Temporary Discontinuation Research Articles

Neurotoxicity of Calcineurin Inhibitors.

Cyclosporine and tacrolimus belong to the immunosuppressive drugs of the calcineurin inhibitors group. They are widely used in the treatment of patients after organ transplants. One of their complications is neurotoxicity, the mechanism of which is still not fully understood. The main risk factor for neurotoxicity is hypertension. The most common symptoms include muscle tremors, which are more common in the upper limbs, as well as migraine headaches and peripheral neuropathies. The diagnosis of neurotoxicity is based on imaging tests (magnetic resonance imaging being the most commonly used) and assessment of clinical symptoms. Preventive measures should be initiated as soon as possible to prevent permanent damage to the nerve tissue. The possible preventive methods include reduction of the dose of the administered drug, temporary or complete discontinuation of drugs, or conversion to another immunosuppressive drug. It is also essential to monitor the patient's condition, correct hypertension, electrolyte disturbances, and fight possible infections. So far, effective methods of preventing calcineurin inhibitor-induced neurotoxicity have not been demonstrated.

Continuance intention to use mobile fitness applications: the role of switching costs, guilt and neutralization techniques

PurposeThe study investigates the factors influencing the continuance intention to use Mobile Fitness Applications (MFAs), focusing on the roles of switching costs, guilt, and neutralization techniques in addressing temporary discontinuance.Design/methodology/approachA total of 212 valid responses were collected via an online survey in Malaysia. The data were analyzed using Partial Least Squares Structural Equation Modeling (PLS-SEM) to understand the relationships between the constructs.FindingsThe study confirms the significant impact of the Expectation Confirmation Model (ECM) constructs on the continuance intention to use MFAs. It highlights how users employ neutralization techniques to mitigate guilt from temporary discontinuance. Additionally, the study reveals that switching costs moderate the relationship between cognitive satisfaction and continuance intention, as well as between guilt and continuance intention. However, the direct effect of switching costs on continuance intention is negligible.Originality/valueThis research extends continuance intention literature by integrating switching costs, guilt, and neutralization techniques into the ECM framework, providing novel insights into user behavior regarding MFA discontinuance.

Optimising pirfenidone dosage regimens in idiopathic pulmonary fibrosis: towards a guide for personalised treatment

Idiopathic Pulmonary Fibrosis (IPF) is a chronic respiratory disorder for which pirfenidone is the recommended first-line anti-fibrotic treatment. While pirfenidone has demonstrated efficacy in slowing the progression of IPF, its use is associated with several challenges and unresolved issues that impact patient outcomes. Pirfenidone administration can result in gastrointestinal side effects, photosensitivity reactions, and significant drug interactions, particularly in patients with hepatic impairment. For those who experience intolerable side effects, dose reductions or temporary discontinuations are frequently employed. However, there is limited data on the efficacy of reduced doses, creating uncertainty about the balance between tolerability and therapeutic benefit. The aim of this study is to evaluate the currently proposed dosage adjustments and to develop new dosage regimens tailored to the needs of patients. Simulations were conducted to explore pirfenidone pharmacokinetics under various challenging conditions, including dose titration, withdrawal, retitration, moderate and severe hepatic impairment, co-administration of moderate (e.g. omeprazole) and strong (e.g. smoking) inducers of the CYP1A2 enzyme, gastrointestinal adverse events, and photosensitivity reactions. Simulations led to specific recommendations for physicians regarding dosage regimens in each condition. The recommended dosage adjustments are designed to maintain concentrations within acceptable levels, ensuring both safe and effective treatment.

