The Early HOSPITAL Score to Predict 30-Day Readmission Soon After Hospitalization: a Prospective Multicenter Study.

BACKGROUND: The simplified HOSPITAL score is an easy-to-use prediction model to identify patients at high risk of 30-day readmission before hospital discharge. An earlier stratification of this risk would allow more preparation time for transitional care interventions. OBJECTIVE: To assess whether the simplified HOSPITAL score would perform similarly by using hemoglobin and sodium level at the time of admission instead of discharge. DESIGN: Prospective national multicentric cohort study. PARTICIPANTS: In total, 934 consecutively discharged medical inpatients from internal general services. MAIN MEASURES: We measured the composite of the first unplanned readmission or death within 30 days after discharge of index admission and compared the performance of the simplified score with lab at discharge (simplified HOSPITAL score) and lab at admission (early HOSPITAL score) according to their discriminatory power (Area Under the Receiver Operating characteristic Curve (AUROC)) and the Net Reclassification Improvement (NRI). KEY RESULTS: During the study period, a total of 3239 patients were screened and 934 included. In total, 122 (13.2%) of them had a 30-day unplanned readmission or death. The simplified and the early versions of the HOSPITAL score both showed very good accuracy (Brier score 0.11, 95%CI 0.10-0.13). Their AUROC were 0.66 (95%CI 0.60-0.71), and 0.66 (95%CI 0.61-0.71), respectively, without a statistical difference (p value 0.79). Compared with the model at discharge, the model with lab at admission showed improvement in classification based on the continuous NRI (0.28; 95%CI 0.08 to 0.48; p value 0.004). CONCLUSION: The early HOSPITAL score performs, at least similarly, in identifying patients at high risk for 30-day unplanned readmission and allows a readmission risk stratification early during the hospital stay. Therefore, this new version offers a timely preparation of transition care interventions to the patients who may benefit the most.

The effect of thyroid hormone therapy on muscle function, strength and mass in older adults with subclinical hypothyroidism-an ancillary study within two randomized placebo controlled trials.

BACKGROUND: loss of skeletal muscle function, strength and mass is common in older adults, with important socioeconomic impacts. Subclinical hypothyroidism is common with increasing age and has been associated with reduced muscle strength. Yet, no randomized placebo-controlled trial (RCT) has investigated whether treatment of subclinical hypothyroidism affects muscle function and mass. METHODS: this is an ancillary study within two RCTs conducted among adults aged ≥65 years with persistent subclinical hypothyroidism (thyrotropin (TSH) 4.60-19.99 mIU/l, normal free thyroxine). Participants received daily levothyroxine with TSH-guided dose adjustment or placebo and mock titration. Primary outcome was gait speed at final visit (median 18 months). Secondary outcomes were handgrip strength at 1-year follow-up and yearly change in muscle mass. RESULTS: we included 267 participants from Switzerland and the Netherlands. Mean age was 77.5 years (range 65.1-97.1), 129 (48.3%) were women, and their mean baseline TSH was 6.36 mIU/l (standard deviation [SD] 1.9). At final visit, mean TSH was 3.8 mIU/l (SD 2.3) in the levothyroxine group and 5.1 mIU/l (SD 1.8, P < 0.05) in the placebo group. Compared to placebo, participants in the levothyroxine group had similar gait speed at final visit (adjusted between-group mean difference [MD] 0.01 m/s, 95% confidence interval [CI] -0.06 to 0.09), similar handgrip strength at one year (MD -1.22 kg, 95% CI -2.60 to 0.15) and similar yearly change in muscle mass (MD -0.15 m2, 95% CI -0.49 to 0.18). CONCLUSIONS: in this ancillary analysis of two RCTs, treatment of subclinical hypothyroidism did not affect muscle function, strength and mass in individuals 65 years and older.

Thyroid antibodies and levothyroxine effects in subclinical hypothyroidism: A pooled analysis of two randomized controlled trials.

