Min Jun

Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis

BACKGROUND Several clinical trials have reported inconsistent findings for the effect of fibrates on cardiovascular risk. We undertook a systematic review and meta-analysis to investigate the effects of fibrates on major clinical outcomes. METHODS We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and March, 2010. We included prospective randomised controlled trials assessing the effects of fibrates on cardiovascular outcomes compared with placebo. Summary estimates of relative risk (RR) reductions were calculated with a random effects model. Outcomes analysed were major cardiovascular events, coronary events, stroke, heart failure, coronary revascularisation, all-cause mortality, cardiovascular death, non-vascular death, sudden death, new onset albuminuria, and drug-related adverse events. FINDINGS We identified 18 trials providing data for 45 058 participants, including 2870 major cardiovascular events, 4552 coronary events, and 3880 deaths. Fibrate therapy produced a 10% RR reduction (95% CI 0-18) for major cardiovascular events (p=0.048) and a 13% RR reduction (7-19) for coronary events (p<0.0001), but had no benefit on stroke (-3%, -16 to 9; p=0.69). We noted no effect of fibrate therapy on the risk of all-cause mortality (0%, -8 to 7; p=0.92), cardiovascular mortality (3%, -7 to 12; p=0.59), sudden death (11%, -6 to 26; p=0.19), or non-vascular mortality (-10%, -21 to 0.5; p=0.063). Fibrates reduced the risk of albuminuria progression by 14% (2-25; p=0.028). Serious drug-related adverse events were not significantly increased by fibrates (17 413 participants, 225 events; RR 1.21, 0.91-1.61; p=0.19), although increases in serum creatinine concentrations were common (1.99, 1.46-2.70; p<0.0001). INTERPRETATION Fibrates can reduce the risk of major cardiovascular events predominantly by prevention of coronary events, and might have a role in individuals at high risk of cardiovascular events and in those with combined dyslipidaemia. FUNDING National Health and Medical Research Council of Australia.

Intensive glucose control improves kidney outcomes in patients with type 2 diabetes

The effect of intensive glucose control on major kidney outcomes in type 2 diabetes remains unclear. To study this, the ADVANCE trial randomly assigned 11,140 participants to an intensive glucose-lowering strategy (hemoglobin A1c target 6.5% or less) or standard glucose control. Treatment effects on end-stage renal disease ((ESRD), requirement for dialysis or renal transplantation), total kidney events, renal death, doubling of creatinine to above 200 μmol/l, new-onset macroalbuminuria or microalbuminuria, and progression or regression of albuminuria, were then assessed. After a median of 5 years, the mean hemoglobin A1c level was 6.5% in the intensive group, and 7.3% in the standard group. Intensive glucose control significantly reduced the risk of ESRD by 65% (20 compared to 7 events), microalbuminuria by 9% (1298 compared to 1410 patients), and macroalbuminuria by 30% (162 compared to 231 patients). The progression of albuminuria was significantly reduced by 10% and its regression significantly increased by 15%. The results were almost identical in analyses taking account of potential competing risks. The number of participants needed to treat over 5 years to prevent one ESRD event ranged from 410 in the overall study to 41 participants with macroalbuminuria at baseline. Thus, improved glucose control will improve major kidney outcomes in patients with type 2 diabetes.

Omega 3 Fatty Acids and Cardiovascular Outcomes Systematic Review and Meta-Analysis

Background—Early trials evaluating the effect of omega 3 fatty acids (&ohgr;-3 FA) reported benefits for mortality and cardiovascular events but recent larger studies trials have variable findings. We assessed the effects of &ohgr;-3 FA on cardiovascular and other important clinical outcomes. Methods and Results—We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for all randomized studies using dietary supplements, dietary interventions, or both. The primary outcome was a composite of cardiovascular events (mostly myocardial infarction, stroke, and cardiovascular death). Secondary outcomes were arrhythmia, cerebrovascular events, hemorrhagic stroke, ischemic stroke, coronary revascularization, heart failure, total mortality, nonvascular mortality, and end-stage kidney disease. Twenty studies including 63030 participants were included. There was no overall effect of &ohgr;-3 FA on composite cardiovascular events (relative risk [RR]=0.96; 95% confidence interval [CI], 0.90–1.03; P=0.24) or on total mortality (RR=0.95; 95% CI, 0.86–1.04; P=0.28). &ohgr;-3 FA did protect against vascular death (RR=0.86; 95% CI, 0.75–0.99; P=0.03) but not coronary events (RR=0.86; 95% CI, 0.67–1.11; P=0.24). There was no effect on arrhythmia (RR=0.99; 95% CI, 0.85–1.16; P=0.92) or cerebrovascular events (RR=1.03; 95% CI, 0.92–1.16; P=0.59). Adverse events were more common in the treatment group than the placebo group (RR=1.18, 95% CI, 1.02–1.37; P=0.03), predominantly because of an excess of gastrointestinal side effects. Conclusions—&ohgr;-3 FA may protect against vascular disease, but the evidence is not clear-cut, and any benefits are almost certainly not as great as previously believed.

Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis

Background: Recent guidelines suggest lowering the target blood pressure for patients with chronic kidney disease, although the strength of evidence for this suggestion has been uncertain. We sought to assess the renal and cardiovascular effects of intensive blood pressure lowering in people with chronic kidney disease. Methods: We performed a systematic review and meta-analysis of all relevant reports published between 1950 and July 2011 identified in a search of MEDLINE, Embase and the Cochrane Library. We included randomized trials that assigned patients with chronic kidney disease to different target blood pressure levels and reported kidney failure or cardiovascular events. Two reviewers independently identified relevant articles and extracted data. Results: We identified 11 trials providing information on 9287 patients with chronic kidney disease and 1264 kidney failure events (defined as either a composite of doubling of serum creatinine level and 50% decline in glomerular filtration rate, or end-stage kidney disease). Compared with standard regimens, a more intensive blood pressure–lowering strategy reduced the risk of the composite outcome (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.68–0.98) and end-stage kidney disease (HR 0.79, 95% CI 0.67–0.93). Subgroup analysis showed effect modification by baseline proteinuria (p = 0.006) and markers of trial quality. Intensive blood pressure lowering reduced the risk of kidney failure (HR 0.73, 95% CI 0.62–0.86), but not in patients without proteinuria at baseline (HR 1.12, 95% CI 0.67–1.87). There was no clear effect on the risk of cardiovascular events or death. Interpretation: Intensive blood pressure lowering appears to provide protection against kidney failure events in patients with chronic kidney disease, particularly among those with proteinuria. More data are required to determine the effects of such a strategy among patients without proteinuria.

Effects of fibrates in kidney disease: a systematic review and meta-analysis.

OBJECTIVES The purpose of this systematic review and meta-analysis was to determine the efficacy and safety of fibrate therapy in the chronic kidney disease (CKD) population. BACKGROUND Fibrate therapy produces modest cardiovascular benefits in people at elevated cardiovascular risk. There is limited evidence about the clinical benefits and safety of fibrate therapy in the CKD population. METHODS MEDLINE, EMBASE, and the Cochrane Library were systematically searched (1950 to January 2012) for prospective randomized controlled trials assessing the effects of fibrate therapy compared with placebo in people with CKD or on kidney-related outcomes were included. RESULTS Ten studies including 16,869 participants were identified. In patients with mild-to-moderate CKD (estimated glomerular filtration rate [eGFR] ≤60 ml/min/1.73 m(2)), fibrates improved lipid profiles (lowered total cholesterol [-0.32 mmol/l, p = 0.05] and triglyceride levels [-0.56 mmol/l, p = 0.03] but not low-density lipoprotein cholesterol [-0.01 mmol/l, p = 0.83]; increased high-density lipoprotein cholesterol [0.06 mmol/l, p = 0.001]). In people with diabetes, fibrates reduced the risk of albuminuria progression (relative risk [RR]: 0.86; 95% confidence interval [CI]: 0.76 to 0.98; p = 0.02). Serum creatinine was elevated by fibrate therapy (33 μmol/l, p < 0.001), calculated GFR was reduced (-2.67 ml/min/1.73 m(2), p = 0.01) but there was no detectable effect on the risk of end-stage kidney disease (RR: 0.85; 95% CI: 0.49 to 1.49; p = 0.575). In patients with eGFR of 30 to 59.9 ml/min/1.73 m(2), fibrates reduced the risk of major cardiovascular events (RR: 0.70; 95% CI: 0.54 to 0.89; p = 0.004) and cardiovascular death (RR: 0.60; 95% CI: 0.38 to 0.96; p = 0.03) but not all-cause mortality. There were no clear safety concerns specific to people with CKD but available data were limited. CONCLUSIONS Fibrates improve lipid profiles and prevent cardiovascular events in people with CKD. They reduce albuminuria and reversibly increase serum creatinine but the effects on major kidney outcomes remain unknown. These results suggest that fibrates have a place in reducing cardiovascular risk in people with mild-to-moderate CKD.

