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Intermediate Dose Low-Molecular-Weight Heparin for Thromboprophylaxis

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Intermediate Dose Low-Molecular-Weight Heparin for Thromboprophylaxis PROTOCOL Intermediate dose low-molecular-weight heparin for thromboprophylaxis. A systematic review with meta-analysis and trial sequential analysis Ruben J. Eck, Jørn Wetterslev, Wouter Bult, Iwan C.C. van der Horst, Frederik Keus Correspondence R.J. Eck, M.D. University of Groningen University Medical Center Groningen Department of Critical Care P.O. Box 30.001 9700 RB Groningen The Netherlands Phone: +31 6 42514894 Fax: +31-503619986 Email: [email protected] 23-03-2016 V 1.4 Ruben J. Eck, Wouter Bult, Iwan C.C. van der Horst, Frederik Keus Department of Critical Care, University of Groningen, University Medical Center Groningen, The Netherlands Wouter Bult Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands Jørn Wetterslev The Copenhagen Trial Unit (CTU), Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark. 1 INTRODUCTION Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a frequent cause of increased morbidity and mortality among hospitalized patients (1). VTE may either be clinically obvious and diagnosed, or may remain undetected (2). Commonly recognized risk factors for VTE are active cancer, previous VTE, reduced mobility, known thrombophilic condition, recent trauma and/or surgery, elderly age (>70), heart and/or respiratory failure, acute myocardial infarction or stroke, acute infection, obesity and ongoing hormonal treatment (3). Several pharmacological agents for thromboprophylaxis are available, of which unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are most commonly used. Two recent reviews with meta-analysis suggested benefit of LMWH over UFH in acutely ill medical patients and critically ill ICU patients based on decreased risk of DVT (4). No such beneficial effect was shown in a Cochrane review on LMWH versus UFH in oncologic surgery patients (5). Many systematic reviews with meta-analyses have been conducted on LMWH thromboprophylaxis in specific patient groups such as cardiac and thoracic surgery patients (6), non-surgical medically ill patients (4,7-9), patients with cancer (10-13), patients having non-major orthopaedic surgery (14), pregnant and postnatal woman at risk of VTE (15) and bariatric surgery patients (16,17). None of these reviews evaluated the efficacy of LMWH in all patient categories. Only few reviews compared different doses of LMWH in selected populations (orthopaedic and bariatric surgery) (16,17). The American College of Chest Physicians (ACCP) guidelines provide no recommendations regarding the dose of LMWH in patients at high risk of VTE (18-20). No systematic review has been conducted specifically 2 addressing the research question of intermediate dose LMWH versus placebo for thromboprophylaxis including all patient populations. Objective The objective is to perform a systematic review with meta-analyses and trial sequential analyses (TSA) of randomized clinical trials (RCT´s) according to the Cochrane Handbook for Systematic Reviews of Interventions comparing the benefits and harms of intermediate dose LMWH versus placebo or no treatment in patients at risk of VTE (21). Available evidence will be evaluated in the perspective of the three dimensions of possible risks of errors: the systematic error (bias), the random error (`the play of chance´), and the design error (the outcome measure chosen) (22). 3 METHODS This protocol will be online available at PROSPERO. Criteria for considering trials for this review We will consider all randomized clinical trials for inclusion irrespective of language, blinding, publication status, or sample size. Quasi-randomized trials and observational studies will be excluded. Patients Only randomized trials with adult patients at risk for VTE allocated to receive either intermediate dose LMWH, a placebo, or no treatment will be eligible for inclusion, regardless their underlying disease and whether they were admitted to the hospital or visited the outpatients clinic. Alternative intervention The alternative intervention is intermediate dose LMWH. All trials will be considered that evaluate LMWH in an intermediate dose, independent of the type of LMWH or duration of treatment. Trials investigating ultra-low-molecular-weight heparin will also be included in this review. As the process of depolymerization of native heparin is different for each product, the U.S. Food and Drug Administration (FDA) and World Health Organization (WHO) have classified each LMWH as a separate drug (23). Different types of LMWH can therefore not be used interchangeably and each type may be registered for different clinical applications in different doses. In