Deprescribing of antidepressants: development of indicators of high-risk and overprescribing using the RAND/UCLA Appropriateness Method.

BACKGROUND: Antidepressants are first-line medications for many psychiatric disorders. However, their widespread long-term use in some indications (e.g., mild depression and insomnia) is concerning. Particularly in older adults with comorbidities and polypharmacy, who are more susceptible to adverse drug reactions, the risks and benefits of treatment should be regularly reviewed. The aim of this consensus process was to identify explicit criteria of potentially inappropriate antidepressant use (indicators) in order to support primary care clinicians in identifying situations, where deprescribing of antidepressants should be considered. METHODS: We used the RAND/UCLA Appropriateness Method to identify the indicators of high-risk and overprescribing of antidepressants. We combined a structured literature review with a 3-round expert panel, with results discussed in moderated meetings in between rounds. Each of the 282 candidate indicators was scored on a 9-point Likert scale representing the necessity of a critical review of antidepressant continuation (1-3 = not necessary; 4-6 = uncertain; 7-9 = clearly necessary). Experts rated the indicators for the necessity of review, since decisions to deprescribe require considerations of patient risk/benefit balance and preferences. Indicators with a median necessity rating of ≥ 7 without disagreement after 3 rating rounds were accepted. RESULTS: The expert panel comprised 2 general practitioners, 2 clinical pharmacologists, 1 gerontopsychiatrist, 2 psychiatrists, and 3 internists/geriatricians (total N = 10). After 3 assessment rounds, there was consensus for 37 indicators of high-risk and 25 indicators of overprescribing, where critical reviews were felt to be necessary. High-risk prescribing indicators included settings posing risks of drug-drug, drug-disease, and drug-age interactions or the occurrence of adverse drug reactions. Indicators with the highest ratings included those suggesting the possibility of cardiovascular risks (QTc prolongation), delirium, gastrointestinal bleeding, and liver injury in specific patient subgroups with additional risk factors. Overprescribing indicators target patients with long treatment durations for depression, anxiety, and insomnia as well as high doses for pain and insomnia. CONCLUSIONS: Explicit indicators of antidepressant high-risk and overprescribing may be used directly by patients and health care providers, and integrated within clinical decision support tools, in order to improve the overall risk/benefit balance of this commonly prescribed class of prescription drugs.

Addressing the gaps in evaluation of new drugs for older adults: Strategies from the International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee.

The International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee aims to improve the use of drugs in older adults and develop new therapeutic approaches for the syndromes and diseases of old age through advocacy, education, and research. In the present paper, we propose strategies relevant to drug development and evaluation, spanning preclinical and the full range of clinical studies. Drugs for older adults need to consider not only age, but also other characteristics common in geriatric patients, such as multimorbidity, polypharmacy, falls, cognitive impairment, and frailty. The IUPHAR Geriatric Committee's position statement on 'Measurement of Frailty in Drug Development and Evaluation' is included, highlighting 12 key principles that cover the spectrum of translational research. We propose that where older adults are likely to be major users of a drug, that frailty is measured at baseline and as an outcome. Preclinical models that replicate the age, frailty, duration of exposure, comorbidities, and co-medications of the proposed patients may improve translation. We highlight the potential application of recent technologies, such as physiologically based pharmacokinetic-pharmacodynamic modeling informed by frailty biology, and Artificial Intelligence, to inform personalized medicine for older patients. Considerations for the rapidly aging populations in low- and middle-income countries related to health-care and clinical trials are outlined. Involving older adults, their caregivers and health-care providers in all phases of research should improve drug development, evaluation, and outcomes for older adults internationally.

Safety outcomes of direct oral anticoagulants in older adults with atrial fibrillation: a systematic review and meta-analysis of (subgroup analyses from) randomized controlled trials.

