Inter-expert agreement of seven criteria in causality assessment of adverse drug reactions

AIMS: To evaluate agreement between five senior experts when assessing seven causality criteria and the probability of drug causation. METHODS: A sample of 31 adverse event-drug pairs was constituted. For each pair, five experts separately assessed (i) the probability of drug causation, which was secondarily divided into seven causality levels: ruled out (0-0.05), unlikely (0.06-0.25), doubtful (0.26-0.45), indeterminate (0.46-0.55), plausible (0.56-0.75), likely (0.76-0.95), and certain (0.96-1); and (ii) seven causality criteria. To test discrepancies between experts, the kappa index was used. RESULTS: The agreement of the five experts was very poor (kappa = 0.05) for the probability of drug causation. Among the seven levels of causality, only 'doubtful' showed a significant rate of agreement (kappa = 0.32, P < 0.001). For all criteria, the kappa index was significant except for the item 'risk(s) factor(s)' (kappa = 0.09). Agreement between experts was good (0.64, P < 0.001) only for the criterion 'reaction at site of application or toxic plasma concentration of the drug or validated test'. However, the rate of agreement with kappa indices of the causality criteria ranged from 0.12 to 0.38. CONCLUSIONS: This study confirms that in the absence of an operational procedure, agreement between experts is low. This should be considered when designing a causality assessment method. In particular, criteria inducing a low level of agreement should have their weight reduced.     

Monitoring of incidence, severity, and causality of adverse drug reactions in hospitalized patients with cardiovascular disease

Background:

Patients admitted to cardiology department are mostly on polypharmacy. So drug-drug interactions and adverse effects of drugs are quite common. Yet, there is a paucity of data regarding adverse drug reaction (ADR) monitoring in cardiology department in India. The present study is an effort to fill up these lacunae.

Materials and Methods:

A prospective, observational study registering 966 indoor cardiology patients according to predetermined inclusion and exclusion criteria was conducted for one year. ADR profile was noted by spontaneous reporting and intensive monitoring. Naranjo ADR probability scale was used to establish the causality.

Results:

A total of 208 ADRs were reported from 188 patients (19.5%). Of these 188 patients, 62 patients (33%) were hospitalized primarily due to the development of ADRs, while 126 (67%) patients developed ADRs during hospital stay. Nitrates were the most common offender drug group (17.8%).

Conclusion:

Development of ADR in one of every five cardiac patient points toward a grave situation, but a higher incidence of Type A reactions in cardiology department means that these can be avoided.     

药物不良反应因果关系评价方法的探讨

机体在不同情况下的生物反应不同，使药物不良反应的评估有时会有一定的困难。通过实践，我们提出以提问回答形式，主要围绕不良反应的详细病史包括合并用药，以及既往药物不良反应史提问。顺序逐一回答问题，得出结论：肯定、很可能、可能、可疑、无关。８４例应用此法与经验评估法的评估结果进行比较，完全符合率为７９％。     

某院3181例药品不良反应报告分析

目的 了解药品不良反应(ADR)发生的一般规律及特点,为临床合理用药提供参考.方法 采用回顾性分析方法 ,对3 181例ADR报告从ADR发生的年龄与性别分布、给药途径、药品种类、累及的系统/器官及临床表现、ADR报告类型及ADR转归等方面进行统计分析.结果 3 181例ADR报告中,男性1 501例(47.19%),女性1 680例(52.81%);ADR在各年龄段均有分布,>50~60岁者ADR发生率最高,有829 例,占26.06%;引起ADR药品以抗感染药物居多,且主要为头孢菌素类,其次为心血管系统用药;引发ADR的给药途径以静脉滴注为主,占73.09%;ADR最常累及系统/器官为全身性损害,占23.07%;一般ADR占87.11%,大多好转或治愈,新的ADR占12.39%,严重ADR占0.69%,其中1 例留有后遗症,参麦注射液发生过敏性休克而死亡1例.结论 临床应高度重视ADR监测和报告工作,降低用药风险.     

Adverse drug reactions: Can consumers provide early warning?

