Suspected survivor bias in case–control studies: stratify on survival time and use a negative control

AbstractObjectivesSelection bias in case–control studies occurs when control selection is inappropriate. However, selection bias due to improper case sampling is less well recognized. We describe how to recognize survivor bias (i.e., selection on exposed cases) and illustrate this with an example study.Study Design and SettingA case–control study was used to analyze the effect of statins on major bleedings during treatment with vitamin K antagonists. A total of 110 patients who experienced such bleedings were included 18–1,018 days after the bleeding complication and matched to 220 controls.ResultsA protective association of major bleeding for exposure to statins (odds ratio [OR]: 0.56; 95% confidence interval: 0.29–1.08) was found, which did not become stronger after adjustment for confounding factors. These observations lead us to suspect survivor bias. To identify this bias, results were stratified on time between bleeding event and inclusion, and repeated for a negative control (an exposure not related to survival): blood group non-O. The ORs for exposure to statins increased gradually to 1.37 with shorter time between outcome and inclusion, whereas ORs for the negative control remained constant, confirming our hypothesis.ConclusionWe recommend the presented method to check for overoptimistic results, that is, survivor bias in case–control studies

Statin use decreases coagulation in users of vitamin K antagonists

Purpose: The purpose of the study is to determine the immediate and long-term effect of statins on coagulation in patients treated with vitamin K antagonists (VKAs). Methods: We selected patients on VKAs of two Dutch anticoagulation clinics who initiated treatment with a statin between 2009 and 2013. Patients who initiated or stopped concomitant drugs that interact with VKAs or were hospitalised during follow-up were excluded. The VKA dosage (mg/day) after statin initiation was compared with the last VKA dosage before the statin was started. Immediate and long-term differences in VKA dosage (at 6 and 12 weeks) were calculated with a paired student t test. Results: Four hund

Adherence to protocols for the use of reversal agents in patients treated with direct oral anticoagulants

OBJECTIVES: This study aimed to evaluate the adherence to protocols for the use of reversal agents in direct oral anticoagulant (DOAC) users in Dutch hospitals.METHODS: A retrospective cohort study was conducted in seven hospitals in the Netherlands. Treatment protocols for bleeding and (urgent) procedures in patients on DOAC were collected from each hospital. All patient data on the use of reversal agents were retrospectively collected from September 2021 to April 2022 and compared to the protocols. The degree of per-protocol adherence (compliance score) was categorized into four levels as follows: poor (&lt;45%), moderate (45-79%), high (80-89%), and full (&gt; 90%) adherence rates.RESULTS: A total of 290 patients were included in our study. In patients with bleeding under DOAC, the protocol adherence for prothrombin complex concentrate (PCC) was "moderate" (61%). In the remaining cases (39%), non-adherence was mainly caused by underdosing (68%), overdosing (12%), and a lack of indication (14%). Furthermore, idarucizumab was administered for bleeding with "full" adherence (96%). For andexanet alfa, adherence to the hospital bleeding protocol was "moderate" (67%), with a lack of indication being the only reason for non-adherence. In case of reversal for an urgent procedure, the protocol adherence for PCC was "low" (45%), with underdosing, a lack of indication, and missing lab data being the main reasons for non-adherence. Missing lab data on dabigatran plasma concentration before reversal was the main reason for "low" adherence (26%) in idarucizumab. The adherence for andexanet alfa was also "low" (0%).CONCLUSION: In case of reversal for bleeding under DOAC, overall adherence to the protocol was "moderate"; however, in patients needing an urgent procedure, it was "low." The major reasons for non-adherence were underdosing, off-label use, and a lack of specific lab testing. The results of this study can assist in improving the implementation of hospital protocols.</p

Development of a multivariable prediction model for identification of patients at risk for medication transfer errors at ICU discharge

