Publications by authors named "Nicolas Rodondi"

345 Publications

Prevalence of drug-drug interactions in older people before and after hospital admission: analysis from the OPERAM trial.

BMC Geriatr 2021 10 18;21(1):571. Epub 2021 Oct 18.

Clinical Pharmacy Research Group, Université Catholique de Louvain, Louvain Drug Research Institute, Avenue Mounier, 73 bte B1.73.06, 1200 Woluwe-Saint-Lambert, Brussels, Belgium.

Background: Drug-drug interactions (DDIs) are highly prevalent in older patients but little is known about prevalence of DDIs over time. Our main objective was to assess changes in the prevalence and characteristics of drug-drug interactions (DDIs) during a one-year period after hospital admission in older people, and associated risk factors.

Methods: We conducted a sub-study of the European OPERAM trial (OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people), which assessed the effects of a structured medication review (experimental arm) compared to usual care (control arm) on reducing drug-related hospital readmissions. All OPERAM patients (≥70 years, with multimorbidity and polypharmacy, hospitalized in four centers in Bern, Brussels, Cork and Utrecht between December 2016 and October 2018, followed over 1 year) who were alive at hospital discharge and had full medication data during the index hospitalization (at baseline i.e., enrolment at admission, and at discharge) were included. DDIs were assessed using an international consensus list of potentially clinically significant DDIs in older people. The point-prevalence of DDIs was evaluated at baseline, discharge, and at 2, 6 and 12 months after hospitalization. Logistic regression models were performed to assess independent variables associated with changes in DDIs 2 months after baseline.

Results: Of the 1950 patients (median age 79 years) included, 1045 (54%) had at least one potentially clinically significant DDI at baseline; point-prevalence rates were 58, 57, 56 and 57% at discharge, and 2, 6 and 12 months, respectively. The prevalence increased significantly from baseline to discharge (P < .001 [significant only in the control group]), then remained stable over time (P for trend .31). The five most common DDIs -all pharmacodynamic in nature- accounted for 80% of all DDIs and involved drugs that affect potassium concentrations, centrally-acting drugs and antithrombotics. At 2 months, DDIs had increased in 459 (27%) patients and decreased in 331 (19%). The main factor predictive of a change in the prevalence of DDIs was hyperpolypharmacy (≥10 medications).

Conclusions: DDIs were very common; their prevalence increased during hospitalization and tended to remain stable thereafter. Medication review may help control this increase and minimize the risk of adverse drug events.
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http://dx.doi.org/10.1186/s12877-021-02532-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524798PMC
October 2021

How blood pressure predicts frailty transitions in older adults in a population-based cohort study: a multi-state transition model.

Int J Epidemiol 2021 Oct 15. Epub 2021 Oct 15.

Population Health Laboratory (#PopHealthLab), University of Fribourg, Fribourg, Switzerland.

Background: Low blood pressure (BP) is associated with frailty in older adults. Our aim was to explore how BP predicts transitions between frailty states.

Methods: We used data from the Lausanne cohort Lc65+, a population-based cohort of older adults randomly drawn from a population registry in Switzerland, in 2004, 2009 and 2014. BP was measured using a clinically validated oscillometric automated device and frailty was defined using Fried's phenotype, every 3 years. We used an illness-death discrete multi-state Markov model to estimate hazard ratios of forward and backward transitions between frailty states (outcome) in relation to BP categories (predictor of interest) with adjustment for sex, age and antihypertensive medication (other predictors).

Results: Among 4200 participants aged 65-70 years (58% female) at baseline, 70% were non-frail, 27% pre-frail and 2.0% frail. Over an average follow-up of 5.8 years, 2422 transitions were observed, with 1575 (65%) forward and 847 (35%) backward. Compared with systolic BP (SBP) <130 mmHg, the hazard ratio (95% confidence interval) of the transition from non-frail to pre-frail was 0.86 (0.74 to 1.00) for SBP 130-150 mmHg, and 0.89 (0.74 to 1.06) for SBP ≥150 mmHg. Compared with SBP <130 mmHg, the hazard ratio of the transition from pre-frail to frail was 0.71 (0.50 to 1.01) for SBP 130-150 mmHg, and 0.90 (0.62 to 1.32) for SBP ≥150 mmHg. Diastolic BP was a weaker predictor of forward transitions.

Conclusions: BP categories had no strong relationship with either forward transitions or backward transitions in frailty states. If our findings are confirmed with greater precision and assuming a causal relationship, they would suggest that there is no well-defined optimal BP level to prevent frailty among older adults.
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http://dx.doi.org/10.1093/ije/dyab210DOI Listing
October 2021

Cysteine-Rich Angiogenic Inducer 61 Improves Prognostic Accuracy of GRACE (Global Registry of Acute Coronary Events) 2.0 Risk Score in Patients With Acute Coronary Syndromes.

J Am Heart Assoc 2021 Oct 8;10(20):e020488. Epub 2021 Oct 8.

Department of Cardiology University Heart CenterUniversity Hospital Zurich Zurich Switzerland.

Background It remains unclear whether the novel biomarker cysteine-rich angiogenic inducer 61 (CCN1) adds incremental prognostic value to the GRACE 2.0 (Global Registry of Acute Coronary Events) risk score and biomarkers high-sensitivity Troponin T, hsCRP (high-sensitivity C-reactive protein), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in patients with acute coronary syndromes. Methods and Results Patients referred for coronary angiography with a primary diagnosis of acute coronary syndromes were enrolled in the Special Program University Medicine - Acute Coronary Syndromes and Inflammation cohort. The primary/secondary end points were 30-day/1-year all-cause mortality and the composite of all-cause mortality or myocardial infarction as used in the GRACE risk score. Associations between biomarkers and outcome were assessed using log-transformed biomarker values and the GRACE risk score (versions 1.0 and 2.0). The incremental value of CCN1 beyond a reference model was assessed using Harrell's C-statistics calculated from a Cox proportional-hazard model. The value of the C-statistics was derived from a likelihood ratio test. Among 2168 patients recruited, 1732 could be analyzed. CCN1 was the strongest single predictor of all-cause mortality at 30 days (hazard ratio [HR], 1.77 [1.31, 2.40]) and 1 year (HR, 1.81 [1.47, 2.22]). Adding CCN1 alone to the GRACE 2.0 risk score improved C-statistics for prognostic accuracy of all-cause mortality at 30 days (0.87-0.88) and 1 year (0.81-0.82) and when combined with high-sensitivity Troponin T, hsCRP, NT-proBNP for 30 days (0.87-0.91), and for 1-year follow-up (0.81-0.84). CCN1 also increased the prognostic value for the composite of all-cause mortality or myocardial infarction. Conclusions CCN1 predicts adverse outcomes in patients with acute coronary syndromes adding incremental information to the GRACE risk score, suggesting distinct underlying molecular mechanisms. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01000701.
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http://dx.doi.org/10.1161/JAHA.120.020488DOI Listing
October 2021

CCN family member 1 (CCN1) is an early marker of infarct size and left ventricular dysfunction in STEMI patients.

Atherosclerosis 2021 10 17;335:77-83. Epub 2021 Sep 17.