In order to investigate the potential value of a drug monitoring system based on consumer reports we asked community pharmacists to distribute previously validated event report forms to users of two popular non-steroidal anti-inflammatory drugs (NSAIDs), piroxicam and diclofenac, in the Hunter Region of New South Wales, Australia. Although response rates were low, comparisons of replies from NSAID users and drug-free subjects in the community identified a range of established symptomatic reactions from NSAIDs affecting the gastrointestinal tract, central nervous system and lower urinary tract. In comparison, analysis of adverse reaction reports from health professionals revealed a tendency to report more severe but rarer reactions affecting the upper gastrointestinal tract, liver, skin and haematological system. It is likely that a system based on consumer reports could augment current sources of information on adverse drug effects by revealing reactions which are important to consumers and yet often evade detection during pre-marketing clinical trials. Such a system might also have a capacity to generate very early signals of previously unsuspected symptomatic reactions with new drugs.     

儿童中常见的药物不良反应

病人特别是儿童常发生药物不良反应,在新生儿监护室中发生的不良反应高达30％。甲氧氟普胺引起的肌张力障碍,抗惊厥药引起嗜睡,氯霉素引起灰婴综合征以及皮质类固醉造成的发育障碍都可在儿童中出现。药物有关不良反应在儿童中发生率比成人高的主要原因可能是儿童代谢功能不成熟之故。     

104例肿瘤病人药品不良反应发生特点分析

目的 探讨肿瘤病人住院期间药品不良反应(ADR)的发生规律和特点,为临床安全、合理用药提供依据.方法 对104例肿瘤病人发生ADR的病例按病人年龄、性别、给药途径、药品类型、ADR 涉及器官和(或)系统及临床表现等进行分类统计与分析.结果 104例药品不良反应报告中,静脉给药导致药品不良反应为96.15%;由抗肿瘤药物引起的药品不良反应最多,占48.08%;不良反应临床表现以皮肤及附件损害最为常见,占24.41%.结论 医院应加强与重视肿瘤病人药品不良反应的监测工作,保证肿瘤病人用药的安全性.     

Causality assessment of adverse drug reactions using decision support and informatics tools

Informatics information organizing techniques have been applied to the causality assessment of adverse drug reactions since the 1970s. There has not appeared an easily applied and accurate method. The problem has to do with low quality and poorly organized input information or the attempted application of methods that are too rigid for some problems and inapplicable for others. Potentially the best current method, based on Bayesian probability, is difficult to use because of low quality or quantity of information. This handicap requires extrapolations which tend to result in a form of numerical global introspection. We suggest that the problem might be approached by using a generalized decision support algorithm which can be used with many different decision methods and proper informatics support for the immediate environment of the assessor in drug safety. The decision support algorithm we apply is based on an analytical hierarchical process algorithm implemented in the software CRITERIUM©. We give as an example the application of the algorithm to a suspected adverse drug reaction, cholestatic jaundice, as a result of treatment by chloropromazine. However, to support any decision-making method, the information and informatics environment around the decision-maker must be planned and developed. A set of requirements that best reflect adverse drug reaction causality assessment needs is discussed.     

噻唑烷二酮类药物致不良反应文献分析

目的：分析噻唑烷二酮类药物不良反应的发生情况及临床特点,为合理用药提供参考。方法：检索噻唑烷二酮类在中国上市以来CNKI、VIP数据库收载的不良反应文献进行统计分析。结果：噻唑烷二酮类不良反应的文献报道共24例次;年龄60岁以上发生率较高(16例,66.7％);多发生在用药1月后(11例,45.8%);分别涉及红细胞异常、心血管系统一般损害、代谢和营养障碍、肝胆系统损害等多个系统/器官。结论：临床合理使用噻唑烷二酮类药物的同时,加强用药监测,以减少不良反应的发生。     

孟鲁司特致不良反应文献分析

目的：分析孟鲁司特药品不良反应的发生情况及临床特点,为合理用药提供参考。方法：检索孟鲁司特在中国2002年上市以来-2013年8月CNKI、VIP数据库收载的不良反应文献进行统计分析。结果：孟鲁司特药品不良反应的文献报道共17例次;年龄60岁以上发生率较高(7例,41.2％);多发生在用药1周以内(14例,82.3%);累及的器官或系统较多,以神经系统损害为主(6例,35.3%),主要表现为行为及精神异常。结论：临床合理使用孟鲁司特的同时,加强用药监测,以减少不良反应的发生。     

Adverse drug reaction profile of nanoparticle versus conventional formulation of paclitaxel: An observational study

Objectives:

Conventional polyethoxylated castor oil (PCO)-based paclitaxel is associated with major adverse drug reactions (ADRs). Nanoxel, a nanoparticle-based formulation, may improve its tolerability by removing the need for PCO vehicle, and also permit its use in a higher dose. We conducted intensive monitoring of the ADR profile of Nanoxel in comparison with conventional paclitaxel in a public tertiary care set-up.