Why Do Users Take Breaks? Exploring the Pathways from Stressors to Temporary Discontinuance in Social Media Use

Why Do Users Take Breaks? Exploring the Pathways from Stressors to Temporary Discontinuance in Social Media Use

Mechanisms of Action and Clinical Applications of β-Blockers

β blockers are widely used to treat cardiovascular diseases such as hypertension, coronary artery disease, and heart failure because they inhibit β adrenergic receptors. These drugs reduce heart rate, myocardial contractility, and oxygen demand, which is essential for managing a variety of heart conditions. Despite their therapeutic benefits, recent studies have highlighted their limitations in diagnostic imaging, particularly in myocardial perfusion imaging (MPI), where they may reduce sensitivity by altering blood flow patterns. Current research has made significant progress in understanding the pharmacological effects of β blockers, including their effects on heart rate, blood pressure, and myocardial function. However, optimization of use remains challenging, especially in critical care settings and diagnostic procedures. It is important to note that β blockers may affect the accuracy of stress testing, leading to misdiagnosis of ischemic areas on imaging. This study provides a comprehensive analysis of the mechanism of action of β blockers, their clinical applications, and the challenges they pose in diagnostic imaging. The results suggest that while β blockers are effective in reducing cardiovascular mortality, their impact on imaging requires careful management. Temporary discontinuation prior to stress testing may improve diagnostic outcomes, but this approach must be weighed against potential risks. Future research should focus on developing advanced imaging protocols to alleviate diagnostic limitations and explore the potential of novel β blockers that combine β and alphablocking properties. These advancements may improve the efficacy of β blockers while minimizing adverse effects, thereby providing better patient outcomes.

Buprenorphine: An anesthesia-centric review.

Buprenorphine was synthesized in the 1960s as a result of a search for a safe and effective opioid analgesic. Present formulations of buprenorphine are approved for the treatment of both acute and chronic pain. Its long duration of action, high affinity, and partial agonism at the µ-opioid receptor have established it as a mainstay treatment for opioid use disorder (OUD). Full agonist opioids (FAOs) remain a primary choice for perioperative pain in both opioid-naïve and opioid-tolerant patients despite well-known harms and new emphasis on multimodal analgesia strategies prioritizing nonopioid analgesics. We review the evidence supporting the use of buprenorphine as an effective analgesic alternative to more commonly prescribed FAOs in acute and chronic pain management. For the patient prescribed buprenorphine for OUD, prior conventionalism advised temporary discontinuation of buprenorphine preoperatively; this paradigm has shifted toward continuing buprenorphine throughout the perioperative period. Questions remain whether dose adjustments may improve patient outcomes.

EchiNam: multicenter retrospective study on the experience, challenges, and pitfalls in the diagnosis and treatment of alveolar echinococcosis in Belgium

ObjectivesThe aim of this retrospective study was to collect epidemiological, clinical, laboratory, imaging, management, and follow-up data on cases of alveolar echinococcosis (AE) diagnosed and/or followed up within the Namur Hospital Network (NHN) in order to gather information on the challenges, pitfalls, and overall experience in the diagnosis and treatment of AE.MethodsEchiNam was a multicenter retrospective study. Patients diagnosed and/or treated for probable or confirmed AE in the NHN between 2002 and 2023 were included in the study. Patient selection was based on diagnosis codes, laboratory results, and albendazole (ABZ) dispensing.ResultsA total of 22 AE cases were retrieved, of which four were classified as probable and 18 as confirmed cases. Nine patients were either asymptomatic or had symptoms attributed to another disease. Clinical examination yielded pathologic findings in 10 patients. The median duration from the first AE-suggestive laboratory abnormalities to diagnosis was 176 days, and the median duration from the first AE-related imaging abnormalities to diagnosis was 133 days. Overall, 12 patients underwent surgical resection, with only four achieving complete lesion resection. Nine patients experienced ABZ-related adverse effects, with temporary ABZ discontinuation in five.ConclusionDue to various factors such as a long incubation period and a lack of awareness among Belgian physicians, AE is often diagnosed at advanced disease stages. Treatment then becomes more complex or even suboptimal, resulting in prolonged therapy, higher risk of adverse effects, significantly impaired quality of life, poor prognosis, and higher mortality rates. Measures should be taken to achieve early diagnosis in endemic areas.

