Change in Proteinuria or Albuminuria as a Surrogate for Cardiovascular and Other Major Clinical Outcomes: A Systematic Review and Meta-analysis

Background

There is ongoing controversy around the surrogacy of proteinuria or albuminuria, particularly for cardiovascular (CV) outcomes, which remain the leading cause of morbidity and mortality among patients with chronic kidney disease. We performed a systematic review and meta-analysis of the literature to assess the surrogacy of changing proteinuria or albuminuria for CV events, end-stage renal disease (ESRD), and all-cause mortality.

Cardiovascular Implications of Albuminuria

Microalbuminuria is a major independent risk factor for cardiovascular disease (CVD) events in persons with diabetes or hypertension, the general population, and persons with known CVD. Although microalbuminuria is a stronger risk factor in men, women with increased albuminuria levels are also at a higher risk of CVD. Microalbuminuria is an indicator of generalized endothelial injury, a hallmark of systemic atherosclerosis. Treatments that decrease albuminuria, particularly agents that inhibit the renin-angiotensin system, reduce CVD risk in various populations, including those with and without diabetes or hypertension. Whether albuminuria should be a treatment target for CVD is not yet proven. Nevertheless, the measurement of albuminuria is clinically useful to identify high-risk individuals who should receive intensive risk factor management based on current treatment guidelines.     

Associations among Estimated Glomerular Filtration Rate,Proteinuria, and Adverse Cardiovascular Outcomes

Summary

Background and objectives

Most studies of chronic kidney disease (CKD) and outcomes focus on mortality and ESRD, with limited data on other adverse outcomes. This study examined the associations among proteinuria, eGFR, and adverse cardiovascular (CV) events.

Design, setting, participants, & measurements

This was a population-based longitudinal study with patients identified from province-wide laboratory data from Alberta, Canada, between 2002 and 2007. Selected for this study from a total of 1,526,437 patients were 920,985 (60.3%) patients with at least one urine dipstick measurement and 102,701 patients (6.7%) with at least one albumin-creatinine ratio (ACR) measurement. Time to hospitalization was considered for one of four indications: congestive heart failure (CHF), coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), peripheral vascular disease (PVD), and stroke/transient ischemic attacks [TIAs] (cerebrovascular accident [CVA]/TIA).

Results

After a median follow-up of 35 months, in fully adjusted models and compared with patients with estimated GFR (eGFR) of 45 to 59 ml/min per 1.73 m² and no proteinuria, patients with heavy proteinuria by dipstick and eGFR ≥ 60 ml/min per 1.73 m² had higher rates of CABG/PCI and CVA/TIA. Similar results were obtained in patients with proteinuria measured by ACR.

Conclusions

Risks of major CV events at a given level of eGFR increased with higher levels of proteinuria. The findings extend current data on risk of mortality and ESRD. Measurement of proteinuria is of incremental prognostic benefit at every level of eGFR. The data support use of proteinuria measurement with eGFR for definition and risk stratification in CKD.     

Effects of ACEIs Versus ARBs on Proteinuria or Albuminuria in Primary Hypertension: A Meta-Analysis of Randomized Trials

Although angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) belong to a family of therapies that block the renin–angiotensin system and are suggested to improve proteinuria/albuminuria, it is unclear which is more effective.To compare the effects of ACEIs and ARBs on proteinuria in primary hypertension by performing a meta-analysis covering randomized controlled trials (RCTs).We systematically searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from January 1990 to November 2014. Eligible studies were RCTs of ACEI therapy versus ARB therapy that reported the albumin excretion rate (AER), albumin (Alb), and urinary albumin excretion (UAE) as outcomes.Seventeen RCTs, including 17,951 patients (without limit of race, age, or sex) with a mean duration of 62.6 weeks, were included. Pooled analysis suggested that ACEIs and ARBs showed no significant differences in AER/Alb/UAE/24-h urine protein/24-h urine total protein in a comparison of 10 trials (SMD 0.09; 95% CI –0.18–0.36; P = 0.52). No significant differences were observed in urinary protein/creatinine ratio (UPCR)/urinary albumin/creatinine ratio (UACR), or albumin/creatinine ratio (ACR) in 7 trials (SMD 0.15; 95% CI –1.88–2.19; P = 0.88). The total outcome of ACEIs and ARBs also showed no significant difference (SMD 0.13; 95% CI –1.03–1.29; P = 0.83). The efficacies of ACEIs and ARBs in controlling blood pressure as a secondary indicator were also similar (SMD –0.50; 95% CI –1.58–0.58; P = 0.37).Based on a meta-analysis of 17 randomized controlled trials including 17,951 patients, we found that ACEIs and ARBs can reduce urine protein levels, improve blood pressure, and were similarly effective in terms of reducing urinary protein excretion.     

