Scoping Review of Randomized Trials With Discontinuation of Medicines in Older Adults

ObjectivesTo map the randomized trial evidence describing the feasibility of discontinuing active medications with potential adverse effects in older patients.DesignScoping review with systematic search of PubMed, Embase, and Cochrane Library.Setting and ParticipantsRandomized trials investigating discontinuation of a single medicine or medicine class in patients with mean age ≥65 years.MethodsWe extracted trial characteristics including study design and assessed bias. As proxies for the “feasibility of discontinuation,” we extracted the “dropout rate” and “disease recurrence rate.”ResultsWe identified 40 trials investigating discontinuation of symptomatic (n = 26), preventive (n = 6), or both preventive and symptomatic medicines (n = 8) against psychiatric (n = 10), neurologic (n = 9), musculoskeletal (n = 8), cardiovascular (n = 5), respiratory (n = 4), and urologic diseases (n = 4). Five discontinuation designs were used, 75% (30/40) of trials were placebo-controlled, and 48% (19/40) of trials had bias disfavoring discontinuation. The dropout rate was similar between the discontinuation group and the continuation group in 79% of the trials (30/38), whereas disease recurrence was similar in 72% (23/32) of the trials. In 42% (13/31) of trials reporting both dropout rate and disease recurrence rate, the differences between groups were statistically insignificant and less than 10%; these trials investigated discontinuation of cholinesterase inhibitors for Alzheimer's disease in various settings (n = 3), alendronate for osteoporosis (n = 3), glucosamine for osteoarthritis, lithium as adjunct for unipolar depression, statins for cardiovascular disease in patients with limited life expectancy, droxidopa for neurogenic orthostatic hypotension, tamsulosin for lower urinary tract symptoms, sertraline for major depressive episode, and fentanyl patch for low back or osteoarthritis pain.Conclusions and ImplicationsWe identified 40 randomized trials using a variety of designs investigating discontinuation of both symptomatic and preventive medicines in older patients. Discontinuation of medicines seems feasible for most of the investigated medicines. This scoping review can guide clinical practice and future trials on deprescribing.     

The impact of lithium prophylaxis on the course of bipolar disorder: a review of the research evidence

A critical review is provided of the available research evidence concerning the efficacy and effectiveness of lithium prophylaxis in bipolar disorder. It is emphasized that, in spite of the limitations of available placebo-controlled trials and naturalistic studies, lithium is the only drug whose prophylactic activity in bipolar disorder is convincingly proved, and remains the first-choice medication in the long-term treatment of bipolar patients. The impact of lithium prophylaxis is likely to be less significant on atypical and comorbid cases of bipolar disorder than in typical manic–depressive illness, but the superiority of other medications over lithium in the long-term treatment of those cases is at present not convincingly proved by research. Currently available research evidence does not seem to support the idea that lithium exerts its prophylactic effect on relapses but not on recurrences of bipolar disorder. Clinicians should be aware of the fact that the drop-out rate in bipolar patients receiving long-term lithium prophylaxis is high even if treatment surveillance is accurate, and that complete suppression of recurrences is a relatively rare outcome of prophylaxis.     

停止配戴角膜塑形镜后眼部参数的变化及相关性

【目的】观察配戴角膜塑形镜1年并停戴1月后的屈光状态和角膜前表面参数的恢复情况,并分析屈光度变化的相关因素。【方法】回顾性病例研究。收集66例（66眼）配戴角膜塑形镜并自愿停戴的8~15岁近视儿童,配戴时间约1年,平均13（S=3）月,停戴平均29（S=4）d。观察戴镜前及停戴1月的屈光度、眼轴、眼压、前房深度及角膜地形图参数,采用配对t检验和Pearson相关性分析停戴后的各参数变化及其相关性。【结果】与配戴角膜塑形镜前相比,停戴1月后的等效球镜度增长了-0.13（-0.50~0.00）D（P<0.001）,其中柱镜度数增长了0.00（-0.25~0.00）D,（P=0.013）。停戴1月的角膜陡峭K值、平坦K值、平坦和陡峭偏心率较戴镜前分别减少了0.10（-0.10~0.30）D、0.20（0.00~0.48）D、-0.10（-0.30~0.20）D,（P1=0.001、P2<0.001、P3=0.015）。戴角膜塑形镜1年并停戴1月后屈光度增长量（Y）仅与眼轴增长值（X）具有密切联系,并建立回归方程＾y=-1.294X+0.095（P<0.001）。【结论】儿童停戴角膜塑形镜1月后的屈光状态已经超过戴镜前水平,角膜前表面形态基本恢复到戴镜前的初始形态。     

