Moritz C. Wyler von Ballmoos

Systematic Review and Meta-analysis of Methotrexate Use and Risk of Cardiovascular Disease

Inflammation predicts risk for cardiovascular disease (CVD) events, but the relation of drugs that directly target inflammation with CVD risk is not established. Methotrexate is a disease-modifying antirheumatic drug broadly used for the treatment of chronic inflammatory disorders. A systematic review and meta-analysis of evidence of relations of methotrexate with CVD occurrence were performed. Cohorts, case-control studies, and randomized trials were included if they reported associations between methotrexate and CVD risk. Inclusions and exclusions were independently adjudicated, and all data were extracted in duplicate. Pooled effects were calculated using inverse variance-weighted meta-analysis. Of 694 identified publications, 10 observational studies in which methotrexate was administered in patients with rheumatoid arthritis, psoriasis, or polyarthritis met the inclusion criteria. Methotrexate was associated with a 21% lower risk for total CVD (n = 10 studies, 95% confidence interval [CI] 0.73 to 0.87, p <0.001) and an 18% lower risk for myocardial infarction (n = 5, 95% CI 0.71 to 0.96, p = 0.01), without evidence for statistical between-study heterogeneity (p = 0.30 and p = 0.33, respectively). Among prespecified sources of heterogeneity explored, stronger associations were observed in studies that adjusted for underlying disease severity (relative risk 0.64, 95% CI 0.43 to 0.96, p <0.01) and for other concomitant medication (relative risk 0.73, 95% CI 0.63 to 0.84, p <0.001). Publication bias was potentially evident (funnel plot, Beggs test, p = 0.06); excluding studies with extreme risk estimates did not, however, alter results (relative risk 0.81, 95% CI 0.74 to 0.89). In conclusion, methotrexate use is associated with a lower risk for CVD in patients with chronic inflammation. These findings suggest that a direct treatment of inflammation may reduce CVD risk.

Meta-analysis: Diagnostic Performance of Low-Radiation-Dose Coronary Computed Tomography Angiography

BACKGROUND A new radiation dose-saving technique for noninvasive coronary artery imaging with computed tomography (CT) is available. PURPOSE To summarize current evidence about the ability of low-dose coronary CT angiography to rule out coronary artery disease (CAD) in symptomatic adults. DATA SOURCES Online databases, including MEDLINE, EMBASE, and the Cochrane Library, from inception through 31 October 2010; abstract databases; gray literature; reference lists of identified articles; and experts. No language restrictions were applied. STUDY SELECTION All investigators screened and selected studies that compared prospective electrocardiography-gated coronary CT angiography with catheter coronary angiography (the reference standard) in symptomatic patients with suspected CAD. DATA EXTRACTION Two investigators independently extracted patient and study protocol characteristics and rated methodological quality; differences were resolved by consensus or by a third reader. Multivariate random-effects models were used to obtain pooled estimates. DATA SYNTHESIS 16 studies, comprising 960 patients, were found (7 studies of single-source, 64-slice CT; 4 of dual-source, 64-slice CT; 2 of single-source, 320-slice CT; 1 dual-source, 128-slice CT; 1 of single-source, 128-slice CT; and 1 of single-source, 256-slice CT). On average, 2.4% of the coronary arterial segments were of nondiagnostic image quality, and 1 or more segments were nondiagnostic in 9.5% of the patients. The patient-level sensitivity and specificity of CT angiography were 1.00 (95% CI, 0.98 to 1.00) and 0.89 (CI, 0.85 to 0.92), respectively. The pooled vessel- and segment-level estimates showed lower sensitivity and higher specificity than the patient-level estimates. Statistically significant heterogeneity was found between studies for vessel- and segment-level estimates, which seemed to be associated with body mass index and prevalence of CAD but not with CT scanner characteristics. LIMITATIONS The small number of studies, half of which were from a single tertiary center, limits generalizability. The potential harms of the imaging tests were not well-evaluated. CONCLUSION Early evidence suggests that low-dose coronary CT angiography matches the sensitivity of catheter-based angiography, has low radiation exposure, and is a potentially valid alternative to catheter angiography for triaging symptomatic patients with a clinical suspicion of CAD. PRIMARY FUNDING SOURCE None.

Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results From the Women's Health Initiative Memory Study

Background Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning. Methods and Results Prospective follow‐up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Womens Health Initiative Memory Study (WHIMS). CVD was determined by self‐report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini‐mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow‐up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95% CI: 1.40, 3.15 or HR, 1.97; 95% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity. Conclusions CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.

The risk of cardiovascular events with increased apolipoprotein CIII: A systematic review and meta-analysis

BACKGROUND Apolipoprotein CIII (apoC-III) is an atherogenic protein found on HDL, VLDL and LDL. OBJECTIVE The objective of this study is to review the literature on the association of blood apoC-III level with cardiovascular events and the dose-response relationship for this association. METHODS AND RESULTS MEDLINE, EMBASE, BIOSIS, CINAHL, Clinicaltrials.gov, grey-literature sources, contact with investigators, and reference lists of studies, without language restrictions, were reviewed. Twelve studies (5 retrospective and 7 prospective) with a total of 3163 cases of cardiovascular events met inclusion criteria for this systematic review. The pooled standardized mean difference showed significantly higher levels of apoC-III in the non-HDL fraction of plasma (representing apoC-III in VLDL and LDL) in those with cardiovascular disease compared with controls; no difference for apoC-III levels in HDL; and, a trend toward higher total plasma apoC-III in the cases. Pooled risk estimates from the meta-analysis were 2.48 (1.48-4.32; non-HDL apoC-III), 1.09 (0.65-1.82; HDL apoC-III), and 1.33 (1.07-1.66; total apoC-III) for a cardiovascular event with a 5-mg/dL increase in apoC-III. CONCLUSIONS The current body of literature includes several methodologically sound studies that together provide consistent evidence for an association of cardiovascular events with blood apoC-III level in total plasma or in VLDL and LDL. More data are needed to determine importance of levels of apoC-III in specific lipoproteins for cardiovascular risk assessment and management and to elucidate the interaction between triglycerides and apoC-III in relation to risk of cardiovascular disease.

Dietary Protein Intake and Coronary Heart Disease in a Large Community Based Cohort: Results from the Atherosclerosis Risk in Communities (ARIC) Study

Background Prospective data examining the relationship between dietary protein intake and incident coronary heart disease (CHD) are inconclusive. Most evidence is derived from homogenous populations such as health professionals. Large community-based analyses in more diverse samples are lacking. Methods We studied the association of protein type and major dietary protein sources and risk for incident CHD in 12,066 middle-aged adults (aged 45–64 at baseline, 1987–1989) from four U.S. communities enrolled in the Atherosclerosis Risk in Communities (ARIC) Study who were free of diabetes mellitus and cardiovascular disease at baseline. Dietary protein intake was assessed at baseline and after 6 years of follow-up by food frequency questionnaire. Our primary outcome was adjudicated coronary heart disease events or deaths with following up through December 31, 2010. Cox proportional hazard models with multivariable adjustment were used for statistical analyses. Results During a median follow-up of 22 years, there were 1,147 CHD events. In multivariable analyses total, animal and vegetable protein were not associated with an increased risk for CHD before or after adjustment. In food group analyses of major dietary protein sources, protein intake from red and processed meat, dairy products, fish, nuts, eggs, and legumes were not significantly associated with CHD risk. The hazard ratios [with 95% confidence intervals] for risk of CHD across quintiles of protein from poultry were 1.00 [ref], 0.83 [0.70–0.99], 0.93 [0.75–1.15], 0.88 [0.73–1.06], 0.79 [0.64–0.98], P for trend  = 0.16). Replacement analyses evaluating the association of substituting one source of dietary protein for another or of decreasing protein intake at the expense of carbohydrates or total fats did not show any statistically significant association with CHD risk. Conclusion Based on a large community cohort we found no overall relationship between protein type and major dietary protein sources and risk for CHD.