Materials and Methods:

ADR data were collected from 10 patients receiving Nanoxel and 10 age-matched controls receiving conventional paclitaxel in this longitudinal observational study, conducted in a medical oncology ward over 18 months. Severity was graded as per US National Cancer Institute Common Terminology Criteria for Adverse Events.

Results:

The groups had comparable demography at baseline. The median disease duration and per cycle median dose of paclitaxel were greater in the Nanoxel arm. Total 119 ADRs were noted with Nanoxel and 123 with conventional paclitaxel. Of these, 25 (21.0%, 95% CI 13.69–28.33%) in the Nanoxel and 20 (16.2%, 95% CI 9.74–22.78%) in paclitaxel group were of grade 3/4 severity. Common events included myalgia, nausea, anemia, paresthesia, alopecia, diarrhea, and vomiting with Nanoxel, and paresthesia, anemia, myalgia, anorexia, alopecia, vomiting, diarrhea, stomatitis, and nausea with paclitaxel. Of the less common events (<5%), grade 2 or 3 arthralgia was seen exclusively with Nanoxel while motor neuropathy with muscular weakness was more frequent and severe with conventional paclitaxel. Hypersensitivity reactions were not encountered in either arm, although no antiallergy premedication was employed for Nanoxel.

Conclusions:

Despite its ADR profile being statistically comparable to conventional paclitaxel, this observational study suggests that Nanoxel tolerability could be better, considering that a significantly higher dose was employed. This hypothesis needs confirmation through an interventional study.     

头孢曲松钠的不良反应

目的探讨头孢曲松钠的药物不良反应类型及其相应的不良反应机制。方法检索CNKI、维普、Pubmed、OVID等数据库中头孢曲松钠不良反应、产生不良反应的机制和对应的预防处理措施的相关报道,进行回顾性分析。结果头孢曲松钠所致的不良反应涉及人体多个系统,以变态反应最多,最严重的是过敏性休克;其次为神经系统、血液系统、泌尿系统、消化系统等不良反应。部分不良反应是由给药途径不同、剂量过大、不合理配伍用药所致。结论通过对头孢曲松钠的不良反应及其不良反应机制的分析,以期合理应用头孢曲松钠。     

应用Hill标准评价达沙替尼与呼吸系统不良反应的因果关系

目的：以挖掘的信号为基础,评价达沙替尼与呼吸系统不良反应的因果关系,以期为临床安全用药提供参考。方法：检索相关文献,根据纳入与排除标准所得的文献以及不良事件自发呈报系统（adverse events reporting system,AERS）与临床试验注册平台的数据,应用Hill标准对其进行评价。结果：共纳入5个符合标准的临床试验（Random clinical trial,RCT）,30例个案报道及AERS中384例患者信息,结果显示除了Hill标准中合理性、量效关系不明确及可类比性较弱外,达沙替尼与呼吸系统ADR满足了关联的强度、结果一致性、可重复性、试验证据、时序性、和特异性6个方面。结论：达沙替尼与呼吸系统ADR存在因果关联的可能性较大,临床用药时应注意呼吸系统ADR的发生,但由于研究的数据有限,且Hill标准不能反映出ADR的发生率、严重程度和危险因素等,故仍需进一步相关研究分析。     

我院190例药品不良反应报告分析

目的探讨我院药品不良反应(ADR)发生的特点及规律,为临床合理用药提供参考。方法采用描述性研究方法,对我院2006-2009年上报的190份ADR报告进行分类、统计及分析。结果涉及ADR的药品共16类,总计86个品种,以抗微生物类药物最多(25种,86例),其次为营养神经系统药物和心血管系统药物(分别为27例和21例);ADR累及器官或系统以皮肤及其附件损害为最多(65例)。结论临床应当重视ADR监测并及时报告,以减少或避免ADR的重复发生,促进临床合理用药。     

某医院277例药品不良反应报告分析

目的 了解药品不良反应(ADR)发生的特点与规律,为临床合理用药提供参考。方法 回顾性统计并分析有效ADR 277例。结果 277例ADR报告中,男性发生率(55.60%)略高于女性(44.40%);ADR可发生于各年龄段患者,但以51～60岁的患者所占的比例最大(占20.58%);静脉滴注给药引发的ADR最常见(占84.12%);引发ADR最多的药物为抗感染药物(占25.27%),其中左氧氟沙星、头孢哌酮钠舒巴坦钠位列前二位,其次为中药制剂(占24.91%);ADR损害类型主要以皮肤及其附件损害为主(占38.36%)。结论 掌握ADR发生的特点与规律,有助于减少或避免ADR重复发生。     

