranged between $3923 and $6073 when grouped by patient satisfaction ratings with a mean value $4779 for all individuals who rated perceived satisfaction of their healthcare. We found that there is no statistically signif­icant relationship between patient satisfaction and total healthcare expenditure (?p?=?0.60) and a non-monotonic relationship is not identified either. All sensitivity analyses results revealed a lack of relationship between patient satisfaction and healthcare expenditures.

Limitations: Patient satisfaction might not reflect the quality of healthcare from an objective clinical standpoint. The identified cost–satisfaction relationship may not be extrapolated to other quality indicators. Due to the cross-sectional study design, no causal relationship could be inferred between patient satisfaction and healthcare expenditure.

Conclusions: Our study adds to the literature on health­care cost and quality by suggesting that the improvement of patient satisfaction may not require additional health­care spending.     

Dosing patterns of three tumor necrosis factor blockers among patients with rheumatoid arthritis in a large United States managed care population

Abstract

Objective:

To describe dosing patterns of etanercept, adalimumab, and infliximab in rheumatoid arthritis (RA) patients in US managed care.     

Assessment of effectiveness and safety of biosimilar infliximab (CT-P13) in a real-life setting for treatment of patients with active rheumatoid arthritis or ankylosing spondylitis

Objective: To assess the effectiveness and safety of infliximab biosimilar, CT-P13, administered in a real-life setting to adult patients with active rheumatoid arthritis (RA) or ankylosing spondylitis (AS).

Methods: This multi-center, non-interventional, observational study was conducted in Bulgaria, the Czech Republic, and Romania. A total of 151 patients with severe active RA (n?=?81) or AS (n?=?70) were enrolled and treated with CT-P13 for 24 weeks, according to current medical recommendations. Effectiveness was assessed using the 4-item Disease Activity Score 28 with C-reactive protein (DAS28-CRP) for RA patients, and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS patients. Safety was assessed by withdrawals and adverse events (AEs).

Results: A total of 129 patients (RA: 67; AS: 62) were included in the effectiveness analysis. CT-P13 treatment significantly improved DAS28-CRP scores at 12 and 24 weeks (p?=?.0001 vs baseline for both timepoints) in patients with RA and BASDAI scores at 12 and 24 weeks (p?=?.0001 vs baseline for both timepoints) in patients with AS. CRP levels were significantly reduced at 12 and 24 weeks (p?=?.0001 vs baseline for both timepoints). Among 713 infusions, 34 AEs were reported (4.8% of infusions), of which 11 were considered related to CT-P13 treatment. Two of seven serious AEs were considered possibly (hepatocellular injury) or definitely (dyspnoea due to allergic infusion reaction) treatment-related. Eight patients discontinued CT-P13 due to AEs and four patients were withdrawn due to therapeutic failure.

Conclusions: CT-P13 was effective and safe in a real-life setting in patients with active RA or AS.     

Prediction of successful dose reduction or discontinuation of adalimumab,etanercept, or infliximab in rheumatoid arthritis patients using serum drug levels and antidrug antibody measurement

Background: To evaluate if TNF inhibitor serum drug levels (DL) or anti-drug antibodies (ADAb) can predict successful dose reduction (in patients with high DL) or discontinuation (in patients with no/low DL or ADAb) in rheumatoid arthritis (RA) patients.

Research design and methods: RA patients that were using adalimumab (n = 42), etanercept (n = 76) or infliximab (n = 51) and were doing well, were tapered until discontinuation or flare (1–1.5 year follow up). Random timed DL for adalimumab and etanercept and trough DL for infliximab were measured before dose reduction: Receiver-Operator-Curves (ROC) analyses with optimal cut-off DL were determined.

Results: No predictive value of adalimumab and infliximab DL for all outcomes were found, except for an inverse association of lower etanercept DL and higher chance for successful dose reduction (Area Under the Curve (AUC) 0.36, 95% CI 0.23–0.49; cut-off <2.6 mg/l). In sub analyses, higher adalimumab trough DL predicted successful dose reduction (AUC 0.86, 0.58–1.00; cut-off >7.8). ADAb were infrequent and not predictive of successful discontinuation.

Conclusions: No predictive value of baseline adalimumab, etanercept and infliximab DL or ADAb for successful dose reduction or discontinuation in RA was found in this context, with the possible exception of high adalimumab trough levels for successful dose reduction.     

Medication patterns and costs associated with olanzapine and other atypical antipsychotics in the treatment of bipolar disorder

ABSTRACT

Objective: Atypical antipsychotics are playing an increasing role in the treatment of bipolar disorder. The objective of this study was to assess the medication treatment patterns and costs associated with different atypical antipsychotics.

Methods: PharMetrics Integrated Database for medical and pharmacy claims was used to assess medication patterns and healthcare costs associated with atypical antipsychotics in the treatment of bipolar disorder. Patients who initiated on olanzapine, risperidone, quetiapine or ziprasidone as monotherapy or in combination with other bipolar medications between 01/2003 and 01/2004 were followed for 1 year. Pair-wise group comparisons were made between olanzapine and other atypical antipsychotics using Wilcoxon without adjustment, log linear regression model with adjustment, and propensity score-adjusted bootstrapping methods.

