Real world evidence of use of anti-VEGF therapy in Denmark

Objective: This study evaluates real-world evidence regarding the frequency of anti-vascular-endothelial-growth-factor (VEGF) injections during the first year of therapy of treatment-naïve patients with neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME) and retinal vein occlusion (RVO) from the Danish National Patient Registry. There was a switch in anti-VEGF treatment for naïve nAMD patients during the study period, following the introduction of aflibercept, which was expected to reduce the injection frequency relative to ranibizumab due to a perception of prolonged treatment duration of aflibercept.

Methods: All treatment-naïve nAMD, DME or RVO patients who received an intravitreal injection in Denmark from 1 January 2012 to 31 July 2015 were eligible for inclusion. Patients were required to have been treated for at least one year and, for nAMD, to have received at least three injections during the first four months of treatment. Patients were allocated to half-year groupings (2012/1 to 2014/1) based on registration of their first intravitreal injection. Injection frequency during the first year of treatment was calculated for each group and t-tests investigated whether injection frequencies changed over time.

Results: In treatment naïve nAMD patients (n?=?500), the mean (SD) number of anti-VEGF injections increased significantly from 6.04 (1.71) in 2012/1 to 6.73 (1.62) in 2014/1 (p?=?.001; 2012/1 and 2012/2 vs. 2014/1) across all treatments. A similar trend was found for DME patients (n?=?76) from 2012/1 to 2014/1 and RVO patients (n?=?82) from 2012/2 to 2014/1, with mean injection frequencies increasing significantly from 5.14 (2.29) to 5.93 (1.98) (p?=?.007), and from 4.83 (1.21) to 6.08 (1.55) (p?=?.024), respectively. Post hoc sensitivity analysis also found a significant increase in injection frequency in nAMD patients who did not receive a loading phase (4.55 in 2012/1 and 5.05 in 2014/1; p?=?.006; n?=?616).

Conclusions: In contrast to the decrease in injection frequency predicted with a switch to aflibercept treatment for nAMD, our study showed that injection frequencies increased significantly from 2012 to 2014 in patients initiating therapy across the three diseases.     

Impact of renal function on ischemic stroke and major bleeding rates in nonvalvular atrial fibrillation patients treated with warfarin or rivaroxaban: a retrospective cohort study using real-world evidence

Objectives: Renal dysfunction is associated with increased risk of cardiovascular disease and is an independent predictor of stroke and systemic embolism. Nonvalvular atrial fibrillation (NVAF) patients with renal dysfunction may face a particularly high risk of thromboembolism and bleeding. The current retrospective cohort study was designed to assess the impact of renal function on ischemic stroke and major bleeding rates in NVAF patients in the real-world setting (outside a clinical trial).

Methods: Medical claims and Electronic Health Records were retrieved retrospectively from Optum’s Integrated Claims–Clinical de-identified dataset from May 2011 to August 2014. Patients with NVAF treated with warfarin (2468) or rivaroxaban (1290) were selected. Each treatment cohort was stratified by baseline estimated creatinine clearance (eCrCl) levels. Confounding adjustments were made using inverse probability of treatment weights (IPTWs). Incidence rates and hazard ratios of ischemic stroke and major bleeding events were calculated for both cohorts.

Results: Overall, patients treated with rivaroxaban had an ischemic stroke incidence rate of 1.9 per 100 person-years (PY) while patients treated with warfarin had a rate of 4.2 per 100 PY (HR?=?0.41 [0.21–0.80], p?=?.009). Rivaroxaban patients with an eCrCl below 50?mL/min (N?=?229) had an ischemic stroke rate of 0.8 per 100 PY, while the rate for the warfarin cohort (N?=?647) was 6.0 per 100 PY (HR?=?0.09 [0.01–0.72], p?=?.02). For the other renal function levels (i.e. eCrCl 50–80 and ≥80?mL/min) HRs indicated no statistically significant differences in ischemic stroke risks. Bleeding events did not differ significantly between cohorts stratified by renal function.

Conclusions: Ischemic stroke rates were significantly lower in the overall NVAF population for rivaroxaban vs. warfarin users, including patients with eCrCl below 50?mL/min. For all renal function groups, major bleeding risks were not statistically different between treatment groups.     

