The multimorbidity interaction severity index (MISI): A proof of concept study.

Therapeutic decision-making for patients with multimorbidity (MM) is challenging. Clinical practice guidelines inadequately address harmful interactions and resulting therapeutic conflicts within and among diseases. A patient-specific measure of MM severity that takes account of this conflict is needed.As a proof of concept, we evaluated whether the new Multimorbidity Interaction Severity Index (MISI) could be used to reliably differentiate patients in terms of lower versus higher potential for harmful interactions.Two hypothetical patient cases were generated, each with 6 concurrent morbidities. One case had a low (i.e., low conflict case) and the other a high (i.e., high conflict case) potential for harmful interactions. All possible interactions between conditions and treatments were extracted from each case's record into a multimorbidity interaction matrix. Experienced general internists (N = 18) judged each interaction in the matrix in terms of likely resource utilization needed to manage the interaction. Based on these judgements, a composite index of MM interaction severity, that is, the MISI, was generated for each physician and case.The difference between each physician's MISI score for the 2 cases (MISIdiff) was computed. Based on MISIdiff, the high conflict case was judged to be of significantly greater MM severity than was the low conflict case. The positive values of the inter-quartile range, a measure of variation (or disagreement) between the 2 cases, indicated general consistency of individual physicians in judging MM severity.The data indicate that the MISI can be used to reliably differentiate hypothetical multimorbid patients in terms of lesser versus greater severity of potentially harmful interactive effects. On this basis, the MISI will be further developed for use in patient-specific assessment and management of MM. The clinical relevance of the MISI as an alternative approach to defining MM severity is discussed.

Physician's Prescribing Preference as an Instrumental Variable: Exploring Assumptions Using Survey Data.

BACKGROUND: Physician's prescribing preference is increasingly used as an instrumental variable in studies of therapeutic effects. However, differences in prescribing patterns among physicians may reflect differences in preferences or in case-mix. Furthermore, there is debate regarding the possible assumptions for point estimation using physician's preference as an instrument. METHODS: A survey was sent to general practitioners (GPs) in The Netherlands, the United Kingdom, New Zealand, Ireland, Switzerland, and Germany, asking whether they would prescribe levothyroxine to eight fictitious patients with subclinical hypothyroidism. We investigated (1) whether variation in physician's preference was observable and to what extent it was explained by characteristics of GPs and their patient populations and (2) whether the data were compatible with deterministic and stochastic monotonicity assumptions. RESULTS: Levothyroxine prescriptions varied substantially among the 526 responding GPs. Between-GP variance in levothyroxine prescriptions (logit scale) was 9.9 (95% confidence interval: 8.0, 12) in the initial mixed effects logistic model, 8.3 (6.7, 10) after adding a fixed effect for country and 8.2 (6.6, 10) after adding GP characteristics. The occurring prescription patterns falsified the deterministic monotonicity assumption. All cases in all countries were more likely to receive levothyroxine if a different case of the same GP received levothyroxine, which is compatible with the stochastic monotonicity assumption. The data were incompatible with this assumption for a different definition of the instrument. CONCLUSIONS: Our study supports the existence of physician's preference as a determinant in treatment decisions. Deterministic monotonicity will generally not be plausible for physician's preference as an instrument. Depending on the definition of the instrument, stochastic monotonicity may be plausible.

Subclinical Thyroid Dysfunction and Depressive Symptoms among the Elderly: A Prospective Cohort Study.

