Follow-up after acute Pulmonary Embolism

Frederikus A. Klok; Stefano Barco

doi:10.5482/HAMO-17-06-0020

Hämostaseologie, Table of Contents

Hamostaseologie 2018; 38(01): 22-32
DOI: 10.5482/HAMO-17-06-0020

Review

Schattauer GmbH

Follow-up after acute Pulmonary Embolism

Predicting chronic thromboembolic pulmonary hypertension and post-pulmonary embolism syndromeNachsorge bei akuter Lungenembolie: Vorhersage einer chronisch thromboembolischen pulmonalen Hypertonie und eines chronischen Lungenembolie-Syndroms

Frederikus A. Klok

¹Center for Thrombosis and Hemostasis, University Hospital of the Johannes Gutenberg University Mainz, Mainz, Germany

²Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands

,

Stefano Barco

¹Center for Thrombosis and Hemostasis, University Hospital of the Johannes Gutenberg University Mainz, Mainz, Germany

› Author Affiliations

Abstract

Full Text

PDF Download

Keywords

Pulmonary embolism - CTEPH - post-PE syndrome - quality of life

Schlüsselwörter

Lungenembolie - CTEPH - chronisches Lungen-embolie-Syndrom - Lebensqualität

References

Reference List
1 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a metaanalysis. Ann Intern Med 2003; 139: 893-900.
2 Klok FA, Zondag W, van Kralingen KW, van Dijk AP, Tamsma JT, Heyning FH. et al. Patient outcomes after acute pulmonary embolism. A pooled survival analysis of different adverse events. Am J Respir Crit Care Med 2010; 181: 501-506.
3 Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R. 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.
4 den Exter PL, van der Hulle T, Lankeit M, Huisman MV, Klok FA. Long-term clinical course of acute pulmonary embolism. Blood Rev 2013; 27: 185-192.
5 Konstantinides SV, Vicaut E, Danays T, Becattini C, Bertoletti L, Beyer-Westendorf J. et al. Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. J Am Coll Cardiol 2017; 69: 1536-1544.
6 Klok FA, Mos IC, Broek L, Tamsma JT, Rosendaal FR, de RA. et al. Risk of arterial cardiovascular events in patients after pulmonary embolism. Blood 2009; 114: 1484-1488.
7 Klok FA, van Kralingen KW, van Dijk AP, Heyning FH, Vliegen HW, Kaptein AA. et al. Quality of life in long-term survivors of acute pulmonary embolism. Chest 2010; 138: 1432-1440.
8 Kahn SR, Akaberi A, Granton JT, Anderson DR, Wells PS, Rodger MA. et al. Quality of Life, Dyspnea, and Functional Exercise Capacity Following a First Episode of Pulmonary Embolism: Results of the ELOPE Cohort Study. Am J Med. 2017
9 Klok FA, van der Hulle T, den Exter PL, Lankeit M, Huisman MV, Konstantinides S. The post-PE syndrome: a new concept for chronic complications of pulmonary embolism. Blood Rev 2014; 28: 221-226.
10 Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F. et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350: 2257-2264.
11 Kim NH, Delcroix M, Jenkins DP, Channick R, Dartevelle P, Jansa P. et al. Chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol 2013; 62: D92-D99.
12 Lang IM, Madani M. Update on chronic thromboembolic pulmonary hypertension. Circulation 2014; 130: 508-18.
13 Simonneau G, Torbicki A, Dorfmuller P, Kim N. The pathophysiology of chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2017; 26.
14 Morris TA. Why acute pulmonary embolism becomes chronic thromboembolic pulmonary hypertension: clinical and genetic insights. Curr Opin Pulm Med 2013; 19: 422-429.
15 Lang IM, Dorfmuller P, Vonk NA. The Pathobiology of Chronic Thromboembolic Pulmonary Hypertension. Ann Am Thorac Soc 2016; 13 (Suppl. 03) S215-S221.
16 Bochenek ML, Rosinus NS, Lankeit M, Hobohm L, Bremmer F, Schutz E. et al. From thrombosis to fibrosis in chronic thromboembolic pulmonary hypertension. Thromb Haemost 2017; 117: 769-783.
17 Morris TA, Marsh JJ, Chiles PG, Auger WR, Fedullo PF, Woods Jr VL. Fibrin derived from patients with chronic thromboembolic pulmonary hypertension is resistant to lysis. Am J Respir Crit Care Med 2006; 173: 1270-1275.
