Christine Baumgartner

Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial

BACKGROUND Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for treatment of community-acquired pneumonia. We assessed whether short-term corticosteroid treatment reduces time to clinical stability in patients admitted to hospital for community-acquired pneumonia. METHODS In this double-blind, multicentre, randomised, placebo-controlled trial, we recruited patients aged 18 years or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerland within 24 h of presentation. Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg daily for 7 days or placebo. The computer-generated randomisation was done with variable block sizes of four to six and stratified by study centre. The primary endpoint was time to clinical stability defined as time (days) until stable vital signs for at least 24 h, and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00973154. FINDINGS From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for eligibility, 785 patients were randomly assigned to either the prednisone group (n=392) or the placebo group (n=393). Median time to clinical stability was shorter in the prednisone group (3·0 days, IQR 2·5-3·4) than in the placebo group (4·4 days, 4·0-5·0; hazard ratio [HR] 1·33, 95% CI 1·15-1·50, p<0·0001). Pneumonia-associated complications until day 30 did not differ between groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0·49 [95% CI 0·23-1·02]; p=0·056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR 1·96, 95% CI 1·31-2·93, p=0·0010). Other adverse events compatible with corticosteroid use were rare and similar in both groups. INTERPRETATION Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency. FUNDING Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefliger Stiftung, Julia und Gottfried Bangerter-Rhyner Stiftung.

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.)

Local delivery of soluble platelet collagen receptor glycoprotein VI inhibits thrombus formation in vivo.

Platelet-mediated thrombus formation at the site of vascular injury is a major trigger for thrombo-ischemic complications after coronary interventions. The platelet collagen receptor glycoprotein VI (GPVI) plays a critical role in the initiation of arterial thrombus formation. Endothelial denudation of the right carotid artery in rabbits was induced through balloon injury. Subsequently, local delivery of soluble, dimeric fusion protein of GPVI (GPVI-Fc) (n = 7) or control Fc (n = 7) at the site of vascular injury was performed with a modified double-balloon drug-delivery catheter. Thrombus area within the injured carotid artery was quantified using a computer-assisted image analysis and was used as index of thrombus formation. The extent of thrombus formation was significantly reduced in GPVI-Fc- compared with control Fc-treated carotid arteries (relative thrombus area, GPVI-Fc vs. Fc: 9.3 +/- 4.2 vs. 2.3 +/- 1.7, p < 0.001). Local delivery of soluble GPVI resulted in reduced thrombus formation after catheter-induced vascular injury. These data suggest a selective pharmacological modulation of GPVI-collagen interactions to be important for controlling onset and progression of pathological arterial thrombosis, predominantly or even exclusively at sites of injured carotid arteries in the absence of systemic platelet therapy.

Subclinical hypothyroidism and the risk of stroke events and fatal stroke: An individual participant data analysis

OBJECTIVE The objective was to determine the risk of stroke associated with subclinical hypothyroidism. DATA SOURCES AND STUDY SELECTION Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels. DATA EXTRACTION AND SYNTHESIS We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95% CI, 0.86-1.18) or ≥ 80 years old (HR, 1.31; 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations. CONCLUSIONS Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.

Subclinical Thyroid Dysfunction and the Risk for Fractures: A Systematic Review and Meta-analysis

