Association of Blood Pressure with Cardiovascular Outcome and Mortality: Results from the KNOW-CKD Study

2021 ◽  
Author(s):  
Jee Young Lee ◽  
Jung Tak Park ◽  
Young Su Joo ◽  
Changhyun Lee ◽  
Hae-Ryong Yun ◽  
...  
Keyword(s):  
Cardiovascular Events ◽  
Structural Models ◽  
Cardiovascular Outcome ◽  
Marginal Structural Models ◽  
Potential Hazard ◽  
Composite Outcome ◽  
Hazard Ratios ◽  
Adverse Cardiovascular Outcome ◽  
Primary Composite Outcome

Abstract Background Optimal BP control is a major therapeutic strategy to reduce adverse cardiovascular events and mortality in patients with CKD. We studied the association of BP with adverse cardiovascular outcome and all-cause death in patients with CKD. Methods Among 2,238 participants from the KoreaN cohort study for Outcome in patients With CKD, 2,226 patients with baseline BP measurements were enrolled. Main predictor was SBP categorized by 5 levels: <110, 110-119, 120-129, 130-139, and ≥140 mmHg. Primary endpoint was a composite outcome of all-cause death or incident cardiovascular events. We primarily used marginal structural models using averaged and the most recent time-updated SBPs. Results During a median follow-up of 10233.79 person-years (median 4.60 years), the primary composite outcome occurred in 240 (10.8%) participants, with a corresponding incidence rate of 23.5 (95% CI, 20.7–26.6) per 1,000 patient-years. Marginal structural models with averaged SBP showed a U-shaped relationship with the primary outcome. Compared to time-updated SBP of 110–119 mmHg, hazard ratios (95% CI) for <110, 120–129, 130–139, and ≥140 mmHg were 2.47 (1.48–4.11), 1.29 (0.80–2.08), 2.15 (1.26–3.69), and 2.19 (1.19–4.01), respectively. Marginal structural models with the most recent SBP also showed similar findings. Conclusions In Korean patients with CKD, there was a U-shaped association of SBP with the risk of adverse clinical outcome. Our findings highlight the importance of BP control and suggest a potential hazard of SBP <110 mmHg.

On-treatment blood pressure and long-term outcomes in chronic kidney disease

2021 ◽  
Author(s):  
Hae Hyuk Jung
Keyword(s):  
Cardiovascular Events ◽  
Composite Outcome ◽  
Long Term Outcomes ◽  
Major Cardiovascular Events ◽  
Hazard Ratios ◽  
All Cause Mortality ◽  
Composite Risk ◽  
Information Database

ABSTRACT Background The treatment BP target in CKD remains unclear, and whether the benefit of intensive BP-lowering is comparable between CKD and non-CKD patients is debated. Methods Using the Korean National Health Information Database, 359,492 CKD patients who had received antihypertensives regularly were identified from 12.1 million participants of nationwide health screening. The composite risk of major cardiovascular events, kidney failure, and all-cause mortality was assessed according to timely-averaged, on-treatment systolic BP. Results Over 9-year follow-up, the composite outcome noted in 18.4% of 239,700 participants with eGFR <60 ml/min/1.73 m2 and 18.9% of 155,004 with dipstick albuminuria. The thresholds of systolic BP, above which the composite risk increased significantly, in the reduced eGFR and the proteinuric population were 135 mm Hg and 125 mm Hg, respectively. For all-cause mortality, the respective thresholds were 145 mm Hg and 135 mm Hg. When comparing the composite risk between propensity score-matched groups, the hazard ratios of on-treatment BP of systolic 135–144 mm Hg (reference, 115–124 mm Hg) in the reduced eGFR and non-CKD pairs were 1.18 and 0.98, respectively (P = 0.13 for interaction), and those in the proteinuria and non-CKD pairs were 1.30 and 1.01, respectively (P = 0.003 for interaction). Conclusions The findings support the recommendation that, based on office BP, the systolic target in CKD with proteinuria is ≤ 130 mm Hg, and the target in CKD with no proteinuria is ≤ 140 mm Hg. The benefit of intensive BP-lowering may be greater in CKD patients particularly with proteinuria than in their non-CKD counterparts.