Brief Report: Final overall survival and long-term safety of lorlatinib in patients with ALK-positive non-small cell lung cancer from the pivotal phase 2 study

IntroductionLorlatinib is a potent, brain-penetrant, third-generation inhibitor of anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinases with broad coverage of ALK resistance mutations. We present overall survival (OS) and long-term safety of lorlatinib in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) from the final analyses of the pivotal phase 2 study. MethodsAdults with ALK-positive NSCLC, enrolled in expansion cohorts based on prior therapy (EXP1-5), received lorlatinib 100 mg orally once daily in continuous 21-day cycles. The primary endpoint was objective response rate; secondary endpoints included OS and safety. ResultsThirty patients were enrolled in EXP1 (treatment naïve), 59 in EXP2-3A (disease progression following crizotinib ± chemotherapy), 28 in EXP3B (disease progression following one second-generation ALK tyrosine kinase inhibitor [TKI] ± chemotherapy), 111 in EXP4-5 (disease progression following ≥2 ALK TKIs ± chemotherapy), and 139 in EXP3B-5 (disease progression following ≥1 ALK TKI ± chemotherapy). Median OS was not reached (NR) (95% CI, NR-NR) in EXP1, NR (95% CI, 51.5-NR) in EXP2-3A, 37.4 months (95% CI, 12.3-NR) in EXP3B, 19.2 months (95% CI, 15.4-30.2) in EXP4-5, and 20.7 months (95% CI, 16.1-30.3) in EXP3B-5. All-cause adverse events leading to dose reduction were reported in 77 (28%) patients, temporary treatment discontinuation in 158 (57%), and permanent discontinuation in 35 (13%). ConclusionsAfter a minimum follow-up of 5 years, final analyses from the global phase 2 study confirmed substantial activity, prolonged OS, and generally consistent safety findings with lorlatinib in treatment-naïve and previously treated patients with ALK-positive NSCLC.

Abstract 4139196: Long-term effectiveness and safety of mavacamten in a real-world, multi-center, global study: Preliminary results of COLLIGO-HCM from a diverse cohort in the United States

Introduction: The mavaCamten ObservationaL evIdence Global cOnsortium in hypertrophic cardiomyopathy (COLLIGO-HCM; ClinicalTrials.gov ID NCT06372457) is a multinational, multicenter observational research initiative aiming to describe the real-world outcomes of mavacamten for the treatment of obstructive HCM. Aims: Describe the real-world effectiveness and safety of mavacamten, measured by echo measurements and NYHA class. Methods: This retrospective study used data from medical records from two participating HCM centers in the US. Patient-level data was extracted to assess the effectiveness and safety of mavacamten post-treatment initiation through 60 weeks. Patient characteristics and outcomes were described, including echocardiogram measurements, New York Heart Association (NYHA) functional class, and safety. Results: A total of 93 patients were treated with mavacamten (mean age 60.6 ± 13.9 years, 23.7% black, 57.0% female, and 77.4% NYHA class III at baseline) with a mean follow-up of 37.0 ± 28.1 weeks ( Table ). From baseline to week 60, 3 (3.2%) patients experienced temporary treatment discontinuation, and 3 (3.2%) discontinued mavacamten due to left ventricular ejection fraction (LVEF) <50%. By week 12, 77.1% of patients had improved by ≥1 NYHA class. The percentage increased to 89.5% by week 24 and remained stable through week 60. Mean changes from baseline in resting and Valsalva left ventricular outflow tract gradients were 31.8 ± 32.8 and 57.3 ± 47.3 mmHg, respectively, at week 24, and remained similar through week 60. Mean change in LVEF from baseline was 4.1 ± 7.1% at week 12 and remained largely unchanged through week 60 (Figure) . Conclusions: This study demonstrated the early and sustained effectiveness of mavacamten with one of the longest follow-ups to date, in a real-world population with a higher racial diversity and disease burden than those in the clinical trials. This data further substantiates the effectiveness and safety profile of mavacamten.