Expert opinion on interleukin-12/23 and interleukin-23 antagonists as potential therapeutic options for the treatment of inflammatory bowel disease

Introduction: Blockade of interleukin (IL)-12 and IL-23 is a novel therapeutic target for inflammatory bowel disease (IBD). The monoclonal antibody targeting the shared p40 subunit of IL-12 and IL23, namely ustekinumab, has been approved for Crohn’s disease (CD) and has demonstrated promising results in the treatment of ulcerative colitis. Several agents targeting the IL-23-specific p19 subunit are currently in various stages of development. These newer agents have the potential to provide safety benefits.

Areas covered: This review discusses the current state of IL-12/23 and IL-23 antagonists for the treatment of IBD. With multiple biologic classes available, we make recommendations for positioning of these agents in clinical practice.

Expert opinion: While tumor necrosis factor (TNF) antagonists remain the biologic of choice for majority of patients with moderate-to-severe IBD, IL-12/23, and IL-23 antagonists should be considered for first- or second-line therapy because of their efficacy in biologic-naïve and experienced patients. Additionally, IL-12/23 and IL-23 antagonists may be preferred over anti-TNF therapy in older patients who are at increased risk for infections and malignancy. The safety compared to anti-TNF may be even greater when one considers that concurrent immunosuppression is probably not necessary when using this class of drug, owing to the low rates of immunogenicity.     

Increased subsequent risk of inflammatory bowel disease association in patients with chronic pancreatitis: a nationwide population-based cohort study

Purpose: To investigate the relationship between chronic pancreatitis (CP) and inflammatory bowel disease (IBD) in a large population-based cohort study.

Methods: Data was obtained from the Taiwan National Health Insurance Research Database. The cohort study comprised 17,796 patients newly diagnosed with CP between 2000 and 2010 and 71,164 matched controls. A Cox proportional hazards model was used for evaluating the risk of IBD in the CP and comparison cohorts.

Results: When examined with a mean follow-up period of 4.87 and 6.04 years for the CP and comparison cohorts, respectively, the overall incidence of IBD was 10.3 times higher in the CP cohort than in the comparison cohort (5.75 vs. 0.56 per 10,000 person-years). Compared with the comparison cohort, the CP cohort exhibited a higher risk of IBD, irrespective of age, sex, and presence or absence of comorbidities. Moreover, the CP cohort was associated with a significantly higher risk of Crohn’s disease (adjusted hazard ratio [aHR]?=?12.9, 95% confidence interval [CI]?=?5.15–32.5) and ulcerative colitis (aHR?=?2.80, 95% CI?=?1.00–7.86).

Conclusions: This nationwide population-based cohort study revealed a significantly higher risk of IBD in patients with CP compared with control group. Clinicians should notice this association to avoid delayed diagnosis of IBD in patients with CP.     

The effect of antibiotic prophylaxis for acute pelvic inflammatory disease after hysterosalpingography: a retrospective cohort study

Aims: Concerns about acute pelvic inflammatory disease (PID) after hysterosalpingography (HSG) have been raised since 1980. However, the effectiveness of prophylactic antibiotics remains unclear. This study investigated the effect of antibiotic prophylaxis in women undergoing HSG.

Methods: Women undergoing HSG between 2000 and 2012 were screened from the Taiwan National Health Insurance Research Database for eligibility. The prophylactic cohort included patients using any antibiotics of 1st-generation cephalosporins, doxycycline, clindamycin, and metronidazole, within 7 days before HSG (n?=?3257). Patients not using any antibiotics were registered as the non-prophylactic cohort (n?=?4662). An unconditional logistic regression model was applied to calculate the odds ratio (OR) and 95% confidence interval (CI) of acute PID after HSG associated with prophylactic antibiotics.

Results: The cumulative incidences of acute PID after HSG were 0.46% and 1.42% in the prophylactic and non-prophylactic cohorts, respectively. Prophylactic patients had a significantly reduced estimated relative risk of acute PID compared with non-prophylactic patients (adjusted OR?=?0.33, 95% CI?=?0.19–0.58; p?=?.001). Doxycycline users had the lowest adjusted OR of 0.20 (95% CI?=?0.04–0.81; p?=?.02), followed by users of 1st-generation cephalosporins (adjusted OR?=?0.35, 95% CI?=?0.18–0.68; p?=?.002). Multivariate sub-group analysis verified this protective effect for almost all sub-groups of prophylactic patients.

