The drug risks of cilostazol: A pharmacovigilance study of FDA Adverse Event Reporting System database.

Cilostazol is indicated for alleviating intermittent claudication (IC) in stable-phase peripheral arterial disease (PAD) patients. Conducting data mining on adverse events (AEs) of cilostazol in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to explore its potential medication risks and advance more rational and secure clinical medication practices. This study utilized the Open Vigil 2.1-MedDRA tool to retrieve and extract AE reporting data related to cilostazol from the FAERS database spanning the first quarter of 2004 to the first quarter of 2024. The primary methodology employed was the application of the reporting odds ratio (ROR) method to detect risk signals associated with AEs of cilostazol. A total of 2,130 AE reports involving cilostazol were identified as the primary suspect drug, with a total of 7,134 AEs reported. These reports were predominantly concentrated among patients aged 60 and above, with a higher occurrence in males compared to females. Japan ranked first among the reporting countries, and the majority of reports were submitted by healthcare professionals. Through the screening of cilostazol, a total of 323 positive risk signals for AEs were identified, encompassing 23 system organ classes (SOCs). A comparison with the existing cilostazol product label revealed 8 AEs that were not included based on the number of AE reports, and 19 AEs that were not included based on the strength of the risk signals. Cilostazol exhibited positive risk signals for AEs primarily affecting 8 organ systems based on the SOC classification. Among these, cardiac disorders ranked highest, with a total of 53 positive risk signals for cardiovascular-related AEs identified. In terms of the number of reports, cardiac failure ranked first, aligning with the black box warning issued by the FDA regarding cilostazol. The occurrence of adverse reactions related to cilostazol is primarily concentrated within the first month of treatment. However, a certain proportion of adverse reactions have been reported to occur after long-term use (exceeding 360 days) of cilostazol therapy. Our results have further enriched the observations from existing clinical and real-world studies, uncovering new AE signals for cilostazol, including fall, cerebral infarction, pneumonia, loss of consciousness, acute kidney injury, renal impairment, renal failure, cardiac vein perforation, basal ganglia haematoma, cerebral hyperperfusion syndrome, et al. This study also highlights the significant impact of cilostazol on the cardiovascular system, necessitating close attention to potential cardiovascular toxicities. In addition to focusing on the short-term adverse reactions following cilostazol administration, thorough research into its long-term safety profile is also imperative. This study provides recommendations and guidance for the rational and safe clinical use of cilostazol. In the future, prospective studies are needed to explore the occurrence of related AEs further.

Peng L ，Li X ，Li J ，Liu S ，Liang G ... -  《PLoS One》

Real-world study of adverse events associated with triptan use in migraine treatment based on the U.S. Food and Drug Administration (FDA) adverse event reporting system (FAERS) database.

Triptans selectively agoniste 5-Hydroxytryptamine(5-HT) receptors and are widely used in the treatment of migraine. Nevertheless, there is a dearth of comprehensive real-world clinical research on the safety of triptans. In light of the growing prevalence of migraine, it is imperative to gain a deeper understanding of the true extent of adverse events (AEs) associated with triptans in the clinical management of migraine. A database query of AEs reported to the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for triptans was performed using the online platform Open Vigil 2.1. The query spanned the period from 1 January 2018 to 31 December 2023 and extracted all AEs for 'sumatriptan', 'zolmitriptan', 'rizatriptan', and 'naratriptan' from the 15-49 years old population and retrospective quantitative analyses. A proportional reporting ratio (PRR), reporting odds ratio (ROR), and Bayesian Confidence Propagation Neural Network (BCPNN) methodology were utilized to contrast AEs across the four triptans. A total of 1.272 AEs reports for sumatriptan, 114 for zolmitriptan, 162 for rizatriptan, and 15 for naratriptan were identified. The ratio of females to males was approximately three times higher in all cases, with the highest number of reports originating from the Americas. A review of the FAERS database revealed that nervous system disorders were the primary SOC category for four drugs, with all four drugs exhibiting the AE indicative of reversible cerebral vasoconstriction syndrome, also classified as Nervous system disorders. The most frequently reported AE signal for sumatriptan was dyspnea, which is classified as respiratory, thoracic and mediastinal disorders. The most frequently reported AEs signals for the remaining three drugs were nausea, vomiting and terminal ileitis, all of which are classified as gastrointestinal disorders. Analyses have demonstrated that AEs are present in a range of systems, including cardiac, nervous, gastrointestinal, and musculoskeletal disorders. It should be noted, however, that the incidence and signal intensity of these AEs vary depending on the specific drug in question. In clinical practice, the selection of an appropriate drug and the monitoring of AEs should be tailored to the individual patient's and specific characteristics.

