The Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) Classification System: A Taxonomy for Young Women With Acute Myocardial Infarction.

BACKGROUND: Current classification schemes for acute myocardial infarction (AMI) may not accommodate the breadth of clinical phenotypes in young women. METHODS AND RESULTS: We developed a novel taxonomy among young adults (≤55 years) with AMI enrolled in the Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study. We first classified a subset of patients (n=600) according to the Third Universal Definition of MI using a structured abstraction tool. There was heterogeneity within type 2 AMI, and 54 patients (9%; including 51 of 412 women) were unclassified. Using an inductive approach, we iteratively grouped patients with shared clinical characteristics, with the aims of developing a more inclusive taxonomy that could distinguish unique clinical phenotypes. The final VIRGO taxonomy classified 2802 study participants as follows: class 1, plaque-mediated culprit lesion (82.5% of women; 94.9% of men); class 2, obstructive coronary artery disease with supply-demand mismatch (2a: 1.4% women; 0.9% men) and without supply-demand mismatch (2b: 2.4% women; 1.1% men); class 3, nonobstructive coronary artery disease with supply-demand mismatch (3a: 4.3% women; 0.8% men) and without supply-demand mismatch (3b: 7.0% women; 1.9% men); class 4, other identifiable mechanism (spontaneous dissection, vasospasm, embolism; 1.5% women, 0.2% men); and class 5, undetermined classification (0.8% women, 0.2% men). CONCLUSIONS: Approximately 1 in 8 young women with AMI is unclassified by the Universal Definition of MI. We propose a more inclusive taxonomy that could serve as a framework for understanding biological disease mechanisms, therapeutic efficacy, and prognosis in this population.

Trends in left ventricular assist device use and outcomes among Medicare beneficiaries, 2004-2011.

OBJECTIVE: To characterise the trends in the left ventricular assist device (LVAD) implantation rates and outcomes between 2004 and 2011 in the Medicare population. Since the approval of the HeartMate II in 2008, the use of LVADs has steadily climbed. Given the increase in LVAD use, issues around discharge disposition, post-implant hospitalisations and costs require further understanding. METHODS: We examined LVAD implantation rates and short-term and long-term outcomes among Medicare fee-for-service beneficiaries hospitalised for LVAD implantation. We also conducted analyses among survivors 1-year post-discharge to examine rehospitalisation rates. Lastly, we reported Centers for Medicare & Medicaid Services (CMS) payments for both index hospitalisation and rehospitalisations 1 year post-discharge. RESULTS: A total of 2152 LVAD implantations were performed with numbers increasing from 107 in 2004 to 612 in 2011. The 30-day mortality rate decreased from 52% to 9%, and 1-year mortality rate decreased from 69% to 31%. We observed no change in overall length of stay, but post-procedure length of stay increased. We also found an increase in home discharge dispositions from 26% to 53%. Between 2004 and 2010, the rehospitalisation rate increased and the number of hospital days decreased. The adjusted CMS payment for the index hospitalisation increased from $188 789 to $225 697 over time but decreased for rehospitalisation from $60 647 to $53 630. CONCLUSIONS: LVAD implantations increased over time. We found decreasing 30-day and 1-year mortality rates and increasing home discharge disposition. The proportion of patients rehospitalised among 1-year survivors remained high with increasing index hospitalisation cost, but decreasing post-implantation costs over time.

Most important outcomes research papers on treatment of stable coronary artery disease.

The following are highlights from the new series, Circulation: Cardiovascular Quality and Outcomes Topic Review. This series will summarize the most important manuscripts, as selected by the Editor, that have been published in the Circulation portfolio. The objective of this series is to provide our readership with a timely, comprehensive selection of important papers that are relevant to the quality and outcomes, and general cardiology audience. The studies included in this article represent the most significant research related to treatment of stable coronary artery disease (CAD).

Most important outcomes research papers on anticoagulation for cardiovascular disease.

The following are highlights from the new series, Circulation: Cardiovascular Quality and Outcomes Topic Review. This series will summarize the most important manuscripts, as selected by the Editor, that have been published in the Circulation portfolio. The objective of this new series is to provide our readership with a timely, comprehensive selection of important papers that are relevant to the quality and outcomes, and general cardiology audience. The studies included in this article represent the most significant research in the area of anticoagulation for cardiovascular disease.

Most important articles on cardiovascular disease among racial and ethnic minorities.

The following are highlights from the new series, Circulation: Cardiovascular Quality and Outcomes Topic Review. This series will summarize the most important manuscripts, as selected by the Editor, that have published in the Circulation portfolio. The objective of this new series is to provide our readership with a timely, comprehensive selection of important papers that are relevant to the quality and outcomes, and general cardiology audience. The studies included in this article represent the most significant research in the area of cardiovascular disease among racial and ethnic minorities.

