Tinzaparin Versus Dalteparin for Peri-Procedure Thromboembolic Prophylaxis in Patients with Dialysis Dependent Renal Disease.
Authors: Rodger Marc , Ramsay Tim , Mackinnon Martin , Westphal Margit , Spero Melissa , Levac-Mbanga Angele , Knoll Greg 
Published: October 2019

Abstract
Abstract 3136
Poster Board III-73

Background
Low-molecular-weight heparins (LMWHs) can be administered in fixed subcutaneous doses permitting predictable parenteral anticoagulation in an out-of-hospital setting. The renal clearance of LMWHs leads to uncertainty about the safety of use of LMWHs in patients on hemodialysis given the potential for bioaccumulation of anticoagulant effect which may lead to bleeding.

Methods
We conducted a randomized open label trial to investigate the feasibility and safety of a perioperative anticoagulation protocol in hemodialysis patients comparing two LMWHs preparations as outpatient bridging therapy when warfarin is interrupted for invasive procedures. The primary objective of the study was to compare if tinzaparin and dalteparin differentially bioaccumulate in hemodialysis (HD) patients after three therapeutic doses. Warfarin therapy was discontinued in these patients 5 to 6 days prior to surgery. Patients were randomized to either 3 doses of tinzaparin (175 IU/kg/day) or dalteparin (200 IU/kg/day) with two dialyses in the interval between the first dose of study drug and inavsive procedure. Primary outcome was pre-dialysis anti-Xa levels 20-24hrs post third therapeutic LMWH dose to determine if these LMWHs accumulated in HD patients, and if they differentially accumulated. After procedure, patients received a daily prophylactic dose of tinzaparin (4500 IU) and dalteparin (5000 IU) for 3 to 4 days along with dialysis. Post- procedure pre- and post- dialysis anti-Xa levels were also monitored.

Results
Of 29 eligible and consenting patients, 17 patients (58.6%) received tinzaparin sodium and 12 patients (41.4%) received dalteparin sodium. Two patients were withdrawn prior to invasive procedure and the invasive procedures were canceled (1 for important bio-accumulation in the dalteparin arm; 1 for major bleed in the tinzaparin arm). Primary outcome anti-Xa samples were not analyzable in 2 patients (1 contaminated with heparin; 1 drawn too early). There was important and significant bioaccumulation in both study drug arms. The mean primary outcome pre-dialysis anti-Xa level 20-24hrs post third tinzaparin dose was 0.40 IU/ml (SD= 0.21). The mean primary outcome pre-dialysis anti-Xa level 20-24hrs post third dalteparin dose was 0.57 IU/ml (SD= 0.43). There was no statistically significant difference between the two study drug groups (student's t-test (p value = 0.33). Postoperatively 16/21 (76%) of patients tested had undetectable pre-dialysis anti-Xa levels 20-24hrs post prophylactic dose, with the remaining 5 patients having a mean anti-Xa level of 0.23 IU/ml (SD = 0.25). During subsequent follow-up, 2 patients experienced serious adverse events (one non-STEMI in patient who died of sepsis (tinzaparin group) and one upper extremity DVT (dalteparin group)).

Conclusions
Tinzaparin and Dalteparin significantly accumulate at therapeutic doses in HD patients with no statistically significant difference detected in accumulation between the drugs. Neither drug importantly accumulates at prophylactic doses in HD patients. “Bridging therapy” with LMWHs at therapeutic doses in patients on hemodialysis who require temporary interruption of warfarin for invasive procedures is risky and of uncertain risk benefit.

Disclosures
Rodger: Bayer: Research Funding; Leo Pharma: Research Funding; Pfizer: Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Biomerieux: Research Funding; GTC Therapeutics: Research Funding.