About 10% of women and 3% of men older than 60 years have subclinical hypothyroidism (13), and prevalence increases with age. Subclinical hypothyroidism is defined as elevated thyroid-stimulating hormone (TSH) and normal free thyroxine (FT4) levels (4). Subclinical hyperthyroidism, defined as decreased TSH and normal FT4 and triiodothyronine (T3) levels (4), is less common and affects about 1.5% of women and 1% of men older than 60 years. Subclinical thyroid dysfunction has previously been associated with an increased risk for coronary heart disease and heart failure events (57). Thyroid hormones influence the homeostasis and remodeling of bone (8). Overt hyperthyroidism is a risk factor for fractures (9). A few observational studies have also found an increased risk for fracture in persons with overt hypothyroidism (10, 11). The association between subclinical thyroid dysfunction and fractures remains unclear. A prospective cohort study of 3567 elderly participants found an increased risk for hip fractures in men with endogenous subclinical hyperthyroidism and a similar trend in women, whereas subclinical hypothyroidism was associated with an increased risk for hip fracture in men only (12). Conversely, a casecohort study of 1526 ambulatory men older than 65 years found no significant relationship between subclinical hyperthyroidism and fractures, but low-normal TSH levels were significantly associated with an increased risk for hip fractures (13). Other prospective studies (14) did not adjust for common relevant potential confounders between subclinical thyroid dysfunction and fractures, such as age, sex, body mass index, smoking, and corticosteroid use (1524). Two meta-analyses of postmenopausal women with exogenous subclinical hyperthyroidism due to thyroxine substitution showed a reduction in bone mineral density (BMD), which is a surrogate marker for osteoporosis (25, 26). To our knowledge, no meta-analysis has been done on the risk for fractures related with subclinical thyroid dysfunction. Therefore, we did a meta-analysis to determine whether subclinical thyroid dysfunction and TSH levels were associated with an increased risk for fractures in prospective cohort studies. Methods Data Sources and Searches We followed a standardized protocol to do this meta-analysis. Similar to our previous study (27), we conducted a systematic literature search for articles in any language on the association between subclinical thyroid dysfunction (both subclinical hypothyroidism and hyperthyroidism) and fractures published between 1946 and 16 March 2014 in the MEDLINE and EMBASE databases. In Ovid MEDLINE, we used the following broadly defined Medical Subject Headings: thyroid diseases, hypothyroidism, hyperthyroidism, thyroid hormones, thyrotropin, subclinical hyperthyroidism, subclinical hypothyroidism, subclinical dysthyroidism, subclinical thyroid, and fractures or osteoporosis. These headings were combined with the filter designed by British Medical Journal knowledge information specialists to identify randomized, controlled trials; cohorts; and casecontrol studies without year limitation or exclusion of comments, editorials, meta-analyses, practice guidelines, reviews, letters, journal correspondences, books, conference papers, or animal studies (28). We used a similar procedure in EMBASE. We also searched the bibliographies of key articles in the field and those included in this review, and we contacted authors for unpublished studies. Study Selection Similar to our previous study (27), 2 authors independently screened the abstracts and titles of the search results and retained articles on prospective cohorts studying the association between thyroid dysfunction and osteoporotic fractures. The same reviewers independently assessed the remaining full-text articles for eligibility on the basis of predefined criteria. Any disagreement was resolved by discussion with a third author. Because some prospective studies that measured thyroid function and assessed multiple outcomes may not have reported fracture outcomes in the abstract, we also assessed the full text and tables for reported fracture data in these studies. We included only studies that fulfilled the following a prioridefined criteria: measurement of thyroid function, prospective follow-up of participants, assessment of fracture outcomes, comparison group with euthyroidism, and provision of hazard ratios (HRs) or sufficient data to calculate them. We excluded studies that examined only persons with a history of overt thyroid dysfunction or thyroid cancer. We considered nonspine, hip, and any fractures, but we excluded spine fractures because vertebral fracture age is difficult to assess without serial radiographs and the accuracy of self-report is poor (29). Agreement among reviewers was 97.9% for the first screening of titles and abstracts (= 0.69) and 100% for full-text screening (= 1.0). Data Extraction and Quality Assessment We used a standardized data abstraction form to extract information about participant characteristics, the criteria used to define subclinical thyroid dysfunction, and fractures. We evaluated study quality using slightly updated criteria (27, 30), adding inclusion of testing for the assumption of proportional hazards. One physician reviewer extracted data, and another checked data. We assessed key indicators for the quality of the cohort studies (31, 32): the population studied (convenience sample vs. population-based, which was defined as a random sample of the general population) and methods of fracture ascertainment and adjudication (considered adequate if done by an expert panel blinded to thyroid status using a clear outcome definition); assessment of the proportional hazard assumption; completeness of follow-up; and adjustment for potential confounders. We defined age, sex, body mass index, smoking, and corticosteroid use (1524) as common relevant potential confounders for the relationship between subclinical thyroid dysfunction and fractures based on a literature search considering their prevalence and strength of association with fractures and thyroid dysfunction. We required adjustment for most of these risk factors and lack of violation of the proportional hazard assumption for a study to be rated as higher quality. If an article did not clearly mention one of these criteria, we considered that it had not been done. Two reviewers independently rated all studies for quality, and disagreement was resolved with a third reviewer. We contacted the authors of all cohorts to request more detailed data on the association between subclinical thyroid dysfunction and fractures. We used the most adjusted HRs and 95% CIs available. Data Synthesis and Statistical Analysis We used TSH cutoff levels as reported by each cohort. If not otherwise specified by a cohort, we used a common definition of subclinical thyroid disease based on expert reviews (4, 33) and the definition used in the Cardiovascular Health Study (12, 34), as done in previous articles (57). Subclinical hypothyroidism was defined as a TSH level greater than 4.5 to 20.0 mIU/L and an FT4 level in the reference range. Subclinical hyperthyroidism was defined as a TSH level less than 0.45 mIU/L and an FT4 level in the reference range. Euthyroidism was defined as a TSH cutoff level from 0.45 to 4.5 mIU/L. For FT4, we used study-specific cutoff levels because these measurements show greater intermethod variation than TSH. Three studies (14, 35, 36) did not include FT4 in their definition of subclinical thyroid dysfunction. Two of these studies (35, 36) were included in the main analysis of the higher-quality studies, but we did a sensitivity analysis excluding studies without FT4 measurement or with abnormal FT4 because some participants may have overt thyroid dysfunction. Two of these studies differentiated between low and suppressed TSH levels (14, 35). We used data from the group with low but not suppressed TSH levels because, according to unpublished data in our previous individual- participant data analysis (7), about one fourth of persons with a TSH level less than 0.1 mIU/L had overt hyperthyroidism, but only about 5% of those with a TSH level greater than 0.1 mIU/L had overt hyperthyroidism. We qualitatively synthesized data and assessed which participants were included, the definition of thyroid dysfunction, and which types of fractures were studied. First, for the higher-quality studies, we calculated pooled estimates and 95% CIs of the risk for subclinical hyperthyroidism and hypothyroidism on hip and nonspine fractures using random-effects models based on the KnappHartung approach (37) to account for the uncertainty associated with statistical heterogeneity (tau-square estimation) and the small number of studies included (38). Second, we assessed overall pooled estimates for all studies using the same approach. Because the Cardiovascular Health Study only reported estimates stratified by sex, we used fixed effects to combine these estimates before pooling them with other cohorts (12). To assess heterogeneity among studies, we quantified the Q statistic with a conservative P value of 0.10 (39) and used the I 2 statistic, which describes the total variation across studies attributable to heterogeneity rather than chance (I 2> 50%, indicating at least moderate statistical heterogeneity) (40). To explore sources of heterogeneity, we did several predefined sensitivity analyses from all included studies using random-effects models. We also did analyses stratified by age and sex. Stratified analysis were accompanied by interaction tests based on Z scores, which are defined as the difference in effect estimates between strata divided by the SE of the difference. We used an adjusted rank correlation test to assess for publication bias (41). However, graphical and statistical methods may not be reliable because of their limited power due to the small number of studies include

