Use of combination therapy is associated with improved LDL-cholesterol management: 1-year follow-up results from the European observational SANTORINI study.

AIM: To assess whether implementation of the 2019 ESC/EAS dyslipidaemia guidelines observed between 2020-2021 improved between 2021-2022 in the SANTORINI study. METHODS: High- or very-high cardiovascular (CV) risk patients were recruited across 14 European countries from March 2020-February 2021, with 1-year prospective follow-up until May 2022. Lipid-lowering therapy (LLT) and 2019 ESC/EAS risk-based low-density lipoprotein cholesterol (LDL-C) goal attainment (defined as <1.4 mmol/L for patients at very high CV risk and <1.8 mmol/L for patients at high CV risk) at 1-year follow-up were compared with baseline. . RESULTS: Of 9559 patients enrolled, 9136 (2626 high risk, 6504 very high risk) had any follow-up data, and 7210 (2033 high risk, 5173 very high risk) had baseline and follow-up LDL-C data. LLT was escalated in one-third of patients and unchanged in two-thirds. Monotherapy and combination therapy usage rose from 53.6% and 25.6% to 57.1% and 37.9%, respectively. Mean LDL-C levels decreased from 2.4 mmol/L to 2.0 mmol/L. Goal attainment improved from 21.2% to 30.9%, largely driven by LLT use among those not on LLT at baseline. Goal attainment was greater with combination therapy compared with monotherapy at follow-up (39.4 vs 25.5%). CONCLUSIONS: LLT use and achievement of risk-based lipid goals increased over 1-year follow-up particularly when combination LLT was used. Nonetheless, most patients remained above goal, hence strategies are needed to improve implementation of combination LLT.

Cardiovascular diseases, a group of disorders of the heart and blood vessels, are the most common cause of death worldwide. Lowering low-density lipoprotein (LDL) cholesterol in the bloodstream reduces the risk of developing cardiovascular diseases, such as heart attacks and strokes. Guidelines recommend that those at highest risk of cardiovascular disease should achieve the lowest levels of LDL cholesterol. Several medications are available that help lower LDL cholesterol levels and prevent cardiovascular events, however, recent studies have shown that the majority of patients continue to have LDL cholesterol levels above optimal value in part due to suboptimal use of these medications. Here we report the results after 1 year of follow-up of the SANTORINI study (started in 2020) which aimed to document the management of LDL cholesterol in clinical practice across 14 countries in Europe. We found that better control of LDL cholesterol occurred when more than one drug was used (combination therapy). Use of combination therapy was low at the start of the study 25.6% but increased over 1 year to 37.9%, resulting in better control of LDL cholesterol at 1 year than observed at the start of the study. Nonetheless, only 31% of patients achieved their LDL cholesterol target levels based on the European guidelines. Greater use of combination therapies is needed in order to improve the overall population level control of LDL cholesterol.

J-AVENUE: A retrospective, real-world study evaluating patient characteristics and outcomes in patients with advanced urothelial carcinoma treated with avelumab first-line maintenance therapy in Japan.

OBJECTIVES: The JAVELIN Bladder 100 phase 3 trial showed that avelumab first-line maintenance + best supportive care significantly prolonged overall survival and progression-free survival versus best supportive care alone in patients with advanced urothelial carcinoma who were progression-free following first-line platinum-based chemotherapy. We report findings from J-AVENUE (NCT05431777), a real-world study of avelumab first-line maintenance therapy in Japan. METHODS: Medical charts of patients with advanced urothelial carcinoma without disease progression following first-line platinum-based chemotherapy, who received avelumab maintenance between February and November 2021, were reviewed. Patients were followed until June 2022. The primary endpoint was patient characteristics; secondary endpoints included time to treatment failure and progression-free survival. RESULTS: In 79 patients analyzed, median age was 72 years (range, 44-86). Primary tumor site was upper tract in 45.6% and bladder in 54.4%. The most common first-line chemotherapy regimen was cisplatin + gemcitabine (63.3%). Median number of chemotherapy cycles received was four. Best response to chemotherapy was complete response in 10.1%, partial response in 58.2%, and stable disease in 31.6%. Median treatment-free interval before avelumab was 4.9 weeks. With avelumab first-line maintenance therapy, the disease control rate was 58.2%, median time to treatment failure was 4.6 months (95% CI, 3.3-6.4), and median progression-free survival was 6.1 months (95% CI, 3.6-9.7). CONCLUSIONS: Findings from J-AVENUE show the effectiveness of avelumab first-line maintenance in patients with advanced urothelial carcinoma in Japan in clinical practice, with similar progression-free survival to JAVELIN Bladder 100 and previous real-world studies, supporting its use as a standard of care.