Department of Cardiology, Lausanne University Center Hospital, Lausanne, Switzerland. Electronic address:

Background And Aims: CCN family member 1 (CCN1) has recently been proposed as a novel biomarker of myocardial injury, improving prediction of 30-day and one-year mortality following acute coronary syndromes. Among ST-elevation myocardial infarction (STEMI) patients, we evaluated the utility of CCN1 measured immediately before primary percutaneous coronary intervention (PPCI) as a predictor of two earlier endpoints: final myocardial infarct size and post-infarction left ventricular ejection fraction (LVEF). Furthermore, we evaluated the impact of CCN1 on the discriminatory power of the CADILLAC score.

Methods: STEMI patients were obtained from the SPUM-ACS cohort. Serum CCN1 was measured prior to PPCI. Linear regression assessed the association between CCN1, peak creatinine kinase (CK), and post-infarction LVEF. Cox models assessed an association between CCN1 and 30-day all-cause mortality.

Results: CCN1 was measured in 989 patients with a median value of 706.2 ng/l (IQR 434.3-1319.6). A significant correlation between CCN1, myocardial infarct size (peak CK) and LVEF was observed in univariate and multivariate analysis (both p < 0.001). Even among patients with normal classical cardiac biomarker levels at the time of PPCI, CCN1 correlated significantly with final infarct size. CCN1 significantly improved prediction of 30-day all-cause mortality by the CADILLAC score (C-index 0.864, likelihood-ratio chi-square test statistic 6.331, p = 0.012; IDI 0.026, p= 0.050).

Conclusions: Compared with classical cardiac biomarkers, CCN1 is potentially the earliest predictor of final myocardial infarct size and post-infarction LVEF. CCN1 improved the discriminatory capacity of the CADILLAC score suggesting a potential role in the very-early risk stratification of STEMI patients.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.09.019DOI Listing
October 2021

Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.

JAMA Intern Med 2021 Sep 7. Epub 2021 Sep 7.

Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea.

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings.

Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia.

Design, Setting, And Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021.

Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values.

Main Outcomes And Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated.

Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia.

Conclusions And Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.
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http://dx.doi.org/10.1001/jamainternmed.2021.5078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424529PMC
September 2021

Development and validation of a life expectancy estimator for multimorbid older adults: a cohort study protocol.

BMJ Open 2021 08 25;11(8):e048168. Epub 2021 Aug 25.

Population Health Laboratory (#PopHealthLab), University of Fribourg, Fribourg, Switzerland.

Background: Older multimorbid adults have a high risk of mortality and a short life expectancy (LE). Providing high-value care and avoiding care overuse, including of preventive care, is a serious challenge among multimorbid patients. While guidelines recommend to tailor preventive care according to the estimated LE, there is no tool to estimate LE in this specific population. Our objective is therefore to develop an LE estimator for older multimorbid adults by transforming a mortality prognostic index, which will be developed and internally validated in a prospective cohort.

Methods And Analysis: We will analyse data of the Optimising Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older People cohort study in Bern, Switzerland. 822 participants were included at hospitalisation with age of 70 years or older, multimorbidity (three or more chronic medical conditions) and polypharmacy (use of five drugs or more for 30 days). All-cause mortality will be assessed during 3 years of follow-up. We will apply a flexible parametric survival model with backward stepwise selection to identify the mortality risk predictors. The model will be internally validated using bootstrapping techniques. We will derive a point-based risk score from the regression coefficients. We will transform the 3-year mortality prognostic index into an LE estimator using the Gompertz survival function. We will perform a qualitative assessment of the clinical usability of the LE estimator and its application. We will conduct the development and validation of the mortality prognostic index following the Prognosis Research Strategy (PROGRESS) framework and report it following the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) statement.

Ethics And Dissemination: Written informed consent by patients themselves or, in the case of cognitive impairment, by a legal representative, was required before enrolment. The local ethics committee (Kantonale Ethikkommission Bern) has approved the study. We plan to publish the results in peer-reviewed journals and present them at national and international conferences.
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http://dx.doi.org/10.1136/bmjopen-2020-048168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388271PMC
August 2021

Tolerability of statin-based management of patients with a history of statin-associated muscle symptoms: protocol for a systematic review.

BMJ Open 2021 08 3;11(8):e052341. Epub 2021 Aug 3.

Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland

Introduction: Statin-associated muscle symptoms (SAMSs) are a major clinical issue in the primary and secondary prevention of cardiovascular events. Current guidelines advise various approaches mainly based on expert opinion. We will lead a systematic review and meta-analysis to explore the tolerability and acceptability and effectiveness of statin-based therapy management of patients with a history of SAMS. We aim to provide evidence on the tolerability and different strategies of statin-based management of patients with a history of SAMS.

Methods And Analysis: We will conduct a systematic review of randomised controlled trials (RCTs) and non-randomised studies with a control group. We will search in Data sources MEDLINE, EMBASE, Cochrane Central Register of Controlled Clinical Trials, Scopus, Clinicaltrials.gov and Proquest from inception until April 2021. Two independent reviewers will carry out the study selection based on eligibility criteria. We will extract data following a standard data collection form. The reviewers will use the Cochrane Collaboration's tools and Newcastle-Ottawa Scale to appraise the study risk of bias. Our primary outcome will be tolerability and our secondary outcomes will be acceptability and effectiveness. We will conduct a qualitative analysis of all included studies. In addition, if sufficient and homogeneous data are available, we will conduct quantitative analysis. We will synthesise dichotomous data using OR with 95% CI and continuous outcomes by using mean difference or standardised mean difference (with 95% CI). We will determine heterogeneity visually with forest plots and quantitatively with I and Q-test. We will summarise the confidence in the quantitative estimate by using Grading of Recommendations Assessment, Development and Evaluation approach.

Ethics And Dissemination: As a systematic review of literature without collection of new clinical data, there will be no requirement for ethical approval. We will disseminate findings through peer-reviewed publications.

Prospero Registration Number: CRD42020202619.
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http://dx.doi.org/10.1136/bmjopen-2021-052341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336172PMC
August 2021

Barriers and potential solutions in the recruitment and retention of older patients in clinical trials-lessons learned from six large multicentre randomized controlled trials.

Age Ageing 2021 Jul 29. Epub 2021 Jul 29.

Department of Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, Berlin, Germany.

Background: older people remain underrepresented in clinical trials, and evidence generated in younger populations cannot always be generalized to older patients.

Objective: to identify key barriers and to discuss solutions to specific issues affecting recruitment and retention of older participants in clinical trials based on experience gained from six current European randomised controlled trials (RCTs) focusing on older people.

Methods: a multidisciplinary group of experts including representatives of the six RCTs held two networking conferences and compiled lists of potential barriers and solutions. Every item was subsequently allocated points by each study team according to how important it was perceived to be for their RCTs.

Results: the six RCTs enrolled 7,612 older patients. Key barriers to recruitment were impaired health status, comorbidities and diverse health beliefs including priorities within different cultural systems. All trials had to increase the number of recruitment sites. Other measures felt to be effective included the provision of extra time, communication training for the study staff and a re-design of patient information. Key barriers for retention included the presence of severe comorbidities and the occurrence of adverse events. Long study duration, frequent study visits and difficulties accessing the study site were also mentioned. Solutions felt to be effective included spending more time maintaining close contact with the participants, appropriate measures to show appreciation and reimbursement of travel arrangements.

Conclusion: recruitment and retention of older patients in trials requires special recognition and a targeted approach. Our results provide scientifically-based practical recommendations for optimizing future studies in this population.
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http://dx.doi.org/10.1093/ageing/afab147DOI Listing
July 2021

Interventions for preventing falls and fall-related fractures in community-dwelling older adults: A systematic review and network meta-analysis.

