WARFARIN USE, MORTALITY, BLEEDING AND STROKE IN ...



WARFARIN USE, MORTALITY, BLEEDING AND STROKE IN HEMODIALYSIS PATIENTS WITH ATRIAL FIBRILLATION.

*Simonetta Genovesi (a,c) MD, Emanuela Rossi (b) PhD, Maurizio Gallieni (d) MD, Andrea Stella (a,c) MD, Fabio Badiali (e) MD, Ferruccio Conte (f) MD, Sonia Pasquali (g) MD, Silvio Bertoli (h) MD, Patrizia Ondei (i) MD, Giuseppe Bonforte (l) MD, Claudio Pozzi (m) MD, Maria Grazia Valsecchi (b) PhD, Antonio Santoro (n) MD

Short title: Warfarin, hemodialysis and atrial fibrillation

Author Affiliations

a) Department of Health Science, University of Milano-Bicocca, Monza, Italy

b) Center of Biostatistics for Clinical Epidemiology, Department of Health Science, University of Milano-Bicocca, Monza, Italy

c) Nephrology Unit, San Gerardo Hospital, Monza, Italy

d) Nephrology Unit, San Carlo Borromeo Hospital, Milano, Italy

e) Nephrology Unit, Infermi Hospital, Rimini, Italy

f) Nephrology Unit, S. Uboldo Hospital, Cernusco sul Naviglio, Italy

g) Nephrology Unit, S. Maria Nuova Hospital, Reggio Emilia, Italy

h) Nephrology Unit, IRCCS Multimedica, Sesto S. Giovanni, Italy

i) Nephrology Unit, Ospedali Riuniti, Bergamo, Italy

l) Nephrology Unit, S. Anna Hospital, Como, Italy

m) Nephrology Unit, Bassini Cinisello, Hospital, Milano, Italy

n) Nephrology Unit, S. Orsola-Malpighi Hospital, Bologna, Italy

*Corresponding author:

Dipartimento di Scienze della Salute, Università di Milano-Bicocca

Via Cadore 48, 20900, Monza (MB), Italy

tel: +39 039 2332426

Fax: +390392332376

Email: simonetta.genovesi@unimib.it

Abstract:

Background: Atrial fibrillation (AF) increases the risk of thrombo-embolic stroke and oral anticoagulation therapy (OAT) is the choice treatment for thrombo-embolism prevention, although data on OAT use in HD patients with AF are contradictory.

Study design: In a population of HD patients with AF, the effect of OAT on the risk of mortality, stroke and bleeding was prospectively evaluated.

Setting and Participants: All the patients of 10 HD centers alive at 31/10/2010 with documented AF episode/s were recruited and followed-up for two years.

Predictors and outcomes: OAT and antiplatelet taking, age, dialytic age, comorbidities, percentage time in the target INR range (TTR) and INR variability (VGR) were considered as predictors of hazard of death, thrombo-embolic and bleeding events.

Results: At recruitment, 134 patients over 290 were taking OAT. During the 2 years of follow-up 115 patients died. Antiplatelet therapy, but not OAT, was significantly associated to an increased risk of death (HR 1.71, P=0.02). The estimated survival of patients always taking OAT tended to be higher than that of patients who had stopped taking (68.6% vs 49.6%, P=0.07). OAT was not correlated to a decreased risk of , thrombo-embolic events, while it was associated to an increased risk of bleeding (HR 8.88, P75 years, dialytic age>3 year, male gender, permanent AF, hypertension and bleedings/hemorrhagic stroke. Other regressors included in the models and selected by a backward selection (criteria for exclusion: P>0.1) were diabetes mellitus, ischemic heart disease, heart failure and ischemic stroke. Permanent AF, ischemic heart disease, heart failure, bleedings/hemorrhagic stroke and ischemic stroke were considered as time-dependent factors.

To explore differences in the outcome of subjects that interrupted OAT, Kaplan-Meier 2-year survival curves were estimated grouping patients in 4 categories: OAT at recruitment and during the follow-up; OAT at recruitment, but interrupted during follow-up; no OAT at recruitment, but assumed during follow-up; neither OAT at recruitment nor during the follow-up. Comparisons between couples of groups were done using log-rank test.

TTR and VGR distributions were described by means of median, interquartile range and box-plot and whiskers. Given the not normal distribution of VGR, in the following analyses a logarithmic transformation was adopted.

Cox regression models were applied to estimate the effect of OAT on new thrombo-embolic and bleeding events during follow-up. In both models, OAT was considered as a time-dependent factor. Due to the low number of thrombo-embolic events during follow-up, the regressors included in the thrombo-embolic events model were only age>75 years, dialytic age>3 year, male gender, TTR and log(VGR), while the bleedings model was adjusted for the same factors included in the mortality model plus TTR and log(VGR); permanent AF, ischemic heart disease , heart failure and ischemic stroke were considered as time-dependent factors. A sub analysis on hemorrhagic events was done separately on patients who had already experienced bleedings before recruitment and those who had not. Results of the Cox models are expressed in terms of estimated hazard ratios (HR), 95% confidence intervals (CI95%) and p-values.

Analyses were carried out by means of the statistical software SAS v.9.2 (SAS Institute Inc, Cary, NC), while figures were made by the freeware R statistical software v.2.12.2 ().

RESULTS

At recruitment, 134 patients out of 290 were taking warfarin. Patients characteristics are described in Table 1. Patients with permanent AF were more likely taking OAT at recruitment (P ................
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