Safety and Efficacy of Vitamin K Antagonists versus Rivaroxaban in Hemodialysis Patients with Atrial Fibrillation: A Multicenter Randomized Controlled Trial

2021 ◽  
pp. ASN.2020111566
Author(s):  
An S. De Vriese ◽  
Rogier Caluwé ◽  
Hans Van Der Meersch ◽  
Koen De Boeck ◽  
Dirk De Bacquer
Keyword(s):  
Atrial Fibrillation ◽  
Major Bleeding ◽  
Cardiovascular Events ◽  
Vitamin K Antagonists ◽  
Vitamin K2 ◽  
Composite Outcome ◽  
End Point ◽  
Life Threatening ◽  
K2 Group

BackgroundIn patients with normal renal function or early stage CKD, the risk-benefit profile of direct oral anticoagulants (DOACs) is superior to that of vitamin K antagonists (VKAs). In patients on hemodialysis, the comparative efficacy and safety of DOACs versus VKAs are unknown.MethodsIn the Valkyrie study, 132 patients on hemodialysis with atrial fibrillation were randomized to a VKA with a target INR of 2–3, 10 mg rivaroxaban daily, or rivaroxaban and vitamin K2 for 18 months. Patients continued the originally assigned treatment and follow-up was extended for at least an additional 18 months. The primary efficacy end point was a composite of fatal and nonfatal cardiovascular events. Secondary efficacy end points were individual components of the composite outcome and all-cause death. Safety end points were life-threatening, major, and minor bleeding.ResultsMedian (IQR) follow-up was 1.88 (1.01–3.38) years. Premature, permanent discontinuation of anticoagulation occurred in 25% of patients. The primary end point occurred at a rate of 63.8 per 100 person-years in the VKA group, 26.2 per 100 person-years in the rivaroxaban group, and 21.4 per 100 person-years in the rivaroxaban and vitamin K2 group. The estimated competing risk–adjusted hazard ratio for the primary end point was 0.41 (95% CI, 0.25 to 0.68; P=0.0006) in the rivaroxaban group and 0.34 (95% CI, 0.19 to 0.61; P=0.0003) in the rivaroxaban and vitamin K2 group, compared with the VKA group. Death from any cause, cardiac death, and risk of stroke were not different between the treatment arms, but symptomatic limb ischemia occurred significantly less frequently with rivaroxaban than with VKA. After adjustment for competing risk of death, the hazard ratio for life-threatening and major bleeding compared with the VKA group was 0.39 (95% CI, 0.17 to 0.90; P=0.03) in the rivaroxaban group, 0.48 (95% CI, 0.22 to 1.08; P=0.08) in the rivaroxaban and vitamin K2 group and 0.44 (95% CI, 0.23 to 0.85; P=0.02) in the pooled rivaroxaban groups.ConclusionsIn patients on hemodialysis with atrial fibrillation, a reduced dose of rivaroxaban significantly decreased the composite outcome of fatal and nonfatal cardiovascular events and major bleeding complications compared with VKA.Clinical Trial registry name and registration number:Oral Anticoagulation in Hemodialysis, NCT03799822

scholarly journals Proton pump inhibitor use is not associated with severe COVID-19 related outcomes: A propensity score weighted analysis of a national veteran cohort

2021 ◽  
Author(s):  
Shailja C. Shah ◽  
Alese Halvorson ◽  
Brandon McBay ◽  
Chad Dorn ◽  
Otis Wilson ◽  
...  
Keyword(s):  
Propensity Score ◽  
Proton Pump ◽  
Index Date ◽  
Individual Component ◽  
Composite Outcome ◽  
Logistic Regression Models ◽  
Weighted Analysis ◽  
National Cohort ◽  
Primary Composite Outcome

