Gastrointestinal Bleeding During Direct Oral Anticoagulants Therapy in Patients With Nonvalvular Atrial Fibrillation and Risk of Polypharmacy

Although concomitant medications have been raised as a factor affecting hemorrhage during direct oral anticoagulants (DOACs) therapy, details remain unelucidated. This study was conducted to clarify the relationship between concomitant medications with possible pharmacokinetic interactions and number of concomitant medications, and bleeding and embolism in patients with nonvalvular atrial fibrillation on DOACs. The subjects were 1,010 patients prescribed DOACs between April 2011 and June 2018. The study investigated their course between the first prescription and December 2018, including the presence or absence of clinically relevant bleeding, gastrointestinal bleeding (GIB), and major cardiovascular and cerebrovascular events (MACCE). Impacts of medications were evaluated by the general linear model with inverse probability-weighted propensity score. The observation period was 2,272 patient-years. The rate of bleeding was 4.7%/year, GIB was 2.8%/year, and MACCE was 2.0%/year. Taking 10 or more oral medications concurrently was a significant risk for GIB (hazard ratio, 2.046 [1.188–3.526]; p = 0.010). Nonsteroidal anti-inflammatory drugs (NSAIDs) was the only significant risk for GIB. Clinicians should be aware of gastrointestinal bleeding when using DOACs with patients taking more than 10 medications and/or NSAIDs.

Dosing Cariprazine Within and Beyond Clinical Trials: Recommendations for the Treatment of Schizophrenia

Although the optimal dosing of an antipsychotic medication is known to be essential in the long-term management of schizophrenia, in case of novel drugs such as cariprazine, determining the right dosing strategy is not that simple. Without decades of experience with a particular compound, evidence regarding dosing and titration comes primarily from double-blind, placebo controlled clinical trials that are not necessarily mirroring the real-life experiences of doctors. Via summarizing data from both clinical data (n = 3275) and real-world evidence (observational study n = 116, case studies n = 29), this perspective paper aims to shed a light on the appropriate dosing strategies of cariprazine from treatment initiation through switching strategies to concomitant medications.

Examining the Use of Antidepressants for Adolescents with Depression/Anxiety Who Regularly Use Cannabis: A Narrative Review

Depression and anxiety disorders are two of the most common and growing mental health concerns in adolescents. Consequently, antidepressant medication (AD) use has increased widely during the last decades. Several classes of antidepressants are used mainly to treat depression, anxiety, and obsessive-compulsive disorders by targeting relevant brain neurochemical pathways. Almost all randomized clinical trials of antidepressants examined patients with no concomitant medications or drugs. This does not address the expected course of therapy and outcome in cannabis users. Cannabis is the most commonly used illicit substance globally. Substantial changes in its regulation are recently taking place. Many countries and US states are becoming more permissive towards its medical and recreational use. The psychological and physiological effects of cannabis (mainly of its major components, tetrahydrocannabinol (THC) and cannabidiol (CBD)) have been extensively characterized. Cannabis use can be a risk factor for depressive and anxiety symptoms, but some constituents or mixtures may have antidepressant and/or anxiolytic potential. The aim of this literature review is to explore whether simultaneous use of AD and cannabis in adolescence can affect AD treatment outcomes. Based on the current literature, it is reasonable to assume that antidepressants are less effective for adolescents with depression/anxiety who frequently use cannabis. The mechanisms of action of antidepressants and cannabis point to several similarities and conjunctions that merit future investigation regarding the potential effectiveness of antidepressants among adolescents who consume cannabis regularly.

Prevalence of comorbidities and concomitant medication use in acromegaly: analysis of real-world data from the United States

