Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies

BACKGROUND: The CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies. METHODS: We analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per microL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989-95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per microL. FINDINGS: Data were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251-350 cells per microL was associated with higher rates of AIDS and death than starting therapy in the range 351-450 cells per microL (hazard ratio [HR] 1.28, 95% CI 1.04-1.57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1.13, 0.80-1.60, for deferred initiation of treatment at CD4 cell count 251-350 cells per microL compared with initiation at 351-450 cells per microL). INTERPRETATION: Our results suggest that 350 cells per microL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment.

Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics

PURPOSE To explore whether population-related pharmacogenomics contribute to differences in patient outcomes between clinical trials performed in Japan and the United States, given similar study designs, eligibility criteria, staging, and treatment regimens. METHODS We prospectively designed and conducted three phase III trials (Four-Arm Cooperative Study, LC00-03, and S0003) in advanced-stage, non-small-cell lung cancer, each with a common arm of paclitaxel plus carboplatin. Genomic DNA was collected from patients in LC00-03 and S0003 who received paclitaxel (225 mg/m(2)) and carboplatin (area under the concentration-time curve, 6). Genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2-206, ABCB1, ERCC1, and ERCC2 were analyzed by pyrosequencing or by PCR restriction fragment length polymorphism. Results were assessed by Cox model for survival and by logistic regression for response and toxicity. Results Clinical results were similar in the two Japanese trials, and were significantly different from the US trial, for survival, neutropenia, febrile neutropenia, and anemia. There was a significant difference between Japanese and US patients in genotypic distribution for CYP3A4*1B (P = .01), CYP3A5*3C (P = .03), ERCC1 118 (P < .0001), ERCC2 K751Q (P < .001), and CYP2C8 R139K (P = .01). Genotypic associations were observed between CYP3A4*1B for progression-free survival (hazard ratio [HR], 0.36; 95% CI, 0.14 to 0.94; P = .04) and ERCC2 K751Q for response (HR, 0.33; 95% CI, 0.13 to 0.83; P = .02). For grade 4 neutropenia, the HR for ABCB1 3425C-->T was 1.84 (95% CI, 0.77 to 4.48; P = .19). CONCLUSION Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese and US patients. In an exploratory analysis, genotype-related associations with patient outcomes were observed for CYP3A4*1B and ERCC2 K751Q. This common-arm approach facilitates the prospective study of population-related pharmacogenomics in which ethnic differences in antineoplastic drug disposition are anticipated.

CD4 count slope and mortality in HIV-infected patients on antiretroviral therapy: multicohort analysis from South Africa

BACKGROUND In many resource-limited settings monitoring of combination antiretroviral therapy (cART) is based on the current CD4 count, with limited access to HIV RNA tests or laboratory diagnostics. We examined whether the CD4 count slope over 6 months could provide additional prognostic information. METHODS We analyzed data from a large multicohort study in South Africa, where HIV RNA is routinely monitored. Adult HIV-positive patients initiating cART between 2003 and 2010 were included. Mortality was analyzed in Cox models; CD4 count slope by HIV RNA level was assessed using linear mixed models. RESULTS About 44,829 patients (median age: 35 years, 58% female, median CD4 count at cART initiation: 116 cells/mm) were followed up for a median of 1.9 years, with 3706 deaths. Mean CD4 count slopes per week ranged from 1.4 [95% confidence interval (CI): 1.2 to 1.6] cells per cubic millimeter when HIV RNA was <400 copies per milliliter to -0.32 (95% CI: -0.47 to -0.18) cells per cubic millimeter with >100,000 copies per milliliter. The association of CD4 slope with mortality depended on current CD4 count: the adjusted hazard ratio (aHRs) comparing a >25% increase over 6 months with a >25% decrease was 0.68 (95% CI: 0.58 to 0.79) at <100 cells per cubic millimeter but 1.11 (95% CI: 0.78 to 1.58) at 201-350 cells per cubic millimeter. In contrast, the aHR for current CD4 count, comparing >350 with <100 cells per cubic millimeter, was 0.10 (95% CI: 0.05 to 0.20). CONCLUSIONS Absolute CD4 count remains a strong risk for mortality with a stable effect size over the first 4 years of cART. However, CD4 count slope and HIV RNA provide independently added to the model.