[Biologic therapy in patients with severe NSAID-exacerbated respiratory disease and previous aspirin desensitization : Results of a multicentric study]. / Biologikatherapie bei schwer erkrankten Patienten mit "NSAID-exacerbated respiratory disease" und stattgehabter ASS­Desaktivierung : Ergebnisse einer multizentrischen Studie.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type­2 inflammatory disease of the upper airways, with severe impairment of quality of life. Persons affected by NSAID-exacerbated respiratory disease (NERD) usually present with highly dynamic recurrence of polyps and disease despite prior treatment with sinus surgeries, oral corticosteroids, and aspirin desensitization (ATAD). Biologic therapy has fundamentally changed the choice of therapeutic concept; however, limited data exist on subgroups such as NERD patients. The aim of the current article is to report on a multicenter retrospective study on add-on therapy with dupilumab, omalizumab, and mepolizumab in patients with NERD. METHODS: This is a retrospective cohort study of patients (NERD+, status after ATAD) in three reference centers in Germany (Munich, Mainz, Berlin). Subjective and objective parameters were collected at 4, 8, and 12 months after biologic therapy initiation in accordance with current EPOS/EUFOREA (European Position Paper on Rhinosinusitis and Nasal Polyps/European Forum for Research and Education in Allergy and Airway Diseases) guidelines. Biologic agents were chosen depending on availability and patient characteristics. RESULTS: Treatment was commenced in 122 patients meeting the criteria for CRSwNP and NERD. The endoscopic polyp score, SNOT-22 questionnaire score, visual analogue scoring of total symptoms/severity of disease, and sense of smell (psychophysical testing with Sniffin'Sticks/Brief Smell Identification Test, B­SIT; Sensonics, Inc., Haddon Heights, NJ, USA) improved significantly after 4 and 12 months of add-on therapy (p < 0.0001). All three biologic agents significantly improved one or more disease parameter. Adverse events were not life threatening but led to change of biologic agent in 4 cases. Patients rated biologic therapy significantly better than ATAD, with improved long-term disease control. CONCLUSION: Add-on biologic therapy is effective, safe, and widely accepted among CRSwNP + NERD patients. Future studies might allow for personalized algorithms with sequential surgery, ATAD, and/or biologic therapy.

Meta-research on pragmatism of randomized trials: rationale and design of the PragMeta database.

BACKGROUND: Pragmatic trials provide decision-oriented, real-world evidence that is highly applicable and generalizable. The interest in real-world evidence is fueled by the assumption that effects in the "real-world" are different to effects obtained under artificial, controlled, research conditions as often used for traditional explanatory trials. However, it is unknown which features of pragmatism, generalizability, and applicability would be responsible for such differences. There is a need to provide empirical evidence and promote meta-research to answer these fundamental questions on the pragmatism of randomized trials and real-world evidence. Here, we describe the rationale and design of the PragMeta database which pursues this goal ( www.PragMeta.org ). METHODS: PragMeta is a non-commercial, open data platform and infrastructure to facilitate research on pragmatic trials. It collects and shares data from published randomized trials that either have a specific design feature or other characteristic related to pragmatism or they form clusters of trials addressing the same research question but having different aspects of pragmatism. This lays the foundation to determine the relationship of various features of pragmatism, generalizability, and applicability with intervention effects or other trial characteristics. The database contains trial data actively collected for PragMeta but also allows to import and link existing datasets of trials collected for other purposes, forming a large-scale meta-database. PragMeta captures data on (1) trial and design characteristics (e.g., sample size, population, intervention/comparison, outcome, longitudinal structure, blinding), (2) effects estimates, and (3) various determinants of pragmatism (e.g., the use of routinely collected data) and ratings from established tools used to determine pragmatism (e.g., the PRagmatic-Explanatory Continuum Indicator Summary 2; PRECIS-2). PragMeta is continuously provided online, inviting the meta-research community to collaborate, contribute, and/or use the database. As of April 2023, PragMeta contains data from > 700 trials, mostly with assessments on pragmatism. CONCLUSIONS: PragMeta will inform a better understanding of pragmatism and the generation and interpretation of real-world evidence.