BACKGROUND: Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4). OBJECTIVE: To determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies. METHODS: We pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti-thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1-year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire. RESULTS: Among 660 participants (54% women) ≥65 years, 188 (28.5%) had positive anti-TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between-group difference of -2.07 (95% confidence interval: -6.04 to 1.90) for positive antibodies versus 0.89 (-1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores-adjusted between-group difference 1.75 (-3.60 to 7.09) for positive antibodies versus 1.14 (-1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti-TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment. CONCLUSIONS: Among older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4.

Barriers and facilitators to mobility of patients hospitalised on an acute medical ward: a systematic review.

BACKGROUND: low patient mobility is common during hospitalisation and is associated with adverse outcomes. To change practice, interventions should address barriers and facilitators to mobility. Our aim was to systematically review the literature to provide a synthesised overview of patient-, health care professional (HCP)- and environment-/system-related barriers and facilitators to mobility of patients hospitalised on an acute care medical ward. METHODS: we searched Medline, Embase, PsycInfo, Web of Science Core Collection, Cochrane CENTRAL, CINHAHL and Google Scholar (inception to 18 October 2021) to identify studies reporting barriers and/or facilitators to mobility of adults hospitalised on an acute medical ward. We applied a deductive and inductive thematic analysis to classify barriers and facilitators into themes and subthemes relevant for clinical practice. RESULTS: among 26 studies (16 qualitative, 7 quantitative and 3 mixed methods), barriers and facilitators were categorised into 10 themes: patient situation, knowledge, beliefs, experiences, intentions, emotions, social influences, role/identity, implementation/organisation and environment/resources. Barriers included patient characteristics (e.g. impaired cognitive/physical status) and symptoms, HCPs prioritising other tasks over mobility, HCPs labelling patients as 'too sick', fear of injury, lack of time, lack of clarity about responsibility, patient medical devices and non-encouraging environment. Facilitators included knowledge of mobility importance, HCP skills, interdisciplinarity, documentation and unit expectations, encouraging staff, goal individualisation, activity programme, family/visitor/volunteer support and availability of equipment. CONCLUSION: this synthesised overview of patient-, HCP- and environment-/system-related barriers and facilitators to mobility of adults hospitalised on an acute medical ward can help researchers and clinicians focus on what can realistically be influenced to improve mobility. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021285954.

Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.

BACKGROUND: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

[Polypharmacy and inappropriate medications in multimorbid elderly patients - What OPERAM taught us and will teach us]. / Polypharmacie et medicaments inappropriés chez les patients âgés multimorbides - Ce que l'étude OPERAM nous apprend et va nous apprendre.

Polypharmacy and inappropriate medication use are very common in multimorbid older patients. This population has unfortunately been excluded from most large, randomized studies. In a recent multicenter randomized study (OPERAM), we included over 2000 multimorbid patients. We found that 86% of the patients aged 70 years and more had inappropriate medications and that these medications could be discontinued without negative impact on the health of these patients. This cohort of multimorbid patients will be followed for 10 years to evaluate their prognosis, life expectancy, treatments and quality of life, with numerous projects to better understand the inappropriate prescribing of individual drugs and their consequences on the health of this population.

La polypharmacie et les médicaments inappropriés sont très fréquents chez les patients âgés multimorbides. Cette population a malheureusement été exclue de la plupart des grandes études randomisées. Dans une récente étude randomisée multicentrique (OPERAM), nous avons inclus plus de 2000 patients multimorbides. Celle-ci a montré que 86 % des patients âgés de 70 ans et plus avaient des médicaments inappropriés et qu'il était possible de stopper leur administration, sans répercussion négative sur leur santé. Ces patients multimorbides constituent une cohorte qui va être suivie sur 10 ans pour évaluer leurs pronostic, espérance de vie, traitements et qualité de vie. Cela permettra la réalisation de nombreux projets, notamment pour mieux comprendre les conséquences de la prescription inappropriée de médicaments.

Single early palliative care intervention added to usual oncology care for patients with advanced cancer: A randomized controlled trial (SENS Trial).