8012 A Severe Thrombotic Event Following Blood Thinner Interruption for Thyroid Fine Needle Aspiration Biopsy: A Case Report

Abstract Disclosure: V.A. Mendpara: None. P.P. Rao: None. M.V. Kellis: None. M.D. Lundholm: None. Background: This case highlights the potential severe thrombotic consequences of blood thinner medication interruption for thyroid fine needle aspiration (FNA). Case Presentation: A 77-year-old woman came to the endocrinology clinic for follow-up on thyroid nodules. She was a former smoker with controlled type 2 diabetes, hypertension, hyperlipidemia, and atrial fibrillation with patent foramen ovale on apixaban. She had no family history of thyroid cancer and no radiation exposure. Thyroid nodules were found incidentally, and she denied compressive symptoms. She had annual surveillance for the past 4 years, and her latest thyroid US redemonstrated 4 solid, hypoechoic nodules. The largest nodule, previously biopsied and benign in 2020, remained stable on the right. The next largest nodule in the left mid-thyroid was now 1.1 x 0.8 x 0.9 cm—a 30% growth from the previous year—with new punctate echogenic foci consistent with the TIRADS 5 classification. This finding was shared with the patient, who favored investigating with an FNA. At the recommendation of her PCP and the performing provider, she held her apixaban for approximately 48 hours before the FNA procedure.The US-guided thyroid FNA biopsy was uneventful, and the results indicated a benign nodule. However, 4 hours post-procedure, the patient suddenly became unresponsive while in the middle of cooking dinner. She was taken to the ED and found to have an ischemic stroke by basilar embolism, attributed to her interruption in apixaban therapy. Tenectaplase led to initial improvement but had subsequent hemorrhagic transformations affecting the midbrain, thalamus, and pons. This marked the beginning of a complex 2-month hospitalization requiring tracheostomy and percutaneous endoscopic gastrostomy (PEG) placement, followed by nearly a year of physical, occupational, and speech rehabilitation. Despite these efforts, she has not been able to return to her pre-stroke level of function and independence. Discussion: There is no consensus on the safety of performing a thyroid fine needle aspiration (FNA) biopsy for patients on blood thinner medications. Providers who favor holding blood thinners before FNA cite concerns for post-procedural hematoma formation or increased risk of non-diagnostic results. However, there is less discussion about the risks of interrupting these medications. This case emphasizes the potential for severe consequences from interrupting medically-indicated blood thinner therapy. The temporary discontinuation of apixaban for a routine thyroid FNA led to a life-threatening thrombotic event in our patient’s case. This outcome highlights the importance of carefully weighing the risks and benefits of medication interruptions for vulnerable populations. Further study is needed to investigate the safety of thyroid FNA on uninterrupted blood thinner therapy. Presentation: 6/2/2024

Amyloid-related imaging abnormalities in antiamyloid therapy for Alzheimer's disease: a narrative review

Summary Antiamyloid therapies have sparked a new hope for a potential disease-modifying therapy for Alzheimer's disease. Antiamyloid therapy targets amyloid-beta, which is a key feature of the disease. However, adverse effects such as amyloid-related imaging abnormalities (ARIA) have raised significant concerns about the safety of these therapies. ARIA, which includes vasogenic edema (ARIA-E) and microhemorrhages or hemosiderosis (ARIA-H), is a common adverse effect to antiamyloid therapies. Patient-related risk factors for ARIA include carrying the APOE-ε4 allele and cerebral amyloid angiopathy (CAA). Drug-related risk factors for ARIA include higher drug doses, early initiation of treatment, and concomitant use of antithrombotic medications, all of which increase the likelihood of vascular disruptions. Management of ARIA involves regular MRI monitoring and possibly temporary or permanent discontinuation of therapy if adverse effects develop during therapy. A gradual dose titration is recommended to minimize the risk of ARIA. Although antiamyloid therapies have demonstrated efficacy in reducing amyloid burden, the clinical benefit remains at best modest and must be weighed against the risks of developing adverse effects such as ARIA.

Targeted orbital intervention in the management of sino-orbital mucormycosis cases.

