Case-control analysis of paternal age and trisomic anomalies.

OBJECTIVES: To determine whether older paternal age increases the risk of fathering a pregnancy with Patau (trisomy 13), Edwards (trisomy 18), Klinefelter (XXY) or XYY syndrome. DESIGN: Case-control: cases with each of these syndromes were matched to four controls with Down syndrome from within the same congenital anomaly register and with maternal age within 6 months. SETTING: Data from 22 EUROCAT congenital anomaly registers in 12 European countries. PARTICIPANTS: Diagnoses with observed or (for terminations) predicted year of birth from 1980 to 2005, comprising live births, fetal deaths with gestational age ≥ 20 weeks and terminations after prenatal diagnosis of the anomaly. Data include 374 cases of Patau syndrome, 929 of Edwards syndrome, 295 of Klinefelter syndrome, 28 of XYY syndrome and 5627 controls with Down syndrome. MAIN OUTCOME MEASURES: Odds ratio (OR) associated with a 10-year increase in paternal age for each anomaly was estimated using conditional logistic regression. Results were adjusted to take account of the estimated association of paternal age with Down syndrome (1.11; 95% CI 1.01 to 1.23). RESULTS: The OR for Patau syndrome was 1.10 (95% CI 0.83 to 1.45); for Edwards syndrome, 1.15 (0.96 to 1.38); for Klinefelter syndrome, 1.35 (1.02 to 1.79); and for XYY syndrome, 1.99 (0.75 to 5.26). CONCLUSIONS: There was a statistically significant increase in the odds of Klinefelter syndrome with increasing paternal age. The larger positive associations of Klinefelter and XYY syndromes with paternal age compared with Patau and Edwards syndromes are consistent with the greater percentage of these sex chromosome anomalies being of paternal origin.

Steady State Concentrations of the Enantiomers of Mianserin and Desmethylmianserin in Poor and in Homozygous and Heterozygous Extensive Metabolizers of Debrisoquine.

AB Summary: Steady state concentrations of (S)- and (R)-mianserin and desmethylmianserin were measured in 21 homozygous extensive metabolizers (as determined by genotyping for mutations 3 [or A] and 4 [or B]), in seven heterozygous extensive metabolizers and in one poor metabolizer of debrisoquine, as well as in one patient receiving very high doses of mianserin (360 mg/day) and fluoxetine (160 mg/day), a strong cytochrome P450IID6 inhibitor. The mean dose of mianserin was (mean +/- SD, range: 67 +/- 63, 10 to 360 mg/day). High dispersions of the (S)/(R)-mianserin and desmethylmianserin ratios were observed (mean +/- SD, range: 2.10+/- 1.01, 0.64 to 4.76, and 0.29 +/- 0.14, 0.08 to 0.57, respectively). The highest (S)/(R)-mianserin ratio was calculated for the poor metabolizer (4.76) agreeing with those results of a single-dose study with poor and extensive metabolizers of debrisoquine, in that the cytochrome P450IID6 is probably involved in the metabolism of mianserin with an enantioselectivity for the (S)-enantiomer. Nevertheless, the mean concentration-to-dose ratios for (S)- or (R)-mianserin or desmethylmianserin were not significantly different between homozygous and heterozygous extensive metabolizers, and no particular values were measured in the poor metabolizer nor in the patient receiving fluoxetine. Furthermore, the(S)/(R)-mianserin ratio measured in the PM was only slightly higher than the second highest ratio (3.85) of an homozygous extensive metabolizer, whereas no particular value (2.92) was calculated for the patient taking fluoxetine. Finally, no significant differences in (S)/(R)-mianserin or(S)/(R)-desmethylmianserin were calculated between homozygous and heterozygous extensive metabolizers. Although the number of patients included in this study is too low to allow definite conclusions, the results suggest that the debrisoquine genotype has only a moderate influence on the steady state concentrations of the enantiomers of mianserin and desmethylmianserin. (C) Lippincott-Raven Publishers

Predictors of functional recovery in patients admitted to geriatric postacute rehabilitation.

