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1.
Effects of tolvaptan add-on therapy in patients with acute heart failure: meta-analysis on randomised controlled trials.
Ma, G, Ma, X, Wang, G, Teng, W, Hui, X
BMJ open. 2019;(4):e025537
Abstract
OBJECTIVES Treating acute decompensated heartfailure (ADHF) for improving congestion with diuretics may cause worsening renal function (WRF), but the clinical efficacy of tolvaptan add-on therapy on reducing WRF in ADHF patients is inconsistent. This analysis is to evaluate the effects of tolvaptan add-on therapy on reducing WRF in ADHF patients. METHODS Meta-analysis of randomised trials of tolvaptan add-on therapy on reducing WRF in ADHF patients. The MEDLINE, Embase and Cochrane Central Register of Controlled Trials databases were searched for relevant articles from their inception to 31 October, 2017. Two reviewers filtrated the documents on WRF, short-term all-cause mortality, body weight decreased, elevated sodium level for calculating pooled relatives risks, weighted mean difference and associated 95% CIs. We used fixed-effects or random-effects models according to I2 statistics. ACHIEVEMENTS Seven random controlled trials with 937 patients were included for analysis. Compared with the control, tolvaptan add-on therapy did not improve incidence of worsening renal function (RR 0.78, 95% CI 0.48 to 1.26, p=0.31, I2=66%) and short-term all-cause mortality (RR 0.85, 95% CI 0.47 to 1.56, p=0.61, I2=0%). On subgroup analyses, there was a suggestion of possible effect modification by dose of tolvaptan, in which benefit was observed in low-dose (≤15 mg/day) group (RR 0.48, 95% CI 0.23 to 1.02, p=0.05, I2=54%), but not with high-dose (30 mg) group (RR 1.33, 95% CI 0.99 to 1.78, p=0.05, I2=0%). However, tolvaptan add-on therapy reduced body weight in 2 days (standardised mean difference -0.49, 95% CI -0.64 to -0.34, p<0.00001, I2=0%), increased sodium level (mean difference 1.56, 95% CI 0.04 to 3.07, p=0.04, I2=0%). CONCLUSION The result suggests that comparing with the standard diuretic therapy, tolvaptan add-on therapy did not reduce the incidence of WRF and short-term mortality, however, it can decrease body weight and increase the sodium level in patients who are with ADHF. Further researches are still required for confirmation.
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SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment: A systematic review and meta-analysis.
Seidu, S, Kunutsor, SK, Cos, X, Gillani, S, Khunti, K, ,
Primary care diabetes. 2018;(3):265-283
Abstract
BACKGROUND Sodium-glucose co-transporter 2 (SGLT2) inhibitors may have renal protective effects in people with impaired kidney function. We assessed the use of SGLT2 inhibitors in people with type 2 diabetes with or without renal impairment [defined as estimated glomerular filtration rate (eGFR) of ≥30 and <60ml/min/1.73m2 and/or UACR>300 and ≤5000mg/g] by conducting a systematic review and meta-analysis of available studies. METHODS Randomised controlled trials (RCTs) were identified from MEDLINE, EMABASE, Web of Science, the Cochrane Library, and search of bibliographies to March 2017. No relevant observational study was identified. Summary measures were presented as mean differences and narrative synthesis performed for studies that could not be pooled. RESULTS 42 articles which included 40 RCTs comprising 29,954 patients were included. In populations with renal impairment, SGLT2 inhibition compared with placebo was consistently associated with an initial decrease in eGFR followed by an increase and return to baseline levels. In pooled analysis of 17 studies in populations without renal impairment, there was no significant change in eGFR comparing SGLT2 inhibitors with placebo (mean difference, 0.51ml/min/1.73m2; 95% CI: -0.69, 1.72; p=403). SGLT2 inhibition relative to placebo was associated with preservation in serum creatinine levels or initial increases followed by return to baseline levels in patients with renal impairment, but levels were preserved in patients without renal impairment. In populations with or without renal impairment, SGLT2 inhibitors (particularly canagliflozin and empagliflozin) compared with placebo were associated with decreased urine albumin, improved albuminiuria, slowed progression to macroalbuminuria, and reduced the risk of worsening renal impairment, the initiation of kidney transplant, and death from renal disease. CONCLUSIONS Emerging data suggests that with SGLT2 inhibition, renal function seems to be preserved in people with diabetes with or without renal impairment. Furthermore, SGLT2 inhibition prevents further renal function deterioration and death from kidney disease in these patients.