Purpose Patients receiving treatment for acromegaly often experience significant associated comorbidities for which they are prescribed additional medications. We aimed to determine the real-world prevalence of comorbidities and concomitant medications in patients with acromegaly, and to investigate the association between frequency of comorbidities and number of concomitantly prescribed medications. Methods Administrative claims data were obtained from the IBM® MarketScan® database for a cohort of patients with acromegaly, identified by relevant diagnosis codes and acromegaly treatments, and a matched control cohort of patients without acromegaly from January 2010 through April 2020. Comorbidities were identified based on relevant claims and assessed for both cohorts. Results Overall, 1175 patients with acromegaly and 5875 matched patients without acromegaly were included. Patients with acromegaly had significantly more comorbidities and were prescribed concomitant medications more so than patients without acromegaly. In the acromegaly and control cohorts, respectively, 67.6% and 48.4% of patients had cardiovascular disorders, the most prevalent comorbidities, and 89.0% and 68.3% were prescribed > 3 concomitant medications (p < 0.0001). Hypopituitarism and hypothalamic disorders, sleep apnea, malignant neoplasms and cancer, and arthritis and musculoskeletal disorders were also highly prevalent in the acromegaly cohort. A moderate, positive correlation (Spearman correlation coefficient 0.60) was found between number of comorbidities and number of concomitant medications in the acromegaly cohort. Conclusion Compared with patients without acromegaly, patients with acromegaly have significantly more comorbidities and are prescribed significantly more concomitant medications. Physicians should consider the number and type of ongoing medications for individual patients before prescribing additional acromegaly treatments.

Tracing all patients who received insured dialysis treatment in Japan and the present situation of their number of deaths

Background The survival rate of chronic dialysis patients in Japan remains the highest worldwide, so there is value in presenting Japan’s situation internationally. We examined whether aggregate figures on dialysis patients in the National Database of Health Insurance Claims and Special Health Checkups of Japan (NDB), which contains data on insured procedures of approximately 100 million Japanese residents, complement corresponding figures in the Japanese Society for Dialysis Therapy Renal Data Registry (JRDR). Methods Subjects were patients with medical fee points for dialysis recorded in the NDB during 2014–2018. We analyzed annual numbers of dialysis cases, newly initiated dialysis cases– and deaths. Results Compared with the JRDR, the NDB had about 6–7% fewer dialysis cases but a similar number of newly initiated dialysis cases. In the NDB, the number of deaths was about 6–10% lower, and the number of hemodialysis cases was lower, while that of peritoneal dialysis cases was higher. The cumulative survival rate at dialysis initiation was approximately 6 percentage points lower in the NDB than in the JRDR, indicating that some patients die at dialysis initiation. Cumulative survival rate by age group was roughly the same between the NDB and JRDR in both sexes. Conclusion The use of the NDB enabled us to aggregate data of dialysis patients. With the definition of dialysis patients used in this study, analyses of concomitant medications, comorbidities, surgeries, and therapies will become possible, which will be useful in many future studies.

Long-acting injectable antipsychotic (LAI) prescribing trends during COVID-19 restrictions in Canada: a retrospective observational study

Background The COVID-19 pandemic has had significant impacts on how mental health services are delivered to patients throughout Canada. The reduction of in-person healthcare services have created unique challenges for individuals with psychotic disorders that require regular clinic visits to administer and monitor long-acting injectable antipsychotic medications. Methods To better understand how LAI usage was impacted, national and provincial patient-level longitudinal prescribing data from Canadian retail pharmacies were used to examine LAI prescribing practices during the pandemic. Prescribing data on new starts of medication, discontinuations of medications, switches between medications, antipsychotic name, concomitant medications, payer plan, gender and age were collected from January 2019 to December 2020 for individuals ≥18-years of age, and examined by month, as well as by distinct pandemic related epochs characterized by varying degrees of public awareness, incidence of COVID-19 infections and public health restrictions. Results National, and provincial level data revealed that rates of LAI prescribing including new starts, discontinuations and switches between LAI products remained highly stable (i.e., no statistically significant differences) throughout the study period. Conclusions Equal numbers of LAI new starts and discontinuations prior to and during the pandemic suggests prescribing of LAI antipsychotics, for those already in care, continued unchanged throughout the pandemic. The observed consistency of LAI prescribing contrasts with other areas of healthcare, such as cardiovascular and diabetes care, which experienced decreases in medication prescribing during the COVID-19 pandemic.