BACKGROUND: International oncology societies recommend early palliative care. Specific models to integrate early palliative care efficiently into clinical practice are debated. The authors designed a study to look at the quantitative and qualitative outcomes of an early palliative care intervention in oncological care to decrease stress and improve quality of life. AIMS: To compare a single structured early palliative care intervention added to a usual oncology care in terms of distress and health-related quality of life at baseline compared to 6 months after enrollment. DESIGN: This multicenter randomized controlled trial (NCT01983956) enrolled adult patients with advanced cancer. Participants were either randomly assigned to usual oncology care alone or usual care plus a structured early palliative care intervention. SETTING/PARTICIPANTS: One hundred fifty adult patients with a variety of advanced cancer diagnoses were randomized. Seventy-four participants were in the intervention and 76 participants in the control group. The primary outcome was the change in patient distress assessed by the National Comprehensive Cancer Network distress thermometer at 6 months. Health-related quality of life, the secondary outcome, was assessed by the Functional Assessment of Cancer Therapy-General Questionnaire. RESULTS: The results showed no significant effect of the early palliative care intervention neither on patient distress nor on health-related quality of life. CONCLUSION: The addition of an early intervention to usual care for patients with advanced cancer did not improve distress or quality of life. Thus, patients may need more intensive early palliative care with continuous professional support to identify and address their palliative needs early.

L-Thyroxine Therapy for Older Adults With Subclinical Hypothyroidism and Hypothyroid Symptoms: Secondary Analysis of a Randomized Trial.

BACKGROUND: L-thyroxine does not improve hypothyroid symptoms among adults with subclinical hypothyroidism (SCH). However, those with greater symptom burden before treatment may still benefit. OBJECTIVE: To determine whether L-thyroxine improves hypothyroid symptoms and tiredness among older adults with SCH and greater symptom burden. DESIGN: Secondary analysis of the randomized, placebo-controlled trial TRUST (Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism Trial). (ClinicalTrials.gov: NCT01660126). SETTING: Switzerland, Ireland, the Netherlands, and Scotland. PARTICIPANTS: 638 persons aged 65 years or older with persistent SCH (thyroid-stimulating hormone level of 4.60 to 19.9 mIU/L for >3 months and normal free thyroxine level) and complete outcome data. INTERVENTION: L-thyroxine or matching placebo with mock dose titration. MEASUREMENTS: 1-year change in Hypothyroid Symptoms and Tiredness scores (range, 0 to 100; higher scores indicate more symptoms) on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire among participants with high symptom burden (baseline Hypothyroid Symptoms score >30 or Tiredness score >40) versus lower symptom burden. RESULTS: 132 participants had Hypothyroid Symptoms scores greater than 30, and 133 had Tiredness scores greater than 40. Among the group with high symptom burden, the Hypothyroid Symptoms score improved similarly between those receiving L-thyroxine (mean within-group change, -12.3 [95% CI, -16.6 to -8.0]) and those receiving placebo (mean within-group change, -10.4 [CI, -15.3 to -5.4]) at 1 year; the adjusted between-group difference was -2.0 (CI, -5.5 to 1.5; P = 0.27). Improvements in Tiredness scores were also similar between those receiving L-thyroxine (mean within-group change, -8.9 [CI, -14.5 to -3.3]) and those receiving placebo (mean within-group change, -10.9 [CI, -16.0 to -5.8]); the adjusted between-group difference was 0.0 (CI, -4.1 to 4.0; P = 0.99). There was no evidence that baseline Hypothyroid Symptoms score or Tiredness score modified the effects of L-thyroxine versus placebo (P for interaction = 0.20 and 0.82, respectively). LIMITATION: Post hoc analysis, small sample size, and examination of only patients with 1-year outcome data. CONCLUSION: In older adults with SCH and high symptom burden at baseline, L-thyroxine did not improve hypothyroid symptoms or tiredness compared with placebo. PRIMARY FUNDING SOURCE: European Union FP7.

[Smarter Medicine in General Internal Medicine in Hospitals: Where are we now?] / Smarter Medicine in der stationären Allgemeinen Inneren Medizin: Wo stehen wir?

