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A Summary of the Agency for Healthcare Research and Quality's Evidence Report on Breastfeeding in Developed Countries

OBJECTIVESnThis article summarizes the Agency for Healthcare Research and Qualitys evidence report on the effects of breastfeeding on term infant and maternal health outcomes in developed countries.nnnEVIDENCE REPORT DATA SOURCESnMedline, CINAHL, Cochrane Library, bibliographies of selected reviews, and suggestions from domain experts were surveyed. Searches were limited to English-language publications.nnnEVIDENCE REPORT REVIEW METHODSnEligible comparisons examined the association between differential exposure to breastfeeding and health outcomes. We assessed 15 infant and six maternal outcomes. For four outcomes, we also updated previously published systematic reviews. For the rest of the outcomes, we either summarized previous systematic reviews or conducted new systematic reviews; randomized and non-randomized comparative trials, prospective cohorts, and case-control studies were included. Adjusted estimates were extracted from non-experimental designs. The studies were graded for methodological quality. We did not draw conclusions from poor quality studies.nnnEVIDENCE REPORT RESULTSnWe screened over 9,000 abstracts. Thirty-two primary studies on term infant health outcomes, 43 primary studies on maternal health outcomes, and 28 systematic reviews or meta-analyses that covered approximately 400 individual studies were included in this review. A history of breastfeeding was associated with a reduction in the risk of acute otitis media, nonspecific gastroenteritis, severe lower respiratory tract infections, atopic dermatitis, asthma (young children), obesity, type 1 and 2 diabetes, childhood leukemia, and sudden infant death syndrome. There was no relationship between breastfeeding in term infants and cognitive performance. There were insufficient good quality data to address the relationship between breastfeeding and cardiovascular diseases and infant mortality. For maternal outcomes, a history of lactation was associated with a reduced risk of type 2 diabetes, breast, and ovarian cancer. Early cessation of breastfeeding or no breastfeeding was associated with an increased risk of maternal postpartum depression. There was no relationship between a history of lactation and the risk of osteoporosis. The effect of breastfeeding in mothers on return-to-prepregnancy weight was negligible, and the effect of breastfeeding on postpartum weight loss was unclear.nnnEVIDENCE REPORT CONCLUSIONSnA history of breastfeeding is associated with a reduced risk of many diseases in infants and mothers. Future research would benefit from clearer selection criteria, definitions of breastfeeding exposure, and adjustment for potential confounders. Matched designs such as sibling analysis may provide a method to control for hereditary and household factors that are important in certain outcomes.

Interventions in Primary Care to Promote Breastfeeding: An Evidence Review for the U.S. Preventive Services Task Force