BACKGROUND: Subclinical hypothyroidism has been associated with depressive symptoms in cross-sectional studies, but prospective data and data on subclinical hyperthyroidism are scarce. METHODS: In the Leiden substudy of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), thyroid-stimulating hormone and free T4 levels were measured at baseline and repeated after 6 months in adults aged 70-82 years with preexisting cardiovascular disease or known cardiovascular risk factors to define persistent thyroid functional status. Main outcome measures were depressive symptoms, assessed with the Geriatric Depression Scale 15 (GDS-15) at baseline and after 3 years. All analyses were adjusted for age, gender and education. RESULTS: In 606 participants (41% women; mean age 75 years) without antidepressant medication, GDS-15 scores at baseline did not differ for participants with subclinical hypothyroidism (n = 47; GDS-15 score 1.75, 95% CI 1.29-2.20, p = 0.53) or subclinical hyperthyroidism (n = 13; GDS-15 score 1.64, 95% CI 0.78-2.51, p = 0.96) compared to euthyroid participants (n = 546; mean GDS-15 score 1.60, 95% CI 1.46-1.73). After 3 years, compared to the euthyroid participants, changes in GDS-15 scores did not differ for participants with subclinical hypothyroidism (x0394;GDS-15 score -0.03, 95% CI -0.50 to 0.44, p = 0.83), while subclinical hyperthyroidism was associated with an increase in GDS scores (x0394;GDS-15 score 1.13, 95% CI 0.32-1.93, p = 0.04). All results were similar for persistent subclinical thyroid dysfunction. CONCLUSIONS: In this largest prospective study on the association of persistent subclinical thyroid dysfunction and depression, subclinical hypothyroidism was not associated with increased depressive symptoms among older adults at high cardiovascular risk. Persistent subclinical hyperthyroidism might be associated with increased depressive symptoms, which requires confirmation in a larger prospective study.

Subclinical Thyroid Dysfunction and Frailty Among Older Men.

CONTEXT: Both subclinical thyroid dysfunction and frailty are common among older individuals, but data on the relationship between these 2 conditions are conflicting. OBJECTIVE: The purpose of this study was to assess the cross-sectional and prospective associations between subclinical thyroid dysfunction and frailty and the 5 frailty subdomains (sarcopenia, weakness, slowness, exhaustion, and low activity). SETTING AND DESIGN: The Osteoporotic Fractures in Men Study is a prospective cohort study. PARTICIPANTS: Men older than 65 years (n = 1455) were classified into 3 groups of thyroid status: subclinical hyperthyroidism (n = 26, 1.8%), subclinical hypothyroidism (n = 102, 7.0%), and euthyroidism (n = 1327, 91.2%). MAIN OUTCOME MEASURES: Frailty was defined using a slightly modified Cardiovascular Health Study Index: men with 3 or more criteria were considered frail, men with 1 to 2 criteria were considered intermediately frail, and men with no criteria were considered robust. We assessed the cross-sectional relationship between baseline thyroid function and the 3 categories of frailty status (robust/intermediate/frail) as well as the prospective association between baseline thyroid function and subsequent frailty status and mortality after a 5-year follow-up. RESULTS: At baseline, compared with euthyroid participants, men with subclinical hyperthyroidism had an increased likelihood of greater frailty status (adjusted odds ratio, 2.48; 95% confidence interval, 1.15-5.34), particularly among men aged <74 years at baseline (odds ratio for frailty, 3.63; 95% confidence interval, 1.21-10.88). After 5 years of follow-up, baseline subclinical hypothyroidism and hyperthyroidism were not consistently associated with overall frailty status or frailty components. CONCLUSION: Among community-dwelling older men, subclinical hyperthyroidism, but not subclinical hypothyroidism, is associated with increased odds of prevalent but not incident frailty.

International variation in GP treatment strategies for subclinical hypothyroidism in older adults: a case-based survey.

