Utilization and long‐term persistence of direct oral anticoagulants among patients with nonvalvular atrial fibrillation and liver disease

Aims: We characterized the utilization and long-term treatment persistence of direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation (NVAF) and liver disease. Method: Using the UK Clinical Practice Research Datalink, we assembled a population-based cohort of NVAF patients with liver disease initiating oral anticoagulants between 2011 and 2020. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) of the association between patient characteristics and initiation of DOACs vs vitamin K antagonists (VKAs). Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs of the association between patient characteristics and the switch from VKAs to DOACs vs remaining on VKAs. We also assessed the 5-year treatment persistence with DOACs vs VKAs, and whether ischemic stroke or bleeding preceded treatment discontinuation. Results: Our cohort included 3167 NVAF patients with liver disease initiating DOACs (n = 2247, 71%) or VKAs (n = 920, 29%). Initiators of DOACs were more likely to have prior ischemic stroke (OR 1.44, 95% CI 1.12-1.85) than VKA initiators but less likely to have used antiplatelet agents (OR 0.66, 95% CI 0.53-0.82). Patients switching to DOACs were more likely to have used selective serotonin reuptake inhibitors (HR 1.64, 95% CI 1.13-2.37) than those remaining on VKAs. At 5 years, 31% of DOAC initiators and 9% of VKA initiators remained persistent. Only few patients were diagnosed with ischemic stroke or bleeding prior to treatment discontinuation. Conclusion: Most NVAF patients with liver disease initiated treatment with DOACs. Long-term persistence with DOACs was higher than with VKAs but remained relatively low

Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study

Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face- to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed

Self-reported medication in community-dwelling older adults in Germany: results from the Berlin Initiative Study

Background: Older adults have the highest drug utilization due to multimorbidity. Although the number of people over age 70 is expected to double within the next decades, population-based data on their medication patterns are scarce especially in combination with polypharmacy and potentially inappropriate medication (PIM). Our objective was to analyse the frequency of polypharmacy, pattern of prescription (PD) and over-the-counter (OTC) drug usage, and PIMs according to age and gender in a population-based cohort of very old adults in Germany. Methods: Cross-sectional baseline data of the Berlin Initiative Study, a prospective cohort study of community-dwelling adults aged ≥70 years with a standardized interview including demographics, lifestyle variables, co-morbidities, and medication assessment were analysed. Medication data were coded using the Anatomical Therapeutic Chemical (ATC) classification. Age- and sex-standardized descriptive analysis of polypharmacy (≥5 drugs, PD and OTC vs. PD only and regular and on demand drugs vs regular only), medication frequency and distribution, including PIMs, was performed by age (</≥80) and gender. Results: Of 2069 participants with an average age of 79.5 years, 97% (95%CI [96%;98%]) took at least one drug and on average 6.2 drugs (SD = 3.5) with about 40 to 66% fulfilling the criteria of polypharmacy depending on the definition. Regarding drug type more female participants took a combination of PD and OTC (male: 68%, 95%CI [65%;72%]); female: 78%, 95%CI [76%;80%]). Most frequently used were drugs for cardiovascular diseases (85%, 95%CI [83%;86%]). Medication frequency increased among participants aged ≥80 years, especially for cardiovascular drugs, antithrombotics, psychoanaleptics and dietary supplements. Among the top ten prescription drugs were mainly cardiovascular drugs including lipid-lowering agents (simvastatin), beta-blockers (metoprolol, bisoprolol) and ACE inhibitors (ramipril). The most common OTC drug was acetylsalicylic acid (35%; 95%CI [33%;37%])). Dose-independent PIM were identified for 15% of the participants. Conclusions: Polypharmacy was excessive in older adults, with not only PD but also OTC drugs contributing to the high point prevalence. The medication patterns reflected the treatment of chronic diseases in this age group. There was even an increase in medication frequency between below and above 80 years especially for drugs of cardiovascular diseases, antithrombotic medication, psychoanaleptics, and dietary supplements

Functional inhibition of the fibronectin receptor α5β1 integrin in human neuroendocrine tumor cells