Smarter Medicine in General Internal Medicine in Hospitals: Where are we now? Abstract. In accordance to the "Choosing Wisely" initiative in the United States, Switzerland has launched the "Smarter Medicine" movement in 2014 with the aim to tackle overdiagnosis and overtreatment. A "Smarter Medicine" Top Five List has been developed for Hospital Medicine, pointing out diagnostic tests and treatments with an unfavorable risk-benefit ratio. The five recommendations include: 1) do not order repetitive blood tests or x-rays without specific clinical questions, 2) avoid urinary catheters for the sole purpose of convenience or monitoring urine output in non-critically ill patients, 3) transfuse only the minimum number of red blood cell units necessary, 4) promote the mobilization of hospitalized older patients, and 5) do not prescribe benzodiazepines or other sedative agents to treat insomnia or agitation in older patients. The following article discusses the rationale for the "Smarter Medicine" recommendations for Hospitalists and provides an overview on various interventions implemented in Switzerland and elsewhere aimed at enforcing these recommendations.

Individualised nutritional support in medical inpatients at nutritional risk: a randomised clinical trial.

BACKGROUND: Guidelines recommend the use of nutritional support during hospital stays for medical patients (patients not critically ill and not undergoing surgical procedures) at risk of malnutrition. However, the supporting evidence for this recommendation is insufficient, and there is growing concern about the possible negative effects of nutritional therapy during acute illness on recovery and clinical outcomes. Our aim was thus to test the hypothesis that protocol-guided individualised nutritional support to reach protein and caloric goals reduces the risk of adverse clinical outcomes in medical inpatients at nutritional risk. METHODS: The Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT) is a pragmatic, investigator-initiated, open-label, multicentre study. We recruited medical patients at nutritional risk (nutritional risk screening 2002 [NRS 2002] score ≥3 points) and with an expected length of hospital stay of more than 4 days from eight Swiss hospitals. These participants were randomly assigned (1:1) to receive either protocol-guided individualised nutritional support to reach protein and caloric goals (intervention group) or standard hospital food (control group). Randomisation was done with variable block sizes and stratification according to study site and severity of malnutrition using an interactive web-response system. In the intervention group, individualised nutritional support goals were defined by specialist dietitians and nutritional support was initiated no later than 48 h after admission. Patients in the control group received no dietary consultation. The composite primary endpoint was any adverse clinical outcome defined as all-cause mortality, admission to intensive care, non-elective hospital readmission, major complications, and decline in functional status at 30 days, and it was measured in all randomised patients who completed the trial. This trial is registered with ClinicalTrials.gov, number NCT02517476. FINDINGS: 5015 patients were screened, and 2088 were recruited and monitored between April 1, 2014, and Feb 28, 2018. 1050 patients were assigned to the intervention group and 1038 to the control group. 60 patients withdrew consent during the course of the trial (35 in the intervention group and 25 in the control group). During the hospital stay, caloric goals were reached in 800 (79%) and protein goals in 770 (76%) of 1015 patients in the intervention group. By 30 days, 232 (23%) patients in the intervention group experienced an adverse clinical outcome, compared with 272 (27%) of 1013 patients in the control group (adjusted odds ratio [OR] 0·79 [95% CI 0·64-0·97], p=0·023). By day 30, 73 [7%] patients had died in the intervention group compared with 100 [10%] patients in the control group (adjusted OR 0·65 [0·47-0·91], p=0·011). There was no difference in the proportion of patients who experienced side-effects from nutritional support between the intervention and the control group (162 [16%] vs 145 [14%], adjusted OR 1·16 [0·90-1·51], p=0·26). INTERPRETATION: In medical inpatients at nutritional risk, the use of individualised nutritional support during the hospital stay improved important clinical outcomes, including survival, compared with standard hospital food. These findings strongly support the concept of systematically screening medical inpatients on hospital admission regarding nutritional risk, independent of their medical condition, followed by a nutritional assessment and introduction of individualised nutritional support in patients at risk. FUNDING: The Swiss National Science Foundation and the Research Council of the Kantonsspital Aarau, Switzerland.

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism.

