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INTRODUCTION AND AIM q Low-‐grade chronic inflamma1on is common in haemodialysis (HD) pa1ents. q Previous studies1-‐3 suggest an an1-‐inflammatory effect of angiotensin II receptor blocker
(ARB) treatment. q The aim of this study was to compare the effect of ARB (irbesartan) versus placebo on plasma
concentra1ons of inflammatory markers in HD pa1ents.
Chris0an D. Peters1,2,3, Krista D. Kjaergaard2,3, Claus H. Nielsen4, Jens D. Jensen2,3, Kent L. Christensen5, Bo M. Bibby6, Bente Jespersen2,3 1) Aalborg University Hospital, Aalborg, Denmark, 2) Ins1tute of Clinical Medicine, Aarhus University, Denmark 3) Dept. of Renal Medicine, Aarhus University Hospital, Denmark, 4) Ins1tute for Inflamma1on Research, Copenhagen University Hospital Rigshospitalet, Denmark, 5) Dept. of Cardiology, Aarhus University Hospital, 6) Dept. of Biosta1s1cs, Aarhus University
METHODS Design: Double-‐blind, randomised, placebo-‐controlled, interven1on trial with a 12-‐month follow-‐up period. Main inclusion criteria: Urine output > 300 mL/day, HD vintage < 1 year, and LV EF > 30 %. Interven0on: Irbesartan 1trated up to 300 mg per day. Blood pressure (BP) target: Predialy1c systolic BP of 140 mmHg in all pa1ents. An0hypertensive medica0on: Drugs blocking the renin-‐angiotensin-‐aldosterone-‐system were not allowed. All other classes of an1hypertensive drugs were accepted. Measurements: At baseline, 1 week, 3, 6, 9, and 12 months plasma high sensi1vity C-‐reac1ve protein (hsCRP), interleukin (IL) 1β, IL-‐6, IL-‐8, IL-‐18, and transforming growth factor β (TGF-‐β) were measured using Luminex immunoassay technology. Sampling: Venous blood samples were taken before HD in EDTA-‐coated tubes a_er 30 minutes of rest in the supine posi1on. Samples were centrifuged, and the separated plasma was stored at -‐80°C. Sta0s0cs: Data were analysed based on a mul1variate repeated measurements model (xtmixed) with 1me and drug (placebo or ARB) and the interac1on between them as factors which allows for missing values and dropout.
RESULTS q Predialy1c BP decreased to similar levels during the study (Placebo/
ARB systolic BP: -‐8/-‐10 mmHg; P=0.8). q Use of addi1onal an1hypertensive medica1on in the study period
besides placebo/ARB was similar in the two groups. q Adverse events were not significantly different in the two groups. q The groups were comparable at baseline with similar levels of
hsCRP, IL-‐1β, IL-‐6, IL-‐8, IL-‐18, and TGF-‐β. q hsCRP, IL-‐6, IL-‐8, and TGF-‐β:
There were no significant differences between the groups during the study period, and hsCRP, IL-‐6, IL-‐8, and TGF-‐β were rela1vely stable during the study period.
q IL-‐1β: The mean level was slightly different in the two groups over 1me, but not significantly and it was also rela1vely stable during the study period.
q IL-‐18: The mean level was not constant during the study period, but there was no significant difference between placebo and ARB treated.
Development over 0me (log-‐transformed data)
Placebo vs. ARB Test for parallel curves: P = 0.8 Test for equal levels: P = 0.3 Test for constant level: P = 0.2
Placebo vs. ARB Test for parallel curves: P = 0.09 Test for equal levels: P = 0.7 Test for constant level: P = 0.5
Placebo vs. ARB Test for parallel curves: P = 0.4 Test for equal levels: P = 0.6 Test for constant level: P = 0.3
Placebo vs. ARB Test for parallel curves: P = 0.7 Test for equal levels: P = 0.4 Test for constant level: P = 0.7
Placebo vs. ARB Test for parallel curves: P = 0.6 Test for equal levels: P = 0.5 Test for constant level: P = 0.001
Placebo vs. ARB Test for parallel curves: P = 0.5 Test for equal levels: P = 0.2 Test for constant level: P = 0.3
Addi1onal informa1on (SAFIR study): • ClinicalTrials.gov NCT00791830 • Peters et al. Danish Medical Journal 2013 Apr;60(4):A4602. • Peters et al. Kidney Int. 2014 Sep;86(3):625-‐37 • Kjaergaard et al. Am J Kidney Dis 2014 Dec; 64(6):892-‐901
CONCLUSION q No significant effect of irbesartan treatment was observed. q Our findings suggest that in HD pa1ents an1hypertensive treatment
with irbesartan (and most likely ARBs in general) does not have clinically relevant BP-‐independent effects that favourably impact on inflamma1on.
Change (∆) baseline vs. 12 months
Median values with range
Sta1s1cal analysis was performed a_er logarithmic transforma1on due to skewed data and p-‐values given are based on the log-‐transformed data. *) 0.05 > P ≥ 0.01 vs. baseline within the placebo or ARB group; **) 0.01 > P ≥ 0.001 vs. baseline within the placebo or ARB group
EFFECTS OF ANGIOTENSIN II BLOCKADE WITH IRBESARTAN ON INFLAMMATORY MARKERS IN HAEMODIALYSIS PATIENTS: A RANDOMISED DOUBLE BLIND PLACEBO CONTROLLED ONE-‐YEAR FOLLOW-‐UP TRIAL (SAFIR STUDY)
For further info please contact: Chris1an D. Peters, MD, PhD +45 22983880 or e-‐mail [email protected]
Es1mates and P-‐values were based on mul1variate repeated measurements model (xtmixed) Model 1 assuming different development over 1me in the two groups. A posi1ve value indicates an increase from baseline.
References: 1) Gamboa et al. J Am Soc Nephrol 2012; 23: 334-‐342. 2) Kayabasi et al. Eur Rev Med Pharmacol Sci 2013; 17: 235-‐242. 3) Merino et al. Nephrol Dial Transplant 2012; 27: 2907-‐2912.