J Am Geriatr Soc 2021 Oct 28;69(10):2973-2984. Epub 2021 Jul 28.

Department of Geriatric Medicine, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

Objective: To compare the effectiveness of single, multiple, and multifactorial interventions to prevent falls and fall-related fractures in community-dwelling older persons.

Methods: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) evaluating the effectiveness of fall prevention interventions in community-dwelling adults aged ≥65 years, from inception until February 27, 2019. Two large RCTs (published in 2020 after the search closed) were included in post hoc analyses. Pairwise meta-analysis and network meta-analysis (NMA) were conducted.

Results: NMA including 192 studies revealed that the following single interventions, compared with usual care, were associated with reductions in number of fallers: exercise (risk ratio [RR] 0.83; 95% confidence interval [CI] 0.77-0.89) and quality improvement strategies (e.g., patient education) (RR 0.90; 95% CI 0.83-0.98). Exercise as a single intervention was associated with a reduction in falls rate (RR 0.79; 95% CI 0.73-0.86). Common components of multiple interventions significantly associated with a reduction in number of fallers and falls rate were exercise, assistive technology, environmental assessment and modifications, quality improvement strategies, and basic falls risk assessment (e.g., medication review). Multifactorial interventions were associated with a reduction in falls rate (RR 0.87; 95% CI 0.80-0.95), but not with a reduction in number of fallers (RR 0.95; 95% CI 0.89-1.01). The following single interventions, compared with usual care, were associated with reductions in number of fall-related fractures: basic falls risk assessment (RR 0.60; 95% CI 0.39-0.94) and exercise (RR 0.62; 95% CI 0.42-0.90).

Conclusions: In keeping with Tricco et al. (2017), several single and multiple fall prevention interventions are associated with fewer falls. In addition to Tricco, we observe a benefit at the NMA-level of some single interventions on preventing fall-related fractures.
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http://dx.doi.org/10.1111/jgs.17375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518387PMC
October 2021

High regional variation in prostate surgery for benign prostatic hyperplasia in Switzerland.

PLoS One 2021 22;16(7):e0254143. Epub 2021 Jul 22.

Department of General Internal Medicine, Bern University Hospital, Inselspital, University of Bern, Bern, Switzerland.

Background: Among various treatment options for benign prostatic hyperplasia (BPH), surgical therapy is the most invasive. As Switzerland has the highest transurethral prostatectomy rate among OECD countries, we assessed the regional variation in prostate surgery for BPH and explored potential determinants of variation.

Methods: We conducted a population-based analysis using discharge data for men aged ≥40 years with transurethral or simple prostatectomy from all Swiss hospitals during 2013-2018. After excluding patients with genitourinary/prostate cancer, we derived hospital service areas (HSAs) by analyzing patient flows. We calculated age-standardized mean procedure rates and variation indices (extremal quotient [EQ] and systematic component of variation [SCV]). We estimated the reduction in variance across HSAs of prostatectomy rates in multilevel regression models, with incremental adjustment for age, regional cultural and socioeconomic factors, disease burden, density of urologists, and the time since urologists' graduation.

Results: Overall, 44,253 prostatectomies (42,710 transurethral and 1543 simple) from 44 HSAs were analyzed. The mean age-standardized prostate surgery rate was 314 (range 166-500) per 100,000 men aged ≥40 years per year. The EQ was 3.01 and the SCV 5.53, indicating a high regional variation. In multivariate models, men aged 75-79 years had an 11.6-fold higher prostatectomy rate than those aged 50-54 years. French/Italian language areas had a 21% lower rate than Swiss German speaking areas. Socioeconomic factors, disease burden, and density of urologist/time since graduation were not associated with prostatectomy rates. After full adjustment, 80% of the variance in prostate surgery across HSAs remained unexplained.

Conclusion: We found a remarkably high regional variation in prostate surgery rates for BPH within Switzerland.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254143PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297757PMC
July 2021

Optimizing Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older Adults (OPERAM): cluster randomised controlled trial.

BMJ 2021 07 13;374:n1585. Epub 2021 Jul 13.

Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Objective: To examine the effect of optimising drug treatment on drug related hospital admissions in older adults with multimorbidity and polypharmacy admitted to hospital.

Design: Cluster randomised controlled trial.

Setting: 110 clusters of inpatient wards within university based hospitals in four European countries (Switzerland, Netherlands, Belgium, and Republic of Ireland) defined by attending hospital doctors.

Participants: 2008 older adults (≥70 years) with multimorbidity (≥3 chronic conditions) and polypharmacy (≥5 drugs used long term).

Intervention: Clinical staff clusters were randomised to usual care or a structured pharmacotherapy optimisation intervention performed at the individual level jointly by a doctor and a pharmacist, with the support of a clinical decision software system deploying the screening tool of older person's prescriptions and screening tool to alert to the right treatment (STOPP/START) criteria to identify potentially inappropriate prescribing.

Main Outcome Measure: Primary outcome was first drug related hospital admission within 12 months.

Results: 2008 older adults (median nine drugs) were randomised and enrolled in 54 intervention clusters (963 participants) and 56 control clusters (1045 participants) receiving usual care. In the intervention arm, 86.1% of participants (n=789) had inappropriate prescribing, with a mean of 2.75 (SD 2.24) STOPP/START recommendations for each participant. 62.2% (n=491) had ≥1 recommendation successfully implemented at two months, predominantly discontinuation of potentially inappropriate drugs. In the intervention group, 211 participants (21.9%) experienced a first drug related hospital admission compared with 234 (22.4%) in the control group. In the intention-to-treat analysis censored for death as competing event (n=375, 18.7%), the hazard ratio for first drug related hospital admission was 0.95 (95% confidence interval 0.77 to 1.17). In the per protocol analysis, the hazard ratio for a drug related hospital admission was 0.91 (0.69 to 1.19). The hazard ratio for first fall was 0.96 (0.79 to 1.15; 237 263 first falls) and for death was 0.90 (0.71 to 1.13; 172 203 deaths).

Conclusions: Inappropriate prescribing was common in older adults with multimorbidity and polypharmacy admitted to hospital and was reduced through an intervention to optimise pharmacotherapy, but without effect on drug related hospital admissions. Additional efforts are needed to identify pharmacotherapy optimisation interventions that reduce inappropriate prescribing and improve patient outcomes.

Trial Registration: ClinicalTrials.gov NCT02986425.
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http://dx.doi.org/10.1136/bmj.n1585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276068PMC
July 2021

Subclinical thyroid function and cardiovascular events in patients with atrial fibrillation.

Eur J Endocrinol 2021 Aug 3;185(3):375-385. Epub 2021 Aug 3.

Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland.

Objective: To evaluate if subclinical thyroid dysfunction is associated with cardiovascular (CV) risk in patients with atrial fibrillation (AF).

Methods: Swiss-AF is a prospective cohort of community-dwelling participants aged ≥ 65 years with AF. Primary outcome was a composite endpoint of CV events (myocardial infarctions, stroke/transitory ischemic events, systemic embolism, heart failure (HF) hospitalizations, CV deaths). Secondary outcomes were component endpoints, total mortality, and AF-progression. Exposures were thyroid dysfunction categories, TSH and fT4. Sensitivity analyses were performed for amiodarone use, thyroid hormones use, and competing events.

