Patient-reported outcomes in capmatinib-treated patients with METex14-mutated advanced NSCLC: Results from the GEOMETRY mono-1 study.

INTRODUCTION: Capmatinib, a MET inhibitor, showed substantial antitumour activity with manageable side effects in patients with MET exon 14 (METex14)-mutated advanced non-small cell lung cancer (aNSCLC) in the GEOMETRY mono-1 study. We report patient-reported outcomes (PROs) from this study. METHODS: Enrolled treatment-naïve (1L) or pre-treated (2L+) patients with aNSCLC with a METex14-skipping mutation received 400 mg capmatinib twice daily during 21-day treatment cycles. PROs were collected at baseline and every six weeks thereafter using EORTC QLQ-C30 global health status/quality of life (GHS/QoL), QLQ-LC13 symptoms, and EQ-5D-5L visual analogue scale (VAS) questionnaires. RESULTS: As of 6 January 2020, 27/28 1L and 65/69 2L+ patients had completed PROs at baseline; compliance rates remained >70%. Cough improved early, with meaningful improvements (≥10-point change from baseline) observed throughout cycles (mean change from baseline [SD] by week 7: 1L -13.0 [39.9], 2L+ -8.2 [28.4]; week 43: 1L -28.2 [26.7], 2L+ -10.5 [27.3]). QoL, assessed by GHS/QoL and VAS, improved by week 7 in 1L and 2L+ patients, with improvements generally sustained over time. Median time to definitive deterioration (TTDD) in GHS/QoL was 16.6 months (95% CI: 9.7, not estimable [NE]) in 1L and 12.4 months (95% CI: 4.2, 19.4) in 2L+ patients. Median TTDD for dyspnoea was 19.4 months (95% CI: 12.4, NE) and 22.1 months (95% CI: 9.9, NE) for 1L and 2L+ patients, respectively, and NE for cough and chest pain. CONCLUSIONS: Capmatinib was associated with clinically meaningful improvements in cough and preserved QoL, further supporting its use in patients with METex14-mutated aNSCLC. TRIAL REGISTRATION: ClinicalTrials.gov registry number: NCT02414139.

Health-related quality-of-life analyses from a multicenter, randomized, double-blind phase 2 study of patients with differentiated thyroid cancer treated with lenvatinib 18 or 24 mg/day.

BACKGROUND: In the phase 2 double-blind Study 211, a starting dose of lenvatinib 18 mg/day was compared with the approved starting dose of 24 mg/day in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). Predefined criteria for noninferiority for efficacy in the 18 mg arm were not met; safety was similar in both arms. Impact of lenvatinib treatment on health-related quality-of-life (HRQoL) was a secondary endpoint of Study 211. METHODS: Patients with RR-DTC were randomly assigned to a blinded starting dose of lenvatinib 18 mg/day or 24 mg/day. HRQoL was assessed at baseline, every 8 weeks until Week 24, then every 16 weeks, and at the off-treatment visit, using the EQ-5D-3L and FACT-G instruments. Completion and compliance rates, mean change from baseline, and times to first and definitive deterioration were evaluated. RESULTS: Baseline EQ-5D and FACT-G scores, and overall changes from baseline, were comparable between patients in the lenvatinib 18 mg/day (n = 77) and 24 mg/day arms (n = 75). For the 18 mg versus 24 mg arms, least squares mean differences were -0.42 (95% CI -4.88, 4.03) for EQ-5D-VAS and 0.47 (95% CI -3.45, 4.39) for FACT-G total. Time to first deterioration did not significantly favor either arm; EQ-5D-VAS HR [18 mg/24 mg] 0.93 (95% CI 0.61-1.40), EQ-5D-HUI HR [18 mg/24 mg] 0.68 (95% CI 0.44-1.05), FACT-G total HR [18 mg/24 mg] 0.73 (95% CI 0.48-1.12). Time to definitive deterioration did not significantly favor either arm, though EQ-5D-VAS showed a trend in favor of the 24 mg arm (HR [18 mg/24 mg] 1.72; 95% CI 0.99-3.01); EQ-5D-HUI HR [18 mg/24 mg] was 0.96 (95% CI 0.57-1.63), FACT-G total HR [18 mg/24 mg] was 0.72 (95% CI 0.43-1.21). CONCLUSIONS: In Study 211, HRQoL for patients in the lenvatinib 18 mg/day arm was not statistically different from that of patients in the 24 mg/day arm. These data further support the use of the approved lenvatinib starting dose of 24 mg/day in patients with RR-DTC. GOV NUMBER: NCT02702388.

The effect of secukinumab on patient-reported outcomes in patients with active psoriatic arthritis in a randomised phase 3 trial.