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 ClinicalTrials.gov number, NCT01660126 .).

Delayed Diagnosis in Pulmonary Embolism: Frequency, Patient Characteristics, and Outcome.

BACKGROUND: The incidence and the outcomes of pulmonary embolism (PE) missed during emergency department (ED) workup are largely unknown. OBJECTIVES: To describe the frequency, demographics, and outcomes of patients with delayed diagnosis of PE. METHODS: We retrospectively compared patients diagnosed with PE during ED workup (early diagnosis) with patients diagnosed with PE thereafter (delayed diagnosis). Electronic health records (EHR) of 123,560 consecutive patients who attended a tertiary hospital ED were screened. Data were matched with radiology and pathology results from the EHR. RESULTS: Of 1,119 patients presenting to the ED with early workup for PE, PE was diagnosed in 182 patients (80.5%) as early diagnosis. Delayed diagnosis was established in 44 cases (19.5%) using radiology and/or autopsy data. Median age of patients with early diagnosis was significantly lower as compared to delayed diagnosis (67 vs. 77.5 years). Main symptoms were dyspnea (109 patients [59.9%] in early, 20 patients [45.5%] in delayed diagnosis), chest pain (90 patients [49.5%] in early, 8 patients [18.2%] in delayed diagnosis), and nonspecific complaints (16 patients [8.8%] in early, 13 patients [29.5%] in delayed diagnosis). In-hospital mortality was 1.6% in early diagnosis and 43.2% in delayed diagnosis. CONCLUSIONS: Delayed diagnosis of PE carries a worse prognosis than early diagnosis. This discrepancy may arise from either delayed therapy, confounding variables (e.g., older age), or both. Possible reasons for delayed diagnoses are nonspecific presentations and symptoms overlapping with preexisting conditions.

Venous Thromboembolism and Renal Impairment: Insights from the SWIss Venous ThromboEmbolism Registry (SWIVTER).

Renal impairment (RI) has increased substantially over the last decades. In the absence of data from confirmatory research, real-life data on anticoagulation treatment and clinical outcomes of venous thromboembolism (VTE) in patients with RI are needed. In the SWIss Venous ThromboEmbolism Registry (SWIVTER), 2,062 consecutive patients with objectively confirmed VTE were enrolled. In the present analysis, we compared characteristics, initial and maintenance anticoagulation, and adjusted 90-day clinical outcomes of those with (defined as estimated creatinine clearance < 30 mL/min) and without severe RI. Overall, 240 (12%) patients had severe RI; they were older, and more frequently had chronic and acute comorbidities. VTE severity was similar between patients with and without severe RI. Initial anticoagulation in patients with severe RI was more often performed with unfractionated heparin (44 vs. 24%), and less often with low-molecular-weight heparin (LMWH) (52 vs. 61%) and direct oral anticoagulants (DOACs; 4 vs. 12%). Maintenance anticoagulation in patients with severe RI was more frequently managed with vitamin K antagonists (70 vs. 60%) and less frequently with DOAC (12 vs. 21%). Severe RI was associated with increased risk of 90-day mortality (9.2 vs. 4.2%, hazard ratio [HR]: 2.27, 95% confidence interval [CI]: 1.41-3.65), but with similar risk of recurrent VTE (3.3 vs. 2.8%, HR: 1.19, 95% CI: 0.57-2.52) and major bleeding (2.1 vs. 2.0%, HR: 1.05, 95% CI: 0.41-2.68). In patients with severe RI, the use of LMWH versus any other treatment was associated with reduced mortality (HR: 0.37; 95% CI: 0.14-0.94; p = 0.036) and similar rate of major bleeding (HR: 0.59, 95% CI: 0.17-2.00; p = 0.39). Acute or chronic comorbidities rather than VTE severity or recurrence may explain increased early mortality in patients with severe RI. The higher rate of VTE recurrence, specifically fatal events, than major bleeding reinforces the need for effective anticoagulation in VTE patients with severe RI.

Risk stratification of elderly patients with acute pulmonary embolism.