Long-term outcomes of biodegradable polymer versus durable polymer drug-eluting stents in patients with diabetes a pooled analysis of individual patient data from 3 randomized trials

BACKGROUND There is ongoing debate on the optimal drug-eluting stent (DES) in diabetic patients with coronary artery disease. Biodegradable polymer drug-eluting stents (BP-DES) may potentially improve clinical outcomes in these high-risk patients. We sought to compare long-term outcomes in patients with diabetes treated with biodegradable polymer DES vs. durable polymer sirolimus-eluting stents (SES). METHODS We pooled individual patient-level data from 3 randomized clinical trials (ISAR-TEST 3, ISAR-TEST 4 and LEADERS) comparing biodegradable polymer DES with durable polymer SES. Clinical outcomes out to 4years were assessed. The primary end point was the composite of cardiac death, myocardial infarction and target-lesion revascularization. Secondary end points were target lesion revascularization and definite or probable stent thrombosis. RESULTS Of 1094 patients with diabetes included in the present analysis, 657 received biodegradable polymer DES and 437 durable polymer SES. At 4years, the incidence of the primary end point was similar with BP-DES versus SES (hazard ratio=0.95, 95% CI=0.74-1.21, P=0.67). Target lesion revascularization was also comparable between the groups (hazard ratio=0.89, 95% CI=0.65-1.22, P=0.47). Definite or probable stent thrombosis was significantly reduced among patients treated with BP-DES (hazard ratio=0.52, 95% CI=0.28-0.96, P=0.04), a difference driven by significantly lower stent thrombosis rates with BP-DES between 1 and 4years (hazard ratio=0.15, 95% CI=0.03-0.70, P=0.02). CONCLUSIONS In patients with diabetes, biodegradable polymer DES, compared to durable polymer SES, were associated with comparable overall clinical outcomes during follow-up to 4years. Rates of stent thrombosis were significantly lower with BP-DES.

Mid-term results in relation to age and analysis of predictive factors after fixation of acetabular fractures using the modified Stoppa approach.

INTRODUCTION Data concerning outcome after management of acetabular fractures by anterior approaches with focus on age and fractures associated with roof impaction, central dislocation and/or quadrilateral plate displacement are rare. METHODS Between October 2005 and April 2009 a series of 59 patients (mean age 57 years, range 13-91) with fractures involving the anterior column was treated using the modified Stoppa approach alone or for reduction of displaced iliac wing or low anterior column fractures in combination with the 1st window of the ilioinguinal approach or the modified Smith-Petersen approach, respectively. Surgical data, accuracy of reduction, clinical and radiographic outcome at mid-term and the need for endoprosthetic replacement in the postoperative course (defined as failure) were assessed; uni- and multivariate regression analysis were performed to identify independent predictive factors (e.g. age, nonanatomical reduction, acetabular roof impaction, central dislocation, quadrilateral plate displacement) for a failure. Outcome was assessed for all patients in general and in accordance to age in particular; patients were subdivided into two groups according to their age (group "<60yrs", group "≥60yrs"). RESULTS Forty-three of 59 patients (mean age 54yrs, 13-89) were available for evaluation. Of these, anatomic reduction was achieved in 72% of cases. Nonanatomical reduction was identified as being the only multivariate predictor for subsequent total hip replacement (Adjusted Hazard Ratio 23.5; p<0.01). A statistically significant higher rate of nonanatomical reduction was observed in the presence of acetabular roof impaction (p=0.01). In 16% of all patients, total hip replacement was performed and in 69% of patients with preserved hips the clinical results were excellent or good at a mean follow up of 35±10 months (range: 24-55). No statistical significant differences were observed between both groups. CONCLUSION Nonanatomical reconstruction of the articular surfaces is at risk for failure of joint-preserving management of acetabular fractures through an isolated or combined modified Stoppa approach resulting in total joint replacement at mid-term. In the elderly, joint-preserving surgery is worth considering as promising clinical and radiographic results might be obtained at mid-term.

Cancer, meta-analysis and reporting biases: the case of erythropoiesis-stimulating agents.