Introduction Discharge from the intensive care unit (ICU) is a high-risk process, leading to numerous potentially harmful medication transfer errors (PH-MTE). PH-MTE could be prevented by medication reconciliation by ICU pharmacists, but resources are scarce, which renders the need for predicting which patients are at risk for PH-MTE. The aim of this study was to develop a prognostic multivariable model in patients discharged from the ICU to predict who is at increased risk for PH-MTE after ICU discharge, using predictors of PH-MTE that are readily available at the time of ICU discharge. Material and methods Data for this study were derived from the Transfer ICU Medication reconciliation study, which included ICU patients and scored MTE at discharge of the ICU. The potential harm of every MTE was estimated with a validated score, where after MTE with potential for harm were indicated as PH-MTE. Predictors for PH-MTE at ICU discharge were identified using LASSO regression. The c statisticprovided a measure of the overall discriminative ability of the prediction model and the prediction model was internally validated by bootstrap resampling. Based on sensitivity and specificity, the cut-off point of the prediction model was determined. Results The cohort contained 258 patients and six variables were identified as predictors for PH-MTE: length of ICU admission, number of home medications and patient taking one of the following medication groups at home: vitamin/mineral supplements, cardiovascular medication, psycholeptic/analeptic medication and medication for obstructive airway disease. The c of the final prediction model was 0.73 (95%CI 0.67–0.79) and decreased to 0.62 according to bootstrap resampling. At a cut-off score of two the prediction model yielded a sensitivity of 70% and a specificity of 61%. Conclusions A multivariable prediction model was developed to identify patients at risk for PH-MTE after ICU discharge. The model contains predictors that are available on the day of ICU discharge. Once external validation and evaluation of this model in daily practice has been performed, its incorporation into clinical practice could potentially allow institutions to identify patients at risk for PH-MTE after ICU discharge, on the day of ICU discharge, thus allowing for efficient, patient-specific allocation of clinical pharmacy services

Clinical, Histologic, and Molecular Characteristics of Anaplastic Lymphoma Kinase-positive Primary Cutaneous Anaplastic Large Cell Lymphoma

Unlike systemic anaplastic large cell lymphoma, the vast majority of primary cutaneous anaplastic large cell lymphomas (C-ALCL) do not carry translocations involving the ALK gene and do not express ALK. Expression of ALK protein therefore strongly suggests secondary cutaneous involvement of a systemic anaplastic large cell lymphoma. Recent studies described a small subgroup of ALK-positive C-ALCL, but information on frequency, prognosis, and translocation partners is virtually lacking. A total of 6/309 (2%) C-ALCL patients included in the Dutch registry for cutaneous lymphomas between 1993 and 2019 showed immunohistochemical ALK expression. Clinical and histopathologic characteristics, immunophenotype and disease course were evaluated. Underlying ALK translocations were analyzed with anchored multiplex polymerase chain reaction-based targeted next-generation sequencing. Median age at diagnosis was 39 years (range: 16 to 53 y). All patients presented with a solitary lesion. Treatment with radiotherapy (n=5) or anthracycline-based chemotherapy (n=1) resulted in complete responses in all 6 patients. Three patients developed a relapse, of whom 2 extracutaneous. After a median follow-up of 41 months, 5 patients were alive without disease and 1 patient died of lymphoma. Immunohistochemically, 3 cases (50%) showed combined nuclear and cytoplasmic ALK expression with underlying NPM1-ALK fusions, while 3 cases (50%) showed solely cytoplasmic ALK expression with variant ALK fusion partners (TRAF1, ATIC, TPM3). ALK-positive C-ALCL is extremely uncommon, has a comparable favorable prognosis to ALK-negative C-ALCL, and should be treated in the same way with radiotherapy as first-line treatment

A comparison of pharmacoepidemiological study designs in medication use and traffic safety research

In order to explore how the choice of different study designs could influence the risk estimates, a case–crossover and case–time–control study were carried out and their outcomes were compared with those of a traditional case–control study design that evaluated the association between the exposure to psychotropic medications and the risk of having a motor vehicle accident (MVA). A record-linkage database availing data for 3,786 cases and 18,089 controls during the period 2000–2007 was used. The study designs (i.e., case–crossover and case–time–control) were derived from published literature, and the following psychotropic medicines were examined: antipsychotics, anxiolytics, hypnotics and sedatives, and antidepressants, stratified in the two groups selective serotonin reuptake inhibitors (SSRIs) and other antidepressants. Moreover, in order to further investigate the effects of frequency of psychoactive medication exposure on the outcomes of the case–crossover analysis, the data were also stratified by the number of defined daily doses (DDDs) and days of medication use in the 12 months before the motor vehicle accident. Three-thousand seven-hundred fifty-two cases were included in this second part of the case–crossover analysis. The case–crossover design did not show any statistically significant association between psychotropic medication exposure and MVA risk [e.g., SSRIs—Adj. OR = 1.00 (95 % CI: 0.69–1.46); Anxiolytics—Adj. OR = 0.95 (95 % CI: 0.68–1.31)]. The case–time–control design only showed a borderline statistically significant increased traffic accident risk in SSRI users [Adj. OR = 1.16 (95 % CI: 1.01–1.34)]. With respect to the stratifications by the number of DDDs and days of medication use, the analyses showed no increased traffic accident risk associated with the exposure to the selected medication groups [e.g., SSRIs, <20 DDDs—Adj. OR = 0.65 (95 % CI: 0.11–3.87); SSRIs, 16–150 days—Adj. OR = 0.55 (95 % CI: 0.24–1.24)]. In contrast to the above-mentioned results, our recent case–control study found a statistically significant association between traffic accident risk and exposure to anxiolytics [Adj. OR = 1.54 (95 % CI: 1.11–2.15)], and SSRIs [Adj. OR = 2.03 (95 % CI: 1.31–3.14)]. Case–crossover and case–time–control analyses produced different results than those of our recent case–control study (i.e., case–crossover and case–time–control analyses did not show any statistically significant association whereas the case–control analysis showed an increased traffic accident risk in anxiolytic and SSRI users). These divergent results can probably be explained by the differences in the study designs. Given that the case–crossover design is only appropriate for short-term exposures and the case–time–control design is an elaboration of this latter, it can be concluded that, probably, these two approaches are not the most suitable ones to investigate the relation between MVA risk and psychotropic medications, which, on the contrary, are often use chronically