Real-world therapeutic effectiveness of lorlatinib after alectinib in Japanese patients with ALK-positive non-small-cell lung cancer.

Alectinib, an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is the recommended first-line treatment for ALK-positive non-small-cell lung cancer (NSCLC) in Japan. Lorlatinib was approved as a subsequent therapeutic option after progression while receiving ALK TKI treatment. However, data on the use of lorlatinib in the second- or third-line setting after alectinib failure are limited in Japanese patients. This retrospective real-world observational study investigated the clinical effectiveness of lorlatinib in second- or later-line settings after alectinib failure in Japanese patients. Clinical and demographic data collected in the Japan Medical Data Vision (MDV) database between December 2015 and March 2021 were used. Patients diagnosed with lung cancer who received lorlatinib following alectinib failure after the November 2018 marketing approval of lorlatinib in Japan were included. Of 1954 patients treated with alectinib, 221 were identified from the MDV database as receiving lorlatinib after November 2018. The median age of these patients was 62 years. Second-line lorlatinib treatment was reported for 154 patients (70%); third- or later-line lorlatinib treatment was reported for 67 patients (30%). The median duration of treatment (DOT) for all lorlatinib-treated patients was 161 days (95% confidence interval [CI], 126-248), and 83 patients (37.6%) continued treatment after data cut-off (March 31, 2021). Median DOTs of 147 days (95% CI, 113-242) and 244 days (95% CI, 109 to not reached) were reported with second-line and third- or later-line treatment, respectively. Consistent with clinical trial data, this real-world observational study supports data suggesting the effectiveness of lorlatinib after alectinib failure in Japanese patients.

Carfilzomib plus dexamethasone in patients with relapsed and refractory multiple myeloma: A retro-prospective observational study.

OBJECTIVE: We investigate safety and efficacy in common clinical practice of the combination of carfilzomib and dexamethasone (Kd56) approved for the ENDEAVOR trial for the treatment of relapsed or refractory multiple myeloma. METHODS: We retro-prospective analyzed 75 patients in three centers in Tuscany, 48 of whom had a clinically relevant comorbidity and 50 of whom were older than 65 years, treated with a median use in the fourth line of therapy. We assessed the efficacy based on the International Myeloma Working Group criteria. RESULTS: The overall response rate was 60%. Median PFS was 10 months in the general cohort; in patients treated for more than 1 cycle of therapy PFS was 12 months. Quality of response to Kd56 treatment was found to positively impact PFS. Refractory status to previous line of therapy or to lenalidomide or an history of exposure to pomalidomide, seemed to have no impact on survival. We also showed a low adverse events rate, with no neuropathy events, and a relatively small number of cardiovascular events above grade 3 (10%). CONCLUSION: Kd56 is an effective and well tolerated regimen in highly pretreated and elderly patients with a good safety profile.

Real-Life Experience with Pomalidomide plus Low-Dose Dexamethasone in Patients with Relapsed and Refractory Multiple Myeloma: A Retrospective and Prospective Study.

