Publications by authors named "Manuel R Blum"

40 Publications

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, 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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August 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: NCT02986425.
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July 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: [], identifier [NCT01660126] (TRUST); Netherlands Trial Register: NTR3851 (IEMO80+).
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May 2021

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

J Clin Pharmacol 2021 May 25. Epub 2021 May 25.

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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May 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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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:; Unique identifier: NCT02105844.
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April 2021

Eligibility for PCSK9 inhibitors based on the 2019 ESC/EAS and 2018 ACC/AHA guidelines.

Eur J Prev Cardiol 2021 03 20;28(1):59-65. Epub 2020 Jul 20.

Department of Cardiology, University Hospital Bern, Switzerland.

Aims: The 2018 American College of Cardiology (ACC)/American Heart Association (AHA) and 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) lipid guidelines recently updated their recommendations regarding proprotein convertase subtilisin/kexin-9 inhibitors (PCSK9i). We assessed the potential eligibility for PCSK9i according to the new guidelines in patients with acute coronary syndromes.

Methods And Results: We analysed a contemporary, prospective Swiss cohort of patients hospitalised for acute coronary syndromes. We modelled a statin intensification effect and an incremental ezetimibe effect on low-density lipoprotein-cholesterol levels among patients who were not on high-intensity statins or ezetimibe. One year after the index acute coronary syndrome event, treatment eligibility for PCSK9i was defined as low-density lipoprotein-cholesterol of 1.4 mmol/l or greater according to ESC/EAS guidelines. For ACC/AHA guidelines, treatment eligibility was defined as low-density lipoprotein-cholesterol of 1.8 mmol/l or greater in the presence of very high-risk atherosclerotic cardiovascular disease, defined by multiple major atherosclerotic cardiovascular disease events and/or high-risk conditions. Of 2521 patients, 93.2% were treated with statins (53% high-intensity statins) and 7.3% with ezetimibe at 1 year, and 54.9% had very high-risk atherosclerotic cardiovascular disease. Low-density lipoprotein-cholesterol levels less than 1.8 mmol/l and less than 1.4 mmol/l at 1 year were observed in 37.5% and 15.7% of patients, respectively. After modelling the statin intensification and ezetimibe effects, these numbers increased to 76.1% and 49%, respectively. The proportion of patients eligible for PCSK9i was 51% according to ESC/EAS criteria versus 14% according to ACC/AHA criteria.

Conclusions: In this analysis, the 2019 ESC/EAS guidelines rendered half of all post-acute coronary syndrome patients potentially eligible for PCSK9i treatment, as compared to a three-fold lower eligibility rate based on the 2018 ACC/AHA guidelines.
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March 2021

County-Level Factors Associated With Cardiovascular Mortality by Race/Ethnicity.

J Am Heart Assoc 2021 03 3;10(6):e018835. Epub 2021 Mar 3.

Division of Cardiovascular Medicine and the Cardiovascular Institute Stanford University School of Medicine Stanford CA.

Background Persistent racial/ethnic disparities in cardiovascular disease (CVD) mortality are partially explained by healthcare access and socioeconomic, demographic, and behavioral factors. Little is known about the association between race/ethnicity-specific CVD mortality and county-level factors. Methods and Results Using 2017 county-level data, we studied the association between race/ethnicity-specific CVD age-adjusted mortality rate (AAMR) and county-level factors (demographics, census region, socioeconomics, CVD risk factors, and healthcare access). Univariate and multivariable linear regressions were used to estimate the association between these factors; values were used to assess the factors that accounted for the greatest variation in CVD AAMR by race/ethnicity (non-Hispanic White, non-Hispanic Black, and Hispanic/Latinx individuals). There were 659 740 CVD deaths among non-Hispanic White individuals in 2698 counties; 100 475 deaths among non-Hispanic Black individuals in 717 counties; and 49 493 deaths among Hispanic/Latinx individuals across 267 counties. Non-Hispanic Black individuals had the highest mean CVD AAMR (320.04 deaths per 100 000 individuals), whereas Hispanic/Latinx individuals had the lowest (168.42 deaths per 100 000 individuals). The highest CVD AAMRs across all racial/ethnic groups were observed in the South. In unadjusted analyses, the greatest variation () in CVD AAMR was explained by physical inactivity for non-Hispanic White individuals (32.3%), median household income for non-Hispanic Black individuals (24.7%), and population size for Hispanic/Latinx individuals (28.4%). In multivariable regressions using county-level factor categories, the greatest variation in CVD AAMR was explained by CVD risk factors for non-Hispanic White individuals (35.3%), socioeconomic factors for non-Hispanic Black (25.8%), and demographic factors for Hispanic/Latinx individuals (34.9%). Conclusions The associations between race/ethnicity-specific age-adjusted CVD mortality and county-level factors differ significantly. Interventions to reduce disparities may benefit from being designed accordingly.
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March 2021

Association of the CHAD(S)-VASc Score and Its Components With Overt and Silent Ischemic Brain Lesions in Patients With Atrial Fibrillation.

Front Neurol 2020 12;11:609234. Epub 2021 Jan 12.

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

Silent and overt ischemic brain lesions are common and associated with adverse outcome. Whether the CHADS-VASc score and its components predict magnetic resonance imaging (MRI)-detected ischemic silent and overt brain lesions in patients with atrial fibrillation (AF) is unclear. In this cross-sectional analysis, patients with AF were enrolled in a multicenter cohort study in Switzerland. Outcomes were clinically overt, silent [in the absence of a history of stroke/transient ischemic attack (TIA)] and any MRI-detected ischemic brain lesions. Logistic regression analyses were performed to assess the relationship of the CHADS-VASc score and its components with ischemic brain lesions. An adapted CHAD-VASc score (excluding history of stroke/TIA) for the analyses of clinically overt and silent ischemic brain lesions was used. Overall, 1,741 patients were included in the analysis (age 73 ± 8 years, 27.4% female). At least one ischemic brain lesion was observed in 36.8% (clinically overt: 10.5%; silent: 22.9%; transient ischemic attack: 3.4%). The CHAD-VASc score was strongly associated with clinically overt and silent ischemic brain lesions {odds ratio (OR) [95% confidence interval (CI)] 1.32 (1.17-1.49), < 0.001 and 1.20 (1.10-1.30), < 0.001, respectively}. Age 65-74 years (OR 2.58; 95%CI 1.29-5.90; = 0.013), age ≥75 years (4.13; 2.07-9.43; < 0.001), hypertension (1.90; 1.28-2.88; = 0.002) and diabetes (1.48; 1.00-2.18; = 0.047) were associated with clinically overt brain lesions, whereas age 65-74 years (1.95; 1.26-3.10; = 0.004), age ≥75 years (3.06; 1.98-4.89; < 0.001) and vascular disease (1.39; 1.07-1.79; = 0.012) were associated with silent ischemic brain lesions. A higher CHAD-VASc score was associated with a higher risk of both overt and silent ischemic brain lesions., identifier: NCT02105844.
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January 2021

Insulin-like growth factor-binding protein 7 and risk of congestive heart failure hospitalization in patients with atrial fibrillation.

