Long-term clinical outcomes of bariatric surgery in adults with severe obesity: A population-based retrospective cohort study.

BACKGROUND: Bariatric surgery leads to sustained weight loss in a majority of recipients, and also reduces fasting insulin levels and markers of inflammation. We described the long-term associations between bariatric surgery and clinical outcomes including 30 morbidities. METHODS: We did a retrospective population-based cohort study of 304,157 adults with severe obesity, living in Alberta, Canada; 6,212 of whom had bariatric surgery. We modelled adjusted time to mortality, hospitalization, surgery and the adjusted incidence/prevalence of 30 new or ongoing morbidities after 5 years of follow-up. RESULTS: Over a median follow-up of 4.4 years (range 1 day-22.0 years), bariatric surgery was associated with increased risk of hospitalization (HR 1.46, 95% CI 1.41,1.51) and additional surgery (HR 1.42, 95% CI 1.32,1.52) but with a decreased risk of mortality (HR 0.76, 95% CI 0.64,0.91). After 5 years (median of 9.9 years), bariatric surgery was associated with a lower risk of severe chronic kidney disease (HR 0.45, 95% CI 0.27,0.75), coronary disease (HR 0.49, 95% CI 0.33,0.72), diabetes (HR 0.51, 95% CI 0.47,0.56), inflammatory bowel disease (HR 0.55, 95% CI 0.37,0.83), hypertension (HR 0.70, 95% CI 0.66,0.75), chronic pulmonary disease (HR 0.75, 95% CI 0.66,0.86), asthma (HR 0.79, 95% 0.65,0.96), cancer (HR 0.79, 95% CI 0.65,0.96), and chronic heart failure (HR 0.79, 95% CI 0.64,0.96). In contrast, after 5 years, bariatric surgery was associated with an increased risk of peptic ulcer (HR 1.99, 95% CI 1.32,3.01), alcohol misuse (HR 1.55, 95% CI 1.25,1.94), frailty (HR 1.28, 95% 1.11,1.46), severe constipation (HR 1.26, 95% CI 1.07,1.49), sleep disturbance (HR 1.21, 95% CI 1.08,1.35), depression (HR 1.18, 95% CI 1.10,1.27), and chronic pain (HR 1.12, 95% CI 1.04,1.20). INTERPRETATION: Bariatric surgery was associated with lower risks of death and certain morbidities. However, bariatric surgery was also associated with increased risk of hospitalization and additional surgery, as well as certain other morbidities. Since values and preferences for these various benefits and harms may differ between individuals, this suggests that comprehensive counselling should be offered to patients considering bariatric surgery.

Associations between body mass index and all-cause mortality: A systematic review and meta-analysis.

Fasting insulin and c-reactive protein confound the association between mortality and body mass index. An increase in fat mass may mediate the associations between hyperinsulinemia, hyperinflammation, and mortality. The objective of this study was to describe the "average" associations between body mass index and the risk of mortality and to explore how adjusting for fasting insulin and markers of inflammation might modify the association of BMI with mortality. MEDLINE and EMBASE were searched for studies published in 2020. Studies with adult participants where BMI and vital status was assessed were included. BMI was required to be categorized into groups or parametrized as non-first order polynomials or splines. All-cause mortality was regressed against mean BMI squared within seven broad clinical populations. Study was modeled as a random intercept. ß coefficients and 95% confidence intervals are reported along with estimates of mortality risk by BMIs of 20, 30, and 40 kg/m2 . Bubble plots with regression lines are drawn, showing the associations between mortality and BMI. Splines results were summarized. There were 154 included studies with 6,685,979 participants. Only five (3.2%) studies adjusted for a marker of inflammation, and no studies adjusted for fasting insulin. There were significant associations between higher BMIs and lower mortality risk in cardiovascular (unadjusted ß -0.829 [95% CI -1.313, -0.345] and adjusted ß -0.746 [95% CI -1.471, -0.021]), Covid-19 (unadjusted ß -0.333 [95% CI -0.650, -0.015]), critically ill (adjusted ß -0.550 [95% CI -1.091, -0.010]), and surgical (unadjusted ß -0.415 [95% CI -0.824, -0.006]) populations. The associations for general, cancer, and non-communicable disease populations were not significant. Heterogeneity was very large (I2 ≥ 97%). The role of obesity as a driver of excess mortality should be critically re-examined, in parallel with increased efforts to determine the harms of hyperinsulinemia and chronic inflammation.

Associations of body mass index, fasting insulin, and inflammation with mortality: a prospective cohort study.

