REVIEW ARTICLES The Russian Archives of Internal Medicine • № 5 • 2019 DOI: 10.20514/2226-6704-2019-9-5-348-366 UDC: 616.24-005.7+615.273.53 G. A. Ignatenko1, G. G. Taradin*1,2, N. T. Vatutin1,2, I. V. Kanisheva1 1 State Educational Organization of Higher Professional Education M. Gorky Donetsk National Medical University, Donetsk, Ukraine 2 State Institution V. K. Gusak Institute of Urgent and Recovery Surgery, Donetsk, 283045, Ukraine CURRENT VIEW ON ANTICOAGULANT AND THROMBOLYTIC TREATMENT OF ACUTE PULMONARY EMBOLISM Abstract The presented review concerns contemporary views on specific aspects of anticoagulant and thrombolytic treatment of venous thromboembolism and mostly of acute pulmonary embolism. Modern classifications of patients with acute pulmonary embolism, based on early mortality risk and severity of thromboembolic event, are represented. The importance of multidisciplinary approach to the management of patients with pulmonary embolism with the assistance of cardiologist, intensive care specialist, pulmonologist, thoracic and cardiovascular surgeon, aimed at the management of pulmonary embolism at all stages: from clinical suspicion to the selection and performing of any medical intervention, is emphasized. Anticoagulant treatment with the demonstration of results of major trials, devoted to efficacy and safety evaluation of anticoagulants, is highlighted in details. Moreover, characteristics, basic dosage and dosage scheme of direct (new) oral anticoagulants, including apixaban, rivaroxaban, dabigatran, edoxaban and betrixaban are described in the article. In particular, the management of patients with bleeding complications of anticoagulant treatment and its application in cancer patients, who often have venous thromboembolism, is described. Additionally, modern approaches to systemic thrombolysis with intravenous streptokinase, urokinase and tissue plasminogen activators are presented in this review. The indications, contraindications, results of clinical trials devoted to various regimens of thrombolytic therapy, including treatment of pulmonary embolism with lower doses of fibrinolytic agents, are described. Key words: pulmonary embolism, venous thromboembolism, thromboembolism of pulmonary artery, treatment, risk stratification, anticoagulant therapy, direct oral anticoagulants, systemic thrombolysis, fibrinolysis, bleeding complications Conflict of interests The authors declare no conflict of interests. Source of financing The authors state that no funding for the study has been provided. Article received on 22.04.2019 Accepted for publication on 03.07.2019 For citation: Ignatenko G. A., Taradin G. G., Vatutin N. T. et al. CURRENT VIEW ON ANTICOAGULANT AND THROMBO- LYTIC TREATMENT OF ACUTE PULMONARY EMBOLISM. The Russian Archives of Internal Medicine. 2019; 9(5): 348-366. [In Russian]. DOI: 10.20514/2226-6704-2019-9-5-348-366 ESC — European Society of Cardiology, FDA — Food and Drugs Administration, MOPPET — moderate pulmonary embolism treated with thrombolysis, PEITHO — pulmonary embolism thrombolysis study, PERT — Pulmonary Embolism Response Team, PESI — Pulmonary Embolism Severity Index, tPA — tissue plasminogen activator, VKA — vitamin K antagonists, ACD — anticoagulant drug, ACT — anticoagulant therapy, APTT — activated partial thromboplastin * Contacts: Gennady G. Taradin, e-mail: [email protected] 348 Архивъ внутренней медицины • № 5 • 2019 ОБЗОРНЫЕ СТАТЬИ time, VTE — venous thromboembolism, CI — confidence interval, PE — pulmonary embolism, INR — international normalized ratio, LMWH — low molecular weight heparin, UFH — unfractionated heparin, HR — hazard ratio, DOAC — direct oral anticoagulants, PTT — prothrombin time, PTS — post-thrombotic syndrome, RCT — randomized clinical trial, STL — systemic thrombolysis, DVT — deep vein thrombosis, CTEPH — chronic thromboembolic pulmonary hypertension Introduction the basic therapy of VTE, including anticoagulant therapy (ACT) and systemic thrombolysis (STL), as Venous thromboembolism (VTE), including deep a rule, is available in almost all specialized hospitals. vein thrombosis (DVT) and pulmonary embo- The purpose of this review was to discuss modern lism (PE), is a common and potentially fatal dis- approaches to the treatment of patients with acute ease [1, 2]. The incidence of the first acute event PE with ACT and STL. of VTE is 0.7–1.4 per 1 thousand people/years, and is most common in people aged over 55 years Clinical classification of [2, 3]. In persons, aged 70 years and older, VTE rate pulmonary embolism severity reaches 7 cases per 1 thousand people [4]. At the same time, though DVT rate remains constant over Assessment of the massiveness of PE or calcula- time, the hospitalization for PE in the United States tion of the mortality