The Overview on the Pharmacokinetic and Pharmacodynamic Interactions of Triazoles

Second generation triazoles are widely used as first-line drugs for the treatment of invasive fungal infections, including aspergillosis and candidiasis. This class, along with itraconazole, voriconazole, posaconazole, and isavuconazole, is characterized by a broad range of activity, however, individual drugs vary considerably in safety, tolerability, pharmacokinetics profiles, and interactions with concomitant medications. The interaction may be encountered on the absorption, distribution, metabolism, and elimination (ADME) step. All triazoles as inhibitors or substrates of CYP isoenzymes can often interact with many drugs, which may result in the change of the activity of the drug and cause serious side effects. Drugs of this class should be used with caution with other agents, and an understanding of their pharmacokinetic profile, safety, and drug-drug interaction profiles is important to provide effective antifungal therapy. The manuscript reviews significant drug interactions of azoles with other medications, as well as with food. The PubMed and Google Scholar bases were searched to collect the literature data. The interactions with anticonvulsants, antibiotics, statins, kinase inhibitors, proton pump inhibitors, non-nucleoside reverse transcriptase inhibitors, opioid analgesics, benzodiazepines, cardiac glycosides, nonsteroidal anti-inflammatory drugs, immunosuppressants, antipsychotics, corticosteroids, biguanides, and anticoagulants are presented. We also paid attention to possible interactions with drugs during experimental therapies for the treatment of COVID-19.

Efficacy and safety of Pidotimod in childhood wheezing: a pilot study

Background: There is a growing need for effective therapies for the management of wheezing in the pediatric population. Aim: We conducted a pilot, mono-centre, prospective, follow-up study to assess the efficacy and the safety of Pidotimod (PDT) in the treatment of wheezing in children. Methods: Globally, 90 children (M:F=58:62, mean age 4.7±1.64 years) with recurrent viral wheezing were enrolled in the study between October-November 2018. At baseline, children received treatment with PDT as 1 vial of 400mg daily for 3 consecutive months. We evaluated the therapeutic efficacy of PDT treatment at the end of 3 (T3) months of therapy as well as the long efficacy and preventive efficacy of PDT treatment during a 3-months follow-up (T6) by using the following outcomes: (i) How many patients showed one or more episodes of viral wheezing? (ii) How many patients were taking concomitant medications (ICS, SABA, antibiotics)? (iii) How many patients required ED visits? (iv) How many patients required hospitalization? Results: A significant decrease in the number of patients with at least one or more episodes of wheezing and taking antibiotics was recorded after 3 months of treatment, and a further significant decrease for both outcomes was reported at 3-months follow-up period (p<0.05). Differently, after 3 months of treatment, we found a significant decrease in the number of patients taking ICS and SABA and in the number of patients requiring ED visits and/or hospitalization (p<0.05); however, for all these outcomes, no further significant decrease was reported at follow-up period. Conclusion: We first showed that the administration of PDT is useful in the management of patients with recurrent viral wheezing because we found a reduction in the number of patients requiring ED visits and/or hospitalization as well as the number of patients taking drugs during the treatment period. Moreover, to date, we found a long-term clinical effect over three months after treatment suspension counteracting the recurrence of the disease.

Evaluation of the Incidence and Risk Factors Associated with Bleeding Events in Patients Receiving Acalabrutinib Therapy