Liu WH ，Hu HM ，Li C ，Shi Q ，Liu CH ，Liu AX ，Li YF ，Zhang Y ，Mao P ，Fan BF ... -  《-》

Falls prevention interventions for community-dwelling older adults: systematic review and meta-analysis of benefits, harms, and patient values and preferences.

About 20-30% of older adults (≥ 65 years old) experience one or more falls each year, and falls are associated with substantial burden to the health care system, individuals, and families from resulting injuries, fractures, and reduced functioning and quality of life. Many interventions for preventing falls have been studied, and their effectiveness, factors relevant to their implementation, and patient preferences may determine which interventions to use in primary care. The aim of this set of reviews was to inform recommendations by the Canadian Task Force on Preventive Health Care (task force) on fall prevention interventions. We undertook three systematic reviews to address questions about the following: (i) the benefits and harms of interventions, (ii) how patients weigh the potential outcomes (outcome valuation), and (iii) patient preferences for different types of interventions, and their attributes, shown to offer benefit (intervention preferences). We searched four databases for benefits and harms (MEDLINE, Embase, AgeLine, CENTRAL, to August 25, 2023) and three for outcome valuation and intervention preferences (MEDLINE, PsycINFO, CINAHL, to June 9, 2023). For benefits and harms, we relied heavily on a previous review for studies published until 2016. We also searched trial registries, references of included studies, and recent reviews. Two reviewers independently screened studies. The population of interest was community-dwelling adults ≥ 65 years old. We did not limit eligibility by participant fall history. The task force rated several outcomes, decided on their eligibility, and provided input on the effect thresholds to apply for each outcome (fallers, falls, injurious fallers, fractures, hip fractures, functional status, health-related quality of life, long-term care admissions, adverse effects, serious adverse effects). For benefits and harms, we included a broad range of non-pharmacological interventions relevant to primary care. Although usual care was the main comparator of interest, we included studies comparing interventions head-to-head and conducted a network meta-analysis (NMAs) for each outcome, enabling analysis of interventions lacking direct comparisons to usual care. For benefits and harms, we included randomized controlled trials with a minimum 3-month follow-up and reporting on one of our fall outcomes (fallers, falls, injurious fallers); for the other questions, we preferred quantitative data but considered qualitative findings to fill gaps in evidence. No date limits were applied for benefits and harms, whereas for outcome valuation and intervention preferences we included studies published in 2000 or later. All data were extracted by one trained reviewer and verified for accuracy and completeness. For benefits and harms, we relied on the previous review team's risk-of-bias assessments for benefit outcomes, but otherwise, two reviewers independently assessed the risk of bias (within and across study). For the other questions, one reviewer verified another's assessments. Consensus was used, with adjudication by a lead author when necessary. A coding framework, modified from the ProFANE taxonomy, classified interventions and their attributes (e.g., supervision, delivery format, duration/intensity). For benefit outcomes, we employed random-effects NMA using a frequentist approach and a consistency model. Transitivity and coherence were assessed using meta-regressions and global and local coherence tests, as well as through graphical display and descriptive data on the composition of the nodes with respect to major pre-planned effect modifiers. We assessed heterogeneity using prediction intervals. For intervention-related adverse effects, we pooled proportions except for vitamin D for which we considered data in the control groups and undertook random-effects pairwise meta-analysis using a relative risk (any adverse effects) or risk difference (serious adverse effects). For outcome valuation, we pooled disutilities (representing the impact of a negative event, e.g. fall, on one's usual quality of life, with 0 = no impact and 1 = death and ~ 0.05 indicating important disutility) from the EQ-5D utility measurement using the inverse variance method and a random-effects model and explored heterogeneity. When studies only reported other data, we compared the findings with our main analysis. For intervention preferences, we used a coding schema identifying whether there were strong, clear, no, or variable