Reporting and publication bias is a well-known problem in meta-analysis and healthcare research. In 2002 we conducted a meta-analysis on the effects of erythropoiesis-stimulating agents (ESAs) on overall survival in cancer patients, which suggested some evidence for improved survival in patients receiving ESAs compared with controls. However, a meta-analysis of individual patient data conducted several years later showed the opposite of our first meta-analysis, that is, evidence for increased on-study mortality and reduced overall survival in cancer patients receiving ESAs. We aimed to determine whether the results of our first meta-analysis could have been affected by publication and reporting biases and, if so, whether timely access to clinical study reports and individual patient data could have prevented this. We conducted a hypothetical meta-analysis for overall survival including all studies and study data that could have been available in 2002, at the time when we conducted our first meta-analysis. Compared with our original meta-analysis, which suggested an overall survival benefit for cancer patients receiving ESAs [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.67‒0.99], our hypothetical meta-analysis based on the results of all studies conducted at the time of the first analysis did not show evidence for a beneficial effect of ESAs on overall survival (HR 0.97, 95% CI 0.83‒1.12). Thus we have to conclude that our first meta-analysis showed misleading overall survival benefits due to publication and reporting biases, which could have been prevented by timely access to clinical study reports and individual patient data. Unrestricted access to clinical study protocols including amendments, clinical study reports and individual patient data is needed to ensure timely detection of both beneficial and harmful effects of healthcare interventions.

Stent thrombosis with ticagrelor versus clopidogrel in patients with acute coronary syndromes: an analysis from the prospective, randomized PLATO trial

BACKGROUND We aimed to describe the effects of ticagrelor versus clopidogrel on stent thrombosis in the Platelet Inhibition and Patient Outcomes (PLATO) trial. METHODS AND RESULTS Of 18 624 patients hospitalized for acute coronary syndromes, 11 289 (61%) had at least 1 intracoronary stent. Ticagrelor reduced stent thrombosis compared with clopidogrel across all definitions: definite, 1.37% (n=71) versus 1.93% (n=105; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.50-0.90; P=0.0091); definite or probable, 2.21% (n=118) versus 2.87% (n=157; HR, 0.75; 95% CI, 0.59-0.95; P=0.017); and definite, probable, and possible, 2.94% (n=154) versus 3.77 (n=201; HR, 0.77; 95% CI, 0.62-0.95). The reduction in definite stent thrombosis was consistent regardless of acute coronary syndrome type, presence of diabetes mellitus, stent type (drug-eluting or bare metal stent), CYP2C19 genetic status, loading dose of aspirin, dose of clopidogrel before randomization, and use of glycoprotein IIb/IIIa inhibitors at randomization. The reduction in stent thrombosis with ticagrelor was numerically greater for late (>30 days; HR, 0.48; 95% CI, 0.24-0.96) and subacute (4 hours-30 days; HR, 0.60; 95% CI, 0.39-0.93) compared with acute (<24 hours; HR, 0.94; 95% CI, 0.43-2.05) stent thrombosis or for patients compliant to therapy (ie, taking blinded study treatment ≥80% of the time) compared with less compliant patients. Randomization to ticagrelor was a strong independent inverse predictor of definite stent thrombosis (HR, 0.65; 95% CI, 0.48-0.88). CONCLUSION Ticagrelor compared with clopidogrel reduces the incidence of stent thrombosis in patients with acute coronary syndromes, with consistent benefit across a broad range of patient, stent, and treatment characteristics.

Long-term outcomes of biodegradable versus durable polymer drug-eluting stents in patients with acute ST-segment elevation myocardial infarction: a pooled analysis of individual patient data from three randomised trials