Most important outcomes research papers in cardiovascular disease in the elderly.

The following are highlights from the new series, Circulation: Cardiovascular Quality and Outcomes Topic Review. This series will summarize the most important manuscripts, as selected by the Editor, that have published in the Circulation portfolio. The objective of this new series is to provide our readership with a timely, comprehensive selection of important papers that are relevant to the quality and outcomes and general cardiology audience. The studies included in this article represent the most significant research in the area of cardiovascular disease in the elderly.

Natural history of nonfunctioning pituitary adenomas and incidentalomas: a systematic review and metaanalysis.

CONTEXT: The natural history of pituitary incidentalomas (PIs) and nonfunctioning pituitary adenomas (NFPAs) remains poorly understood. OBJECTIVE: The objective of the study was to synthesize the literature on the prognostic factors involved in the progression of PIs and NFPAs in patients followed up conservatively. DATA SOURCES: We searched MEDLINE, EMBASE, and Cochrane CENTRAL. We sought to identify further studies by reviewing the reference lists from selected studies and reviews and by querying experts. STUDY SELECTION: Eligible studies were longitudinal observational cohort studies that enrolled patients with PIs/NFPAs and followed them up without any treatment from the time of detection and reported on mortality, lesion progression, and development of pituitary hormonal deficiency, apoplexy, or visual field defects. DATA EXTRACTION: Reviewers working independently and in duplicate determined studies' eligibility and collected descriptive, methodological quality, and outcome data. Event rates per 100 person-years (PYs) and associated 95% confidence intervals (CIs) were estimated from each study and pooled using the random-effects model. DATA SYNTHESIS: The 11 included studies had noncomparative single-cohort design. Follow-up duration ranged from 3 to 15 yr. There was a greater tendency for tumor growth in macroadenomas (12.5 per 100 PYs; 95% CI 7.9, 17.2) and in solid lesions (5.7 per 100 PYs; 95% CI 2.3, 9.2) in comparison with microadenomas (3.3 per 100 PYs; 95% CI 2.1, 4.5) and cystic lesions (0.05 per 100 PYs; 95% CI 0.0, 0.2). The development of pituitary apoplexy and worsening of visual field defects were rare. The overall incidence of new endocrine dysfunction was 2.4 per 100 PYs; 95% CI 0.0, 6.4. The majority of these analyses were associated with significant heterogeneity. There was a trend that did not reach statistical significance for greater incidence of pituitary apoplexy and new endocrine dysfunction worsening in macroadenomas compared with microadenomas. The quality of the evidence (risk of bias) was very low due to heterogeneity, methodological limitations, and imprecision caused by the small number of events. CONCLUSIONS: Despite the relatively high prevalence of PIs/NFPAs, the evidence on the natural history of these entities is scarce and of low quality. PIs/NFPAs seem to have fairly rare complications that may be more common when lesions are large (>10 mm) and solid.

Outcomes of surgical treatment for nonfunctioning pituitary adenomas: a systematic review and meta-analysis.

BACKGROUND: Surgery is commonly used in the management of pituitary nonfunctioning adenomas (NFPA). The goal of this systematic review and meta-analysis is to evaluate the effect of surgery on mortality, surgical complications, pituitary function and vision. METHODS: We searched MEDLINE, EMBASE and Cochrane CENTRAL, queried experts and reviewed the reference list of included publications. Eligible studies were comparative and noncomparative longitudinal studies that enroled patients with NFPA who underwent surgery (alone or in combination with other therapies). Reviewers, working independently and in duplicate, determined study eligibility with adequate reproducibility and extracted descriptive, quality and outcome data. Risks, relative risks (RR) and 95% confidence intervals (CIs) were estimated from each study and pooled using random-effects meta-analysis. RESULTS: Most included studies were uncontrolled case series in which patients received a combination of surgery and radiotherapy. The overall quality of the evidence was very low. Median follow-up was 4·29 years. When surgery was not combined with radiotherapy, there was an increased risk of tumour recurrence (RR 1·97; 95% CI, 1·15-3·35). Complications were more likely with the transcranial than with the transsphenoidal approach (mortality RR 4·89; 95% CI, 3·15-6·47; new anterior pituitary deficits RR 4·90; 95% CI, 2·94-7·82; and persistent diabetes insipidus RR 2·50; 95% CI, 1·05-5·35). Overall, transsphenoidal surgery had fairly low perioperative mortality (≤ 1%) and low complication rate (≤ 5% for all patient-important outcomes), but only less than a third of the patients had improvement in pituitary function. CONCLUSIONS: Observational evidence supports the association between a combined approach of transsphenoidal surgery with radiotherapy and improvements in visual field defects and reduction in tumour recurrence.