Results: 2415 patients were included (mean age: 73.2 years; 27% women). 196 (8.4%) had subclinical hypothyroidism and 53 (2.3%) subclinical hyperthyroidism. Subclinical thyroid dysfunction was not associated with CV events, during a median follow-up of 2.1 years (max 5 years): age- and sex-adjusted hazard ratio (adjHR) of 0.99 (95% CI: 0.69-1.41) for subclinical hypothyroidism and 0.55 (95% CI: 0.23-1.32) for subclinical hyperthyroidism. Results remained robust following multivariable adjustment and sensitivity analyses. In euthyroid patients, fT4 levels were associated with an increased risk for the composite endpoint and HF (adjHR: 1.46, 95% CI: 1.04-2.05; adjHR: 1.70, 95% CI: 1.08-2.66, respectively, for the highest quintile vs the middle quintile). Results remained similar following multivariable adjustment and remained significant for HF in sensitivity analyses. No association between subclinical thyroid dysfunction and total mortality or AF-progression was found.

Conclusions: Subclinical hypothyroidism was not associated with increased CV risk in AF patients. Higher levels of fT4 with normal TSH were associated with a higher risk for HF.
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http://dx.doi.org/10.1530/EJE-20-1442DOI Listing
August 2021

Baseline characteristics and comparability of older multimorbid patients with polypharmacy and general practitioners participating in a randomized controlled primary care trial.

BMC Fam Pract 2021 06 22;22(1):123. Epub 2021 Jun 22.

Institute of Primary Health Care (BIHAM), University of Bern, Mittelstrasse 43, 3012, Bern, Switzerland.

Objectives: Recruiting general practitioners (GPs) and their multimorbid older patients for trials is challenging for multiple reasons (e.g., high workload, limited mobility). The comparability of study participants is important for interpreting study findings. This manuscript describes the baseline characteristics of GPs and patients participating in the 'Optimizing PharmacoTherapy in older multimorbid adults In primary CAre' (OPTICA) trial, a study of optimization of pharmacotherapy for multimorbid older adults. The overall aim of this study was to determine if the GPs and patients participating in the OPTICA trial are comparable to the real-world population in Swiss primary care.

Design: Analysis of baseline data from GPs and patients in the OPTICA trial and a reference cohort from the FIRE ('Family medicine ICPC Research using Electronic medical records') project.

Setting: Primary care, Switzerland.

Participants: Three hundred twenty-three multimorbid (≥ 3 chronic conditions) patients with polypharmacy (≥ 5 regular medications) aged ≥ 65 years and 43 GPs recruited for the OPTICA trial were compared to 22,907 older multimorbid patients with polypharmacy and 227 GPs from the FIRE database.

Methods: We compared the characteristics of GPs and patients participating in the OPTICA trial with other GPs and other older multimorbid adults with polypharmacy in the FIRE database. We described the baseline willingness to have medications deprescribed of the patients participating in the OPTICA trial using the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire.

Results: The GPs in the FIRE project and OPTICA were similar in terms of sociodemographic characteristics and their work as a GP (e.g. aged in their fifties, ≥ 10 years of experience, ≥ 60% are self-employed, ≥ 80% work in a group practice). The median age of patients in the OPTICA trial was 77 years and 45% of trial participants were women. Patients participating in the OPTICA trial and patients in the FIRE database were comparable in terms of age, certain clinical characteristics (e.g. systolic blood pressure, body mass index) and health services use (e.g. selected lab and vital data measurements). More than 80% of older multimorbid patients reported to be willing to stop ≥ 1 of their medications if their doctor said that this would be possible.

Conclusion: The characteristics of patients and GPs recruited into the OPTICA trial are relatively comparable to characteristics of a real-world Swiss population, which indicates that recruiting a generalizable patient sample is possible in the primary care setting. Multimorbid patients in the OPTICA trial reported a high willingness to have medications deprescribed.

Trial Registration: Clinicaltrials.gov ( NCT03724539 ), KOFAM (Swiss national portal) ( SNCTP000003060 ), Universal Trial Number (U1111-1226-8013).
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http://dx.doi.org/10.1186/s12875-021-01488-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220761PMC
June 2021

Cardiac autonomic function and cognitive performance in patients with atrial fibrillation.

Clin Res Cardiol 2021 Jun 22. Epub 2021 Jun 22.

Department of Cardiology, Cardiovascular Research Institute Basel, University Hospital Basel, Basel, Switzerland.

Background: Atrial fibrillation (AF) is associated with loss of cognition and dementia. Cardiac autonomic dysfunction has been linked to cognitive decline. We aimed to investigate if reduced cardiac autonomic function (CAF) is associated with cognitive impairment in AF patients.

Methods: Patients with paroxysmal, persistent and permanent AF were enrolled from a multicenter cohort study if they had AF ("AF group") or sinus rhythm ("SR group") on a baseline 5 min ECG recording. Parameters quantifying CAF (heart rate variability triangular index (HRVI), mean heart rate (MHR), RMSSD, SDNN, total power and power in the VLF, LF, HF ranges) were calculated. We used the Montreal Cognitive Assessment (MoCA) to assess global cognitive function.

Results: 1685 AF patients with a mean age of 73 ± 8 years, 29% females, were included. MoCA score was 24.5 ± 3.2 in the AF group (N = 710 patients) and 25.4 ± 3.2 in the SR group (N = 975 patients). After adjusting for multiple confounders, lower HRVI was associated with lower MoCA scores, both in the SR group [β = 0.049; 95% confidence interval (CI) 0.016-0.081; p = 0.003] and in the AF group (β = 0.068; 95% CI 0.020-0.116; p = 0.006). In the AF group, higher MHR was associated with a poorer performance in the MoCA (β =  - 0.008; 95% CI - 0.014 to - 0.002; p = 0.014). We found no convincing evidence of association for other CAF parameters with cognition.

Conclusion: Our data suggest that impaired CAF is associated with worse cognitive performance in patients with AF. Among standard HRV parameters, HRVI might be the most promising ECG index.

Trial Registration: ClinicalTrials.gov Identifier: NCT02105844.
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http://dx.doi.org/10.1007/s00392-021-01900-4DOI Listing
June 2021

Clinical outcomes of modifying hypertension treatment intensity in older adults treated to low blood pressure.

J Am Geriatr Soc 2021 Oct 7;69(10):2831-2841. Epub 2021 Jun 7.

Center for Clinical Management Research, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA.

Background/objectives: Hypertension treatment reduces cardiovascular events. However, uncertainty remains about benefits and harms of deintensification or further intensification of antihypertensive medication when systolic blood pressure (SBP) is tightly controlled in older multimorbid patients, because of their frequent exclusion in trials. We assessed the association of hypertension treatment deintensification or intensification with clinical outcomes in older adults with tightly controlled SBP.

Design: Longitudinal cohort study (2011-2013) with 9-month follow-up.

Setting: U.S.-nationwide primary care Veterans Health Administration healthcare system.

Participants: Veterans aged 65 and older with baseline SBP <130 mmHg and ≥1 antihypertensive medication during ≥2 consecutive visits (N = 228,753).

Exposure: Deintensification or intensification, compared with stable treatment.

Main Outcomes And Measures: Cardiovascular events, syncope, or fall injury, as composite and distinct outcomes, within 9 months after exposure. Adjusted logistic regression and inverse probability of treatment weighting (IPTW, sensitivity analysis).