Background and Aims: Low pH deactivates most pathogens, including coronaviruses. Proton pump inhibitors (PPIs) are potent gastric acid suppressing medications. Whether PPI use vs non-use is associated with severe Coronavirus disease-2019 (COVID-19) outcomes remains uncertain. We aimed to compare severe COVID-19 outcomes between current outpatient PPI users and non-users. Methods: We conducted a retrospective propensity score-weighted analysis of a national cohort of US veterans with established care who tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) through January 9, 2021, and who had 60 days of follow-up. The positive test date was the index date. Current outpatient PPI use up to and including the index date (primary exposure) was compared to non-use, defined as no PPI prescription fill in the 365 days prior to the index date. The primary outcome was a composite of use of mechanical ventilation or death within 60 days. Weighted logistic regression models evaluated severe COVID-19 outcomes between current PPI users vs non-users. Results: Of 97,674 Veterans with SARS-CoV-2 testing, 14,958 tested positive (6262 [41.9%] current PPI users, 8696 [58.1%] non-users) and comprised the analytic cohort. After weighting, all covariates were well-balanced. In the weighted cohort, there was no difference in the primary composite outcome (8.2% vs 8.0%; OR 1.03, 95% CI 0.91-1.16), secondary composite outcome, nor individual component outcomes between current PPI users and non-users. There was no significant interaction between age and PPI use on outcomes. Conclusion: Among patients with SARS-CoV-2 infection, current PPI use vs non-use is not associated with severe COVID-19 outcomes.

Abstract P640: Incident Atrial Fibrillation and Cardiovascular Risk Increases in Patients With Increased Burden of Atrial Ectopy

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Michael N Sattin ◽  
Zhe Li ◽  
Marko Mrkobrada ◽  
Erin I Spicer
Keyword(s):  
Atrial Fibrillation ◽  
Cardiovascular Events ◽  
Univariate Analysis ◽  
Composite Outcome ◽  
Ecg Monitoring ◽  
Reduced Ejection Fraction ◽  
Final Sample ◽  
Atrial Ectopy ◽  
The Relationship

Introduction: Atrial fibrillation (AF) is a major risk factor for cerebral ischemia in North America. Atrial ectopy has been associated with incident AF and increased stroke risk on short-duration ECG monitoring. The objective of this study was to characterize the relationship between the burden of atrial ectopy with future AF, stroke, and cardiovascular events on prolonged ECG monitoring. Methods: A retrospective, observational study was conducted at a single centre enrolling patients >18 years old referred from TIA clinic. Data was collected from 7- and 14-day Holter monitor reports, patient charts, and cardiac investigations. The final sample included 1124 patients; a subgroup of 759 patients had echocardiograms. Univariate and multivariate logistic regression determined the odds ratio (OR) of developing the composite outcome (AF, TIA/stroke, ACS, death) or secondary outcomes (AF or TIA/stroke). Results: The population was high-risk with a mean CHA 2 DS 2 -VASc of 4.0 (±1.8); during 1-year of follow-up, the primary outcome occurred amongst 116 (10.3%) patients. Univariate analysis ORs are displayed in Table 1. There was a statistically significant relationship (p<0.001) between percentage of PACs and the composite outcome (OR 4.066), and AF (11.886) for patients with 2-5% PACs. PAC runs/day was significant if >5/day for AF (OR 5.989, p<0.01) and for the composite (OR 2.231, p<0.05). Long PAC runs (>30 beats) also had significant ORs for AF (2.849, p<0.01) and the composite (5.320, p<0.01). In the subgroup analysis, reduced ejection fraction had an OR of 2.172 (1.407-5.771) for the composite outcome, and atrial dilatation had an OR of 2.778 (1.390-5.551) for AF. Conclusions: Increased burden of atrial ectopy is associated with increased odds of developing AF and a composite of cardiovascular events. Patients with increased ectopy should be considered for further, future ECG monitoring and risk stratification with echocardiogram.