BACKGROUND/OBJECTIVES: Obesity is often considered to increase the risk for premature mortality. Higher fasting insulin and c-reactive protein are associated with higher body mass index (BMI) and all-cause mortality, so may confound the association between obesity and mortality. Our objective was to determine the independent associations between BMI, fasting insulin, c-reactive protein, and all-cause mortality in a general population sample. METHODS: This prospective cohort study included non-institutionalized US adults (≥20 years) from the National Health and Nutrition Examination Surveys 1999-2000 to 2013-2014. The main exposures of interest were BMI, fasting insulin, c-reactive protein. Mortality data were obtained through linking participants to the National Death Index (ending December 31, 2015). RESULTS: There were 12,563 participants with a median age of 45 years (range 20-85) and 47.9% were male. The median BMI was 27 kg/m2 (IQR 24-32), median fasting insulin was 54 pmol/L (IQR 35-87), and median c-reactive protein was 1.9 mg/L (IQR 0.8-4.4). In a Cox model adjusted for age, biological sex, cigarette smoking, and ten chronic conditions, higher BMI parameterized with quadratic and linear terms was not associated with mortality. When fasting insulin and the natural logarithm of c-reactive protein were included in the model, an inverse association between BMI and mortality was present (compared to the referent category of 5th percentile: 1st percentile, HR 1.10, 95% CI 1.06-1.13; 99th percentile, HR 0.48, 95% CI 0.34-0.69). In contrast, higher levels of fasting insulin and c-reactive protein were associated with an increased risk of mortality (for fasting insulin: 1st percentile, HR 0.98, 95% CI 0.97-0.99; 99th percentile, HR 1.83, 95% CI 1.48-2.26; for c-reactive protein, 1st percentile, HR 0.87, 95% CI 0.84-0.90; 99th percentile, HR 2.77, 95% CI 2.12-3.62). CONCLUSIONS: Higher fasting insulin and higher c-reactive protein confound the association between BMI and the risk of all-cause mortality. The increase in mortality that has been attributed to higher BMI is more likely due to hyperinsulinemia and inflammation rather than obesity.

Incident Cardiovascular Disease Among Adults With Cancer: A Population-Based Cohort Study.

Background: Patients with cancer and cancer survivors are at increased risk for incident heart failure, but there are conflicting data on the long-term risk for other cardiovascular events and how such risk may vary by cancer site. Objectives: The aim of this study was to determine the impact of a new cancer diagnosis on the risk for fatal and nonfatal cardiovascular events. Methods: Using administrative health care databases, a population-based retrospective cohort study was conducted among 4,519,243 adults residing in Alberta, Canada, from April 2007 to December 2018. Participants with new cancer diagnoses during the study period were compared with those without cancer with respect to risk for subsequent cardiovascular events (cardiovascular mortality, myocardial infarction, stroke, heart failure, and pulmonary embolism) using time-to-event survival models after adjusting for sociodemographic data and comorbidities. Results: A total of 224,016 participants with new cancer diagnoses were identified, as well as 73,360 cardiovascular deaths and 470,481 nonfatal cardiovascular events during a median follow-up period of 11.8 years. After adjustment, participants with cancer had HRs of 1.33 (95% CI: 1.29-1.37) for cardiovascular mortality, 1.01 (95% CI: 0.97-1.05) for myocardial infarction, 1.44 (95% CI: 1.41-1.47) for stroke, 1.62 (95% CI: 1.59-1.65) for heart failure, and 3.43 (95% CI: 3.37-3.50) for pulmonary embolism, compared with participants without cancer. Cardiovascular risk was highest for patients with genitourinary, gastrointestinal, thoracic, nervous system and hematologic malignancies. Conclusions: A new cancer diagnosis is independently associated with a significantly increased risk for cardiovascular death and nonfatal morbidity regardless of cancer site. These findings highlight the need for a collaborative approach to health care for patients with cancer and cancer survivors.

Changes in mammography screening in Ontario and Alberta following national guideline dissemination: an interrupted time series analysis.

Background: In November 2011, the Canadian Task Force on Preventive Health Care released guidelines for screening women at average breast cancer risk. Weak recommendations (framed using GRADE methodology) were made for screening women aged 50 to 74 years every two to three years, and for not screening women aged 40 to 49 years. Methods: We conducted an interrupted time series analysis using administrative data to examine bilateral mammography use before and after a release of a national breast screening guideline. Women aged 40 to 74 years living in Ontario or Alberta from 30th November 2008 to 30th November 2014 were included. Strata included age, region of residence, neighbourhood income quintile, immigration status, and education level. Results: In both provinces, mammography use rates were lower in the post-intervention period (527 vs. 556 and 428 vs. 465/1000 women in Ontario and Alberta, respectively). In Ontario, mammography trends decreased following guideline release to align with recommendations for women aged 40 to 74 (decrease of 2.21/1000 women, SE 0.26/1000, p<0.0001). In Alberta, mammography trends decreased for women aged 40 to 49 years (3/1000 women, SE 0.32, p<0.001) and 50 to 69 (2.9/1000 women, SE 0.79, p<0.001), but did not change for women aged 70 to 74 (0.7/1000 women, SE 1.23, p=0.553). In both provinces, trends in mammography use rates were sustained for up to three years after guideline release. Conclusions: We observed a decrease in screening for women aged 40-49. Additional research to explore whether shared decision making was used to optimize guideline-concordant screening for women aged 50-74 is needed.