Background and Objectives: The treatment of Myeloma after the second relapse is still challenging. The aim of the study was to investigate the outcomes of the POM-DEX regimen in real clinical practice. Materials and Methods: We retrospectively and prospectively analyzed 121 patients with MM treated with POM-DEX in three Italian sites in Tuscany. We assessed the efficacy based on IMWG Uniform Response Criteria in 106 patients who had received at least two courses of the POM-DEX regimen. The median time from diagnosis to use of POM-DEX was 65 months. POM-DEX median use was in the fourth-line therapy. 63.6% were exposed to lenalidomide or thalidomide, 40.5% to bortezomib or carfilzomib or ixazomib, 5.8% to mAbs in the immediately preceding line of therapy. Results: ORR was 43.4%. Median PFS and OS were 8.5 and 14 months. Eighty-nine patients received more than two courses: their median PFS and OS were 11 and 16 months. When used as the third line of therapy, median PFS and OS were 9 and 20 months and, when patients received POM-DEX for more than two courses, median PFS and OS were 14.5 and 22.5 months. Conclusions: POM-DEX is effective in RRMM, regardless of the latest exposure to IMiDs, PIs, and mAbs in the previous line of therapy.

Impact of Lurasidone and Other Antipsychotics on Body Weight: Real-World, Retrospective, Comparative Study of 15,323 Adults with Schizophrenia.

PURPOSE: The primary objectives were to describe weight changes following initiation of lurasidone versus other antipsychotics and estimate the risk of clinically relevant (≥7%) weight changes. PATIENTS AND METHODS: This retrospective, longitudinal comparative cohort study was based on electronic medical records (EMRs) of United States (US) adult patients with schizophrenia who were prescribed lurasidone or other antipsychotics as monotherapy between 1 April 2013 and 30 June 2019. RESULTS: Overall, the study included 15,323 patients with a diagnosis of schizophrenia; 6.1% of patients received lurasidone, 60.4% received antipsychotics associated with a medium-high risk of weight gain (clozapine, olanzapine, quetiapine, risperidone, paliperidone) and 33.5% received antipsychotics with a low risk of weight gain (aripiprazole, first-generation antipsychotics, ziprasidone). Lurasidone was associated with the smallest proportion of patients experiencing clinically relevant weight gain and the greatest proportion of patients with clinically relevant weight loss. The risk of clinically relevant weight gain was numerically higher with all antipsychotics versus lurasidone and was statistically significant for olanzapine (hazard ratio [HR]=1.541; 95% confidence interval [CI]=1.121; 2.119; p=0.0078) versus lurasidone. The likelihood of ≥7% weight loss was significantly greater with lurasidone versus all antipsychotics (p<0.05), except ziprasidone. CONCLUSION: This real-world study suggests that lurasidone has a lower risk of clinically relevant weight gain and a higher likelihood of clinically relevant weight loss than other commonly used antipsychotics.

Effectiveness and safety of dolutegravir two-drug regimens in virologically suppressed people living with HIV: a systematic literature review and meta-analysis of real-world evidence.

OBJECTIVES: Dolutegravir (DTG) is widely recommended within three-drug regimens. However, similar efficacy and tolerability have also been achieved with DTG within two-drug regimens in clinical trials. This study evaluated the real-world effectiveness and discontinuations in people living with HIV-1 (PLHIV) switching to DTG with lamivudine (3TC) or rilpivirine (RPV). METHODS: This was a one-arm meta-analysis utilizing data from a systematic literature review. Data from real-world evidence studies of DTG + RPV and DTG + 3TC were extracted, pooled and analysed. The primary outcome was the proportion of patients with viral failure (VF; ≥ 50 copies/mL in two consecutive measurements and/or ≥ 1000 copies/mL in a single measurement) at week 48 (W48) and week 96 (W96). Other outcomes included virological suppression (VS; < 50 copies/mL) and discontinuations (W48 and W96). Estimates were calculated for VF, VS as per snapshot (VSS) and on treatment analysis (VSOT), and discontinuations. RESULTS: Pooled mean estimates of VF for DTG + 3TC and DTG + RPV were 0.8% [95% confidence interval (CI): 0.4-1.3] and 0.6% (95% CI: 0.0-1.6), respectively, at W48. VSS rate at W48 was 85.0% (95% CI: 82.3-87.5) for DTG + 3TC regimen and 92.4% (95% CI: 85.0-97.7) in the DTG + RPV regimen. The DTG + 3TC and DTG + RPV regimens led to discontinuations in 13.6% (95% CI: 11.1-16.2) and 7.2% (95% CI: 2.1-14.4) of patients, respectively, at W48. Similar results were observed at W96. CONCLUSIONS: Treatment with DTG + 3TC or DTG + RPV in clinical practice provides a low rate of VF and a high rate of VS when initiated in virologically suppressed PLHIV with diverse backgrounds.