Clinical review: Adult height in patients with congenital adrenal hyperplasia: a systematic review and metaanalysis.

CONTEXT: Treatment for patients with congenital adrenal hyperplasia (CAH) may affect the final height of these patients. OBJECTIVE: Our objective was to determine the distribution of achieved height in patients with classic CAH diagnosed at infancy or early childhood and treated with glucocorticoids. DATA SOURCES: We searched MEDLINE, EMBASE, Cochrane Library, ISI Web of Science, and Scopus through September 2008; the reference sections of included studies; and expert files. STUDY SELECTION: Eligible studies included patients diagnosed with CAH before age 5 and followed to final height. DATA EXTRACTION: Reviewers working in duplicate independently extracted data on study characteristics and outcomes and determined each study's risk of bias. DATA SYNTHESIS: The sd score (SDS) for final height and corrected height (defined as final height SDS - midparental height SDS) were estimated from each study and pooled using random-effects metaanalysis. The I(2) statistic was used to assess inconsistency in results across studies. RESULTS: We found 35 eligible studies, most of which were retrospective single-cohort studies. The final height SDS achieved by CAH patients was -1.38 (-1.56 to -1.20; I(2) = 90.2%), and the corrected height SDS was -1.03 (-1.20 to -0.86; I(2) = 63.1%). This was not significantly associated with age at diagnosis, gender, type and dose of steroid, and age of onset of puberty. Mineralocorticoid users had a better height outcome in comparison with the nonusers (P = 0.02). CONCLUSION: Evidence derived from observational studies suggests that the final height of CAH patients treated with glucocorticoids is lower than the population norm and is lower than expected given parental height.

Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia because of 21-hydroxylase (CYP21A2) deficiency: a systematic review and meta-analyses.

CONTEXT: Prenatal treatment with dexamethasone to prevent virilization in pregnancies at risk for classical congenital adrenal hyperplasia (CAH) remains controversial. OBJECTIVE: To conduct a systematic review and meta-analyses of studies that evaluated the effects of dexamethasone administration during pregnancies at risk for classical CAH because of 21-hydroxylase deficiency (CYP21A2). DATA SOURCES: We searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception through August 2009. Review of reference lists and contact with CAH experts further identified candidate studies. STUDY SELECTION: Reviewers working independently and in duplicate determined trial eligibility. Eligible studies reported the effects on either foetal or maternal outcomes of dexamethasone administered during pregnancy compared to a control group that did not receive any treatment. DATA EXTRACTION: Reviewers working independently and in duplicate determined the methodological quality of studies and collected data on patient characteristics, interventions, and outcomes. DATA SYNTHESIS: We identified only four eligible observational studies (325 pregnancies treated with dexamethasone). The methodological quality of the included studies was overall low. Meta-analysis demonstrates a reduction in foetus virilization measured by Prader score in female foetuses treated with dexamethasone initiated early during pregnancy (weighted mean difference, -2.33, 95% CI, -3.38, -1.27). No deleterious effects of dexamethasone on stillbirths, spontaneous abortions, foetal malformations, neuropsychological or developmental outcomes were found although these data are quite sparse. There was increased oedema and striae in the mothers treated with dexamethasone. There were no data on long-term follow-up of physical and metabolic outcomes in children exposed to dexamethasone. CONCLUSIONS: The observational nature of the available evidence and the overall small sample size of the whole body of the literature significantly weaken inferences about the benefits and harms of dexamethasone in this setting. Dexamethasone seems to be associated with reduction in foetus virilization without significant maternal or foetal adverse effects. However, this review underscores the current uncertainty and further investigation is clearly needed. The decision about initiating treatment should be based on patients' values and preferences and requires fully informed and consenting parents.

Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis.