Results: Among 1516 patients with bipolar disorder, olanzapine (n = 507, 51%) was significantly (?p < 0.01) more likely to be initiated as the mono-bipolar medication than risperidone (n = 424, 40%), quetiapine (n = 463, 36%) or ziprasidone (n = 122, 25%). Post-initiation, olanzapine was used as the mono-bipolar medication for significantly (?p < 0.01) more days (73.4) than risperidone (52.9), quetiapine (56.2) and ziprasidone (36.6). Annual healthcare costs incurred by patients with bipolar disorder varied from $14?216 for risperidone, $15?208 for olanzapine, $18?087 for quetiapine to $18?729 for ziprasidone treatments. No statistically significant differences in the annual healthcare costs were observed between olanzapine and risperidone treatments. Statistically significant differences between olanzapine and quetiapine were observed in two of the three models compared (?p < 0.01, Wilcoxon; p = 0.024, log linear; p = 0.390, propensity score-adjusted bootstrapping) and between olanzapine and ziprasidone in one of the three models (?p < 0.01, Wilcoxon; p = 0.068, log linear; p = 0.394, propensity score-adjusted bootstrapping).

Limitations: Those arising from the data source and nature of retrospective assessments. Potential bias may also exist due to the presence of confounding factors and unobserved conditions and characteristics. As such, results of this study need to be considered in the context of its limitations and generalizability should be reserved to similar patient populations.

Conclusions: Antipsychotic medication use patterns were statistically significantly different among atypical antipsychotics in the usual treatment of bipolar disorder. Olanzapine appears to be more likely used as a mono-bipolar medication compared with risperidone, quetiapine, and ziprasidone. The annual healthcare costs associated with the treatment of bipolar disorder by olanzapine and risperidone were similar, and the costs of these treatments were lower than with quetiapine or ziprasidone.     

Warfarin time in therapeutic range and its impact on healthcare resource utilization and costs among patients with nonvalvular atrial fibrillation

Background:

Warfarin is efficacious for reducing stroke risk among patients with nonvalvular atrial fibrillation (NVAF). However, the efficacy and safety of warfarin are influenced by its time in therapeutic range (TTR).

Objective:

To assess differences in healthcare resource utilization and costs among NVAF patients with low (<60%) and high (≥60%) warfarin TTRs in an integrated delivery network (IDN) setting.

Methods:

Patients with NVAF were identified from an electronic medical record database. Patients were required to have ≥6 international normalized prothrombin time ratio (INR) tests. NVAF patients were grouped into two cohorts: those with warfarin TTR <60% (low TTR) and those with warfarin TTR ≥60% (high TTR). Healthcare resource utilization and costs were evaluated during a 12 month follow-up period. Multivariable regressions were used to assess the impact of different warfarin TTRs on healthcare costs.

Results:

Among the study population, greater than half (54%, n?=?1595) had a low TTR, and 46% (n?=?1356) had a high TTR. Total all-cause healthcare resource utilization was higher among patients in the low TTR cohort vs. the high TTR cohort (number of encounters: 70.2 vs. 56.1, p?<?0.001). After adjusting for patient characteristics, total all-cause healthcare costs and stroke-related healthcare costs were $2398 (p?<?0.001) and $687 (p?=?0.02) higher, respectively, for patients in the low TTR cohort vs. the high TTR cohort.

Limitations:

In this retrospective study, we were only able to evaluate the association and not the causality between healthcare resource utilization and costs with the different warfarin TTRs.

Conclusion:

Many warfarin-treated NVAF patients have a low warfarin TTR. NVAF patients with low vs. patients with high warfarin TTR used healthcare resources to a greater extent, which was reflected in higher healthcare costs.     

The costs of Crohn's disease in the United States and other Western countries: a systematic review

ABSTRACT

Objective: To conduct a critical and systematic literature review of the costs of Crohn's disease (CD) in Western industrialized countries.

Research design and methods: Studies published in English that described the cost of CD in Western industrialized countries were identified using three major databases (Medline, EMBASE, and ISI Web of Science). Studies were reviewed and rated based on their relevance to cost of illness and the reliability of the estimates. All costs were adjusted for inflation to 2006 values.

Results: Estimated direct medical costs were $18 022–18 932 per patient with CD per year in the United States, and €2898–6960 in other Western countries. Hospital­izations accounted for 53–66% of direct medical costs, with an average cost-per-hospitalization of $37?459 in the United States. Estimated indirect costs accounted for 28% of the total cost in the United States and 64–69% in Europe. Costs differed greatly by disease severity. Costs of patients with severe disease were 3- to 9-fold higher than patients in remission. Direct medical costs in the United States for patients in the top 25% of total costs averaged $60?582 per year; costs of patients in the top 2% averaged more than $300?000 per year. Combining prevalence rates, the total economic burden of CD was $10.9–15.5 billion in the United States and €2.1–16.7 billion in Europe.

Limitations: This review is limited by the research quality and variations of the individual studies reviewed, and only includes English articles.

Conclusions: This updated literature synthesis demonstrated the substantial total cost burden of CD, of which hospital­izations accounted for more than half of direct medical costs.