Secular Changes in Mortality and Hospitalization over Time in People with Kidney Failure or Severe CKD as Compared with Other Noncommunicable Diseases.

BACKGROUND: Few new treatments have been developed for kidney failure or CKD in recent years, leading to perceptions of slower improvement in outcomes associated with CKD or kidney failure than for other major noncommunicable diseases. METHODS: Our retrospective cohort study included 548,609 people with an incident noncommunicable disease, including cardiovascular diseases, diabetes, various cancers, and severe CKD or kidney failure treated with renal replacement (KF-RRT), treated in Alberta, Canada, 2004-2015. For each disease, we assessed presence or absence of 8 comorbidities; we also compared secular trends in relative (compared to a referent year of 2004) and absolute risks of mortality and mean annual days in the hospital associated with each disease after 1 year and 5 years. RESULTS: Comorbidities increased significantly in number over time for all noncommunicable diseases except diabetes, and increased most rapidly for CKD and KF-RRT. Significant but relatively small reductions over time in the risk ratio of mortality at 1 year occurred for nearly all noncommunicable diseases. Secular trends in the absolute risk of mortality were similar; CKD and KF-RRT had a relatively favorable ranking at 1 year. Breast cancer, KF-RRT, diabetes, and colorectal cancer displayed the largest relative reductions in number of hospital days at 1 year. Significant absolute reductions in the number of hospital days were observed for both KF-RRT and CKD; the former had the highest absolute reduction among all noncommunicable diseases. Results were similar at 5 years. CONCLUSIONS: We observed secular reductions in mortality and annual hospital days at 1 year and 5 years among incident patients with KF-RRT and severe CKD, as well as several other common noncommunicable diseases.

Associations of Chronic Inflammation, Insulin Resistance, and Severe Obesity With Mortality, Myocardial Infarction, Cancer, and Chronic Pulmonary Disease.

Importance: Chronic inflammation and insulin resistance often accompany severe obesity, and all are associated with disease risk. Objective: To examine how the association of severe obesity with adverse outcomes may be modified by the presence of systemic inflammation and/or insulin resistance. Design, Setting, and Participants: This population-based, retrospective cohort study included all residents of Alberta, Canada, aged 18 years and older with at least 1 procedure to ascertain severe obesity and measures of C-reactive protein, fasting glucose, triglyceride, and high-density lipoprotein cholesterol levels. Participants were observed from April 2003 to March 2017, and data analysis was conducted from June 2018 to December 2018. Exposures: Severe obesity (body mass index ≥35 or ≥40 after January 1, 2017, as indicated with a procedure-fee modifier), chronic inflammation (all measures of C-reactive protein >10 mg/L), and a surrogate measure of insulin resistance. Main Outcomes and Measures: All-cause death, first acute myocardial infarction during follow-up, first cancer diagnosis during follow-up, and new chronic pulmonary disease. Results: Among 420 636 participants, the median age was 45 years (interquartile range, 34-56 years; range, 18-97 years), 157 799 (37.5%) were male, 185 782 (44.2%) had insulin resistance, 71 987 (17.1%) had severe obesity, and 10 770 (2.6%) had inflammation. In women with chronic inflammation, the presence of severe obesity was associated with a lower mortality risk (hazard ratio [HR], 0.75; 95% CI, 0.65-0.86), but there was no difference in risk in men with inflammation (HR, 0.89; 95% CI, 0.78-1.02). In contrast, the presence of severe obesity was associated with a higher mortality risk in men without inflammation (HR, 1.20; 95% CI, 1.13-1.26), but there was no difference in risk in women without inflammation (HR, 1.00; 95% CI, 0.95-1.06). For myocardial infarction, severe obesity was associated with increased risk in both women and men without inflammation (women: HR, 1.26; 95% CI, 1.17-1.36; men: HR, 1.35; 95% CI, 1.27-1.43) but not in women and men with inflammation (women: HR, 0.85; 95% CI, 0.67-1.07; men: HR, 0.90; 95% CI, 0.71-1.14). Severe obesity was associated with increased risk in women and men, irrespective of chronic inflammation, for new chronic pulmonary disease (women with inflammation: HR, 1.34; 95% CI, 1.23-1.46; women without inflammation: HR, 1.58; 95% CI, 1.54-1.62; men with inflammation: HR, 1.41; 95% CI, 1.29-1.54; men without inflammation: HR, 1.65; 95%, CI, 1.60-1.71) and cancer (women with inflammation: HR, 1.16; 95% CI, 1.03-1.30; women without inflammation, HR, 1.32; 95% CI, 1.28-1.36; men with inflammation: HR, 1.17; 95% CI, 1.04-1.32; men without inflammation: HR, 1.33; 95% CI, 1.28-1.39). Similar to chronic inflammation, severe obesity was not always associated with higher risk in participants with insulin resistance. Conclusions and Relevance: The findings suggest that severe obesity with systemic inflammation is associated with a different prognosis than severe obesity without inflammation.