BACKGROUND: Combining high-sensitivity cardiac Troponin T (hs-cTnT), NT-pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) may improve risk stratification of patients with pulmonary embolism (PE) beyond the PESI risk score. METHODS: In the prospective multicentre SWITCO65+ study, we analysed 214 patients ≥ 65 years with a new submassive PE. Biomarkers and clinical information for the PESI risk score were ascertained within 1 day after diagnosis. Associations of hs-TnT, NT-proBNP, hs-CRP and the PESI risk score with the primary endpoint defined as 6-month mortality were assessed. The discriminative power of the PESI risk score and its combination with hs-cTnT, NT-proBNP and hs-CRP for 6-month mortality was compared using integrated discrimination improvement (IDI) index and net reclassification improvement (NRI). RESULTS: Compared with the lowest quartile, patients in the highest quartile had a higher risk of death during the first 6 months for hs-cTnT (adjusted HR 10.22; 95% CI 1.79-58.34; P = 0.009) and a trend for NT-proBNP (adjusted HR 4.3; 95% CI 0.9-20.41; P = 0.067) unlike hs-CRP (adjusted HR 1.97; 95% CI 0.48-8.05; P = 0.344). The PESI risk score (c-statistic 0.77 (95% CI 0.69-0.84) had the highest prognostic accuracy for 6-month mortality, outperforming hs-cTnT, NT-proBNP and hs-CRP (c-statistics of 0.72, 0.72, and 0.54), respectively. Combining all three biomarkers had no clinically relevant impact on risk stratification when added to the PESI risk score (IDI = 0.067; 95% CI 0.012-0.123; P = 0.018; NRI = 0.101 95% CI -0.099-0.302; P = 0.321). CONCLUSIONS: In elderly patients with PE, 6-month mortality can adequately be predicted by the PESI risk score alone.

Multimorbidity and healthcare resource utilization in Switzerland: a multicentre cohort study.

BACKGROUND: Multimorbidity is associated with higher healthcare resource utilization, but we lack data on the association of specific combinations of comorbidities with healthcare resource utilization. We aimed to identify the combinations of comorbidities associated with high healthcare resource utilization among multimorbid medical inpatients. METHODS: We performed a multicentre retrospective cohort study including 33,871 multimorbid (≥2 chronic diseases) medical inpatients discharged from three Swiss hospitals in 2010-2011. Healthcare resource utilization was measured as 30-day potentially avoidable readmission (PAR), prolonged length of stay (LOS) and difference in median LOS. We identified the combinations of chronic comorbidities associated with the highest healthcare resource utilization and quantified this association using regression techniques. RESULTS: Three-fourths of the combinations with the strongest association with PAR included chronic kidney disease. Acute and unspecified renal failure combined with solid malignancy was most strongly associated with PAR (OR 2.64, 95%CI 1.79;3.90). Miscellaneous mental health disorders combined with mood disorders was the most strongly associated with LOS (difference in median LOS: 17 days) and prolonged LOS (OR 10.77, 95%CI 8.38;13.84). The number of chronic diseases was strongly associated with prolonged LOS (OR 9.07, 95%CI 8.04;10.24 for ≥10 chronic diseases), and to a lesser extent with PAR (OR 2.16, 95%CI 1.75;2.65 for ≥10 chronic diseases). CONCLUSIONS: Multimorbidity appears to have a higher impact on LOS than on PAR. Combinations of comorbidities most strongly associated with healthcare utilization included kidney disorders for PAR, and mental health disorders for LOS.

Diagnosis of Pulmonary Embolism During Pregnancy: A Multicenter Prospective Management Outcome Study.