Kidney,Cardiovascular, and Safety Outcomes of Canagliflozin according to Baseline Albuminuria: A CREDENCE Secondary Analysis

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Controversy Regarding the Association of High Calcium Intake and Increased Risk for Cardiovascular Disease

Calcium intake has been shown to be associated with beneficial effects regarding hypertension, coronary heart disease (CHD), vascular disease, and stroke by several prospective cohort studies. However, recent studies have questioned the beneficial cardiovascular effects of calcium intake and instead have shown that high calcium intake is associated with an increased risk for CHD and stroke. These findings have created controversy and concern among physicians, because calcium is consumed by a large number of older men and women to prevent osteoporosis and bone fractures. Based on the methods of patient self‐reporting of calcium intake and cardiovascular events, the conclusions drawn from the studies may not be entirely valid. Therefore, until more confirmatory data are available, physicians should not be dissuaded from prescribing calcium supplements to their patients. The best candidates are patients with low calcium intake, but their calcium supplementation should not exceed the recommended 1200 mg/d to 1500 mg/d.     

Implications of the CANVAS Study in Reducing Cardiovascular Outcomes

Purpose of Review

In recent years, Cardiovascular Outcome Event Trials (CVOTs) in type 2 diabetes mellitus (T2DM) have demonstrated that sodium glucose transporter 2 inhibitors (SGLT2i) could reduce major adverse cardiovascular events (MACE) and cardiovascular mortality independent of a glucose lowering mechanism. SGLT2i trials reported significant results that have generated biologically plausible theories with regard to the macrovascular benefit. In this review, we have summarized and discussed the results of the CANVAS program.

Recent Findings

The CANVAS program is unique as it is an analysis of two aggregated cohorts. The two cohorts were similar at baseline but had different durations of exposure to canagliflozin. It showed a 14% reduction in the primary MACE composite. However, the individual components of the MACE composite were not significantly different from placebo. Initial analysis also indicated a reno-protective effect.

Summary

The results of the CANVAS program are similar overall yet different when compared to the EMPA-REG OUTCOMES trial, especially with regard to cardiovascular mortality and adverse event profile. This could possibly be due to the differences in the cardiovascular risk profile of the enrolled population in the two trials. Other possibilities include drug-specific effects and different mechanisms of lowering overall MACE. In addition, a brief comparison of CANVAS to the CVD-REAL indicates that the CANVAS trial results may apply to a larger, more generalized population than those in the CANVAS program.

     

Outcomes of National Community Organization Cardiovascular Prevention Programs for High-Risk Women

The purpose of this study was to reduce cardiovascular disease (CVD) risk in women by implementing a cardiovascular prevention health promotion program in faith- and community-based sites. The primary outcomes were reducing obesity and increasing physical activity. A longitudinal cohort of high-risk (age > 40, ethnic minority) women (n = 1,052) was enrolled at 32 sites across the USA. The pre- or post-educational intervention consisted of eight biweekly counseling sessions conducted over 4 months each addressing one of six of the major CVD risk factors (smoking, diabetes, hypertension, cholesterol, obesity, and physical inactivity) as well as signs and symptoms of a heart attack and stroke; plus 4–6 maintenance sessions over three additional months. A multifaceted approach delivered by lay and medically trained personnel involving medical screenings, health behavior counseling, risk behavior modification, and stage of change were determined at baseline and end of counseling or maintenance. Following list-wise deletion, data were analyzed on 423 women who completed all follow-up time-points. Overall, significant improvement was attained in most of 28 secondary outcomes but not in the primary outcomes. Knowledge and awareness of heart disease as the leading killer or women, all of the signs and symptoms of a heart attack, calling 911, and CVD risk factors increased significantly (p < 0.05) by 8.8%, 13.6%, 5.8%, and 10%, respectively. There was a 10% (p < 0.05) increase in participants attaining control for hypertension (blood pressure < 140/90) coupled with a significant reduction in mean blood pressure in the entire cohort. Knowledge of effective CVD risk modification strategies for all CVD risk factors increased significantly (p < 0.05), except for obesity. In addition, there were significant (p < 0.05) increases in forward movement in stage of change for each CVD risk factor (range +10% to +39%). Thus, a heart disease prevention intervention built around a model of community engagement, advocacy, self-efficacy, resource knowledge, and health promotion in faith- and community-based organizations is successful at improving cardiovascular knowledge and awareness outcomes in high-risk women. Limitations of our study include the high dropout rate, significant time demands on site coordinators, limited resources for program implementation, lack of morbidity and mortality endpoints, and failure to attain the primary outcomes of weight loss and physical activity. Future studies should not only assess the effect of community education interventions on lifestyle change and knowledge and awareness of participants but should also address program duration, cost, and resources required to attain improved outcomes.     