Conclusions: Antibiotic prophylaxis is associated with a decreased estimated relative risk of acute PID in HSG patients. Doxycycline and 1st-generation cephalosporins may be effective prophylactic regimens for HSG.     

Increased healthcare resource utilization in higher disease activity levels in initiators of TNF inhibitors among US rheumatoid arthritis patients

Objective: Determine healthcare resource utilization (HCRU) in biologic-naïve initiators of TNF inhibitors (TNFis) associated with their disease activity from a national cohort of rheumatoid arthritis (RA) patients.

Methods: RA patients were identified at their first TNFi initiation (index date) in the Corrona registry. Patients with age of RA onset <18, comorbid psoriasis/psoriatic arthritis, fibromyalgia, or osteoarthritis were excluded. Patients were categorized into disease activity (DA) strata by the lowest level of DA (and sustaining low levels for at least two visits) using the Clinical Disease Activity Index (CDAI) across all visits in Corrona while on a TNFi during 1 year after initiation. Rates of all-cause and RA-related hospitalizations, rheumatologist visits, and joint surgeries while on TNFi therapy were reported and compared across DA levels along with the incidence rate ratio (IRR) adjusted for age, gender, and RA duration using Poisson mixed models.

Results: Of 1931 RA patients: 15% achieved sustained remission, 22% remission, 14% sustained low DA, 23% low DA and 27% moderate/high DA (M/HDA). Those in M/HDA had statistically higher rates of hospitalizations (37.3 per 100 patient years (py), 95% CI: 31.6–43.7 and joint surgeries (20.8 per 100 py, 95% CI: 16.6–25.8) compared to the sustained remission cohort, resulting in respective IRRs of 2.3 (p?<?0.001) and 1.7 (p?=?0.046).

Conclusion: Many biologic naïve RA patients initiating TNFi failed to achieve sustained remission during a 1 year period while remaining on TNFi therapy. Patients in higher DA levels had higher HCRU rates vs. patients in sustained remission, suggesting that achieving treat-to-target goals would reduce health care expenses.     

Real-world evaluation of glycemic control among patients with type 2 diabetes mellitus treated with canagliflozin versus dipeptidyl peptidase-4 inhibitors

Objective To evaluate glycemic control among patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin (CANA) vs. dipeptidyl peptidase-4 (DPP-4) inhibitors.

Methods Using integrated claims and lab data from a US health plan of commercial and Medicare Advantage enrollees, this matched-control cohort study assessed adult T2DM patients receiving treatment with CANA or DPP-4 inhibitors (1 April 2013–31 December 2013). Cohorts were chosen hierarchically; the first pharmacy claim for CANA was identified as the index date; then the first pharmacy claim for a DPP-4 inhibitor was identified and index date set. Eligible patients had 6 months of continuous health plan enrollment before the index date (baseline) and 9 months after (follow-up) and no evidence of index drug in baseline. Patients were matched 1:1 using propensity score matching. Changes in glycated hemoglobin (HbA1c) and percentages of patients with HbA1c <8% and <7% during the follow-up were evaluated.

Results The matched CANA and DPP-4 inhibitor cohorts (53.2% treated with sitagliptin) included 2766 patients each (mean age: 55.7 years). Among patients with baseline and follow-up HbA1c results, mean baseline HbA1c values were similar, 8.62% and 8.57% (p?=?0.615) for the CANA (n?=?729) and DPP-4 inhibitor (n?=?710) cohorts, respectively. Change in HbA1c was greater among patients in the CANA cohort than for those in the DPP-4 inhibitor cohort (?0.92% vs. ?0.63%, p?<?0.001), and also among the subset of patients with baseline HbA1c ≥7% (-1.07% [n?=?624] vs. ?0.79% [n?=?603], p?=?0.004). During follow-up, greater percentages of the CANA cohort relative to the DPP-4 inhibitor cohort achieved HbA1c of <8% (66.0% vs. 58.6%, p?=?0.004) and <7% (35.4% vs. 29.9%, p?=?0.022).

Limitations This study was observational and residual confounding remains a possibility.