Results: Among 228,753 patients (mean age 75 [SD 7.5] years), the composite outcome occurred in 11,982/93,793 (12.8%) patients with stable treatment, 14,768/72,672 (20.3%) with deintensification, and 11,821/62,288 (19.0%) with intensification. Adjusted absolute outcome risk (95% confidence interval) was higher for deintensification (18.3% [18.1%-18.6%]) and intensification (18.7% [18.4%-19.0%]), compared with stable treatment (14.8% [14.6%-15.0%]), p < 0.001 for both effects in the multivariable model). Deintensification was associated with fewer cardiovascular events than intensification. At baseline SBP <95 mmHg, cardiovascular event risk was similar for deintensification and stable treatment, and fall risk lower for deintensification than intensification. IPTW yielded similar results. Mean follow-up SBP was 124.1 mmHg for stable treatment, 125.1 mmHg after deintensification (p < 0.001), and 124.0 mmHg after intensification (p < 0.001).

Conclusion: Antihypertensive treatment deintensification in older patients with tightly controlled SBP was associated with worse outcomes than continuing same treatment intensity. Given higher mortality among patients with treatment modification, confounding by indication may not have been fully corrected by advanced statistical methods for observational data analysis.
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http://dx.doi.org/10.1111/jgs.17295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497391PMC
October 2021

Levothyroxine Treatment and Cardiovascular Outcomes in Older People With Subclinical Hypothyroidism: Pooled Individual Results of Two Randomised Controlled Trials.

Front Endocrinol (Lausanne) 2021 20;12:674841. Epub 2021 May 20.

Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands.

Background: The cardiovascular effects of treating older adults with subclinical hypothyroidism (SCH) are uncertain. Although concerns have been raised regarding a potential increase in cardiovascular side effects from thyroid hormone replacement, undertreatment may also increase the risk of cardiovascular events, especially for patients with cardiovascular disease (CVD).

Objective: To determine the effects of levothyroxine treatment on cardiovascular outcomes in older adults with SCH.

Methods: Combined data of two parallel randomised double-blind placebo-controlled trials TRUST (Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial) and IEMO80+ (the Institute for Evidence-Based Medicine in Old Age 80-plus thyroid trial) were analysed as one-stage individual participant data. Participants aged ≥65 years for TRUST (n=737) and ≥80 years for IEMO80+ (n=105) with SCH, defined by elevated TSH with fT4 within the reference range, were included. Participants were randomly assigned to receive placebo or levothyroxine, with titration of the dose until TSH level was within the reference range. Cardiovascular events and cardiovascular side effects of overtreatment (new-onset atrial fibrillation and heart failure) were investigated, including stratified analyses according to CVD history and age.

Results: The median [IQR] age was 75.0 [69.7-81.1] years, and 448 participants (53.2%) were women. The mean TSH was 6.38± SD 5.7 mIU/L at baseline and decreased at 1 year to 5.66 ± 3.3 mIU/L in the placebo group, compared with 3.66 ± 2.1 mIU/L in the levothyroxine group (p<0.001), at a median dose of 50 μg. Levothyroxine did not significantly change the risk of any of the prespecified cardiovascular outcomes, including cardiovascular events (HR 0.74 [0.41-1.25]), atrial fibrillation (HR 0.69 [0.32-1.52]), or heart failure (0.41 [0.13-1.35]), or all-cause mortality (HR 1.28 [0.54-3.03]), irrespective of history of CVD and age.

Conclusion: Treatment with levothyroxine did not significantly change the risk of cardiovascular outcomes in older adults with subclinical hypothyroidism, irrespective of a history of cardiovascular disease and age.

Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT01660126] (TRUST); Netherlands Trial Register: NTR3851 (IEMO80+).
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http://dx.doi.org/10.3389/fendo.2021.674841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173189PMC
May 2021

The impact of nutritional support on malnourished inpatients with aging-related vulnerability.

Nutrition 2021 09 22;89:111279. Epub 2021 Apr 22.

Medical University Department, Division of General Internal and Emergency Medicine, Kantonsspital Aarau, Aarau, Switzerland; Medical Faculty of the University of Basel, Switzerland. Electronic address:

Objectives: Malnutrition is highly prevalent in patients with aging-related vulnerability defined by very old age (≥80 y), physical frailty or cognitive impairment, and increases the risks for morbidity and mortality. The effects of individualized nutritional support for patients with aging-related vulnerability in the acute hospital setting on mortality and other clinical outcomes remains understudied.

Methods: For this secondary analysis of the randomized-controlled Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), we analyzed data of patients at a nutritional risk (Nutritional Risk Screening 2002 score ≥3 points) with aging-related vulnerability, randomized to receive protocol-guided individualized nutritional support to reach specific protein and energy goals (intervention group) or routine hospital food (control group). The primary endpoint was all-cause 30-d mortality.

Results: Of the 881 patients with aging-related vulnerability, 23.4% presented with a frailty syndrome, 81.8% were age ≥80 y and 15.3% showed cognitive impairment. Patients with aging-related vulnerability receiving individualized nutritional support compared with routine hospital food showed a >50% reduction in the risk of 30-day mortality (60 of 442 [13.6%] versus 31 of 439 [7.1%]; odds ratio: 0.48; 95% confidence interval, 0.31-0.76; P = 0.002). Significant improvements were also found for long-term mortality at 180 days, as well as functional outcomes and quality of life measures.

Conclusions: Malnourished patients with aging-related vulnerability show a significant and clinically relevant reduction in the risk of mortality and other adverse clinical outcomes after individualized in-hospital nutritional support compared to routine hospital nutrition. These data support the early screening of patients with aging-related vulnerability for nutritional risk, followed by a nutritional assessment and implementation of individualized nutritional interventions.
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http://dx.doi.org/10.1016/j.nut.2021.111279DOI Listing
September 2021

Influence of Prednisone on Inflammatory Biomarkers in Community-Acquired Pneumonia: Secondary Analysis of a Randomized Trial.

J Clin Pharmacol 2021 11 27;61(11):1406-1414. Epub 2021 Jul 27.

Department of General Internal and Emergency Medicine and Department of Endocrinology, Diabetology and Metabolism, Medical University Clinic, Aarau, Switzerland.

Glucocorticoids are frequently prescribed in inflammatory diseases and have recently experienced a boom in the treatment of COVID-19. Small studies have shown an effect of glucocorticoids on inflammatory marker levels, but definitive proof is lacking. We investigated the influence of prednisone on inflammatory biomarkers in a previous multicenter, randomized, placebo-controlled trial that compared a 7-day treatment course of 50-mg prednisone to placebo in patients hospitalized with community-acquired pneumonia. We compared levels of C-reactive protein (CRP), procalcitonin (PCT), leukocyte and neutrophil count between patients with and without glucocorticoid treatment at baseline and on days 3, 5, and 7 and at discharge by Wilcoxon tests and analysis of variance. A total of 356 patient data sets in the prednisone group and 355 in the placebo group were available for analysis. Compared to placebo, use of prednisone was associated with reductions in levels of CRP on days 3, 5, and 7 (mean difference of 46%, P < .001 for each time point). For PCT, no such difference was observed. Leukocyte and neutrophil count were higher in the prednisone group at all time points (mean difference of 27% for leukocytes and 33% for neutrophils, P <.001 for all time points). We conclude that after administration of glucocorticoids in community-acquired pneumonia, patients had lower CRP levels and increased leukocyte and neutrophil count as compared to the placebo group. PCT levels were not different between treatment groups. PCT levels thus may more appropriately mirror the resolution of infection compared to more traditional inflammatory markers.
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http://dx.doi.org/10.1002/jcph.1914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242868PMC
November 2021

Improving 1-year mortality prediction in ACS patients using machine learning.