18 Morris TA, Marsh JJ, Chiles PG, Magana MM, Liang NC, Soler X. et al. High prevalence of dysfibrinogenemia among patients with chronic thromboembolic pulmonary hypertension. Blood 2009; 114: 1929-1936.
19 Marsh JJ, Chiles PG, Liang NC, Morris TA. Chronic thromboembolic pulmonary hypertension-associated dysfibrinogenemias exhibit disorganized fibrin structure. Thromb Res 2013; 132: 729-734.
20 Quarck R, Wynants M, Verbeken E, Meyns B, Delcroix M. Contribution of inflammation and impaired angiogenesis to the pathobiology of chronic thromboembolic pulmonary hypertension. Eur Respir J 2015; 46: 431-443.
21 Zabini D, Heinemann A, Foris V, Nagaraj C, Nierlich P, Balint Z. et al. Comprehensive analysis of inflammatory markers in chronic thromboembolic pulmonary hypertension patients. Eur Respir J 2014; 44: 951-962.
22 Dorfmuller P, Gunther S, Ghigna MR, Thomas dMV, Boulate D, Paul JF. et al. Microvascular disease in chronic thromboembolic pulmonary hypertension: a role for pulmonary veins and systemic vasculature. Eur Respir J 2014; 44: 1275-1288.
23 Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993; 103: 685-692.
24 Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM. et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 2004; 43: 25S-32S.
25 Vonk NA, Westerhof BE, Westerhof N. The Relationship Between the Right Ventricle and its Load in Pulmonary Hypertension. J Am Coll Cardiol 2017; 69: 236-243.
26 Claessen G, La GA, Wielandts JY, Bogaert J, Van CJ, Wuyts W. et al. Exercise pathophysiology and sildenafil effects in chronic thromboembolic pulmonary hypertension. Heart 2015; 101: 637-644.
27 Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001; 345: 1465-1472.
28 Klok FA, van Kralingen KW, van Dijk AP, Heyning FH, Vliegen HW, Huisman MV. Prospective cardiopulmonary screening program to detect chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism. Haematologica 2010; 95: 970-975.
29 Held M, Hesse A, Gott F, Holl R, Hubner G, Kolb P. et al. A symptom-related monitoring program following pulmonary embolism for the early detection of CTEPH: a prospective observational registry study. BMC Pulm Med 2014; 14: 141.
30 Golpe R, Perez-de-Llano LA, Castro-Anon O, Vazquez-Caruncho M, Gonzalez-Juanatey C, VeresRacamonde A. et al. Right ventricle dysfunction and pulmonary hypertension in hemodynamically stable pulmonary embolism. Respir Med 2010; 104: 1370-1376.
31 Klok FA, Tesche C, Rappold L, Dellas C, Hasenfuss G, Huisman MV. et al. External validation of a simple non-invasive algorithm to rule out chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. Thromb Res 2015; 135: 796-801.
32 Giuliani L, Piccinino C, D’Armini MA, Manganiello S, Ferrarotti L, Balbo PE. et al. Prevalence of undiagnosed chronic thromboembolic pulmonary hypertension after pulmonary embolism. Blood Coagul Fibrinolysis 2014; 25: 649-653.
33 Guerin L, Couturaud F, Parent F, Revel MP, Gillaizeau F, Planquette B. et al. Prevalence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. Prevalence of CTEPH after pulmonary embolism. Thromb Haemost 2014; 112: 598-605.
34 Marti D, Gomez V, Escobar C, Wagner C, Zamarro C, Sanchez D. et al. [Incidence of symptomatic and asymptomatic chronic thromboembolic pulmonary hypertension]. Arch Bronconeumol 2010; 46: 628-633.
35 Pesavento R, Filippi L, Palla A, Visona A, Bova C, Marzolo M. et al. Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism. Eur Respir J. 2017 49..
36 Gall H, Hoeper MM, Richter MJ, Cacheris W, Hinzmann B, Mayer E. An epidemiological analysis of the burden of chronic thromboembolic pulmonary hypertension in the USA, Europe and Japan. Eur Respir Rev. 2017 26..
37 Ende-Verhaar YM, Cannegieter SC, Vonk NA, Delcroix M, Pruszczyk P, Mairuhu AT. et al. Incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: a contemporary view of the published literature. Eur Respir J. 2017 49..