Red cell distribution width associations with clinical outcomes: A population-based cohort study.

IMPORTANCE: Higher levels of red cell distribution width (RDW) are associated with adverse outcomes, especially in selected cohorts with or at risk for chronic disease. Whether higher RDW or the related parameter standard deviation of the red blood cell distribution (SD-RBC) can predict a broader range of outcomes in the general population is unknown. OBJECTIVE: To evaluate the association of RDW and SD-RBC with the risk of adverse outcomes in people from the general population. DESIGN: Population-based retrospective cohort study. SETTING: Health care system in a Canadian province (Alberta). PARTICIPANTS: All 3,156,863 adults living in Alberta, Canada with at least one measure of RDW and SD-RBC between 2003 and 2016. Data were analyzed in September 2018. EXPOSURE: RDW and SD-RBC, classified into percentiles (<1, 1-5, 5-25, 25-75, 75-95, 95-99, >99). MAIN OUTCOMES: All-cause death, first myocardial infarction, first stroke or transient ischemic attack, placement into long-term care (LTC), progression to renal replacement therapy (initiation of chronic dialysis or pre-emptive kidney transplantation), incident solid malignancy, and first hospitalization during follow-up. RESULTS: Over median follow-up of 6.8 years, 209,991 of 3,156,863 participants (6.7%) died. The risk of death increased with increasing RDW percentile. After adjustment, and compared to RDW in the 25th to 75th percentiles, the risk of death was lower for participants in the <25th percentiles but higher for participants in the 75th-95th percentiles (HR 1.42, 95% CI 1.40,1.43), the 95th-99th percentiles (HR 1.86, 95% CI 1.83,1.89) and the >99th percentile (HR 2.18, 95% CI 2.12,2.23). Similar results were observed for MI, stroke/TIA, incident cancer, hospitalization and LTC placement, but no association was found between RDW and ESRD. Findings were generally similar for SD-RBC, except that all associations tended to be stronger than for RDW, and both lower and higher values of SD-RBC were independently associated with ESRD. CONCLUSION AND RELEVANCE: RDW and SD-RBC may be useful as prognostic markers for people in the general population, especially for outcomes related to chronic illness. SD-RBC may be superior to RDW.

Comorbidity as a driver of adverse outcomes in people with chronic kidney disease.

Chronic kidney disease (CKD) is associated with poor outcomes, perhaps due to a high burden of comorbidity. Most studies of CKD populations focus on concordant comorbidities, which cause CKD (such as hypertension and diabetes) or often accompany CKD (such as heart failure or coronary disease). Less is known about the burden of mental health conditions and discordant conditions (those not concordant but still clinically relevant, like dementia or cancer). Here we did a retrospective population-based cohort study of 530,771 adults with CKD residing in Alberta, Canada between 2003 and 2011. Validated algorithms were applied to data from the provincial health ministry to assess the presence/absence of 29 chronic comorbidities. Linkage between comorbidity burden and adverse clinical outcomes (mortality, hospitalization or myocardial infarction) was examined over median follow-up of 48 months. Comorbidities were classified into three categories: concordant, mental health/chronic pain, and discordant. The median number of comorbidities was 1 (range 0-15) but a substantial proportion of participants had 3 and more, or 5 and more comorbidities (25 and 7%, respectively). Concordant comorbidities were associated with excess risk of hospitalization, but so were discordant comorbidities and mental health conditions. Thus, discordant comorbidities and mental health conditions as well as concordant comorbidities are important independent drivers of the adverse outcomes associated with CKD.

Methods for identifying 30 chronic conditions: application to administrative data.

BACKGROUND: Multimorbidity is common and associated with poor clinical outcomes and high health care costs. Administrative data are a promising tool for studying the epidemiology of multimorbidity. Our goal was to derive and apply a new scheme for using administrative data to identify the presence of chronic conditions and multimorbidity. METHODS: We identified validated algorithms that use ICD-9 CM/ICD-10 data to ascertain the presence or absence of 40 morbidities. Algorithms with both positive predictive value and sensitivity ≥70% were graded as "high validity"; those with positive predictive value ≥70% and sensitivity <70% were graded as "moderate validity". To show proof of concept, we applied identified algorithms with high to moderate validity to inpatient and outpatient claims and utilization data from 574,409 people residing in Edmonton, Canada during the 2008/2009 fiscal year. RESULTS: Of the 40 morbidities, we identified 30 that could be identified with high to moderate validity. Approximately one quarter of participants had identified multimorbidity (2 or more conditions), one quarter had a single identified morbidity and the remaining participants were not identified as having any of the 30 morbidities. CONCLUSIONS: We identified a panel of 30 chronic conditions that can be identified from administrative data using validated algorithms, facilitating the study and surveillance of multimorbidity. We encourage other groups to use this scheme, to facilitate comparisons between settings and jurisdictions.

Cause of Death in Patients with Reduced Kidney Function.