Eur Heart J Acute Cardiovasc Care 2021 May 20. Epub 2021 May 20.

Department of Cardiology, University Heart Center, University Hospital of Zurich, Switzerland.

Background: The Global Registry of Acute Coronary Events (GRACE) score is an established clinical risk stratification tool for patients with acute coronary syndromes (ACS). We developed and internally validated a model for 1-year all-cause mortality prediction in ACS patients.

Methods: Between 2009 and 2012, 2'168 ACS patients were enrolled into the Swiss SPUM-ACS Cohort. Biomarkers were determined in 1'892 patients and follow-up was achieved in 95.8% of patients. 1-year all-cause mortality was 4.3% (n = 80). In our analysis we consider all linear models using combinations of 8 out of 56 variables to predict 1-year all-cause mortality and to derive a variable ranking.

Results: 1.3% of 1'420'494'075 models outperformed the GRACE 2.0 Score. The SPUM-ACS Score includes age, plasma glucose, NT-proBNP, left ventricular ejection fraction (LVEF), Killip class, history of peripheral artery disease (PAD), malignancy, and cardio-pulmonary resuscitation. For predicting 1-year mortality after ACS, the SPUM-ACS Score outperformed the GRACE 2.0 Score which achieves a 5-fold cross-validated AUC of 0.81 (95% CI 0.78-0.84). Ranking individual features according to their importance across all multivariate models revealed age, trimethylamine N-oxide, creatinine, history of PAD or malignancy, LVEF, and haemoglobin as the most relevant variables for predicting 1-year mortality.

Conclusions: The variable ranking and the selection for the SPUM-ACS Score highlight the relevance of age, markers of heart failure, and comorbidities for prediction of all-cause death. Before application, this score needs to be externally validated and refined in larger cohorts.

Clinical Trial Registration: NCT01000701.
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http://dx.doi.org/10.1093/ehjacc/zuab030DOI Listing
May 2021

Individualized Nutritional Support for Hospitalized Patients With Chronic Heart Failure.

J Am Coll Cardiol 2021 May;77(18):2307-2319

Medical University Department, Division of General Internal and Emergency Medicine, Kantonsspital Aarau, Aarau, Switzerland; Medical Faculty of the University of Basel, Basel, Switzerland. Electronic address:

Background: Deterioration of nutritional status during hospitalization in patients with chronic heart failure increases mortality. Whether nutritional support during hospitalization reduces these risks, or on the contrary, may be harmful due to an increase in salt and fluid intake, remains unclear.

Objectives: The purpose of this trial was to study the effect of nutritional support on mortality in patients hospitalized with chronic heart failure who are at nutritional risk.

Methods: A total of 645 patients with chronic heart failure (36% [n = 234] with acute decompensation) participated in the investigator-initiated, open-label EFFORT (Effect of early nutritional support on Frailty, Functional Outcomes and Recovery of malnourished medical inpatients) trial. Patients were randomized to protocol-guided individualized nutritional support to reach energy, protein, and micronutrient goals (intervention group) or standard hospital food (control group). The primary endpoint was all-cause mortality at 30 days.

Results: Mortality over 180 days increased with higher severity of malnutrition (odds ratio per 1-point increase in Nutritional Risk Screening 2002 score: 1.65; 95% confidence interval [CI]: 1.21 to 2.24; p = 0.001). By 30 days, 27 of 321 intervention group patients (8.4%) died, compared with 48 of 324 (14.8%) control group patients (odds ratio: 0.44; 95% CI: 0.26 to 0.75; p = 0.002). Patients at high nutritional risk showed the most benefit from nutritional support. Mortality effects remained significant at 180-day follow-up. Intervention group patients also had a lower risk for major cardiovascular events at 30 days (17.4% vs. 26.9%; odds ratio: 0.50; 95% CI: 0.34 to 0.75; p = 0.001).

Conclusions: Among hospitalized patients with chronic heart failure at high nutritional risk, individualized nutritional support reduced the risk for mortality and major cardiovascular events compared with standard hospital food. These data support malnutrition screening upon hospital admission followed by an individualized nutritional support strategy in this vulnerable patient population. (Effect of Early Nutritional Therapy on Frailty, Functional Outcomes and Recovery of Undernourished Medical Inpatients Trial [EFFORT]; NCT02517476).
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http://dx.doi.org/10.1016/j.jacc.2021.03.232DOI Listing
May 2021

Admission kidney function is a strong predictor for the response to nutritional support in patients at nutritional risk.

Clin Nutr 2021 05 15;40(5):2762-2771. Epub 2021 Mar 15.

Medical University Department, Division of General Internal and Emergency Medicine, Kantonsspital Aarau, Aarau, Switzerland; Medical Faculty of the University of Basel, Switzerland. Electronic address:

Background: Patients with chronic kidney disease (CKD) are at substantial risk of malnutrition, which negatively affects clinical outcomes. We investigated the association of kidney function assessed at hospital admission and effectiveness of nutritional support in hospitalized medical patients at risk of malnutrition.

Methods: This is a secondary analysis of an investigator-initiated, randomized-controlled, Swiss multicenter trial (EFFORT) that compared individualised nutritional support with usual hospital food on clinical outcomes. We compared effects of nutritional support on mortality in subgroups of patients stratified according to kidney function at the time of hospital admission (estimated glomerular filtration rates [eGFR] <15, 15-29, 30-59, 60-89 and ≥ 90 ml/min/1.73 m).

Results: We included 1943 of 2028 patients (96%) from the original trial with known admission creatinine levels. Admission eGFR was a strong predictor for the beneficial effects of nutritional support in regard to lowering of 30-day mortality. Patients with an eGFR <15, 15-29 and 30-59 had the strongest mortality benefit (odds ratios [95%CI] of 0.24 [0.05 to 1.25], 0.37 [0.14 to 0.95] and 0.39 [0.21 to 0.75], respectively), while patients with less severe impairment in kidney function had a less pronounced mortality benefits (p for interaction 0.001). A similar stepwise association of kidney function and response to nutritional support was found also for other secondary outcomes.

Conclusion: In medical inpatients at nutritional risk, admission kidney function was a strong predictor for the response to nutritional therapy. Initial kidney function may help to individualize nutritional support in the future by identification of patients with most clinical benefit.

Clinical Trial Registration: Registered under ClinicalTrials.gov Identifier no. NCT02517476.
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http://dx.doi.org/10.1016/j.clnu.2021.03.013DOI Listing
May 2021

Comparison of Bleeding Risk Scores in Elderly Patients Receiving Extended Anticoagulation with Vitamin K Antagonists for Venous Thromboembolism.

Thromb Haemost 2021 Apr 30. Epub 2021 Apr 30.

Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Background:  In elderly patients with venous thromboembolism (VTE), the decision to extend anticoagulation beyond 3 months must be weighed against the bleeding risk. We compared the predictive performance of 10 clinical bleeding scores (VTE-BLEED, Seiler, Kuijer, Kearon, RIETE, ACCP, OBRI, HEMORRHAGES, HAS-BLED, ATRIA) in elderly patients receiving extended anticoagulation for VTE.