Aims: Arterial plaque rupture and thrombus characterise ST-elevation myocardial infarction (STEMI) and may aggravate delayed arterial healing following durable polymer drug-eluting stent (DP-DES) implantation. Biodegradable polymer (BP) may improve biocompatibility. We compared long-term outcomes in STEMI patients receiving BP-DES vs. durable polymer sirolimus-eluting stents (DP-SES). Methods and results: We pooled individual patient-level data from three randomised clinical trials (ISAR-TEST-3, ISAR-TEST-4 and LEADERS) comparing outcomes from BP-DES with DP-SES at four years. The primary endpoint (MACE) comprised cardiac death, MI, or target lesion revascularisation (TLR). Secondary endpoints were TLR, cardiac death or MI, and definite or probable stent thrombosis. Of 497 patients with STEMI, 291 received BP-DES and 206 DP-SES. At four years, MACE was significantly reduced following treatment with BP-DES (hazard ratio [HR] 0.59, 95% CI: 0.39-0.90; p=0.01) driven by reduced TLR (HR 0.54, 95% CI: 0.30-0.98; p=0.04). Trends towards reduction were seen for cardiac death or MI (HR 0.63, 95% CI: 0.37-1.05; p=0.07) and definite or probable stent thrombosis (3.6% vs. 7.1%; HR 0.49, 95% CI: 0.22-1.11; p=0.09). Conclusions: In STEMI, BP-DES demonstrated superior clinical outcomes to DP-SES at four years. Trends towards reduced cardiac death or myocardial infarction and reduced stent thrombosis require corroboration in specifically powered trials.

A Comparative Analysis of Bronchial Stricture After Lung Transplantation in Recipients With and Without Early Acute Rejection

BACKGROUND: Risk factors and outcomes of bronchial stricture after lung transplantation are not well defined. An association between acute rejection and development of stricture has been suggested in small case series. We evaluated this relationship using a large national registry. METHODS: All lung transplantations between April 1994 and December 2008 per the United Network for Organ Sharing (UNOS) database were analyzed. Generalized linear models were used to determine the association between early rejection and development of stricture after adjusting for potential confounders. The association of stricture with postoperative lung function and overall survival was also evaluated. RESULTS: Nine thousand three hundred thirty-five patients were included for analysis. The incidence of stricture was 11.5% (1,077/9,335), with no significant change in incidence during the study period (P=0.13). Early rejection was associated with a significantly greater incidence of stricture (adjusted odds ratio [AOR], 1.40; 95% confidence interval [CI], 1.22-1.61; p<0.0001). Male sex, restrictive lung disease, and pretransplantation requirement for hospitalization were also associated with stricture. Those who experienced stricture had a lower postoperative peak percent predicted forced expiratory volume at 1 second (FEV1) (median 74% versus 86% for bilateral transplants only; p<0.0001), shorter unadjusted survival (median 6.09 versus 6.82 years; p<0.001) and increased risk of death after adjusting for potential confounders (adjusted hazard ratio 1.13; 95% CI, 1.03-1.23; p=0.007). CONCLUSIONS: Early rejection is associated with an increased incidence of stricture. Recipients with stricture demonstrate worse postoperative lung function and survival. Prospective studies may be warranted to further assess causality and the potential for coordinated rejection and stricture surveillance strategies to improve postoperative outcomes.

Discrete Improvement in Racial Disparity in Survival among Patients with Stage IV Colorectal Cancer: a 21-Year Population-Based Analysis

Purpose Recently, multiple clinical trials have demonstrated improved outcomes in patients with metastatic colorectal cancer. This study investigated if the improved survival is race dependent. Patients and Methods Overall and cancer-specific survival of 77,490 White and Black patients with metastatic colorectal cancer from the 1988–2008 Surveillance Epidemiology and End Results registry were compared using unadjusted and multivariable adjusted Cox proportional hazard regression as well as competing risk analyses. Results Median age was 69 years, 47.4 % were female and 86.0 % White. Median survival was 11 months overall, with an overall increase from 8 to 14 months between 1988 and 2008. Overall survival increased from 8 to 14 months for White, and from 6 to 13 months for Black patients. After multivariable adjustment, the following parameters were associated with better survival: White, female, younger, better educated and married patients, patients with higher income and living in urban areas, patients with rectosigmoid junction and rectal cancer, undergoing cancer-directed surgery, having well/moderately differentiated, and N0 tumors (p<0.05 for all covariates). Discrepancies in overall survival based on race did not change significantly over time; however, there was a significant decrease of cancer-specific survival discrepancies over time between White and Black patients with a hazard ratio of 0.995 (95 % confidence interval 0.991–1.000) per year (p=0.03). Conclusion A clinically relevant overall survival increase was found from 1988 to 2008 in this population-based analysis for both White and Black patients with metastatic colorectal cancer. Although both White and Black patients benefitted from this improvement, a slight discrepancy between the two groups remained.