scholarly journals Comparison of Cystatin C and Creatinine as Predictors of Cardiovascular Events in a Community-Based Elderly Population

2010 ◽  
Vol 56 (5) ◽  
pp. 799-804 ◽  
Author(s):  
John Beilby ◽  
Mark L Divitini ◽  
Matthew W Knuiman ◽  
Enrico Rossi ◽  
Joseph Hung
Keyword(s):  
Cardiovascular Disease ◽  
Coronary Heart Disease ◽  
Renal Function ◽  
Heart Disease ◽  
Creatinine Clearance ◽  
Cystatin C ◽  
Cardiovascular Events ◽  
Community Based ◽  
Hazard Ratios

Abstract Background: Reduced renal function is an established risk factor for cardiovascular events. We compared 3 measures of renal function—serum cystatin C, serum creatinine, and calculated creatinine clearance—as predictors of subsequent cardiovascular events in a community-based population of elderly individuals. Methods: Comprehensive cardiovascular risk factor data were available for 1410 surviving participants of previous Busselton health surveys who were ≥60 years old. Hazard ratios for risk of incident coronary heart disease and cardiovascular disease over 10 years of follow-up were derived for each baseline measure of renal function by use of Cox regression. Results: All measures of renal function were significantly related to risks of morbidity and mortality from coronary heart disease and cardiovascular disease. There were 453 incident cardiovascular disease events; and the age- and sex-adjusted hazard ratios (95% CIs) were 1.34 (1.23–1.46), 1.32 (1.20–1.45), and 1.22 (1.06–1.41) per 1-SD deterioration in cystatin C, creatinine, and creatinine clearance, respectively. All 3 measures gave approximately the same age-adjusted relative risk estimates. After further adjustment for established cardiovascular risk factors, the relative risk estimates were all reduced but remained statistically significant (P &lt; 0.05). Cystatin C was not a significant predictor for cardiovascular disease after adjustment for creatinine clearance. Conclusions: In relation to predicting risk for coronary heart disease or cardiovascular disease over a 10-year follow-up in a community-based population of elderly subjects, there was no evidence that cystatin C was a better risk predictor than creatinine or creatinine clearance.

scholarly journals Use of sodium glucose cotransporter 2 inhibitors and risk of major cardiovascular events and heart failure: Scandinavian register based cohort study

BMJ ◽  
2019 ◽  
pp. l4772 ◽  
Author(s):  
Björn Pasternak ◽  
Peter Ueda ◽  
Björn Eliasson ◽  
Ann-Marie Svensson ◽  
Stefan Franzén ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiovascular Events ◽  
Sglt2 Inhibitor ◽  
Cardiovascular Death ◽  
Sglt2 Inhibitors ◽  
Major Cardiovascular Events ◽  
Hazard Ratios ◽  
History Of