Methods:  In a multicenter Swiss cohort study, we analyzed 743 patients aged ≥65 years who received extended treatment with vitamin K antagonists after VTE. The outcomes were the time to a first major and clinically relevant bleeding. For each score, we classified patients into two bleeding risk categories (low/moderate vs. high). We calculated likelihood ratios and the area under the receiver operating characteristic (ROC) curve for each score.

Results:  Over a median anticoagulation duration of 10.1 months, 45 patients (6.1%) had a first major and 127 (17.1%) a clinically relevant bleeding. The positive likelihood ratios for predicting major bleeding ranged from 0.69 (OBRI) to 2.56 (Seiler) and from 1.07 (ACCP) to 2.36 (Seiler) for clinically relevant bleeding. The areas under the ROC curves were poor to fair and varied between 0.47 (OBRI) and 0.70 (Seiler) for major and between 0.52 (OBRI) and 0.67 (HEMORRHAGES) for clinically relevant bleeding.

Conclusion:  The predictive performance of most clinical bleeding risk scores does not appear to be sufficiently high to identify elderly patients with VTE who are at high risk of bleeding and who may therefore not be suitable candidates for extended anticoagulation.
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http://dx.doi.org/10.1055/s-0041-1726345DOI Listing
April 2021

An International Consensus List of Potentially Clinically Significant Drug-Drug Interactions in Older People.

J Am Med Dir Assoc 2021 10 24;22(10):2121-2133.e24. Epub 2021 Apr 24.

Clinical Pharmacy Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium; Pharmacy Department, CHU UCL Namur, Université Catholique de Louvain, Yvoir, Belgium. Electronic address:

Objectives: We aimed to establish an explicit list of potentially clinically significant drug-drug interactions (DDIs) in people aged ≥65 years.

Design: A preliminary list of potentially clinically significant DDIs was compiled, based on 154 DDIs identified from literature review. Subsequently, a 2-round online Delphi survey was undertaken with a multidisciplinary expert panel. A consensus meeting and a final round were conducted to validate the final DDI list and the scope of information provided.

Setting And Participants: Twenty nine experts, including geriatricians and clinical pharmacists from 8 European countries.

Measures: For each DDI, in the first 2 rounds, experts were asked to score the severity of potential harm on a 5-point Likert-type scale. DDIs were directly included on the final list if the median score was 4 (major) or 5 (catastrophic). DDIs with a median score of 3 (moderate) were discussed at a consensus meeting and included if ≥75% of participants voted for inclusion in the final round.

Results: Consensus was achieved on 66 potentially clinically significant DDIs (28 had a median score of 4/5 and 48 of 3 in the Delphi survey). Most concerned cardiovascular, antithrombotic, and central nervous system drugs. The final list includes information on the mechanism of interaction, harm, and management. Treatment modification is recommended for three-quarters of DDIs.

Conclusion And Implications: We validated a list of potentially clinically significant DDIs in older people, which can be used in clinical practice and education to support identification and management of DDIs or to assess prevalence in epidemiologic and intervention studies.
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http://dx.doi.org/10.1016/j.jamda.2021.03.019DOI Listing
October 2021

Heart rate and adverse outcomes in patients with prevalent atrial fibrillation.

Open Heart 2021 04;8(1)

Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada

Objective: The optimal target heart rate in patients with prevalent atrial fibrillation (AF) is not well defined. The aim of this study was to analyse the associations between heart rate and adverse outcomes in a large contemporary cohort of patients with prevalent AF.

Methods: From two prospective cohort studies, we included stable AF outpatients who were in AF on the baseline ECG. The main outcome events assessed during prospective follow-up were heart failure hospitalisation, stroke or systemic embolism and death. The associations between heart rate and adverse outcomes were evaluated using multivariable Cox regression models.

Results: The study population consisted of 1679 patients who had prevalent AF at baseline. Mean age was 74 years, and 24.6% were women. The mean heart rate on the baseline ECG was 78 (±19) beats per minute (bpm). The median follow-up was 3.9 years (IQR 2.2-5.0). Heart rate was not significantly associated with heart failure hospitalisation (adjusted HR (aHR) per 10 bpm increase, 1.00, 95% CI 0.94 to 1.07, p=0.95), stroke or systemic embolism (aHR 0.95, 95% CI 0.84 to 1.07, p=0.38) or death (aHR 1.02, 95% CI 0.95 to 1.09, p=0.66). There was no evidence of a threshold effect for heart rates <60 bpm or 100 bpm.

Conclusions: In this large contemporary cohort of outpatients with prevalent AF, we found no association between heart rate and adverse outcome events. These data are in line with recommendations that strict heart rate control is not needed in otherwise stable outpatients with AF.
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http://dx.doi.org/10.1136/openhrt-2021-001606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061854PMC
April 2021

Biomarkers of Inflammation and Risk of Hospitalization for Heart Failure in Patients With Atrial Fibrillation.

J Am Heart Assoc 2021 04 10;10(8):e019168. Epub 2021 Apr 10.

Population Health Research Institute McMaster University Hamilton Canada.

Background Hospitalization for heart failure (HF) is very common in patients with atrial fibrillation (AF). We hypothesized that biomarkers of inflammation can identify patients with AF at increased risk of this important complication. Methods and Results Patients with established AF were prospectively enrolled. Levels of hs-CRP (high-sensitivity C-reactive protein) and interleukin-6 were measured from plasma samples obtained at baseline. We calculated an inflammation score ranging from 0 to 4 (1 point for each biomarker between the 50th and 75th percentile, 2 points for each biomarker above the 75th percentile). Individual associations of biomarkers and the inflammation score with HF hospitalization were obtained from multivariable Cox proportional hazards models. A total of 3784 patients with AF (median age 72 years, 24% prior HF) were followed for a median of 4.0 years. The median (interquartile range) plasma levels of hs-CRP and interleukin-6 were 1.64 (0.81-3.69) mg/L and 3.42 (2.14-5.60) pg/mL, respectively. The overall incidence of HF hospitalization was 3.04 per 100 person-years and increased from 1.34 to 7.31 per 100 person-years across inflammation score categories. After multivariable adjustment, both biomarkers were significantly associated with the risk of HF hospitalization (per increase in 1 SD, adjusted hazard ratio [HR], 1.22; 95% CI, 1.11-1.34 for log-transformed hs-CRP; adjusted HR, 1.48; 95% CI, 1.35-1.62 for log-transformed interleukin-6). Similar results were obtained for the inflammation score (highest versus lowest score, adjusted HR, 2.43; 95% CI, 1.80-3.30; value for trend <0.001). Conclusions Biomarkers of inflammation strongly predicted HF hospitalization in a large, contemporary sample of patients with AF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.
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http://dx.doi.org/10.1161/JAHA.120.019168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174180PMC
April 2021

Prognostic value of total testosterone levels in patients with acute coronary syndromes.

Eur J Prev Cardiol 2021 04;28(2):235–242

Cardiology Division, Geneva University Hospitals, Switzerland.

Background: Endogenous testosterone levels decrease in men with aging. Controversies persist regarding the screening and treatment of low testosterone levels in patients with acute coronary syndromes (ACS).