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Multinational Assessment of Accuracy of Equations for Predicting Risk of Kidney Failure: A Meta-analysis.
Tangri, N, Grams, ME, Levey, AS, Coresh, J, Appel, LJ, Astor, BC, Chodick, G, Collins, AJ, Djurdjev, O, Elley, CR, et al
JAMA. 2016;(2):164-74
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Abstract
IMPORTANCE Identifying patients at risk of chronic kidney disease (CKD) progression may facilitate more optimal nephrology care. Kidney failure risk equations, including such factors as age, sex, estimated glomerular filtration rate, and calcium and phosphate concentrations, were previously developed and validated in 2 Canadian cohorts. Validation in other regions and in CKD populations not under the care of a nephrologist is needed. OBJECTIVE To evaluate the accuracy of the risk equations across different geographic regions and patient populations through individual participant data meta-analysis. DATA SOURCES Thirty-one cohorts, including 721,357 participants with CKD stages 3 to 5 in more than 30 countries spanning 4 continents, were studied. These cohorts collected data from 1982 through 2014. STUDY SELECTION Cohorts participating in the CKD Prognosis Consortium with data on end-stage renal disease. DATA EXTRACTION AND SYNTHESIS Data were obtained and statistical analyses were performed between July 2012 and June 2015. Using the risk factors from the original risk equations, cohort-specific hazard ratios were estimated and combined using random-effects meta-analysis to form new pooled kidney failure risk equations. Original and pooled kidney failure risk equation performance was compared, and the need for regional calibration factors was assessed. MAIN OUTCOMES AND MEASURES Kidney failure (treatment by dialysis or kidney transplant). RESULTS During a median follow-up of 4 years of 721,357 participants with CKD, 23,829 cases kidney failure were observed. The original risk equations achieved excellent discrimination (ability to differentiate those who developed kidney failure from those who did not) across all cohorts (overall C statistic, 0.90; 95% CI, 0.89-0.92 at 2 years; C statistic at 5 years, 0.88; 95% CI, 0.86-0.90); discrimination in subgroups by age, race, and diabetes status was similar. There was no improvement with the pooled equations. Calibration (the difference between observed and predicted risk) was adequate in North American cohorts, but the original risk equations overestimated risk in some non-North American cohorts. Addition of a calibration factor that lowered the baseline risk by 32.9% at 2 years and 16.5% at 5 years improved the calibration in 12 of 15 and 10 of 13 non-North American cohorts at 2 and 5 years, respectively (P = .04 and P = .02). CONCLUSIONS AND RELEVANCE Kidney failure risk equations developed in a Canadian population showed high discrimination and adequate calibration when validated in 31 multinational cohorts. However, in some regions the addition of a calibration factor may be necessary.
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Meta-analysis on risk of bleeding with apixaban in patients with renal impairment.
Pathak, R, Pandit, A, Karmacharya, P, Aryal, MR, Ghimire, S, Poudel, DR, Shamoun, FE
The American journal of cardiology. 2015;(3):323-7
Abstract
Apixaban is a novel oral anticoagulant which is approved for the management of atrial fibrillation and venous thromboembolism prophylaxis. There have been concerns regarding bleeding risks with apixaban in patients with renal impairment. We performed a systematic review and meta-analysis to evaluate the risk of bleeding with apixaban in these patients. Relevant studies were identified through electronic literature searches of MEDLINE, EMBASE, Cochrane library, and clinicaltrials.gov (from inception to February 24, 2014). Phase III randomized controlled trials that compared apixaban with conventional agents (vitamin K antagonist and/or warfarin, low molecular weight heparin, aspirin, and placebo) were included. We defined mild renal impairment as creatinine clearance of 50 to 80 ml/min and moderate to severe renal impairment as creatinine clearance <50 ml/min. Study-specific risk ratios were calculated, and between-study heterogeneity was assessed using the I(2) statistics. In 6 trials involving 40,145 patients, the risk of bleeding with apixaban in patients with mild renal impairment was significantly less (risk ratio 0.80, 95% confidence interval 0.66 to 0.96, I(2) = 13%) compared with conventional anticoagulants. In patients with moderate to severe renal impairment, the risk of bleeding with was found to be similar (risk ratio 1.01, 95% confidence interval 0.49 to 2.10, I(2) = 72%). In conclusion, compared with the conventional agents, bleeding risk with apixaban in patients with mild and moderate to severe renal insufficiency is lower and similar, respectively.