Normal Thyroid Function and the Risk of Atrial Fibrillation: the Rotterdam Study

CONTEXT Hyperthyroidism is an established risk factor for atrial fibrillation (AF), but information concerning the association with variations within the normal range of thyroid function and subgroups at risk is lacking. OBJECTIVE This study aimed to investigate the association between normal thyroid function and AF prospectively and explore potential differential risk patterns. DESIGN, SETTING, AND PARTICIPANTS From the Rotterdam Study we included 9166 participants ≥ 45 y with TSH and/or free T4 (FT4) measurements and AF assessment (1997-2012 median followup, 6.8 y), with 399 prevalent and 403 incident AF cases. MAIN OUTCOME MEASURES Outcome measures were 3-fold: 1) hazard ratios (HRs) for the risk of incident AF by Cox proportional-hazards models, 2) 10-year absolute risks taking competing risk of death into account, and 3) discrimination ability of adding FT4 to the CHARGE-AF simple model, an established prediction model for AF. RESULTS Higher FT4 levels were associated with higher risks of AF (HR 1.63, 95% confidence interval, 1.19-2.22), when comparing those in the highest quartile to those in lowest quartile. Absolute 10-year risks increased with higher FT4 in participants ≤ 65 y from 1-9% and from 6-12% in subjects ≥ 65 y. Discrimination of the prediction model improved when adding FT4 to the simple model (c-statistic, 0.722 vs 0.729; P = .039). TSH levels were not associated with AF. CONCLUSIONS There is an increased risk of AF with higher FT4 levels within the normal range, especially in younger subjects. Adding FT4 to the simple model slightly improved discrimination of risk prediction.