risk in this event is a crucial increased more than twofold in recent decades, step in determining the principles and sequence of mainly due to the widespread introduction of sen- treatment strategy stages. The clinical classification sitive imaging that can determine small emboli [5]. of PE severity is based on the calculated risk of early (up to 30 days) mortality due to thromboembolic With the obvious success of modern diagnostic event [1]. This distribution (or stratification), which methods, the management of patients with PE is important both diagnostically and therapeu- presents significant challenges. This is due to the tically, is based on an assessment of the patient’s diverse clinical presentation and different hemo- clinical status at the time of presentation. High- dynamic response to the embolization of pul- risk PE is assumed or confirmed in the presence monary vasculature, which in turn is associated of shock or persistent hypotension, and non-high- with the massiveness of the emboli, the state and risk PE (intermediate or low) — in their absence compensatory capabilities of the heart, the pres- (Table 1) [1]. ence and severity of concomitant diseases. Thera- peutic measures include the use of anticoagu- Classification of PE severity based on massiveness lant drugs (ACD), thrombolytics, interventional (scope) of the thromboembolism case was previ- approaches described earlier [6], surgical embo- ously widely used. However, even in the recom- lectomy and maintenance therapy. In addition, mendations of the European Society of Cardiology if the use of endovascular therapeutic methods, (ESC) 2008 it was noted that PE severity should unfortunately, is limited to large medical centers, be understood more as an individual assessment Table 1. Classification of patients with acute pulmonary embolism based on early mortality risk Risk parameters and scores PESI Sign of RV Early mortality risk Shock or Cardiac laboratory class III–V dysfunction on hypotension biomarkers or sPESI > I an imaging test High +(+)+(+) High – + Both positive Intermediate- Low – + Either one (or none) positive Assessment optional; Low – – if assessed, both negative Note: PESI — Pulmonary Embolism Severity Index; RV — right ventricular; sPESI — simplified Pulmonary Embolism Severity Index; sPESI ≥1 point(s) indicates high 30-day mortality risk. Adapted from S. V. Konstantinides et al. [1] 349 REVIEW ARTICLES The Russian Archives of Internal Medicine • № 5 • 2019 of early mortality due to PE [7], rather than the embolectomy, etc. Therapeutic strategy should anatomical volume, shape and disposition of the optimally integrate all of the available range of intrapulmonary embolus assessment. Therefore, in therapeutic techniques in compliance with, albeit ESC Guidelines for the diagnosis and treatment of multidisciplinary, a unified approach to the man- acute PE 2008 it was proposed to replace the incor- agement of such patients [18]. rect, according to experts, terms of massive, sub- massive and non-massive PE with the correspond- Anticoagulant therapy ing risk categories of early mortality presented in Table 1 [7]. However, in the literature, especially in The clinical study by D. W. Barritt and S. C. Jordan North America, there are widespread definitions of published in The Lancet [19] in 1960 was of funda- massive, submassive PE, which correspond to cases mental importance in the development of modern of high and intermediate risk, respectively [8–11]. guidelines for the management of patients with The assessment of the lesion massiveness should PE based on PE treatment with ACT [20]. ACT is ideally take into account the angiographic control the main method of treatment for the majority of of the scale and distribution of the embolic mate- patients with acute PE and, in addition, represents rial using the Miller index [12]. the basis of therapy for the prevention of acute and chronic complications, including relapses of In addition to assessing the risk of early mortality PE (leading to hemodynamic insufficiency), lower (or massiveness) for PE after diagnosis, it is consid- limb DVT, which is often a source of PE and post- ered extremely important to calculate the progno- PE syndrome [15, 21]. The ACT is usually con- sis of the disease using the clinical index of PESI sidered in the management of hemodynamically (Pulmonary Embolism Severity Index) in the stable patients [22]. original [13] and simplified versions — sPESI [14]. The ACT plays one of the key roles, if not the basis Interdisciplinary approach of the therapeutic strategy in VTE and, in par- ticular, acute PE [23]. There are 3 phases of VTE Timely diagnosis, accurate risk stratification, and treatment: initial (first 5–10 days), long-term (from adequate use of reperfusion