Heart Rhythm 2021 04 3;18(4):512-519. Epub 2020 Dec 3.

Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland; Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada. Electronic address:

Background: The occurrence of congestive heart failure (CHF) hospitalization among patients with atrial fibrillation (AF) is a poor prognostic marker.

Objective: The purpose of this study was to assess whether insulin-like growth factor-binding protein 7 (IGFBP-7), a marker of myocardial damage, identifies AF patients at high risk for this complication.

Methods: We analyzed 2 prospective multicenter observational cohort studies that included 3691 AF patients. Levels of IGFBP-7 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured from frozen plasma samples at baseline. The primary endpoint was hospitalization for CHF. Multivariable adjusted Cox regression analyses were constructed.

Results: Mean patient age was 69 ± 12 years, 1028 (28%) were female, and 879 (24%) had a history of CHF. The incidence per 1000 patient-years across increasing IGFBP-7 quartiles was 7, 10, 32, and 85. The corresponding multivariable adjusted hazard ratios (aHRs) (95% confidence interval [CI]) were 1.0, 1.05 (0.63-1.77), 2.38 (1.50-3.79), and 4.37 (2.72-7.04) (P for trend <.001). In a subgroup of 2812 patients without pre-existing CHF at baseline, the corresponding aHRs were 1.0, 0.90 (0.47-1.72), 1.69 (0.94-3.04), and 3.48 (1.94-6.24) (P for trend <.001). Patients with IGFBP-7 and NT-proBNP levels above the biomarker-specific median had a higher risk of incident CHF hospitalization (aHR 5.20; 3.35-8.09) compared to those with only 1 elevated marker (elevated IGFBP-7 aHR 2.17; 1.30-3.60); elevated NT-proBNP aHR 1.97; 1.17-3.33); or no elevated marker (reference).

Conclusion: Higher plasma levels of IGFBP-7 were strongly and independently associated with CHF hospitalization in AF patients. The prognostic information provided by IGFBP-7 was additive to that of NT-proBNP.
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April 2021

Multimethod, multidataset analysis reveals paradoxical relationships between sociodemographic factors, Hispanic ethnicity and diabetes.

BMJ Open Diabetes Res Care 2020 11;8(2)

Division of Pediatric Endocrinology, Stanford University School of Medicine, Stanford, California, USA

Introduction: Population-level and individual-level analyses have strengths and limitations as do 'blackbox' machine learning (ML) and traditional, interpretable models. Diabetes mellitus (DM) is a leading cause of morbidity and mortality with complex sociodemographic dynamics that have not been analyzed in a way that leverages population-level and individual-level data as well as traditional epidemiological and ML models. We analyzed complementary individual-level and county-level datasets with both regression and ML methods to study the association between sociodemographic factors and DM.

Research Design And Methods: County-level DM prevalence, demographics, and socioeconomic status (SES) factors were extracted from the 2018 Robert Wood Johnson Foundation County Health Rankings and merged with US Census data. Analogous individual-level data were extracted from 2007 to 2016 National Health and Nutrition Examination Survey studies and corrected for oversampling with survey weights. We used multivariate linear (logistic) regression and ML regression (classification) models for county (individual) data. Regression and ML models were compared using measures of explained variation (area under the receiver operating characteristic curve (AUC) and R).

Results: Among the 3138 counties assessed, the mean DM prevalence was 11.4% (range: 3.0%-21.1%). Among the 12 824 individuals assessed, 1688 met DM criteria (13.2% unweighted; 10.2% weighted). Age, gender, race/ethnicity, income, and education were associated with DM at the county and individual levels. Higher county Hispanic ethnic density was negatively associated with county DM prevalence, while Hispanic ethnicity was positively associated with individual DM. ML outperformed regression in both datasets (mean R of 0.679 vs 0.610, respectively (p<0.001) for county-level data; mean AUC of 0.737 vs 0.727 (p<0.0427) for individual-level data).

Conclusions: Hispanic individuals are at higher risk of DM, while counties with larger Hispanic populations have lower DM prevalence. Analyses of population-level and individual-level data with multiple methods may afford more confidence in results and identify areas for further study.
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November 2020

Effect of Thyroid Hormone Therapy on Fatigability in Older Adults With Subclinical Hypothyroidism: A Nested Study Within a Randomized Placebo-Controlled Trial.

J Gerontol A Biol Sci Med Sci 2020 09;75(9):e89-e94

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

Background: Fatigue often triggers screening for and treatment of subclinical hypothyroidism. However, data on the impact of levothyroxine on fatigue is limited and previous studies might not have captured all aspects of fatigue.

Method: This study is nested within the randomized, placebo-controlled, multicenter TRUST trial, including community-dwelling participants aged ≥65 and older, with persistent subclinical hypothyroidism (TSH 4.60-19.99 mIU/L, normal free thyroxine levels) from Switzerland and Ireland. Interventions consisted of daily levothyroxine starting with 50 μg (25 μg if weight <50 kg or known coronary heart diseases) together with dose adjustments to achieve a normal TSH and mock titration in the placebo group. Main outcome was the change in physical and mental fatigability using the Pittsburgh Fatigability Scale over 1 year, assessed through multivariable linear regression with adjustment for country, sex, and levothyroxine starting dose.