BACKGROUND: The phase 3 FUTURE 5 trial (NCT02404350) showed the clinical and radiographical efficacy of secukinumab in patients with psoriatic arthritis. This analysis aimed to assess the effect of secukinumab on patient-reported outcomes (PROs). METHODS: FUTURE 5 was a phase 3, multicentre, parallel-group randomised trial in which patients who were 18 years old or older, met the classification criteria for psoriatic arthritis at screening, and had symptoms of moderate-to-severe psoriatic arthritis for at least 6 months were randomly assigned to receive secukinumab 300 mg, 150 mg, 150 mg no loading dose (NL), or placebo weekly from baseline to week 4 and every 4 weeks thereafter. The prespecified PROs of the FUTURE 5 trial were assessed first in the overall population. We report mean changes from baseline and the proportion of patients reporting improvements equal to or more than the minimum clinically important differences (MCIDs) and scores equal to or more than the normative values for patient global assessments (PtGA) of disease activity; psoriasis and arthritis visual analogue scale (VAS) scores; pain VAS; Health Assessment Questionnaire Disability Index (HAQ-DI); 36-item Short Form Health Survey (SF-36); Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F); and quality of life questionnaires. Patients were then stratified and assessed according to their tumour necrosis factor (TNF) inhibitor status (TNF-naive and TNF-inadequate responder [TNF-IR] populations) as a post-hoc analysis. FINDINGS: Patients in all secukinumab groups reported significant least-squares mean changes from placebo at week 16 in all PROs except SF-36 mental component summary (MCS), irrespective of TNF inhibitor use. These included PtGA (300 mg difference vs placebo -12·2 [95% CI -16·3 to -8·1], 150 mg -8·22 [-12·4 to -4·1], 150 mg NL -8·3 [-12·5 to -4·2]; all p<0·0001), pain VAS (300 mg -14·3 [-18·3 to -10·2], 150 mg -11·5 [-15·6 to -7·5], 150 mg NL -11·3 [-15·3 to -7·2]; all p<0·0001), HAQ-DI (300 mg -0·33 [-0·42 to -0·24], 150 mg -0·23 [-0·32 to -0·14], 150 mg NL -0·24 [-0·33 to -0·15]; all p<0·0001), and FACIT-F (300 mg 4·8 [3·2 to 6·4], 150 mg 4·2 [2·6 to 5·8], 150 mg NL 3·5 [1·9 to 5·1]; all p<0·0001). Similarly, the proportion of patients with improvements equal to or better than MCID at week 16 was higher in the secukinumab group compared with the placebo group for most PROs except SF-36 (MCS), regardless of TNF inhibitor use. INTERPRETATION: Secukinumab resulted in early, statistically significant, clinically meaningful, sustained improvements in PROs across all doses compared with placebo in patients with active psoriatic arthritis. These improvements were seen irrespective of previous TNF inhibitor use, in a post-hoc analysis. These results indicate that secukinumab provides comprehensive improvement for patients with psoriatic arthritis, regardless of previous therapy. FUNDING: Novartis.

Achievement of Remission Endpoints with Secukinumab Over 3 Years in Active Ankylosing Spondylitis: Pooled Analysis of Two Phase 3 Studies.

INTRODUCTION: Clinical remission in patients with ankylosing spondylitis (AS) has been determined using composite indices such as the AS Disease Activity Score inactive disease (ASDAS-ID), Assessment of SpondyloArthritis international Society criteria partial remission (ASAS-PR), and low Bath AS Disease Activity Index (BASDAI) scores. The objective of this exploratory analysis was to evaluate the proportion of secukinumab-treated patients with AS achieving remission defined based on the ASDAS-ID (score < 1.3), ASAS-PR or BASDAI score ≤ 2. METHODS: The analysis pooled data from the MEASURE 1 and 2 studies over 3 years. The proportion of patients who achieved ASDAS-ID, ASAS-PR, or BASDAI ≤ 2 with secukinumab was compared with placebo at week 16; results for secukinumab-treated patients were summarized through week 156. Sustainability of each criterion was assessed from week 16 to 156 using shift analysis. The association between each of these criteria and specific patient-reported outcomes (PROs), such as health-related quality of life, function, fatigue, and work impairment, was also explored. RESULTS: At week 16, a higher proportion of secukinumab-treated patients versus placebo achieved ASDAS-ID (17.6 vs. 3.5%), ASAS-PR (15.4 vs. 4.1%), or BASDAI ≤ 2 (22.3 vs. 6.4%) criteria (all P < 0.0001), which were sustained through 156 weeks. Shift analysis showed that the majority of secukinumab-treated patients achieving remission at week 16 maintained their status at week 156 (ASDAS-ID, 57.1%; ASAS-PR, 68.0% and BASDAI ≤ 2, 74.3%). Remission was also associated with improved PROs over 156 weeks. CONCLUSIONS: Secukinumab-treated patients maintained ASDAS-ID, ASAS-PR, or BASDAI ≤ 2 from week 16 up to 3 years. Patients who achieved at least one of the three responses/states, reported improvement in PROs, which suggests an association of clinical remission/ID with PROs in patients with active AS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01358175, NCT01863732, and NCT01649375.