Balancing stroke prevention and risk of bleeding in patients with atrial fibrillation (AF) is challenging. Direct oral anticoagulants (DOACs) are by now considered standard of care for treating patients with AF in international guidelines. Our objective was to assess the safety of long-term intake of DOACs in older adults with AF. We included RCTs in elderly (≥ 65 years) patients with AF. A systematic search in MEDLINE and EMBASE was performed on 19 April 2022. For determination of risk of bias, the RoB 2 tool was applied. We pooled outcomes using random-effects meta-analyses. The quality of evidence was assessed using GRADE. Eleven RCTs with a total of 63,374 patients were identified. Two RCTs compared apixaban with either warfarin or aspirin, four edoxaban with either placebo, aspirin, or vitamin K antagonists (VKAs), two dabigatran with warfarin and three rivaroxaban with warfarin. DOACs probably reduce mortality in elderly patients with AF (HR 0.89 95%CI 0.77 to 1.02). Low-dose DOACs likely reduce bleeding compared to VKAs (HR ranged from 0.47 to 1.01). For high-dose DOACS the risk of bleeding varied widely (HR ranged from 0.80 to 1.40). We found that low-dose DOACs probably decrease mortality in AF patients. Moreover, apixaban and probably edoxaban are associated with fewer major or clinically relevant bleeding (MCRB) events compared to VKAs. For dabigatran and rivaroxaban, the risk of MCRB varies depending on dose. Moreover, subgroup analyses indicate that in the very old (≥ 85) the risk for MCRB events might be increased when using DOACs.Registration: PROSPERO: CRD42020187876.

The role of qualification and quality management in the prescription of antipsychotics and potentially inappropriate medication (PIM) in nursing home residents in Germany: results of the HIOPP-3-iTBX study.

BACKGROUND: Nursing home residents (NHR) show high rates of polypharmacy. The HIOPP-3-iTBX study is the first cRCT on medication optimization in nursing homes (NH) in Germany. The intervention did not result in a reduction of PIM and/or antipsychotics. This analysis looks at structure quality in the HIOPP-3-iTBX study participants. AIMS: Evaluation of structure quality as part of a cluster-randomized controlled intervention study. METHODS: Structure quality in multiprofessional teams from n = 44 NH (n = 44 NH directors, n = 91 family doctors (FD), and n = 52 pharmacies with n = 62 pharmacists) was assessed using self-designed questionnaires at baseline. Main aspects of the questionnaires related to the qualification of participants, quality management, the medication process and size of the facilities. All completed questionnaires were included. number of PIM/antipsychotics was drawn from the baseline medication analysis in 692 NHR. Data were analyzed by descriptive statistics and mixed model logistic regression. RESULTS: The presence of a nurse with one of the additional qualifications pain nurse or Zertifiziertes Curriculum (Zercur) Geriatrie in the participating NH was associated with a lower risk for the prescription of PIM/antipsychotics. No association between any characteristic in the other participants at baseline was observed. CONCLUSIONS AND DISCUSSION: The results support the known role of nursing qualification in the quality and safety of care. Further studies need to look more closely at how use is made of the additional qualifications within the multiprofessional teams. Perspectively, the results can contribute to the development of quality standards in NH in Germany.

Clinical utility of overviews on adverse events of pharmacological interventions.

BACKGROUND: Overviews (i.e., systematic reviews of systematic reviews, meta-reviews, umbrella reviews) are a relatively new type of evidence synthesis. Among others, one reason to conduct an overview is to investigate adverse events (AEs) associated with a healthcare intervention. Overviews aim to provide easily accessible information for healthcare decision-makers including clinicians. We aimed to evaluate the clinical utility of overviews investigating AEs. METHODS: We used a sample of 27 overviews exclusively investigating drug-related adverse events published until 2021 identified in a prior project. We defined clinical utility as the extent to which overviews are perceived to be useful in clinical practice. Each included overview was assigned to one of seven pharmacological experts with expertise on the topic of the overview. The clinical utility and value of these overviews were determined using a self-developed assessment tool. This included four open-ended questions and a ranking of three clinical utility statements completed by clinicians. We calculated frequencies for the ranked clinical utility statements and coded the answers to the open-ended questions using an inductive approach. RESULTS: The overall agreement with the provided statements was high. According to the assessments, 67% of the included overviews generated new knowledge. In 93% of the assessments, the overviews were found to add value to the existing literature. The overviews were rated as more useful than the individual included systematic reviews (SRs) in 85% of the assessments. The answers to the open-ended questions revealed two key aspects of clinical utility in the included overviews. Firstly, it was considered useful that they provide a summary of available evidence (e.g., along with additional assessments, or across different populations, or in different settings that have not been evaluated together in the included SRs). Secondly, it was found useful if overviews conducted a new meta-analysis to answer specific research questions that had not been answered previously. CONCLUSIONS: Overviews on drug-related AEs are considered valuable for clinical practice by clinicians. They can make available evidence on AEs more accessible and provide a comprehensive view of available evidence. As the role of overviews evolves, investigations such as this can identify areas of value.