Results: Among 230 participants, the mean ± standard deviation (SD) TSH was 6.2 ± 1.9 mIU/L at baseline and decreased to 3.1 ± 1.3 with LT4 (n = 119) versus 5.3 ± 2.3 with placebo (n = 111, p < .001) after 1 year. After adjustment we found no between-group difference at 1 year on perceived physical (0.2; 95% CI -1.8 to 2.1; p = .88), or mental fatigability (-1.0; 95% CI -2.8 to 0.8; p = .26). In participants with higher fatigability at baseline (≥15 points for the physical score [n = 88] or ≥13 points for the mental score [n = 41]), the adjusted between-group differences at 1 year were 0.4 (95% CI -3.6 to 2.8, p = .79) and -2.2 (95% CI -8.8 to 4.5, p = .51).

Conclusions: Levothyroxine in older adults with mild subclinical hypothyroidism provides no change in physical or mental fatigability.
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September 2020

Functional health and white matter hyperintensities as effect modifiers of blood pressure-lowering on cognitive function and vascular events in older Secondary Prevention of Small Subcortical Strokes trial participants.

J Hypertens 2020 08;38(8):1578-1585

Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA.

Objective: To determine whether cerebral small vessel disease or disability modify the effect of SBP treatment on cognitive and vascular outcomes in older patients with recent lacunar stroke.

Methods: Participants aged at least 65 years of the Secondary Prevention of Small Subcortical Strokes Trial were randomized to a higher (130-149 mmHg) or lower (<130 mmHg) SBP target. The primary outcome was change in cognitive function (Cognitive Abilities Screening Instrument); secondary outcomes were incident mild cognitive impairment, stroke, major vascular events (all-stroke, myocardial infarction), and all-cause death. Results were stratified by severity of white matter hyperintensities (WMH; none/mild, moderate, severe) on baseline MRI, and by disability (no vs. at least one limitation in activities of daily living).

Results: One thousand, two hundred and sixty-three participants (mean age 73.8 ± 5.9 years, 40% women) were included. Participants with severe WMH or disability had worse cognitive function at baseline and after a mean follow-up of 3.9 years. No significant interactions existed between treatment group and effect modifiers (WMH, disability) for change in cognitive function (P for interaction 0.42 and 0.66, respectively). A lower SBP target appeared more beneficial among those with worse WMH burden for vascular outcomes (P for interaction = 0.01 for stroke and 0.03 for major vascular events).

Conclusion: There was no difference in the effect of lowering SBP to less than 130 mmHg on cognitive function by cerebral small vessel disease or disability among older adults with a history of lacunar stroke. Those with evidence of small vessel disease may derive greater benefit from lower SBP on prevention of subsequent vascular events.

Trial Registration: Identifier: NCT00059306.
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August 2020

The Impact of Levothyroxine on Cardiac Function in Older Adults With Mild Subclinical Hypothyroidism: A Randomized Clinical Trial.

Am J Med 2020 07 12;133(7):848-856.e5. Epub 2020 Mar 12.

Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland; Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland. Electronic address:

Background: Subclinical hypothyroidism has been associated with heart failure, but only small trials assessed whether treatment with levothyroxine has an impact on cardiac function.

Methods: In a randomized, double-blind, placebo-controlled, trial nested within the TRUST trial, Swiss participants ages ≥65 years with subclinical hypothyroidism (thyroid-stimulating hormone [TSH] 4.60-19.99 mIU/L; free thyroxine level within reference range) were randomized to levothyroxine (starting dose of 50 µg daily) to achieve TSH normalization or placebo. The primary outcomes were the left ventricular ejection fraction for systolic function and the ratio between mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e' ratio) for diastolic function. Secondary outcomes included e' lateral/septal, left atrial volume index, and systolic pulmonary artery pressure.

Results: A total of 185 participants (mean age 74.1 years, 47% women) underwent echocardiography at the end of the trial. After a median treatment duration of 18.4 months, the mean TSH decreased from 6.35 mIU/L to 3.55 mIU/L with levothyroxine (n = 96), and it remained elevated at 5.29 mIU/L with placebo (n = 89). The adjusted between-group difference was not significant for the mean left ventricular ejection fraction (62.7% vs 62.5%, difference = 0.4%, 95% confidence interval -1.8% to 2.5%, P = 0.72) and the E/e' ratio (10.6 vs 10.1, difference 0.4, 95% confidence interval -0.7 to 1.4, P = 0.47). No differences were found for the secondary diastolic function parameters or for interaction according to sex, baseline TSH, preexisting heart failure, and treatment duration (P value >0.05).

Conclusion: Systolic and diastolic heart function did not differ after treatment with levothyroxine compared with placebo in older adults with mild subclinical hypothyroidism.
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July 2020

Cost-Effectiveness of Transitional Care Services After Hospitalization With Heart Failure.

Ann Intern Med 2020 02 28;172(4):248-257. Epub 2020 Jan 28.

Stanford University, Stanford, California (J.D.G.).

Background: Patients with heart failure (HF) discharged from the hospital are at high risk for death and rehospitalization. Transitional care service interventions attempt to mitigate these risks.

Objective: To assess the cost-effectiveness of 3 types of postdischarge HF transitional care services and standard care.

Design: Decision analytic microsimulation model.

Data Sources: Randomized controlled trials, clinical registries, cohort studies, Centers for Disease Control and Prevention life tables, Centers for Medicare & Medicaid Services data, and National Inpatient Sample (Healthcare Cost and Utilization Project) data.

Target Population: Patients with HF who were aged 75 years at hospital discharge.

Time Horizon: Lifetime.

Perspective: Health care sector.

Intervention: Disease management clinics, nurse home visits (NHVs), and nurse case management.

Outcome Measures: Quality-adjusted life-years (QALYs), costs, net monetary benefits, and incremental cost-effectiveness ratios (ICERs).

Results Of Base-case Analysis: All 3 transitional care interventions examined were more costly and effective than standard care, with NHVs dominating the other 2 interventions. Compared with standard care, NHVs increased QALYs (2.49 vs. 2.25) and costs ($81 327 vs. $76 705), resulting in an ICER of $19 570 per QALY gained.

Results Of Sensitivity Analysis: Results were largely insensitive to variations in in-hospital mortality, age at baseline, or costs of rehospitalization. Probabilistic sensitivity analysis confirmed that transitional care services were preferred over standard care in nearly all 10 000 samples, at willingness-to-pay thresholds of $50 000 or more per QALY gained.

Limitation: Transitional care service designs and implementations are heterogeneous, leading to uncertainty about intervention effectiveness and costs when applied in particular settings.