A case study applying a novel approach to estimate the social impact of a medical innovation - the use of secukinumab for psoriatic arthritis in Germany.

OBJECTIVES: Psoriatic arthritis (PsA) is associated with serious productivity impairment. Secukinumab, a fully human IL-17A inhibitor, provides sustained relief from PsA symptoms. This study estimates the societal economic benefits of using secukinumab instead of conventional disease-modifying anti-rheumatic drugs (DMARDs) for treating patients with active PsA in Germany from 2016 to 2030. METHODS: A Markov and a population model simulated the functional impairment of German PsA patients. The relationship between functional impairment and work productivity was used to determine the productivity difference in the populations treated with secukinumab and csDMARDs. The corresponding gains in productive time were allocated to paid and unpaid activities and valued according to gross value added (GVA). Since increased productivity has the potential to stimulate greater macroeconomic effects, indirect and induced GVA effects were calculated as well. RESULTS: The use of secukinumab reduces the productivity impairment in the target population on average by 13 percentage points. This difference could generate 32 million active and productive hours until the year 2030, which translates to GVA equivalents of €1.3 billion. Including indirect and induced effects yield an economic estimate of €2.7 billion GVA equivalent. CONCLUSIONS: The improvements in PsA-related functional impairment could lead to sizable productivity effects within the economy.

Secukinumab provides rapid and persistent relief in pain and fatigue symptoms in patients with ankylosing spondylitis irrespective of baseline C-reactive protein levels or prior tumour necrosis factor inhibitor therapy: 2-year data from the MEASURE 2 study.

OBJECTIVES: To evaluate improvement in pain and fatigue in ankylosing spondylitis (AS) patients treated with secukinumab over 2 years (MEASURE 2 study). METHODS: Patients with active AS were randomised to receive secukinumab 150 mg, 75 mg, or placebo weekly until Week 4, and every 4 weeks thereafter. This post hoc analysis included assessment of spinal and nocturnal back pain, FACIT-Fatigue, and association between pain and either FACIT-Fatigue or ASQoL item 5 (sleep quality) for the approved secukinumab 150 mg dose in the overall population, and stratified by baseline high-sensitivity C-reactive protein (hsCRP) levels (normal [<5 mg/L] or elevated [≥5 mg/L]) or prior TNF inhibitor therapy status (TNFi-naïve or inadequate response [TNFi-IR]). RESULTS: Secukinumab-treated patients reported rapid improvement in pain and fatigue scores in overall population by Weeks 1 and 4, respectively; this trend of improvement was also observed irrespective of baseline hsCRP levels or prior TNFi therapy. Mean change at Week 16 in spinal/nocturnal pain (secukinumab vs. placebo) for the subgroups were -34.6/-30.2 vs. -16.6/-10.0, p<0.05/0.01 (normal hsCRP); -26.7/-31.6 vs. -7.8/-9.3, p<0.001/0.0001 (elevated hsCRP); -33.2/-35.4 vs. -13.2/-14.9, both p<0.0001 (TNFi-naïve); and -22.5/-22.8 vs. -9.4/-4.0, p=0.06/p<0.01 (TNFi-IR). FACIT-Fatigue was 7.1 vs. 3.3, p=0.15 (normal hsCRP); 8.7 vs. 3.6, p<0.05 (elevated hsCRP); 10.0 vs. 5.2, p<0.05 (TNFi-naïve); and 5.7 vs. 0.5, p=0.06 (TNFi-IR). These improvements were sustained or further improved through Week 104. CONCLUSIONS: Secukinumab provides rapid and sustained relief of pain and fatigue over 2 years in patients with AS regardless of baseline hsCRP levels and prior TNFi therapy.

Longitudinal Modeling Approaches to Assess the Association Between Changes in 2 Clinical Outcome Assessments.