Causality assessment of adverse drug reactions: comparison of the results obtained from published decisional algorithms and from the evaluations of an expert panel

PURPOSE: To compare the results of causality assessments of reported adverse drug reactions (ADR's) obtained from decisional algorithms with those obtained from an expert panel using the WHO global introspection method (GI) and to further evaluate the influence of confounding variables on algorithms ability in assessing causality. METHOD: Two hundred sequentially reported ADR's were included in this study. An independent researcher used algorithms, while an expert panel assessed the same reports using the GI, both aimed at evaluating causality. Reports were divided into three groups according to the presence, absence or lack of information on confounding variables. RESULTS: For the total sample, observed agreements between decisional algorithms compared with GI varied from 21% to 56%, average of 47%. When confounding variables were taken into account, agreements varied between 41% and 69%, average of 58%; 8% and 65%, average of 46% and 15% and 53%, average of 42% accordingly to the absence, lack of information or presence of confounding variables, respectively. The extend of reproducibility beyond chance was low for the total sample (average Kappa = 0.26) and within the groups considered. CONCLUSION: The overall observed agreement between algorithm and GI was moderate although poorly different from chance, confounding variables being a shortcoming of algorithms ability in assessing causality.     

Adverse reactions related to drugs for headache treatment: clinical impact

Objective To assess the clinical impact of adverse reactions related to drugs for primary headache treatment.Methods We examined the adverse reactions to 360 medications prescribed by the specialists of the Headache Centre of the University of Modena and Reggio Emilia to 256 consecutive outpatients (214 female, 42 male; mean age: 38.88±14.06 years; range 10–72 years). Adverse reactions were reported by patients during scheduled follow-up visits, classified by specialists and reassessed by a clinical pharmacologist.Results Adverse reactions with a causal relationship classified as definite/probable/possible were 202 (56%): 62% (80/129) were due to acute treatments and 53% (122/231) to prophylactic treatments (² test, P= 0.115 ns). More than 90% of the adverse reactions were of limited intensity [mild (58%) or moderate (36%)]. Only 5% were severe, and two reactions (1%) were serious. The most affected apparatus was the nervous system (41%). Of these adverse reactions, 43% caused the discontinuance of the treatment, especially of prophylaxis (54%). Patients evaluated 70% of the medications as effective, but, at the same time, they considered most of the adverse reactions (69%) unacceptable.Conclusion Adverse reactions related to headache medications have a strong impact on patients management, even if their real intensity and severity are usually very limited. Drugs for headache treatment are still far from being ideal drugs. To prevent the discontinuance of effective medications, the physician, prior to prescribing, should assess, together with the patient, the acceptability of the more common adverse drug reactions.     

药品不良反应报告因果关系评价方法概述

药品不良反应因果关系的评价方法是药物警戒过程中比较重要的一种工具,该研究提供一个这些方法总的概述,并阐述他们的特点.药品不良反应因果关系评价方法大致分为三种:专家判断或全面内省法、计分推算法、概率法或贝叶斯法.专家判断法是基于先前已有的知识和经验的非标准化方法对个案进行评估,以得出因果关系的结论;计分推算法是设计一系列的问题,通过计算回答问题的分数来判断因果关系的可能性;贝叶斯法是通过使用个例报告的相关信息把药品因果关系的先验概率转化为后验概率的过程.先验概率是用流行病学信息计算得来,后验概率与这个背景信息相比得出因果关系的可能性.另外,不同的评价方法因果关系的分类也不同,因果关系评价的标准也不同.总之,目前仍然没有一种通用的因果关系评价方法.     

我院2010年药品不良反应监测分析

目的了解该院药品不良反应(ADR)发生情况,促进临床合理用药。方法对该院2010年收集到的806份ADR报告进行分类统计和分析评价。结果 806份ADR中,老年患者较多,占总例数的39.1%(316例);以静脉滴注方式给药引发的ADR最多,占总例数的93%(749例);抗菌药引起的ADR最多,占总例数的40.69%(328例);临床表现以消化系统损伤最常见,占总例数的39.2%(316例)。结论继续做好并加强ADR监测工作,避免或减少ADR发生。