Outcomes of cardiac surgery in patients > or = 80 years: results from the National Cardiovascular Network

OBJECTIVES: The purpose of this study was to evaluate characteristics and outcomes of patients age > or =80 undergoing cardiac surgery. BACKGROUND: Prior single-institution series have found high mortality rates in octogenarians after cardiac surgery. However, the major preoperative risk factors in this age group have not been identified. In addition, the additive risks in the elderly of valve replacement surgery at the time of bypass are unknown. METHODS: We report in-hospital morbidity and mortality in 67,764 patients (4,743 octogenarians) undergoing cardiac surgery at 22 centers in the National Cardiovascular Network. We examine the predictors of in-hospital mortality in octogenarians compared with those predictors in younger patients. RESULTS: Octogenarians undergoing cardiac surgery had fewer comorbid illnesses but higher disease severity and surgical urgency than younger patients. Octogenarians had significantly higher in-hospital mortality after cardiac surgery than younger patients: coronary artery bypass grafting (CABG) only (8.1% vs. 3.0%), CABG/aortic valve (10.1% vs. 7.9%), CABG/mitral valve (19.6% vs. 12.2%). In addition, they had twice the incidence of postoperative stroke and renal failure. The preoperative clinical factors predicting CABG mortality in the very elderly were quite similar to those for younger patients with age, emergency surgery and prior CABG being the powerful predictors of outcome in both age categories. Of note, elderly patients without significant comorbidity had in-hospital mortality rates of 4.2% after CABG, 7% after CABG with aortic valve replacement (CABG/AVR), and 18.2% after CABG with mitral valve replacement (CABG/MVR). CONCLUSIONS: Risks for octogenarians undergoing cardiac surgery are less than previously reported, especially for CABG only or CABG/AVR. In selected octogenarians without significant comorbidity, mortality approaches that seen in younger patients.     

Introduction to the Canadian Cardiovascular Outcomes Research Team's (CCORT) Canadian Cardiovascular Atlas project

The Canadian Cardiovascular Outcomes Research Team's (CCORT) Canadian Cardiovascular Atlas project was developed to provide Canadians with a national report on the state of cardiovascular health and health services in Canada. Written by a group of Canada's leading experts in cardiovascular outcomes research, the CCORT cardiac Atlas will cover a wide variety of topics ranging from cardiac risk factors and cardiac mortality rates to the treatment of patients with acute myocardial infarction and congestive heart failure and the outcomes of invasive cardiac procedures across Canada. Data in the Atlas will be presented at a national, provincial and health region level. The Atlas will be published as a series of 20 articles and chapters in future issues of The Canadian Journal of Cardiology and on CCORT's web site (www.ccort.ca). The journal version of the Atlas chapters will be written for a clinical audience and will include editorials written by invited experts, whereas the web-based version of each chapter will be written for a more general audience and will include additional supplemental information (for example, interactive colour maps and tables) that cannot be included in the journal version. Material from the Journal and the web will eventually be compiled into a book that will be distributed across Canada. This article serves as an introduction to the Atlas project and describes the rationale for and objectives of the CCORT national cardiac Atlas project.     

Fatigue Is a Predictor for Cardiovascular Outcomes in Patients Undergoing Hemodialysis