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A Systematic Review on the Efficacy of Amlodipine in the Treatment of Patients With Hypertension With Concomitant Diabetes Mellitus and/or Renal Dysfunction, When Compared With Other Classes of Antihypertensive Medication.
Jeffers, BW, Robbins, J, Bhambri, R, Wajsbrot, D
American journal of therapeutics. 2015;(5):322-41
Abstract
The long-term cardiovascular (CV) effects of calcium channel blockers, with special focus on amlodipine, were compared with other classes of antihypertensive medications in high-risk hypertensive patient subgroups. A systematic literature review and meta-analysis was undertaken of 38 unique randomized, active-controlled, parallel-group trials comparing amlodipine/calcium channel blockers with diuretics, β-blockers, α-blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers, with ≥6-month follow-up, and which had included assessment of blood pressure (BP) and CV events [all-cause death, CV death, myocardial infarction (MI), stroke, congestive heart failure (CHF), or major CV events (MACE: MI, CHF, stroke, and CV death)], in hypertensive patients (baseline systolic/diastolic BP ≥140/≥90 mm Hg) with either concomitant diabetes and/or renal dysfunction. In hypertensive patients with diabetes, no difference was found for amlodipine versus comparators with respect to all-cause death, CV death, MACE, and MI; a decrease in stroke risk, and an increase in CHF risk, was seen. In hypertensive patients with renal dysfunction, no difference was found for amlodipine versus comparators with respect to all-cause death, CV death, MACE, MI, and CHF; a decrease in stroke risk was seen. Amlodipine was found to be at least as efficacious as all the other classes of antihypertensive agents in reducing systolic and diastolic BP. Long-term control of BP is critical for avoiding complications of hypertension in high-risk patients, particularly CV and cerebrovascular events such as stroke. This analysis has provided evidence that amlodipine is an appealing therapeutic option in the long-term management of hypertension in both diabetic and renal dysfunction patients.
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The efficacy of sodium bicarbonate in preventing contrast-induced nephropathy in patients with pre-existing renal insufficiency: a meta-analysis.
Zhang, B, Liang, L, Chen, W, Liang, C, Zhang, S
BMJ open. 2015;(3):e006989
Abstract
OBJECTIVE The aim of this meta-analysis was to explore the efficacy of sodium bicarbonate in preventing contrast-induced nephropathy (CIN). METHODS We searched PubMed, Medline and the Cochrane Library from 1 January 2004 to 1 August 2014. The effect estimate was expressed as a pooled OR with 95% CI, using the fixed-effects or random-effects model. RESULTS 20 randomised controlled trials (n=4280) were identified. Hydration with sodium bicarbonate was associated with a significant decrease in CIN among patients with pre-existing renal insufficiency (OR 0.67, 95% CI 0.47 to 0.96; p=0.027). However, moderate heterogeneity was noted across trials (I(2)=48%; p=0.008). Subgroup analyses indicated a better effect of sodium bicarbonate in studies using low-osmolar (OR 0.59, 95% CI 0.37 to 0.93; p=0.024) compared with iso-osmolar contrast agents (OR 0.76, 95% CI 0.43 to 1.34; p=0.351). The odds of CIN with sodium bicarbonate were lower in studies including only patients undergoing emergency (OR 0.16, 95% CI 0.05 to 0.51; p=0.002) compared with elective procedures (OR 0.76, 95% CI 0.54 to 1.06; p=0.105). Sodium bicarbonate was more beneficial in patients given a bolus injection before procedures (OR 0.15, 95% CI 0.04 to 0.54; p=0.004) compared with continuous infusion (OR 0.75, 95% CI 0.53 to 1.05; p=0.091). Sodium bicarbonate plus N-acetylcysteine (OR 0.17, 95% CI 0.04 to 0.79; p=0.024) was better than sodium bicarbonate alone (OR 0.71, 95% CI 0.48 to 1.03; p=0.071). The effect of sodium bicarbonate was considered greater in papers published before (OR 0.19, 95% CI 0.09 to 0.41; p=0.000) compared with after 2008 (OR 0.85, 95% CI 0.62 to 1.16; p=0.302). However, no significant differences were found in mortality (OR 0.69, 95% CI 0.36 to 1.32; p=0.263) or requirement for dialysis (OR 1.08, 95% CI 0.52 to 2.25; p=0.841). CONCLUSIONS Sodium bicarbonate is effective in preventing CIN among patients with pre-existing renal insufficiency. However, it fails to lower the risks of dialysis and mortality and therefore cannot improve the clinical prognosis of patients with CIN.