Conclusions In this real-world study of patients with T2DM, CANA use was associated with greater HbA1c reduction and higher percentages of patients attaining HbA1c goals than those treated with DPP-4 inhibitors.     

Sensory profiles are comparable in patients with distal and proximal entrapment neuropathies,while the pain experience differs

Objective: Distal and proximal entrapment neuropathies such as carpal tunnel syndrome (CTS) and cervical radiculopathy (CR) share similar etiologies. Experimental models suggest that, despite comparable etiology, pathomechanisms associated with injuries of the peripheral and central axon branches are distinct. This study therefore compared self-reported and elicited sensory profiles in patients with distal and proximal entrapment neuropathies.

Methods: Patients with electrodiagnostically confirmed CTS (n?=?103) and patients with CR (n?=?23) were included in this study. A group of healthy participants served as controls (n?=?39). Symptoms and sensory profiles were evaluated using quantitative sensory testing (QST) and a self-reported neuropathic pain questionnaire (painDETECT).

Results: Both patient groups were characterized by a loss of function in thermal and mechanical detection in the main pain area and dermatome compared to healthy reference data (p?<?.001). There was no significant difference between patients with CTS and CR in pain and detection thresholds except for reduced vibration sense in the main pain area (p?<?.001) and reduced pressure pain sensitivity in the dermatome in patients with CR (p?<?.001). However, patients with CR reported higher pain intensities (p?=?.008), more severe pain attacks (p?=?.009) and evoked pain by light pressure (p?=?.002) compared to patients with CTS.

Conclusion: While QST profiles were similar between patients with CTS and CR, self-reported pain profiles differed and may suggest distinct underlying mechanisms in these patient cohorts.     

Comparison of real-world outcomes of adalimumab and infliximab for patients with ulcerative colitis in the United States

Objective: We compared the real-world effectiveness of initiating adalimumab and infliximab among patients in the US who were naïve to tumor necrosis factor (TNF) inhibitors. Methods: A retrospective chart review was conducted to evaluate the real-world effectiveness among adults with ulcerative colitis (UC) initiating adalimumab or infliximab. Charts of patients with UC were abstracted by treating physicians (randomly selected from a nationally representative panel) in April 2014. Patient eligibility criteria included: adalimumab or infliximab initiation on/after 1 October 2012; no prior anti-TNF therapy, history of Crohn’s disease, or colectomy; and ≥6 months of follow-up. Information on clinical outcomes (partial Mayo score, remission rate, physician global assessment (PGA), stool frequency, and rectal bleeding) and treatment patterns (dose escalations, discontinuations, switches, and treatment augmentations) were retrospectively reported by treating physicians. Kaplan–Meier curves and multivariate Cox proportional hazards regression models were used to assess the time to clinical outcomes and treatment changes for each therapy. Results: Overall, 170 physicians participated, contributing data on 380 and 424 patients who initiated adalimumab and infliximab, respectively. Baseline clinical characteristics were similar between groups. Both adalimumab- and infliximab-treated patients showed substantial improvements from baseline to follow-up in effectiveness measures; results of these measures were similar between the adalimumab and infliximab cohorts. Time to remission (p?=?0.5241), no rectal bleeding (p?=?0.7648), normal stool count (p?=?0.9941), and normal PGA (p?=?0.7697) showed no significant differences between therapies in unadjusted and adjusted comparisons. Unadjusted and adjusted time to event analysis of discontinuation (p?=?0.7151), dose escalation (p?=?0.6310), treatment augmentation (p?=?0.1209), and switching (p?=?0.7975) showed no significant differences between the two cohorts. Limitations: Retrospective, observational design. Conclusions: Adalimumab and infliximab were similarly effective in the treatment of moderate-to-severe UC in the real-world clinical setting.     

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.     

Effects of non-medical switching on outcomes among patients prescribed tumor necrosis factor inhibitors

Objective: To evaluate health care use and outcomes among patients who experienced a non-medical switch of their prescribed anti-tumor-necrosis-factor biological agent (anti-TNF) for cost containment reasons.