Neuroendokrine Tumoren (NETs) konstituieren eine relativ seltene Gruppe von Neoplasien, die am häufigsten im Gastrointestinaltrakt entstehen. Die Operation stellt die einzige kurative Option dar, während in der palliativen Therapie neben der Unterdrückung der Hypersekretionssyndrome die Kontrolle des Tumorwachstums als Hauptziel gilt. Angesichts der biologischen Merkmale von NETs (hohe Vaskulasierung, molekulare Heterogenität, langsame Progression) könnte sich eine Therapie, die direkte Effekte an den Tumorzellen mit antiangiogener Wirkung kombiniert, als erfolgversprechend erweisen. Im Rahmen dieser Studie charakterisierten wir die biologischen Effekte des α5β1 Integrin-Inhibitors JSM8757 in zwei gut etablierten humanen NET Zelllinien (BON, QGP-1). Integrine sind transmembranäre Heterodimere und bilden eine Familie von zellulären EZM-Rezeptoren. A5β1 Integrin fungiert als Fibronekrinrezeptor und nimmt somit an vielen zellulären Funktionen teil. Zudem gibt es gute präklinische Evidenz für antiangiogene Effekte infolge Antagonisierung von α5β1 Integrin. In NET Zelllinien verminderte die Inhibition des Fibronektinrezeptors die Adhäsion und Proliferation, ohne dass eine Induktion von Apoptose beobachtet wurde. Die Zellzyklusanalysen an G1-synchronisierten Zellkulturen ergaben eine Inhibition der Zellzyklusprogression infolge eines verzögerten G1/ S-Übergangs. Mittels Western-Blot-Analysen untersuchten wir weiter nach JSM8757-induzierten Modifikationen in der Expression von Zellzyklusmolekülen. Als wichtigste Effekte fanden sich eine Inhibition der Zyklin A-Induktion in BON Zellen und eine starke Erhöhung der Expression der Zellzyklusinhibitoren p21 und p27 in QGP-1 Zellen. Zusammenfassend stellt die Inhibition des Fibronektinrezeptors α5β1 Integrin einen attraktiven Therapieansatzpunkt in NET Zellen dar.Neuroendocrine tumors (NETs) compose a relatively rare category of neoplasms that mostly grow in the gastrointestinal tract. While surgery remains the only therapeutic option with a curative prospect, several other strategies were pursued in order to suppress the often occurring hypersecretion syndromes and to control tumor growth. Regarding certain biological features of NETs, such as their high vascularisation, molecular heterogeneity and slow progression, an agent combining antiangiogenic action with direct effects on tumor cells appears most promising. This study investigated the biological effects of the α5β1 integrin antagonist JSM8757 on two well-characterized human NET cell lines (BON, QGP-1). Integrins are transmembrane heterodimers and constitute a family of cellular receptors for the extracellular matrix. Α5β1 integrin serves as a fibronectin receptor, plays a key role in many cellular procedures, and its antagonists have shown consistent antiangiogenic results in a preclinical context. Inhibition of the fibronectin receptor in NET cell lines led to reduced adhesion and proliferation, whereas induction of apoptosis was not observed. Cell cycle analysis with G1 synchronized cell cultures revealed a G1 cell cycle arrest in both cell lines. Via western blot analysis we searched for JSM8757-induced modifications in the expression of cell cycle molecules. The major effects were an inhibition of the induction of cyclin A in BON cells and a strong up-regulation of the cyclin-dependent kinase inhibitors p21 and p27 in QGP-1 cells. Summing up, inhibition of the fibronectin receptor α5β1 integrin illustrates an attractive therapeutic approach in NET cells

Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study

Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed

Risk of venous thromboembolism in cancer patients treated with epoetins or blood transfusions

AIMS: Anaemia is common in cancer patients, with treatments including epoetins and blood transfusions. Although an increased risk of venous thromboembolism (VTE) has been associated with both therapeutics, studies comparing the risk of VTE between epoetins and transfusions in cancer patients are lacking. METHODS: A nested case–control study investigated this risk using the German Pharmacoepidemiological Research Database. Cohort members were incident cancer patients receiving first time treatment with epoetin or transfusion. A subcohort including only patients receiving chemotherapy was created, since the formally approved indication of epoetins is chemotherapy‐induced anaemia. Cases were defined as patients developing VTE. For each case up to 10 gender‐ and age‐matched controls were selected from the cohort. Multiple confounder adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for VTE and recent treatment with epoetins or transfusions (last 28 days before index date) compared with past anti‐anaemic treatment were calculated by conditional logistic regression. RESULTS: Among 69 888 patients receiving first time treatment with epoetin or transfusion, 3316 VTE cases were identified. The aOR for VTE was 1.31 (95% CI 1.03, 1.65) for epoetins, 2.33 (95% CI 2.03, 2.66) for transfusions, and 2.24 (95% CI 1.34, 3.77) for epoetins and transfusions. Sensitivity analyses with a stricter VTE definition or an expanded time window yielded similar results. In the chemotherapy only subcohort the risk difference between epoetins and transfusions could not be verified (aOR 1.48, 95% CI 1.10, 1.98 vs. aOR 1.80, 95% CI 1.49, 2.19). Our study confirmed known VTE risk factors including previous VTE (aOR 14.76, 95% CI 12.79, 17.03) or surgery (aOR 1.83, 95% CI 1.67, 2.01). Epoetin‐associated risk decreased after a safety warning by the European Medicines Agency setting maximum haemoglobin target values to 12 g dl–1. CONCLUSIONS: Transfusions could be associated with a higher VTE risk than epoetins in cancer patients. Moreover, current prescribing patterns may have decreased the VTE risk for epoetins

Data from: Degree of serotonin reuptake inhibition of antidepressants and ischemic risk: a cohort study

Objective: To assess whether the use of antidepressants with strong inhibition of serotonin reuptake is associated with a decreased incidence of ischemic stroke and myocardial infarction (MI). Methods: We conducted a cohort study using the United Kingdom Clinical Practice Research Datalink and considering new users of selective serotonin reuptake inhibitors (SSRIs) or third-generation antidepressants aged ≥18 years between 1995 and 2014. Using a nested case-control approach, each case of a first ischemic stroke or MI identified during follow-up was matched with up to 30 controls on age, sex, calendar time, and duration of follow-up. We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) of each outcome associated with current use of strong compared with weak inhibitors of serotonin reuptake using conditional logistic regression. Results: The cohort included 938,388 incident users of SSRIs (n = 868,755) or third-generation antidepressants (n = 69,633). Mean age at cohort entry was 46 years (64% women). During follow-up, 15,860 cases of ischemic stroke and 8626 cases of MI were identified and matched to 473,712 and 258,022 controls, respectively. Compared with current use of weak inhibitors of serotonin reuptake, current use of strong inhibitors was associated with a decreased rate of ischemic stroke (RR, 0.88; 95% CI 0.80-0.97), but the effect size was smaller in some sensitivity analyses. The rate of MI was similar between strong versus weak inhibitors (RR, 1.00; 95% CI, 0.87-1.15). Conclusion: Our large population-based study suggests that antidepressants strongly inhibiting serotonin reuptake could modestly decrease the rate of ischemic stroke

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