BACKGROUND: Understanding how one clinical outcome assessment (COA) (eg, a patient-reported outcome [PRO]) relates to a second COA (eg, a clinician-reported outcome [ClinRO]) may provide insights into disease burden or treatment efficacy. We aimed to briefly review commonly used cross-sectional methods to evaluate the association between a PRO and a ClinRO and to demonstrate the advantages of longitudinal modeling approaches, particularly a joint mixed model for repeated measures (MMRM), to evaluate this association. METHODS: We generated an example longitudinal data set that included a PRO measured on an 11-point numeric rating scale and a binary ClinRO. The association between change in PRO score and ClinRO response at each time point was examined using 2 cross-sectional analyses: point biserial correlation and logistic regression. We conducted longitudinal analyses of the association between the 2 COAs across time points using MMRM and joint MMRM approaches. RESULTS: Point-biserial correlation and logistic regression analyses correctly captured the "built in" associations between the 2 COAs that strengthened over time, but each association was applicable only for a single time point. The MMRM approach provided correlations over time but only for a single outcome variable. The joint MMRM approach modeled the relationship between both outcome variables simultaneously, allowing for evaluation of the correlations both within and between the variables over time. CONCLUSION: Each analysis demonstrated the relationship between PRO score changes and ClinRO response. Longitudinal analysis methods, particularly the joint MMRM, allow for a more thorough examination of the correlations among the 2 outcomes than cross-sectional analysis methods.

Minimal Disease Activity Among Active Psoriatic Arthritis Patients Treated With Secukinumab: 2-Year Results From a Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Phase III Study.

OBJECTIVE: To evaluate minimal disease activity (MDA) among psoriatic arthritis (PsA) patients receiving secukinumab through 2 years in the FUTURE 2 study. METHODS: Patients with active PsA were randomized to receive subcutaneous secukinumab 300, 150, or 75 mg or placebo. MDA was assessed in the overall population (anti-tumor necrosis factor [anti-TNF]-naive and inadequate responders [anti-TNF-IR]) and in patients stratified by prior anti-TNF exposure and by time since diagnosis at weeks 16, 24, 52, and 104. Function and patient-reported outcomes (PROs), including health-related quality of life (QoL) and work productivity, were assessed in MDA responders versus nonresponders. RESULTS: Overall, 28% of patients (27 of 98) and 23% (23 of 100) achieved MDA at week 16 with secukinumab 300 and 150 mg, respectively, versus 10% (9 of 94) with placebo. In the anti-TNF-naive cohort, a higher proportion of patients achieved MDA at week 16 with secukinumab 300 and 150 mg (34% and 32%, respectively) versus placebo (13%). The corresponding value in the anti-TNF-IR cohort was 15% and 8% with secukinumab 300 and 150 mg, respectively, versus with placebo (3%). At week 16, 27.1% of MDA responders (16 of 59) achieved a very low disease activity (VLDA) response, with the percentage being numerically greater with secukinumab 300 and 150 mg (30% [8 of 27] and 26% [6 of 23], respectively) versus placebo (22% [2 of 9]). The MDA and VLDA responses with secukinumab 300 and 150 mg were sustained through 2 years. MDA responders showed greater improvements in QoL outcomes compared to nonresponders through 2 years. CONCLUSION: A greater proportion of patients achieved MDA with secukinumab versus placebo at week 16, with response rates sustained through 2 years. MDA was associated with improved PROs, including QoL, through 2 years.

Effect of secukinumab on quality of life and psoriasis-related symptoms: A comparative analysis versus ustekinumab from the CLEAR 52-week study.

BACKGROUND: Secukinumab has demonstrated greater sustained skin clearance than ustekinumab through week 52, greater improvement in symptoms and health-related quality of life, and comparable safety profile. OBJECTIVE: To assess the impact of secukinumab versus that of ustekinumab on complete relief from psoriasis-related symptoms, time to response in terms of health-related quality of life, and cumulative benefit among patients with moderate-to-severe plaque psoriasis. METHODS: Psoriasis-related pain, itching, and scaling and the Dermatology Life Quality Index (DLQI) score were compared between treatments on the basis of time to complete relief of symptoms and time to DLQI response in the CLEAR trial. Cumulative benefit over 52 weeks based on Psoriasis Area and Severity Index score, symptom relief, and DLQI response were evaluated by area under the curve analysis. RESULTS: Significantly more patients treated with secukinumab achieved complete relief of pain at weeks 16 and 52 (all P < .05). Complete relief of itching and scaling occurred significantly faster with secukinumab (median, 4 weeks faster for itching and 8 weeks faster for scaling [P < .001]). Response as measured by the DLQI was 4 weeks faster with secukinumab (P < .0001). Cumulative benefits were greater with secukinumab (all P < .05). LIMITATIONS: Analyses were post hoc. CONCLUSION: This patient-reported outcome analysis confirms greater and sustained benefits of secukinumab versus those of ustekinumab treatment on patients' lives.

Psoriasis patients with psoriasis Area and Severity Index (PASI) 90 response achieve greater health-related quality-of-life improvements than those with PASI 75-89 response: results from two phase 3 studies of secukinumab.