Conclusion: In older patients with HF, transitional care services are economically attractive, with NHVs being the most cost-effective strategy in many situations. Transitional care services should become the standard of care for postdischarge management of patients with HF.

Primary Funding Source: Swiss National Science Foundation, Research Council of Norway, and an Intermountain-Stanford collaboration.
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February 2020

Use of E-values for addressing confounding in observational studies-an empirical assessment of the literature.

Int J Epidemiol 2020 10;49(5):1482-1494

Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA, USA.

Background: E-values are a recently introduced approach to evaluate confounding in observational studies. We aimed to empirically assess the current use of E-values in published literature.

Methods: We conducted a systematic literature search for all publications, published up till the end of 2018, which cited at least one of two inceptive E-value papers and presented E-values for original data. For these case publications we identified control publications, matched by journal and issue, where the authors had not calculated E-values.

Results: In total, 87 papers presented 516 E-values. Of the 87 papers, 14 concluded that residual confounding likely threatens at least some of the main conclusions. Seven of these 14 named potential uncontrolled confounders. 19 of 87 papers related E-value magnitudes to expected strengths of field-specific confounders. The median E-value was 1.88, 1.82, and 2.02 for the 43, 348, and 125 E-values where confounding was felt likely to affect the results, unlikely to affect the results, or not commented upon, respectively. The 69 case-control publication pairs dealt with effect sizes of similar magnitude. Of 69 control publications, 52 did not comment on unmeasured confounding and 44/69 case publications concluded that confounding was unlikely to affect study conclusions.

Conclusions: Few papers using E-values conclude that confounding threatens their results, and their E-values overlap in magnitude with those of papers acknowledging susceptibility to confounding. Facile automation in calculating E-values may compound the already poor handling of confounding. E-values should not be a substitute for careful consideration of potential sources of unmeasured confounding. If used, they should be interpreted in the context of expected confounding in specific fields.
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October 2020

Infographic. How does exercise treatment compare with antihypertensive medications?

Br J Sports Med 2020 Jun 19;54(12):746-747. Epub 2019 Dec 19.

Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, USA.

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June 2020

Skeletal Effects of Levothyroxine for Subclinical Hypothyroidism in Older Adults: A TRUST Randomized Trial Nested Study.

J Clin Endocrinol Metab 2020 01;105(1)

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

Context: Both thyroid dysfunction and levothyroxine (LT4) therapy have been associated with bone loss, but studies on the effect of LT4 for subclinical hypothyroidism (SHypo) on bone yielded conflicting results.

Objective: To assess the effect of LT4 treatment on bone mineral density (BMD), Trabecular Bone Score (TBS), and bone turnover markers (BTMs) in older adults with SHypo.

Design And Intervention: Planned nested substudy of the double-blind placebo-controlled TRUST trial. Participants with SHypo were randomized to LT4 with dose titration versus placebo with computerized mock titration.

Setting And Participants: 196 community-dwelling adults over 65 years enrolled at the Swiss TRUST sites had baseline and 1-year follow-up bone examinations; 4 participants withdrew due to adverse events not related to treatment.

Main Outcome Measures: One-year percentage changes of BMD, TBS, and 2 serum BTMs (serum CTX-1 [sCTX] and procollagen type 1 N-terminal polypeptide [P1NP]). Student's t-test for unadjusted analyses and linear regression adjusted for clinical center and sex were performed.

Results: Mean age was 74.3 years ± 5.7, 45.4% were women, and 19.6% were osteoporotic. The unadjusted 1-year change in lumbar spine BMD was similar between LT4 (+0.8%) and placebo-treated groups (-0.6%; between-groups difference +1.4%: 95% confidence interval [CI] -0.1 to 2.9, P = .059). Likewise, there were no between-group differences in 1-year change in TBS (-1.3%: 95% CI -3.1 to 0.6, P = .19), total hip BMD (-0.2%: 95% CI -1.1 to 0.1, P = .61), or BTMs levels (sCTX +24.1%: 95% CI -7.9 to 56.2, P = .14), or after adjustment for clinical centers and sex.

Conclusions: Over 1-year levothyroxine had no effect on bone health in older adults with SHypo.

Registration: NCT01660126 and NCT02491008.
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January 2020

Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism.

JAMA 2019 Nov;322(20):1977-1986

Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.

Importance: It is unclear whether levothyroxine treatment provides clinically important benefits in adults aged 80 years and older with subclinical hypothyroidism.

Objective: To determine the association of levothyroxine treatment for subclinical hypothyroidism with thyroid-related quality of life in adults aged 80 years and older.

Design, Setting, And Participants: Prospectively planned combined analysis of data involving community-dwelling adults aged 80 years and older with subclinical hypothyroidism. Data from a randomized clinical trial were combined with a subgroup of participants aged 80 years and older from a second clinical trial. The trials were conducted between April 2013 and May 2018. Final follow-up was May 4, 2018.

Exposures: Participants were randomly assigned to receive levothyroxine (n = 112; 52 participants from the first trial and 60 from the second trial) or placebo (n = 139; 53 participants from the first trial and 86 from the second trial).

Main Outcomes And Measures: Co-primary outcomes were Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire scores for the domains of hypothyroid symptoms and tiredness at 1 year (range, 0-100; higher scores indicate worse quality of life; minimal clinically important difference, 9).

Results: Of 251 participants (mean age, 85 years; 118 [47%] women), 105 were included from the first clinical trial and 146 were included from the second clinical trial. A total of 212 participants (84%) completed the study. The hypothyroid symptoms score decreased from 21.7 at baseline to 19.3 at 12 months in the levothyroxine group vs from 19.8 at baseline to 17.4 at 12 months in the placebo group (adjusted between-group difference, 1.3 [95% CI, -2.7 to 5.2]; P = .53). The tiredness score increased from 25.5 at baseline to 28.2 at 12 months in the levothyroxine group vs from 25.1 at baseline to 28.7 at 12 months in the placebo group (adjusted between-group difference, -0.1 [95% CI, -4.5 to 4.3]; P = .96). At least 1 adverse event occurred in 33 participants (29.5%) in the levothyroxine group (the most common adverse event was cerebrovascular accident, which occurred in 3 participants [2.2%]) and 40 participants (28.8%) in the placebo group (the most common adverse event was pneumonia, which occurred in 4 [3.6%] participants).