CONTEXT: Theory and simulation suggest that randomized controlled trials (RCTs) stopped early for benefit (truncated RCTs) systematically overestimate treatment effects for the outcome that precipitated early stopping. OBJECTIVE: To compare the treatment effect from truncated RCTs with that from meta-analyses of RCTs addressing the same question but not stopped early (nontruncated RCTs) and to explore factors associated with overestimates of effect. DATA SOURCES: Search of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify truncated RCTs up to January 2007; search of MEDLINE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects to identify systematic reviews from which individual RCTs were extracted up to January 2008. STUDY SELECTION: Selected studies were RCTs reported as having stopped early for benefit and matching nontruncated RCTs from systematic reviews. Independent reviewers with medical content expertise, working blinded to trial results, judged the eligibility of the nontruncated RCTs based on their similarity to the truncated RCTs. DATA EXTRACTION: Reviewers with methodological expertise conducted data extraction independently. RESULTS: The analysis included 91 truncated RCTs asking 63 different questions and 424 matching nontruncated RCTs. The pooled ratio of relative risks in truncated RCTs vs matching nontruncated RCTs was 0.71 (95% confidence interval, 0.65-0.77). This difference was independent of the presence of a statistical stopping rule and the methodological quality of the studies as assessed by allocation concealment and blinding. Large differences in treatment effect size between truncated and nontruncated RCTs (ratio of relative risks <0.75) occurred with truncated RCTs having fewer than 500 events. In 39 of the 63 questions (62%), the pooled effects of the nontruncated RCTs failed to demonstrate significant benefit. CONCLUSIONS: Truncated RCTs were associated with greater effect sizes than RCTs not stopped early. This difference was independent of the presence of statistical stopping rules and was greatest in smaller studies.

Aspirin for the primary prevention of cardiovascular events: a systematic review and meta-analysis comparing patients with and without diabetes.

OBJECTIVE: The negative results of two randomized controlled trials (RCTs) have challenged current guideline recommendations for using aspirin for primary prevention of cardiovascular events among patients with diabetes. We therefore sought to determine if the effect of aspirin for primary prevention of cardiovascular events and mortality differs between patients with and without diabetes. RESEARCH DESIGN AND METHODS: We conducted a systematic search of MEDLINE, EMBASE, Cochrane Library, Web of Science, and Scopus since their inceptions until November 2008 for RCTs of aspirin for primary prevention of cardiovascular events. Blinded pairs of reviewers evaluated studies and extracted data. Random-effects meta-analysis and Bayesian logistic regression were used to estimate the ratios of relative risks (RRs) of outcomes of interest among patients with and without diabetes. A 95% CI that crosses 1.00 indicates that the effect of aspirin does not differ between patients with and without diabetes. RESULTS: Nine RCTs with moderate to high methodological quality contributed data to the analyses. The ratios of RRs comparing the benefit of aspirin among patients with diabetes compared with patients without diabetes for mortality, myocardial infarction, and ischemic stroke were 1.12 (95% CI 0.92-1.35), 1.19 (0.82-1.17), and 0.70 (0.25-1.97), respectively. CONCLUSIONS: Whereas estimates of benefit among patients with diabetes remain imprecise, our analysis suggests that the relative benefit of aspirin is similar in patients with and without diabetes.

Stopping randomized trials early for benefit: a protocol of the Study Of Trial Policy Of Interim Truncation-2 (STOPIT-2).

BACKGROUND: Randomized clinical trials (RCTs) stopped early for benefit often receive great attention and affect clinical practice, but pose interpretational challenges for clinicians, researchers, and policy makers. Because the decision to stop the trial may arise from catching the treatment effect at a random high, truncated RCTs (tRCTs) may overestimate the true treatment effect. The Study Of Trial Policy Of Interim Truncation (STOPIT-1), which systematically reviewed the epidemiology and reporting quality of tRCTs, found that such trials are becoming more common, but that reporting of stopping rules and decisions were often deficient. Most importantly, treatment effects were often implausibly large and inversely related to the number of the events accrued. The aim of STOPIT-2 is to determine the magnitude and determinants of possible bias introduced by stopping RCTs early for benefit. METHODS/DESIGN: We will use sensitive strategies to search for systematic reviews addressing the same clinical question as each of the tRCTs identified in STOPIT-1 and in a subsequent literature search. We will check all RCTs included in each systematic review to determine their similarity to the index tRCT in terms of participants, interventions, and outcome definition, and conduct new meta-analyses addressing the outcome that led to early termination of the tRCT. For each pair of tRCT and systematic review of corresponding non-tRCTs we will estimate the ratio of relative risks, and hence estimate the degree of bias. We will use hierarchical multivariable regression to determine the factors associated with the magnitude of this ratio. Factors explored will include the presence and quality of a stopping rule, the methodological quality of the trials, and the number of total events that had occurred at the time of truncation.Finally, we will evaluate whether Bayesian methods using conservative informative priors to "regress to the mean" overoptimistic tRCTs can correct observed biases. DISCUSSION: A better understanding of the extent to which tRCTs exaggerate treatment effects and of the factors associated with the magnitude of this bias can optimize trial design and data monitoring charters, and may aid in the interpretation of the results from trials stopped early for benefit.