OBJECTIVE: To examine characteristics associated with functional recovery in older patients undergoing postacute rehabilitation. DESIGN: Observational study. SETTING: Postacute rehabilitation facility. PARTICIPANTS: Patients (N=2754) aged ≥65 years admitted over a 4-year period. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Functional status was assessed at admission and again at discharge. Functional recovery was defined as achieving at least 30% improvement on the Barthel Index score from admission compared with the maximum possible room for improvement. RESULTS: Patients who achieved functional recovery (70.3%) were younger and were more likely to be women, live alone, and be without any formal home care before admission, and they had fewer chronic diseases (all P<.01). They also had better cognitive status and a higher Barthel Index score both at admission (mean ± SD, 63.3±18.0 vs 59.6±24.7) and at discharge (mean ± SD, 86.8±10.4 vs 62.2±22.9) (all P<.001). In multivariate analysis, patients <75 years of age (adjusted odds ratio [OR]=1.51; 95% confidence interval [CI], 1.16-1.98; P=.003), women (adjusted OR=1.24; 95% CI, 1.01-1.52; P=.045), patients living alone (adjusted OR=1.61; 95% CI, 1.31-1.98; P<.001), and patients without in-home help prior to admission (adjusted OR=1.39; 95% CI, 1.15-1.69; P=.001) remained at increased odds of functional recovery. In addition, compared with those with moderate-to-severe cognitive impairment (Mini-Mental State Examination score <18), patients with mild-to-moderate impairment (Mini-Mental State Examination score 19-23) and those cognitively intact also had increased odds of functional recovery (adjusted OR=1.56; 95% CI, 1.13-2.15; P=.007; adjusted OR=2.21; 95% CI, 1.67-2.93; P<.001, respectively). CONCLUSIONS: Apart from sociodemographic characteristics, cognition is the strongest factor that identifies older patients more likely to improve during postacute rehabilitation. Further study needs to determine how to best adapt rehabilitation processes to better meet the specific needs of this population and optimize their outcome.

How to interprete subclinical thyroid dysfunction in the prevention and management of heart failure events? Individual participant data analysis from six prospective cohorts

Background: Guidelines of the Diagnosis and Management of Heart Failure (HF) recommend investigating exacerbating conditions, such as thyroid dysfunction, but without specifying impact of different TSH levels. Limited prospective data exist regarding the association between subclinical thyroid dysfunction and HF events. Methods: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of HF events. Individual data on 25,390 participants with 216,247 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH 0.45-4.49 mIU/L, subclinical hypothyroidism as TSH 4.5-19.9 mIU/L and subclinical hyperthyroidism as TSH <0.45 mIU/L, both with normal free thyroxine levels. HF events were defined as acute HF events, hospitalization or death related to HF events. Results: Among 25,390 participants, 2068 had subclinical hypothyroidism (8.1%) and 648 subclinical hyperthyroidism (2.6%). In age- and gender-adjusted analyses, risks of HF events were increased with both higher and lower TSH levels (P for quadratic pattern<0.01): hazard ratio (HR) was 1.01 (95% confidence interval [CI] 0.81-1.26) for TSH 4.5-6.9 mIU/L, 1.65 (CI 0.84-3.23) for TSH 7.0-9.9 mIU/L, 1.86 (CI 1.27-2.72) for TSH 10.0-19.9 mIUL/L (P for trend <0.01), and was 1.31 (CI 0.88-1.95) for TSH 0.10-0.44 mIU/L and 1.94 (CI 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 HF events were increased with both higher and lower TSH levels, particularly for TSH ≥10 mIU/L and for TSH <0.10 mIU/L. Our findings might help to interpret TSH levels in the prevention and investigation of HF.

The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals.

OBJECTIVE: To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication. DESIGN: A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) that includes 62 760 HIV-infected, therapy-naive individuals followed for an average of 3.3 years. Inverse probability weighting of marginal structural models was used to adjust for measured confounding by indication. RESULTS: Two thousand and thirty-nine individuals died during the follow-up. The mortality hazard ratio was 0.48 (95% confidence interval 0.41-0.57) for cART initiation versus no initiation. In analyses stratified by CD4 cell count at baseline, the corresponding hazard ratios were 0.29 (0.22-0.37) for less than 100 cells/microl, 0.33 (0.25-0.44) for 100 to less than 200 cells/microl, 0.38 (0.28-0.52) for 200 to less than 350 cells/microl, 0.55 (0.41-0.74) for 350 to less than 500 cells/microl, and 0.77 (0.58-1.01) for 500 cells/microl or more. The estimated hazard ratio varied with years since initiation of cART from 0.57 (0.49-0.67) for less than 1 year since initiation to 0.21 (0.14-0.31) for 5 years or more (P value for trend <0.001). CONCLUSION: We estimated that cART halved the average mortality rate in HIV-infected individuals. The mortality reduction was greater in those with worse prognosis at the start of follow-up.

Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease.

BACKGROUND: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD. OBJECTIVE: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD. DESIGN: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(-8)) were tested for association with CAD in 31,400 cases and 92,927 controls. RESULTS: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 Ã- 10(-9)), SLC17A3 (1.0 Ã- 10(-8)), GTPB10 (1.7 Ã- 10(-8)), CUBN (7.5 Ã- 10(-10)), HNF1A (1.2 Ã- 10(-12)), and FUT2 (6.6 Ã- 10(-9)), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 Ã- 10(-36)). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49). CONCLUSIONS: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.

Alcohol drinking and cardiovascular risk in a population with high mean alcohol consumption

Résumé : Description : Ce travail de thèse évalue l'impact de la consommation importante d'alcool sur les facteurs de risque cardiovasculaire et l'estimation du risque cardiovasculaire à 10 ans (risque de développer une maladie coronarienne}, dans une population avec une consommation moyenne élevée d'alcool. La consommation modérée d'alcool a été liée à un risque plus faible de développer une maladie coronarienne. Cependant, les données concernant la consommation importante d'alcool et le risque de développer une maladie coronarienne sont conflictuelles. Il y a également peu d'études dans lesquelles les consommations importantes d'alcool ont pu être évaluées en raison du petit nombre de sujets présentant une telle consommation. Résultats: Nous avons utilisé les données de l'étude CoLaus, une étude populationnelle qui inclut des adultes, âgés de 35 à 75 ans, de la ville de Lausanne. Nous avons inclus 5'769 participants, sans maladie cardiovasculaire, pour lesquels la consommation d'alcool d'une semaine a été catégorisée en 0, 1 à 6, 7 à 13, 14 à 20, 21 à 27, 28 à 34 et >=35 verres/semaine et en non-consommateur (0 verre/semaine), consommateur modéré (1 à 13 verres/semaine), important (14 à 34 verres/semaine) et très important (>= 35). La tension artérielle et les lipides ont été mesurés et le risque de développer une maladie coronarienne à 10 ans a été calculé en utilisant le score de Framingham. 73% des participants consommaient de l'alcool; 16% étaient des consommateurs importants et 2% des consommateurs très importants. L'analyse rnultivariée a montré une augmentation du cholestérol HDL avec la consommation d'alcool (de 1.570.01 [moyenne +- erreur standard] chez les non consommateurs à 1.880.03 mmol/L chez les consommateurs très importants), des triglycérides (1.17+-1.01 à 1.32+-1.05 mmol/L) et des valeurs de tension artérielle systolique (127.4+-0.4 à 132.2+-.4 mm Hg) et diastolique (78.7+-0.3 à 81.7+-0.9 mm Hg, toutes les valeurs de p pour trend<0.001). Quant au risque de développer une maladie coronarienne à 10 ans, il a augmenté de 4.31%+-0.10 à 4.90%+-0.37 (p=0.03) avec la consommation d'alcool, en décrivant une courbe en J. En examinant le type de consommation, on a vu que la consommation de vin a plus d'effet sur l'augmentation des valeurs de cholestérol HDL, alors que la consommation de bière ou de spiritueux a plus d'effet sur l'augmentation des valeurs de triglycérides. Conclusions et perspectives: Nos résultats montrent qu'en ce qui concerne l'estimation du risque cardiovasculaire à 10 ans, l'effet protecteur de la consommation d'alcool disparaît pour des consommations très importantes, car l'effet bénéfique des valeurs augmentées de cholestérol HDL est contrecarré par l'augmentation des valeurs de tension artérielle. Quant aux différents types d'alcool, d'autres études sont nécessaires pour mieux évaluer leur effet spécifique sur les facteurs de risque cardiovasculaire.

Beta-adrenergic blockade and intravenous nutrient-induced thermogenesis in lean and obese women.