Coronary Revascularization and Out-of-hospital Cardiac Arrest: Past, Present and Future.

Cardiologists and the cardiac catheter laboratory have key roles to play in the management of patients after out-of-hospital cardiac arrest (OHCA). Although immediate catheter laboratory activation is the standard of care in cardiogenic shock and ST elevation myocardial infarction, the majority of patients will present without these features and with an uncertain diagnosis. Even in the latter, early assessment and invasive management may be beneficial, but this is counterbalanced by significant resource utilization, potential to cause harm and the possibility that any diagnostic or therapeutic gains are offset by a poor neurological outcome. Past consensus on the management of the OHCA patient without ST elevation or cardiogenic shock is being challenged by emerging results from new trials in this field. Further randomized trials are ongoing, and are expected to deliver robust data from over 4,000 patients, allowing us to further refine the optimal management strategy in this challenging cohort. This article describes the benefits and pitfalls of a strategy of immediate coronary angiography in these patients, examines the recently published COACT and TOMAHAWK trials in detail, and describes a framework with which to approach the patient after resuscitated OHCA, based on the available evidence to date.

Feasibility of using Clinical Practice Research Datalink data to identify patients with chronic obstructive pulmonary disease to enrol into real-world trials.

PURPOSE: To assess the feasibility of using Clinical Practice Research Datalink (CPRD) data for identifying populations of patients with chronic obstructive pulmonary disease (COPD) eligible for a hypothetical pragmatic trial. METHODS: A retrospective multidatabase cohort study using CPRD primary care and linked secondary care data to describe the characteristics of populations of patients with COPD. Patients' demographic and lifestyle factors, comorbidity profile, spirometry measurements and treatment changes were evaluated, as was the distribution of follow-up time and types of losses during follow-up. Characteristics were evaluated using descriptive statistics. RESULTS: A total of 322 991 patients from 1148 primary care practices in the United Kingdom across two CPRD primary care databases, CPRD GOLD and CPRD Aurum, were potentially eligible to participate in a hypothetical trial using CPRD, starting on 31 December 2017. Patients with COPD in CPRD GOLD and CPRD Aurum were comparable in terms of age (median age 70 vs. 68 years), gender (50% vs. 52% male), disease severity (e.g., 25% vs. 24% Medical Research Council [MRC] dyspnoea score grades 3-5) and history of respiratory conditions (e.g., 43% vs. 38% asthma). High proportions of patients with COPD in CPRD GOLD and CPRD Aurum were available on 31 December 2012 for follow-up at 1, 2, and 5 years (92%, 85% and 67%, respectively). CONCLUSIONS: Patients and data from CPRD GOLD and CPRD Aurum were comparable across key aspects relevant to COPD trials. A pragmatic trial using CPRD to recruit patients with COPD is scientifically feasible.

Challenges for Optimizing Real-World Evidence in Alzheimer's Disease: The ROADMAP Project.

ROADMAP is a public-private advisory partnership to evaluate the usability of multiple data sources, including real-world evidence, in the decision-making process for new treatments in Alzheimer's disease, and to advance key concepts in disease and pharmacoeconomic modeling. ROADMAP identified key disease and patient outcomes for stakeholders to make informed funding and treatment decisions, provided advice on data integration methods and standards, and developed conceptual cost-effectiveness and disease models designed in part to assess whether early treatment provides long-term benefit.