Many countries from South-East Asia reported an epidemic of sino-orbital mucormycosis (SOM), otherwise a rare disease, during the coronavirus disease 2019 pandemic. SOM, a potentially fatal disease, is typically treated with orbital exenteration and systemic antifungals after metabolic stabilization. There is no clear evidence of survival benefit of exenteration in the literature, and thus, there have been attempts at globe conserving treatments like orbital infusion after limited debridement and intraorbital injections with Amphotericin B (IOAB). We conducted a prospective comparative interventional study at a tertiary eye care hospital to evaluate treatment outcomes with the use of adjunctive IOAB in cases of SOM with mild to moderate orbital disease. Thirty-six patients of SOM with mild to moderate orbital disease were recruited in the study. In the intervention group, 23/26 (885%) eyes had stable orbital disease at the end of treatment (4-6 weeks). No deterioration in visual acuity was noted as a result of treatment. In 8/26 (30.77%) patients, inflammation was noted as a side effect of IOAB requiring temporary discontinuation of injections. The mean follow-up for cases was 14.2 months (range 12-15 months). 1/23 (4.35%) patients had relapse of orbital disease at 3 months. Twenty-one patients are alive on last follow-up. Of the patients who refused treatment (controls), 2/9 (22.22%) patients relapsed. One of these patients with relapse underwent exenteration, while the other was managed with IOAB. At a follow-up of 14 months (range 12-15 months), eight patients are alive. On evaluating the ocular parameters in salvaged eyes, improvement in extraocular movements was noted in 75-80% cases. The degree of proptosis and resistance to retropulsion did not change significantly. In the current study, an improvement in the globe salvage rates was noted in cases of SOM with mild to moderate orbital disease treated with adjunctive IOAB as compared to controls at a mean follow-up of 14 months, although it did not achieve statistical significance. The study supports the inclusion of IOAB in routine management of mild to moderate orbital disease.

Withdrawal pain following patients discontinuing Trk inhibitors.

This article aims to expand on the existing literature regarding the incidence of withdrawal pain following discontinuation of Trk inhibitors and to explore strategies that mitigate this withdrawal pain. A retrospective observational study was conducted among patients who were at least 18 years-old or older and had documentation of starting larotrectinib or entrectinib at University of California, San Francisco (UCSF) between November 2018 and November 2022. Data were collected from electronic records and pharmacy databases and a total of 21 patients were identified in this study. Of the 21 patients included in this study, five patients (24%) experienced pain during temporary or permanent discontinuation of Trk inhibitor with the onset of withdrawal pain ranging from a few hours to three days following discontinuation. Various strategies were implemented to manage this pain including restarting of Trk inhibitor, tapering of Trk inhibitor on discontinuation, minimizing dose interruptions and use of prescription pain medications. This article illustrates the presence of withdrawal pain syndrome in patients stopping a Trk inhibitor treatment and highlight the need for patient education to avoid missing any doses and for development of a guideline for Trk inhibitor discontinuation.

Open-Label Phase 1/2 Study of Daratumumab-Based Desensitization Before Kidney Transplantation

BackgroundThe safety and benefit of the anti-CD38 monoclonal antibody daratumumab, which induces lysis of antibody-producing plasma cells in sensitized patients prior to kidney transplantation, remain to be determined. MethodsA two-phase (I/II), monocentric open-label study was conducted to evaluate the M6 safety and efficacy of daratumumab in kidney transplant candidates with calculated panel reactive antibody (cPRA) > 95%. In the first (safety) Phase, we used four-weekly escalating doses of daratumumab. Phase II tested desensitization with 8 weekly infusions of 16mg/kg daratumumab. cPRA10000 was calculated considering only anti-HLA antibodies with MFI of > 10000. ResultsNine patients were enrolled in Phase I and 14 in Phase II. Safety analysis showed 4 serious non-treatment-emergent adverse events (NTEAEs), 36 mild treatment-emergent adverse events (TEAEs), mostly infusion-related reactions, grade 1 and 2 (causing 2 temporary drug discontinuations), but no serious TEAEs. Significant reductions in anti-HLA antibodies were observed at M3, with cPRA 10000 (P=0.003), number of anti-HLA (P<0.001), MFI max (P=0.053), and MFI sum (P<0.001), with complete return to baseline levels at M12. At M6, 46.15% [19.22%-74.87%] and 76.92% [46.19%-94.96%] of patients showed sustained response (1% decrease in cPRA) for cPRA 2000 and 10000, respectively. At M1, immune cells (T-reg, CD8+TEMRA, CD19+CD138+ B cells, and NK cells) significantly decreased. At M3, other antibodies decreased significantly, but returned to baseline levels at M12, except for gamma globulins, without any infectious complications. ConclusionThe first use of daratumumab in desensitization demonstrated infusion-related AEs and rapid, albeit transient, reductions in anti-HLA antibodies, with less than 40% of durable responders, limiting its potential clinical use.