Information on common causes of death in people with CKD is limited. We hypothesized that, as eGFR declines, cardiovascular mortality and mortality from infection account for increasing proportions of deaths. We calculated eGFR using the CKD Epidemiology Collaboration equation for residents of Alberta, Canada who died between 2002 and 2009. We used multinomial logistic regression to estimate unadjusted and age- and sex-adjusted differences in the proportions of deaths from each cause according to the severity of CKD. Cause of death was classified as cardiovascular, infection, cancer, other, or not reported using International Classification of Diseases codes. Among 81,064 deaths, the most common cause was cancer (31.9%) followed by cardiovascular disease (30.2%). The most common cause of death for those with eGFR≥60 ml/min per 1.73 m(2) and no proteinuria was cancer (38.1%); the most common cause of death for those with eGFR<60 ml/min per 1.73 m(2) was cardiovascular disease. The unadjusted proportion of patients who died from cardiovascular disease increased as eGFR decreased (20.7%, 36.8%, 41.2%, and 43.7% of patients with eGFR≥60 [with proteinuria], 45-59.9, 30-44.9, and 15-29.9 ml/min per 1.73 m(2), respectively). The proportions of deaths from heart failure and valvular disease specifically increased with declining eGFR along with the proportions of deaths from infectious and other causes, whereas the proportion of deaths from cancer decreased. In conclusion, we found an inverse association between eGFR and specific causes of death, including specific types of cardiovascular disease, infection, and other causes, in this cohort.

Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis.

BACKGROUND: Several erythropoiesis-stimulating agents (ESAs) are available for treating anaemia in people with chronic kidney disease (CKD). Their relative efficacy (preventing blood transfusions and reducing fatigue and breathlessness) and safety (mortality and cardiovascular events) are unclear due to the limited power of head-to-head studies. OBJECTIVES: To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs, against each other, placebo, or no treatment) to treat anaemia in adults with CKD. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 11 February 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, or biosimilar ESA) with another ESA, placebo or no treatment in adults with CKD and that reported prespecified patient-relevant outcomes were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two independent authors screened the search results and extracted data. Data synthesis was performed by random-effects pairwise meta-analysis and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore for sources of heterogeneity or inconsistency. We assessed our confidence in treatment estimates for the primary outcomes within network meta-analysis (preventing blood transfusions and all-cause mortality) according to adapted GRADE methodology as very low, low, moderate, or high. MAIN RESULTS: We identified 56 eligible studies involving 15,596 adults with CKD. Risks of bias in the included studies was generally high or unclear for more than half of studies in all of the risk of bias domains we assessed; no study was low risk for allocation concealment, blinding of outcome assessment and attrition from follow-up. In network analyses, there was moderate to low confidence that epoetin alfa (OR 0.18, 95% CI 0.05 to 0.59), epoetin beta (OR 0.09, 95% CI 0.02 to 0.38), darbepoetin alfa (OR 0.17, 95% CI 0.05 to 0.57), and methoxy polyethylene glycol-epoetin beta (OR 0.15, 95% CI 0.03 to 0.70) prevented blood transfusions compared to placebo. In very low quality evidence, biosimilar ESA therapy was possibly no better than placebo for preventing blood transfusions (OR 0.27, 95% CI 0.05 to 1.47) with considerable imprecision in estimated effects. We could not discern whether all ESAs were similar or different in their effects on preventing blood transfusions and our confidence in the comparative effectiveness of different ESAs was generally very low. Similarly, the comparative effects of ESAs compared with another ESA, placebo or no treatment on all-cause mortality were imprecise.All proprietary ESAs increased the odds of hypertension compared to placebo (epoetin alfa OR 2.31, 95% CI 1.27 to 4.23; epoetin beta OR 2.57, 95% CI 1.23 to 5.39; darbepoetin alfa OR 1.83, 95% CI 1.05 to 3.21; methoxy polyethylene glycol-epoetin beta OR 1.96, 95% CI 0.98 to 3.92), while the effect of biosimilar ESAs on developing hypertension was less certain (OR 1.18, 95% CI 0.47 to 2.99). Our confidence in the comparative effects of ESAs on hypertension was low due to considerable imprecision in treatment estimates. The comparative effects of all ESAs on cardiovascular mortality, myocardial infarction (MI), stroke, and vascular access thrombosis were uncertain and network analyses for major cardiovascular events, end-stage kidney disease (ESKD), fatigue and breathlessness were not possible. Effects of ESAs on fatigue were described heterogeneously in the available studies in ways that were not useable for analyses. AUTHORS' CONCLUSIONS: In the CKD setting, there is currently insufficient evidence to suggest the superiority of any ESA formulation based on available safety and efficacy data. Directly comparative data for the effectiveness of different ESA formulations based on patient-centred outcomes (such as quality of life, fatigue, and functional status) are sparse and poorly reported and current research studies are unable to inform care. All proprietary ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta) prevent blood transfusions but information for biosimilar ESAs is less conclusive. Comparative treatment effects of different ESA formulations on other patient-important outcomes such as survival, MI, stroke, breathlessness and fatigue are very uncertain.For consumers, clinicians and funders, considerations such as drug cost and availability and preferences for dosing frequency might be considered as the basis for individualising anaemia care due to lack of data for comparative differences in clinical benefits and harms.