Conclusions And Relevance: In this prospectively planned analysis of data from 2 clinical trials involving adults aged 80 years and older with subclinical hypothyroidism, treatment with levothyroxine, compared with placebo, was not significantly associated with improvement in hypothyroid symptoms or fatigue. These findings do not support routine use of levothyroxine for treatment of subclinical hypothyroidism in adults aged 80 years and older.

Trial Registration: Identifier: NCT01660126; Netherlands Trial Register: NTR3851.
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November 2019

Atherosclerotic Cardiovascular Disease Risk Prediction in Disaggregated Asian and Hispanic Subgroups Using Electronic Health Records.

J Am Heart Assoc 2019 07 11;8(14):e011874. Epub 2019 Jul 11.

3 Division of Primary Care and Population Health Stanford University School of Medicine Stanford CA.

Background Risk assessment is the cornerstone for atherosclerotic cardiovascular disease ( ASCVD ) treatment decisions. The Pooled Cohort Equations ( PCE ) have not been validated in disaggregated Asian or Hispanic populations, who have heterogeneous cardiovascular risk and outcomes. Methods and Results We used electronic health record data from adults aged 40 to 79 years from a community-based, outpatient healthcare system in northern California between January 1, 2006 and December 31, 2015, without ASCVD and not on statins. We examined the calibration and discrimination of the PCE and recalibrated the equations for disaggregated race/ethnic subgroups. The cohort included 231 622 adults with a mean age of 53.1 (SD 9.7) years and 54.3% women. There were 56 130 Asian (Chinese, Asian Indian, Filipino, Japanese, Vietnamese, and other Asian) and 19 760 Hispanic (Mexican, Puerto Rican, and other Hispanic) patients. There were 2703 events (332 and 189 in Asian and Hispanic patients, respectively) during an average of 3.9 (SD 1.5) years of follow-up. The PCE overestimated risk for NHW s, African Americans, Asians, and Hispanics by 20% to 60%. The extent of overestimation of ASCVD risk varied by disaggregated racial/ethnic subgroups, with a predicted-to-observed ratio of ASCVD events ranging from 1.1 for Puerto Rican patients to 1.9 for Chinese patients. The PCE had adequate discrimination, although it varied significantly by race/ethnic subgroups (C-indices 0.66-0.83). Recalibration of the PCE did not significantly improve its performance. Conclusions Using electronic health record data from a large, real-world population, we found that the PCE generally overestimated ASCVD risk, with marked heterogeneity by disaggregated Asian and Hispanic subgroups.
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July 2019

Diabetes-attributable mortality in the United States from 2003 to 2016 using a multiple-cause-of-death approach.

Diabetes Res Clin Pract 2019 Feb 11;148:169-178. Epub 2019 Jan 11.

Division of Primary Care and Population Health, Stanford University School of Medicine, Stanford, CA, United States.

Aims: Deaths attributable to diabetes may be underestimated using an underlying cause of death (COD) approach in U.S. death records. This study sought to characterize the burden of diabetes deaths using a multiple-cause of death approach (underlying and contributing COD) and to identify temporal changes in co-reported causes of death among those with diabetes listed anywhere on their death records.

Methods: COD were identified using data from the National Center for Health Statistics from 2003 to 2016. We calculated age-adjusted mortality rates for diabetes as the underlying or contributing COD by race/ethnicity. We used ICD-10 codes to identify leading causes of death among those with and without diabetes on their death records. We compared temporal changes in deaths due to cardiovascular disease, cerebrovascular disease, cancer, and other causes.

Results: The study population included 34,313,964 decedents aged ≥25 from 2003 to 2016. Diabetes was listed as an underlying COD in approximately 3.0% (n = 1,031,000) and 6.7% (n = 2,295,510) of the death records, respectively. Decedents with diabetes listed as an underlying COD experienced a 16% decline in mortality, and the race/ethnicity-specific average annual percentage changes (AAPC) showed significant declining trends for most groups (AAPC ranged from 0.18 to -2.83%). Cardiovascular disease remained the leading underlying COD among diabetes-attributable deaths, although its proportion of deaths fell from 31 to 27% over time. Co-reported COD diversified, and were more likely to include hypertension and hypertensive renal disease among those with diabetes on their death records.

Conclusions: Our findings underscore the importance of using a multiple-cause-of-death approach for more completely characterizing diabetes' contribution to mortality.
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February 2019

Limitations and Misinterpretations of E-Values for Sensitivity Analyses of Observational Studies.

Ann Intern Med 2019 01 1;170(2):108-111. Epub 2019 Jan 1.

Meta-Research Innovation Center at Stanford (METRICS), Stanford University Stanford, California; and Bern University Hospital, University of Bern, Bern, Switzerland (M.R.B.).

The E-value was recently introduced on the basis of earlier work as "the minimum strength of association…that an unmeasured confounder would need to have with both the treatment and the outcome to fully explain away a specific treatment-outcome association, conditional on the measured covariates." E-values have been proposed for wide application in observational studies evaluating causality. However, they have limitations and are prone to misinterpretation. E-values have a monotonic, almost linear relationship with effect estimates and thus offer no additional information beyond what effect estimates can convey. Whereas effect estimates are based on real data, E-values may make unrealistic assumptions. No general rule can exist about what is a "small enough" E-value, and users of the biomedical literature are not familiar with how to interpret a range of E-values. Problems arise for any measure dependent on effect estimates and their CIs-for example, bias due to selective reporting and dependence on choice of exposure contrast and level of confidence. The automation of E-values may give an excuse not to think seriously about confounding. Moreover, biases other than confounding may still undermine results. Instead of misused or misinterpreted E-values, the authors recommend judicious use of existing methods for sensitivity analyses with careful assumptions; systematic assessments of whether and how known confounders have been handled, along with consideration of their prevalence and magnitude; thorough discussion of the potential for unknown confounders considering the study design and field of application; and explicit caution in making causal claims from observational studies.
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January 2019

How does exercise treatment compare with antihypertensive medications? A network meta-analysis of 391 randomised controlled trials assessing exercise and medication effects on systolic blood pressure.

Br J Sports Med 2019 Jul 18;53(14):859-869. Epub 2018 Dec 18.

Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, USA.

Objective: To compare the effect of exercise regimens and medications on systolic blood pressure (SBP).

Data Sources: Medline (via PubMed) and the Cochrane Library.