Anifrolumab for systemic lupus erythematosus with multi-refractory skin disease: A case series of 18 patients.

Skin involvement is common in systemic lupus erythematosus (SLE), but may be resistant to conventional treatment. We sought to evaluate the efficacy of anifrolumab (ANI) in refractory cutaneous manifestations of SLE. Case series of patients with refractory cutaneous SLE from three Rheumatology Departments in Greece. Outcome measures were improvement in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), physician global assessment (PGA) and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Clinically relevant improvement in skin was defined as decrease ≥50% (CLASI50) from baseline values. Eighteen patients received ANI; all had active skin involvement at baseline. Mean (SD) SLEDAI and PGA at ANI initiation were 7.4 (2.7) and 1.4 (0.5), respectively, with a mean prednisone dose 4.9 (4.5) mg/day. Mean CLASI (Activity/Damage) at baseline was 13.9 (9.7)/2.9 (4.6). Patients were refractory to a mean 6.3 (1.5) immunomodulatory agents (including hydroxychloroquine and glucocorticoids) before the initiation of ANI. After a mean 8.5 (4.6) months, 89% (n = 16/18) of patients demonstrated significant improvement in general lupus and cutaneous disease activity, and glucocorticoid tapering. Mean SLEDAI and mean CLASI at last visit were 3.4 (1.9) and 2.1 (2.4)/1.4 (2.2), respectively, and mean daily prednisone dose decreased to 2.4 (2.2). Of note, in this group of highly refractory patients CLASI50 was achieved in 16/18 (89%) patients. One patient discontinued ANI after 4 infusions due to a varicella-zoster virus infection and one patient, who initially responded to treatment with ANI, experienced a skin flare due to temporary discontinuation due to Covid 19 infection. DORIS remission and LLDAS were attained in two (11.1%) and eleven (61.1%) patients, respectively. Anifrolumab is highly effective in various skin manifestations of SLE, even after prior failure to multiple treatments.

Clinical Performance and Persistence on Dual Pathway Inhibition with Rivaroxaban and Aspirin in Real-World Setting.

The dual pathway inhibition (DPI) with low-dose rivaroxaban and aspirin in patients with stable atherosclerotic vascular disease reduces the occurrence of cardiovascular events, with no significant increase of intracranial or other critical organ bleedings. Our observational study aimed to describe the clinical performance, adherence, and persistence of DPI therapy among a real-world setting of patients with an established diagnosis of coronary artery (CAD) and/or peripheral artery disease (PAD). We prospectively included all consecutive patients with an established diagnosis of CAD and/or PAD treated with aspirin (ASA) 100 mg once daily and rivaroxaban 2.5 mg twice daily. Clinical evaluation was performed at baseline, before starting treatment, at 1 month, and every 6 months after the study drug administration. A total of 202 consecutive patients (mean age 66 ± 10 years; male 80%) eligible to DPI therapy were included. During a mean follow-up of 664 ± 177 days, the incidence rate of major bleedings and of major adverse cardiovascular events was 0.8 and 1.1 per 100 patients/year, respectively. The adherence to pharmacological treatment was 99%. Additionally, 13.4% of patients suspended the DPI therapy during the follow-up. Minor bleedings resulted the most common cause of both temporary and permanent DPI therapy discontinuation. This observational study supports the safety of DPI with low-dose rivaroxaban and aspirin among patients with CAD and PAD in a real-world setting, showing high persistence and maximum adherence to medical treatment.