How and why educational interventions work to increase knowledge of delirium among healthcare professionals in nursing homes: a protocol for a realist review.

BACKGROUND: Delirium is a neuropathological condition that impairs cognitive performance, attention and consciousness and can be potentially life-threatening. Nursing home residents are particularly vulnerable to developing delirium, but research thus far tends to focus on the acute hospital setting. Healthcare professionals (HCPs) working in nursing homes seem to be little aware of delirium. To improve healthcare for affected or at-risk individuals, increasing knowledge among HCPs is highly relevant. Using the realist review method helps to understand how and why an educational intervention for HCPs on delirium in nursing homes works. METHODS AND ANALYSIS: In accordance with the Realist And Meta-narrative Evidence Syntheses: Evolving Standards publication standards for realist syntheses, the review process will include the following five steps: (1) search strategy and literature review; (2) study selection and assessment; (3) data extraction; (4) data synthesis and (5) development of an initial programme theory. The literature search will be conducted in the databases Medline (PubMed), CINAHL (Ebsco), Scopus, Web of Science, GeroLit and Carelit. Additional focuses are on snowballing techniques, hand research and grey literature. Studies of any design will be included to develop the initial programme theory. The literature will be selected by two researchers independently. In addition, the experiences of HCPs from nursing homes will be reflected in group discussions. To this end, Context-Mechanism-Outcome configurations (CMOcs) will be established to develop an initial programme theory. ETHICS AND DISSEMINATION: The results will be disseminated within the scientific community. For this purpose, presentations at scientific conferences as well as publications in peer-reviewed journals are scheduled. In the next step, the CMOcs could serve for the development of a complex educational intervention to increase the knowledge of HCPs on delirium in nursing homes. REGISTRATION DETAILS: This protocol has been registered at Open Science Framework (https://doi.org/10.17605/OSF.IO/HTFU4).

Impact of timing and combination of different BNT162b2 and ChAdOx1-S COVID-19 basic and booster vaccinations on humoral immunogenicity and reactogenicity in adults.

In this single-center observational study with 1,206 participants, we prospectively evaluated SARS-CoV-2-antibodies (anti-S RBD) and vaccine-related adverse drug reactions (ADR) after basic and booster immunization with BNT162b2- and ChAdOx1-S-vaccines in four vaccination protocols: Homologous BNT162b2-schedule with second vaccination at either three or six weeks, homologous ChAdOx1-S-vaccination or heterologous ChAdOx1-S/BNT162b2-schedule, each at 12 weeks. All participants received a BNT162b2 booster. Blood samples for anti-S RBD analysis were obtained multiple times over a period of four weeks to six months after basic vaccination, immediately before, and up to three months after booster vaccination. After basic vaccination, the homologous ChAdOx1-S-group showed the lowest anti-S RBD levels over six months, while the heterologous BNT162b2-ChAdOx1-S-group demonstrated the highest anti-S levels, but failed to reach level of significance compared with the homologous BNT162b2-groups. Antibody levels were higher after an extended vaccination interval with BNT162b2. A BNT162b2 booster increased anti-S-levels 11- to 91-fold in all groups, with the homologous ChAdOx1-S-cohort demonstrated the highest increase in antibody levels. No severe or serious ADR were observed. The findings suggest that a heterologous vaccination schedule or prolonged vaccination interval induces robust humoral immunogenicity with good tolerability. Extending the time to boost-immunization is key to both improving antibody induction and reducing ADR rate.