BACKGROUND: The emergence of new biological therapies showing high and sustained level of Psoriasis Area and Severity Index (PASI) 90 response has provided the possibility of both greater skin clearance and increased quality of life (QOL). OBJECTIVE: To evaluate the association of greater response in skin clearance with improvements in skin-related QOL up to 52 weeks. METHODS: Subjects achieving various levels of skin clearance (PASI 90-100 or PASI 75-89) and Dermatology Life Quality Index (DLQI) (0/1) response were compared using ERASURE and FIXTURE trial data. Similar analyses with IGA ratings of Clear or Almost Clear were performed. RESULTS: Significantly more PASI 90-100 responders at week 12 had DLQI 0/1 response than PASI 75-89 (69.4% vs. 47.1%; p < .001) and sustained DLQI 0/1 response at week 52 (74.0% vs. 56.7%; p < .001). IGA results were similar. CONCLUSIONS: These results show that PASI 90-100 is a relevant therapeutic goal in moderate to severe psoriasis compared to PASI 75-89 when considering patients' QOL.

Secukinumab sustains early patient-reported outcome benefits through 1 year: Results from 2 phase III randomized placebo-controlled clinical trials comparing secukinumab with etanercept.

BACKGROUND: Psoriasis is a chronic condition with negative impact on patients' quality of life that most often requires lifelong effective and safe treatment. OBJECTIVE: This analysis focused on the effect of secukinumab treatment on patient-reported health-related quality of life as assessed by the Dermatology Life Quality Index (DLQI) in patients with moderate to severe psoriasis. METHODS: The proportion of subjects achieving DLQI score 0/1 response at week 24, time to DLQI score 0/1 response, and sustained DLQI score 0/1 response up to week 52 were compared between secukinumab and etanercept. RESULTS: Of 1470 subjects, 1144 received secukinumab and 326 received etanercept. DLQI score 0/1 response rates were significantly higher for secukinumab than for etanercept at week 24. The median time to DLQI score 0/1 response was significantly shorter for secukinumab versus etanercept (12 vs 24 weeks; P < .01). The majority of secukinumab-treated subjects achieved DLQI score 0/1 response at week 24 and sustained it through week 52 along with a 90% to 100% reduction in the Psoriasis Area and Severity Index total score response. LIMITATIONS: Placebo comparisons are limited during the maintenance period because of rerandomization at week 12. CONCLUSION: Secukinumab treatment provided faster and greater sustained improvements in quality of life than etanercept over 52 weeks, consistent with greater clinical response.

"Same-Day" administration of pegfilgrastim following myelosuppressive chemotherapy: clinical practice and provider rationale.

PURPOSE: To describe patient- and practice-related factors that physicians report affect their clinical decision to administer prophylactic pegfilgrastim to patients <24 h after completion of a myelosuppressive chemotherapy cycle (i.e., "same-day" pegfilgrastim). METHODS: Oncologists, hematologists, and hematologist-oncologists enrolled in a US national physician panel were invited to participate in a cross-sectional, web-based survey to assess physicians' reasons for prescribing "same-day" pegfilgrastim. Physicians were screened as eligible if they reported prescribing "same-day" pegfilgrastim within the previous 6 months. The survey assessed physician perspectives and physician-perceived patient/caregiver preferences. RESULTS: Of 17,478 invited physicians, 386 answered the screening questions; 151 (39.1 %) were eligible, agreed to participate, and completed the survey. Physicians estimated that overall 41.3 % of their patients treated with myelosuppressive chemotherapy received pegfilgrastim and that 31.6 % treated with pegfilgrastim received it on a "same-day" schedule. Approximately 36 % of physicians relied primarily on their clinical judgment when deciding to administer "same-day" pegfilgrastim. The clinical consideration reported most commonly by physicians as moderately or very important when deciding to administer "same-day" pegfilgrastim was previous febrile neutropenia (77.6 %). The most important patient-related consideration in the decision to administer "same-day" pegfilgrastim was patient/caregiver travel distance, and the most important practice-related consideration was the burden to the physician's practice of "next-day" administration (vs. same-day), reported by 84.7 % and 65.1 % of physicians as moderately or very important, respectively. CONCLUSIONS: While clinical judgment, patients' risk factors, and practice burden were principal influences favoring "same-day" pegfilgrastim administration, physician-perceived patient preferences and logistical barriers also have important roles in this decision.

Systematic review and network meta-analysis of the relative efficacy and safety of edoxaban versus other nonvitamin K antagonist oral anticoagulants among patients with nonvalvular atrial fibrillation and CHADS2 score ⩾ 2.

