Dataset Information

Can we IMPROVE cardiovascular outcomes through phosphate lowering in CKD? Rationale and protocol for the IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease (IMPROVE-CKD) study.

ABSTRACT:

Introduction

Patients with chronic kidney disease (CKD) are at heightened cardiovascular risk, which has been associated with abnormalities of bone and mineral metabolism. A deeper understanding of these abnormalities should facilitate improved treatment strategies and patient-level outcomes, but at present there are few large, randomised controlled clinical trials to guide management. Positive associations between serum phosphate and fibroblast growth factor 23 (FGF-23) and cardiovascular morbidity and mortality in both the general and CKD populations have resulted in clinical guidelines suggesting that serum phosphate be targeted towards the normal range, although few randomised and placebo-controlled studies have addressed clinical outcomes using interventions to improve phosphate control. Early preventive measures to reduce the development and progression of vascular calcification, left ventricular hypertrophy and arterial stiffness are crucial in patients with CKD.

Methods and analysis

We outline the rationale and protocol for an international, multicentre, randomised parallel-group trial assessing the impact of the non-calcium-based phosphate binder, lanthanum carbonate, compared with placebo on surrogate markers of cardiovascular disease in a predialysis CKD population-the IM pact of P hosphate R eduction O n V ascular E nd-points (IMPROVE)-CKD study. The primary objective of the IMPROVE-CKD study is to determine if the use of lanthanum carbonate reduces the burden of cardiovascular disease in patients with CKD stages 3b and 4 when compared with placebo. The primary end-point of the study is change in arterial compliance measured by pulse wave velocity over a 96-week period. Secondary outcomes include change in aortic calcification and biochemical parameters of serum phosphate, parathyroid hormone and FGF-23 levels.

Ethics and dissemination

Ethical approval for the IMPROVE-CKD trial was obtained by each local Institutional Ethics Committee for all 17 participating sites in Australia, New Zealand and Malaysia prior to study commencement. Results of this clinical trial will be published in peer-reviewed journals and presented at conferences.

Trial registration number

ACTRN12610000650099.

SUBMITTER: Lioufas N

PROVIDER: S-EPMC6398689 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

Can we IMPROVE cardiovascular outcomes through phosphate lowering in CKD? Rationale and protocol for the IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease (IMPROVE-CKD) study.

Lioufas Nicole N Toussaint Nigel D ND Pedagogos Eugenia E Elder Grahame G Badve Sunil V SV Pascoe Elaine E Valks Andrea A Hawley Carmel C

BMJ open 20190221 2

<h4>Introduction</h4>Patients with chronic kidney disease (CKD) are at heightened cardiovascular risk, which has been associated with abnormalities of bone and mineral metabolism. A deeper understanding of these abnormalities should facilitate improved treatment strategies and patient-level outcomes, but at present there are few large, randomised controlled clinical trials to guide management. Positive associations between serum phosphate and fibroblast growth factor 23 (FGF-23) and cardiovascul ...[more]

PMID: 30796122

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Project description:BackgroundHyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain.MethodsTo assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate >1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism.ResultsA total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m2; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings.ConclusionsIn patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia.Clinical trial registry name and registration numberAustralian Clinical Trials Registry, ACTRN12610000650099.

Project description:BACKGROUND AND OBJECTIVES:In the Systolic Blood Pressure Intervention Trial (SPRINT), intensive systolic BP treatment (target <120 mm Hg) was associated with fewer cardiovascular events and higher incidence of kidney function decline compared with standard treatment (target <140 mm Hg). We evaluated the association between mean arterial pressure reduction, kidney function decline, and cardiovascular events in patients without CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We categorized patients in the intensive treatment group of the SPRINT according to mean arterial pressure reduction throughout follow-up: <20, 20 to <40, and ?40 mm Hg. We defined the primary outcome as kidney function decline (?30% reduction in eGFR to <60 ml/min per 1.73 m2 on two consecutive determinations at 3-month intervals), and we defined the secondary outcome as cardiovascular events. In a propensity score analysis, patients in each mean arterial pressure reduction category from the intensive treatment group were matched with patients from the standard treatment group to calculate the number needed to treat regarding cardiovascular events and the number needed to harm regarding kidney function decline. RESULTS:In the intensive treatment group, 1138 (34%) patients attained mean arterial pressure reduction <20 mm Hg, 1857 (56%) attained 20 to <40 mm Hg, and 309 (9%) attained ?40 mm Hg. Adjusted hazard ratios for kidney function decline were 2.10 (95% confidence interval, 1.22 to 3.59) for mean arterial pressure reduction between 20 and 40 mm Hg and 6.22 (95% confidence interval, 2.75 to 14.08) for mean arterial pressure reduction ?40 mm Hg. In propensity score analysis, mean arterial pressure reduction <20 mm Hg presented a number needed to treat of 44 and a number needed to harm of 65, reduction between 20 and <40 mm Hg presented a number needed to treat of 42 and a number needed to harm of 35, and reduction ?40 mm Hg presented a number needed to treat of 95 and a number needed to harm of 16. CONCLUSIONS:In the intensive treatment group of SPRINT, larger declines in mean arterial pressure were associated with higher incidence of kidney function decline. Intensive treatment seemed to be less favorable when a larger reduction in mean arterial pressure was needed to attain the BP target.