Abstract Objective To investigate the cardiovascular effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in routine clinical practice. Design Cohort study using data from nationwide registers and an active-comparator new-user design. Setting Denmark, Norway, and Sweden, from April 2013 to December 2016. Participants 20 983 new users of SGLT2 inhibitors and 20 983 new users of dipeptidyl peptidase 4 (DPP4) inhibitors, aged 35-84, matched by age, sex, history of major cardiovascular disease, and propensity score. Main outcome measures Primary outcomes were major cardiovascular events (composite of myocardial infarction, stroke, and cardiovascular death) and heart failure (hospital admission for heart failure or death due to heart failure). Secondary outcomes were the individual components of the cardiovascular composite and any cause death. In the primary analyses, patients were defined as exposed from treatment start throughout follow-up (analogous to intention to treat); additional analyses were conducted with an as-treated exposure definition. Cox regression was used to estimate hazard ratios. Results Mean age of the study cohort was 61 years, 60% were men, and 19% had a history of major cardiovascular disease. Of the total 27 416 person years of follow-up in the SGLT2 inhibitor group, 22 627 (83%) was among patients who initiated dapagliflozin, 4521 (16%) among those who initiated empagliflozin, and 268 (1%) among those who initiated canagliflozin. During follow-up, 467 SGLT2 inhibitor users (incidence rate 17.0 events per 1000 person years) and 662 DPP4 inhibitor users (18.0) had a major cardiovascular event, whereas 130 (4.7) and 265 (7.1) had a heart failure event, respectively. Hazard ratios were 0.94 (95% confidence interval 0.84 to 1.06) for major cardiovascular events and 0.66 (0.53 to 0.81) for heart failure. Hazard ratios were consistent among subgroups of patients with and without history of major cardiovascular disease and with and without history of heart failure. Hazard ratios for secondary outcomes, comparing SGLT2 inhibitors with DPP4 inhibitors, were 0.99 (0.85 to 1.17) for myocardial infarction, 0.94 (0.77 to 1.15) for stroke, 0.84 (0.65 to 1.08) for cardiovascular death, and 0.80 (0.69 to 0.92) for any cause death. In the as-treated analyses, hazard ratios were 0.84 (0.72 to 0.98) for major cardiovascular events, 0.55 (0.42 to 0.73) for heart failure, 0.93 (0.76 to 1.14) for myocardial infarction, 0.83 (0.64 to 1.07) for stroke, 0.67 (0.49 to 0.93) for cardiovascular death, and 0.75 (0.61 to 0.91) for any cause death. Conclusions In this large Scandinavian cohort, SGLT2 inhibitor use compared with DPP4 inhibitor use was associated with reduced risk of heart failure and any cause death, but not with major cardiovascular events in the primary intention-to-treat analysis. In the additional as-treated analyses, the magnitude of the association with heart failure and any cause death became larger, and a reduced risk of major cardiovascular events that was largely driven by the cardiovascular death component was observed. These data help inform patients, practitioners, and authorities regarding the cardiovascular effectiveness of SGLT2 inhibitors in routine clinical practice.

Abstract 123: Replicating the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial in Real-World Claims Data

2012 ◽  
Vol 5 (suppl_1) ◽  
Author(s):  
Bijan J Borah ◽  
Nilah D Shah ◽  
Victor M Montori
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Risk ◽  
Risk Reduction ◽  
Composite Outcome ◽  
Cardiovascular Risk Reduction ◽  
All Cause Mortality ◽  
Secondary Outcomes ◽  
Primary Composite Outcome

Background: The ACCORD-Lipid Trial’s finding that statin-fibrate combination therapy (CT) provides no incremental cardiovascular risk reduction in type 2 diabetese over statin monotherapy (MT) prompted FDA to issue a public communication on 11/9/2011 stating that fenofibrate may not reduce risk of heart attack or stroke. Yet, fibrate use continues unabated with over $1 billion in sales in the US that raises concern regarding the inconsistency in diffusion of scientific evidence into clinical practice. Critics of ACCORD findings maintain that ACCORD trial adopted flexible thresholds for qualifying HDL and triglyceride levels and that it left unanswered whether the effects of non-ACCORD statins or fibrates or combinations thereof will be different. By replicating the ACCORD-Lipid trial as closely as possible using 16-year longitudinal claims database from a large national health plan, our study seeks to compare the following ACCORD outcomes between CT and MT cohorts: (i) primary composite outcome of nonfatal MI, nonfatal stroke and cardiovascular death; (ii) secondary outcomes of all-cause mortality, expanded macrovascular outcome, major CAD events and CHF. Methods (Research Design, Data Source and Data Analysis Methods) : Retrospective claims analysis that included patients enrolled between 1995 and 2010 using ACCORD inclusion/exclusion criteria including type 2 diabetes patients aged 40 to 79 with baseline A1C≥7.5 and on statin. Patients in the two study cohorts, CT and MT, were required to have minimum of 1-year baseline and 90-day follow-up periods. Propensity score (PS) matching was used to adjust for patient baseline characteristics. T- and Chi-squared tests were used to assess differences in continuous and categorical covariates and Cox proportional hazard model was used to assess the hazard of study events. Results: The study included 6765 patients (CT=954; MT=5811) with a mean follow-up of 2.4 years. An average patient in the sample was a White male aged 57 years from the South. The two study cohorts differed in demographics (age, female, ethnicity, income categories), baseline lipids (HDL, LDL, triglyceride and HbA1c), and in numerous comorbid conditions. After 1-to-1 PS matching, baseline LDL, triglycerides and total cholesterol were similar but HDL (HbA1c) was higher (lower) in CT than in MT cohort (n=943 in each cohort). Most other baseline covariates were balanced. Unadjusted results showed that compared to MT, CT cohort had higher primary composite outcomes (62 vs 45), all-cause deaths (113 vs 105), macrovascular events (16 vs 9), major CAD (84 vs 59), nonfatal stroke (35 vs 33) and CHF (60 vs 51). Adjusted results show no difference in the rate of primary composite outcome (hazard rate or HR=1.44, p=0.09) and in secondary outcomes of macrovascular events (HR=1.61), all-cause mortality (HR=1.22), major CAD (HR=1.45), CHF (HR=1.24) and non-fatal stroke (HR=0.98) [all p>.05] Conclusion: The study results appear to confirm the non-significance of CT over MT in cardiovascular risk reduction among type 2 diabetes patients in a large US commercial health plan.