BACKGROUND: The nonvitamin K antagonist oral anticoagulants pivotal clinical trials for stroke prevention in atrial fibrillation have important differences in trial designs and baseline patient characteristics. OBJECTIVE: We sought to evaluate the relative efficacy and safety of edoxaban versus other nonvitamin K antagonist oral anticoagulants in the management of stroke prevention in atrial fibrillation by adjusting for differences in baseline stroke risk and the length of follow-up among the four phase 3 randomized controlled trials. METHODS: We conducted a systematic literature review of randomized controlled trials evaluating the nonvitamin K antagonist oral anticoagulants for stroke prevention in atrial fibrillation and performed a network meta-analysis using data from ENGAGE AF-TIMI 48, RE-LY, ROCKET-AF, and ARISTOTLE, with warfarin as a common comparator. To adjust for between-trial differences in CHADS2 score and length of follow-up, annualized event rates among patients with CHADS2 score ⩾ 2 were analyzed using a mixed Poisson's regression model. RESULTS: Once-daily high-dose edoxaban was associated with significant lower major bleeding episodes compared with once-daily rivaroxaban (risk ratio, 0.76; 95% confidence interval, 0.66-0.89), twice-daily dabigatran 150 mg (risk ratio, 0.78; 95% confidence interval, 0.61-0.84), and twice-daily dabigatran 110 mg (risk ratio, 0.83; 95% confidence interval, 0.71-0.98) and similar bleeding risk compared with twice-daily apixaban (risk ratio, 1.08; 95% confidence interval, 0.91-1.28). Risk of stroke and systemic embolism was similar for the high-dose edoxaban and other nonvitamin K antagonist oral anticoagulant regimens. The low-dose edoxaban regimen was associated with a significant lower risk of major bleeding than other nonvitamin K antagonist oral anticoagulants and a significant higher risk of stroke and systemic embolism compared with apixaban and dabigatran 150 mg. CONCLUSION: Among patients with atrial fibrillation and CHADS2 score ⩾ 2, the high-dose edoxaban regimen may offer similar efficacy to the other nonvitamin K antagonist oral anticoagulants but with a significant major bleeding benefit over rivaroxaban and dabigatran.

Relationship between diclofenac dose and risk of gastrointestinal and cardiovascular events: meta-regression based on two systematic literature reviews.

BACKGROUND: NSAIDs are associated with risks of gastrointestinal (GI) and cardiovascular (CV) toxicities. It has been reported that the risks of GI and CV events are dose related, resulting in guidance explicitly emphasizing the use of NSAIDs at the lowest effective dose for the shortest duration. To understand the potential benefits of using lower doses of diclofenac, a more detailed understanding of the relationship of diclofenac dose and the risks of GI and CV events is required. OBJECTIVE: The objective of this study was to extend previous research quantifying the NSAID dose-toxicity relationship by modeling dose as a continuous measure, allowing for an assessment of the risks of major GI and CV events for patients taking specific diclofenac doses compared with NSAID nonusers. METHODS: We used studies identified in 2 recently published systematic reviews of observational studies that examined the risks of major GI and CV events associated with the use of oral NSAIDs. We developed meta-regression models, considering dose as a continuous measure, to estimate the risks of major GI and CV events for different daily doses of conventional oral diclofenac relative to nonuse of NSAIDs. RESULTS: Seven of the 59 GI publications, contributing 11 dose-specific risk ratio observations, and 12 of the 51 CV studies, contributing 21 dose-specific risk ratio observations, were eligible for inclusion in the meta-regression. The models indicated positive linear relationships between diclofenac dose and the relative risks of major GI and CV events for the range of doses examined. CONCLUSIONS: To our knowledge, this is the first study to quantify and aggregate the continuous relationship between the risk of GI or CV events and the dosage of an NSAID. With the recent availability of new low doses of diclofenac, the models may be used to estimate the potential reduction in risk of adverse events at these doses.

Effect of ethnicity on weight loss among adolescents 1 year after bariatric surgery.

AIM: To investigate whether or not bariatric surgery weight outcomes vary by ethnicity in a large, nationally representative sample of adolescents. METHODS: The Bariatric Outcomes Longitudinal Database was used for analysis and contains data on surgeries performed on adolescents from 2004 to 2010 from 423 surgeons at 360 facilities across the United States Adolescents (n = 827) between 11 and 19 years old who underwent either gastric bypass or adjustable gastric banding surgery were included in the analysis. Outcome measures included changes in anthropometric measurements [weight (kg) and body mass index] from baseline to 3 (n = 739), 6 (n = 512), and 12 (n = 247) mo after surgery. RESULTS: A year after patients underwent either gastric bypass (51%) or adjustable gastric banding (49%) surgery, mean estimated weight loss for all ethnic groups differed by a maximum of only 1.5 kg, being 34.3 kg (95%CI: 30.0-38.5 kg) for Hispanics, 33.8 kg (95%CI: 27.3-40.3 kg) for non-Hispanic blacks, and 32.8 kg (95%CI: 30.9-34.7 kg) for non-Hispanic whites. No overall pairwise group comparisons were significant, indicating that no ethnic group had better weight loss outcomes than did another. CONCLUSION: Bariatric surgery substantially reduces the weight of severely obese adolescents at 1 year post-procedure with little variation by ethnicity and/or gender. These results suggest that bariatric surgery is a safe and reasonable treatment for all severely obese adolescents with the appropriate indications.