BACKGROUND: There is limited evidence about the impact of treatment for subclinical hypothyroidism, especially among older people. AIM: To investigate the variation in GP treatment strategies for older patients with subclinical hypothyroidism depending on country and patient characteristics. DESIGN AND SETTING: Case-based survey of GPs in the Netherlands, Germany, England, Ireland, Switzerland, and New Zealand. METHOD: The treatment strategy of GPs (treatment yes/no, starting-dose thyroxine) was assessed for eight cases presenting a woman with subclinical hypothyroidism. The cases differed in the patient characteristics of age (70 versus 85 years), vitality status (vital versus vulnerable), and thyroid-stimulating hormone (TSH) concentration (6 versus 15 mU/L). RESULTS: A total of 526 GPs participated (the Netherlands n = 129, Germany n = 61, England n = 22, Ireland n = 21, Switzerland n = 262, New Zealand n = 31; overall response 19%). Across countries, differences in treatment strategy were observed. GPs from the Netherlands (mean treatment percentage 34%), England (40%), and New Zealand (39%) were less inclined to start treatment than GPs in Germany (73%), Ireland (62%), and Switzerland (52%) (P = 0.05). Overall, GPs were less inclined to start treatment in 85-year-old than in 70-year-old females (pooled odds ratio [OR] 0.74 [95% confidence interval [CI] = 0.63 to 0.87]). Females with a TSH of 15 mU/L were more likely to get treated than those with a TSH of 6 mU/L (pooled OR 9.49 [95% CI = 5.81 to 15.5]). CONCLUSION: GP treatment strategies of older people with subclinical hypothyroidism vary largely by country and patient characteristics. This variation underlines the need for a new generation of international guidelines based on the outcomes of randomised clinical trials set within primary care.

Check-up examination: recommendations in adults.

Check-up examinations, or periodic health examinations (PHEs), have gained in importance during the last decades and are nowadays among the most common reasons for consultations in primary care settings. The aim of PHEs is to identify risk factors and early signs of disease, but also to prevent future illness by early intervention. Therefore, each PHE should include counselling, immunisation and physical examination according to the patient's age and gender. However, deciding whether to screen a patient and choosing the most appropriate screening method can be challenging for general practitioners. The U.S. Preventive Service Task Force (USPSTF) provides updated recommendations on different existing preventive care measures based on relevant literature review. The aim of this review is to provide an updated statement of recommendations regarding preventive care measures based mostly on the guidelines derived from the USPSTF and the Swiss Medical Board. Among the major updates, there is no recommendation anymore to routinely screen for breast cancer and prostate cancer in asymptomatic adults. Since 2013, however, the USPSTF recommends annual screening for lung cancer with low-dose CT in patients aged 55 to 80 years with a smoking history of ≥30 pack years. During PHEs, the physician should be alert to the patients' hidden agendas, which are the reason for one third of all consultations in primary care.

Patient and physician gender concordance in preventive care in university primary care settings.

OBJECTIVE: To assess the quality of preventive care according to physician and patient gender in a country with universal health care coverage. METHODS: We assessed a retrospective cohort study of 1001 randomly selected patients aged 50-80 years followed over 2 years (2005-2006) in 4 Swiss university primary care settings (Basel, Geneva, Lausanne, Zürich). We used indicators derived from RAND's Quality Assessment Tools and examined percentages of recommended preventive care. Results were adjusted using hierarchical multivariate logistic regression models. RESULTS: 1001 patients (44% women) were followed by 189 physicians (52% women). Female patients received less preventive care than male patients (65.2% vs. 72.1%, p<0.001). Female physicians provided significantly more preventive care than male physicians (p=0.01) to both female (66.7% vs. 63.6%) and male patients (73.4% vs. 70.7%). After multivariate adjustment, differences according to physician (p=0.02) and patient gender (p<0.001) remained statistically significant. Female physicians provided more recommended cancer screening than male physicians (78.4 vs. 71.9%, p=0.01). CONCLUSIONS: In Swiss university primary care settings, female patients receive less preventive care than male patients, with female physicians providing more preventive care than male physicians. Greater attention should be paid to female patients in preventive care and to why female physicians tend to provide better preventive care.

Subclinical thyroid dysfunction and functional capacity among elderly.