Human milk is the natural nutrition for all infants. According to the American Academy of Pediatrics, it is the preferred choice of feeding for all infants (1). The goals of Healthy People 2010 for breastfeeding are an initiation rate of 75% and continuation rate of 50% at 6 months and 25% at 12 months after delivery (2). A survey of U.S. children in 2002 indicated that only 71% had ever been breastfed, and the percentage of infants who continue to be breastfed to some extent is 35% at 6 months and 16% at 12 months (3). Although the breastfeeding initiation rate is close to the goal set by Healthy People 2010, according to this survey, the breastfeeding continuation rates at 6 and 12 months fall short. Evidence suggests that breastfeeding decreases risks for many diseases in infants and mothers. In children, breastfeeding has been associated with a reduction in the risk for acute otitis media, nonspecific gastroenteritis, severe lower respiratory tract infections, atopic dermatitis, childhood leukemia, and the sudden infant death syndrome. In mothers, a history of lactation has been associated with a reduced risk for type 2 diabetes and breast and ovarian cancer (4). According to the American Academy of Pediatrics, some of the obstacles to initiation and continuation of breastfeeding include insufficient prenatal education about breastfeeding, disruptive maternity care practices, and lack of family and broad societal support (5). Effective interventions reported to date include changes in maternity care practices, such as those implemented in pursuit of the Baby-Friendly Hospital Initiative (BFHI) designation (6, 7), and worksite lactation programs (8). Some of the other interventions implemented include peer-to-peer support, maternal education, and media marketing (9). Our review is based on an evidence report (10) that was requested by the Center on Primary Care, Prevention, and Clinical Partnerships at the Agency for Healthcare Research and Quality, on behalf of the U.S. Preventive Services Task Force, to support the Task Forces update of its 2003 recommendations on counseling to promote breastfeeding (11). Together with the Tufts Evidence-based Practice Center, these agencies jointly developed an analytic framework for study questions to evaluate the available evidence to promote and support breastfeeding (Figure 1). Five linked key questions were proposed in the analytic framework: Figure 1. Analytic framework and study questions. 1. What are the effects of breastfeeding interventions on child and maternal health outcomes? 2. What are the effects of breastfeeding interventions on breastfeeding initiation, duration, and exclusivity? 3. Are there harms from interventions to promote and support breastfeeding? 4. What are the benefits and harms of breastfeeding on infant or child health outcomes? 5. What are the benefits and harms of breastfeeding on maternal health outcomes? The contextual questions regarding the effectiveness of health care system influences on interventions to promote breastfeeding and the potential benefits and harms related to such interventions can be answered by synthesizing the available scientific evidence for each key question. To avoid redundant work, a joint decision was made to adopt results from our earlier Agency for Healthcare Research and Quality evidence report (4) to address questions 4 and 5 on the benefits and harms of breastfeeding for infants and mothers. Table 1 (1284) presents a synopsis of that reports findings on questions 4 and 5. We address only questions 1 to 3 in this article. Specifically, we examine the effects of primary careinitiated interventions to support or promote breastfeeding on child and maternal health outcomes and breastfeeding rates, as reported in randomized, controlled trials (RCTs) from developed countries. We also document reported harms from interventions to promote and support breastfeeding. Table 1. Findings from the Previous Systematic Review Methods Data Sources This systematic review focuses on recent evidence (September 2001 to February 2008) and updates a previous systematic review (85) conducted for the U.S. Preventive Services Task Force to support its 2003 recommendation on counseling to promote breastfeeding (available at www.ahrq.gov/clinic/uspstf/uspsbrfd.htm). We searched for English-language articles in MEDLINE, the Cochrane Central Register of Controlled Trials, and CINAHL from September 2001 to February 2008 by using such Medical Subject Heading terms and keywords as breastfeeding, breast milk feeding, breast milk, human milk, nursing, breastfed, infant nutrition, lactating, and lactation. We also reviewed reference lists of a related systematic review (86) for additional studies. Study Selection We included RCTs published from September 2001 to February 2008 that included any counseling or behavioral intervention initiated from a clinicians practice (office or hospital) to improve the breastfeeding initiation rate or duration of breastfeeding among healthy mothers or members of the motherchild support system (such as partners, grandparents, or friends) and their healthy term or near-term infants (35 weeks gestation or 2500 g). We focused our review on studies conducted in developed countries; however, because of the widespread interest in the BFHI, we also included RCTs of the BFHI that were conducted in Brazil and Belarus. We considered interventions conducted by various providers (lactation consultants, nurses, peer counselors, midwives, and physicians) in various settings (hospital, home, clinic, or elsewhere) to be eligible as long as they originated from a health care setting. We considered maternity services to be primary care for this review. We also included such health care system interventions as staff training. We excluded community- or peer-initiated interventions. Control comparisons were any usual prenatal, peripartum, or postpartum care, as defined in each study. Studies needed to report rates of breastfeeding initiation, duration of breastfeeding, or exclusivity of breastfeeding to be included. Figure 2 shows our search and selection process. Data Extraction and Quality Assessment One investigator extracted data from each study, and another confirmed them. The extracted data included study setting, population, control, description of intervention (type, person, frequency, and duration), definitions of breastfeeding outcomes (initiation, exclusivity, and duration), definitions of health outcomes in both mothers and children (when provided), and analytic methods. Classification of Breastfeeding Interventions Breastfeeding interventions can include a combination of individual components, such as structured breastfeeding education or professional or lay support. We defined 3 categories of breastfeeding intervention: those that included a component of formal or structured breastfeeding education, those that included a component of either professional or lay breastfeeding support, or those that did not include the aforementioned components. The first 2 categories are not mutually exclusive. Table 2 shows complete details. Table 2. Interventions to Support or Promote Breastfeeding Definitions We classified breastfeeding regimens as exclusive or nonexclusive. Studies used different definitions of exclusive breastfeeding (no supplement of any kind, including water while breastfeeding, or occasional formula is permissible while breastfeeding); we adopted all of those definitions. We classified all other breastfeeding regimens (full, partial, mixed, or nonspecified) as nonexclusive. We defined breastfeeding initiation as any breastfeeding at discharge or up to 2 weeks after delivery. We also defined a priori breastfeeding durations of 1 to 3 months as short-term, 4 to 5 months as intermediate-term, 6 to 8 months as long-term, and 9 or more months as prolonged. We categorized studies with breastfeeding durations shorter than 1 month as no breastfeeding in our meta-analyses. Two investigators assessed the methodological quality of all eligible studies by using criteria developed by the U.S. Preventive Services Task Force (87). We assigned each article a quality rating of good, fair, or poor. The criteria for quality assessment of primary studies included randomization techniques, allocation concealment, clear definitions of outcomes, intention-to-treat analysis, and statistical methods. A third investigator reviewed studies for which the first 2 investigators gave discordant quality ratings. We reached final grades for those studies via consensus. We performed subgroup analyses to examine the effects of study quality on the meta-analysis results. We also based our qualitative conclusions on good- or fair-quality studies. Data Synthesis and Analysis We calculated the rates of breastfeeding initiation and short-term, intermediate-term, long-term, and prolonged breastfeeding for both the intervention and control groups in each study. We recorded the exclusivity of breastfeeding and did the same calculations for the exclusive breastfeeding rates. Meta-analysis and Meta-regression We used the rate ratio (relative risk) as the metric of choice to quantify the effectiveness of each breastfeeding promotion intervention. We used the DerSimonian and Laird model for random-effects meta-analysis (88) to obtain summary estimates across studies. We tested for heterogeneity by using the Cochran Q test, which follows a chi-square distribution to make inferences about the null hypothesis of homogeneity (considered significant at P< 0.100) and quantified its extent with I 2 (89, 90). The I 2 statistic ranges between 0% and 100% and quantifies the proportion of between-study variability that is attributed to heterogeneity rather than chance. We used random-effects meta-regression (fitted with restricted maximum likelihood) to explore whether the effectiveness of breastfeeding interventions depends on breastfeeding duration, provided th

Effectiveness of Management Strategies for Renal Artery Stenosis: A Systematic Review