Methods: Retrospective evaluation of Humedica electronic health records of patients ≥18 years old with anti-TNF treatment for immune conditions. Using natural language processing, stable patients who experienced a non-medical switch (for cost reasons) of their anti-TNF between 2007 and 2013 were identified (NMS cohort, n?=?158) and matched to patients who did not (control cohort, n?=?4804). Rates of office visits, emergency department visits, and hospitalizations at 30, 90, and 365 days following were evaluated. Medication-related adverse events, defined as subsequent medication change due to a side effect and/or efficacy-related reason were also compared.

Results: Adjusted rates of office visits were higher among the NMS cohort than the control cohort at 30 (46.4% vs. 31.7%, p?p?p?p?=?.003), 90 (31.6% vs 9.6%, p?p?p?=?.001).

Conclusion: Non-medical switching among patients prescribed anti-TNFs was associated with increased health care use, medication-related side effects, and reports of diminished efficacy.     

Continuation with apixaban treatment is associated with lower risk for hospitalization and medical costs among elderly patients

Objective: To compare the risk of hospitalization and costs associated with major bleeding (MB) or stroke/systemic embolism (SE) among elderly patients with nonvalvular atrial fibrillation (NVAF) who initiated apixaban then switched to another oral anticoagulant (OAC) vs. those who continued with apixaban treatment.

Methods: NVAF patients (≥65?years) initiating apixaban were identified from the Humana database (1 January 2013–30 September 2017) and grouped into switcher and continuer cohorts. For switchers, the earliest switch from apixaban to another OAC was defined as the index event/date. A random date during apixaban treatment was selected as the index date for continuers. Patients were followed from index date to health plan disenrollment or 31 December 2017, whichever was earlier. Multivariable regression analyses were used to examine the association of switchers vs. continuers with risk of MB-related or stroke/SE-related hospitalization and healthcare costs during follow-up.

Results: Of 7858 elderly NVAF patients included in the study, 14% (N?=?1110; mean age: 78?years) were switchers; 86% (N?=?6748; mean age: 79?years) were continuers. Apixaban switchers vs. continuers had significantly greater risk of MB-related hospitalization (hazard ratio [HR]: 2.00; 95% CI: 1.52–2.64; p?<?.001) during follow-up; risk of stroke/SE hospitalization did not differ significantly (HR: 1.36, 95% CI: 0.89–2.06, p?=?.154). MB- and stroke/SE-related medical costs were higher for switchers vs. continuers, although total all-cause healthcare costs were similar.

Conclusion: Elderly patients with NVAF in the US who continued with apixaban treatment had a lower risk of MB-related hospitalization and lower MB- and stroke/SE-related medical costs compared to patients who switched to another OAC.     

Comparison of effectiveness and safety of treatment with apixaban vs. other oral anticoagulants among elderly nonvalvular atrial fibrillation patients

Objective: To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) of elderly (≥65 years of age) nonvalvular atrial fibrillation (NVAF) patients initiating apixaban vs. rivaroxaban, dabigatran, or warfarin.

Methods: NVAF patients with Medicare Advantage coverage in the US initiating oral anticoagulants (OACs, index event) were identified from the Humana database (1 January 2013–30 September 2015) and grouped into cohorts depending on OAC initiated. Propensity score matching (PSM), 1:1, was conducted among patients treated with apixaban vs. each other OAC, separately. Rates of S/SE and MB were evaluated in the follow-up. Cox regressions were used to compare the risk of S/SE and MB between apixaban and each of the other OACs during the follow-up.

Results: The matched pairs of apixaban vs. rivaroxaban (n?=?13,620), apixaban vs. dabigatran (n?=?4654), and apixaban vs. warfarin (n?=?14,214) were well balanced for key patient characteristics. Adjusted risks for S/SE (hazard ratio [HR] vs. rivaroxaban: 0.72, p?=?.003; vs. warfarin: 0.65, p?p?p?p?=?.27) and MB (HR: 0.82, p?=?.23) of NVAF patients treated with apixaban vs. dabigatran trended to be lower, but did not reach statistical significance.

Conclusions: In the real-world setting after controlling for differences in patient characteristics, apixaban is associated with significantly lower risk of S/SE and MB than rivaroxaban and warfarin, and a trend towards better outcomes vs. dabigatran among elderly NVAF patients in the US.     