Risks of bleeding and thromboembolic events in patients undergoing colonoscopy on uninterrupted and interrupted anticoagulant therapy in real-world setting

BackgroundAlthough anticoagulants may potentially increase the risk of post-colonoscopy bleeding events, temporary discontinuation of medications could elevate the risk of thromboembolism (TE). There is a paucity of data regarding the incidence of bleeding and TE events in patients undergoing colonoscopy while on uninterrupted or interrupted anticoagulant therapy. Therefore, we aimed to ascertain the risks of post-colonoscopy TE and bleeding in patients with continuous or interrupted use of anticoagulant agents. MethodsThe electronic databases of PubMed, Embase, and the Cochrane library were comprehensively searched from inception to March 15, 2024. We identified studies reporting the incidence of bleeding and TE events in patients undergoing colonoscopy with uninterrupted or interrupted anticoagulant therapy. The pooled incidence rate of bleeding and TE events was estimated using a random-effects model. ResultsThis study included a total of 15 studies involving 63, 017 patients. Overall, the incidence of post-procedural bleeding for uninterrupted and interrupted direct oral anticoagulants (DOACs) was found to be 3.60 % (95 % CI: 1.60 %–5.60 %), and 0.90 % (95 % CI: 0.10 %–10.30 %), respectively. Subgroup analysis revealed that older age patients (≥65 years) had a significantly higher rate of bleeding with uninterrupted DOACs therapy compared to younger age patients (< 65 years) (7.20 % vs. 2.00 %). The highest rate of bleeding was observed in Asia (7.20 %, 95 % CI: 2.20 %–12.10 %). Similarly, the risk of bleeding was significantly increased among patients interrupting DOACs therapy in Asia compared to North America (1.40 % vs. 0.26 %). For patients on uninterrupted and interrupted warfarin, a higher rate of bleeding events was observed in older age patients than younger age patients (4.90 % vs. 0.80 %, and 2.20 % vs. 1.70 %, respectively). Uninterrupted warfarin showed a more significant risk of bleeding in Asia (4.20 %, 95%CI: 1.90 %–6.60 %) compared to North America (1.00 %, 95%CI: 0.50 %–1.50 %). Among those who did not interrupt DOACs therapy, the incidence of TE was the lowest (0.08 %, 95%CI: 0.04 %–0.11 %). ConclusionThis study provides a comprehensive assessment of bleeding and TE risks in patients undergoing colonoscopy while receiving uninterrupted or interrupted anticoagulant therapy in the real-world setting. The overall incidence of post-colonoscopy bleeding and TE events is relatively low. However, the uninterrupted DOACs and warfarin are associated with an elevated risk of bleeding, particularly among elderly patients and the Asian population.

Optimizing anticoagulation therapy for in-hospital patients on direct oral anticoagulants: a single-centre modified Delphi study.

The management of patients treated with direct oral anticoagulants (DOACs) during hospitalization is a common challenge in clinical practice. Although bridging is generally not recommended, too often DOACs are switched to parenteral therapy with low molecular weight heparins. Our objectives were to update a local guideline for perioperative DOAC management and to develop a guideline for the anticoagulation management in non-surgical patients regarding temporary DOAC discontinuation. We executed a two-step modified Delphi study in a 1000-bed university hospital in Belgium. The Delphi questionnaires were developed based on a literature review and a telephone survey of prescribers. Two expert panels were established: one dedicated to perioperative DOAC management and the other to DOAC management in non-surgical patients. Both panels completed two rounds, commencing with an individual and online round, followed by a face-to-face group session. After the two-round Delphi process, the updated perioperative guideline on DOAC management included reasons for delaying the resumption of DOACs following surgery, such as oral intake not possible, the probability of re-intervention within 3 days, and insufficient haemostasis (e.g. active clinically significant haematoma, haemorrhagic drains or wounds). Furthermore, a guideline for non-surgical hospitalized patients was developed, outlining possible reasons for interrupting DOAC therapy. Both guidelines offer clear anticoagulation therapy strategies corresponding to the identified scenarios. We have updated and developed guidelines for DOAC management in surgical and non-surgical patients during hospitalization, which aim to support prescribers and to enhance targeted prescription review by hospital pharmacists.