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Risk of renal failure with the non-vitamin K antagonist oral anticoagulants: systematic review and meta-analysis.
Caldeira, D, Gonçalves, N, Pinto, FJ, Costa, J, Ferreira, JJ
Pharmacoepidemiology and drug safety. 2015;(7):757-64
Abstract
PURPOSE Vitamin K antagonists (VKA)-related nephropathy is a novel entity characterized by acute kidney injury related to International Normalized Ratio supratherapeutic levels. Non-vitamin K antagonists oral anticoagulants (NOACs) have a predictable dose-response relationship and an improved safety profile. We hypothesized that these drugs do not have an increased risk of incident renal failure, which may be detrimental for the use of NOACs. METHODS Systematic review and meta-analysis of phase III randomized controlled trials (RCTs). Trials were searched through Medline, Cochrane Library and public assessment reports in August 2014. Primary outcome was renal failure. NOACs were evaluated against any comparator. Random-effects meta-analysis was performed by default, and pooled estimates were expressed as Risk Ratio (RR) and 95%CI. Heterogeneity was evaluated with I(2) test. RESULTS Ten RCTs fulfilled inclusion criteria (one apixaban RCT, three dabigatran RCTs, and six rivaroxaban RCTs), enrolling 75 100 patients. Overall NOACs did not increase the risk of renal failure with an RR 0.96, 95%CI 0.88-1.05 compared with VKA or Low-molecular weight heparin (LMWH), without significant statistical heterogeneity (I(2) = 3.5%). Compared with VKA, NOACs did not increase the risk of renal failure (RR 0.96, 95%CI 0.87-1.07; I(2) = 17.8%; six RCTs). Rivaroxaban did not show differences in the incidence of renal failure compared with LMWH (RR 1.20, 95%CI 0.37-3.94; four trials), but there was an increased risk of creatinine elevation RR 1.25, 95%CI 1.08-1.45; I(2) = 0%. CONCLUSIONS NOACs had a similar risk of renal failure compared with VKA/LMWH in phase III RCTs. Post-marketing surveillance should be warranted.
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Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on safety and efficacy outcomes in atrial fibrillation patients: a systemic review and meta-regression analysis.
Nielsen, PB, Lane, DA, Rasmussen, LH, Lip, GY, Larsen, TB
Clinical research in cardiology : official journal of the German Cardiac Society. 2015;(5):418-29
Abstract
OBJECTIVE To investigate the relative effect of warfarin versus non-vitamin K oral anticoagulants (NOACs) in thrombotic and bleeding outcomes in subgroups of atrial fibrillation (AF) patients with varying degrees of renal dysfunction. METHODS Systemic review and meta-regression analyses on NOACs versus warfarin, supplemented with indirect comparisons were conducted. The eligibility criteria for inclusion were randomised controlled trials comparing NOACs against warfarin for stroke prevention in AF patients. Outcomes of interest were stroke or systemic embolism (SE) and major bleeding. RESULTS Five studies comprising 72,845 AF patients randomised to either a NOAC or warfarin were included in the meta-regression analysis. A shift in strata from no renal impairment to renal impairment resulted in a non-significant impact on bleeding and stroke/SE, indicating similar safety and efficacy, despite renal function status. Apixaban was associated with less major bleeding compared to dabigatran and rivaroxaban but not edoxaban in patients with moderate renal impairment. For efficacy outcomes, only dabigatran 150 mg was statistically significantly favoured compared to edoxaban 30 mg. For efficacy outcomes in mild renal impairment, both dabigatran 150 mg and rivaroxaban 10 mg (J-ROCKET) were statistically significantly favoured against edoxaban 30 mg. CONCLUSION Non-vitamin K oral anticoagulants had similar efficacy and safety compared to warfarin across different levels of renal function. Indirect comparisons suggest that apixaban and edoxaban were associated with a better safety profile in patients with moderate renal impairment. However, caution is warranted when interpreting indirect comparisons of drugs investigated in different trials. Prescribers should fit the most appropriate NOAC to the AF patient characteristics (and vice versa) to individualise effective stroke prevention.
