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.

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.

Safety of dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.

REGISTRATION: PROSPERO: CRD42020210645. INTRODUCTION: We aimed to assess the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors in older patients with type 2 diabetes with inadequate glycaemic control. METHODS: We included randomized controlled trials (RCTs) in older (⩾65 years) patients with type 2 diabetes. The intervention group was randomized to treatment with any DPP-4 inhibitors. A systematic search in MEDLINE and Embase was performed in December 2020. For assessing the risk of bias, RoB 2 tool was applied. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. We pooled outcomes using random effects meta-analyses. RESULTS: We identified 16 RCTs that included 19,317 patients with a mean age of greater than 70 years. The mean HbA1c level ranged between 7.1 and 10.0 g/dl. Adding DPP-4 inhibitors to standard care alone may increase mortality slightly [risk ratio (RR) 1.04; 95% confidence interval (CI) 0.89-1.21]. Adding DPP-4 inhibitors to standard care increases the risk for hypoglycaemia (RR 1.08; 95% CI 1.01-1.16), but difference in overall adverse events is negligible. DPP-4 inhibitors added to standard care may reduce mortality compared with sulfonylureas (RR 0.88; 95% CI 0.75-1.04). DPP-4 inhibitors probably reduce the risk for hypoglycaemia compared with sulfonylureas (magnitude of effect not quantifiable because of heterogeneity) but difference in overall adverse events is negligible. There is insufficient evidence on hospitalizations, falls, fractures, renal impairment and pancreatitis. CONCLUSION: There is no evidence that DPP-4 inhibitors in addition to standard care decrease mortality but DPP-4 inhibitors increase hypoglycaemia risk. Second-line therapy in older patients should be considered cautiously even in drugs with a good safety profile such as DPP-4 inhibitors. In case second-line treatment is necessary, DPP-4 inhibitors appear to be preferable to sulfonylureas. PLAIN LANGUAGE SUMMARY: Safety of dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetes: Introduction:: We performed the review to assess the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors in older type 2 diabetes patients with blood sugar outside the normal level.Methods:: To answer the question, we searched various electronic databases. We included studies in older (⩾65 years) patients with type 2 diabetes that assessed the safety of DPP-4 inhibitors. The data from the different studies were quantitatively summarized using statistical methods. We assessed the quality of the data to judge the certainty of the findings.Results:: We identified 16 studies that included 19,317 patients with a mean age greater than 70 years. The average blood sugar level of patients in the included studies was slightly or moderately increased. Adding DPP-4 inhibitors to standard care alone may increase mortality slightly. Adding DPP-4 inhibitors to standard care increases the risk for hypoglycaemia, but difference in overall adverse events is negligible. DPP-4 inhibitors added to standard care may reduce mortality compared with sulfonylureas. DPP-4s probably reduce the risk of hypoglycaemia compared with sulfonylureas (magnitude of effect not quantifiable because of heterogeneity) but difference in overall adverse events is negligible. There is insufficient evidence on hospitalizations, falls, fractures, renal impairment and pancreatitis.Conclusion:: There is no evidence that DPP-4 inhibitors in addition to standard care decrease mortality but DPP-4 inhibitors increase the risk that blood sugar falls below normal. Adding DPP-4 inhibitorss to standard care in older patients should be considered cautiously even in drugs with a good safety profile such as DPP-4 inhibitors. In case additional treatment is necessary, DPP-4 inhibitors appear to be preferable to sulfonylureas.

Family conferences and shared prioritisation to improve patient safety in the frail elderly (COFRAIL): study protocol of a cluster randomised intervention trial in primary care.

BACKGROUND: Frailty in elderly patients is associated with an increased risk of poor health outcomes, including falls, delirium, malnutrition, hospitalisation, and mortality. Because polypharmacy is recognised as a possible major contributor to the pathogenesis of geriatric frailty, reducing inappropriate medication exposure is supposed to be a promising approach to improve health-related quality of life and prevent adverse outcomes. A major challenge for the process of deprescribing of inappropriate polypharmacy is to improve the communication between general practitioner (GPs), patient and family carer. This study investigates the effects of a complex intervention in frail elderly patients with polypharmacy living at home. METHODS: This is a cluster randomised controlled trial including 136 GPs and 676 patients. Patients with a positive clinical screening for frailty are eligible if they are aged 70 years or older, receiving family or professional nursing care at home, and taking in five or more drugs per day. Exclusion criteria are higher grade of dementia and life expectancy of 6 months or less. The GPs of the intervention group receive an educational training promoting a deprescribing guideline and providing information on how to conduct a family conference focussing on prioritisation of treatment goals concerning drug therapy. During the 1-year intervention, GPs are expected to perform a total of three family conferences, each including a structured medication review with patients and their family carers. GPs of the control group will receive no training and will deliver care as usual. Geriatric assessment of all patients will be performed by study nurses during home visits at baseline and after 6 and 12 months. The primary outcome is the hospitalisation rate during the observation period of 12 months. Secondary outcomes are number and appropriateness of medications, mobility, weakness, cognition, depressive disorder, health-related quality of life, activities of daily living, weight, and costs of health care use. DISCUSSION: This study will provide evidence for a pragmatic co-operative and patient-centred educational intervention using family conferences to improve patient safety in frail elderly patients with polypharmacy. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00015055 (WHO International Clinical Trials Registry Platform [ICTRP]). Registered on 6 February 2019.