Europe, several LMWH preparations (e.g., enoxaparin, tinzaparin, dalteparin, nadroparin, reviparin, etc) are licensed for the prevention and treatment of VTE. In the United States three different preparations (e.g., enoxaparin, tinzaparin and dalteparin) are 4 currently approved for a range of clinical applications. Table 1 summarizes the recommended low and intermediate prophylactic and therapeutic LMWH doses according to the ‘Summary of Product Characteristics’ (SPC) as approved by different medicine evaluation boards across a variety of nations (24-29). Randomized clinical trials may occasionally use custom doses of LMWH that are not covered by Table 1. We have therefore classified LMWH doses to be either in the low prophylactic range or in the intermediate prophylactic range (Table 2). This classification between low and intermediate dose ranges is based on the recommended SPC doses as summarized in Table 1. This systematic review seeks to answer the question whether intermediate dose LMWH is preferred over placebo or no treatment for the prevention of VTE, therefore, we will only include randomized trials in which LMWH was used in the intermediate dose range as indicated according to Table 2. There will be no restrictions on durations of interventions. In case different types or doses (or weight adjusted doses) were used in one trial or even in one patient, we will classify the trial according to what was used most of the time. Randomized trials will be included based on the intention for LMWH use, i.e., prophylactic or therapeutic use. We will classify other unforeseen types of (infrequently used) LMWH not listed in table 1 and 2 following the dosage regimens applied in the identified trials. Control intervention The control intervention will be placebo or no treatment. There will be no restrictions on durations of interventions. 5 Table 1. Dose recommendation of commonly used LMWHs according to Summary of Product Characteristics in national registries Product Prophylactic Therapeutic dose Low dose Intermediate dose Nadroparin 2850 IU (=0,3 ml) 5700 IU (=0,6 ml)* 171 IU /kg once daily (Fraxiparine®) or 86 IU /kg twice daily Dalteparin (Fragmin®) 2500 IU (=0,2 ml) 5000 IU (=0,2 ml) 200 IU /kg once daily or 100 IU /kg twice daily Enoxaparin (Clexane®) 20 or 30 mg (=0,2 – 40 mg (=0,4 ml) 1,5 mg /kg once daily 0,3 ml) once, or 30 mg or 1 mg /kg twice (=0,3 ml) twice daily daily Tinzaparin (Innohep®) 3500 IU (=0,35 ml) 4500 IU (=0,45 ml) 175 IU /kg once daily Parnaparin (Fluxum®) 3200 IU (= 0,3 ml) 4250 IU (= 0,4 ml) 6400 IU twice daily Bemiparin (Zibor®) 2500 IU (=0,2 ml) 3500 IU (=0,2 ml) 115 IU /kg once daily Reviparin (Clivarin®) 1432 IU (=0,25 ml) 3436 IU (=0,6 ml) 143 IU /kg over two gifts IU: International Units; ml: milliliters; kg: kilograms; mg: milligrams. All doses are administered once daily unless specified otherwise. *Not in SPC; based on Dutch thromboprophylaxis guidelines (30). 6 Table 2. Classification of low and intermediate dose prophylactic ranges, based on Table 1 Product Prophylactic Low dose range Intermediate dose range Nadroparin < 5700 IU ≥ 5700 IU (Fraxiparine®) Dalteparin (Fragmin®) < 5000 IU ≥ 5000 IU Enoxaparin (Clexane®) < 40 mg ≥ 40 mg Tinzaparin (Innohep®) < 4500 IU ≥ 4500 IU Parnaparin (Fluxum®) < 4250 IU ≥ 4250 IU Bemiparin (Zibor®) < 3500 IU ≥ 3500 IU Reviparin (Clivarin®) < 3436 IU ≥ 3436 IU IU: International Units; mg: milligrams. Outcomes Primary outcomes The primary outcome will be all-cause mortality at maximal follow-up. Secondary outcomes Our secondary outcomes will be the number of patients with at least one serious adverse event (SAE), symptomatic VTE, major bleeding, VTE diagnosed through screening of all patients in the trial (including both symptomatic and asymptomatic events), and heparin-induced thrombocytopenia (HIT). SAE will be defined as the composite outcome measure summarizing all serious events necessitating an intervention, operation, or prolonged hospital stay according to the International Conference on Harmonisation of Good Clinical Practice (ICH-GCP) definitions (31). Mortality will be excluded in our definition of SAE to avoid double counts. VTE, symptomatic or asymptomatic, includes DVT and PE. A diagnosis of DVT will be accepted 7 when objectified by either ultrasound, a fibrinogen uptake test, venography, or plethysmography. A diagnosis of PE will be accepted when objectified by a ventilation- perfusion scan, computed tomography, pulmonary angiography or autopsy. Major bleeding will be defined according to the criteria used in the individual trials. In case the author’s definitions are unclear, we will attempt to define major bleeding according to the definitions of the Scientific and Standardization Committee of the International Society
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