Background and objectives: Despite potential significance of fatigue and its underlying components in the occurrence of cardiovascular diseases, epidemiologic data showing the link are virtually limited. This study was designed to examine whether fatigue symptoms or fatigue''s underlying components are a predictor for cardiovascular diseases in high-risk subjects with ESRD.Design, setting, participants, & measurements: 788 volunteer patients under hemodialysis therapy (506 male, 282 female) completed the survey between October and November 2005, with the follow-up period up to 26 months to monitor occurrence of fatal or nonfatal cardiovascular events. The questionnaire consisted of 64 questions, and promax rotation analysis of the principal component method conceptualized eight fatigue-related factors: fatigue itself, anxiety and depression, loss of attention and memory, pain, overwork, autonomic imbalance, sleep problems, and infection.Results: 14.7% of the patients showed fatigue scores higher than twice the SD of the mean for healthy volunteers. These highly fatigued patients exhibited a significantly higher risk for cardiovascular events (hazard ratio: 2.17; P < 0.01), with the relationship independent of the well-known risk factors, including age, diabetes, cardiovascular disease history, and inflammation and malnutrition markers. Moreover, comparisons of the risk in key subgroups showed that the risk of high fatigue score for cardiovascular events was more prominent in well-nourished patients, including lower age, absence of past cardiovascular diseases, higher serum albumin, and high non-HDL cholesterol.Conclusions: Fatigue can be an important predictor for cardiovascular events in patients with ESRD, with the relationship independent of the nutritional or inflammatory status.The importance of behavioral and psychosocial factors in the prevention, development, and treatment of cardiovascular diseases (CVDs) has been increasingly recognized in the medical and scientific communities (1–3). Physical and mental activities, including anger, sadness, frustration, and tension, can trigger daily life ischemia in patients with coronary artery disease (1,4–6). The presence of mental stress-induced ischemia is associated with significantly higher rates of subsequent fatal and nonfatal cardiac events, potentially mediated by the occurrence of myocardial ischemia (7). Conversely, the addition of psychosocial treatments or stress management to standard rehabilitation regimens is shown to reduce mortality and morbidity in patients with acute myocardial infarction (8,9).Among behavioral and psychosocial factors, fatigue is an important bio-alarm for human health, as well as fever and pain (10). Fatigue has come to be recognized as a newly recognized important syndrome (chronic fatigue syndrome) (11–13), as well as a serious symptom of many chronic illnesses. Fatigue can not only significantly impair a person''s functioning and have a negative effect on his or her health-related quality of life (QoL), without which a person might drop into unrecoverable exhaustive state and, in the most severe case, can even die, referred to in Japanese as Karoshi. The major medical causes of Karoshi deaths are heart attack and stroke due to stress (14,15).Despite the potential significance of fatigue symptoms in the occurrence of CVD, epidemiologic data showing the link are virtually limited. Hardy and Studenski (16) recently reported that a single simple question, “Do you feel tired most of the time?” identifies older adults with a higher risk of mortality. Epidemiologic evidence also suggests that vital exhaustion as assessed by simple questionnaires belongs to the precursors of different manifestations of coronary artery disease (17–19). Although the vitality construct captures a mild reduction in energy level, it fails to capture the negative aspects of fatigue, such as weakness, lack of motivation, and difficulty with concentration (20,21). Thus, these reports emphasize the need to identify and characterize the significance of fatigue and its underlying components (overwork, autonomic imbalance, depression and anxiety, loss of attention, etc.) to develop and test specific treatments, and to determine whether improvement leads to decreased morbidity and mortality. Moreover, it is intriguing to test whether fatigue and its related components are predictors for cardiovascular events in subjects at higher risk, such as patients with ESRD (22).Fatigue is one of the most frequent symptoms of patients with ESRD undergoing maintenance dialysis therapy. The prevalence of fatigue ranges from 60% to as high as 97% in ESRD patients on long-term dialysis therapy (23–26). Recognition of fatigue in dialysis patients may be difficult because recovery from fatigue has great interpatient variability (27). Despite the importance of fatigue symptoms in ESRD patients, both the presence and severity of fatigue remain largely unrecognized (28).In this study, we surveyed the prevalence and severity of fatigue in 788 hemodialysis patients by using recently established new fatigue scale (29). We examined whether the subjective fatigue scores can be a predictor for future cardiovascular events.     

Role of Metabolic Surgery in Less Obese or Non-Obese Subjects with Type 2 Diabetes: Influence Over Cardiovascular Events

Bariatric surgery was initially developed as a tool for weight reduction only, but it is gaining increasing popularity because of its remarkable effect on glucose metabolism in morbidly obese and less obese patients. Recent publications have shown the good results of metabolic surgery, creating a new field of clinical research that is currently overflowing in the medical community with outstanding high-quality data. In morbidly obese population, there is compelling data on long term cardiovascular risk reduction and mortality, coming from longitudinal prospective studies and systematic reviews. Numbers range from 33 to 92 % of decrease in fatal and nonfatal cardiovascular events . In low body mass index (BMI) diabetics, there is an increasing number of reported good outcomes after metabolic surgery with the aim to treat type 2 diabetes (T2DM). There is scarce information on cardiovascular outcomes in non–morbidly obese subjects, but the extraordinary glucose, lipid and blood pressure control in the published series are suggesting good long-term effects on cardiovascular risk profile and mortality. The papers review was comprehensive, including the available randomized controlled trials, long-term prospective series and systematic reviews.     

Cardiovascular Outcomes With Anti-Inflammatory Therapies: Review of Literature

Inflammation is a major contributing factor in the development of cardiovascular disease (CVD) and has been a popular topic of discussion as it provides a potential therapeutic target to reduce disease progression. Multiple inflammatory markers have been linked with progressive atherosclerosis which includes interleukin-6, tumor necrosis factor-α, C-reactive protein amongst others, this article aims to review current literature to evaluate the effectiveness of anti-inflammatory therapies in cardiovascular disease.     

Albuminuria and heart failure: is it an albuminuria or the hypertension? reply

We are grateful to Dr Parmar for raising this important issue.Dr Parmar appears to be under the impression that our studysample consisted of elderly men with hypertension.