Background: Data on the optimal diagnostic management of pregnant women with suspected pulmonary embolism (PE) are limited, and guidelines provide inconsistent recommendations on use of diagnostic tests. Objective: To prospectively validate a diagnostic strategy in pregnant women with suspected PE. Design: Multicenter, multinational, prospective diagnostic management outcome study involving pretest clinical probability assessment, high-sensitivity D-dimer testing, bilateral lower limb compression ultrasonography (CUS), and computed tomography pulmonary angiography (CTPA). (ClinicalTrials.gov: NCT00740454). Setting: 11 centers in France and Switzerland between August 2008 and July 2016. Patients: Pregnant women with clinically suspected PE in emergency departments. Intervention: Pulmonary embolism was excluded in patients with a low or intermediate pretest clinical probability and a negative D-dimer result. All others underwent lower limb CUS and, if results were negative, CTPA. A ventilation-perfusion (V/Q) scan was done if CTPA results were inconclusive. Pulmonary embolism was excluded if results of the diagnostic work-up were negative, and untreated pregnant women had clinical follow-up at 3 months. Measurements: The primary outcome was the rate of adjudicated venous thromboembolic events during the 3-month follow-up. Results: 441 women were assessed for eligibility, and 395 were included in the study. Among these, PE was diagnosed in 28 (7.1%) (proximal deep venous thrombosis found on ultrasonography [n = 7], positive CTPA result [n = 19], and high-probability V/Q scan [n = 2]) and excluded in 367 (clinical probability and negative D-dimer result [n = 46], negative CTPA result [n = 290], normal or low-probability V/Q scan [n = 17], and other reason [n = 14]). Twenty-two women received extended anticoagulation during follow-up, mainly for previous venous thromboembolic disease. The rate of symptomatic venous thromboembolic events was 0.0% (95% CI, 0.0% to 1.0%) among untreated women after exclusion of PE on the basis of negative results on the diagnostic work-up. Limitation: There were several protocol deviations, reflecting the difficulty of performing studies in pregnant women with suspected PE. Conclusion: A diagnostic strategy based on assessment of clinical probability, D-dimer measurement, CUS, and CTPA can safely rule out PE in pregnant women. Primary Funding Source: Swiss National Foundation for Scientific Research, Groupe d'Etude de la Thrombose de Bretagne Occidentale, and International Society on Thrombosis and Haemostasis.

Thyroid Function Within the Normal Range, Subclinical Hypothyroidism, and the Risk of Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF. METHODS: We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF. RESULTS: Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5%) had subclinical hypothyroidism and 2574 individuals (8.6%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio, 1.45; 95% confidence interval, 1.26-1.66, for the highest quartile versus the lowest quartile of fT4; P for trend ≤0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardiovascular disease. CONCLUSIONS: In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF.

Association of Thyroid Hormone Therapy With Quality of Life and Thyroid-Related Symptoms in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis.

Importance: The benefit of thyroid hormone therapy for subclinical hypothyroidism is uncertain. New evidence from recent large randomized clinical trials warrants an update of previous meta-analyses. Objective: To conduct a meta-analysis of the association of thyroid hormone therapy with quality of life and thyroid-related symptoms in adults with subclinical hypothyroidism. Data Sources: PubMed, EMBASE, ClinicalTrials.gov, Web of Science, Cochrane Library, CENTRAL, Emcare, and Academic Search Premier from inception until July 4, 2018. Study Selection: Randomized clinical trials that compared thyroid hormone therapy with placebo or no therapy in nonpregnant adults with subclinical hypothyroidism were eligible. Two reviewers independently evaluated eligibility based on titles and abstracts of all retrieved studies. Studies not excluded in this first step were independently assessed for inclusion after full-text evaluation by 2 reviewers. Data Extraction and Synthesis: Two independent reviewers extracted data, assessed risk of bias (Cochrane risk-of-bias tool), and evaluated the quality of evidence (GRADE tool). For synthesis, differences in clinical scores were transformed (eg, quality of life) into standardized mean differences (SMDs; positive values indicate benefit of thyroid hormone therapy; 0.2, 0.5, and 0.8 correspond to small, moderate, and large effects, respectively). Random-effects models for meta-analyses were applied. Main Outcomes and Measures: General quality of life and thyroid-related symptoms after a minimum follow-up of 3 months. Results: Overall, 21 of 3088 initially identified publications met the inclusion criteria, with 2192 adults randomized. After treatment (range, 3-18 months), thyroid hormone therapy was associated with lowering the mean thyrotropin value into the normal reference range compared with placebo (range, 0.5-3.7 mIU/L vs 4.6 to 14.7 mIU/L) but was not associated with benefit regarding general quality of life (n = 796; SMD, -0.11; 95% CI, -0.25 to 0.03; I2=66.7%) or thyroid-related symptoms (n = 858; SMD, 0.01; 95% CI, -0.12 to 0.14; I2=0.0%). Overall, risk of bias was low and the quality of evidence assessed with the GRADE tool was judged moderate to high. Conclusions and Relevance: Among nonpregnant adults with subclinical hypothyroidism, the use of thyroid hormone therapy was not associated with improvements in general quality of life or thyroid-related symptoms. These findings do not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism.