Trends and outcomes in the use of surgery and radiation for the treatment of locally advanced esophageal cancer: a propensity score adjusted analysis of the surveillance, epidemiology, and end results registry from 1998 to 2008

We examined outcomes and trends in surgery and radiation use for patients with locally advanced esophageal cancer, for whom optimal treatment isn't clear. Trends in surgery and radiation for patients with T1-T3N1M0 squamous cell or adenocarcinoma of the mid or distal esophagus in the Surveillance, Epidemiology, and End Results database from 1998 to 2008 were analyzed using generalized linear models including year as predictor; Surveillance, Epidemiology, and End Results doesn't record chemotherapy data. Local treatment was unimodal if patients had only surgery or radiation and bimodal if they had both. Five-year cancer-specific survival (CSS) and overall survival (OS) were analyzed using propensity-score adjusted Cox proportional-hazard models. Overall 5-year survival for the 3295 patients identified (mean age 65.1 years, standard deviation 11.0) was 18.9% (95% confidence interval: 17.3-20.7). Local treatment was bimodal for 1274 (38.7%) and unimodal for 2021 (61.3%) patients; 1325 (40.2%) had radiation alone and 696 (21.1%) underwent only surgery. The use of bimodal therapy (32.8-42.5%, P = 0.01) and radiation alone (29.3-44.5%, P < 0.001) increased significantly from 1998 to 2008. Bimodal therapy predicted improved CSS (hazard ratios [HR]: 0.68, P < 0.001) and OS (HR: 0.58, P < 0.001) compared with unimodal therapy. For the first 7 months (before survival curve crossing), CSS after radiation therapy alone was similar to surgery alone (HR: 0.86, P = 0.12) while OS was worse for surgery only (HR: 0.70, P = 0.001). However, worse CSS (HR: 1.43, P < 0.001) and OS (HR: 1.46, P < 0.001) after that initial timeframe were found for radiation therapy only. The use of radiation to treat locally advanced mid and distal esophageal cancers increased from 1998 to 2008. Survival was best when both surgery and radiation were used.

Treatment modalities for T1N0 esophageal cancers: a comparative analysis of local therapy versus surgical resection

BACKGROUND To investigate the role of nonsurgical treatment for early-stage esophageal cancer, we compared the outcomes of local therapy to esophagectomy, using a large, national database. METHODS Five-year cancer-specific and overall survival (OS) of patients, with T1N0M0 squamous cell or adenocarcinoma of the mid or distal esophagus treated with either surgery or local therapy, with ablative and/or excision techniques, in the Surveillance Epidemiology and End Results cancer registry from 1998 to 2008, were compared using the Kaplan-Meier approach, and multivariable and propensity-score adjusted Cox proportional hazard, and competing risk models. RESULTS Of 1458 patients with T1N0 esophageal cancer, 1204 (83%) had surgery and 254 (17%) had local therapy only. The use of local therapy increased significantly from 8.1% in 1998 to 24.1% in 2008 (p < 0.001). The 5-year OS after local excisional therapy and surgery was not significantly different (55.5% versus 64.1% respectively, p = 0.07), and 5-year cancer-specific survival (CSS) also did not differ (81.7% versus 75.8%, p = 0.10). However, after propensity-score adjustment, CSS was better for patients who underwent local therapy compared with those who underwent surgery (hazard ratio: 0.46, 95% confidence interval: 0.27-0.77, p = 0.003), whereas OS remained similar. CONCLUSION The use of local therapy for T1N0 esophageal cancers increased significantly from 1998 to 2008. Compared with those treated with esophagectomy, patients treated with local therapy had similar OS but improved CSS, indicating a higher chance of dying from other causes. Further studies are needed to confirm the oncologic efficacy of local therapy when used in patients whose lifespans are not limited by conditions other than esophageal cancer.

Drug-eluting stents vs. bare metal stents in patients with cardiogenic shock: a comparison by propensity score analysis.