Context Is medical therapy as effective as revascularization for atherosclerotic renal artery stenosis? Contribution This systematic review found no trials that compared aggressive medical therapy and angioplasty with stent in adults with atherosclerotic renal artery stenosis. Some evidence suggested similar kidney outcomes but better blood pressure outcomes with angioplasty, particularly in patients with bilateral renal disease. Weak evidence suggested no large differences in mortality or cardiovascular events between medical and revascularization treatments. No evidence directly compared adverse event rates between treatments. Implications Available evidence comparing benefits and harms of modern treatments for atherosclerotic renal artery stenosis is sparse and inconclusive. The Editors Renal artery stenosis is defined as narrowing of the renal artery lumen. Atherosclerosis, which usually involves the ostium and proximal third of the main renal artery and the perirenal aorta, accounts for 90% of cases of renal artery stenosis (1). Atherosclerotic renal artery stenosis is increasingly common in aging populations, particularly elderly people with diabetes, hyperlipidemia, aortoiliac occlusive disease, coronary artery disease, or hypertension. Atherosclerotic renal artery stenosis is a progressive disease that may occur alone or in combination with hypertension and ischemic kidney disease (1). Although the prevalence of atherosclerotic renal artery stenosis is poorly defined, it may vary from 30% among patients with coronary artery disease identified by angiography (2) to 50% among elderly people or those with diffuse atherosclerotic vascular diseases (3). In the United States, 12% to 14% of patients in whom dialysis is initiated have been found to have atherosclerotic renal artery stenosis (4). Most authorities consider blood pressure control, preservation or salvage of kidney function, and prevention of flash pulmonary edema to be important treatment goals for patients with atherosclerotic renal stenosis. Treatment options include medication alone or revascularization of the stenosed artery or arteries. Combination therapy with multiple antihypertensive agents, often including angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, calcium-channel blockers, and -blockers, is frequently prescribed. Some clinicians also use statins to decrease low-density lipoprotein cholesterol levels and antiplatelet agents, such as aspirin or clopidogrel, to reduce the risk for thrombosis. The current standard for revascularization in most patients is percutaneous transluminal angioplasty with stent placement across the stenosis. Angioplasty without stent placement is less commonly used. Revascularization by surgical reconstruction is generally done only in patients with complicated renal artery anatomy or in those who require pararenal aortic reconstructions for aortic aneurysms or severe aortoiliac occlusive disease. The American College of Cardiology and the American Heart Association recently published guidelines for management of patients with peripheral arterial disease, including renal artery stenosis (5, 6). Although these guidelines provide recommendations about which patients should be considered for revascularization, considerable uncertainty remains about which intervention provides the best clinical outcomes. Among patients treated with medical therapy alone, experts are concerned about the risk for deterioration of kidney function and worsening cardiovascular morbidity and mortality. Revascularization procedures may provide immediate improvement in kidney function and blood pressure, but they are invasive interventions that could result in substantial morbidity or death, and because of the risk for restenosis the durability of their benefits is questioned. Although evidence regarding the optimal management of atherosclerotic renal artery stenosis appears uncertain, a Medicare claims analysis found that the rate of percutaneous renal artery revascularization has rapidly increased between 1996 and 2000, with the number of interventions increasing from 7660 to 18520 (7). To determine which patients, if any, with atherosclerotic renal artery stenosis would most benefit from angioplasty with stent placement, as opposed to continued aggressive medical treatment, the National Institutes of Health has sponsored the large, multicenter Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial. Participants are currently being enrolled in the trial, and results should be reported in 2010. Meanwhile, the Agency for Healthcare Research and Quality, under Section 1013 of the Medicare Modernization Act, commissioned a review asking key questions related to the effectiveness of aggressive medical therapy compared with renal artery angioplasty with stent placement. However, because no published evidence directly compared angioplasty with stent placement and aggressive medical treatment with currently available drugs, the review covered direct comparisons of revascularization, including angioplasty with or without stent placement and surgery, and various medical regimens and indirect comparisons of angioplasty (with stent placement) and surgical interventions, various medical therapies, and natural history (8). Methods Data Sources and Selection To identify articles relevant to several key questions, we searched the MEDLINE database from inception to 6 September 2005 for studies involving adults with atherosclerotic renal artery stenosis. The Figure shows the search and selection process. The full technical report (available at www.effectivehealthcare.ahrq.gov/reports/final.cfm) provides a more detailed description of the study methods. We also reviewed reference lists of related systematic reviews, selected narrative reviews, and primary articles, and we invited domain experts to provide additional citations. We combined search terms for renal artery stenosis, renal hypertension, and renal vascular disease, and we limited the search to English-language articles of studies in adult humans that had relevant research designs. We included peer-reviewed primary studies of adult patients treated for atherosclerotic renal artery stenosis and excluded studies that evaluated patients with renal artery stenosis in the setting of a transplanted kidney, renal artery aneurysm requiring repair, aortic disease requiring invasive intervention, or concurrent cancer or patients who had had previous surgical or angioplasty interventions for renal artery stenosis. We included only studies that reported outcomes of interest (mortality rate, kidney function, blood pressure, and cardiovascular events) at 6 months or more after the initial intervention. We excluded studies in which more than 20% of patients had renal artery stenosis due to other causes. We categorized studies according to whether they evaluated medical treatment, angioplasty, or surgical revascularization or were natural history studies, and by whether they directly compared interventions. Figure. Search and selection of studies for review. *Prospective study; enrolled 10 or more patients; study duration at least 6 months. Prospective study; angioplasty included stent placement; enrolled 30 or more patients; study duration at least 6 months; patients recruited in 1993 or later; patients did not have previous angioplasty. One study has data both for direct comparison of medical treatment to angioplasty and for natural history. Any study design; enrolled 10 or more patients; study duration at least 6 months. Studies with surgical intervention must have recruited patients in 1993 or later. Any study design; enrolled 10 or more patients; study duration at least 6 months; patients recruited in 1993 or later. Any study design; enrolled 100 or more patients (10 or more if the study was prospective); study duration at least 6 months; patients recruited in 1993 or later. We used different eligibility criteria for studies of different interventions, based on the varying number of studies available for each intervention and the relevance of the intervention to current practice. We included all direct comparisons of medical treatment with angioplasty and all uncontrolled (cohort) studies of medical treatment that had at least 10 patients in each group, regardless of study design. For angioplasty, surgical, or natural history studies, we included only those in which at least some patients were recruited in 1993 or later, after the publication of the Fifth Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. These guidelines marked a substantial change from previous guidelines in treatment recommendations for hypertension, including more aggressive blood pressure targets (9). In addition, at this time point, angiotensin-converting enzyme inhibitors began to be used more routinely in the treatment of patients with severe hypertension. We included only angioplasty studies that used stent placement, were prospective, and had at least 30 patients and retrospective surgery studies that included at least 100 patients. Any prospective surgery study that otherwise met criteria was eligible. Data Extraction and Quality and Applicability Assessments Data from each study were extracted by one of the authors and confirmed by another. The extracted data included information about patient samples, interventions, outcomes, adverse events, study design, quality, and applicability. We used predefined criteria to grade study quality as good, fair, or poor; study applicability as high, moderate, or low; and the strength of the overall body of evidence as robust, acceptable, or weak (Appendix Table). Each included study was graded by at least 2 of the authors. Appendix Table. Study Quality, Applicability, and Strength of Evidence Ratings Data Synthesis Because the study designs, participants, interventions, and reported outcome measures varied marke

Predictors of Atrial Fibrillation Recurrence After Radiofrequency Catheter Ablation: A Systematic Review

AF Recurrence After RFA: Systematic Review.u2002Introduction: The relationship between success of radiofrequency ablation for atrial fibrillation (AF) and patient characteristics has not been systematically evaluated.

Systematic Review: Association of Low-Density Lipoprotein Subfractions With Cardiovascular Outcomes

A critical component of lowering the cardiovascular disease burden across the population is identification and aggressive treatment of high-risk individuals. The Adult Treatment Panel III of the Expert Panel of the National Cholesterol Education Program (1) has identified a group of risk factors associated with cardiovascular disease, including elevated low-density lipoprotein (LDL) cholesterol concentrations, cigarette smoking, hypertension, reduced high-density lipoprotein (HDL) cholesterol concentrations, family history of premature coronary heart disease, and older age. Current efforts have focused on determining whether additional diagnostic criteria could improve the accuracy of cardiovascular disease risk estimation (25). Measures of LDL subfractions have been suggested as a potential risk factor. Many terms are used to describe the characteristics and distribution of LDL particles; these include LDL subclasses, particles, particle concentration, particle numbers, and various patterns. These terms describe separate, but sometimes overlapping, features of the LDL particle. To simplify matters, we use the generic term subfractions except when describing specific measurements. Despite this simplification, we are not suggesting that the disparate methods for analyzing LDL can be fully subsumed in a single concept. Numerous methods are used to measure or define LDL subfractions. Table 1 lists the principal methods used and the most commonly reported subfraction measures. Only a few of these disparate systems to estimate LDL subfractions are routinely available, and only from selected clinical laboratories. Table 1. Commonly Used LDL Subfraction Tests and Terms If LDL subfractions are predictive of cardiovascular risk and are of incremental value when added to established cardiovascular risk factors, it remains to be determined whether the different characteristics of the LDL subfractions assessed by various methods would result in similar predictive abilities for estimating cardiovascular risk. Lipid researchers have proposed that small, dense LDL particles confer greater atherogenic risk than larger, less dense LDL particles (6, 7). In vitro, small, dense LDL particles are more avidly taken up by macrophages than larger, less dense LDL particles; are more susceptible to oxidative modification, have a greater propensity for transport into the arterial subendothelial space; and have a greater binding potential to arterial wall proteoglycans (8, 9). The American Diabetes Association and the American College of Cardiology Foundation convened a panel of experts to develop a consensus position for patients with cardiometabolic risk (10). They noted that limited data from cross-sectional and prospective studies suggest that LDL particle number may be a better discriminator of cardiometabolic risk than LDL cholesterol concentrations. They pointed out several limitations, including availability and accuracy of the method and consistency of the predictive power across ethnic groups, ages, and conditions that affect lipid metabolism. They concluded that it is yet to be determined whether treatment decisions would be improved if LDL subfraction measurements were added to the current risk factors used to estimate cardiovascular risk. We sought to evaluate the association between LDL subfractions and incidence and progression of clinical cardiovascular disease. We focus primarily on the LDL subfraction tests that are available for routine use by clinical laboratories and are thus available to all U.S. clinicians and their patients. We also summarize the potential value of LDL subfraction tests used only in research laboratories. An earlier version of this systematic review was conducted as part of a Technology Assessment for the Centers for Medicare & Medicaid Services (11). Methods Data Sources and Searches We conducted a comprehensive search of the scientific literature to identify relevant studies in MEDLINE (1950 to 5 January 2009), CAB Abstracts (1973 to 30 June 2008), and the Cochrane Central Register of Controlled Trials (second quarter of 2008). Appendix Table 1 lists search terms for LDL, particle size or subfractions, and test methodologies. We limited the literature searches to humans and English-language publications. The searches were supplemented by screening reference lists of included studies and selected reviews and requesting more information from domain experts. Appendix Table 1. Search Strategy Study Selection Three investigators screened all citations and retrieved articles for eligibility. We included studies of any prospective, longitudinal design that reported an association between any measure of LDL subfractions and either incident cardiovascular disease (cardiac, cerebrovascular, or peripheral vascular disease) or progression of disease severity (for example, coronary atherosclerosis) and had at least 10 adults per study group. Serum (or plasma) samples must have been obtained before determination of outcomes. We evaluated only clinical outcomes or measures of atherosclerosis on which clinical decisions are made (for example, minimum lumen diameter). We placed no further restrictions on study populations and included studies of people with and without cardiovascular disease at baseline. No minimum follow-up duration was required. Data Extraction One of the three authors extracted data from each study, and at least 1 additional author reviewed and verified the extractions. Full data extraction, including quality assessment, was performed for studies that used specific methods or kits that are currently available to clinical laboratories (as opposed to research laboratories). From the best information available to us from the Centers for Medicare & Medicaid Services, the U.S. Food and Drug Administration, domain experts, the reviewed studies, internet searches, invited reviewers, and conversations with several laboratories, we limited the full analysis to nuclear magnetic resonance (NMR), the LipoPrint kit (Quantimetrix, Redondo Beach, California) for linear polyacrylamide gel electrophoresis, gradient gel electrophoresis performed at Berkeley HeartLab (LDL-S3 GGE Test, Berkeley HeartLab, Burlingame, California), an ultracentrifugation technique performed at the University of Washingtons Northwest Lipid Research Laboratory, and the Vertical Auto Profile (Atherotech, Birmingham, Alabama). For other laboratory methods, we extracted only limited results data: the type of LDL subfraction measurement (particle size, particle concentration or number, or pattern of LDL subfraction distribution [small, medium, or large LDL, or other subfractions]) and the direction and statistical significance of the association. These other laboratory methods included a range of gel electrophoresis and ultracentrifugation methods that are generally not standardized and are used only in the research setting, high-pressure liquid chromatography, capillary isotachophoresis, and other techniques. We analyzed both unadjusted and adjusted associations between LDL subfractions and clinical cardiovascular outcomes. For the purposes of this review, adjusted analyses were multivariable analyses in which the association between LDL subfraction and cardiovascular outcomes were adjusted for LDL cholesterol, HDL cholesterol, non-HDL cholesterol, or triglyceride concentrations; unadjusted analyses did not adjust for cholesterol concentrations but may have adjusted for other variables, such as other lipoprotein subfractions, clinical history, demographic characteristics, or blood pressure. Quality Assessment We assessed the methodological quality of each fully extracted study on the basis of predefined criteria (12). The primary data extractor determined the study quality, and at least 1 other extractor confirmed it. We used a 3-category grading system to denote the methodological quality of each study. Good-quality studies adhere most closely to the commonly held concepts of high quality, including clear descriptions of the population, setting, LDL subfraction measures, and analytic technique; appropriate measurement of outcomes; appropriate statistical analysis, including multivariable analysis adjusting for lipid measures; no obvious reporting omissions or errors; clear reporting of dropouts; and complete reporting of associations of interest for this systematic review. Fair-quality studies have some deficiencies, but these are unlikely to cause major bias. Poor-quality studies failed to adequately describe the measures, analyses, or results of interest or had substantial flaws in reporting or statistical analyses, such that major bias could not be excluded. The quality assessment was based specifically on the analysis of LDL subfractions and clinical cardiovascular outcomes, regardless of the primary analysis of interest to the original researchers. Role of the Funding Source The Agency for Healthcare Research and Quality participated in formulating the study questions but did not participate in the literature search; determination of study eligibility; data analysis or interpretation; or preparation, review, or approval of the manuscript for publication. Results The literature searches yielded 6724 citations (Figure), of which 476 were retrieved for further consideration for this and other research questions of interest. Of these, 24 met eligibility criteria. Ten studies (1322) used NMR to measure LDL subfractions. Although LipoPrint gel electrophoresis is among the methods more commonly used by clinical laboratories, we identified no study that used this kit to evaluate incidence or progression of cardiovascular disease (at least 6 LipoPrint studies all evaluated prevalent disease). Also, none of the eligible studies used the gradient gel electrophoresis performed at the Berkeley HeartLab or the ultracentrifugation method available at the Northwest Lipid Research Laboratory or the Vertical Auto Profile. An additional 14 studies

Systematic Review: Comparative Effectiveness of Radiofrequency Catheter Ablation for Atrial Fibrillation

Context Is radiofrequency catheter ablation a better alternative than medical therapy for patients with atrial fibrillation? Contribution This systematic review found that radiofrequency ablation after a failed drug course maintained sinus rhythm more often than continuation of drug therapy alone. Some studies found that ablation improved quality of life but did not necessarily reduce stroke rates compared with medical therapy. Fewer than 5% of patients undergoing ablation reportedly experienced major adverse events, such as pulmonary-vein stenosis or cardiac tamponade. Caution Most available evidence was obtained in middle-age adults with preserved left ventricular function and involved follow-up periods of 1 year or less. The Editors Atrial fibrillation is the most common sustained arrhythmia in clinical practice (1). Its prevalence increases with age, from 0.1% in people younger than 55 years to more than 9% by 80 years of age (2). The heavy burden of atrial fibrillation on morbidity, mortality, and health care resources creates a pressing need for novel approaches to management. In some patients, adequate pharmacologic slowing of the ventricular response rate (a rate-control strategy) is sufficient to control symptoms. However, many patients remain symptomatic from the lack of organized atrial contraction and the persistent irregularity of the ventricular response in atrial fibrillation. In such patients, the appropriate treatment is restoration of normal sinus rhythm, achieved electrically or chemically (a rhythm-control strategy) (2). Overall, a rhythm-control strategy with antiarrhythmic drugs offered no survival advantage over a rate-control strategy in 1 large trial (3). An on-treatment analysis, however, suggested that sinus rhythm was associated with a considerable reduction in the risk for death, although antiarrhythmic drugs resulted in increased mortality (4). The benefits of maintaining sinus rhythm with antiarrhythmic drugs appeared to be offset by the serious adverse effects of the drugs. Radiofrequency catheter ablation is a promising approach that offers the benefits of maintaining sinus rhythm without the adverse effects of antiarrhythmic drugs. Catheter ablation for atrial fibrillation is based on the understanding that electrical activity emanating from the pulmonary veins frequently serves as a trigger for atrial fibrillation. In the late 1990s, Hassaguerre and colleagues (5) observed that elimination of local electrograms at these foci with radiofrequency energy reduced the risk for recurrence of atrial fibrillation. Currently, the foundation of most atrial fibrillation ablation procedures is to target and electrically isolate the pulmonary veins (6). This may be achieved by delivering lesions immediately outside the ostia of the pulmonary veins or along a wider area in the left atrium encircling the veins. Additional lesion sets have been used to ablate nonpulmonary vein triggers of atrial fibrillation and to target atrial areas thought to be responsible for maintaining atrial fibrillation (6). These linear lesions may be created in the posterior left atrium, the roof of the left atrium, the interatrial septum, and the isthmus formed between the mitral annulus and the pulmonary vein or left atrial appendage. The Agency for Healthcare Research and Quality commissioned this report to review the evidence for the clinical effects and safety of radiofrequency catheter ablation for the management of atrial fibrillation. At present, the Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation, put forth by the Heart Rhythm Society and endorsed by several professional organizations, states that the foundation of most atrial fibrillation ablation procedures is to target the pulmonary veins, pulmonary vein antra, or both (6). After discussion with a technical expert panel convened for this comparative effectiveness review and in accordance with the Heart Rhythm Societys consensus statement, we reviewed only studies that included the targeting of the pulmonary veins or pulmonary vein antra, with or without the addition of other strategies. Methods We developed and followed a standard protocol for all steps of the review. A technical report that describes our methods in detail, including the literature search strategies, results, and conclusions, is published elsewhere (7). Key Questions Key questions on the effectiveness of radiofrequency catheter ablation compared with other available treatments (for example, medical treatment or surgery) were refined with input from the technical expert panel. The panel advised us that 8-mmtip and irrigated-tip catheters are now the catheters of choice for radiofrequency ablation of atrial fibrillation in the United States. The conventional 4-mmtip catheter is rapidly being phased out of use for this indication. Thus, we limited our review to studies that used 8-mmtip or irrigated-tip catheters as a comparator. The following 3 key questions were formulated: 1. What is the effect of radiofrequency catheter ablation on short-term (6 to 12 months) and long-term (>12 months) rhythm control; rates of congestive heart failure; changes in the size of the left atrium and ventricle; rates of stroke; quality of life; avoiding anticoagulation; and readmissions for paroxysmal, persistent, and long-standing persistent (chronic) atrial fibrillation? 2. How does the effect of radiofrequency ablation on rhythm control differ among the various techniques used? 3. What are the short- and long-term complications and harms associated with radiofrequency ablation? Data Sources and Selection We searched MEDLINE and the Cochrane Central Register of Controlled Trials from 2000 to December 2008 for studies of adults with atrial fibrillation who underwent radiofrequency catheter ablation. We combined keywords and Medical Subject Heading terms for atrial fibrillation, pulmonary vein, radiofrequency ablation, and catheter ablation. We limited the search to English-language reports of primary studies in adults that were published in peer-reviewed journals. We did not include unpublished data. Six reviewers screened titles and abstracts to identify potentially relevant articles. They also examined the full-text articles of the potentially relevant abstracts for inclusion eligibility. We accepted longitudinal studies and excluded case series. We included randomized trials of any sample size. For pragmatic reasons, we restricted the sample sizes in nonrandomized studies. For nonrandomized comparative studies and casecontrol studies, we included only those with at least 10 patients per intervention group. Noncomparative prospective cohort studies had to have at least 50 patients receiving radiofrequency catheter ablation, and retrospective cohort studies must have had at least 100 patients. We included studies of adults (18 years of age) with paroxysmal, persistent, or permanent or chronic atrial fibrillation. We accepted the definitions of the various types of atrial fibrillation used by the study authors, using the terms permanent and chronic atrial fibrillation as reported in the individual studies, even though the definitions varied. Notably, the consensus statement on radiofrequency catheter ablation for the treatment of atrial fibrillation published by the Heart Rhythm Society in 2007 no longer used the term chronic, instead adopting the term long-standing persistent for continuous atrial fibrillation lasting more than 1 year (6). For a study to be included, at least 80% of the patients had to be treated with first-time radiofrequency ablation for atrial fibrillation. We excluded studies that were limited to patients with congenital heart disease, hypertrophic cardiomyopathy, or the WolffParkinsonWhite syndrome. The intervention of interest was catheter-directed radiofrequency ablation of the left atrium to prevent atrial fibrillation by using an 8-mmtip or irrigated-tip catheter. We included studies that compared 4-mmtip catheters to other catheters, but not studies that evaluated only 4-mmtip catheters. Radiofrequency ablation could be used as first- or second-line treatment (that is, before or after a course of antiarrhythmic drugs) and with or without concurrent antiarrhythmic drugs. We included studies of radiofrequency ablation strategies in which the explicit or intended goal was targeting of the pulmonary veins or pulmonary vein antra, with or without additional ablation. We did not evaluate cryoablation or microwave ablation. We included only studies that reported outcomes of interest at 6 months or more after the initial intervention or that reported adverse events at any time. Outcomes of interest included rhythm control, congestive heart failure, changes in the size of the left atrium or ventricle, stroke, quality-of-life measures, avoidance of anticoagulation, readmissions, and reinterventions for atrial fibrillation. We excluded arrhythmia outcomes that occurred during the blanking period, which is defined as a postprocedure period (typically between 1 and 3 months) during which an episode of atrial fibrillation was not considered a recurrence. Data Extraction and Quality Assessment Data from each study were extracted by 1 of 4 reviewers and were confirmed by a clinical cardiac electrophysiologist author. The extracted data included information on patient characteristics, ablation characteristics (for example, type of catheter tip, verification of electrical isolation, and ablation techniques), other interventions, outcomes, study design, and quality. For most outcomes, 6-month, 12-month, and last-reported-time-point data were included. All mortality and adverse event data were extracted. We used predefined criteria to grade study quality as good, fair, or poor. We also rated the strength of the overall body of evidence for each key question as high, moderate, low, or insufficient (Appendix Table). The quality assessment and strength of the overall bod

The Vulnerable Atherosclerotic Plaque: Scope of the Literature

The scope of recent literature on the concept of vulnerable plaque was reviewed by examining 463 abstracts of primary and review articles identified through MEDLINE (2003 to April 2010). Proposed definition criteria of vulnerable plaque included active inflammation, a thin cap with a large lipid core, endothelial denudation, fissured cap, severe stenosis, or combinations of these findings. In 242 primary studies, histopathology, biomarkers, and imaging of carotid and coronary artery plaques were evaluated for features suggestive of vulnerability. Notably, 89% of these studies were cross-sectional in design and were exclusively conducted in patients with known cardiovascular disease. None of the imaging studies documented whether the identified lesions were responsible for cardiovascular events. Cross-sectional design precludes evaluation of the predictive utility of biomarkers. Because vulnerable plaque is not an established medical diagnosis, no studies have been done that explicitly evaluate the treatment of vulnerable plaques. Few studies examined potential systemic treatments (for example, statins) to modify vulnerability features. Large prospective studies in patients with and without previous cardiovascular events during long follow-up are required to validate this concept.

Systematic Review: Charged-Particle Radiation Therapy for Cancer

Context Charged-particle radiation therapy is an alternative mode of radiation delivery for patients with cancer. This treatment is expensive but is becoming increasingly available. Contribution This review found that published evidence about the benefits and harms of charged-particle radiation therapy was derived mostly from small, single-group, retrospective studies. Of the 17 studies that compared treatments with or without charged particles, none reported statistically significant or important differences in overall or cancer-specific survival or in total serious adverse events. Implication We need better evidence to guide decision making about the indications for and the relative safety of charged-particle radiation therapy for cancer. The Editors In 2008, there were 1.4 million new cases of cancer in the United States (1). Radiation therapy has a pivotal role in the management of many types of cancer, either as the only treatment or as part of a multimodal approach that can include surgery, chemotherapy, or immunotherapy (2). Conventional cancer radiation therapy uses several types of ionizing radiation (x-rays, gamma rays, or electron beams) to treat tumors. Ionizing radiation damages the DNA of tumor and healthy cells alike, triggering complex biochemical reactions and eventually resulting in cell death. Cellular damage increases with absorbed radiation dose (measured in Gy)that is, the amount of energy that ionizing radiation deposits to a volume of tissue. In clinical practice, lethal tumor doses are not always achieved because radiation oncologists aim to balance the desired damage to the tumor and the undesirable radiation-induced injury to adjacent healthy tissues (3). This is generally achieved by targeting the beam to the tumor area through paths that spare nearby critical and radiosensitive anatomical structures; selecting multiple fields that cross in the tumor area through different paths; and splitting the total dose into multiple smaller dose fractions delivered over several days to weeks, which allows damaged normal tissues to recover between treatments. Appropriate targeting and delivery of radiation dose is particularly important for tumors adjacent to critical body structures. One of several technologies that can achieve precise delivery of radiation doses is charged-particlebeam radiation therapy. Charged-particlebeam therapy has been clinically available since 1954 (4), and many investigations of its use have been published. However, its appropriate clinical utilization is controversial, in part because documented clinical superiority over other modern radiation techniques is lacking and it is expensive. We sought to systematically review clinical outcomes and adverse events with charged-particle radiation therapy compared with other treatments in patients with cancer. Methods This article is based on a technical brief produced by the Tufts Medical Center Evidence-based Practice Center for the Agency for Healthcare Research and Quality (5). We applied the following protocol for all steps of our review. We defined charged-particle radiation therapy as irradiation with protons, helium ions, or heavier ions. This explicitly excludes radiation therapy with neutrons or other particles, such as -mesons. We defined conventional radiation therapy as external photon-beam radiation guided by 2- or 3-dimensional imaging with or without the use of treatment planning computers or older technologies and without beam-intensity modulation. The Glossary defines commonly used terms. Overview of Contemporary Conformal Radiation Therapies On the basis of a fact sheet posted on the National Cancer Institutes Web site (6), the following alternative contemporary conformal radiation therapy modalities were considered: photon intensity-modulated radiation therapy, stereotactic radiosurgery, stereotactic body radiation therapy, brachytherapy, and intraoperative radiation therapy. Three of the authors summarized contemporary radiation therapy techniques on the basis of selected review articles and Internet sources. Two of the authors independently screened the first 100 reviews from PubMed and the first 100 results from Google (Google, Menlo Park, California) for relevance to the brief overview by using free text terms (such as particle-beam therapy, proton beam therapy, intensity modulated radiotherapy, stereotactic radiosurgery, stereotactic body radiotherapy, brachytherapy, and intraoperative radiotherapy). Systematic Review of Particle-Beam Radiation Therapy Data Sources and Searches We searched MEDLINE from inception to 2 February 2008 by using such terms as proton, charged particle, and helium ion and text and Medical Subject Heading terms for cancer. The complete search strategy is published elsewhere (5). We limited searches to studies in humans. The search was updated to 11 July 2009 to include only randomized, controlled trials or nonrandomized comparative studies. Study Selection Four of the authors screened abstracts and further examined the full-text articles of all potentially eligible abstracts. We included studies of any design describing charged-particle radiation therapy in at least 10 patients with cancer and reporting any clinical outcome (survival, local tumor control, and change in symptoms) or any adverse event. We included studies regardless of whether charged-particle radiation therapy was used as standalone treatment or as part of multimodal therapy. We accepted studies published in English, German, French, Italian, and Japanese. We excluded studies that evaluated only treatment planning or dosimetry without providing any data on clinical outcomes or adverse event. We also excluded studies in which more than 20% of the patients did not have malignant conditions. Studies with fewer than 10 patients were screened for adverse events. Data Extraction and Assessment of Evidence Four authors independently recorded study characteristics (design, eligibility criteria, and follow-up period), patient characteristics (type of cancer, age, sex, and comorbidity), treatment characteristics (type of particle, total biologically effective dose, number of fractions, duration of radiation therapy, and prior and concurrent treatments), clinical outcomes (overall or cause-specific survival, outcomes related to local or distant tumor control, and others), and adverse events. One of the authors abstracted quantitative data on the rates of clinical outcomes only from comparative studies, which another author verified. Disagreements were resolved by consensus. We considered clinically significant adverse events to be those that were grade 3 (severe and undesirable adverse events, which included any adverse event resulting in inpatient hospitalization or prolongation of hospitalization, any persistent or substantial disability or incapacity, or a congenital anomaly or birth defect), grade 4 (life-threatening adverse events), or grade 5 (adverse eventrelated death). We also defined late adverse events as those that were reported 3 or more months after irradiation (unless the primary study used a different definition) (7). We also recorded authors opinions on whether the reported toxicities and adverse events were specifically attributable to radiation therapy. We assessed the hierarchy of evidence of cancer-related health outcomes by adapting an established classification system (8, 9). We considered randomized, controlled trials to provide the strongest evidence, nonrandomized comparative studies the next strongest, and single-group studies the weakest. We categorized efficacy outcomes as overall survival, cancer-specific survival, and all other efficacy outcomes (for example, quality of life; a surrogate outcome of overall survival, such as disease-free survival or progression-free survival; or local control rates). Data Synthesis and Analysis For all included studies, we provided descriptive statistics for study designs, clinical and treatment characteristics, and clinical outcomes and adverse events reported, using the publication as the unit of analysis. For comparative studies, we identified those with overlapping populations by comparing author lists, years, and centers of treatment. Role of the Funding Source The study was funded by the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, which helped formulate the initial study questions but did not participate in the interpretation of the findings, or preparation, review, or approval of the manuscript for publication. Results Charged-Particle Radiation Therapy and Alternative Contemporary Conformal Radiation Therapy Techniques Contemporary conformal radiation therapy techniques have better dose distribution than conventional external photon radiation therapy; investigators claim that the former offer better tumor control because of safe dose escalation and fewer radiation-induced complications because of superior sparing of normal tissue. This makes conformal radiation therapy particularly appealing for surgically unapproachable tumors located adjacent to critical structures, such as the brainstem, cranial nerves, or the spinal cord. Charged-Particle Radiation Therapy Charged-particle radiation therapy uses beams of protons or other charged particles, such as helium, carbon, neon, or silicon, but only protons and carbon ions are currently in clinical use (10). Charged particles represent advancement over photons because the former have superior depthdose distribution. Photons or electron beams deposit most of their energy near the surface (skin and normal tissues), with progressively smaller dose at larger depths, where the tumor may be located. In addition, photons continue to deposit the dose of radiation in normal tissues beyond the tumor. In contrast, charged particles deposit a low dose near the surface and almost all their energy in the final millimeters of their trajectory in the tumor; tissues beyond the

Electrocardiogram Screening for Disorders That Cause Sudden Cardiac Death in Asymptomatic Children: A Meta-analysis

BACKGROUND AND OBJECTIVES: Pediatric sudden cardiac death (SCD) occurs in an estimated 0.8 to 6.2 per 100u2009000 children annually. Screening for cardiac disorders causing SCD in asymptomatic children has public appeal because of its apparent potential to avert tragedy; however, performance of the electrocardiogram (ECG) as a screening tool is unknown. We estimated (1) phenotypic (ECG- or echocardiogram [ECHO]-based) prevalence of selected pediatric disorders associated with SCD, and (2) sensitivity, specificity, and predictive value of ECG, alone or with ECHO. METHODS: We systematically reviewed literature on hypertrophic cardiomyopathy (HCM), long QT syndrome (LQTS), and Wolff-Parkinson-White syndrome, the 3 most common disorders associated with SCD and detectable by ECG. RESULTS: We identified and screened 6954 abstracts, yielding 396 articles, and extracted data from 30. Summary phenotypic prevalences per 100u2009000 asymptomatic children were 45 (95% confidence interval [CI]: 10–79) for HCM, 7 (95% CI: 0–14) for LQTS, and 136 (95% CI: 55–218) for Wolff-Parkinson-White. The areas under the receiver operating characteristic curves for ECG were 0.91 for detecting HCM and 0.92 for LQTS. The negative predictive value of detecting either HCM or LQTS by using ECG was high; however, the positive predictive value varied by different sensitivity and specificity cut-points and the true prevalence of the conditions. CONCLUSIONS: Results provide an evidence base for evaluating pediatric screening for these disorders. ECG, alone or with ECHO, was a sensitive test for mass screening and negative predictive value was high, but positive predictive value and false-positive rates varied.

Active Surveillance in Men With Localized Prostate Cancer: A Systematic Review

BACKGROUND Active surveillance (AS) and watchful waiting (WW) have been proposed as management strategies for low-risk, localized prostate cancer. PURPOSE To systematically review strategies for observational management of prostate cancer (AS or WW), factors affecting their utilization, and comparative effectiveness of observational management versus immediate treatment with curative intent. DATA SOURCES MEDLINE and Cochrane databases (from inception to August 2011). STUDY SELECTION Screened abstracts and reviewed full-text publications to identify eligible studies. DATA EXTRACTION One reviewer extracted data, and another verified quantitative data. Two independent reviewers rated study quality and strength of evidence for comparative effectiveness. DATA SYNTHESIS Sixteen independent cohorts defined AS, 42 studies evaluated factors that affect the use of observational strategies, and 2 evidence reports and 22 recent studies reported comparisons of WW versus treatment with curative intent. The most common eligibility criteria for AS were tumor stage (all cohorts), Gleason score (12 cohorts), prostate-specific antigen (PSA) concentration (10 cohorts), and number of biopsy cores positive for cancer (8 cohorts). For monitoring, studies used combinations of periodic PSA testing (all cohorts), digital rectal examination (14 cohorts), and rebiopsy (14 cohorts). Predictors of receiving no active treatment included older age, comorbid conditions, lower Gleason score, tumor stage, PSA concentration, and favorable risk group. No published studies compared AS with immediate treatment with curative intent. Watchful waiting was generally less effective than treatment with curative intent; however, applicability to contemporary patients may be limited. LIMITATIONS Active surveillance and WW often could not be differentiated in the reviewed studies. Published randomized trials have assessed only WW and did not enroll patients diagnosed by PSA screening. CONCLUSION Evidence is insufficient to assess whether AS is an appropriate option for men with localized prostate cancer. A standard definition of AS that clearly distinguishes it from WW is needed to clarify scientific discourse. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.