Matching-Adjusted Indirect Comparison of the Efficacy at Week 32 of Tralokinumab and Dupilumab in the Treatment of Moderate-to-Severe Atopic Dermatitis.

INTRODUCTION: Tralokinumab and dupilumab are biological agents licensed for the treatment of moderate-to-severe atopic dermatitis (AD) in adult patients who are candidates for systemic treatment. However, no head-to-head studies of their efficacy have been conducted. This study indirectly compared the efficacy of tralokinumab and dupilumab, both in combination with topical corticosteroids (TCS), at week 32. METHODS: An unanchored matching-adjusted indirect comparison was conducted using individual patient data (IPD) from the ECZTRA 3 tralokinumab trial and aggregate data from the LIBERTY AD CHRONOS dupilumab trial. IPD were selected by applying inclusion criteria from LIBERTY AD CHRONOS and weighting to match summary baseline characteristics-age, sex, race, body mass index, disease duration, Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), Dermatology Life Quality Index (DLQI) and SCORing Atopic Dermatitis index-of patients treated with dupilumab. Week 32 outcomes of interest were 50%, 75% or 90% improvements in EASI (EASI-50, EASI-75 and EASI-90), IGA scores of 0 or 1 (IGA 0/1), ≥ 4-point improvement in worst daily pruritus numerical rating scale (NRS) score, and mean improvements in DLQI and the Patient Oriented Eczema Measure (POEM). RESULTS: After matching, tralokinumab and dupilumab, both in combination with TCS, showed similar efficacy across clinical response endpoints at week 32 (IGA 0/1, tralokinumab 49.9% vs dupilumab 39.3%; EASI-50, 78.9% vs 77.5%; EASI-75, 71.5% vs 71.9%; EASI-90, 53.3% vs 56.2%). The mean change from baseline in DLQI was statistically significantly larger in the matched tralokinumab plus TCS population than in the dupilumab plus TCS arm (- 12.1 vs - 10.4, p = 0.005). Changes in POEM and worst daily pruritus NRS were similar in the two groups. CONCLUSION: The results of this analysis demonstrate that, in combination with TCS, tralokinumab and dupilumab have similar efficacy in the treatment of moderate-to-severe AD at 32 weeks of therapy.

Clinical characteristics of two groups commonly referred to an Irish hypertension service-patients with resistant hypertension and young adults with hypertension.

BACKGROUND: The management of hypertension is primarily performed in primary care settings in many health systems. However, two groups of patients often require specialist input: patients with resistant hypertension (RH) and young adults with hypertension. AIMS: To elucidate these groups by examining the characteristics of patients attending an Irish hypertension service, thus informing future management of hypertension. METHODS: Patients were recruited at consecutive hypertension clinics at St James Hospital, Dublin from July to September 2019. Following patient consent, patient data were recorded to identify patient characteristics as well as the results of investigations, blood pressure (BP) measurements and the anti-hypertensive treatment of the study participants which were then analysed. RESULTS: Two hundred thirty-six patients were included in the study. Compared to those without RH, the RH group were more likely to be obese (OR 2.59 [95% CI 1.06 to 6.33]), to have cardiovascular disease (OR 3.07 [95% CI 1.56 to 6.02]) and to have a non-dipping BP pattern (OR 3.86 [95% CI 1.57 to 9.47]). Young adults comprised 27% of the cohort. Forty-seven percent of these patients were obese, 15.9% had hypertension in pregnancy and 22.2% had chronic headaches. Despite being prescribed less anti-hypertensives (1.41 vs 2.28; p < 0.05), the majority of young patients had a BP less than 140/90 mmHg, comparing favourably with older patients (OR 2.25 [95% CI 1.20 to 4.27]). CONCLUSION: This contemporary study highlights the high prevalence of obesity among RH patients and young adults with hypertension. Findings suggest that programs to combat hypertension must include interventions to address obesity.

Referrals to, and characteristics of patients attending a specialist hypertension clinic.