Changes in weight and co-morbidities among adolescents undergoing bariatric surgery: 1-year results from the Bariatric Outcomes Longitudinal Database.

BACKGROUND: Bariatric surgery is 1 of the few effective treatments of morbid obesity. However, the weight loss and other health-related outcomes for this procedure in large, diverse adolescent patient populations have not been well characterized. Our objective was to analyze the prospective Bariatric Outcomes Longitudinal Database (BOLD) to determine the weight loss and health related outcomes in adolescents. The BOLD data are collected from 423 surgeons at 360 facilities in the United States. METHODS: The main outcome measures included the anthropometric and co-morbidity status at baseline (n = 890) and at 3 (n = 786), 6 (n = 541), and 12 (n = 259) months after surgery. Adolescents (75% female; 68% non-Hispanic white, 14% Hispanic, 11% non-Hispanic black, and 6% other) aged 11 to 19 years were included in the present analyses. RESULTS: The overall 1-year mean weight loss for those who underwent gastric bypass surgery was more than twice that of those who underwent adjustable gastric band surgery (48.6 versus 20 kg, P < .001). Similar results were found for all other anthropometric changes and comparisons within 1 year between surgery types (P < .001). In general, the gastric bypass patients reported more improvement than the adjustable gastric band patients in co-morbidities at 1 year after surgery. A total of 45 readmissions occurred among gastric bypass patients and 10 among adjustable gastric band patients, with 29 and 8 reoperations required, respectively. CONCLUSIONS: The weight loss at 3, 6, and 12 months after surgery is approximately double in adolescent males and females who underwent gastric bypass surgery versus those who underwent adjustable gastric band surgery. Bariatric surgery can safely and substantially reduce weight and related co-morbidities in morbidly obese adolescents for ≥1 year.

Early outcomes of bariatric surgery in patients with metabolic syndrome: an analysis of the bariatric outcomes longitudinal database.

BACKGROUND: Metabolic syndrome (MetS) complicating obesity is endemic in the United States. STUDY DESIGN: Bariatric Outcomes Longitudinal Database, the national database for the American Society for Metabolic and Bariatric Surgery Bariatric Surgery Center of Excellence Program, was queried to identify patients undergoing bariatric surgery from June 2007 through November 2010. MetS was defined as the presence of hypertension, diabetes, and dyslipidemia at presentation for bariatric surgery. Ninety-day and 1-year outcomes were assessed to determine early outcomes in bariatric surgery patients with MetS. RESULTS: Among 186,576 research-consented patients, 23,106 (12%) were diagnosed with MetS. Patients with MetS were more likely to be male (35% vs 20%; p < 0.0001), older (mean age 54 vs 44 years; p < 0.0001), and Caucasian (81% vs 74%; p < 0.0001). Of the 23,106 MetS patients, more underwent gastric bypass (RYGB) (62%) compared with gastric banding (32%), sleeve gastrectomy (4.5%), and biliopancreactic diversion with duodenal switch (BPD/DS)(1.5%). MetS patients had an increase in serious complications (2.4% vs 1.0%; p < 0.0001), readmissions (6.2% vs 4.7%; p < 0.0001), and mortality (0.3% vs 0.1%; p < 0.0001) within 90 days of operation. After adjusting for sex, age, and body mass index, RYGB patients with MetS had an increased risk of 90-day serious complications compared to RYGB patients without MetS (odds ratio 1.43; 95% CI, 1.27 to 1.61; p < 0.0001). The 12-month remission rate of diabetes was least for gastric banding (28%) compared with the other procedures (RYGB 62%, sleeve gastrectomy 52%, BPD/DS 74%). CONCLUSIONS: Patients with MetS undergoing bariatric surgery showed dramatic improvement in diabetes 1-year after surgery; however, an adverse 90-day outcome was more common.

Meta-analysis of the association between progression-free survival and overall survival in metastatic colorectal cancer.