Predicting recurrence after unprovoked venous thromboembolism: prospective validation of the updated Vienna Prediction Model.

The updated Vienna Prediction Model for estimating recurrence risk after an unprovoked venous thromboembolism (VTE) has been developed to identify individuals at low risk for VTE recurrence in whom anticoagulation (AC) therapy may be stopped after 3 months. We externally validated the accuracy of the model to predict recurrent VTE in a prospective multicenter cohort of 156 patients aged ≥65 years with acute symptomatic unprovoked VTE who had received 3 to 12 months of AC. Patients with a predicted 12-month risk within the lowest quartile based on the updated Vienna Prediction Model were classified as low risk. The risk of recurrent VTE did not differ between low- vs higher-risk patients at 12 months (13% vs 10%; P = .77) and 24 months (15% vs 17%; P = 1.0). The area under the receiver operating characteristic curve for predicting VTE recurrence was 0.39 (95% confidence interval [CI], 0.25-0.52) at 12 months and 0.43 (95% CI, 0.31-0.54) at 24 months. In conclusion, in elderly patients with unprovoked VTE who have stopped AC, the updated Vienna Prediction Model does not discriminate between patients who develop recurrent VTE and those who do not. This study was registered at www.clinicaltrials.gov as #NCT00973596.

Clinical Outcomes of Venous Thromboembolism in Patients with and without Cancer: The SWIss Venous ThromboEmbolism Registry (SWIVTER).

Background The association between cancer and venous thromboembolism (VTE) in producing adverse clinical outcomes requires further investigation. Methods In the Swiss Venous ThromboEmbolism Registry (SWIVTER), we compared adverse clinical outcomes between 493 patients with cancer-associated VTE and 1,569 VTE patients without cancer, and identified independent predictors of 90-day mortality. Results Among cancer patients, 351 (71%) had active disease at the time of VTE diagnosis and 232 (47%) had metastatic disease. Cancer patients more frequently had asymptomatic VTE (13 vs. 4%; p < 0.001), iliofemoral deep vein thrombosis (42 vs. 32%; p = 0.017), and upper extremity deep vein thrombosis (16 vs. 7%; p < 0.001). Cancer was associated with an increased risk of cumulative 90-day mortality (13.0 vs. 2.2%; hazard ratio [HR], 6.27; 95% confidence interval [CI], 4.13-9.50; p < 0.001), recurrent VTE (4.7 vs. 2.3%; HR, 2.05; 95% CI, 1.21-3.45; p = 0.007), and bleeding requiring medical attention (5.7 vs. 3.3%; HR, 1.80; 95% CI, 1.13-2.86; p = 0.013). Among cancer patients, the strongest factor associated with mortality was metastatic disease (HR, 4.86; 95% CI, 2.68-8.81; p < 0.001), whereas it was pulmonary embolism among noncancer patients (HR, 4.96; 95% CI, 1.50-16.45; p = 0.009). Symptomatic as compared with asymptomatic VTE predicted neither mortality (12.6 vs. 15.9%; HR, 0.76; 95% CI, 0.39-1.49; p = 0.42) nor recurrent VTE (4.7 vs. 4.8%; HR, 0.98; 95% CI, 0.29-3.31; p = 0.98) in cancer patients. Conclusion In SWIVTER, early mortality of cancer-associated VTE was mainly driven by the extent of cancer disease and not by VTE symptoms or severity.