Healthy Dietary Interventions and Lipoprotein (a) Plasma Levels: Results from the Omni Heart Trial

Background Increased lipoprotein(a) [Lp(a)] levels are associated with atherosclerotic cardiovascular disease. Studies of dietary interventions on changes in Lp(a) are sparse. We aimed to compare the effects of three healthy dietary interventions differing in macronutrient content on Lp(a) concentration. Methods Secondary analysis of a randomized, 3-period crossover feeding study including 155 (89 blacks; 66 whites) individuals. Participants were given DASH-type healthy diets rich in carbohydrates [Carb], in protein [Prot] or in unsaturated fat [Unsat Fat] for 6 weeks each. Plasma Lp(a) concentration was assessed at baseline and after each diet. Results Compared to baseline, all interventional diets increased mean Lp(a) by 2 to 5 mg/dl. Unsat Fat increased Lp(a) less than Prot with a difference of 1.0 mg/dl (95% CI, −0.5, 2.5; p = 0.196) in whites and 3.7 mg/dl (95% CI, 2.4, 5.0; p<0.001) in blacks (p-value between races = 0.008); Unsat Fat increased Lp(a) less than Carb with a difference of −0.6 mg/dl, 95% CI, −2.1, 0.9; p = 0.441) in whites and −1.5 mg/dl (95% CI, −0.2, −2.8; p = 0.021) in blacks (p-value between races = 0.354). Prot increased Lp(a) more than Carb with a difference of 0.4 mg/dl (95% CI, −1.1, 1.9; p = 0.597) in whites and 2.2 mg/dl (95%CI, 0.9, 3.5; p = 0.001) in blacks (p-value between races = 0.082). Conclusion Diets high in unsaturated fat increased Lp(a) levels less than diets rich in carbohydrate or protein with greater changes in blacks than whites. Our results suggest that substitutions with dietary mono- and polyunsaturated fatty acids in healthy diets may be preferable over protein or carbohydrates with regards to Lp(a). Trial Registration Clinicaltrials.gov NCT00051350

Failure to Rescue Rates After Coronary Artery Bypass Grafting: An Analysis From The Society of Thoracic Surgeons Adult Cardiac Surgery Database

BACKGROUND Failure to rescue (FTR) is increasingly recognized as an important quality indicator in surgery. The Society of Thoracic Surgeons National Database was used to develop FTR metrics and a predictive FTR model for coronary artery bypass grafting (CABG). METHODS The study included 604,154 patients undergoing isolated CABG at 1,105 centers from January 2010 to January 2014. FTR was defined as death after four complications: stroke, renal failure, reoperation, and prolonged ventilation. FTR was determined for each complication and a composite of the four complications. A statistical model to predict FTR was developed. RESULTS FTR rates were 22.3% for renal failure, 16.4% for stroke, 12.4% for reoperation, 12.1% for prolonged ventilation, and 10.5% for the composite. Mortality increased with multiple complications and with specific combinations of complications. The multivariate risk model for prediction of FTR demonstrated a C index of 0.792 and was well calibrated, with a 1.0% average difference between observed/expected (O/E) FTR rates. With centers grouped into mortality terciles, complication rates increased modestly (11.4% to 15.7%), but FTR rates more than doubled (6.8% to 13.9%) from the lowest to highest terciles. Centers in the lowest complication rate tercile had an FTR O/E of 1.14, whereas centers in the highest complication rate tercile had an FTR O/E of 0.91. CONCLUSIONS CABG mortality rates vary directly with FTR, but complication rates have little relation to death. FTR rates derived from The Society of Thoracic Surgeons data can serve as national benchmarks. Predicted FTR rates may facilitate patient counseling, and FTR O/E ratios have promise as valuable quality metrics.