38 McIntyre KM, Sasahara AA. The hemodynamic response to pulmonary embolism in patients without prior cardiopulmonary disease. Am J Cardiol 1971; 28: 288-294.
39 Delcroix M, Lang I, Pepke-Zaba J, Jansa P, D’Armini AM, Snijder R. et al. Long-Term Outcome of Patients With Chronic Thromboembolic Pulmonary Hypertension: Results From an International Prospective Registry. Circulation 2016; 133: 859-871.
40 Lang IM. Chronic thromboembolic pulmonary hypertension--not so rare after all. N Engl J Med 2004; 350: 2236-2238.
41 Ende-Verhaar YM, Huisman MV, Klok FA. To screen or not to screen for chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. Thromb Res 2017; 151: 1-7.
42 Klok FA, Mos IC, van Kralingen KW, Vahl JE, Huisman MV. Chronic pulmonary embolism and pulmonary hypertension. Semin Respir Crit Care Med 2012; 33: 199-204.
43 Lang IM, Simonneau G, Pepke-Zaba JW, Mayer E, Ambroz D, Blanco I. et al. Factors associated with diagnosis and operability of chronic thromboembolic pulmonary hypertension. A case-control study. Thromb Haemost 2013; 110: 83-91.
44 Bonderman D, Wilkens H, Wakounig S, Schafers HJ, Jansa P, Lindner J. et al. Risk factors for chronic thromboembolic pulmonary hypertension. Eur Respir J 2009; 33: 325-331.
45 Bonderman D, Jakowitsch J, Adlbrecht C, Schemper M, Kyrle PA, Schonauer V. et al. Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension. Thromb Haemost 2005; 93: 512-516.
46 Frey MK, Alias S, Winter MP, Redwan B, Stubiger G, Panzenboeck A. et al. Splenectomy is modifying the vascular remodeling of thrombosis. J Am Heart Assoc 2014; 03: e000772.
47 Klok FA, Dzikowska-Diduch O, Kostrubiec M, Vliegen HW, Pruszczyk P, Hasenfuss G. et al. Derivation of a clinical prediction score for chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. J Thromb Haemost 2016; 14: 121-128.
48 Pepke-Zaba J, Delcroix M, Lang I, Mayer E, Jansa P, Ambroz D. et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation 2011; 124: 1973-1981.
49 Wong CL, Szydlo R, Gibbs S, Laffan M. Hereditary and acquired thrombotic risk factors for chronic thromboembolic pulmonary hypertension. Blood Coagul Fibrinolysis 2010; 21: 201-206.
50 Grant PJ, Stickland MH, Booth NA, Prentice CR. Metformin causes a reduction in basal and postvenous occlusion plasminogen activator inhibitor-1 in type 2 diabetic patients. Diabet Med 1991; 08: 361-365.
51 Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups. Diabetes Care 1993; 16: 621-629.
52 Lu DY, Huang CC, Huang PH, Chung CM, Lin SJ, Chen JW. et al. Metformin use in patients with type 2 diabetes mellitus is associated with reduced risk of deep vein thrombosis: a non-randomized, pair-matched cohort study. BMC Cardiovasc Disord 2014; 14: 187.
53 Stevinson BG, Hernandez-Nino J, Rose G, Kline JA. Echocardiographic and functional cardiopulmonary problems 6 months after first-time pulmonary embolism in previously healthy patients. Eur Heart J 2007; 28: 2517-2524.
54 Kline JA, Steuerwald MT, Marchick MR, Hernandez-Nino J, Rose GA. Prospective evaluation of right ventricular function and functional status 6 months after acute submassive pulmonary embolism: frequency of persistent or subsequent elevation in estimated pulmonary artery pressure. Chest 2009; 136: 1202-1210.
55 Klok FA, van Kralingen KW, van Dijk AP, Heyning FH, Vliegen HW, Huisman MV. Prevalence and potential determinants of exertional dyspnea after acute pulmonary embolism. Respir Med 2010; 104: 1744-1749.
56 Sista AK, Miller LE, Kahn SR, Kline JA. Persistent right ventricular dysfunction, functional capacity limitation, exercise intolerance, and quality of life impairment following pulmonary embolism: Systematic review with meta-analysis. Vasc Med 2017; 22: 37-43.
57 Held M, Kolb P, Grun M, Jany B, Hubner G, Grgic A. et al. Functional Characterization of Patients with Chronic Thromboembolic Disease. Respiration 2016; 91: 503-509.