Abstract 2365: Pharmacogenomic Application Of The Haptoglobin Genotype To Identify Individuals With Diabetes Mellitus Who Benefit From Vitamin E Supplementation: A Prospective Randomized, Double-blind, Placebo Controlled Trial

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Uzi Milman ◽  
Shany Blum ◽  
Chen Shapira ◽  
Doron Aronson ◽  
Rachel Miller-Lotan ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Myocardial Infarction ◽  
Vitamin E ◽  
Cardiovascular Events ◽  
Cardiovascular Death ◽  
Composite Outcome ◽  
Anti Oxidant ◽  
Primary Composite Outcome ◽  
Fatal Myocardial Infarction ◽  
Vitamin E Supplementation

Background. Large clinical trials of antioxidant therapy with vitamin E have failed to demonstrate a decrease in cardiovascular events. However, these studies did not address possible benefit to subgroups with increased oxidative stress. Haptoglobin (Hp), a major anti-oxidant protein, is a determinant of cardiovascular events in patients with diabetes mellitus (DM). The Hp gene is polymorphic with two common alleles, 1 and 2. The Hp 2 allelic protein product provides inferior anti-oxidant protection as compared to the Hp 1 allelic product. In a retrospective analysis of HOPE participants with DM and the Hp 2–2 genotype, vitamin E significantly reduced the incidence of myocardial infarction and cardiovascular death. We sought to validate this observation in a prospective trial. Methods and Results. 984 DM individuals with the Hp 2–2 genotype were randomized and treated with either natural source vitamin E (400IU/day) or placebo. The primary composite outcome was non-fatal myocardial infarction, stroke and cardiovascular death. The study was intended to last 4 years with initial evaluation of endpoints scheduled 12 months after enrollment of the first patient. At the initial evaluation, the primary composite outcome was significantly reduced in patients receiving vitamin E compared to placebo (1.0% vs. 3.8%, p=0.004). This was predominately due to a significant decrease in the incidence of non-fatal myocardial infarction (0.2% vs. 2.1%, p=0.004) and led to early termination of the study. Conclusions . Vitamin E supplementation appears to reduce cardiovascular events in individuals with DM and the Hp 2–2 genotype. (ClinicalTrials.gov number NCT00220831 ).

