Pulmonary embolism hotline 2012

S. Konstantinides; M. Lankeit

doi:10.5482/HAMO-12-12-0024

Hämostaseologie, Table of Contents

Hamostaseologie 2013; 33(01): 43-50
DOI: 10.5482/HAMO-12-12-0024

Review

Schattauer GmbH

Pulmonary embolism hotline 2012

Recent and expected trialsLungenembolie-Hotline 2012Alte und neue Studien

S. Konstantinides

¹Center for Thrombosis and Haemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany

,

M. Lankeit

¹Center for Thrombosis and Haemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany

› Author Affiliations

Abstract

Summary

Management of acute pulmonary embolism (PE) has advanced considerably in the past year, and progress is expected to continue in 2013. To help determine the optimal management strategy for normotensive patients with intermediate-risk PE, the Pulmonary Embolism Thrombolysis (PEITHO) study completed enrolment of 1006 patients with evidence of right ventricular dysfunction (by echocardiography or computed tomography) plus a positive troponin test. Patients have been randomised to thrombolytic treatment with tenecteplase versus placebo, and the effects on clinical end points (death or haemodynamic collapse) assessed at 7 and 30 days. The results are expected in spring 2013; long-term follow-up is also being performed. The results of a randomised trial on ultrasound- enhanced low-dose catheter-delivered thrombolysis will also become available soon. While optimisation of treatment with vitamin K antagonists incorporating pharmacogenetic testing is still being pursued, new oral anticoagulants are entering the field of PE treatment and secondary prophylaxis. Following the successful use of rivaroxaban as single oral drug therapy in the EINSTEIN-PE trial, the approval of this drug has recently been extended to cover, apart from deep vein thrombosis, PE as well. The apixaban (AMPLIFY) and edoxaban (HOKUSAI) trials have finished recruitment of PE patients, and their results will become available shortly. In the meantime, the AMPLIFY-EXT trial showed that both the therapeutic (5 mg twice daily) and the prophylactic dose (2.5 mg twice daily) of apixaban are effective and safe for longterm secondary prophylaxis after PE. For the extended prophylaxis (after the reommended initial anticoagulation period) of the (few) patients who are unable to tolerate any form of anticoagulation, low-dose asprin may be a safe albeit moderately efficacious option, as indicated by two recent investigator-initiated trials with a total of 1224 patients.

Zusammenfassung

Die Therapie der akuten Lungenembolie (LE) befindet sich im Umbruch. Um die optimale Management-Strategie für normotensive LEPatienten mit erhöhtem (intermediärem) Risiko herauszufinden, hat die Pulmonary Embolism Thrombolysis (PEITHO)-Studie 1006 Patienten mit Nachweis einer rechtsventrikulären Dysfunktion (im EKG oder CT) und einem positiven Troponin-Test eingeschlossen. Evaluiert wird – nach 7 und 30 Tagen – der Einfluss einer frühen thrombolytischen Behandlung auf den klinischen Verlauf. Diese Ergebnisse werden im Frühjahr 2013 erwartet, während die Langzeit-Follow-up-Phase (2 Jahre) der Studie weiterläuft. Eine weitere randomisierte Studie zum Stellenwert der ultraschallverstärkten, niedrig dosierten, kathetergelieferten Thrombolyse ist ebenfalls abgeschlossen und soll 2013 vorgestellt werden. Während die Optimierung der Antikoagulation mit Vitamin- K-Antagonisten (VKA) mittels pharmakogenetischer Tests weiterverfolgt wird, dringen die neuen oralen Anti koagulanzien auch in die Therapie und Sekundärprophylaxe der venösen Thromboembolie Erfolg versprechend ein. Nach dem erfolgreichen Einsatz von Rivaroxaban als „single oral drug”- Strategie in der EINSTEIN-PE Studie, wurde diese Substanz 2012 auch für die LE (nach bereits erfolgter Zulassung für die tiefe Venenthrombose im Jahr 2011) zugelassen. Die entsprechenden Studien mit Apixaban (AMPLIFY) und Edoxaban (HOKUSAI) haben ihre Patientenrekrutierung abgeschlossen, so dass ihre Ergebnisse in Kürze zu erwarten sind. Inzwischen zeigte die AMPLIFY-EXT-Studie, dass Apixaban sowohl in der therapeutischen (5 mg 2-mal täglich) als auch in der prophylaktischen (2,5 mg 2-mal täglich) Dosis für die Langzeitprophylaxe von LE - Rezidiven effektiv und sicher eingesetzt war-den kann. Für diese Spätphase (d.h. nach erfolgter 3- bis 6-monatiger Antikoagulation wie in den Leitlinien empfohlen) erscheint es auch möglich, Patienten, die keinerlei Anti - koagulanzien (weder VKA noch neue orale Faktor-Xa-Inhibitoren) tolerieren, mit niedrig dosierter (100 mg täglich) Azetylsalizylsäure (ASS) prophylaktisch zu behandeln. Zwei kürzlich publizierte, nicht durch die Industrie gesponserte randomisierte Studien mit insgesamt 1224 Patienten zeigten, dass ASS in diesem Zusammenhang eine mäßig effektive aber sichere Prophylaxe von venösen (und arteriellen) Thrombosen leisten kann.

