Tinzaparin for Treatment of Venous Thromboembolism in Renal Insufficiency: A Pilot Study

Background and rationale. Venous thromboembolism (VTE) is an important clinical problem because it is common, preventable, contributes to morbidity and mortality, and is costly. Low molecular weight heparin (LMWH) is the preferred anticoagulant for VTE treatment, but is renally excreted. Consequently, LMWH use in patients with renal insufficiency may result in accumulation of the anticoagulant effects and the potential for avoidable bleeding complications. As a result, most patients with renal insufficiency who also have VTE are unable to benefit from LMWH treatment. These patients are therefore generally treated in hospital using unfractionated heparin (UFH), since it is eliminated by extra-renal mechanisms. In addition to those patients with known renal insufficiency, many elderly patients have previously unrecognized renal insufficiency and treatment of these patients with LMWH can be associated with accumulation of the anticoagulant effect and avoidable bleeding. Tinzaparin, relative to other LMWHs, has a higher molecular weight and greater negative charge: both biochemical features that favour non-renal clearance. There is limited evidence to support the hypothesis that tinzaparin, unlike other LMWHs, does not accumulate in patients with renal insufficiency. 1) Observational studies demonstrated no increase in anti-Xa levels (i.e., no accumulation) when tinzaparin was used for VTE treatment in elderly patients with renal insufficiency. 2) One study showed undetectable LMWH anticoagulant activity by 24 hours after dosing in hemodialysis patients. 3) A systematic review and meta-analysis of the literature in this area performed by our research group found no difference in bleeding and thrombosis complication rates when LMWH (compared to UFH) was used to maintain dialysis circuit patency in patients on hemodialysis. The current factors which limit the use of tinzaparin in the treatment of patients with VTE and renal insufficiency are: 1) the true risk of accumulation is unknown in a spectrum of patients with varying renal function, and 2) the bleeding risk associated with tinzaparin use is unknown. Hypothesis. We hypothesize that accumulation during a 5-day course of tinzaparin will not be related to the degree of renal insufficiency. Study design and methods. We will perform a prospective cohort study of 200 patients with acute VTE, stratified into 4 equal-sized groups by renal function, who will receive initial anticoagulation with tinzaparin for 5 days concurrent with oral anticoagulants. The LMWH anticoagulant effect will be assessed at days 3 and 5 (+/- 1) using trough anti-Xa heparin levels. If accumulation occurs, defined as a trough anti-Xa level > 0.5 IU/mL, the tinzaparin dose will be adjusted according to a nomogram. Patients with an anti-Xa level ≤ 0.5 IU/mL will have no dose adjustment; patients with levels > 0.5 IU/mL will have their tinzaparin dose reduced. The primary outcome of this study is the proportion of patients in each renal function group with accumulation on or before day 5. We will follow the patients for 48 hours after their final tinzaparin injection. Secondary outcomes are bleeding, recurrent thrombosis, accumulation by day 3, and trough anti-Xa levels > 1.0 IU/mL at any point in the study. Significance. We hypothesize that tinzaparin does not accumulate in patients with renal insufficiency. However, if accumulation occurs, we hypothesize that dose adjustment according to our novel nomogram will prevent potentially-dangerous levels occurring by day 5. In either case, we will be able to proceed to the next stage in our research plan: an application for funding for a large simple randomized controlled trial examining the safety and efficacy of tinzaparin compared with UFH in patients with renal insufficiency. If accumulation occurs despite the use of the nomogram, then this surrogate outcome suggests that the use of therapeutic-dose tinzaparin is unlikely to be safe in patients with renal insufficiency, a finding which will limit the need to expend further resources on this line of research.