scholarly journals P0846ESA HYPORESPOSIVENESS AND CLINICAL OUTCOMES DURING TREATMENT WITH EPOETIN BETA PEGOL IN HEMODIALYSIS PATIENTS: A MULTICENTER PROSPECTIVE STUDY; PARAMOUNT-HD STUDY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Takayuki Hamano ◽  
Hideki Fujii ◽  
Ken Tsuchiya ◽  
Kuragano Takahiro ◽  
Nobuhiko Joki ◽  
...  
Keyword(s):  
Prospective Study ◽  
Cardiovascular Events ◽  
Structural Models ◽  
Mixed Effects ◽  
Mixed Effects Model ◽  
Time Dependent ◽  
Marginal Structural Models ◽  
On Line ◽  
Landmark Analyses ◽  
Multicenter Prospective Study

Abstract Background and Aims Hemodialysis (HD) patients hyporesponsive to erythropoiesis stimulating agents (ESAs) were reported to have poor prognosis. However, little is known regarding the association between the hyporesponsiveness to CERA and the types of outcome in HD patients. Moreover, the effect of on-line HDF on hyporesponsiveness to CERA has not been evaluated so far. Method In this multicenter prospective study, we enrolled 4034 maintenance HD patients receiving any kinds of ESA. Prior ESA was changed to CERA in all patients. We studied the association between erythropoietin resistance index (ERI) at 6-month after the change to CERA (baseline ERI) and such outcomes as cardiovascular events and/or mortality using Cox proportional hazards models (landmark analyses). ERI was defined as monthly CERA dose divided by hemoglobin and dry weight. Just before the enrollment of the patients, iron-based phosphate binders became available and on-line hemodiafiltration (HDF) began to be reimbursed in Japan, therefore, we examined whether oral iron-containing drugs and on-line HDF had some effects on the serial trend of ERI by mixed effects model with time-dependent ERI as a dependent variable. When ERI is found to be improved by these changes in practice patterns, we further studied the effect of time-dependent ERI on such outcomes as cardiovascular events, mortality, death due to cancer, and death due to infection by using marginal structural models to eradicate time-dependent confounding by iron parameters, C-reactive protein, iron-containing drugs, and HDF. Missing values were imputed by multiple imputations. Results Mean age was 65.9 years and 43.1% of patients had diabetes. The median dialysis vintage and observation period was 5.0 years and 22.1 months, respectively. The percentage of patients receiving oral iron-containing drugs increased from 11.1% at baseline to 25.0% at 24-month. As a result, mean TSAT level increased from 24.5% to 27.4% at 24-month. The percentage of patients on on-line HDF also increased from 13.5% to 22.6%. ERI gradually decreased as time went by with great improvement especially in patients with highest quintile of ERI (Q5). Mixed effects model with time-dependent ERI as a dependent variable showed that introduction of iron-containing drugs and on-line HDF had improved ERI significantly. The landmark analyses including 3001 patients failed to show significant associations between baseline ERI quintile and cardiovascular events or mortality. We only found that highest quintile of baseline ERI (Q5) was associated with significantly higher composite events of mortality and cardiovascular events as compared to the lowest quintile (Q1) (Hazard ratio [HR], 1.56; 95% CI; 1.04-2.32). However, marginal structural models showed that time-dependent ERI Q5 was significantly associated with higher cardiovascular event rate as compared to Q1 (HR, 2.11; 95% CI; 1.31-3.38). Trend toward higher rate of mortality with the increase in time-dependent ERI quintile was also observed (HR of Q5, 3.07; 95% CI; 1.95-4.83). Similar but stronger relationships were observed for death due to infection (HR of Q5, 6.70; 95% CI; 1.89-23.77) and death due to cancer (HR of Q5, 15.08; 95% CI; 4.08-55.74). Conclusion The prevailing use of iron-containing drugs and on-line HDF has improved hyporesponsiveness to CERA in Japan. Therefore, baseline ERI at 6-month did not predict subsequent cardiovascular events or death. However, high time-dependent ERI was a predictor of cardiovascular events, death due to infection, and death due to cancer as well as all-cause mortality. Strong association of time-dependent ERI was observed especially with death due to cancer.

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