[Polypharmacy in nursing homes: options to improve drug therapy safety]. / Multimedikation in Einrichtungen der stationären Langzeitpflege: Möglichkeiten einer Verbesserung der Arzneimitteltherapiesicherheit (AMTS).

Patients in need of care usually suffer from multiple chronic conditions and therefore receive a high number of drugs. Polypharmacy involves multiple risks, for example, drug-drug and drug-disease interactions, adverse effects and potentially inappropriate medication (PIM), more hospital admissions, and increased mortality.Residents in long-term care facilities are particularly sensitive to adverse drug reactions because of age-related changes, frailty, and the high prevalence of dementia. Numerous drugs have side effects that lead to sedation, particularly in old age, and increase the risk of falls. In addition, anticholinergic effects negatively modify cognition. These PIMs are frequently prescribed to nursing home residents.The medication process in long-term care facilities is complex and requires numerous coordinated processes. In addition to the correct administration, the nursing staff have other important tasks such as monitoring the effects and potential adverse drug reactions and communicating their observations to the prescribing physicians and home-supplying pharmacists. The nursing staff therefore play a crucial role in the prescription of psychotropic drugs and contribute to the medication quality for nursing home residents. National and international studies indicate that improvements of polypharmacy and drug therapy safety in nursing homes can only be achieved by interprofessional collaboration.

Family Conferences to Facilitate Deprescribing in Older Outpatients With Frailty and With Polypharmacy: The COFRAIL Cluster Randomized Trial.

Importance: For older adults with frailty syndrome, reducing polypharmacy may have utility as a safety-promoting treatment option. Objective: To investigate the effects of family conferences on medication and clinical outcomes in community-dwelling older adults with frailty receiving polypharmacy. Design, Setting, and Participants: This cluster randomized clinical trial was conducted from April 30, 2019, to June 30, 221, at 110 primary care practices in Germany. The study included community-dwelling adults aged 70 years or older with frailty syndrome, daily use of at least 5 different medications, a life expectancy of at least 6 months, and no moderate or severe dementia. Interventions: General practitioners (GPs) in the intervention group received 3 training sessions on family conferences, a deprescribing guideline, and a toolkit with relevant nonpharmacologic interventions. Three GP-led family conferences for shared decision-making involving the participants and family caregivers and/or nursing services were subsequently held per patient at home over a period of 9 months. Patients in the control group received care as usual. Main Outcomes and Measures: The primary outcome was the number of hospitalizations within 12 months, as assessed by nurses during home visits or telephone interviews. Secondary outcomes included the number of medications, the number of European Union list of the number of potentially inappropriate medication (EU[7]-PIM) for older people, and geriatric assessment parameters. Both per-protocol and intention-to-treat analyses were conducted. Results: The baseline assessment included 521 individuals (356 women [68.3%]; mean [SD] age, 83.5 [6.17] years). The intention-to-treat analysis with 510 patients showed no significant difference in the adjusted mean (SD) number of hospitalizations between the intervention group (0.98 [1.72]) and the control group (0.99 [1.53]). In the per-protocol analysis including 385 individuals, the mean (SD) number of medications decreased from 8.98 (3.56) to 8.11 (3.21) at 6 months and to 8.49 (3.63) at 12 months in the intervention group and from 9.24 (3.44) to 9.32 (3.59) at 6 months and to 9.16 (3.42) at 12 months in the control group, with a statistically significant difference at 6 months in the mixed-effect Poisson regression model (P = .001). After 6 months, the mean (SD) number of EU(7)-PIMs was significantly lower in the intervention group (1.30 [1.05]) than in the control group (1.71 [1.25]; P = .04). There was no significant difference in the mean number of EU(7)-PIMs after 12 months. Conclusions and Relevance: In this cluster randomized clinical trial with older adults taking 5 or more medications, the intervention consisting of GP-led family conferences did not achieve sustainable effects in reducing the number of hospitalizations or the number of medications and EU(7)-PIMs after 12 months. Trial Registration: German Clinical Trials Register: DRKS00015055.