A rare incidence of severe dermatological toxicities triggered by concomitant administration of all-trans retinoic acid and triazole antifungal in patients with acute promyelocytic leukemia: a case series and review of the literature

BackgroundAll-trans retinoic acid (ATRA) is an indispensable part of the treatment of acute promyelocytic leukemia (APL). Although, mild cutaneous toxicities like mucocutaneous xerosis, rash, and pruritus are well reported, ATRA associated severe dermatological toxicities are extremely rare. ATRA is primary metabolized by cytochrome P450 (CYP450) enzyme system, and triazole antifungals are notorious for their strong inhibitory effect on CYP450.Case presentationThree Asian APL patients experienced rare ATRA-induced severe dermatological toxicities: exfoliative dermatitis (ED) in cases 1 and 2, and necrotic scrotal ulceration in case 3. Both case 1 (33-year-old female), and case 2 (28-year-old male) landed in emergency department with dehydration, generalized skin erythema and xerosis during their induction chemotherapy. Both of these patients also developed invasive aspergillosis and required concomitant triazole antifungals during their chemotherapy. For ED, intravenous fluids and broad-spectrum antibiotics were started along with application of local emollients to prevent transdermal water loss. Although their general condition improved but skin exfoliation continued with complete desquamation of palms and soles. Dermatology was consulted, and clinical diagnosis of ED was established. Discontinuation of ATRA resulted in complete resolution of ED. Case 3 (15-year-old boy) reported two blackish mildly tender scrotal lesions during induction chemotherapy. He also had mucocutaneous candidiasis at presentation and was kept on triazole antifungal. Local bacterial & fungal cultures, and serological testing for herpes simplex virus were reported negative. Despite adequate local care and optimal antibiotic support, his lesions persisted, and improved only after temporary discontinuation of ATRA. After a thorough literature review and considering the temporal association of cutaneous toxicities with triazole antifungals, we speculate that the concomitant use of triazole antifungals inhibited the hepatic metabolism of ATRA, resulting in higher serum ATRA concentration, and markedly accentuated cutaneous toxicities in our patients.ConclusionBy highlighting this crucial pharmacokinetic interaction, we want to caution the fellow oncologists to be mindful of the inhibitory effect of triazole antifungals on CYP450. We propose using a non-myelosuppressive combination of ATRA and arsenic trioxide for management of APL hence, obliterating the need of prophylactic antifungals. However, in the event of invasive fungal infection (IFI), we suggest using alternative class of antifungals.

Exploring the Perioperative Use of DOACs, off the Beaten Track.

A notable increase in direct oral anticoagulant (DOAC) use has been observed in the last decade. This trend has surpassed the prescription of vitamin K antagonists (VKAs) due to the absence of the need for regular laboratory monitoring and the more favorable characteristics in terms of efficacy and safety. However, it is very common that patients on DOACs need an interventional or surgical procedure, requiring a careful evaluation and a challenging approach. Therefore, perioperative anticoagulation management of patients on DOACs represents a growing concern for clinicians. Indeed, while several surgical interventions require temporary discontinuation of DOACs, other procedures that involve a lower risk of bleeding can be conducted, maintaining a minimal or uninterrupted DOAC strategy. Therefore, a comprehensive evaluation of patient characteristics, including age, susceptibility to stroke, previous bleeding complications, concurrent medications, renal and hepatic function, and other factors, in addition to surgical considerations, is mandatory to establish the optimal discontinuation and resumption timing of DOACs. A multidisciplinary approach is required for managing perioperative anticoagulation in order to establish how to face these circumstances. This narrative review aims to provide physicians with a practical guide for DOAC perioperative management, addressing the most controversial issues.