Systematic review of the risk of adverse outcomes associated with vascular endothelial growth factor inhibitors for the treatment of cancer.

BACKGROUND: Anti-angiogenic therapy targeted at vascular endothelial growth factor (VEGF) is now used to treat several types of cancer. We did a systematic review of randomized controlled trials (RCTs) to summarize the adverse effects of vascular endothelial growth factor inhibitors (VEGFi), focusing on those with vascular pathogenesis. METHODS AND FINDINGS: We searched MEDLINE, EMBASE and Cochrane Library until April 19, 2012 to identify parallel RCTs comparing a VEGFi with a control among adults with any cancer. We pooled the risk of mortality, vascular events (myocardial infarction, stroke, heart failure, and thromboembolism), hypertension and new proteinuria using random-effects models and calculated unadjusted relative risk (RR). We also did meta-regression and assessed publication bias. We retrieved 83 comparisons from 72 studies (n = 38,078) on 11 different VEGFi from 7901 identified citations. The risk of mortality was significantly lower among VEGFi recipients than controls (pooled RR 0.96, 95% confidence interval [CI] 0.94 to 0.98, I2 = 0%, tau2 = 0; risk difference 2%). Compared to controls, VEGFi recipients had significantly higher risk of myocardial infarction (MI) (RR 3.54, 95% CI 1.61 to 7.80, I2 = 0%, tau2 = 0), arterial thrombotic events (RR 1.80, 95% CI 1.24 to 2.59, I2 = 0%, tau2 = 0); hypertension (RR 3.46, 95% CI 2.89 to 4.15, I2 = 58%, tau2 = 0.16), and new proteinuria (RR 2.51, 95% CI 1.60 to 3.94, I2 = 87%, tau2 = 0.65). The absolute risk difference was 0.8% for MI, 1% for arterial thrombotic events, 15% for hypertension and 12% for new proteinuria. Meta-regression did not suggest any statistically significant modifiers of the association between VEGFi treatment and any of the vascular events. Limitations include heterogeneity across the trials. CONCLUSIONS: VEGFi increases the risk of MI, hypertension, arterial thromboembolism and proteinuria. The absolute magnitude of the excess risk appears clinically relevant, as the number needed to harm ranges from 7 to 125. These adverse events must be weighed against the lower mortality associated with VEGFi treatment.

Potentially preventable hospitalization as a complication of CKD: a cohort study.

BACKGROUND: Ambulatory care-sensitive conditions have been described as those that (if appropriately managed in an outpatient setting) generally do not require subsequent hospitalization. Our goal was to identify clinical populations of people who are at the highest risk of ambulatory care-sensitive conditions related to chronic kidney disease (CKD). STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 2,003,054 adults (including 238,747 adults with CKD) residing in Alberta, Canada, with at least one serum creatinine measurement between 2002 and 2009. PREDICTORS: Estimated glomerular filtration rate and albuminuria categories, CKD status, demographics, and clinical characteristics. OUTCOMES: Hospitalization with heart failure, hyperkalemia, volume overload, or malignant hypertension. MEASUREMENTS: We used the Alberta Kidney Disease Network database, which incorporates data from Alberta Health, the Northern and Southern Alberta Renal Programs, and clinical laboratories in Alberta. RESULTS: During a median follow-up of 4.1 years, 43,863 participants were hospitalized for heart failure; 6,274 participants, for hyperkalemia; 2,035 participants, for volume overload; and 481 participants, for malignant hypertension. All 4 conditions were more common at lower estimated glomerular filtration rates and in the presence of albuminuria. In the subset of participants with CKD, heart failure, hyperkalemia, and volume overload were associated most strongly with older age, diabetes, chronic liver disease, and prior heart failure. Malignant hypertension was associated with prior hypertension, aboriginal status, and peripheral vascular disease. Remote-dwelling participants were more likely to experience heart failure and malignant hypertension than those living closer to providers. LIMITATIONS: No data for medication use or potentially important process-based outcomes for study participants. CONCLUSIONS: Our findings suggest that future studies seeking to determine how to prevent ambulatory care-sensitive conditions in people with CKD should target remote dwellers and those with comorbid conditions such as concomitant heart failure and liver disease.

Kidney stones and cardiovascular events: a cohort study.