Keywords

Pulmonary embolism - therapy - thrombolysis - anticoagulation - new oral anticoagulants - trials

Schlüsselwörter

Lungenembolie - Therapie - Thrombolyse - Antikoagulation - neue orale Antikoagulanzien - Studien

Full Text

References

References
1 Torbicki A, Perrier A, Konstantinides SV. et al. Guidelines on the diagnosis and management of acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008; 29 2 276-2315.
2 Lualdi JC, Goldhaber SZ. Right ventricular dysfunction after acute pulmonary embolism: pathophysiologic factors, detection, and therapeutic implications. Am Heart J 1995; 130: 1276-1282.
3 Konstantinides S. Pulmonary embolism: impact of right ventricular dysfunction. Curr Opin Cardiol 2005; 20: 496-501.
4 Jaff MR, McMurtry MS, Archer SL. et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123: 1788-1830.
5 Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med 2012; 125: 465-470.
6 Laporte S, Mismetti P, Decousus H. et al. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry. Circulation 2008; 117: 1711-1716.
7 Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation 2006; 113: 577-582.
8 Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest 1995; 108: 978-981.
9 Kasper W, Konstantinides S, Geibel A. et al. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol 1997; 30: 1165-1171.
10 Grifoni S, Olivotto I, Cecchini P. et al. Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation 2000; 101: 2817-2822.
11 Kasper W, Konstantinides S, Geibel A. et al. Prognostic significance of right ventricular afterload stress detected by echocardiography in patients with clinically suspected pulmonary embolism. Heart 1997; 77: 346-349.
12 Konstantinides S, Goldhaber SZ. Pulmonary embolism: risk assessment and management. Eur Heart J 2012; 33: 3014-3022.
13 Goldhaber SZ. Echocardiography in the management of pulmonary embolism. Ann Intern Med 2002; 136: 691-700.
14 Ribeiro A, Lindmarker P, Juhlin-Dannfelt A. et al. Echocardiography Doppler in pulmonary embolism: right ventricular dysfunction as a predictor of mortality rate. Am Heart J 1997; 134: 479-487.
15 Goldhaber SZ, Haire WD, Feldstein ML. et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993; 341: 507-511.
16 Sanchez O, Trinquart L, Colombet I. et al. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. Eur Heart J 2008; 29: 1569-1577.
17 Becattini C, Agnelli G, Vedovati MC. et al. Multidetector computed tomography for acute pulmonary embolism: diagnosis and risk stratification in a single test. Eur Heart J 2011; 32: 1657-1663.
18 Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation 2007; 116: 427-433.
19 Lankeit M, Friesen D, Aschoff J. et al. Highly sensitive troponin T assay in normotensive patients with acute pulmonary embolism. Eur Heart J 2010; 31: 1836-1844.
20 Spirk D, Aujesky D, Husmann M. et al. Cardiac troponin testing and the simplified Pulmonary Embolism Severity Index. The SWIss Venous ThromboEmbolism Registry (SWIVTER). Thromb Haemost 2011; 106: 978-984.
21 Dellas C, Puls M, Lankeit M. et al. Elevated hearttype fatty acid-binding protein levels on admission predict an adverse outcome in normotensive patients with acute pulmonary embolism. J Am Coll Cardiol 2010; 55: 2150-2157.
22 Lankeit M, Kempf T, Dellas C. et al. Growth differentiation factor-15 for prognostic assessment of patients with acute pulmonary embolism. Am J Respir Crit Care Med 2008; 177: 1018-1025.
23 Binder L, Pieske B, Olschewski M. et al. N-terminal pro-brain natriuretic peptide or troponin testing followed by echocardiography for risk stratification of acute pulmonary embolism. Circulation 2005; 112: 1573-1579.
24 Scridon T, Scridon C, Skali H. et al. Prognostic significance of troponin elevation and right ventricular enlargement in acute pulmonary embolism. Am J Cardiol 2005; 96: 303-305.
25 Jimenez D, Aujesky D, Moores L. et al. Combinations of prognostic tools for identification of high-risk normotensive patients with acute symptomatic pulmonary embolism. Thorax 2011; 66: 75-81.
26 Sanchez O, Trinquart L, Caille V. et al. Prognostic factors for pulmonary embolism: the prep study, a prospective multicenter cohort study. Am J Respir Crit Care Med 2010; 181: 168-173.
27 Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 2004; 110: 744-749.
28 Konstantinides S, Geibel A, Heusel G. et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002; 347: 1143-1150.