Potentially Inadequate Medications in the Elderly: PRISCUS 2.0.

BACKGROUND: The term potentially inadequate medication (PIM) is used to describe substances that may be unsuitable for use inthe elderly and should be avoided. The PRISCUS list, published in 2010, was the first catalog of PIM designed for the Germandrug market to become adopted in practice. While 24% of German patients aged ≥ 65 years were prescribed at least one PIMper year in 2009, the proportion in 2019 was only 14.5%. METHODS: In a three-round Delphi process, experts from clinical practice and research evaluated whether selected substancesare PIM for the elderly. The participants were provided with dedicated literature including systematic reviews carried out for theparticular purposes of this project. RESULTS: Fifty-nine persons took part in the Delphi process and, in addition, contributed comments and therapeutic alternatives.Altogether, 187 substances were classed as PIM. One hundred thirty-three of the substances now listed were not in the originalPRISCUS list: these include some oral antidiabetics, all of the selective COX-2 inhibitors, and moderately long acting benzodiazepinessuch as oxazepam. For some other substances, e.g., proton pump inhibitors (PPI), the advisability of treatment formore than 8 weeks was considered as potentially inappropriate, as was the use of ibuprofen in doses >1200 mg/day and formore than 1 week without PPI. Risperidone for more than 6 weeks is also PIM. CONCLUSION: The new, greatly extended PRISCUS list must now be validated in epidemiological and prospective studies and itspracticability in routine daily use must be verified.

Development of a deprescribing manual for frail older people for use in the COFRAIL study and in primary care.

Introduction: Many older adults are affected by multimorbidity and subsequent polypharmacy which is associated with adverse outcomes. This is especially relevant for frail older patients. Polypharmacy may be reduced via deprescribing. As part of the complex intervention in the COFRAIL study, we developed a deprescribing manual to be used by general practitioners (GPs) in family conferences, in which GPs, patients and caregivers jointly discuss treatments. Methods: We selected indications with a high prevalence in older adults in primary care (e.g. diabetes mellitus, hypertension) and conducted a literature search to identify deprescribing criteria for these indications. We additionally reviewed clinical practice guidelines. Based on the extracted information, we created a deprescribing manual which was then piloted in an expert workshop and in family conferences with volunteer patients according to the inclusion and exclusion criteria of the study protocol. Results: Initially, 13 indications/topics were selected. The literature search identified deprescribing guides, reviews and clinical trials as well as lists of potentially inappropriate medication and systematic reviews on the risk and benefits of specific drugs and drug classes in older patients. After piloting and revisions, the deprescribing manual now covers 11 indications/topics. In each chapter, patient- and medication-related deprescribing criteria, monitoring and communication strategies, and information about concerns related to the use of specific drugs in older patients are provided. Discussion: We found varying deprescribing strategies in the literature, which we consolidated in our deprescribing manual. Whether this approach leads to successful deprescribing in family conferences is being investigated in the cluster-randomised controlled COFRAIL study. Plain Language Summary: Development of a manual to help doctors to identify which medications can be withdrawn Many older adults suffer from chronic diseases and take multiple medications concurrently. This can lead to side effects and other undesired events. We developed a manual to help doctors identify which medications can be withdrawn, so that they can discuss this with their patients. This manual was used in the COFRAIL study where doctors, patients and caregivers met in family conferences to discuss their preferences and decide together how future treatments should be handled. The manual contains information on common medications, symptoms and diseases in older patients such as diabetes and high blood pressure. Before the manual was used in the study, it was tested by volunteer patients and their doctors and caregivers to make sure that it is user-friendly.

Assessing the quality of evidence on safety: specifications for application and suggestions for adaptions of the GRADE-criteria in the context of preparing a list of potentially inappropriate medications for older adults.