Selective serotonin reuptake inhibitor use and risk of major bleeding during treatment with vitamin K antagonists: results of a cohort study

Background Selective serotonin reuptake inhibitors (SSRIs) may increase the risk of major bleeding by decreasing platelet function or decreasing vitamin K antagonist (VKA) metabolism via cytochrome P450 (CYP) inhibition. Aims To determine whether SSRIs are associated with major bleeding during VKA treatment and investigate the possible mechanisms. Methods In this cohort study, information on SSRI use and bleeding complications was obtained from patient records of VKA initiators between 2006 and 2018 from two anticoagulation clinics. Conditional logistic regression and time-dependent Cox regression were used to estimate the effect of SSRIs on a high international normalized ratio (INR ≥ 5) within 2 months after SSRI initiation and on major bleeding during the entire period of SSRI use, respectively. SSRI use was stratified for (non-)CYP2C9inhibitors. Results A total of 58,918 patients were included, of whom 1,504 were SSRI users. SSRI initiation versus nonuse was associated with a 2.41-fold (95% confidence interval [CI]: 2.01-2.89) increased risk for a high INR, which was 3.14-fold (95% CI: 1.33-7.43) among CYP2C9-inhibiting SSRI users. The adjusted hazard ratio of major bleeding was 1.22 (95% CI: 0.99-1.50) in all SSRI users and 1.31 (95% CI: 0.62-2.72) in CYP2C9- inhibiting SSRI users compared with nonusers. Conclusion SSRI use is associated with an increased risk of high INR and might be associated with major bleeding. The risk of a high INR was slightly more elevated for CYP2C9-inhibiting SSRI users, suggesting there might be a pharmacokinetic interaction (by CYP2C9 inhibition) next to a pharmacodynamic effect of SSRIs on platelet activation

Verkeersongevallen en psychofarmaca: Een Nederlandse case-controle-studie

OBJECTIVE: To examine the association between the use of commonly prescribed psychotropic medications and road traffic accident risk. DESIGN AND METHODS: A record-linkage database was used to perform a case-control study in The Netherlands. The data came from three sources: pharmacy prescription data, police traffic accident data and driving licence data. Cases were defined as drivers, who had a traffic accident that required medical assistance between 2000 and 2007. Controls were defined as adults, who had a driving licence and had no traffic accident during the study period. Four controls were matched for each case. The following psychotropic medicine groups were examined: antipsychotics, anxiolytics, hypnotics and sedatives, and antidepressants stratified in two groups: SSRIs and other antidepressants. Various variables, such as age, gender, medicine half-life and alcohol use, were considered for the analysis. RESULTS: 3,963 cases and 18,828 controls were included in the case-control analysis. A significant association was found between traffic accident risk and exposure to anxiolytics (OR 1.54, CI95 1.11-2.15) and SSRIs (OR 2.03, CI95 1.31-3.14). A statistically significant increased risk was also seen in chronic, female and young (18 to 29 years old) anxiolytics users, in chronic, female and middle-aged (30 to 59 years old) SSRI users, and in users of hypnotics with intermediate half-life. CONCLUSIONS: The results of this study support previous findings and confirm that psychoactive medications can constitute a problem In traffic safety. Both health care providers and patients should be properly Informed of the potential risks associated with the use of these medicines