The management of hypertension is suboptimal in Ireland and internationally. The role of a specialist hypertension clinic is not always defined but an analysis of the reasons for referral are likely informative. Also, a description of the clinical characteristics of patients with hypertension will inform requirements for comprehensive hypertension management in the community and secondary care. Patients were recruited at consecutive hypertension clinics at St James Hospital, Dublin from July to September 2019. Reasons for referral, clinical characteristics of patients, their investigations and treatment were analyzed. 236 patients were included in the study. The majority of patients, 83%, were obese or overweight. A family history of hypertension was a frequent finding with 70.8% of patients reporting same. 26.7% of patients were under the age of 40. 78% of referrals were from primary care and the most referrals were to investigate secondary causes of hypertension or because the patient was ≤40 years of age. Calcium channel blockers were the treatment most frequently prescribed (51.7%). Clinic blood pressure for the cohort was 137/81 mmHg and this was replicated by their ambulatory BP. This insight into the contemporary management of hypertension highlights the frequency of obesity and a positive family history in those with hypertension. Most referrals were consistent with international guidance though deviations were evident. Findings suggest a national program for hypertension with greater focus on public health interventions and better resourcing of primary care is required.

Emerging nonanticoagulant role of low molecular weight heparins on extravillous trophoblast functions and on heparin binding-epidermal growth factor and cystein-rich angiogenic inducer 61 expression.

OBJECTIVE: To examine the effects of low molecular weight heparins (LMWHs) on extravillous trophoblast (EVTC) invasiveness and on EVTC expression/secretion of heparin binding-EGF (HB-EGF) and cystein-rich angiogenic inducer 61 (Cyr61), both of which are involved in the process of EVTC invasion. Furthermore, to investigate the intracellular DNA binding activity of activator protein (AP)-1. DESIGN: Experimental study. SETTING: Department of Obstetrics Gynecology, Università Cattolica del Sacro Cuore, Rome, Italy. PATIENT(S): Cultures of primary EVTC cells isolated from patients with first trimester unexplained recurrent miscarriage. INTERVENTION(S): The effects of LMWHs on EVTC invasiveness were examined by an in vitro matrigel invasion assay. Matrix metalloprotease-2 activity (MMP-2) was examined by gelatin zimography. HB-EGF and Cyr61 expression and secretion were studied by Western blot analysis and ELISA assay. AP-1 activity was measured through a multiwell colorimetric assay. MAIN OUTCOME MEASURE(S): The EVTC invasiveness, the expression/secretion of HB-EGF and Cyr61 proteins, and the AP-1 DNA binding activity in the presence of increasing concentrations of LMWHs were investigated. RESULT(S): Both LMWHs, and primarily tinzaparin, increased EVTC invasiveness, by enhancing the MMP-2 proteolytic activity, and induced the expression/secretion of HB-EGF and Cyr61 in EVTC. This effect was mediated by an increased DNA binding activity of AP-1. CONCLUSION(S): Both LMWHs are able to promote EVTC development because they are able to stimulate the EVTC invasive properties. Our results may provide a possible biological rationale for the clinical use of LMWH for placental-mediated pregnancy complications unrelated to prothrombotic disorders.

Effect of Low Molecular Weight Heparins (LMWHs) on antiphospholipid Antibodies (aPL)-mediated inhibition of endometrial angiogenesis.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity in the presence of circulating antiphospholipid antibodies (aPL). Different pathogenic mechanisms for aPL-mediated pregnancy failure have been proposed. In particular a direct effect of aPL on both maternal and fetal side of the placental tissue has been reported, since their reactivity with ß2-glycoprotein I (ß2GPI) makes them adhere to trophoblast and human endometrial endothelial cell (HEEC) membranes. ß2GPI can be recognized by aPL that, once bound, interfere with both trophoblast functions and with the HEEC differentiation.APS patients can be successfully treated with Low Molecular Weight Heparin (LMWH). Recent reports suggest that LMWH acts through mechanisms alternative to its well known anticoagulant effect, because of its ability to bind ß2GPI. In our previous studies, we showed that LMWH is able to reduce the aPL binding to trophoblasts and restore cell invasiveness and differentiation. So far, however, no study has described its effects on endometrial angiogenesis.The aim of our research was to evaluate whether two LMWHs, tinzaparin and enoxaparin, have an effect on the aPL-inhibited endometrial angiogenesis. This prompted us to investigate: (i) in vitro HEEC angiogenesis through a Matrigel assay; (ii) VEGF secretion by ELISA; (iii) matrix metalloproteinase-2 (MMP-2) activity by gelatin zymography; (iv) Nuclear Factor-κB (NF-κB) DNA binding activity by colorimetric assay; (v) STAT-3 activation by a sandwich-ELISA kit. Furthermore, using an in vivo murine model we investigated the LMWHs effects on angiogenesis.We demonstrated that the addition of LMWHs prevents aPL-inhibited HEEC angiogenesis, both in vitro and in vivo, and is able to restore the aPL inhibited NF-κB and/or STAT-3 activity, the VEGF secretion and the MMPs activity.The demonstration of a beneficial role for LMWHs on the aPL-inhibited HEEC angiogenesis might provide additional mechanisms whereby this treatment protects early pregnancy in APS.

