Hiddo J. Lambers Heerspink

Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials

Summary Background Patients undergoing dialysis have a substantially increased risk of cardiovascular mortality and morbidity. Although several trials have shown the cardiovascular benefits of lowering blood pressure in the general population, there is uncertainty about the efficacy and tolerability of reducing blood pressure in patients on dialysis. We did a systematic review and meta-analysis to assess the effect of blood pressure lowering in patients on dialysis. Methods We systematically searched Medline, Embase, and the Cochrane Library database for trials reported between 1950 and November, 2008, without language restriction. We extracted a standardised dataset from randomised controlled trials of blood pressure lowering in patients on dialysis that reported cardiovascular outcomes. Meta-analysis was done with a random effects model. Findings We identified eight relevant trials, which provided data for 1679 patients and 495 cardiovascular events. Weighted mean systolic blood pressure was 4·5 mm Hg lower and diastolic blood pressure 2·3 mm Hg lower in actively treated patients than in controls. Blood pressure lowering treatment was associated with lower risks of cardiovascular events (RR 0·71, 95% CI 0·55–0·92; p=0·009), all-cause mortality (RR 0·80, 0·66–0·96; p=0·014), and cardiovascular mortality (RR 0·71, 0·50–0·99; p=0·044) than control regimens. The effects seem to be consistent across a range of patient groups included in the studies. Interpretation Treatment with agents that lower blood pressure should routinely be considered for individuals undergoing dialysis to reduce the very high cardiovascular morbidity and mortality rate in this population. Funding National Health and Medical Research Council of Australia Program.

Aspirin is beneficial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial.

OBJECTIVES The purpose of this study was to determine the benefit and risk associated with antiplatelet therapy in the chronic kidney disease (CKD) population. BACKGROUND Cardiovascular and possibly bleeding risks are elevated in patients with CKD. The balance of benefit and harm associated with antiplatelet therapy remains uncertain. METHODS The HOT (Hypertension Optimal Treatment) study randomly assigned participants with diastolic hypertension to aspirin (75 mg) or placebo. Study treatment effects were calculated using univariate proportional hazards regression models stratified by baseline estimated glomerular filtration rate (eGFR) with trends tested by adding interaction terms. End points included major cardiovascular events, total mortality, and major bleeding. RESULTS The study included 18,597 participants treated for 3.8 years. Baseline eGFR was < 60 ml/min/1.73 m(2) in 3,619 participants. Major cardiovascular events were reduced by 9% (95% confidence interval [CI]: -9% to 24%), 15% (95% CI: -17% to 39%), and 66% (95% CI: 33% to 83%) for patients with baseline eGFR of ≥ 60, 45 to 59, and < 45 ml/min/1.73 m(2), respectively (p trend = 0.03). Total mortality was reduced by 0% (95% CI: -20% to 17%), 11% (95% CI: -31% to 40%), and 49% (95% CI: 6% to 73%), respectively (p trend = 0.04). Major bleeding events were nonsignificantly greater with lower eGFR (hazard ratio [HR]: 1.52 [95% CI: 1.11 to 2.08], HR: 1.70 [95% CI: 0.74 to 3.88], and HR: 2.81 [95% CI: 0.92 to 8.84], respectively; p trend = 0.30). Among every 1,000 persons with eGFR < 45 ml/min/1.73 m(2) treated for 3.8 years, 76 major cardiovascular events and 54 all-cause deaths will be prevented while 27 excess major bleeds will occur. CONCLUSIONS Aspirin therapy produces greater absolute reduction in major cardiovascular events and mortality in hypertensive patients with CKD than with normal kidney function. An increased risk of major bleeding appears to be outweighed by the substantial benefits.

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.

Renal and cardio-protective effects of direct renin inhibition : a systematic literature review

Background Blockade of the renin–angiotensin–aldosterone system (RAAS) at its rate-limiting step by means of renin inhibition has led to the development of direct renin inhibitors (DRIs). Given the renal and cardioprotective effects of RAAS blockade by angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, DRIs may increase the armamentarium for further organ protection. Over the last two decades the effects of DRIs on biomarkers for renal and cardiovascular disease have been investigated. This systematic review aims to delineate the effects of DRIs on surrogate markers of renal and cardiovascular function. Methods MEDLINE and previous systematic reviews were searched for articles reported between 1980 and 2008. A standardized dataset was extracted from articles describing the effects of DRIs on markers of renal and cardiac damage and hard outcomes. Results Fifty-two articles were included. Blood pressure reductions were generally insufficient using early generation DRIs. However, recent DRIs have greater blood pressure-lowering effects. Preclinical and clinical studies showed profound effects of DRIs on markers of renal function, including clear increases in renal plasma flow and reductions in albuminuria. These effects were observed either alone or in combination with other RAAS inhibitors and suggest potential large renal protective benefit. DRIs improved hemodynamic cardiovascular parameters, such as total peripheral resistance, arterial pressure and left ventricular mass index, to a similar extent as those observed with other RAAS inhibitors. Furthermore, addition of DRIs to optimal heart failure treatment resulted in further reductions in B-type natriuretic peptide. Conclusions Evidence from preclinical and clinical studies suggests that DRIs may have renal and cardiovascular effects beyond their ability to lower blood pressure. Results of ongoing hard outcome trials are awaited to definitively assess the renal and cardio-protective effects of these agents.

PS11 - 1. Longitudinal eGFR trajectories in patients with type 2 diabetes

The decline in glomerular filtration rate (GFR) is used as outcome parameter to establish drug efficacy in clinical trials of renal disease progression. For analyzing and interpretation of trial results it is assumed that renal function declines linearly over time. However, a recent study in Afro- Americans with hypertensive nephrosclerosis documented that 42% of patients exhibit > 90% probability of non-linear GFR trajectory or prolonged period of nonprogression.