Background: Acalabrutinib is a more selective, second generation covalent binding Bruton tyrosine kinase (BTK) inhibitor. It was designed with the intent to mitigate adverse events (AEs) associated with ibrutinib, such as bleeding and cardiovascular events. In the phase 3 trial that that led to acalabrutinib approval in the front line setting for chronic lymphocytic leukemia (CLL), 37% and 2% of patients who received acalabrutinib monotherapy experienced grade 1-2 or ≥3 bleeding events, respectively. Currently, there are no long term studies evaluating the incidence of bleeding events associated with acalabrutinib. Therefore, the purpose of this study was to assess the incidence of bleeding events, and risk factors associated with bleeding events for patients treated with acalabrutinib for hematologic malignancies. Methods: This was a single center retrospective study conducted at The Ohio State University. Patients were included if they were ≥18 years old, diagnosed with a hematologic malignancy, and initiated on acalabrutinib (monotherapy or combination therapy) between January 1, 2010 and August 31, 2019. The International Society on Thrombosis and Haemostasis (ISTH) bleeding scale (no bleed, clinically non-relevant bleed, and clinically relevant/major bleed) and Common Terminology Criteria for Adverse Events V5.0 (CTCAE) were used to evaluate the grade and class of bleed events. Descriptive statistics were used to summarize demographic information and bleed events; univariable analysis was used to assess risk factors. Results: We analyzed 289 patients who received acalabrutinib for a hematologic malignancy. The main source of acalabrutinib was from clinical trials (85%) and the median acalabrutinib exposure time for all patients was 40.8 months (range: 0-81.6 months). 89% of patients had CLL, 2% had mantle cell lymphoma, and 9% had other non-Hodgkin's lymphoma. Additionally, 18% of patients had a prior bleed history and 51% were continued on concomitant medications that increase bleeding (Table 1). There were a total of 241 (83%) patients who experienced at least one bleed event. Per ISTH categorization, 143 (59%) patients' most severe bleed event was clinically non-relevant and 98 (41%) patients' was clinically relevant/major; cutaneous bleeds were most common in both groups, 71% and 31%, respectively. Only 6% of patients had a major bleed, hence, clinically relevant and major bleeds were analyzed together for the purpose of this study. There were a total of 633 bleed events that occurred in this study population; 76% were clinically-non relevant and only 3% (n=17) were CTCAE grade ≥3. Acalabrutinib was not discontinued or held for any clinically non-relevant bleeds, was discontinued for six (1%) clinically relevant/major bleeds, and held for 44 (7%) clinically relevant/major bleeds. Clinically relevant /major bleeds also resulted in discontinuations of concomitant anticoagulation and antiplatelet therapy in only 4% (n=24) of cases. 1263 procedures were identified and the incidence of clinically non-relevant and clinically relevant/major bleeds related to surgeries/procedures was 1% (n=12) and 1.3% (n=16), respectively. 10% of clinically non-relevant and 57% of clinically relevant/major bleeds led to hospitalizations, emergency room visits, or physician office visits; including two major CNS bleed events which resulted in death. The overall survival (OS) was not reached in the clinically non-relevant and clinically relevant/major bleed groups and was 14 months (95% CI 6-40) in the no bleed group (p=0.021). Univariate analysis showed that risk factors associated with a clinically relevant/major bleed included concomitant medications (OR 3.06, 95% CI 1.49-6.26) and prior bleed history (OR 4.40, 95% CI 1.45-13.40) (Table 3). Conclusions: Overall, our study had a long acalabrutinib exposure time and demonstrated a low incidence of grade ≥3 bleeds. There was also a low risk of bleeds related to procedures. The majority of bleeds were clinically non-relevant that did not result in significant treatment adjustments, hospitalizations, or death. This study identified prior bleed history and concomitant medications that increase bleeding as risk factors for bleeds and should be evaluated prior to starting acalabrutinib therapy. Our data supports acalabrutinib as a safe long-term treatment in regards to bleeds for patients with hematologic malignancies. Figure 1 Figure 1. Disclosures Wiczer: BTG Specialty Pharmaceuticals: Consultancy. Bhat: Beigene: Consultancy; Aptitude Health: Honoraria; AstraZeneca: Consultancy; Onclive: Honoraria. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Rogers: Janssen Pharmaceuticals, Inc: Research Funding; Pharmacyclics LLC: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; Innate Pharma: Consultancy; ovartis Pharmaceuticals Corporation: Research Funding; AbbVie Inc.: Consultancy, Research Funding. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Kittai: Bristol-Meyers Squibb: Consultancy; Janssen: Consultancy; Abbvie: Consultancy.

Prognostic and Predictive Factors in Advanced Urothelial Carcinoma Treated with Immune Checkpoint Inhibitors: A Review of the Current Evidence

In recent years, the treatment landscape of urothelial carcinoma has significantly changed due to the introduction of immune checkpoint inhibitors (ICIs), which are the standard of care for second-line treatment and first-line platinum-ineligible patients with advanced disease. Despite the overall survival improvement, only a minority of patients benefit from this immunotherapy. Therefore, there is an unmet need to identify prognostic and predictive biomarkers or models to select patients who will benefit from ICIs, especially in view of novel therapeutic agents. This review describes the prognostic and predictive role, and clinical readiness, of clinical and tumour factors, including new molecular classes, tumour mutational burden, mutational signatures, circulating tumour DNA, programmed death-ligand 1, inflammatory indices and clinical characteristics for patients with urothelial cancer treated with ICIs. A classification of these factors according to the levels of evidence and grades of recommendation currently indicates both a prognostic and predictive value for ctDNA and a prognostic relevance only for concomitant medications and patients’ characteristics.