Eligibility Criteria: Randomised controlled trials (RCTs) of angiotensin-converting enzyme inhibitors (ACE-I), angiotensin-2 receptor blockers (ARBs), β-blockers, calcium channel blockers (CCBs) and diuretics were identified from existing Cochrane reviews. A previously published meta-analysis of exercise interventions was updated to identify recent RCTs that tested the SBP-lowering effects of endurance, dynamic resistance, isometric resistance, and combined endurance and resistance exercise interventions (up to September 2018).

Design: Random-effects network meta-analysis.

Outcome: Difference in mean change from baseline SBP between comparator treatments (change from baseline in one group minus that in the other group) and its 95% credible interval (95% CrI), measured in mmHg.

Results: We included a total of 391 RCTs, 197 of which evaluated exercise interventions (10 461 participants) and 194 evaluated antihypertensive medications (29 281 participants). No RCTs compared directly exercise against medications. While all medication trials included hypertensive populations, only 56 exercise trials included hypertensive participants (≥140 mmHg), corresponding to 3508 individuals. In a 10% random sample, risk of bias was higher in exercise RCTs, primarily due to lack of blinding and incomplete outcome data. In analyses that combined all populations, antihypertensive medications achieved higher reductions in baseline SBP compared with exercise interventions (mean difference -3.96 mmHg, 95% CrI -5.02 to -2.91). Compared with control, all types of exercise (including combination of endurance and resistance) and all classes of antihypertensive medications were effective in lowering baseline SBP. Among hypertensive populations, there were no detectable differences in the SBP-lowering effects of ACE-I, ARB, β-blocker and diuretic medications when compared with endurance or dynamic resistance exercise. There was no detectable inconsistency between direct and indirect comparisons. Although there was evidence of small-study effects, this affected both medication and exercise trials.

Conclusions: The effect of exercise interventions on SBP remains under-studied, especially among hypertensive populations. Our findings confirm modest but consistent reductions in SBP in many studied exercise interventions across all populations but individuals receiving medications generally achieved greater reductions than those following structured exercise regimens. Assuming equally reliable estimates, the SBP-lowering effect of exercise among hypertensive populations appears similar to that of commonly used antihypertensive medications. Generalisability of these findings to real-world clinical settings should be further evaluated.
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July 2019

Cosyntropin testing does not predict response to glucocorticoids in community-acquired pneumonia in a randomized controlled trial.

Clin Endocrinol (Oxf) 2019 09 9;91(3):374-382. Epub 2019 Jan 9.

Endocrinology, Diabetology and Metabolism, Department of Internal Medicine and Department of Clinical Research, University Hospital Basel, Basel, Switzerland.

Objective: Glucocorticoids have been shown to improve outcome in community-acquired pneumonia (CAP). However, glucocorticoids have potential side-effects, and treatment response may vary. It is thus crucial to select patients with high likelihood to respond favourably. In critical illness, cosyntropin testing is recommended to identify patients in need for glucocorticoids. We investigated whether cosyntropin testing predicts treatment response to glucocorticoids in CAP.

Design: Predefined secondary analysis of a randomized controlled trial.

Patients: Hospitalized patients with CAP.

Measurements: We performed 1 µg cosyntropin tests in a randomized trial comparing prednisone 50 mg for 7 days to placebo. We investigated whether subgroups based on baseline and stimulated cortisol levels responded differently to glucocorticoids with regard to time to clinical stability (TTCS) and other outcomes by inclusion of interaction terms into statistical models.

Results: A total of 326 patients in the prednisone and 309 patients in the placebo group were evaluated. Neither basal cortisol nor a Δcortisol <250 nmol/L after stimulation nor the combination of basal cortisol and Δcortisol predicted treatment response as measured by TTCS (all P for interaction >0.05). Similarly, we found no effect modification with respect to mortality, rehospitalization, antibiotic treatment duration or CAP-related complications (all P for interaction >0.05). However, glucocorticoids had a stronger effect on shortening length of hospital stay in patients with a baseline cortisol of ≥938 nmol/L (P for interaction = 0.015).

Conclusions: Neither baseline nor stimulated cortisol after low-dose cosyntropin testing at a dose of 1 µg predicted glucocorticoid responsiveness in mild to moderate CAP. A treatment decision for or against adjunct glucocorticoids in CAP should not be made depending on cortisol values or cosyntropin testing results.
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September 2019

Impact of Thyroid Hormone Therapy on Atherosclerosis in the Elderly With Subclinical Hypothyroidism: A Randomized Trial.

J Clin Endocrinol Metab 2018 08;103(8):2988-2997

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

Context: Subclinical hypothyroidism (SHypo) has been associated with atherosclerosis, but no conclusive clinical trials assessing the levothyroxine impact on carotid atherosclerosis exist.

Objective: To assess the impact of treatment of SHypo with levothyroxine on carotid atherosclerosis.

Design And Setting: Randomized, double-blind, placebo-controlled trial nested within the Thyroid Hormone Replacement for Subclinical Hypothyroidism trial.

Participants: Participants aged ≥65 years with SHypo [thyroid-stimulating hormone (TSH), 4.60 to 19.99 mIU/L; free thyroxine level within reference range].

Intervention: Levothyroxine dose-titrated to achieve TSH normalization or placebo, including mock titrations.

Main Outcome Measures: Carotid intima media thickness (CIMT), maximum plaque thickness measured with ultrasound.

Results: One hundred eighty-five participants (mean age 74.1 years, 47% women, 96 randomized to levothyroxine) underwent carotid ultrasound. Overall mean TSH ± SD was 6.35 ± 1.95 mIU/L at baseline and decreased to 3.55 ± 2.14 mIU/L with levothyroxine compared with 5.29 ± 2.21 mIU/L with placebo (P < 0.001). After a median treatment of 18.4 months (interquartile range 12.2 to 30.0 months), mean CIMT was 0.85 ± 0.14 mm under levothyroxine and 0.82 ± 0.13 mm under placebo [between-group difference = 0.02 mm; 95% CI, -0.01 to 0.06; P = 0.30]. The proportion of carotid plaque was similar (n = 135; 70.8% under levothyroxine and 75.3% under placebo; P = 0.46). Maximum carotid plaque thickness was 2.38 ± 0.92 mm under levothyroxine and 2.37 ± 0.91 mm under placebo (between-group difference -0.03; 95% CI, -0.34 to 0.29; P = 0.86). There were no significant interactions between levothyroxine treatment and mean CIMT, according to sex, baseline TSH (categories 4.6 to 6.9, 7.0 to 9.9, and ≥10 mIU/L), or established cardiovascular disease (all P for interaction ≥ 0.14).