BACKGROUND: Systematic reviews that synthesize safety outcomes pose challenges (e.g. rare events), which raise questions for grading the strength of the body of evidence. This is maybe one reason why in many potentially inappropriate medication (PIM) lists the recommendations are not based on formalized systems for assessing the quality of the body of evidence such as GRADE. In this contribution, we describe specifications and suggest adaptions of the GRADE system for grading the quality of evidence on safety outcomes, which were developed in the context of preparing a PIM-list, namely PRISCUS. METHODS: We systematically assessed each of the five GRADE domains for rating-down (study limitations, imprecision, inconsistency, indirectness, publication bias) and the criteria for rating-up, considering if special considerations or revisions of the original approach were indicated. The result was gathered in a written document and discussed in a group-meeting of five members with various background until consensus. Subsequently, we performed a proof-of-concept application using a convenience sample of systematic reviews and applied the approach to systematic reviews on 19 different clinical questions. RESULTS: We describe specifications and suggest adaptions for the criteria "study limitations", imprecision, "publication bias" and "rating-up for large effect". In addition, we suggest a new criterion to account for data from subgroup-analyses. The proof-of-concept application did not reveal a need for further revision and thus we used the approach for the systematic reviews that were prepared for the PRISCUS-list. We assessed 51 outcomes. Each of the proposed adaptions was applied. There were neither an excessive number of low and very low ratings, nor an excessive number of high ratings, but the different methodological quality of the safety outcomes appeared to be well reflected. CONCLUSION: The suggestions appear to have the potential to overcome some of the challenges when grading the methodological quality of harms and thus may be helpful for producers of evidence syntheses considering safety.

A review found heterogeneous approaches and insufficient reporting in overviews on adverse events.

OBJECTIVES: To investigate reporting and methodological characteristics of overviews on adverse (drug-associated) events (AEs) of pharmacological interventions. STUDY DESIGN AND SETTING: We searched MEDLINE, Embase, Epistemonikos, and the Cochrane Database of Systematic Reviews from inception to May 17, 2021 for overviews exclusively investigating AEs of pharmacological interventions. We extracted general, reporting, and methodological characteristics and analyzed data descriptively. RESULTS: We included 27 overviews, 70% of which were published in 2016 or later. The most common nomenclature in the title was "overview" (56%), followed by "umbrella review" (26%). The median number of included systematic reviews (SRs) in each overview was 15 (interquartile range 7-34). Study selection methods were reported in 52%, methods for data extraction in 67%, and methods for critical appraisal in 63% of overviews. An assessment of methodological quality of included SRs was performed in 70% of overviews. Only 22% of overviews reported strategies for dealing with overlapping SRs. An assessment of the certainty of the evidence was performed in 33% of overviews. CONCLUSION: To ensure methodological rigor, authors of overviews on AEs should follow available guidance for the conduct and reporting of overviews.

HIOPP-6 - a pilot study on the evaluation of an electronic tool to assess and reduce the complexity of drug treatment considering patients' views.

BACKGROUND: A complex drug treatment might pose a barrier to safe and reliable drug administration for patients. Therefore, a novel tool automatically analyzes structured medication data for factors possibly contributing to complexity and subsequently personalizes the results by evaluating the relevance of each identified factor for the patient by means of key questions. Hence, tailor-made optimization measures can be proposed. METHODS: In this controlled, prospective, exploratory trial the tool was evaluated with nine general practitioners (GP) in three study groups: In the two intervention groups the tool was applied in a version with (GI_with) and a version without (GI_without) integrated key questions for the personalization of the analysis, while the control group (GC) did not use any tools (routine care). Four to eight weeks after application of the tool, the benefits of the optimization measures to reduce or mitigate complexity of drug treatment were evaluated from the patient perspective. RESULTS: A total of 126 patients regularly using more than five drugs could be included for analysis. GP suggested 117 optimization measures in GI_with, 83 in GI_without, and 2 in GC. Patients in GI_with were more likely to rate an optimization measure as helpful than patients in GI_without (IRR: 3.5; 95% CI: 1.2-10.3). Thereby, the number of optimization measures recommended by the GP had no significant influence (P = 0.167). CONCLUSIONS: The study suggests that an automated analysis considering patient perspectives results in more helpful optimization measures than an automated analysis alone - a result which should be further assessed in confirmatory studies. TRIAL REGISTRATION: The trial was registered retrospectively at the German Clinical Trials register under DRKS-ID DRKS00025257 (17/05/2021).

