Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism

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Abstract

Venous thromboembolism (VTE) is a serious and often fatal medical condition with an increasing incidence. Despite the changing landscape of VTE treatment with the introduction of the new direct oral anticoagulants many uncertainties remain regarding the optimal use of traditional parenteral agents. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance based on existing guidelines and consensus expert opinion where guidelines are lacking. This specific chapter addresses the practical management of heparins including low molecular weight heparins and fondaparinux. For each anticoagulant a list of the most common practice related questions were created. Each question was addressed using a brief focused literature review followed by a multidisciplinary consensus guidance recommendation. Issues addressed included initial anticoagulant dosing recommendations, recommended baseline laboratory monitoring, managing dose adjustments, evidence to support a relationship between laboratory tests and meaningful clinical outcomes, special patient populations including extremes of weight and renal impairment, duration of necessary parenteral therapy during the transition to oral therapy, candidates for outpatient treatment where appropriate and management of over-anticoagulation and adverse effects including bleeding and heparin induced thrombocytopenia. This article concludes with a concise table of clinical management questions and guidance recommendations to provide a quick reference for the practical management of heparin, low molecular weight heparin and fondaparinux.

Keywords: Venous thromboembolism, Anticoagulation, Heparin, Low molecular weight heparin, Enoxaparin, Dalteparin, Fondaparinux, Direct oral anticoagulants (DOAC), New oral anticoagulants (NOAC)

Introduction

Heparin has been a component of the initial treatment of venous thromboembolism (VTE) for decades. Despite its long history, various aspects of the practical use of unfractionated heparin (UFH), whether delivered intravenously (IV) or subcutaneously (SC), continue to challenge clinicians. In 1998, the US FDA approved the low molecular weight heparin (LWMH) enoxaparin (Lovenox) for VTE treatment, followed by approval of the synthetic heparin-like compound fondaparinux (Arixtra) in 2004. In 2007, the LMWH dalteparin (Fragmin) was approved for VTE treatment in patients with cancer. These agents, intended for subcutaneous administration, offer practical advantages over unfractionated heparin, yet present their own challenges, particularly in special populations. This chapter will address the practical use and management of the parenteral heparin anticoagulants available in the US when used in the treatment of VTE.

Methods

To provide guidance on the practical management of the heparin anticoagulants in adults, we first developed a number of pivotal practical questions pertaining to each of the commonly used heparin compounds (UFH, LMWH and fondaparinux) to be reviewed in this document (Table 1 ). Questions were developed by consensus from the authors. The literature addressing the above questions was reviewed by searching electronic databases (PubMed, Medline) and the authors’ personal libraries, with a focus on high quality cohort studies and randomized controlled trials published in the last 10 years, where available. For each question, a brief summary and interpretation of pertinent literature and existing guidelines, where available, are provided, followed by guidance to the reader.

Table 1

Guidance questions to be considered

Guidance

Heparin for the treatment of acute VTE

While heparin therapy for VTE treatment is typically administered by continuous IV infusion, both adjusted dose and fixed dose SC injections can also be utilized. A comparative study of SC and IV heparin using the same initial dose (5000 unit IV bolus followed by 30,000 units/day) reported an increased risk of VTE recurrence with SC heparin (19.3 % vs. 5.2 %; p = 0.024), suggesting the need for higher doses with this route [1]. A meta-analysis comparing IV heparin to dose-adjusted SC heparin (initial dose 5000 units IV then 17,500 units SC twice daily) for initial DVT treatment found a lower risk of VTE recurrence or extension with SC heparin (relative risk [RR] 0.62, 95 % confidence interval [CI] 0.39–0.98) with a similar risk of major bleeding (RR 0.79, 95 % CI 0.42–1.48) [2]. Prandoni et al. conducted an open label multicenter trial in 720 patients comparing LMWH to adjusted dose SC heparin in those with acute, symptomatic VTE. SC heparin regimens were weight based with those over 70 kg receiving an initial 6000 unit IV bolus then 17,500 units twice daily. Objectively confirmed recurrent VTE, major bleeding and overall mortality were similar [3]. In the fixed dose heparin investigators (FIDO) trial, a randomized, open label, non-inferiority trial, fixed dose heparin (333 units/kg bolus then 250 units/kg every 12 h) was compared to LWMH for initial treatment of acute VTE [4]. There was no weight exclusion for the trial. Recurrent VTE at 3 months occurred in 3.8 % of heparin patients compared to 3.4 % of LMWH patients (absolute difference 0.4 %; 95 % CI −2.6 to 3.3 %) while major bleeding occurred in 1.1 % of heparin patients versus 1.4 % of LMWH patients (absolute difference, −0.3 %; 95 % confidence interval, −2.3 to 1.7 %).

The optimal initial dosing of continuous infusion heparin therapy is controversial. In 1989, the second American College of Chest Physicians (ACCP) Clinical Practice Guideline on VTE treatment recommended an initial 5000 unit bolus followed by a 1000 unit/h infusion [5]. In 1993, Raschke et al. compared weight based heparin dosing (80 units/kg followed by 18 units/kg/h) to a standard regimen (5000 units followed by 1000 units/h) in 115 patients with venous or arterial thrombosis [6]. A five-fold reduction in recurrent VTE was observed with weight-based dosing (95 % CI 1.1–21.9). Nevertheless, most VTE treatment trials incorporated a fixed dose initial heparin infusion regimen of 5000 unit bolus followed by infusion of approximately 1300 units/h [7]. In 1992, the ACCP VTE treatment guidelines suggested a 5000–10,000 unit bolus followed by a fixed heparin infusion of 1300 units/h (31,200 units/day) and in 1995 and 2004 they endorsed either a fixed regimen or the Raschke weight based regimen [8–10]. For a 70 kg patient, the Raschke regimen translates into a heparin bolus of 5600 units followed by infusion of 1260 units/h. The 2012 version of the guidelines do not address UFH dosing in the VTE treatment chapter [11]. However, in the chapter on parenteral anticoagulants, UFH dosing recommendations are similar to those in 1995 and include either a weight based regimen (Raschke regimen) or a fixed regimen of 5000 unit bolus followed by a continuous infusion of at least 32,000 units/day [12].

The Joint Commission’s National Patient Safety Goals require that a written policy stating required baseline and ongoing laboratory tests for patients on heparin be in place in healthcare institutions [13]. Pre-treatment hemoglobin and hematocrit are used as a baseline from which to assess subsequent changes that may reflect bleeding. A baseline platelet count is used to compare to subsequent values in order to detect the possible development of heparin-induced thrombocytopenia (HIT). Finally, an elevated pre-treatment prothrombin time (PT) or activated partial thromboplastin time (aPTT) may detect the presence of an underlying coagulation defect.

Guidance Statement

We suggest that total body weight, CBC, PT and aPTT be obtained prior to initiating heparin therapy. Heparin efficacy is related to dose regardless of route. The initial dose is more important than the aPTT in predicting efficacy. Although optimal initial dosing for bolus and continuous infusion remain uncertain, we suggest doses outlined in Table 2 , acknowledging that these options have not been compared in head-to-head clinical trials. Internal audits to determine the dose requirement to produce therapeutic anticoagulation based upon the responsiveness of the health-system’s aPTT reagent and coagulation instrument are strongly encouraged.

Table 2

Recommended initial dosing for UFH in VTE treatment