Continuous respiratory exchange measurements were performed in nine obese and eight lean women for 1 h before, 3 h during, and 1 h after the intravenous administration of a nutrient mixture infused at twice the postabsorptive resting energy expenditure (REE). This experiment was conducted without or with beta-adrenergic blockade (iv propranolol). Propranolol administration did not change the postabsorptive REE [i.e., 1.03 +/- 0.07 before vs. 1.01 +/- 0.02 kcal/min after administration in lean women and 1.16 +/- 0.04 vs. 1.15 +/- 0.03 kcal/min (NS) in obese women]. The mean overall thermogenic response expressed as a percentage of the infused energy was similar in both groups and was not significantly blunted after propranolol infusion [6.9 +/- 0.4 vs. 5.9 +/- 0.6% in the lean women and 7.5 +/- 0.5 vs. 7.1 +/- 0.6% (NS) in the obese women]. During beta-adrenergic blockade the rate of lipid oxidation decreased in the lean group but was unchanged in the obese group and the glycemic response to nutrient administration was significantly higher in both groups than without propranolol. It is concluded that beta-adrenergic blockade has no effect on REE and on intravenous nutrient-induced thermogenesis in both lean and obese women.

Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.

CONTEXT: Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk. OBJECTIVE: The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs). DATA SOURCES AND STUDY SELECTION: A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes. DATA EXTRACTION: Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events. DATA SYNTHESIS: Among 38 274 adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status. CONCLUSIONS: CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.

Comorbidity and nutritional indices as predictors of morbidity after transurethral procedures: A prospective cohort study.

INTRODUCTION: Preoperative scores are widely used predictors of complications after major surgery. These scores, however, are not widely used in transurethral procedures. The aim of this study was to assess the value of the Charlson Comorbidity Index (CCI), the age-adjusted CCI, the American Society of Anesthesiologist score (ASA) and the Nutritional Risk Score (NRS) in predicting early morbidity after transurethral urological procedures. METHODS: Consecutive patients undergoing transurethral resection of the bladder or the prostate were prospectively enrolled. The scores were calculated preoperatively; 30-day complications were prospectively recorded according to the Dindo-Clavien classification. Univariate logistic regression was performed to investigate the value of each score and of other factors (i.e., age, sex, body mass index, anemia, smoking habit, type of operation and anaesthesia) as predictors of complications. A multivariate model was then calculated using these predictors. RESULTS: Overall, 197 patients were included. The mean age was 72 (standard deviation ± 10). In total, 26.9% patients had at least 1 complication. Using univariate analysis, we found that each score significantly predicted complications. In multivariate analysis, only the ASA (odds ration [OR] 2.11; 95% confidence interval [CI] 1.01-4.43) and the NRS (OR 2.42; 95% CI 1.56-3.74) remained independent predictors. The best model incorporated ASA, NRS and gender, and predicted morbidity with an area under the curve of 76%. Our study's main limitations are population heterogeneity and limited sample size. CONCLUSION: The ASA and the NRS are important and independent determinants of early morbidity after transurethral procedures. The use of these indices may assist clinicians in the decision-making process to balance the possible benefits of transurethral procedures with the potential risks.

QUANTIDADE E PREÇOS DA BANANA-'PRATA' COMERCIALIZADA NAS CEASAS DO DISTRITO FEDERAL, SÃO PAULO, BELO HORIZONTE E RIO DE JANEIRO, NO PERÍODO DE 1995 A 1999

A evolução das quantidades e preços médios mensais e anuais da banana-'Prata' comercializada nos entrepostos das CEASAS do Distrito Federal, São Paulo, Belo Horizonte e Rio de Janeiro foi analisada no período de janeiro de 1995 a dezembro de 1999. Os dados foram analisados pelo teste de Tukey, a nível de 5%. A média da quantidade anual comercializada nas CEASAS do DF, SP, BH e RJ foram, respectivamente, de 831; 1.012; 3.101 e 5.597 t no período analisado. A quantidade média anual comercializada variou significativamente em todas as CEASAS. Os preços médios anuais diferiram significativamente, sendo que em todas as CEASAS estes foram maiores em 1995 e menores em 1997. Não houve diferença significativa na quantidade média mensal comercializada apenas na CEAGESP, já o preço médio mensal diferiu significativamente nas CEASAS do DF, SP e BH. O preço médio anual foi maior na CEASA/RJ (R$ 1,01/Kg), que foi 18,8%; 32,9% e 80,4% superior quando comparado ao preço praticado na CEASA/ DF, CEAGESP e CEASA/BH, respectivamente.