BACKGROUND: Subclinical thyroid dysfunction is common among older people and has been associated with decreased functional capacity but with conflicting data. The aim of this study was to assess the association between subclinical thyroid dysfunction and functional capacity in an elderly population. METHODS: We included 5182 participants with a mean age of 75.2 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Self-reported functional capacity was assessed using the Barthel Index (BI) and the Instrumental Activities of Daily Living (IADL) scores at baseline and during follow-up. Participants with subclinical hyperthyroidism (n=65) and subclinical hypothyroidism (n=173) were compared to euthyroid participants (n=4944). The association between persistent subclinical thyroid dysfunction and functional capacity and decline was also investigated. RESULTS: At baseline, compared to euthyroid participants (BI 19.73±SE 0.06; IADL 13.52±0.02), there was no difference in functional capacity for participants with subclinical hyperthyroidism (BI 19.60±0.09; IADL 13.51±0.12, p>0.05) or subclinical hypothyroidism (BI 19.82±0.06; IADL 13.55±0.08, p>0.05). Over a mean 3.2-year follow-up period, there was no association between thyroid function and annual decline of either BI or IADL (p>0.05). No association was found between persistent subclinical thyroid dysfunction and functional capacity at baseline or during follow-up (p>0.05). Results were similar after excluding participants with a maximum BI and/or IADL score at baseline. CONCLUSION: Among well-functioning community-dwelling elderly, we found no evidence that subclinical thyroid dysfunction contributes to decreased functional capacity.

Subclinical thyroid dysfunction and cardiovascular outcomes among prospective cohort studies.

The association between subclinical thyroid dysfunction and cardiovascular outcomes has been recently clarified with the publication of three individual participant data (IPD) analyses from the Thyroid Studies Collaboration. We identified original cohort studies with a systematic review and pooled individual data from over 70'000 participants to obtain a more precise estimate of the risks of cardiovascular outcomes associated with subclinical thyroid dysfunction. Subclinical hypothyroidism and subclinical hyperthyroidism, defined as normal thyroxine (FT4) levels with increased or decreased Thyroid-Stimulating Hormones (TSH or thyrotropin) respectively, are associated with increased risk of cardiovascular outcomes compared to euthyroid state, particularly in those with a more pronounced thyroid dysfunction. Specifically, subclinical hypothyroidism is associated with an increased risk of coronary heart disease (CHD) events, CHD mortality and heart failure (HF) events in individuals with higher TSH levels, particularly in those with TSH levels ≥10.0 mIU/L. Conversely, subclinical hyperthyroidism is associated with an increased risk of total mortality, CHD mortality, HF and atrial fibrillation, particularly in those with suppressed TSH levels <0.10 mIU/L. Pending ongoing randomized controlled trials, these observational findings allow identifying potential TSH thresholds for thyroid medication initiation based on risk of clinical outcomes, although clinical decision based solely on observational data need caution. The impact of thyroid replacement among the elderly with subclinical hypothyroidism is currently studied in a multicenter international randomized controlled trial (Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial, TRUST trial).

Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts.

BACKGROUND: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events. METHODS AND RESULTS: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1%) had subclinical hypothyroidism and 648 (2.6%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors. CONCLUSION: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH ≥10 and <0.10 mIU/L.

[Should we screen and treat subclinical hypothyroidism?]. / Faut-il dépister et traiter l'hypothyroïdie infraclinique?

Subclinical hypothyroidism, defined as an elevated thyroid stimulating hormone and normal thyroxine level, is common with aging, particularly after 65 years old. This condition is potentially associated with important consequences, such as cardiovascular diseases and cognitive disorders. So far, indications for screening and thyroxine replacement therapy are still controversial. In this review, we examine the data on those risks and the potential benefits of the treatment. We also present a large European randomized clinical trial that should clarify this controversy, in order to improve clinical care of patients with subclinical hypothyroidism and to give reliable data on maintaining good health among the elderly.

[New european guidelines for dyslipidemia]. / Nouvelles guidelines européennes pour les dyslipidémies.

Lifestyle changes should be considered before anything else in patients with dyslipidemia according to the new guidelines on dyslipidemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). The guidelines recommend the SCORE system (Systematic Coronary Risk Estimation) to classify cardiovascular risk into four categories (very high, high, medium or low risk) as the basis for treatment decisions. HDL cholesterol, which is inversely proportional to cardiovascular risk, is included to the total risk estimation. In addition to calculating absolute risk, the guidelines contain a table with the relative risk, which could be useful in young patients with a low absolute risk, but high risk compared to individuals of the same age group.