Treatment Discontinuation Impact on Long-Term (10-Year) Weight Gain and Lipid Metabolism in First-Episode Psychosis: Results From the PAFIP-10 Cohort

BackgroundPatients with a first episode of psychosis (FEP) are at higher risk of gaining weight and presenting metabolic disturbances, partly related to antipsychotic exposure. Previous studies suggest that treatment discontinuation might have a positive impact on weight in schizophrenia. The aim of this study was to evaluate the effect of treatment discontinuation on weight and metabolic changes in a FEP cohort.MethodsA total of 209 FEP patients and 57 healthy controls were evaluated at study entry and prospectively at 10-year follow-up. Anthropometric measures and, clinical, metabolic, and sociodemographic data were collected.ResultsPatients discontinuing antipsychotic treatment presented a significantly lower increase in weight and better metabolic parameter results than those still on antipsychotic treatment at 10-year follow-up.ConclusionsTreatment discontinuation had a positive effect on the weight and metabolic changes observed in FEP patients; however, this effect was not sufficient to reaching a complete reversal to normal levels.     

Intention‐to‐treat analysis with treatment discontinuation and missing data in clinical trials

Motivated by a recent National Research Council study, we discuss three aspects of the analysis of clinical trials when participants prematurely discontinue treatments. First, we distinguish treatment discontinuation from missing outcome data. Data collection is often stopped after treatment discontinuation, but outcome data could be recorded on individuals after they discontinue treatment, as the National Research Council study recommends. Conversely, outcome data may be missing for individuals who do not discontinue treatment, as when there is loss to follow up or missed clinic visits. Missing outcome data is a standard missing data problem, but treatment discontinuation is better viewed as a form of noncompliance and treated using ideas from the causal literature on noncompliance. Second, the standard intention to treat estimand, the average effect of randomization to treatment, is compared with three alternative estimands for the intention to treat population: the average effect when individuals continue on the assigned treatment after discontinuation, the average effect when individuals take a control treatment after treatment discontinuation, and a summary measure of the effect of treatment prior to discontinuation. We argue that the latter choice of estimand has advantages and should receive more consideration. Third, we consider when follow‐up measures after discontinuation are needed for valid measures of treatment effects. The answer depends on the choice of primary estimand and the plausibility of assumptions needed to address the missing data. Ideas are motivated and illustrated by a reanalysis of a past study of inhaled insulin treatments for diabetes, sponsored by Eli Lilly. Copyright © 2014 John Wiley & Sons, Ltd.     

Dual Antiplatelet Therapy Discontinuation,Platelet Reactivity,and Adverse Outcomes After Successful Percutaneous Coronary Intervention

ObjectivesThe purpose of this study was to assess the extent to which the association between premature dual antiplatelet therapy (DAPT) discontinuation and excess risk of thrombotic events varies according to the reason and timing of DAPT discontinuation and whether high on-treatment platelet reactivity (HPR) influences the risk of thrombotic events after premature DAPT discontinuation.BackgroundDAPT after percutaneous coronary intervention (PCI) suppresses platelet reactivity, and HPR on clopidogrel after PCI is associated with an increased risk of thrombotic events.MethodsADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) was a prospective, multicenter registry of 8,582 patients successfully treated with coronary drug-eluting stents that assessed HPR on clopidogrel. For patients who discontinued aspirin or clopidogrel at any time during the study, the reasons for discontinuation were systematically categorized.ResultsPlanned DAPT discontinuation occurred within 2 years in 3,203 (37.3%) patients. One thousand four hundred eighteen (16.5%) patients discontinued DAPT for unplanned reasons, including surgery or trauma (n = 768 [8.9%]), patient nonadherence (n = 321 [3.7%]), bleeding complications (n = 264 [3.1%]), and drug allergy or hypersensitivity (n = 113 [1.3%]). Unplanned but not planned DAPT discontinuation was associated with an increased risk of a major adverse cardiac event (MACE, defined as the composite of cardiac death, myocardial infarction, or stent thrombosis); with highest risk within 3 months after PCI (adjusted HR: 7.65, 95% CI: 2.77-21.10 vs adjusted HR: 2.47, 95% CI: 1.70-3.58 for unplanned DAPT discontinuation ≥3 months after PCI). MACE risk after DAPT discontinuation was not moderated by HPR (P_interaction = 0.91).ConclusionsIn this large-scale all-comers registry, premature DAPT discontinuation for unplanned reasons occurred in approximately 1 of 6 patients after DES implantation and was associated with a markedly increased risk of MACEs. (Assessment of Dual AntiPlatelet Therapy With Drug Eluting Stents [ADAPT-DES]; NCT00638794)