The association between kidney function and major bleeding in older adults with atrial fibrillation starting warfarin treatment: population based observational study

Objective To determine rates of major bleeding by level of kidney function for older adults with atrial fibrillation starting warfarin. Design Retrospective cohort study. Setting Community based, using province wide laboratory and administrative data in Alberta, Canada. Participants 12 403 adults aged 66 years or more, with atrial fibrillation who started warfarin treatment between 1 May 2003 and 31 March 2010 and had a measure of kidney function at baseline. Kidney function was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation and participants were categorised based on estimated glomerular filtration rate (eGFR): ≥90, 60-89, 45-59, 30-44, 15-29, <15 mL/min/1.73m2. We excluded participants with end stage renal disease (dialysis or renal transplant) at baseline. Main outcome measures Admission to hospital or visit to an emergency department for major bleeding (intracranial, upper and lower gastrointestinal, or other). Results Of 12 403 participants, 45% had an eGFR <60 mL/min/1.73m2. Overall, 1443 (11.6%) experienced a major bleeding episode over a median follow-up of 2.1 (interquartile range: 1.0-3.8) years. During the first 30 days of warfarin treatment, unadjusted and adjusted rates of major bleeding were higher at lower eGFR (P for trend <0.001 and 0.001, respectively). Adjusted bleeding rates per 100 person years were 63.4 (95% confidence interval 24.9 to 161.6) in participants with eGFR <15 mL/min/1.73m2 compared with 6.1 (1.9 to 19.4) among those with eGFR >90 mL/min/1.73m2 (adjusted incidence rate ratio 10.3, 95% confidence interval 2.3 to 45.5). Similar associations were observed at more than 30 days after starting warfarin, although the magnitude of the increase in rates across eGFR categories was attenuated. Across all eGFR categories, adjusted rates of major bleeding were consistently higher during the first 30 days of warfarin treatment compared with the remainder of follow-up. Increases in major bleeding rates were largely due to gastrointestinal bleeding (3.5-fold greater in eGFR <15 mL/min/1.73m2 compared with ≥90 mL/min/1.73m2). Intracranial bleeding was not increased with worsening kidney function. Conclusions Reduced kidney function was associated with an increased risk of major bleeding among older adults with atrial fibrillation starting warfarin; excess risks from reduced eGFR were most pronounced during the first 30 days of treatment. Our results support the need for careful consideration of the bleeding risk relative to kidney function when assessing the risk-benefit ratio of warfarin treatment in people with chronic kidney disease and atrial fibrillation, particularly in the first 30 days of treatment.

Intensities of Renal Replacement Therapy in Acute Kidney Injury: A Systematic Review and Meta-Analysis

BACKGROUND AND OBJECTIVES Clinical trials of the intensity of renal replacement therapy (RRT) for people with acute kidney injury (AKI) have produced conflicting results. A systematic review and meta-analysis was undertaken to assess the effect of different intensities of RRT on all-cause mortality and renal recovery in AKI patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS MEDLINE, EMBASE, and the Cochrane Library database were systematically searched for trials published between 1950 and 2009. Inclusion criteria were completed, prospective, adult-population, randomized controlled studies. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated. Summary estimates of RR were obtained using a random effects model. Heterogeneity, metaregression, publication bias, and subgroup analyses were conducted. RESULTS Eight trials were identified that provided data on 3841 patients and 1808 deaths. More intense RRT (35 to 48 ml/kg per h or equivalent) had no overall effect on the risk of death (RR 0.89, 95% CI 0.76 to 1.04, P = 0.143) or recovery of renal function (RR 1.12, 95% CI 0.95 to 1.31, P = 0.181) compared with less-intensive regimens (20 to 25 ml/kg per h or equivalent). Significant heterogeneity was identified with contributing factors including publication year (P = 0.004) and Jadad score (P = 0.048). CONCLUSIONS Within the intensity ranges studied, higher intensity RRT does not reduce mortality rates or improve renal recovery among patients with AKI. The results do not negate the importance of RRT intensity in the treatment of AKI patients but rather reinforce the need to better understand the effects of treatment modalities, doses, and timing in this varied, high-risk population.

The Efficacy and Tolerability of ‘Polypills’: Meta-Analysis of Randomised Controlled Trials

Background To assess the blood pressure and lipid-lowering efficacy and tolerability of ‘polypills’ used in cardiovascular disease prevention trials. Methodology/Principal Findings Systematic review and meta-analysis. Search strategy: The Cochrane Central Register of Controlled Trials, Medline, and PubMed databases were searched for eligible trials. Study inclusion criteria: Randomised controlled trials of at least six weeks duration, which compared a ‘polypill’ (that included at least one anti-hypertensive and one lipid-lowering medication) with a placebo (or one active component). Outcome measures: Change from baseline in systolic and diastolic blood pressures, and total and LDL-cholesterol; discontinuation of study medication and reported adverse effects. Of 44 potentially eligible studies, six trials (including 2,218 patients without previous cardiovascular disease) fulfilled the inclusion criteria. Compared with placebo, ‘polypills’ reduced systolic blood pressure by −9.2 mmHg (95% confidence interval (CI): −13.4, −5.0) diastolic blood pressure by −5.0 mmHg (95%CI: −7.4, −2.6), total cholesterol by −1.22 mmol/L (95%CI: −1.60, −0.84) and LDL-cholesterol by −1.02 mmol/L (95%CI: −1.37, −0.67). However, those taking a ‘polypill’ (vs. placebo or component) were more likely to discontinue medication (20% vs 14%) (Odds ratio: 1.5 (95% CI: 1.2, 1.9)). There was no significant difference in reported adverse effects amongst those on a ‘polypill’ (36% vs. 28%) (OR: 1.3 (95%CI: 0.7, 2.5)). There was high statistical heterogeneity in comparisons for blood pressure and lipid-lowering but use of random-effects and quality-effects models produced very similar results. Conclusions/Significance Compared with placebo, the ‘polypills’ reduced blood pressure and lipids. Tolerability was lower amongst those on ‘polypills’ than those on placebo or one component, but differences were moderate. Effectiveness trials are needed to help clarify the status of ‘polypills’ in primary care and prevention strategies.

