Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada2Department of Medicine, McGill University, Montreal, Quebec, Canada3Division of General Medicine and Primary Care, Brigham and Women's Hospital.
Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada2Department of Medicine, McGill University, Montreal, Quebec, Canada.
JAMA Intern Med. 2016 Jan;176(1):55-63. doi: 10.1001/jamainternmed.2015.6058.
Off-label use of prescription drugs has been identified as an important contributor to preventable adverse drug events (ADEs) in children. Despite concerns regarding adverse outcomes, to date, no systematic investigation of the effects of off-label drug use in adult populations has been performed.
To monitor and evaluate off-label use of prescription drugs and its effect on ADEs in an adult population.
DESIGN, SETTING, AND PARTICIPANTS: A cohort of 46,021 patients who received 151,305 incident prescribed drugs was assembled from primary care clinics in Quebec, Canada, using the Medical Office of the XXIst Century electronic health record, which supports documentation of treatment indications and treatment outcomes. Prescriptions dispensed from January 1, 2005, through December 30, 2009, were followed up from the date of the prescription to the date the drug use was discontinued, the end of treatment, or the end of follow-up (December 30, 2010). Data were analyzed from January 5, 2012, to March 15, 2015.
Off-label prescription drug use with and without strong scientific evidence.
Adverse drug events in off-label use with and without strong scientific evidence. Analysis used multivariate marginal Cox proportional hazards regression for clustered data with the drug as the unit of analysis.
A total of 3484 ADEs were found in the 46,021 study patients, with an incidence rate of 13.2 per 10,000 person-months. The rate of ADEs for off-label use (19.7 per 10,000 person-months) was higher than that for on-label use (12.5 per 10,000 person-months) (adjusted hazard ratio [AHR], 1.44; 95% CI, 1.30-1.60). Off-label use lacking strong scientific evidence had a higher ADE rate (21.7 per 10,000 person-months) compared with on-label use (AHR, 1.54; 95% CI, 1.37-1.72). However, off-label use with strong scientific evidence had the same risk for ADEs as on-label use (AHR, 1.10; 95% CI, 0.88-1.38). The risks for ADEs were higher for drugs approved from 1981 to 1995 (14.4 per 10,000 person-months; AHR, 1.62; 95% CI, 1.45-1.80) and for those used by women (14.3 per 10,000 person-months; AHR, 1.17; 95% CI, 1.06-1.28), patients receiving 5 to 7 drugs (12.1 per 10,000 person-months; AHR, 3.23; 95% CI, 2.66-3.92), and patients receiving cardiovascular drugs (15.9 per 10,000 person-months; AHR, 3.30; 95% CI, 2.67-4.08) and anti-infectives (66.2 per 10,000 person-months; AHR, 6.33; 95% CI, 4.58-8.76). Patients with a 1-unit increase in the continuity of care index had a 19% increase in ADEs (AHR, 1.19; 95% CI, 1.12-1.26).
Off-label use of prescription drugs is associated with ADEs. Caution should be exercised in prescribing drugs for off-label uses that lack strong scientific evidence. Future electronic health records should be designed to enable postmarket surveillance of treatment indications and treatment outcomes to monitor the safety of on- and off-label uses of drugs.
处方药物的标签外使用已被确定为导致儿童可预防药物不良事件（ADEs）的一个重要因素。尽管存在对不良后果的担忧，但迄今为止，尚未对成人人群中标签外药物使用的影响进行系统的调查。
监测和评估处方药的标签外使用及其对成人人群中 ADEs 的影响。
设计、设置和参与者：从加拿大魁北克省的一个初级保健诊所中，使用 21 世纪医疗办公室电子健康记录，该记录支持治疗指示和治疗结果的记录，组建了一个由 46021 名接受 151305 例新处方药物的患者组成的队列。从 2005 年 1 月 1 日至 2009 年 12 月 30 日开出的处方，从处方日期到药物使用停止、治疗结束或随访结束（2010 年 12 月 30 日）进行随访。数据分析于 2012 年 1 月 5 日至 2015 年 3 月 15 日进行。
有和没有强有力科学证据的标签外处方药物使用。
有和没有强有力科学证据的标签外药物使用的 ADEs。使用多元边际 Cox 比例风险回归分析，药物为分析单位，进行聚类数据分析。
在 46021 名研究患者中发现了 3484 例 ADEs，发病率为每 10000 人月 13.2 例。标签外使用的 ADEs 发生率（19.7 例/10000 人月）高于标签内使用（12.5 例/10000 人月）（调整后的危险比[AHR]，1.44；95%CI，1.30-1.60）。缺乏强有力科学证据的标签外使用的 ADEs 发生率（21.7 例/10000 人月）高于标签内使用（AHR，1.54；95%CI，1.37-1.72）。然而，有强有力科学证据的标签外使用与标签内使用的 ADEs 风险相同（AHR，1.10；95%CI，0.88-1.38）。药物 ADEs 的风险对于 1981 年至 1995 年批准的药物（14.4 例/10000 人月；AHR，1.62；95%CI，1.45-1.80）和女性使用的药物（14.3 例/10000 人月；AHR，1.17；95%CI，1.06-1.28）较高，接受 5 至 7 种药物的患者（12.1 例/10000 人月；AHR，3.23；95%CI，2.66-3.92）和接受心血管药物（15.9 例/10000 人月；AHR，3.30；95%CI，2.67-4.08）和抗感染药物（66.2 例/10000 人月；AHR，6.33；95%CI，4.58-8.76）的患者较高。连续性护理指数每增加 1 个单位，ADEs 增加 19%（AHR，1.19；95%CI，1.12-1.26）。
处方药物的标签外使用与 ADEs 有关。在为缺乏强有力科学证据的标签外用途开具药物时应谨慎。未来的电子健康记录应设计为能够进行上市后治疗指示和治疗结果的监测，以监测药物的标签内和标签外使用的安全性。