58 Ribeiro A, Lindmarker P, Johnsson H, JuhlinDannfelt A, Jorfeldt L. Pulmonary embolism: oneyear follow-up with echocardiography doppler and five-year survival analysis. Circulation 1999; 99: 1325-1330.
59 Kahn SR, Hirsch AM, Akaberi A, Hernandez P, Anderson DR, Wells PS. et al. Functional and Exercise Limitations After a First Episode of Pulmonary Embolism: Results of the ELOPE Prospective Cohort Study. Chest 2017; 151: 1058-1068.
60 Riedel M, Stanek V, Widimsky J, Prerovsky I. Longterm follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982; 81: 151-158.
61 van EJ, den Exter PL, Kaptein AA, Andela CD, Erkens PM, Klok FA. et al. Quality of life after pulmonary embolism as assessed with SF-36 and PEmb-QoL. Thromb Res 2013; 132: 500-505.
62 Hogg K, Kimpton M, Carrier M, Coyle D, Forgie M, Wells P. Estimating quality of life in acute venous thrombosis. JAMA Intern Med 2013; 173: 1067-1072.
63 Lukas PS, Neugebauer A, Schnyder S, Biasiutti FD, Krummenacher R, Ferrari ML. et al. Depressive symptoms, perceived social support, and prothrombotic measures in patients with venous thromboembolism. Thromb Res 2012; 130: 374-380.
64 Tavoly M, Utne KK, Jelsness-Jorgensen LP, Wik HS, Klok FA, Sandset PM. et al. Health-related quality of life after pulmonary embolism: a crosssectional study. BMJ Open 2016; 06: e013086.
65 Klok FA, Cohn DM, Middeldorp S, Scharloo M, Buller HR, van Kralingen KW. et al. Quality of life after pulmonary embolism: validation of the PEmb-QoL Questionnaire. J Thromb Haemost 2010; 08: 523-532.
66 Lubberts B, Paulino NRPereira, Kabrhel C, Kuter DJ, DiGiovanni CW. What is the effect of venous thromboembolism and related complications on patient reported health-related quality of life? A meta-analysis. Thromb Haemost 2016; 116: 417-431.
67 Lukas PS, Krummenacher R, Biasiutti FD, Begre S, Znoj H, von KR. Association of fatigue and psychological distress with quality of life in patients with a previous venous thromboembolic event. Thromb Haemost 2009; 102: 1219-1226.
68 Klok FA, Tijmensen JE, Haeck ML, van Kralingen KW, Huisman MV. Persistent dyspnea complaints at long-term follow-up after an episode of acute pulmonary embolism: results of a questionnaire. Eur J Intern Med 2008; 19: 625-629.
69 Ma K, Kahn SR, Hirsch AM, Akaberi A, Anderson DR, Wells PS. et al. N-terminal of prohormone brain natriuretic peptide predicts functional limitation one year following pulmonary embolism: Results from the ELOPE study. Thromb Res 2017; 153: 47-49.
70 Krummenacher R, Lukas PS, Biasiutti FD, Begre S, Znoj H, von KR. Independent association of sleep quality, fatigue, and vital exhaustion with platelet count in patients with a previous venous thromboembolic event. Platelets 2009; 20: 566-574.
71 Mathai SC, Ghofrani HA, Mayer E, Pepke-Zaba J, Nikkho S, Simonneau G. Quality of life in patients with chronic thromboembolic pulmonary hypertension. Eur Respir J 2016; 48: 526-537.
72 Roman A, Barbera JA, Castillo MJ, Munoz R, Escribano P. Health-related quality of life in a national cohort of patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Arch Bronconeumol 2013; 49: 181-188.
73 Funabashi S, Kataoka M, Inami T, Kikuchi T, Yanagisawa R, Ishiguro C. et al. Depressive Status in Patients With Chronic Thromboembolic Pulmonary Hypertension. Circ J. 2017
74 Urushibara T, Tanabe N, Suda R, Kato F, Kasai H, Takeuchi T. et al. Effects of Surgical and Medical Treatment on Quality of Life for Patients With Chronic Thromboembolic Pulmonary Hypertension. Circ J 2015; 79: 2696-2702.
75 Jenkins D, Madani M, Fadel E, D’Armini AM, Mayer E. Pulmonary endarterectomy in the management of chronic thromboembolic pulmonary hypertension. Eur Respir Rev. 2017 26..
76 Hoeper MM, Madani MM, Nakanishi N, Meyer B, Cebotari S, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Lancet Respir Med 2014; 02: 573-582.