BACKGROUND AND OBJECTIVES: Kidney stones are common in general clinical practice, and their prevalence is increasing. Kidney stone formers often have risk factors associated with atherosclerosis, but it is uncertain whether having a kidney stone is associated with higher risk of cardiovascular events. This study sought to assess the association between one or more kidney stones and the subsequent risk of cardiovascular events. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Cohort study of 3,195,452 people aged≥18 years registered in the universal health care system in Alberta, Canada, between 1997 and 2009 (median follow-up of 11 years). People undergoing dialysis or with a kidney transplant at baseline were excluded. The primary outcome was the first acute myocardial infarction (AMI) during follow-up. We also considered other cardiovascular events, including death due to coronary heart disease, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass grafting (CABG), and stroke. RESULTS: In total, 25,532 (0.8%) participants had at least one kidney stone, and 91,465 (3%) individuals had at least one cardiovascular event during follow-up. Compared with people without kidney stones and after adjustment for cardiovascular risk factors and other potential confounders, people who had at least one kidney stone had a higher risk of subsequent AMI (adjusted hazard ratio [HR], 1.40; 95% confidence interval [95% CI], 1.30 to 1.51), PTCA/CABG (HR, 1.63; 95% CI, 1.51 to 1.76), and stroke (HR, 1.26; 95% CI, 1.12 to 1.42). The magnitude of the excess risk associated with a kidney stone appeared more pronounced for younger people than for older people (P<0.001) and for women than men (P=0.01). CONCLUSIONS: The occurrence of a kidney stone is associated with a higher risk of cardiovascular events, including AMI, PTCA/CABG, and stroke.

A systematic review and meta-analysis on the safety and efficacy of febuxostat versus allopurinol in chronic gout.

OBJECTIVE: To evaluate the safety and efficacy of febuxostat compared to allopurinol for the treatment of chronic gout. METHODS: We did a systematic review and meta-analysis of randomized and non-randomized controlled trials that compared oral febuxostat to oral allopurinol for treatment of chronic gout. Two reviewers independently selected studies, assessed study quality, and extracted data. Risk ratios (RR) were calculated with random effects and were reported with corresponding 95% confidence intervals (CI). RESULTS: From 1076 potentially relevant citations, 7 studies and 25 associated publications met inclusion criteria; 5 studies were ultimately included in the analysis. Febuxostat did not reduce the risk of gout flares compared with allopurinol (RR = 1.16, 95% CI = 1.03-1.30, I(2) = 44%). Overall, the risk of any adverse event was lower in febuxostat recipients compared to allopurinol (RR = 0.94, 95% CI = 0.90-0.99, I(2) = 13%). Patients receiving febuxostat were more likely to achieve a serum uric acid of <6 mg/dl than allopurinol recipients (RR = 1.56, 95% CI = 1.22-2.00, I(2) = 92%). Subgroup analysis did not indicate any significant difference between high- and low-dose febuxostat on the risk of gout flares. CONCLUSION: Although febuxostat was associated with higher likelihood of achieving a target serum uric acid level of <6 mg/dl, there was significant heterogeneity in the pooled results. There was no evidence that febuxostat is superior to allopurinol for clinically relevant outcomes. Given its higher cost, febuxostat should not be routinely used for chronic gout.

Factors associated with initiation of chronic renal replacement therapy for patients with kidney failure.

BACKGROUND AND OBJECTIVES: Patients with kidney failure sometimes do not receive chronic renal replacement therapy (RRT), even though this may reduce their life expectancy. This study aimed to identify factors associated with initiation of chronic RRT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This cohort study was conducted with Albertans aged >18 years between May 2002 and March 2009, using linked data from the provincial renal programs, clinical laboratories, and provincial health ministry. This study focused on those who developed kidney failure, defined by an estimated GFR (eGFR) <15 ml/min per 1.73 m(2) at last measurement during follow-up, together with prior CKD (eGFR <60 ml/min per 1.73 m(2) at least 90 days earlier). Multivariable Cox proportional hazards models were used to determine factors significantly associated with initiation of chronic RRT. RESULTS: In total, 7901 participants had eGFR <15 ml/min per 1.73 m(2) at last measurement. After adjustment, older participants were less likely to initiate chronic RRT. Remote residence location, dementia, and metastatic cancer also decreased the likelihood of initiating RRT. The cumulative probability of initiating RRT during follow-up was 76.8% for urban-dwelling men aged <50 years without comorbidity, but was only 3.2% among remote-dwelling women aged ≥70 years with dementia and metastatic cancer. In contrast, patients with diabetes and heavy/severe proteinuria were more likely to initiate chronic RRT. CONCLUSIONS: There is substantial variability in the likelihood of RRT initiation for patients with eGFR <15 ml/min per 1.73 m(2). Further studies are needed to delineate factors that influence this outcome.

Health care costs in people with diabetes and their association with glycemic control and kidney function.