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Does belatacept improve outcomes for kidney transplant recipients? A systematic review.
Talawila, N, Pengel, LH
Transplant international : official journal of the European Society for Organ Transplantation. 2015;(11):1251-64
Abstract
BACKGROUND Belatacept was intended to provide better outcomes for kidney transplant (KT) recipients by allowing minimization/withdrawal of calcineurin inhibitors (CNI) and steroids. METHODS We searched for randomized controlled trials (RCTs) in adult KT comparing belatacept with CNIs. Methodological quality was assessed. Meta-analyses were performed to calculate odds ratios (OR) and mean differences (MD). RESULTS Six RCTs were included. Pooled analyses found no differences for acute rejection at any time point. Renal function [Calculated glomerular filtration rate (cGFR)] was better with belatacept at 12 and 24 months (MD = 11.7 and 13.7 ml/min/1.73 m(2) ). New onset diabetes after transplantation was lower with belatacept at 12 months (OR = 0.43). Systolic and diastolic blood pressures were lower at 12 months (MD -7.2 and -3.1 mmHg) as were triglycerides at 12 and 24 months (MD = -32.9 and -41.7 mg/dl). Total and low-density lipoprotein cholesterol were lower with belatacept at 24 months (MD = -19.8 and -10.6 mg/dl). There were no differences for other outcomes. CONCLUSION Limited available data suggest a potential benefit for belatacept by reducing the risk of CNI toxicity, especially renal function, without evidence of increased acute rejection. There were no safety issues apart from a possible risk of post-transplant lymphoproliferative disorder in Epstein-barr virus-seronegative recipients. Further studies are required to confirm this benefit.
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Consistency of safety profile of new oral anticoagulants in patients with renal failure.
Lega, JC, Bertoletti, L, Gremillet, C, Boissier, C, Mismetti, P, Laporte, S
Journal of thrombosis and haemostasis : JTH. 2014;(3):337-43
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Abstract
BACKGROUND The use of new oral anticoagulants (NOACs) in patients with impaired renal function has raised major concerns, in particular the possibility of an increased risk of bleeding due to accumulation. The aims of this work were to assess the safety of NOACs in patients with renal failure and describe the relationship between clinical events and drug renal excretion magnitude. METHODS All phase III trials comparing NOACs with vitamin K antagonists (VKAs) in patients with estimated glomerular filtration (eGFR) rate < 50 mL min(-1) were eligible. The main safety and efficacy outcomes were major bleeding and thrombosis. A meta-regression was performed to estimate the correlation between the treatment effect estimate and the percentage of renal excretion. RESULTS Nine studies (12 272 patients) were included. A significantly greater relative reduction in major bleeding was seen for NOACs with renal excretion <50% (RR, 0.61; CI, 0.51-0.74) than for those with high renal excretion (RR, 0.96; CI, 0.85-1.07) (interaction test, P < 0.0001). A linear relationship between the relative risk of major bleeding and the magnitude of renal excretion was found by meta-regression (R(2) = 0.66, P = 0.03). For thrombosis, a greater treatment effect of NOA vs. INR-adjusted VKA was observed in patients with eGFR < 50 mL min(-1) (RR 0.78, CI 0.67-0.92), but no correlation between treatment effect and renal excretion was found. CONCLUSIONS New oral anticoagulants were at least as effective as VKAs, with reduced risks of major bleeding and thrombosis in patients with eGFR < 50 mL min(-1) . The renal excretion of these new drugs seemed to modify the safety profile, contrary to the efficacy.