Noninferiority of cetuximab every-2-weeks versus standard once-weekly administration schedule for the first-line treatment of RAS wild-type metastatic colorectal cancer

Abstract Aim This study assessed whether cetuximab 500 mg/m2 administered every 2 weeks (Q2W), when combined with chemotherapy as a first-line (1L) treatment, was noninferior to the approved dose (400 mg/m2 followed by 250 mg/m2 once weekly [Q1W]) for overall survival (OS) in adults with RAS wild-type metastatic colorectal cancer (mCRC). Methods This pooled analysis included patients receiving 1L treatment with cetuximab Q1W or Q2W in combination with chemotherapy from post-authorisation studies with patient-level data available to the sponsor. Baseline characteristics were adjusted with a propensity score using inverse probability of treatment weighting (IPTW). Noninferiority in terms of OS was tested with a noninferiority margin for the hazard ratio (HR) of 1.25 using a Cox proportional hazards regression model. Secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and rates of lung/liver metastases resection and serious adverse events. Results OS time was noninferior in the Q2W cohort (n = 554) compared to the Q1W cohort (n = 763), with a HR after IPTW (95% confidence interval) of 0.827 (0.715–0.956) and median OS times of 24.7 (Q1W) and 27.9 (Q2W) months. There were no major differences in PFS (HR: 0.915 [0.804–1.042]). The odds ratios (ORs) after IPTW for ORR (1.292 [1.031–1.617]) and the rates of lung/liver metastases resection (1.419 [1.043–1.932]) favoured the Q2W regimen. No differences were noted in the occurrence rate of any SAE between groups; the OR after IPTW was 1.089 (0.858–1.382). Conclusions The cetuximab Q2W regimen was noninferior to the Q1W regimen for OS in the 1L treatment of mCRC

Incidence of malignancies in patients with multiple sclerosis versus a healthy matched cohort: A population-based cohort study in the Netherlands using the PHARMO Database Network

This study estimated the incidence of malignancy in patients with multiple sclerosis (MS) versus a matched general population cohort in the Netherlands. Adults with a diagnosis of MS between 2006 and 2014 in the General Practitioner (GP) Database of the PHARMO Database Network with ≥ 1 year of patient history were matched to four non-MS individuals based on year of birth, sex, and GP practice. Patients were followed-up until the earliest malignancy diagnosis, death, or end of data collection. Age-adjusted incidence rates (IR) were measured overall and by cancer type. Standardized incidence ratios (SIR) were calculated as the ratio of stratification-specific IRs in the MS and non-MS cohorts. A total of 1,692 MS patients were matched to 6,768 non-MS patients. Age-adjusted IR of any malignancy, excluding non-melanoma skin cancer (n = 27), in the MS cohort was 48.3 (95%CI:30.1–66.5) per 10,000 PY. An increased incidence of any malignancy was observed in the MS cohort versus the non-MS cohort (SIR 1.8 [95%CI:1.1–2.5]). The most commonly observed malignancies in the MS cohort were breast cancer (n = 8; IR 20.4 [95%CI:6.3–34.5] per 10,000 PY) and melanoma (n = 6; IR 14.8 [95%CI:3.0–26.7] per 10,000 PY). The corresponding SIR observed between cohorts was 1.4 (95%CI:0.4–2.4) and 3.4 (95%CI:0.7–6.2), respectively. While the small increased incidence of malignancy in the MS cohort could be an artefact created by a different distribution of risk factors, an increased incidence of malignancy in MS patients in the Netherlands cannot be excluded

Incidence of malignancy in multiple sclerosis:A cohort study in the Danish Multiple Sclerosis Registry