Prevalence and patient-rated relevance of complexity factors in medication regimens of community-dwelling patients with polypharmacy.

PURPOSE: To describe the prevalence of complexity factors in the medication regimens of community-dwelling patients with more than five drugs and to evaluate the relevance of these factors for individual patients. METHODS: Data were derived from the HIOPP-6 trial, a controlled study conducted in 9 general practices which evaluated an electronic tool to detect and reduce complexity of drug treatment. The prevalence of complexity factors was based on the results of the automated analysis of 139 patients' medication data. The relevance assessment was based on the patients' rating of each factor in an interview (48 patients included for analysis). RESULTS: A median of 5 (range 0-21) complexity factors per medication regimen were detected and at least one factor was observed in 131 of 139 patients. Almost half of these patients found no complexity factor in their medication regimen relevant. CONCLUSION: In most medication regimens, complexity factors could be identified automatically, yet less than 15% of factors were indeed relevant for patients as judged by themselves. When assessing complexity of medication regimens, one should especially consider factors that are both particularly frequent and often challenging for patients, such as use of inhalers or tablet splitting. TRIAL REGISTRATION: The HIOPP-6 trial was registered retrospectively on May 17, 2021, in the German Clinical Trials register under DRKS-ID DRKS00025257.

Effect of gender, age and vaccine on reactogenicity and incapacity to work after COVID-19 vaccination: a survey among health care workers.

BACKGROUND: The aim of our study was to assess the impact the impact of gender and age on reactogenicity to three COVID-19 vaccine products: Biontech/Pfizer (BNT162b2), Moderna (mRNA-1273) and AstraZeneca (ChAdOx). Additional analyses focused on the reduction in working capacity after vaccination and the influence of the time of day when vaccines were administered. METHODS: We conducted a survey on COVID-19 vaccinations and eventual reactions among 73,000 employees of 89 hospitals of the Helios Group. On May 19th, 2021 all employees received an email, inviting all employees who received at least 1 dose of a COVID-19 to participate using an attached link. Additionally, the invitation was posted in the group's intranet page. Participation was voluntary and non-traceable. The survey was closed on June 21st, 2021. RESULTS: 8375 participants reported on 16,727 vaccinations. Reactogenicity was reported after 74.6% of COVID-19 vaccinations. After 23.0% vaccinations the capacity to work was affected. ChAdOx induced impairing reactogenicity mainly after the prime vaccination (70.5%), while mRNA-1273 led to more pronounced reactions after the second dose (71.6%). Heterologous prime-booster vaccinations with ChAdOx followed by either mRNA-1273 or BNT162b2 were associated with the highest risk for impairment (81.4%). Multivariable analyses identified the factors older age, male gender and vaccine BNT162b as independently associated with lower odds ratio for both, impairing reactogenicity and incapacity to work. In the comparison of vaccine schedules, the heterologous combination ChAdOx + BNT162b or mRNA-1273 was associated with the highest and the homologue prime-booster vaccination with BNT162b with the lowest odds ratios. The time of vaccination had no significant influence. CONCLUSIONS: Around 75% of the COVID-19 vaccinations led to reactogenicity and nearly 25% of them led to one or more days of work loss. Major risk factors were female gender, younger age and the administration of a vaccine other than BNT162b2. When vaccinating a large part of a workforce against COVID-19, especially in professions with a higher proportion of young and women such as health care, employers and employees must be prepared for a noticeable amount of absenteeism. Assuming vaccine effectiveness to be equivalent across the vaccine combinations, to minimize reactogenicity, employees at risk should receive a homologous prime-booster immunisation with BNT162b2. TRIAL REGISTRATION: The study was approved by the Ethic Committee of the Aerztekammer Berlin on May 27th, 2021 (Eth-37/21) and registered in the German Clinical Trials Register (DRKS 00025745). The study was supported by the Helios research grant HCRI-ID 2021-0272.