Tinzaparin use in pregnancy: an international, retrospective study of the safety and efficacy profile.

OBJECTIVES: This study audited pregnancies where the mother received tinzaparin (at any stage before delivery), with a primary objective of determining the maternal safety of this low molecular weight heparin when administered as treatment and/or prophylaxis; the secondary objective was to audit fetal and neonatal safety in this cohort. Efficacy outcomes were also recorded. STUDY DESIGN: The audit period was 1996-2009; consecutive, retrospective pregnancy records at participating hospitals were reviewed. For those records documenting tinzaparin use and pregnancy outcome, information was extracted into a standardised case report form; these were reviewed for adverse events, which were submitted for adjudication by independent experts in obstetric medicine and haematology. Endpoints were presented using descriptive statistics for all pregnancies, and by reason for tinzaparin use (treatment of venous thromboembolism [VTE] and prophylaxis). RESULTS: There were 28 participating hospital centres in eight countries (Belgium, Canada, Denmark, Ireland, Netherlands, Sweden, Spain and the UK). Data were collected from 1267 pregnancies (1120 women; 1303 fetuses); in 254 pregnancies the women received tinzaparin as treatment (median dose 13,000 international units [IU]/day, range 3500-23,100IU/day; median duration 72 days; 94.1% once-daily), and in 1013 pregnancies the women received tinzaparin for prophylaxis (median dose 4500IU/day, range 2500-21,811IU/day, median duration 183 days, 94.6% once-daily). There were 871 (70.2%) vaginal deliveries (78 assisted) and 369 (29.8%) caesarean sections (27 delivery data missing). Overall, 495 (39.3%) women had neuraxial anaesthesia; however, there were no reported associated haematomas. There were no maternal deaths. Of pregnancies with available data (1060), 86.9% had blood loss ≤500mL, 11.0% of >500 to ≤1000mL, 0.9% >1000 to ≤1500mL and 1.1% >1500mL. There were 1245 (95.5%) live births, 15 (1.2%) stillbirths, 40 (3.1%) miscarriages and 3 (0.2%) terminations. Six (0.5%) neonatal deaths occurred (five at <27 weeks, one Ebstein's anomaly). No neonatal haemorrhages occurred. Adjudicated safety outcomes included 125 (9.9%) 'any bleeding' cases considered related to tinzaparin; 16 (1.3%) of these required medical intervention. In the treatment group, five (2%) recurrent VTEs were reported and 10 (1%) occurred in the prophylaxis group. CONCLUSIONS: These data provide reassuring maternal and fetal outcome information in pregnancies exposed to tinzaparin.

Safety profile of tinzaparin versus subcutaneous unfractionated heparin in elderly patients with impaired renal function treated for acute deep vein thrombosis: the Innohep® in Renal Insufficiency Study (IRIS).

INTRODUCTION: Trials comparing the use of full dose unfractionated heparin (UFH) or low molecular weight heparins (LMWHs) in very elderly patients with impaired renal function are lacking. IRIS aimed to assess whether LMWH is at least as safe as UFH in this population. MATERIALS AND METHODS: The study included renally impaired patients ≥70 years with acute symptomatic lower limb deep vein thrombosis (DVT). Patients were randomized to initial treatment with either tinzaparin 175 IU/kg once daily (n=269) or activated partial thromboplastin time-adjusted UFH twice daily (n=270). After acute management both groups received vitamin K antagonist to day 90. RESULTS: The trial was stopped prematurely due to a difference in mortality favoring the UFH group (11.5 vs. 6.3%; p=0.035). Rates of clinically relevant bleedings by day 90 were similar in the tinzaparin (11.9%) and UFH (11.9%) groups, as were rates of confirmed recurrent venous thromboembolism (VTE) (2.6 vs. 1.1%; p=0.34). As the mortality difference could not be explained by bleedings or recurrent VTE, a post-hoc analysis was performed. This identified six baseline characteristics significantly correlated with mortality, of which five were over-represented in the tinzaparin group. CONCLUSION: The IRIS study was a challenging study involving patients (mean age 83 years) usually excluded from clinical studies, but its early termination has left questions unanswered. The mortality difference observed with tinzaparin vs. UFH in elderly, renally-impaired patients with DVT cannot be explained on the basis of bleedings or recurrent VTE, and may reflect an imbalance of mortality risk factors at baseline.