Conclusion: Normalization of TSH with levothyroxine was associated with no difference in CIMT and carotid atherosclerosis in older persons with SHypo.
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August 2018

Prevalence of potentially inappropriate prescribing in a subpopulation of older European clinical trial participants: a cross-sectional study.

BMJ Open 2018 03 22;8(3):e019003. Epub 2018 Mar 22.

School of Public Health, University College Cork, Cork, Republic of Ireland.

Objectives: To estimate and compare the prevalence and type of potentially inappropriate prescribing (PIP) and potential prescribing omissions (PPOs) among community-dwelling older adults (≥65 years) enrolled to a clinical trial in three European countries.

Design: A secondary analysis of the Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial dataset.

Participants: A subset of 48/80 PIP and 22/34 PPOs indicators from the Screening Tool of Older Persons Prescriptions/Screening Tool to Alert doctors to Right Treatment (STOPP/START) V2 criteria were applied to prescribed medication data for 532/737 trial participants in Ireland, Switzerland and the Netherlands.

Results: The overall prevalence of PIP was lower in the Irish participants (8.7%) compared with the Swiss (16.7%) and Dutch (12.5%) participants (P=0.15) and was not statistically significant. The overall prevalence of PPOs was approximately one-quarter in the Swiss (25.3%) and Dutch (24%) participants and lower in the Irish (14%) participants (P=0.04) and the difference was statistically significant. The hypnotic Z-drugs were the most frequent PIP in Irish participants, (3.5%, n=4), while it was non-steroidal anti-inflammatory drug and oral anticoagulant combination, sulfonylureas with a long duration of action, and benzodiazepines (all 4.3%, n=7) in Swiss, and benzodiazepines (7.1%, n=18) in Dutch participants. The most frequent PPOs in Irish participants were vitamin D and calcium in osteoporosis (3.5%, n=4). In the Swiss and Dutch participants, they were bone antiresorptive/anabolic therapy in osteoporosis (9.9%, n=16, 8.6%, n=22) respectively. The odds of any PIP after adjusting for age, sex, multimorbidity and polypharmacy were (adjusted OR (aOR)) 3.04 (95% CI 1.33 to 6.95, P<0.01) for Swiss participants and aOR 1.74 (95% CI 0.79 to 3.85, P=0.17) for Dutch participants compared with Irish participants. The odds of any PPOs were aOR 2.48 (95% CI 1.27 to 4.85, P<0.01) for Swiss participants and aOR 2.10 (95% CI 1.11 to 3.96, P=0.02) for Dutch participants compared with Irish participants.

Conclusions: This study has estimated and compared the prevalence and type of PIP and PPOs among this cohort of community-dwelling older people. It demonstrated a significant difference in the prevalence of PPOs between the three populations. Further research is urgently needed into the impact of system level factors as this has important implications for patient safety, healthcare provision and economic costs.
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March 2018

[Subclinical hypothyroidism : should we still treat elderly patients? Clinical implications of a new trial in primary care].

Rev Med Suisse 2018 Feb;14(596):470-474

Policlinique médicale, Clinique universitaire de médecine interne générale, Hôpital de l'Ile, et Berner Institut für Hausarztmedizin (BIHAM), Université de Berne, 3000 Berne.

Subclinical hypothyroidism, defined as an elevated level of thyrotropin hormone (TSH) and normal thyroxin, is more frequent in women and above 65 years old. This condition is associated with an increased cardiovascular risk, in particular with TSH > 10,0 mIU/L. Although overt hypothyroidism is rare (prevalence of 0,3 %), levothyroxine has become the most prescribed medication in the US, while its indications are still debated. The European-funded TRUST trial showed no improvement in Hypothyroid Symptoms and Tiredness scores among patients ≥ 65 years with subclinical hypothyroidism treated with levothyroxine, and no improvement in blood pressure, weight, muscle strength and cognition. The results of this study call for a revision of the current international recommendations on the treatment of subclinical hypothyroidism.
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February 2018

Thyroid Function Tests in the Reference Range and Fracture: Individual Participant Analysis of Prospective Cohorts.

J Clin Endocrinol Metab 2017 08;102(8):2719-2728

Leiden University Medical Center, Department of Clinical Chemistry and Laboratory Medicine, 2300 RC Leiden, The Netherlands.

Context: Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower thyroid-stimulating hormone (TSH) and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk.

Objective: To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals.

Design: Individual participant data analysis.

Setting: Thirteen prospective cohort studies with baseline examinations between 1981 and 2002.

Participants: Adults with baseline TSH 0.45 to 4.49 mIU/L.

Main Outcome Measures: Primary outcome was incident hip fracture. Secondary outcomes were any, nonvertebral, and vertebral fractures. Results were presented as hazard ratios (HRs) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45 to 0.99 mIU/L; 1.00 to 1.49 mIU/L; 1.50 to 2.49 mIU/L; 2.50 to 3.49 mIU/L; and 3.50 to 4.49 mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts.

Results: During 659,059 person-years, 2,565 out of 56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05 to 1.49) for TSH 0.45 to 0.99 mIU/L, 1.19 (1.01 to 1.41) for TSH 1.00 to 1.49 mIU/L, 1.09 (0.93 to 1.28) for TSH 1.50 to 2.49 mIU/L, and 1.12 (0.94 to 1.33) for TSH 2.50 to 3.49 mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 [HR (95% CI) 1.22 (1.11 to 1.35) per one standard deviation increase in FT4]. FT4 only was associated with any and nonvertebral fractures. Results remained similar in sensitivity analyses.

Conclusions: Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests.
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August 2017

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism.

N Engl J Med 2017 06 3;376(26):2534-2544. Epub 2017 Apr 3.