preferences within, and then across, studies. We assessed the certainty of evidence for each outcome using CINeMA for benefit outcomes and GRADE for all other outcomes. A total of 290 studies were included across the reviews, with two studies included in multiple questions. For benefits and harms, we included 219 trials reporting on 167,864 participants and created 59 interventions (nodes). Transitivity and coherence were assessed as adequate. Across eight NMAs, the number of contributing trials ranged between 19 and 173, and the number of interventions ranged from 19 to 57. Approximately, half of the interventions in each network had at least low certainty for benefit. The fallers outcome had the highest number of interventions with moderate certainty for benefit (18/57). For the non-fall outcomes (fractures, hip fracture, long-term care [LTC] admission, functional status, health-related quality of life), many interventions had very low certainty evidence, often from lack of data. We prioritized findings from 21 interventions where there was moderate certainty for at least some benefit. Fourteen of these had a focus on exercise, the majority being supervised (for > 2 sessions) and of long duration (> 3 months), and with balance/resistance and group Tai Chi interventions generally having the most outcomes with at least low certainty for benefit. None of the interventions having moderate certainty evidence focused on walking. Whole-body vibration or home-hazard assessment (HHA) plus exercise provided to everyone showed moderate certainty for some benefit. No multifactorial intervention alone showed moderate certainty for any benefit. Six interventions only had very-low certainty evidence for the benefit outcomes. Two interventions had moderate certainty of harmful effects for at least one benefit outcome, though the populations across studies were at high risk for falls. Vitamin D and most single-component exercise interventions are probably associated with minimal adverse effects. Some uncertainty exists about possible adverse effects from other interventions. For outcome valuation, we included 44 studies of which 34 reported EQ-5D disutilities. Admission to long-term care had the highest disutility (1.0), but the evidence was rated as low certainty. Both fall-related hip (moderate certainty) and non-hip (low certainty) fracture may result in substantial disutility (0.53 and 0.57) in the first 3 months after injury. Disutility for both hip and non-hip fractures is probably lower 12 months after injury (0.16 and 0.19, with high and moderate certainty, respectively) compared to within the first 3 months. No study measured the disutility of an injurious fall. Fractures are probably more important than either falls (0.09 over 12 months) or functional status (0.12). Functional status may be somewhat more important than falls. For intervention preferences, 29 studies (9 qualitative) reported on 17 comparisons among single-component interventions showing benefit. Exercise interventions focusing on balance and/or resistance training appear to be clearly preferred over Tai Chi and other forms of exercise (e.g., yoga, aerobic). For exercise programs in general, there is probably variability among people in whether they prefer group or individual delivery, though there was high certainty that individual was preferred over group delivery of balance/resistance programs. Balance/resistance exercise may be preferred over education, though the evidence was low certainty. There was low certainty for a slight preference for education over cognitive-behavioral therapy, and group education may be preferred over individual education. To prevent falls among community-dwelling older adults, evidence is most certain for benefit, at least over 1-2 years, from supervised, long-duration balance/resistance and group Tai Chi interventions, whole-body vibration, high-intensity/dose education or cognitive-behavioral therapy, and interventions of comprehensive multifactorial assessment with targeted treatment plus HHA, HHA plus exercise, or education provided to everyone. Adding other interventions to exercise does not appear to substantially increase benefits. Overall, effects appear most applicable to those with elevated fall risk. Choice among effective interventions that are available may best depend on individual patient preferences, though when implementing new balance/resistance programs delivering individual over group sessions when feasible may be most acceptable. Data on more patient-important outcomes including fall-related fractures and adverse effects would be beneficial, as would studies focusing on equity-deserving populations and on programs delivered virtually. Not registered.