29 Stein PD, Matta F, Steinberger DS, Keyes DC. Intracerebral hemorrhage with thrombolytic therapy for acute pulmonary embolism. Am J Med 2012; 125: 50-56.
30 The PEITHO Steering Committee. Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial. Am Heart J 2012; 163: 33-38.
31 Sharifi M, Bay C, Skrocki L. et al. Moderate Pulmonary Embolism Treated With Thrombolysis (from the „MOPETT” Trial). Am J Cardiol 2013; 111: 273-277.
32 Engelberger RP, Kucher N. Catheter-based reperfusion treatment of pulmonary embolism. Circulation 2011; 124: 2139-2144.
33 Kuo WT, Gould MK, Louie JD. et al. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and metaanalysis of modern techniques. J Vasc Interv Radiol 2009; 20: 1431-1440.
34 Johnson JA. Warfarin pharmacogenetics: a rising tide for its clinical value. Circulation 2012; 125: 1964-1966.
35 Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011; 365: 2002-2012.
36 Hylek EM, Evans-Molina C, Shea C. et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007; 115: 2689-2696.
37 Heneghan C, Ward A, Perera R. et al. Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data. Lancet 2012; 379: 322-334.
38 Carlquist JF, Anderson JL. Using pharmacogenetics in real time to guide warfarin initiation: a clinician update. Circulation 2011; 124: 2554-2559.
39 Epstein RS, Moyer TP, Aubert RE. et al. Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study). J Am Coll Cardiol 2010; 55: 2804-2812.
40 Jonas DE, McLeod HL. Genetic and clinical factors relating to warfarin dosing. Trends Pharmacol Sci 2009; 30: 375-386.
41 Van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
42 Perzborn E, Roehrig S, Straub A. et al. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov 2011; 10: 61-75.
43 Wong PC, Pinto DJ, Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis 2011; 31: 478-492.
44 Camm AJ, Bounameaux H. Edoxaban: a new oral direct factor xa inhibitor. Drugs 2011; 71: 1503-1526.
45 Bauersachs R, Berkowitz SD, Brenner B. et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
46 Buller HR, Prins MH, Lensin AW. et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
47 Buller HR, Cohen AT, Davidson B. et al. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 2007; 357: 1094-1104.
48 Fiessinger JN, Huisman MV, Davidson BL. et al. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA 2005; 293: 681-689.
49 Agnelli G, Gallus A, Goldhaber SZ. et al. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT study. Circulation 2007; 116: 180-187.
50 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
51 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
52 Prandoni P, Noventa F, Ghirarduzzi A. et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007; 92: 199-205.
53 Agnelli G, Prandoni P, Becattini C. et al. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 2003; 139: 19-25.
54 Kearon C, Akl EA, Comerota AJ. et al. Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis. 9^th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e419S-e494S.
55 Kearon C, Gent M, Hirsh J. et al. . A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 341: 298 N Engl J Med 1999; 340: 901-907.
56 Agnelli G, Buller HR, Cohen A. et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2012 DOI:10.1056/NEJMoa1207541..
57 Becattini C, Agnelli G, Schenone A. et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012; 366: 1959-1967.
58 Brighton TA, Eikelboom JW, Mann K. et al. Lowdose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012; 367: 1979-1987.
59 Lankeit M, Konstantinides S. Is it time for home treatment of pulmonary embolism?. Eur Respir J 2012; 40: 742-749.
60 Zondag W, Hiddinga BI, Crobach MJ. et al. Hestia criteria can discriminate high from low risk patients with pulmonary embolism. Eur Respir J. 2012 DOI:10.1183/09031936.00030412..
61 Aujesky D, Roy PM, Verschuren F. et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet 2011; 378: 41-48.
62 Zondag W, Mos IC, Creemers-Schild D. et al. Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study. J Thromb Haemost 2011; 09: 1500-1507.
63 Agterof MJ, Schutgens RE, Snijder RJ. et al. Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level. J Thromb Haemost 2010; 08: 1235-1241.
64 Otero R, Uresandi F, Jimenez D. et al. Home treatment in pulmonary embolism. Thromb Res 2010; 126: e1-e5.
65 Zondag W, Kooiman J, Klok F. et al. Outpatient versus inpatient treatment in patients with pulmonary embolism: a meta-analysis. Eur Respir J. 2012 DOI:10.1183/09031936.00093712..