BACKGROUND In patients with cardiogenic shock, data on the comparative safety and efficacy of drug-eluting stents (DESs) vs. bare metal stents (BMSs) are lacking. We sought to assess the performance of DESs compared with BMSs among patients with cardiogenic shock undergoing percutaneous coronary intervention (PCI). METHODS Out of 236 patients with acute coronary syndromes complicated by cardiogenic shock, 203 were included in the final analysis. The primary endpoint included death, and the secondary endpoint of major adverse cardiac and cerebrovascular events (MACCEs) included the composite of death, myocardial infarction, any repeat revascularization and stroke. Patients were followed for a minimum of 30 days and up to 4 years. As stent assignment was not random, we performed a propensity score analysis to minimize potential bias. RESULTS Among patients treated with DESs, there was a lower risk of the primary and secondary endpoints compared with BMSs at 30 days (29 vs. 56%, P < 0.001; 34 vs. 58%, P = 0.001, respectively) and during long-term follow-up [hazard ratio 0.43, 95% confidence interval (CI) 0.29-0.65, P < 0.001; hazard ratio 0.49, 95% CI 0.34-0.71, P < 0.001, respectively]. After propensity score adjustment, all-cause mortality was reduced among patients treated with DESs compared with BMSs both at 30 days [adjusted odds ratio (OR) 0.26, 95% CI 0.11-0.62; P = 0.002] and during long-term follow-up (adjusted hazard ratio 0.40, 95% CI 0.22-0.72; P = 0.002). The rate of MACCE was lower among patients treated with DESs compared with those treated with BMSs at 30 days (adjusted OR 0.42, 95% CI 0.19-0.95; P = 0.036). The difference in MACCEs between devices approached significance during long-term follow-up (adjusted hazard ratio 0.60, 95% CI 0.34-1.01; P = 0.052). CONCLUSION DESs appear to be associated with improved clinical outcomes, including a reduction in all-cause mortality compared with BMSs among patients undergoing PCI for cardiogenic shock, possibly because of a pacification of the infarct-related artery by anti-inflammatory drug. The results of this observational study require confirmation in an appropriately powered randomized trial.

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.

Subclinical thyroid dysfunction and the risk for fractures: a systematic review and meta-analysis.

BACKGROUND Data on the association between subclinical thyroid dysfunction and fractures conflict. PURPOSE To assess the risk for hip and nonspine fractures associated with subclinical thyroid dysfunction among prospective cohorts. DATA SOURCES Search of MEDLINE and EMBASE (1946 to 16 March 2014) and reference lists of retrieved articles without language restriction. STUDY SELECTION Two physicians screened and identified prospective cohorts that measured thyroid function and followed participants to assess fracture outcomes. DATA EXTRACTION One reviewer extracted data using a standardized protocol, and another verified data. Both reviewers independently assessed methodological quality of the studies. DATA SYNTHESIS The 7 population-based cohorts of heterogeneous quality included 50,245 participants with 1966 hip and 3281 nonspine fractures. In random-effects models that included the 5 higher-quality studies, the pooled adjusted hazard ratios (HRs) of participants with subclinical hyperthyroidism versus euthyrodism were 1.38 (95% CI, 0.92 to 2.07) for hip fractures and 1.20 (CI, 0.83 to 1.72) for nonspine fractures without statistical heterogeneity (P = 0.82 and 0.52, respectively; I2= 0%). Pooled estimates for the 7 cohorts were 1.26 (CI, 0.96 to 1.65) for hip fractures and 1.16 (CI, 0.95 to 1.42) for nonspine fractures. When thyroxine recipients were excluded, the HRs for participants with subclinical hyperthyroidism were 2.16 (CI, 0.87 to 5.37) for hip fractures and 1.43 (CI, 0.73 to 2.78) for nonspine fractures. For participants with subclinical hypothyroidism, HRs from higher-quality studies were 1.12 (CI, 0.83 to 1.51) for hip fractures and 1.04 (CI, 0.76 to 1.42) for nonspine fractures (P for heterogeneity = 0.69 and 0.88, respectively; I2 = 0%). LIMITATIONS Selective reporting cannot be excluded. Adjustment for potential common confounders varied and was not adequately done across all studies. CONCLUSION Subclinical hyperthyroidism might be associated with an increased risk for hip and nonspine fractures, but additional large, high-quality studies are needed. PRIMARY FUNDING SOURCE Swiss National Science Foundation.