BACKGROUND: The association between multiple sclerosis and malignancy is controversial and a current appraisal is needed. OBJECTIVE: To determine the incidence of malignancy in patients with multiple sclerosis compared with the general population and in relation to disease-modifying therapy. METHODS: Patients with multiple sclerosis (1995 – 2015) were matched by birth year and sex to individuals without multiple sclerosis in the general population. Patients with multiple sclerosis initiating disease-modifying therapy were evaluated using landmark period analysis. Malignancy risk was assessed by incidence rates, incidence rate ratios, and standardised incidence ratios. RESULTS: The standardised incidence ratio of any malignancy (excluding non-melanoma skin cancer) in patients with multiple sclerosis (n = 10,557) was 0.96 (95% CI 0.88 – 1.06), and there was no increased incidence of specific malignancy types compared with the general population cohort (n = 103,761). At the 48-month landmark period, the age-adjusted incidence per 100,000 person-years of any malignancy (excluding non-melanoma skin cancer) was 436.7 (95% CI 361.0 – 512.4) in patients newly treated with immunomodulator-only and 675.1 (95% CI 130.4 – 1219.9) in patients newly treated with immunosuppressant-only. CONCLUSIONS: There was no increased incidence of malignancy overall or by type in patients with multiple sclerosis compared neither with the general population nor in relation to disease-modifying therapy

Supplementary materials: Effectiveness of bisoprolol versus other β-blockers and other antihypertensive classes: a cohort study in the Clinical Practice Research Datalink

These are peer-reviewed supplementary materials for the article 'Effectiveness of bisoprolol versus other β-blockers and other antihypertensive classes: a cohort study in the Clinical Practice Research Datalink' published in the Journal of Comparative Effectiveness Research.Supplementary Figure 1: A model showing the progress of each patient through different hypertension states over time.Supplementary Table 1: Antihypertensive drugs considered for each treatment of interest.Supplementary Figure 2: Patient attrition and the number of patients in each analysis set.Supplementary Table 2: Baseline characteristics before matching, in patients fulfilling the study criteria.Supplementary Table 3: Baseline comorbidities and comedications, in patients fulfilling the study definition.Supplementary Table 4: Baseline characteristics of all analysis sets, post-matching. A. Baseline characteristics and comedications after matching, in the T2DM analysis set.Supplementary Figure 3: Distribution of the propensity scores, after matching.Supplementary Table 5: Standardized mean differences before/after matching.Supplementary Table 6: Transition intensities for the multi-state model between controlled and uncontrolled BP states, length of stay in the controlled state, after matching in the BP analysis set.Supplementary Table 7: Number of events and safety event incidence rates after matching, for each event of interest and comparison group. Supplementary Table 8: Cause-specific Cox proportional hazards models and Fine and Gray models for T2DM – sensitivity analysis excluding patients with prior impaired fasting blood glucose levels.Supplementary Table 9: Cause-specific Cox proportional hazards models and Fine and Gray models for competing events of outcome for interest.Aim: To compare blood pressure (BP) and safety outcomes in patients with hypertension initiating bisoprolol, versus other β-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, calcium channel blockers or diuretics. Materials & methods: New user cohort study. Patients initiating bisoprolol were matched with up to four patients, in each comparator cohort using propensity score. BP outcomes were compared using linear mixed models and safety outcomes using Cox proportional hazards. Results: Differences in average systolic and diastolic BP variation were ≤3 mmHg between bisoprolol versus the compared classes. No difference was observed in risk of diabetes, obesity or erectile dysfunction. An increased dyslipidemia risk was only observed versus diuretics (hazard ratio: 0.76; 98.75% CI: 0.58, 0.99). Conclusion: No differences in BP variation and safety outcomes.</p

Metformin in pregnancy and risk of adverse long-term outcomes:a register-based cohort study