Cardiac Overexpression of the Norepinephrine Transporter Uptake-1 Results in Marked Improvement of Heart Failure

A hyperadrenergic state is one of the key features of human and experimental heart failure. Decreased densities and activities of the presynaptic neuronal norepinephrine (NE) transporter uptake-1 occur both in patients and animal models. It is currently unclear to what extent the reduction of uptake-1 contributes to the deterioration of heart failure. Therefore, we investigated the effects of myocardial overexpression of uptake-1 in both nonfailing rabbit hearts and in an animal model of heart failure. Heart failure was induced in rabbits by rapid ventricular pacing. Adenoviral gene transfer was used to overexpress uptake-1 in the myocardium. Uptake-1 overexpression led to increased NE uptake capacity into the myocardium. In contrast, systemic plasma NE levels in uptake-1-overexpressing failing rabbits (uptake-1–CHF) did not differ from controls. Downregulation of SERCA-2 and &bgr;-adrenergic receptors in the failing myocardium was significantly reversed after uptake-1 overexpression. Uptake-1 overexpression significantly improved left ventricular (LV) diameters (LV end-diastolic diameter: in GCP-overexpressing failing rabbits (GFP-CHF), 17.4±0.4 mm; in uptake-1–CHF rabbits, 15.6±0.6 mm) and systolic contractility (fractional shortening: GFP-CHF, 20.7±0.6%; uptake-1–CHF, 27.3±0.7%), as assessed by echocardiography at the end of the heart failure protocol. Intraventricular tip catheter measurements revealed enhanced contractile reserve (dP/dt max with isoproterenol 1.0 &mgr;g/kg: GFP-CHF, 6964±230 mm Hg/sec; uptake-1–CHF, 7660±315 mm Hg/sec) and LV relaxation (dP/dt min with isoproterenol 1.0 &mgr;g/kg: GFP-CHF: −3960±260 mm Hg/sec; uptake-1–CHF, −4910±490 mm Hg/sec). End-diastolic filling pressures (GFP-CHF, 8.5±1.2 mm Hg; uptake-1–CHF, 5.6±0.7 mm Hg) tended to be lower in uptake-1 overexpressing animals. In summary, local overexpression of uptake-1 in the myocardium results in marked structural and functional improvement of heart failure, thus underlining the importance of uptake-1 as a key protein in heart failure.

The GPVI-Fc fusion protein Revacept reduces thrombus formation and improves vascular dysfunction in atherosclerosis without any impact on bleeding times.

Aims Glycoprotein VI (GPVI) is a key platelet receptor which mediates plaque-induced platelet activation and consecutive atherothrombosis, but GPVI is also involved in platelet-mediated atheroprogression. Therefore, interference in GPVI-mediated platelet activation has the potential to combine short-term and long-term beneficial effects, specificity and safety especially regarding bleeding complications. Methods and Results We investigated the effects of the soluble dimeric GPVI receptor fusion protein, Revacept, an antagonist of collagen-mediated platelet activation, in an animal model of atherosclerosis: twenty week old rabbits, which had been fed on a cholesterol-rich diet for 8 weeks, received Revacept (8 mg/kg) or control twice weekly for 4 weeks. Pharmacokinetics indicated a slight accumulation of the drug in the serum after repeated dosing of Revacept for 3 weeks. A significant improvement of endothelial dysfunction after 0.06 and 0.6 µg/min acetylcholine and a significant decrease of vessel wall thickening were found after Revacept treatment. Accordingly, aortic vessel weight was reduced, and plaque sizes, macrophage and T-cell invasion tended to be reduced in histological evaluations. Bleeding time was determined after tail clipping in mice. Revacept alone or in combination with widely used anti-platelet drugs revealed a high safety margin with no prolongation of bleeding times. Conclusion Repeated doses of Revacept led to a significant improvement of endothelial dysfunction and vascular morphology in atherosclerotic rabbits. Furthermore, no influence of Revacept on bleeding time alone or in combinations with various anti-platelet drugs was found in mice. Thus, the inhibition of collagen-mediated platelet interaction with the atherosclerotic endothelium by Revacept exerts beneficial effects on morphology and vascular function in vivo and seems to have a wide therapeutic window without influencing the bleeding time.

Structure Based Drug Design: Development of Potent and Selective Factor IXa (FIXa) Inhibitors

On the basis of our understanding on the binding interactions of the benzothiophene template within the FIXa active site by X-ray crystallography and molecular modeling studies, we developed our SAR strategy by targeting the 4-position of the template to access the S1 beta and S2-S4 sites. A number of highly selective and potent factor Xa (FXa) and FIXa inhibitors were identified by simple switch of functional groups with conformational changes toward the S2-S4 sites.

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.