Assessing adherence to infusion-based biologic therapies in patients with inflammatory bowel disease

BackgroundThe intravenous biologics infliximab and vedolizumab are effective long-term therapies for inflammatory bowel disease (IBD). Though highly effective, suboptimal adherence may result in loss of response and adverse sequelae. The extent and outcomes of suboptimal adherence with intravenous biologics, including in IBD, requires further evaluation.ObjectivesTo ascertain adherence to infliximab and vedolizumab infusions, and determine factors associated with poorer adherence within an IBD cohort.MethodsA retrospective single-centre cohort study of IBD patients, assessing adherence to infliximab and vedolizumab over 2 years (July 1, 2017 to June 30, 2019) was conducted. Medical and pharmacy dispensing records were used to determine date of infusion. Adherence was assessed using the continuous, multiple interval measure of medication gaps (CMG). Objectively measured disease remission was achieved if one or more of endoscopic remission, faecal calprotectin <100 μg/mL and/or CRP <5 mg/mL occurred within 3 months of end of follow-up. Bivariate analysis and multiple linear regression elucidated factors associated with poorer adherence.ResultsOf 193 IBD patients, 132 (68.4%) had Crohn's disease. One hundred and thirty six (70.5%) patients received infliximab and 57 (29.5%) received vedolizumab with a median 13 [IQR 11–14] doses administered per patient over 2 years. Adherence according to CMG was similar between infliximab and vedolizumab groups (median 1.5% vs 1.2%, p = 0.31). In multiple linear regression analysis male sex, shorter IBD duration and clinic non-attendances were each associated with poorer adherence (Beta 4.69, 3.90, 3.56 respectively, p < 0.05) and objective disease remission was inversely associated with poorer adherence (Beta ?3.27, p < 0.05).ConclusionThere was a wide range of adherence to biologic infusions in this IBD cohort with poorer adherence associated with patient related factors. Conversely, objectively measured remission was strongly associated with adherence. This emphasises the need for targeted interventions to improve adherence and monitoring, and mitigate treatment delays.     

Current pharmacologic treatment paradigms for inflammatory bowel disease and the potential role of granulocyte/monocyte apheresis

ABSTRACT

Background: A broad range of pharmacologic therapies are available to treat active inflammatory bowel disease (IBD), including 5-aminosalicylate preparations, corti­costeroids, and immunosuppressants (e.g., azathio­prine/6-mercaptopurine [AZA/6?MP] or methotrexate). Although these therapies are effective, up to 60% of patients are refractory or intolerant. Biologic therapies, such as the anti-TNF agent infliximab, offer promise but are not without controversy; despite many positive reports, steroid-refractory patients are less likely than other individuals to respond to infliximab. Effective, long-term therapies that do not add to the adverse-effects burden in patients with IBD are needed. Of these, granulocyte/monocyte apheresis (GMA) is one promising approach.

Scope: PubMed and relevant congresses databases were searched using the terms ‘granulocyte/monocyte apheresis,’ ‘GMA,’ ‘leukocytapheresis,’ ‘Adacolumn,’ and ‘Cellsorba.’ These studies were further selected to include only those focusing on IBD. A time frame of 2000–2006 was used.

Findings: Data from open-label trials show that patients with moderate-to-severe IBD refractory to conventional pharmacologic treatment achieved clinical response and/or remission after treatment with GMA. Furthermore, recent small open-label trials of GMA show increased rates of induction and maintenance of response/remission in steroid-naïve IBD patients.

Conclusions: The remission rates seen in these open-label clinical trials of GMA are consistent with those of currently available pharmacologic therapies for IBD. However, the majority of these trials enrolled only small numbers of patients, were largely open-label, and were of limited duration. These data must be confirmed in well-controlled, large-scale clinical trials.     

Comparative effectiveness of interferons in relapsing–remitting multiple sclerosis: a meta-analysis of real-world studies

Background: Differences between interferons have been evaluated for over 20 years. While randomized controlled trial (RCT) data is mainly used for assessments and strong data for causal inferences, it does not necessarily reflect everyday practice. Real-world data may provide additional information.

Purpose: To assess the results, quality, and representativeness of observational studies directly comparing interferons (IFNs) in RRMS.