Proteinuria and Rate of Change in Kidney Function in a Community-Based Population

Proteinuria identifies patients at risk for adverse clinical outcomes, but it is unclear whether proteinuria correlates with the rate of renal decline. We examined the association between proteinuria and rate of change in estimated GFR (eGFR) in a cohort of 638,150 adults from a province-wide registry in Alberta, Canada, who had a measure of proteinuria and three or more outpatient serum creatinine measurements over a period of ≥1 year. An adjusted sex-specific linear mixed-effects model was used to determine the rate of change in eGFR per year for patients with normal, mild, and heavy proteinuria, stratified by baseline kidney function (eGFR ≥90, 60-89.9, 45-59.9, 30-44.9, and 15-29.9 ml/min per 1.73 m(2)). In men, heavy proteinuria and a baseline eGFR of 45-59.9 ml/min per 1.73 m(2) correlated with a change in eGFR of -2.16 (95% confidence interval [CI], -2.37 to -1.95) ml/min per 1.73 m(2) per year, whereas mild proteinuria and a baseline eGFR of 30-44.9 ml/min per 1.73 m(2) correlated with a change in eGFR of -0.51 (95% CI, -0.70 to -0.32) ml/min per 1.73 m(2) per year. Similar trends were observed for female, elderly, and diabetic patients. Notably, normal protein levels and a lower baseline eGFR (15-29.9 ml/min per 1.73 m(2)) correlated with stable or improved renal function. In conclusion, our results suggest that proteinuria of increasing severity is associated with a faster rate of renal decline, regardless of baseline eGFR, and the combined effect should be considered in patients with CKD.

Outcomes of Extended-Hours Hemodialysis Performed Predominantly at Home

BACKGROUND Recent evidence suggests that increased frequency and/or duration of dialysis are associated with improved outcomes. We aimed to describe the outcomes associated with patients starting extended-hours hemodialysis and assess for risk factors for these outcomes. STUDY DESIGN Case series. SETTING & PARTICIPANTS Patients were from 6 Australian centers offering extended-hours hemodialysis. Cases were patients who started treatment for 24 hours per week or longer at any time. OUTCOMES All-cause mortality, technique failure (withdrawal from extended-hours hemodialysis therapy), and access-related events. MEASUREMENTS Baseline patient characteristics (sex, primary cause of end-stage kidney disease, age, ethnicity, diabetes, and cannulation technique), presence of a vascular access-related event, and dialysis frequency. RESULTS 286 patients receiving extended-hours hemodialysis were identified, most of whom performed home (96%) or nocturnal (77%) hemodialysis. Most patients performed alternate-daily dialysis (52%). Patient survival rates using an intention-to-treat approach at 1, 3, and 5 years were 98%, 92%, and 83%, respectively. Of 24 deaths overall, cardiac death (n = 7) and sepsis (n = 5) were the leading causes. Technique survival rates at 1, 3, and 5 years were 90%, 77%, and 68%, respectively. Access event-free rates at the same times were 80%, 68%, and 61%, respectively. Access events significantly predicted death (HR, 2.85; 95% CI, 1.14-7.15) and technique failure (HR, 3.76; 95% CI, 1.93-7.35). Patients with glomerulonephritis had a reduced risk of technique failure (HR, 0.31; 95% CI, 0.14-0.69). Higher dialysis frequency was associated with elevated risk of developing an access event (HR per dialysis session, 1.56; 95% CI, 1.03-2.36). LIMITATIONS Selection bias, lack of a comparator group. CONCLUSIONS Extended-hours hemodialysis is associated with excellent survival rates and is an effective treatment option for a select group of patients. The major treatment-associated adverse events were related to complications of vascular access, particularly infection. The risk of developing vascular access complications may be increased in extended-hours hemodialysis, which may negatively affect long-term outcomes.