From the Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences (D.J.S., K.H., P.L., M. McDade, T.J.Q.), the Robertson Centre for Biostatistics, Institute of Health and Wellbeing (I.F., S.K., A.M., M. Messow, R.W.), and the Institute of Cardiovascular and Medical Sciences (N.S.), University of Glasgow, Glasgow, and Care of the Elderly-Rehabilitation, Monklands Hospital, NHS Lanarkshire, Airdrie (G.E.) - all in the United Kingdom; the Department of General Internal Medicine, Inselspital, Bern University Hospital (N.R., C.E.A., D.A., C.B., M.R.B., M.F., C.F., D.K., H.A.V.D.), and the Institute of Primary Health Care (N.R., M.F.), University of Bern, Bern, and the Service of Endocrinology, Diabetes, and Metabolism, University Hospital of Lausanne, Lausanne (T.-H.C.) - all in Switzerland; the Department of Epidemiology and Public Health (P.M.K., J.P.B., C.H., G.M., A.O., D.O., C.S., K.A.W., E.K.W.), the Pharmaceutical Care Research Group, School of Pharmacy (S.B., M.K., K.A.W.), the School of Nursing and Midwifery (V.M.), and the Department of General Practice (A.R., E.K.W.), University College Cork, and the Health Research Board Clinical Research Facility, Mercy University Hospital (M.K.) - all in Cork, Ireland; the Department of Public Health and Center for Healthy Aging, University of Copenhagen (R.G.J.W.), and the Department of Medical Endocrinology, Copenhagen University Hospital Rigshospitalet (T.W.), Copenhagen, and the Department of Internal Medicine, Copenhagen University Hospital Herlev, Herlev (T.W.) - all in Denmark; the Departments of Gerontology and Geriatrics (S.P.M.), Internal Medicine (O.M.D.), Clinical Epidemiology (O.M.D.), Clinical Chemistry and Laboratory Medicine (W.P.J.E.), Public Health and Primary Care (R.S.D.P., R.K.E.P., J.G.), and Cardiology (J.W.J.), Leiden University Medical Center, and the Institute for Evidence-based Medicine in Old Age (S.P.M.), Leiden, and Radboud University Medical Center, Nijmegen (J.W.A.S.) - all in the Netherlands; and the Departments of Medicine, Epidemiology, and Biostatistics, University of California, San Francisco, San Francisco (D.C.B.).

Background: The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition.

Methods: We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points).

Results: The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest.

Conclusions: Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST number, NCT01660126 .).
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June 2017

Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis.

J Clin Endocrinol Metab 2016 11 7;101(11):4270-4282. Epub 2016 Sep 7.

Departments of Internal Medicine (R.P.P., L.C., M.M.) and Epidemiology (R.P.P., O.H.F., A.D., A.H., A.I., L.C., M.L.P.P.), Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands; Rotterdam Thyroid Center (R.P.P., L.C., M.M.) and Department of Radiology and Neurology (M.A.I.), Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands; Department of General Internal Medicine (N.R., C.B., M.R.B.), Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; Service of Endocrinology, Diabetes, and Metabolism (T.-H.C.), University Hospital of Lausanne, 1011 Lausanne, Switzerland; Departments of Clinical Chemistry and Laboratory Medicine (W.P.J.d.E.), Public Health and Primary Care (J.G.), and Cardiology (W.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Departments of Medicine and Epidemiology and Biostatistics (D.C.B.), University of California, San Francisco, San Francisco, California 94143; Division of Endocrinology, Diabetes, and Metabolism (A.R.C.), Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; Department of Epidemiology (A.H.), Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115; Department of Endocrinology (S.R.), Gateshead Health Foundation National Health Service Trust, Gateshead, SE18 4QH, United Kingdom; Department of Endocrinology and Diabetes (J.P.W.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Schools of Medicine and Pharmacology (J.P.W.) and Population Health (A.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; National Council Research Institute of Clinical Physiology (G.I.), 56124 Pisa, Italy; Robertson Centre for Biostatistics (I.F.) and Institute of Cardiovascular and Medical Sciences (D.J.S.), Faculty of Medicine, University of Glasgow, Glasgow G12 8TA, United Kingdom; Department of Epidemiology (A.B.N.), University of Pittsburgh, Pittsburgh, Pennsylvania 15260; Department of Internal Medicine (S.J.L.B., R.P.D.), University Medical Center, University of Groningen, 9700 AB Groningen, The Netherlands; Department of Medicine (C.W., C.D.), Division of Nephrology, University Hospital of Würzburg, and Comprehensive Heart Failure Centre (C.W., C.D.), 97070 Würzburg, Germany; Department of Clinical Studies (M.I.), Radiation Effects Research Foundation, Nagasaki 850-8555, Japan; Department of Clinical and Experimental Medicine (G.C.), University of Parma, 143100 Parma, Italy; National Institute on Aging (L.F.), Baltimore, Maryland 21225; Institute for Community Medicine (H.V.), Clinical-Epidemiological Research/Study of Health in Pomerania, University Medicine, German Centre of Cardiovascular Research, Partner Site, Department of Internal Medicine (M.D.), and University Medicine (M.D.), German Centre of Cardiovascular Research, Partner Site, 17487 Greifswald, Germany; Departments of Neurology and Epidemiology (W.T.L.), and Cardiovascular Health Research Unit (W.T.L.), Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington 98108; Group Health Research Institute (B.M.P.), Group Health Cooperative, Seattle, Washington 98101; Division of Endocrinology (R.M.B.M., J.A.S.), Department of Medicine, Federal University of Sao Paulo, 05508-900 São Paulo, Brazil; Division of Endocrinology (J.A.S.), Faculdade de Medicina de Marília, Marília, Brazil; Department of Public Health and Primary Care (R.N.L., K.-T.K.), University of Cambridge, Cambridge CB2 1TN, United Kingdom; Interuniversity Cardiology Institute of The Netherlands (W.J.), 3508 GA Utrecht, The Netherlands; School of Clinical and Experimental Medicine (J.A.F.), College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and Department of Public Health and Center for Healthy Ageing (R.G.W.), Faculty of Health and Medical Sciences, University of Copenhagen, DK-2400 Copenhagen, Denmark.

Context: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously.

Design And Setting: We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L.

Results: We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1-13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95% confidence interval [CI] 0.65-0.95 across the reference range of TSH) for all stroke and 0.83 (95% CI 0.62-1.09) for fatal stroke. For the free T analyses, the hazard ratio was 1.08 (95% CI 0.99-1.15 per SD increase) for all stroke and 1.10 (95% CI 1.04-1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes.

Conclusion: Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function.
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November 2016