Methods: Medline and Embase were searched for observational studies comparing IFN-beta-1a 30?mcg IM (Avonex¹), IFN-beta-1a 44?mcg SC (Rebif²) and/or IFN-beta-1b 250?mcg SC (Betaseron³). Outcomes included annualized relapse rate (ARR), proportions relapse free, confirmed progression free, treatment persistence, and neutralizing antibodies rates (NABs) measured up to 5 years of treatment. Data was combined using random effects meta-analyses. Categorical values were analyzed using chi-squared and Mann–Whitney tests.

Results: Thirty-six studies examining 32,026 patients (72.5% females, age?=?39.2?±?3.7 years, disease duration?=?5.6?±?2.0 years) were identified. Thirty-three studies investigated IFN-beta-1a IM (N?=?11,925), 30 IFN-beta-1a SC (N?=?10,684) and 34 IFN-beta-1b SC (N?=?9417). Baseline ARRs were similar (1.37?±?0.35, 1.51?±?0.27 and 1.55?±?0.23, respectively; P?=?.101) as were EDSS scores (2.24?±?0.39, 2.33?±?0.30, 2.55?±?0.38; P?=?.070) and >75% were naïve to IFNs. On treatment, ARRs were comparable (IFN-beta-1a IM 0.52?±?0.27, IFN-beta-1a SC 0.51?±?0.24, IFN-beta-1b SC 0.55?±?0.23; P?=?.595). Proportions of relapse-free patients were similar between drugs (P?>?.05 for all data points), except that IFN-beta-1a SC was superior to IFN-beta-1b SC in years 3–5 (all P?≤?.001). After 1 year, EDSS scores were comparable; after 2 years, IFN-beta-1a IM and IFN-beta-1a SC incurred less disease progression than IFN-beta-1b SC (P?P?P?Conclusions: In this comprehensive meta-analysis of real-world studies in RRMS, IFN-beta-1a IM, IFN-beta-1a SC and IFN-beta-1b SC had similar clinical profiles. When selecting an IFN, practitioners should consider observational data in their decision making process.     

Comparison of TTS-fentanyl with sustained-release oral morphine in the treatment of patients not using opioids for mild-to-moderate pain

SUMMARY

Objective: This randomised, multicentre, direct open comparative trial evaluated the efficacy, treatment convenience, tolerability and safety aspects of transdermal therapeutic system (TTS)-fentanyl and sustained-release oral morphine (SRM) in both opioid-naïve patients with moderate-to-severe cancer-related pain and in patients who had already been using opioids for mild-to-moderate pain. The two treatment groups were run in parallel. Special attention was paid to constipation, nausea/vomiting, drowsiness and respiratory depression.

Patients and methods: The 131 enrolled patients started the 4-week treatment at low doses of opioid (25?μg/h TTS-fentanyl for 3 days or 30?mg SRM every 12?h) and were individually titrated. Tolerability, efficacy and safety were assessed throughout the study period. Frequency of constipation was the primary study variable and accordingly the study was powered for this. Both patients and investigators made a global treatment evaluation.

Results: TTS-fentanyl and SRM were shown to be equally effective. Pain control and sleep quality improved with both treatments. None of the patients developed respiratory depression. Statistically significantly more patients in the SRM treatment group discontinued the trial prematurely (59% vs 27%; p?<?0.001), particularly due to adverse events (36% vs 4%; p?<?0.001). Fewer patients in the TTS-fentanyl than in the SRM treatment group reported constipation during the trial. This finding was statistically significant after 1 week of treatment (27% vs 57%; p?=?0.003). The favourable tolerability profile of TTS-fentanyl was also reflected in both the patient and the investigator global evaluation of the treatment. Patient assessment favoured TTS-fentanyl treatment in terms of a significantly lower rate of troublesome side-effects (‘quite a bit’ to ‘very much’ troublesome side-effects in 14% vs 36% of patients; p?=?0.003) and less interruption of daily activities (absence of any interruption of daily activities in 88% vs 63% of patients; p?=?0.012). Investigators scored TTS-fentanyl as significantly better with respect to ‘side-effects’ (p?=?0.039) and ‘overall impression’ (p?=?0.013). Sub-analyses of opioid-naïve users gave similar results.

Conclusion: These data indicate that TTS-fentanyl, when used as an opioid of first choice in the treatment of cancer-related pain, is as effective as, but better tolerated than, SRM, including in opioid-naïve patients.