PURPOSE: The validity of progression-free survival (PFS) as a surrogate endpoint for overall survival (OS) in metastatic colorectal cancer (mCRC) trials has been studied, primarily in first-line treatment. The relationship between PFS and OS has not been well studied in later lines of treatment. METHODS: We conducted a systematic literature review of mCRC phase 2 and 3 clinical trials that reported OS and PFS (or time-to-progression [TTP]) data. Correlation between endpoints (either PFS alone or PFS aggregated with TTP [PFS_TTP]) was estimated within treatment arms. Treatment effect was the ratio of the median time to OS, PFS, or PFS_TTP in the "control" versus "experimental" arm. We conducted meta-regression analyses and performed receiver-operating characteristic (ROC) analysis. RESULTS: We analyzed data from 62 articles (23,527 patients). A high positive correlation was found between median PFS_TTP and median OS within treatment arms (r = 0.87; 95% confidence interval [CI], 0.82-0.91) and also between the median OS and median PFS (r = 0.89, 95% CI, 0.83-0.93)]. R(2) was 0.48 for PFS_TTP and 0.59 for PFS; R (2) for PFS_TTP was higher for first-line (R(2) = 0.54) than second-line studies (R(2) = 0.38). The ROC analysis is presented as a conceptual tool for evaluating the performance of PFS as a surrogate for OS at various thresholds. CONCLUSIONS: The correlation of PFS, alone or aggregated with TTP, with OS in clinical trials of patients with mCRC is robust across lines of therapy and provides a useful means of predicting improvements in OS using PFS data.

Quality-adjusted survival analysis of first-line treatment of hormone-receptor-positive HER2+ metastatic breast cancer with letrozole alone or in combination with lapatinib.

AIM: Compare first-line lapatinib plus letrozole (L + Let) versus letrozole monotherapy (Let) in hormone-receptor-positive HER2 + metastatic breast cancer, employing Q-TWiST (quality-adjusted time without symptoms and toxicity) analysis to account for differences in progression times, with offsets for the impact of adverse events during the treatment period. METHODS: The area under survival curves for each treatment group was partitioned into distinct health states of varying utility: toxicity (TOX), time without toxicity or disease progression (TWiST), and the period following disease progression until death or end of follow-up (REL). The utility-weighted sum of the mean health state durations was derived for each group. The threshold utility analysis evaluates how varying utility values across the states affects Q-TWiST differences between groups, although the method is limited by not varying utilities within each health state. RESULTS: The primary analysis population was the HER2 + subgroup (n = 219). There was no significant difference between treatments in mean duration of grade 3/4 adverse events prior to progression (L + Let = 1.95 weeks; Let = 2.14 weeks; P = 0.90). Using utility weights of 0.5 for TOX and REL, L + Let was favored for quality-adjusted survival by 8.8 weeks (P = 0.09). The Q-TWiST difference between treatment groups ranged from 8 to 9.5 weeks, favoring combination therapy for all hypothetical utility levels, but none of the comparisons were statistically significant at P = 0.05. CONCLUSIONS: No significant differences were found between L + Let versus Let in mean duration of severe adverse events. Quality-adjusted survival was favored for the combination treatment arm for all utility levels examined when toxicity was defined by grade 3/4 AEs, but differences between groups were not statistically significant.

Venous thromboembolism after bariatric surgery performed by Bariatric Surgery Center of Excellence Participants: analysis of the Bariatric Outcomes Longitudinal Database.

BACKGROUND: Venous thromboembolism (VTE) is an uncommon complication of bariatric surgery but a leading cause of postoperative mortality. Studying the factors predictive of low-incidence complications requires the analysis of large cohorts. The Bariatric Outcomes Longitudinal Database, the world's largest prospective database for bariatric surgery, has provided a suitable medium for analyzing low-frequency events. METHODS: The data in the Bariatric Outcomes Longitudinal Database from 73,921 research-consented patients who had undergone bariatric surgery by a participant in the American Society for Metabolic and Bariatric Surgery Bariatric Surgery Center of Excellence program before September 22, 2009, were analyzed for VTE events within 90 days after surgery. RESULTS: The overall risk of VTE within 90 days after surgery was .42%, and 73% of these events occurred after discharge, most within 30 days after surgery. The risk of VTE was greater in the patients undergoing gastric bypass than in those undergoing adjustable gastric banding (.55% versus .16%). VTE was more frequent when the procedure was performed using an open than a laparoscopic approach (1.54% versus .34%). Patients with a VTE event were older (+4.9 yr), had had a greater preoperative body mass index (+3.9 kg/m(2)), and were more likely to have a history of VTE (16.5% versus 3.7%). The risk of VTE was greater in men (hazard ratio 2.32, 95% confidence interval 1.81-2.98) and in patients with an inferior vena cava filter (hazard ratio 7.66, 95% confidence interval 4.55-12.91). CONCLUSION: The overall risk of VTE was low in the population treated by participants in the Bariatric Surgery Center of Excellence program, where clinical pathways to prevent VTE have been mandated. Analysis of this large study population allowed the identification of patient characteristics correlating with increased risk of postoperative VTE and the variable effectiveness of VTE prophylaxis methods.