OBJECTIVE: To determine the association between laboratory-derived measures of glycemic control (HbA1c) and the presence of renal complications (measured by proteinuria and estimated glomerular filtration rate [eGFR]) with the 5-year costs of caring for people with diabetes. RESEARCH DESIGN AND METHODS: We estimated the cumulative 5-year cost of caring for people with diabetes using a province-wide cohort of adults with diabetes as of 1 May 2004. Costs included physician visits, hospitalizations, ambulatory care (emergency room visits, day surgery, and day medicine), and drug costs for people >65 years of age. Using linked laboratory and administrative clinical and costing data, we determined the association between baseline glycemic control (HbA1c), proteinuria, and kidney function (eGFR) and 5-year costs, controlling for age, socioeconomic status, duration of diabetes, and comorbid illness. RESULTS: We identified 138,662 adults with diabetes. The mean 5-year cost of diabetes in the overall cohort was $26,978 per patient, excluding drug costs. The mean 5-year cost for the subset of people >65 years of age, including drug costs, was $44,511 (Canadian dollars). Cost increased with worsening kidney function, presence of proteinuria, and suboptimal glycemic control (HbA1c >7.9%). Increasing age, Aboriginal status, socioeconomic status, duration of diabetes, and comorbid illness were also associated with increasing cost. CONCLUSIONS: The cost of caring for people with diabetes is substantial and is associated with suboptimal glycemic control, abnormal kidney function, and proteinuria. Future studies should assess if improvements in the management of diabetes, assessed with laboratory-derived measurements, result in cost reductions.

Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis.

BACKGROUND: Statins were initially used to improve cardiovascular outcomes in people with established coronary artery disease, but recently their use has become more common in people at low cardiovascular risk. We did a systematic review of randomized trials to assess the efficacy and harms of statins in these individuals. METHODS: We searched MEDLINE and EMBASE (to Jan. 28, 2011), registries of health technology assessments and clinical trials, and reference lists of relevant reviews. We included trials that randomly assigned participants at low cardiovascular risk to receive a statin versus a placebo or no statin. We defined low risk as an observed 10-year risk of less than 20% for cardiovascular-related death or nonfatal myocardial infarction, but we explored other definitions in sensitivity analyses. RESULTS: We identified 29 eligible trials involving a total of 80,711 participants. All-cause mortality was significantly lower among patients receiving a statin than among controls (relative risk [RR] 0.90, 95% confidence interval [CI] 0.84-0.97) for trials with a 10-year risk of cardiovascular disease < 20% [primary analysis] and 0.83, 95% CI 0.73-0.94, for trials with 10-year risk < 10% [sensitivity analysis]). Patients in the statin group were also significantly less likely than controls to have nonfatal myocardial infarction (RR 0.64, 95% CI 0.49-0.84) and nonfatal stroke (RR 0.81, 95% CI 0.68-0.96). Neither metaregression nor stratified analyses suggested statistically significant differences in efficacy between high-and low-potency statins, or larger reductions in cholesterol. INTERPRETATION: Statins were found to be efficacious in preventing death and cardiovascular morbidity in people at low cardiovascular risk. Reductions in relative risk were similar to those seen in patients with a history of coronary artery disease.

Bariatric surgery: a systematic review of the clinical and economic evidence.

CONTEXT: Use of bariatric surgery for severe obesity has increased dramatically. OBJECTIVE: To systematically review 1. the clinical efficacy and safety, 2. cost-effectiveness of bariatric surgery, and 3. the association between number of surgeries performed (surgical volume) and outcomes. DATA SOURCES: MEDLINE (from 1950), EMBASE (from 1980), CENTRAL, EconLit, EURON EED, Harvard Center for Risk Analysis, trial registries and HTA websites were searched to January 2011. STUDY SELECTION: 1. Randomized controlled trials (RCTs) and 2. cost-utility and cost-minimisation studies comparing a contemporary bariatric surgery (i.e., adjustable gastric banding, Roux-en-Y gastric bypass, sleeve gastrectomy) to another contemporary surgical comparator or a non-surgical treatment or 3. Any study reporting the association between surgical volume and outcome. DATA EXTRACTION: Outcomes included changes in weight and obesity-related comorbidity, quality of life and mortality, surgical complications, resource utilization, and incremental cost-utility. RESULTS: RCT data evaluating mortality and obesity-related comorbidity endpoints were lacking. A small RCT of 16 patients reported that adjustable gastric banding reduced weight by 27% (p < 0.01) compared to diet-treated controls over 40 weeks. Six small RCTs reported comparisons of commonly used, contemporary procedures. Gastric banding reduced weight to a lower extent than gastric bypass and sleeve gastrectomy and resulted in shorter operating times, fewer serious complications, lower weight loss efficacy, and more frequent reoperations compared to gastric bypass. Sleeve gastrectomy and gastric bypass reduced weight to a similar extent. A 2-year RCT in 50 adolescents reported that gastric banding substantially reduced weight compared to lifestyle modification (35 kg vs. 3 kg; p <0.001). Based on findings of 14 observational studies, higher volume centers and surgeons had lower mortality and complication rates. Surgery resulted in long-term incremental cost-utility ratios of $ <1.000-$40,000 (2009 USD) per quality-adjusted-life-year compared with non-surgical treatment. CONCLUSIONS: Contemporary bariatric surgery appears to result in sustained weight reduction with acceptable costs but rigorous, longer-term (≥5 year) data are needed and a paucity of RCT data on mortality and obesity related comorbidity is evident. Procedure-specific variations in efficacy and risks exist and require further study to clarify the specific indications for and advantages of different procedures.