77 Taboada D, Pepke-Zaba J, Jenkins DP, Berman M, Treacy CM, Cannon JE. et al. Outcome of pulmonary endarterectomy in symptomatic chronic thromboembolic disease. Eur Respir J 2014; 44: 1635-1645.
78 Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH. et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013; 369: 319-329.
79 Simonneau G, D’Armini AM, Ghofrani HA, Grimminger F, Jansa P, Kim NH. et al. Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial. Lancet Respir Med 2016; 04: 372-380.
80 Simonneau G, D’Armini AM, Ghofrani HA, Grimminger F, Hoeper MM, Jansa P. et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2). Eur Respir J 2015; 45: 1293-1302.
81 Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N. et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014; 35: 3033-3069k.
82 Olsson KM, Wiedenroth CB, Kamp JC, Breithecker A, Fuge J, Krombach GA. et al. Balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension: the initial German experience. Eur Respir J. 2017 49..
83 Lang I, Meyer BC, Ogo T, Matsubara H, Kurzyna M, Ghofrani HA. et al. Balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension. Eur Respir Rev. 2017 26..
84 Akizuki M, Serizawa N, Ueno A, Adachi T, Hagiwara N. Effect of Balloon Pulmonary Angioplasty on Respiratory Function in Patients With Chronic Thromboembolic Pulmonary Hypertension. Chest 2017; 151: 643-649.
85 Andreassen AK, Ragnarsson A, Gude E, Geiran O, Andersen R. Balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension. Heart 2013; 99: 1415-1420.
86 Fukui S, Ogo T, Goto Y, Ueda J, Tsuji A, Sanda Y. et al. Exercise intolerance and ventilatory inefficiency improve early after balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension. Int J Cardiol 2015; 180: 66-68.
87 Voorburg JA, Cats VM, Buis B, Bruschke AV. Balloon angioplasty in the treatment of pulmonary hypertension caused by pulmonary embolism. Chest 1988; 94: 1249-1253.
88 Noack F, Schmidt B, Amoury M, Stoevesandt D, Gielen S, Pflaumbaum B. et al. Feasibility and safety of rehabilitation after venous thromboembolism. Vasc Health Risk Manag 2015; 11: 397-401.
89 Lakoski SG, Savage PD, Berkman AM, Penalosa L, Crocker A, Ades PA. et al. The safety and efficacy of early-initiation exercise training after acute venous thromboembolism: a randomized clinical trial. J Thromb Haemost 2015; 13: 1238-1244.
90 Nagel C, Prange F, Guth S, Herb J, Ehlken N, Fischer C. et al. Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension. PLoS One 2012; 07: e41603.
91 Inagaki T, Terada J, Tanabe N, Kawata N, Kasai H, Sugiura T. et al. Home-based pulmonary rehabilitation in patients with inoperable or residual chronic thromboembolic pulmonary hypertension: a preliminary study. Respir Investig 2014; 52: 357-364.
92 Fukui S, Ogo T, Takaki H, Ueda J, Tsuji A, Morita Y. et al. Efficacy of cardiac rehabilitation after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension. Heart 2016; 102: 1403-1409.
93 Konstantinides SV, Barco S, Rosenkranz S, Lankeit M, Held M, Gerhardt F. et al. Late outcomes after acute pulmonary embolism: rationale and design of FOCUS, a prospective observational multicenter cohort study. J Thromb Thrombolysis 2016; 42: 600-609.
94 Klok FA, Tesche C, Rappold L, Dellas C, Hasenfuss G, Huisman MV. et al. External validation of a simple non-invasive algorithm to rule out chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. Thromb Res 2015; 135: 796-801.
95 Klok FA, Surie S, Kempf T, Eikenboom J, van Straalen JP, van Kralingen KW. et al. A simple noninvasive diagnostic algorithm for ruling out chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism. Thromb Res 2011; 128: 21-26.
96 Rolving N, Brocki BC, Mikkelsen HR, Ravn P, Bloch-Nielsen JR, Frost L. Does an 8-week homebased exercise program affect physical capacity, quality of life, sick leave, and use of psychotropic drugs in patients with pulmonary embolism? Study protocol for a multicenter randomized clinical trial. Trials 2017; 18: 245.