Reconstruction of the right atrium using an extracellular matrix patch in a patient with severe mediastinal aspergillosis

INTRODUCTION We report a case of reconstruction of the right atrial wall using a novel bioresorbable patch derived from porcine small intestinal submucosa. PRESENTATION OF CASE Our patient presented with mediastinal aspergillosis as a result of chronic steroid therapy for an oligodendroglioma. Hemodynamic compromise and syncopal episodes secondary to the mass effect of the aspergilloma prolapsing through tricuspid valve necessitated palliative surgical excision. DISCUSSION Intraoperatively, it was confirmed that the lesion had eroded into the right atrium and partially occluded right ventricular inflow. In order to achieve appropriate palliation a wide resection of the atrial wall was necessary. The atrial reconstruction was then performed using an extracellular matrix-derived biopatch. This case was further complicated by postoperative bleeding requiring re-operation. CONCLUSION We describe the methods used for repair using a novel patch in this rare case of invasive aspergillosis extending into the right atrium and resulting in compromise of diastolic right ventricular filling.

Laxative use and incident falls, fractures and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative

BackgroundLaxatives are among the most widely used over-the-counter medications in the United States but studies examining their potential hazardous side effects are sparse. Associations between laxative use and risk for fractures and change in bone mineral density [BMD] have not previously been investigated.MethodsThis prospective analysis included 161,808 postmenopausal women (8907 users and 151,497 nonusers of laxatives) enrolled in the WHI Observational Study and Clinical Trials. Women were recruited from October 1, 1993, to December 31, 1998, at 40 clinical centers in the United States and were eligible if they were 50 to 79 years old and were postmenopausal at the time of enrollment. Medication inventories were obtained during in-person interviews at baseline and at the 3-year follow-up visit on everyone. Data on self-reported falls (≥2), fractures (hip and total fractures) were used. BMD was determined at baseline and year 3 at 3 of the 40 clinical centers of the WHI.ResultsAge-adjusted rates of hip fractures and total fractures, but not for falls were similar between laxative users and non-users regardless of duration of laxative use. The multivariate-adjusted hazard ratios for any laxative use were 1.06 (95% confidence interval [CI], 1.03-1.10) for falls, 1.02 (95% CI, 0.85-1.22) for hip fractures and 1.01 (95% CI, 0.96-1.07) for total fractures. The BMD levels did not statistically differ between laxative users and nonusers at any skeletal site after 3-years intake.ConclusionThese findings support a modest association between laxative use and increase in the risk of falls but not for fractures. Its use did not decrease bone mineral density levels in postmenopausal women. Maintaining physical functioning, and providing adequate treatment of comorbidities that predispose individuals for falls should be considered as first measures to avoid potential negative consequences associated with laxative use.

Clinical research quo vadis? Trends in reporting of clinical trials and observational study designs over two decades.

Background Multiple classifications have been developed that classify the medical literature into different levels of evidence to facilitate the evaluation of study results and practice of evidence-based medicine. The suggested hierarchies of evidence are generally based on the type of study design; randomized, controlled clinical trials constitute the top level of evidence while case reports rank the lowest among epidemiologic study designs. However, little is known about the frequency with which different study designs appear in the medical literature overall. The purpose of this study was to describe trends in the frequency of reports of randomized control trials (RCTs) as compared to other study designs in the medical literature over two decades. Methods Data about the prevalence of various types of study designs in the medical literature over the last two decades (years 1990 - 2009) were abstracted from PubMed, validated and subjected to cross-sectional and longitudinal analysis. Results In the last 20 years, the annual rate of publication of journal articles has more than doubled. During this period, the percentage of observational studies increased from 29.9% to 40.5%, the percentage of reports of RCTs increased minimally, and there was a striking decline in the percentage of case reports (from 49.8% to 33.6%) in the medical literature overall. In contrast, in three selected, highly cited medical journals, the percentage of reports of RCTs increased by almost 10%. Surprisingly, the percentage of articles classified as case reports also increased (from 36.3% to 43.8%) in these three journals, while the percentage of reports of cohort and case-control studies decreased. Conclusion Though the relative frequency of reports from RCTs has not changed substantially in the last 20 years, cohort studies and case-control studies have largely supplanted simple case reports. In contrast, in high impact journals, the representation of RCTs and case reports has increased, with corresponding declines in reports based on other study designs. Further research will be needed to determine whether those trends in publication have resulted in more robust evidence and faster advancement of medical knowledge.