Statin treatment is associated with improved prognosis in patients with AF-related stroke.

BACKGROUND/OBJECTIVES: The most recent ACC/AHA guidelines recommend high-intensity statin therapy in ischemic stroke patients of presumably atherosclerotic origin. On the contrary, there is no specific recommendation for the use of statin in patients with non-atherosclerotic stroke, e.g. strokes related to atrial fibrillation (AF). We investigated whether statin treatment in patients with AF-related stroke is associated with improved survival and reduced risk for stroke recurrence and future cardiovascular events. METHODS: All consecutive patients registered in the Athens Stroke Registry with AF-related stroke and no history of coronary artery disease nor clinically manifest peripheral artery disease were included in the analysis and categorized in two groups depending on whether statin was prescribed at discharge. The primary outcome was overall mortality; the secondary outcomes were stroke recurrence and a composite cardiovascular endpoint comprising of recurrent stroke, myocardial infarction, aortic aneurysm rupture or sudden cardiac death during the 5-year follow-up. RESULTS: Among 1602 stroke patients, 404 (25.2%) with AF-related stroke were included in the analysis, of whom 102 (25.2%) were discharged on statin. On multivariate Cox-proportional-hazards model, statin treatment was independently associated with a lower mortality (hazard-ratio (HR): 0.49, 95%CI:0.26-0.92) and lower risk for the composite cardiovascular endpoint during the median 22months follow-up (HR: 0.44, 95%CI:0.22-0.88), but not with stroke recurrence (HR: 0.47, 95%CI:0.22-1.01, p: 0.053). CONCLUSIONS: In this long-term registry of patients with AF-related stroke, statin treatment was associated with improved survival and reduced risk for future cardiovascular events.

Treatment modification in human immunodeficiency virus-infected individuals starting combination antiretroviral therapy between 2005 and 2008.

BACKGROUND: Adverse effects of combination antiretroviral therapy (CART) commonly result in treatment modification and poor adherence. METHODS: We investigated predictors of toxicity-related treatment modification during the first year of CART in 1318 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from the Swiss HIV Cohort Study who began treatment between January 1, 2005, and June 30, 2008. RESULTS: The total rate of treatment modification was 41.5 (95% confidence interval [CI], 37.6-45.8) per 100 person-years. Of these, switches or discontinuations because of drug toxicity occurred at a rate of 22.4 (95% CI, 19.5-25.6) per 100 person-years. The most frequent toxic effects were gastrointestinal tract intolerance (28.9%), hypersensitivity (18.3%), central nervous system adverse events (17.3%), and hepatic events (11.5%). In the multivariate analysis, combined zidovudine and lamivudine (hazard ratio [HR], 2.71 [95% CI, 1.95-3.83]; P < .001), nevirapine (1.95 [1.01-3.81]; P = .050), comedication for an opportunistic infection (2.24 [1.19-4.21]; P = .01), advanced age (1.21 [1.03-1.40] per 10-year increase; P = .02), female sex (1.68 [1.14-2.48]; P = .009), nonwhite ethnicity (1.71 [1.18-2.47]; P = .005), higher baseline CD4 cell count (1.19 [1.10-1.28] per 100/microL increase; P < .001), and HIV-RNA of more than 5.0 log(10) copies/mL (1.47 [1.10-1.97]; P = .009) were associated with higher rates of treatment modification. Almost 90% of individuals with treatment-limiting toxic effects were switched to a new regimen, and 85% achieved virologic suppression to less than 50 copies/mL at 12 months compared with 87% of those continuing CART (P = .56). CONCLUSIONS: Drug toxicity remains a frequent reason for treatment modification; however, it does not affect treatment success. Close monitoring and management of adverse effects and drug-drug interactions are crucial for the durability of CART.

Thrombin-receptor antagonist vorapaxar in acute coronary syndromes

Background: Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. Methods: In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS: Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P = 0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P = 0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. Conclusions: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.)

Subclinical thyroid dysfunction and fracture risk: a meta-analysis.

IMPORTANCE: Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE: To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION: Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES: The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS: Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE: Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.