Project description:BACKGROUND:Chronic kidney disease-mineral and bone disorder (CKD-MBD), a complication of chronic kidney disease, has been linked to reduced quality and length of life. High serum phosphate levels that result from CKD-MBD require phosphate-lowering agents, also known as phosphate binders. The objective of this systematic review is to compare the effects of available phosphate binders on laboratory outcomes in patients with CKD-MBD. METHODS:Data sources included MEDLINE and EMBASE from January 1996 to April 2016, and the Cochrane Register of Controlled Trials up to April 2016. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstracted data and assessed risk of bias in eligible randomized controlled trials (RCTs). Eligible trials enrolled patients with CKD-MBD and randomized them to receive calcium-based phosphate binders (delivered as calcium acetate, calcium citrate or calcium carbonate), non-calcium-based phosphate binders (NCBPB) (sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, sucroferric oxyhydroxide and ferric citrate), phosphorus restricted diet (diet), placebo or no treatment and reported effects on serum levels of phosphate, calcium and parathyroid hormone. We performed Bayesian network meta-analyses (NMA) to calculate the effect estimates (mean differences) and 95% credible intervals for serum levels of phosphate, calcium and parathyroid hormone. We calculated direct, indirect and network meta-analysis estimates using random-effects models. We applied the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence for each pairwise comparison. RESULTS:Our search yielded 1108 citations; 71 RCTs were retrieved for full review and 16 proved eligible. Including an additional 13 studies from a previous review, 29 studies that enrolled 8335 participants proved eligible; 26 trials provided data for quantitative synthesis. Sevelamer, lanthanum, calcium, iron, diet and combinations of active treatments (calcium or sevelamer or lanthanum and combination of calcium and sevelamer) resulted in significantly lower serum phosphate as compared to placebo (moderate to very low quality of evidence). We found no statistically significant differences between active treatment categories in lowering serum phosphate. Sevelamer, lanthanum and diet resulted in lower serum calcium compared to calcium (moderate quality evidence for lanthanum and diet; low quality evidence for Sevelamer). Iron, sevelamer and calcium yielded lower parathyroid hormone levels as compared to lanthanum. Meta-regression analyses did not yield a statistically significant association between treatment effect and trial duration. DISCUSSION/CONCLUSIONS:We found few differences between treatments in impact on phosphate and differences in parathyroid hormone. Relative to calcium, sevelamer, lanthanum and diet showed significant reduction in serum calcium from baseline. Treatment recommendations should be based on impact on patient-important outcomes rather than on surrogate outcomes. Systematic review registration: PROSPERO CRD-42016032945.

Project description:BackgroundRecent evidence suggests the systemic accumulation of by-products of gut microbes contributes to cardiovascular morbidity in patients with CKD. Limiting the generation of toxic bacterial by-products by manipulating the intestinal microbiota may be a novel strategy for reducing cardiovascular disease in CKD. Rifaximin is a minimally absorbed, oral antibiotic that targets intestinal pathogens and is commonly used as chronic therapy for the prevention of encephalopathy in patients with cirrhosis.MethodsWe conducted a randomized, double-blinded, placebo-controlled trial to determine the effect of a 10-day course of oral rifaximin 550 mg BID versus placebo on circulating concentrations of gut-derived cardiovascular toxins and proinflammatory cytokines in patients with stage 3-5 CKD (n=38). The primary clinical outcome was change in serum trimethylamine N-oxide (TMAO) concentrations from baseline to study end. Secondary outcomes included change in serum concentrations of p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines (C-reactive protein, IL-6, IL-1β), and change in composition and diversity of fecal microbiota.ResultsA total of 19 patients were randomized to each of the rifaximin and placebo arms, with n=17 and n=14 completing both study visits in these respective groups. We observed no difference in serum TMAO change (post-therapy minus baseline TMAO) between the rifaximin and placebo groups (mean TMAO change -3.9±15.4 for rifaximin versus 0.5±9.5 for placebo, P=0.49). Similarly, we found no significant change in serum concentrations for p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines. We did observe differences in colonic bacterial communities, with the rifaximin group exhibiting significant decreases in bacterial richness (Chao1, P=0.02) and diversity (Shannon H, P=0.05), along with altered abundance of several bacterial genera.ConclusionsShort-term rifaximin treatment failed to reduce gut-derived cardiovascular toxins and inflammatory cytokines in patients with CKD.Clinical trial registry name and registration numberRifaximin Therapy in Chronic Kidney Disease, NCT02342639.

Project description:BackgroundVascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown.MethodsTo determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15-45 ml/min per 1.73 m2). We randomly assigned participants to receive 400 μg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study.ResultsWe included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures.ConclusionsVitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD.Clinical trial registry name and registration numberVitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com).

Dataset Information

Can we IMPROVE cardiovascular outcomes through phosphate lowering in CKD? Rationale and protocol for the IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease (IMPROVE-CKD) study.

Introduction

Methods and analysis

Ethics and dissemination

Trial registration number

Publications

Can we IMPROVE cardiovascular outcomes through phosphate lowering in CKD? Rationale and protocol for the IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease (IMPROVE-CKD) study.

Similar Datasets

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