Methods And Results: Total serum testosterone levels were measured in 1054 men hospitalized for ACS that were part of a Swiss prospective cohort. Total testosterone levels were classified first in tertiles and using the cut-off of 300 ng/dL. Primary endpoint was all-cause mortality at one year. Cox regression models adjusting for the GRACE score (composite of age, heart rate systolic blood pressure, creatinine, cardiac arrest at admission, ST segment deviation, abnormal troponin enzyme and Killip classification), preexisting diabetes and inflammation (high-sensitivity C-reactive protein). A total of 430 men (40.8%) had total testosterone levels ≤300 ng/dL. Low total testosterone levels were correlated with lower high-density lipoprotein cholesterol and higher triglycerides, high-sensitivity C-reactive protein, high-sensitivity troponin T, N-terminal-pro B-type natriuretic peptide and glucose levels (all p < 0.01). Patients in the lowest testosterone tertile had a mortality rate at one-year of 5.4% compared with 2.9% in the highest tertile with an unadjusted hazard ratio of 1.92 (95% confidence interval 0.96-1.90, p = 0.095) and adjusted hazard ratio of 1.26 (95% confidence interval 0.57-2.78, p = 0.565). In an exploratory analysis, the highest mortality rate (10.3%) was observed in men aged >65 years old belonging to the lowest testosterone tertile.

Conclusion: In this large population of men with ACS, we found a prevalence of low total endogenous testosterone levels of almost 40%. However, low testosterone levels were not significantly associated with mortality after adjustment for high-risk confounders.
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http://dx.doi.org/10.1177/2047487319853343DOI Listing
April 2021

Value of handgrip strength to predict clinical outcomes and therapeutic response in malnourished medical inpatients: Secondary analysis of a randomized controlled trial.

Am J Clin Nutr 2021 08;114(2):731-740

Medical University Department, Division of General Internal and Emergency Medicine, Kantonsspital Aarau, Aarau, Switzerland.

Background: Disease-related malnutrition is associated with loss of muscle mass and impaired functional status. Handgrip strength (HGS) has been proposed as an easy-to-use tool to assess muscle strength in clinical practice.

Objectives: We investigated the prognostic implications of HGS in patients at nutritional risk with regard to clinical outcomes and response to nutritional support.

Methods: This was a secondary analysis of the randomized controlled, multicenter, Effect of Early Nutritional Support on Frailty, Functional Outcome, and Recovery of Malnourished Medical Inpatients Trial, which compared the effects of individualized nutritional support with usual hospital food in medical inpatients at nutritional risk. Our primary endpoint was 30-d all-cause mortality. The association between sex-specific HGS and clinical outcomes was investigated using multivariable regression analyses, adjusted for randomization, age, weight, height, nutritional risk, admission diagnosis, comorbidities, interaction terms, and study center. We used interaction terms to investigate possible effect modification regarding the nutritional support intervention.

Results: Mean ± SD HGS in the 1809 patients with available handgrip measurement was 17.0 ± 7.1 kg for females and 28.9 ± 11.3 kg for males. Each decrease of 10 kg in HGS was associated with increased risk of 30-d mortality (female: adjusted OR: 2.11; 95% CI: 1.23, 3.62, P = 0.007; male: adjusted OR: 1.44; 95% CI: 1.07, 1.93, P = 0.015) and 180-d mortality (female: adjusted OR: 1.45; 95% CI: 1.0, 2.10, P = 0.048; male: adjusted OR: 1.55; 95% CI: 1.28, 1.89, P < 0.001). Individualized nutritional support was most effective in reducing mortality in patients with low HGS (adjusted OR: 0.29; 95% CI: 0.10, 0.82 in patients in the ≤10th percentile compared with OR: 0.98; 95% CI: 0.66, 1.48 in patients in the >10th percentile; P for interaction = 0.026).

Conclusions: In medical inpatients at nutritional risk, HGS provided significant prognostic information about expected mortality and complication risks and helps to identify which patients benefit most from nutritional support. HGS may thus improve individualization of nutritional therapy.This trial was registered at clinicaltrials.gov as NCT02517476.
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http://dx.doi.org/10.1093/ajcn/nqab042DOI Listing
August 2021

Validation of the 2019 European Society of Cardiology Risk Stratification Algorithm for Pulmonary Embolism in Normotensive Elderly Patients.

Thromb Haemost 2021 Apr 6. Epub 2021 Apr 6.

Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Background:  The 2019 European Society of Cardiology (ESC) guidelines recommend evaluation for right ventricular dysfunction in all normotensive patients with acute pulmonary embolism (PE). We compared the predictive performance of the 2019 and 2014 ESC risk stratification algorithms and the Pulmonary Embolism Severity Index (PESI).

Methods:  We performed a posthoc analysis of normotensive patients aged ≥ 65 years with acute PE from a prospective cohort. The primary outcome was overall mortality; secondary outcomes were PE-related mortality and adverse outcomes (PE-related death, cardiopulmonary resuscitation, intubation, catecholamine use, recurrent venous thromboembolism) at 30 days. We assessed outcomes in intermediate-high, intermediate-low, and low-risk groups according to the 2019 and 2014 ESC algorithms and the PESI. Discriminative power was compared using the area under the receiver operating characteristic curve (AUC).

Results:  Among 419 patients, 14 (3.3%) died (7 from PE) and 16 (3.8%) had adverse outcomes within 30 days. The 2019 ESC algorithm classified more patients as intermediate-high risk (45%) than the 2014 ESC algorithm (24%) or the PESI (37%), and only 19% as low risk (32% with 2014 ESC or the PESI). Discriminatory power for overall mortality was lower with the 2019 ESC algorithm (AUC: 63.6%), compared with the 2014 ESC algorithm (AUC: 71.5%) or the PESI (AUC: 75.2%), although the difference did not reach statistical significance ( = 0.063). Discrimination for PE-related mortality and adverse outcomes was similar.

Conclusion:  While categorizing more patients in higher risk groups, the 2019 ESC algorithm for PE did not improve prediction of short-term outcomes compared with the 2014 ESC algorithm or the PESI.
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http://dx.doi.org/10.1055/a-1475-2263DOI Listing
April 2021

Novel Blood Biomarkers for a Diagnostic Workup of Acute Aortic Dissection.

Diagnostics (Basel) 2021 Mar 30;11(4). Epub 2021 Mar 30.

Institute of Clinical Chemistry, University Hospital of Zurich, University of Zurich, 8091 Zurich, Switzerland.

Acute aortic dissection (AAD) is a rare condition, but together with acute myocardial infarction (AMI) and pulmonary embolism (PE) it belongs to the most relevant and life-threatening causes of acute chest pain. Until now, there has been no specific blood test in the diagnostic workup of AAD. To identify clinically relevant biomarkers for AAD, we applied Proseek Multiplex assays to plasma samples from patients with AAD, AMI, PE, thoracic aortic aneurysm (TAA), and non-cardiovascular chest pain (nonCVD). Subsequently, we validated top hits using conventional immunoassays and examined their expression in the aortic tissue. Interleukin 10 (IL-10) alone showed the best performance with a sensitivity of 55% and a specificity of 98% for AAD diagnosis. The combination of D-dimers, high-sensitive troponin T (hs-TnT), interleukin 6 (IL-6), and plasminogen activator inhibitor 1 (PAI1) correctly classified 75% of AAD cases, delivering a sensitivity of 83% and specificity of 95% for its diagnosis. Moreover, this model provided the correct classification of 77% of all analyzed cases. Our data suggest that IL-10 shows potential to be a rule-in biomarker for AAD. Moreover, the addition of PAI1 and IL-6 to hs-TnT and D-dimers may improve the discrimination of suspected AAD, AMI, and PE in patients presenting with acute chest pain.
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http://dx.doi.org/10.3390/diagnostics11040615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065878PMC
March 2021
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