Abstract Introduction: This study aimed to investigate if maternal pregnancy exposure to metformin is associated with increased risk of long-term and short-term adverse outcomes in the child. Research design and methods: This register-based cohort study from Finland included singleton children born 2004–2016 with maternal pregnancy exposure to metformin or insulin (excluding maternal type 1 diabetes): metformin only (n=3967), insulin only (n=5273) and combination treatment (metformin and insulin; n=889). The primary outcomes were long-term offspring obesity, hypoglycemia, hyperglycemia, diabetes, hypertension, polycystic ovary syndrome, and challenges in motor–social development. In a sensitivity analysis, the primary outcomes were investigated only among children with maternal gestational diabetes. Secondary outcomes were adverse outcomes at birth. Analyses were conducted using inverse- probability of treatment weighting (IPTW), with insulin as reference. Results: Exposure to metformin or combination treatment versus insulin was not associated with increased risk of long-term outcomes in the main or sensitivity analyses. Among the secondary outcomes, increased risk of small for gestational age (SGA) was observed for metformin (IPTW-weighted OR 1.65, 95% CI 1.16 to 2.34); increased risk of large for gestational age, preterm birth and hypoglycemia was observed for combination treatment. No increased risk was observed for neonatal mortality, hyperglycemia, or major congenital anomalies. Conclusions: This study found no increased long-term risk associated with pregnancy exposure to metformin (alone or in combination with insulin), compared with insulin. The increased risk of SGA associated with metformin versus insulin suggests caution in pregnancies with at-risk fetal undernutrition. The increased risks of adverse outcomes at birth associated with combination treatment may reflect confounding by indication or severity.Members of the CLUE Study Group are Minna Vehkala (Global Database Studies, IQVIA), Robyn Thorén (Global Database Studies, IQVIA), Henrik Svanström (Global Database Studies, IQVIA)

Thrombectomy complications in large vessel occlusions: Incidence, predictors, and clinical impact in the ETIS registry

International audienceBACKGROUND AND PURPOSE: Procedural complications in thrombectomy for large vessel occlusions of the anterior circulation are not well described. We investigated the incidence, risk factors, and clinical implications of thrombectomy complications in daily clinical practice. METHODS: We used data from the ongoing prospective multicenter observational Endovascular Treatment in Ischemic Stroke Registry in France. The present study is a retrospective analysis of 4029 stroke patients with anterior large vessel occlusions treated with thrombectomy between January 2015 and May 2020 in 18 centers. We systematically collected procedural data, incidence of embolic complications, perforations and dissections, clinical outcome at 90 days, and hemorrhagic complications. RESULTS: Procedural complications occurred in 7.99% (95% CI, 7.17%–8.87%), and embolus to a new territory (ENT) was the most frequent (5.2%). Predictors of ENTs were terminal carotid/tandem occlusion (odds ratio [OR], 5 [95% CI, 2.03–12.31]; P<0.001) and an increased total number of passes (OR, 1.22 [95% CI, 1.05–1.41]; P=0.006). ENTs were associated to worse clinical outcomes (90-day modified Rankin Scale score, 0–2; adjusted OR, 0.4 [95% CI, 0.25–0.63]; P<0.001), increased mortality (adjusted OR, 1.74 [95% CI, 1.2–2.53]; P<0.001), and symptomatic intracerebral hemorrhage (adjusted OR, 1.87 [95% CI, 1.15–3.03]; P=0.011). Perforations occurred in 1.69% (95% CI, 1.31%–2.13%). Predictors of perforations were terminal carotid/tandem occlusions (39.7% versus 27.6%; P=0.028). 40.7% of patients died at 90 days, and the overall rate of poor outcome was 74.6% in case of perforation. Dissections occurred in 1.46% (95% CI, 1.11%–1.88%) and were more common in younger patients (median age, 64.2 versus 70.2 years; P=0.002). Dissections did not affect the clinical outcome at 90 days. Besides dissection, complications were independent of the thrombectomy technique. CONCLUSIONS: Thrombectomy complication rate is not negligible, and ENTs were the most frequent. ENTs and perforations were associated with disability and mortality, and terminal carotid/tandem occlusions were a risk factor

Type 1 Diabetes in People Hospitalized for COVID-19: New Insights From the CORONADO Study

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The association between macrovascular complications and intensive care admission, invasive mechanical ventilation, and mortality in people with diabetes hospitalized for coronavirus disease-2019 (COVID-19)

International audienceAbstract Background It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. Methods We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020—October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. Results Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83–2.45 with an I 2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29–1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31–0.75], I 2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40–0.68], I 2 37%) were significantly lower for people with previous macrovascular disease. Conclusions This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup