Mei Chung

Systematic Review: Vitamin D and Cardiometabolic Outcomes

BACKGROUND Vitamin D may modify risk for cardiometabolic outcomes (type 2 diabetes, hypertension, or cardiovascular disease). PURPOSE To examine the association between vitamin D status, including the effect of vitamin D supplementation, and cardiometabolic outcomes in generally healthy adults. DATA SOURCES English-language studies in MEDLINE (inception to 4 November 2009) and the Cochrane Central Register of Controlled Trials (fourth quarter of 2009). STUDY SELECTION 11 reviewers screened citations to identify longitudinal cohort studies that reported associations between vitamin D status and cardiometabolic outcomes, including randomized trials of vitamin D supplementation. DATA EXTRACTION 5 independent reviewers extracted data about study conduct, participant characteristics, outcomes, and quality. Differences were resolved by consensus. DATA SYNTHESIS 13 observational studies (14 cohorts) and 18 trials were eligible. Three of 6 analyses (from 4 different cohorts) reported a lower incident diabetes risk in the highest versus the lowest vitamin D status groups. Eight trials found no effect of vitamin D supplementation on glycemia or incident diabetes. In meta-analysis of 3 cohorts, lower 25-hydroxyvitamin D concentration was associated with incident hypertension (relative risk, 1.8 [95% CI, 1.3 to 2.4]). In meta-analyses of 10 trials, supplementation nonsignificantly reduced systolic blood pressure (weighted mean difference, -1.9 mm Hg [CI, -4.2 to 0.4 mm Hg]) and did not affect diastolic blood pressure (weighted mean difference, -0.1 mm Hg [CI, -0.7 to 0.5 mm Hg]). Lower 25-hydroxyvitamin D concentration was associated with incident cardiovascular disease in 5 of 7 analyses (6 cohorts). Four trials found no effect of supplementation on cardiovascular outcomes. LIMITATIONS Studies included primarily white participants. Observational studies were heterogeneous. Several trials reported post hoc analyses. CONCLUSION The association between vitamin D status and cardiometabolic outcomes is uncertain. Trials showed no clinically significant effect of vitamin D supplementation at the dosages given. PRIMARY FUNDING SOURCE National Institute of Diabetes and Digestive and Kidney Disease, the National Institutes of Health Office of Dietary Supplements, U.S. Food and Drug Administration, Agency for Healthcare Research and Quality, and Public Health Agency of Canada.

Meta-analysis: The Effect of Dietary Counseling for Weight Loss

Key Summary Points This systematic review suggests that, on average, dietary counseling interventions for weight loss have resulted in a net loss of approximately 2 BMI units (6%) at 12 months compared with usual care. This weight difference narrows considerably over the subsequent 4 years. Long-term trials that evaluate the time course of weight changes are needed to confirm these conclusions. Factors that may alter the effectiveness of dietary counseling interventions require additional investigation. Future studies must improve their analyses, reporting of study design and findings, and follow-up of study participants. Obesity-related medical problems are among the most serious health problems facing U.S. adults. Approximately 65% of U.S. adults are overweight (body mass index [BMI] >25 kg/m2), and approximately half of overweight adults are obese (BMI >30 kg/m2) (1). Coronary heart disease is twice as common in obese people as in normal-weight people, and obesity substantially exacerbates all metabolic cardiac risk factors (2, 3). Obesity is associated with decreased longevity (47) and quality of life (8). Dietary and lifestyle modification efforts are the primary methods for treating and preventing obesity. Several important systematic reviews show that dietary-based lifestyle modification efforts can statistically significantly improve body weight and decrease related medical problems (917). The average weight change due to dietary counseling compared with usual care is unclear, particularly over the long term. We systematically reviewed and quantitatively synthesized published data on the net effect of dietary-based counseling compared with usual care over time. We also evaluated various sources of heterogeneity on the effectiveness of weight loss strategies. Methods Data Sources and Searches The starting point for the literature search was an extensive systematic review published in 1998, on which current clinical guidelines regarding identification, evaluation, and treatment of overweight and obesity in adults are based (9). For that report, a 24-member panel of experts methodically and critically examined all relevant scientific literature published between January 1980 and September 1997. After identifying all relevant studies from that report, we conducted a systematic literature search in all languages in MEDLINE and in the Cochrane Central Register of Controlled Trials databases from January 1997 through July 2006 to identify the effect on BMI of dietary-based weight-loss counseling interventions. We found additional studies from reference lists of other systematic reviews and included studies. Terms used in the searches of recent studies were weight loss, body mass index, obesity, diet, behavior therapy, and lifestyle. The search was limited to randomized, controlled trials. Study Selection We included randomized trials that reported original data on the effect of dietary counseling (advice to change dietary patterns) on body weight or BMI compared with the effect of control interventions (usual care or a minimal intervention, such as general verbal or written advice given at baseline, which was designed to approximate usual care). We excluded studies in which patients were younger than 18 years, the goal of the intervention was not weight loss, exercise was the only intervention, mean baseline BMI was less than 25 kg/m2, or SEs could not be determined. In keeping with the eligibility criteria of the 1998 evidence report (9), we also excluded studies with interventions that lasted fewer than 12 weeks and those that did not report effects at a minimum of 16 weeks. Figure 1 shows the number of studies that did not meet the eligibility criteria and the reasons for their exclusion. Figure 1. Study flow diagram. Cochrane = Cochrane Central Register of Controlled Trials; NHLBI/NIDDK = National Heart, Lung, and Blood Institute/National Institute of Diabetes and Digestive and Kidney Diseases. *Not randomized or quasi-randomized; no usual care control; weight loss not goal of intervention; exercise-only intervention; intervention duration less than 12 weeks or follow-up duration less than 16 weeks; baseline body mass index less than 25 kg/m2; no weight change data; insufficient data to calculate standard error; duplicate publication of study; abstract or letter. Data Extraction and Quality Assessment One of 3 reviewers used standardized forms to extract all studies that met the eligibility criteria. A second reviewer reviewed all extracted data. When necessary, disagreements were resolved by consensus of 2 or more authors. For all included studies, we extracted or estimated the net change in BMI and the SE of the net change from the reported data. Net change was defined as the change from baseline in the treatment group minus the change from baseline in the control group. We did not analyze change from baseline in the treatment groups alone (without subtracting changes in the control groups). When necessary, we calculated the change in BMI by using the ratio of baseline BMI to kilograms as the conversion factor. For the 9 studies that did not report such data, we assumed a ratio of 2.7 (equal to a height of 1.64 m), which corresponded well to ratios from other studies. Within studies, we preferentially chose data from intention-to-treat analyses; however, we retained data from all studies regardless of whether their analyses omitted missing data, used last observations carried forward, or replaced missing data with baseline data. For each study that reported change in BMI at multiple time points, we calculated the slopes of the net change in BMI across the different time points. When necessary, the SE of the net change was estimated from the SEs of the changes in BMI in the intervention and control groups, assuming that these values were independent of each other. Similarly, when necessary, the SEs of the intervention and control group changes in BMI were calculated from the SEs of the baseline and final values by using the following equation: where SE1, SE2 and SE12 are the SEs for baseline values, final values, and change in values, respectively, and is the correlation between SE1 and SE2 (18). We arbitrarily chose to be 0.50, the midpoint value. In secondary analyses, we used correlations of 0.25 and 0.75 (18). For the meta-analysis, we calculated the SE of the net BMI slopes by using the same methods. We also extracted data that described the counseling and usual care interventions, participants, study design, and adverse events. Active and maintenance phases of weight loss were defined according to the designations provided by the authors of each study. All studies were assessed for methodological quality according to the design, conduct, and reporting of the clinical study. We used a 3-level classification of study quality (19). Studies rated as good mostly adhered to the commonly held concepts of good quality, including clear description of the sample, setting, intervention, and comparison groups; blinding of outcome assessors; appropriate statistical and analytic methods and reporting of these methods, including randomization technique and intention-to-treat analysis; no obvious reporting errors; participant withdrawal less than 20%; clear reporting of those who withdrew; and no obvious bias. Fair-quality studies had some deficiencies (but none that were likely to cause major bias) or may have had missing information that made it difficult to assess limitations and potential problems. Poor-quality studies had serious errors in design, analysis, or reporting or may have had a large amount of missing information, discrepancies in reporting, or high rates of withdrawal. Data Synthesis and Analysis To summarize the net changes in BMI over time, we used different methods to analyze the data. All analyses were performed separately for data from the active and the maintenance phases of the behavioral weight loss programs. We graphed the net change in BMI for each study against time from the start of the intervention. Separate random-effects model meta-analyses assign a weight to each study on the basis of individual study variance and between-study heterogeneity (20) at each time point for which data were available from at least 3 cohorts of patients. For studies that reported data at multiple time points, not including baseline, we calculated slopes for each available period (for example, if data were reported at 3, 6, and 12 months, we calculated slopes for 3 to 6, 3 to 12, and 6 to 12 months). For periods where we had data from at least 3 cohorts of patients, we meta-analyzed the slopes by using a random-effects model. The calculated SEs of the slopes were used only for weighting the studies in the meta-analysis, not for estimating the statistical significance of the slopes. These SEs capture the relative variances of the net weight changes from baseline at the multiple time points but do not accurately estimate the SEs of the slopes themselves. For each period, we compared the effect of diabetes (inclusion vs. exclusion of patients with diabetes) and intervention (diet and exercise vs. diet alone) by using 2-sample t tests. In addition, all data were analyzed in a random-effects model meta-regressiona meta-analytic technique of multivariable linear regression across studiesaccording to the method of Morris (21) as described by Berkey and colleagues (22). This model is similar to the DerSimonian and Laird (20) random-effects model meta-analysis. We regressed net change BMI against time in months. We also conducted analyses with study-level variables that were potentially associated with the magnitude of the treatment effect, based on known associations within individual studies or on what we considered to be clinically or methodologically relevant from previous studies. These variables included intervention type (diet vs. diet and exercise) (23), frequency of support meetings (prorated for the first

Vitamin D With or Without Calcium Supplementation for Prevention of Cancer and Fractures: An Updated Meta-analysis for the U.S. Preventive Services Task Force

BACKGROUND Studies suggest that vitamin D supplementation may reduce cancer and fracture risks. PURPOSE To examine the benefits and harms of vitamin D with or without calcium supplementation on clinical outcomes of cancer and fractures in adults. DATA SOURCES English-language studies identified from MEDLINE and the Cochrane Central Register of Controlled Trials through July 2011. STUDY SELECTION Randomized, controlled trials (RCTs), prospective cohort studies, and nested case-control studies reporting incidence of or death from cancer and fracture outcomes. DATA EXTRACTION Multiple reviewers extracted details about participant characteristics, including baseline vitamin D status and use of supplements; details of statistical analyses, including adjustments for confounding; and methodological quality. Differences were resolved by consensus. DATA SYNTHESIS 19 RCTs (3 for cancer and 16 for fracture outcomes) and 28 observational studies (for cancer outcomes) were analyzed. Limited data from RCTs suggested that high-dose (1000 IU/d) vitamin D supplementation can reduce the risk for total cancer, and data from observational studies suggested that higher blood 25-hydroxyvitamin D (25-[OH]D) concentrations might be associated with increased risk for cancer. Mixed-effects dose-response meta-analyses showed that each 10-nmol/L increase in blood 25-(OH)D concentration was associated with a 6% (95% CI, 3% to 9%) reduced risk for colorectal cancer but no statistically significant dose-response relationships for prostate and breast cancer. Random-effects model meta-analysis showed that combined vitamin D and calcium supplementation reduced fracture risk (pooled relative risk, 0.88 [CI, 0.78 to 0.99]) in older adults, but the effects differed according to study setting: institution (relative risk, 0.71 [CI, 0.57 to 0.89]) versus community-dwelling (relative risk, 0.89 [CI, 0.76 to 1.04]). One RCT showed adverse outcomes associated with supplementation, including increased risk for renal and urinary tract stones. LIMITATIONS Most trial participants were older (aged≥65 years) postmenopausal women. Observational studies were heterogeneous and were limited by potential confounders. CONCLUSION Combined vitamin D and calcium supplementation can reduce fracture risk, but the effects may be smaller among community-dwelling older adults than among institutionalized elderly persons. Appropriate dose and dosing regimens, however, require further study. Evidence is not sufficiently robust to draw conclusions regarding the benefits or harms of vitamin D supplementation for the prevention of cancer. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

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

OBJECTIVES This 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. EVIDENCE REPORT DATA SOURCES Medline, CINAHL, Cochrane Library, bibliographies of selected reviews, and suggestions from domain experts were surveyed. Searches were limited to English-language publications. EVIDENCE REPORT REVIEW METHODS Eligible 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. EVIDENCE REPORT RESULTS We 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. EVIDENCE REPORT CONCLUSIONS A 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.

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

Omega-3 Fatty Acids and Cardiac Arrhythmias: Prior Studies and Recommendations for Future Research A Report from the National Heart, Lung, and Blood Institute and Office of Dietary Supplements Omega-3 Fatty Acids and Their Role in Cardiac Arrhythmogenesis Workshop

Compared with prehistoric times, the ratio of n-6 to n-3 fatty acids in the modern diet has increased ≈10-fold to 20:1.1,2 A substantial body of evidence suggests that n-3 polyunsaturated fatty acids (PUFAs) provide cardiovascular protection and prevent arrhythmias.3–5 This has led to the recommendation by the American Heart Association that all adults eat fatty fish at least 2 times per week and that patients with coronary heart disease (CHD) are advised to consume ≈1 g/d of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) combined.6,7 The evidence base is not entirely consistent, and a number of randomized trials have failed to show a protective effect of n-3 PUFAs against arrhythmias.8–10 This has led to some uncertainty regarding the appropriate recommendations for their use.11 The present review originates from the Omega-3 Fatty Acids and Their Role in Cardiac Arrhythmogenesis Workshop sponsored by the National Heart, Lung, and Blood Institute and the Office of Dietary Supplements on August 29–30, 2005, and includes the findings from the recently published trials. Data from epidemiological studies, randomized clinical trials, animal studies, and basic science mechanistic studies on the role of n-3 PUFAs in arrhythmia prevention are examined. Areas in which the data are conflicting or our current knowledge is lacking are emphasized. Fatty acids are classified by the length of the carbon chain (long chain, n=20 to 22; intermediate chain, n=18) and the number of double bonds (saturated, monounsaturated, polyunsaturated).1,2 For PUFAs, the location of the first double bond relative to the -CH3 or omega (n-) end is given. Long- and intermediate-chain fatty acids must be ingested as part of the diet because they cannot be synthesized by humans and are therefore referred to as essential. The most common dietary fatty acids include (1) the omega-6 linoleic acid …

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

AF Recurrence After RFA: Systematic Review. Introduction: 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

Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis

Background: Concerns have been raised about the concurrent temporal trend between simple sugar intakes, especially of fructose or high-fructose corn syrup (HFCS), and rates of nonalcoholic fatty liver disease (NAFLD) in the United States. Objective: We examined the effect of different amounts and forms of dietary fructose on the incidence or prevalence of NAFLD and indexes of liver health in humans. Design: We conducted a systematic review of English-language, human studies of any design in children and adults with low to no alcohol intake and that reported at least one predetermined measure of liver health. The strength of the evidence was evaluated by considering risk of bias, consistency, directness, and precision. Results: Six observational studies and 21 intervention studies met the inclusion criteria. The overall strength of evidence for observational studies was rated insufficient because of high risk of biases and inconsistent study findings. Of 21 intervention studies, 19 studies were in adults without NAFLD (predominantly healthy, young men) and 1 study each in adults or children with NAFLD. We found a low level of evidence that a hypercaloric fructose diet (supplemented by pure fructose) increases liver fat and aspartate aminotransferase (AST) concentrations in healthy men compared with the consumption of a weight-maintenance diet. In addition, there was a low level of evidence that hypercaloric fructose and glucose diets have similar effects on liver fat and liver enzymes in healthy adults. There was insufficient evidence to draw a conclusion for effects of HFCS or sucrose on NAFLD. Conclusions: On the basis of indirect comparisons across study findings, the apparent association between indexes of liver health (ie, liver fat, hepatic de novo lipogenesis, alanine aminotransferase, AST, and γ-glutamyl transpeptase) and fructose or sucrose intake appear to be confounded by excessive energy intake. Overall, the available evidence is not sufficiently robust to draw conclusions regarding effects of fructose, HFCS, or sucrose consumption on NAFLD.