Pillay J ，Gaudet LA ，Saba S ，Vandermeer B ，Ashiq AR ，Wingert A ，Hartling L ... -  《Systematic Reviews》

Improving adverse drug event reporting by healthcare professionals.

Adverse drug events, encompassing both adverse drug reactions and medication errors, pose a significant threat to health, leading to illness and, in severe cases, death. Timely and voluntary reporting of adverse drug events by healthcare professionals plays a crucial role in mitigating the morbidity and mortality linked to unexpected reactions and improper medication usage. To assess the effectiveness of different interventions aimed at healthcare professionals to improve the reporting of adverse drug events. We searched CENTRAL, Embase, MEDLINE and several other electronic databases and trials registers, including ClinicalTrials.gov and WHO ICTRP, from inception until 14 October 2022. We also screened reference lists in the included studies and relevant systematic reviews. We included randomised trials, non-randomised controlled studies, controlled before-after studies, interrupted time series studies (ITS) and repeated measures studies, assessing the effect of any intervention aimed at healthcare professionals and designed to increase adverse drug event reporting. Eligible comparators were healthcare professionals' usual reporting practice or a different intervention or interventions designed to improve adverse drug event reporting rate. We excluded studies of interventions targeted at adverse event reporting following immunisation. Our primary outcome measures were the total number of adverse drug event reports (including both adverse drug reaction reports and medication error reports) and the number of false adverse drug event reports (encompassing both adverse drug reaction reports and medication error reports) submitted by healthcare professionals. Secondary outcomes were the number of serious, high-causality, unexpected or previously unknown, and new drug-related adverse drug event reports submitted by healthcare professionals. We used GRADE to assess the certainty of evidence. We followed standard methods recommended by Cochrane and the Cochrane Effective Practice and Organisation of Care (EPOC) Group. We extracted and reanalysed ITS study data and imputed treatment effect estimates (including standard errors or confidence intervals) for the randomised studies. We included 15 studies (eight RCTs, six ITS, and one non-randomised cross-over study) with approximately 62,389 participants. All studies were conducted in high-income countries in large tertiary care hospitals. There was a high risk of performance bias in the controlled studies due to the nature of the interventions. None of the ITS studies had a control arm, so we could not be sure of the detected effects being independent of other changes. None of the studies reported on the number of false adverse drug event reports submitted. There is low-certainty evidence suggesting that an education session, together with reminder card and adverse drug reaction (ADR) report form, may substantially improve the rate of ADR reporting by healthcare professionals when compared to usual practice (i.e. spontaneous reporting with or without some training provided by regional pharmacosurveillance units). These educational interventions increased the number of ADR reports in total (RR 3.00, 95% CI 1.53 to 5.90; 5 studies, 21,655 participants), serious ADR reports (RR 3.30, 95% CI 1.51 to 7.21; 5 studies, 21,655 participants), high-causality ADR reports (RR 2.48, 95% CI 1.11 to 5.57; 5 studies, 21,655 participants), unexpected ADR reports (RR 4.72, 95% CI 1.75 to 12.76; 4 studies, 15,085 participants) and new drug-related ADR reports (RR 8.68, 95% CI 3.40 to 22.13; 2 studies, 7884 participants). Additionally, low-certainty evidence suggests that, compared to usual practice (i.e. spontaneous reporting), making it easier to report ADRs by using a standardised discharge form with added ADR items may slightly improve the total number of ADR reports submitted (RR 2.06, 95% CI 1.11 to 3.83; 1 study, 5967 participants). The discharge form tested was based on the 'Diagnosis Related Groups' (DRG) system for recording patient diagnoses, and the medical and surgical procedures received during their hospital stay. Due to very low-certainty evidence, we do not know if the following interventions have any effect on the total number of adverse drug event reports (including both ADR and ME reports) submitted by healthcare professionals: - sending informational letters or emails to GPs and nurses; - multifaceted interventions, including financial and non-financial incentives, fines, education and reminder cards; - implementing government regulations together with financial incentives; - including ADR report forms in quarterly bulletins and prescription pads; - providing a hyperlink to the reporting form in hospitals' electronic patient records; - improving the reporting method by re-engineering a web-based electronic error reporting system; - the presence of a clinical pharmacist in a hospital setting actively identifying adverse drug events and advocating for the identification and reporting of adverse drug events. Compared to usual practice (i.e. spontaneous reporting with or without some training from regional pharmacosurveillance units), low-certainty evidence suggests that the number of ADR reports submitted may substantially increase following an education session, paired with reminder card and ADR report form, and may slightly increase with the use of a standardised discharge form method that makes it easier for healthcare professionals to report ADRs. The evidence for other interventions identified in this review, such as informational letters or emails and financial incentives, is uncertain. Future studies need to assess the benefits (increase in the number of adverse drug event reports) and harms (increase in the number of false adverse drug event reports) of any intervention designed to improve healthcare professionals' reporting of adverse drug events. Interventions to increase the number of submitted adverse drug event reports that are suitable for use in low- and middle-income countries should be developed and rigorously evaluated.

Shalviri G ，Mohebbi N ，Mirbaha F ，Majdzadeh R ，Yazdizadeh B ，Gholami K ，Grobler L ，Rose CJ ，Chin WY ... -  《Cochrane Database of Systematic Reviews》

Ceftazidime with avibactam for treating severe aerobic Gram-negative bacterial infections: technology evaluation to inform a novel subscription-style payment model.

Harnan S ，Kearns B ，Scope A ，Schmitt L ，Jankovic D ，Hamilton J ，Srivastava T ，Hill H ，Ku CC ，Ren S ，Rothery C ，Bojke L ，Sculpher M ，Woods B ... -  《-》