Predictors for Residual Pulmonary Vascular Obstruction after Unprovoked Pulmonary Embolism: Implications for Clinical Practice—The PADIS-PE Trial

Abstract

Background We aimed to identify risk factors for residual pulmonary vascular obstruction after a first unprovoked pulmonary embolism (PE).

Methods Analyses were based on data from the double-blind randomized “PADIS-PE” trial that included 371 patients with a first unprovoked PE initially treated during 6 uninterrupted months; all patients underwent baseline ventilation–perfusion lung scanning at inclusion (i.e., after 6 months of anticoagulation). Each patient's pulmonary vascular obstruction indexes (PVOIs) at PE diagnosis and at inclusion were centrally assessed.

Results Among the 371 included patients, residual PVOI was available in 356 patients, and 150 (42.1%) patients had PVOI ≥ 5%. At multivariable analysis, age > 65 years (odds ratio [OR], 2.81, 95% confidence interval [CI], 1.58–5.00), PVOI ≥ 25% at PE diagnosis (OR, 3.53, 95% CI, 1.94–6.41), elevated factor VIII (OR, 3.89, 95% CI, 1.41–10.8), and chronic respiratory disease (OR, 2.18, 95% CI, 1.11–4.26) were independent predictors for residual PVOI ≥ 5%. Patients with ≥ 1 of these factors represented 94.5% (123 patients) of all patients with residual PVOI ≥ 5%.

Conclusion Six months after a first unprovoked PE, age > 65 years, PVOI ≥ 25% at PE diagnosis, elevated factor VIII, or chronic respiratory disease were found to be independent predictors for residual pulmonary vascular obstruction.

Clinical Trials Registration URL: http://www.controlled-trials.com. Unique identifier: NCT00740883.

Keywords

unprovoked pulmonary embolism - residual pulmonary vascular obstruction - recurrent venous thromboembolism - risk factors

Authors' Contributions

F.C. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. He obtained funding for the manuscript and supervised the study. F.C., L.R., O.S., L.B., C.T., P.M., and C.L. contributed to study concept and design. F. C., L.R., O.S., C.T., G.M., L.B., S.L., P.G., E.P., and C.L. contributed to drafting of the manuscript. S.M. contributed to acquisition of data. S.L., E.P., and F.C. contributed to statistical analysis. F.C., K.L., P.Y.S, L.B., M.N., and C.L. provided administrative, technical, or material support. All the authors contributed to analysis and interpretation of data and critical revision of the manuscript for important intellectual content. All the authors approved the final manuscript.

^* Members of the Prolongation d'un traitement par Antivitamine K pendant Dix-huit mois versus placebo au décours d'un premier épisode d'embolie pulmonaire Idiopathique traité Six mois (PADIS-PE) Study Group are listed in [Supplementary Appendix] (available in the online version).

• References

• 1 Kearon C, Akl EA, Ornelas J. , et al. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149 (02) 315-352
• 2 Konstantinides SV, Torbicki A, Agnelli G. , et al; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014; 35 (43) 3033-3069
• 3 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 (02) 199-205
• 4 Agnelli G, Prandoni P, Santamaria MG. , et al; Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001; 345 (03) 165-169
• 5 Couturaud F, Sanchez O, Pernod G. , et al; PADIS-PE Investigators. Six months vs extended oral anticoagulation after a first episode of pulmonary embolism: the PADIS-PE randomized clinical trial. JAMA 2015; 314 (01) 31-40
• 6 Lecumberri R, Alfonso A, Jiménez D. , et al; RIETE investigators. Dynamics of case-fatality rates of recurrent thromboembolism and major bleeding in patients treated for venous thromboembolism. Thromb Haemost 2013; 110 (04) 834-843
• 7 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003; 139 (11) 893-900
• 8 Tromeur C, Sanchez O, Presles E. , et al; PADIS-PE Investigators18. Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial. Eur Respir J 2018; 51 (01) 1701202
• 9 Planquette B, Ferré A, Péron J. , et al. Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism. A single center cohort study. Thromb Res 2016; 148: 70-75
• 10 Pesavento R, Filippi L, Palla A. , et al; SCOPE Investigators. Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism. Eur Respir J 2017; 49 (05) 1601980
• 11 Wan T, Rodger M, Zeng W. , et al. Residual pulmonary embolism as a predictor for recurrence after a first unprovoked episode: results from the REVERSE cohort study. Thromb Res 2018; 162: 104-109
• 12 Gottschalk A, Sostman HD, Coleman RE. , et al. Ventilation-perfusion scintigraphy in the PIOPED study. Part II. Evaluation of the scintigraphic criteria and interpretations. J Nucl Med 1993; 34 (07) 1119-1126
• 13 Fanikos J, Rao A, Seger AC, Carter D, Piazza G, Goldhaber SZ. Hospital costs of acute pulmonary embolism. Am J Med 2013; 126 (02) 127-132
• 14 Schembri GP, Miller AE, Smart R. Radiation dosimetry and safety issues in the investigation of pulmonary embolism. Semin Nucl Med 2010; 40 (06) 442-454
• 15 Lukoff J, Olmos J. Minimizing medical radiation exposure by incorporating a new radiation “Vital Sign” into the electronic medical record: quality of care and patient safety. Perm J 2017; 21: 17-007
• 16 Radiation health effects [Internet]. Washington, DC: United States Environmental Protection Agency; 2017
• 17 Initiative to reduce unnecessary radiation exposure from medical imaging [Internet]. Silver Spring, MD: U.S. Food & Drug Administration; 2017
• 18 Schiff GD, Galanter WL, Duhig J, Lodolce AE, Koronkowski MJ, Lambert BL. Principles of conservative prescribing. Arch Intern Med 2011; 171 (16) 1433-1440
• 19 Hill KD, Einstein AJ. New approaches to reduce radiation exposure. Trends Cardiovasc Med 2016; 26 (01) 55-65
• 20 Galiè N, Humbert M, Vachiery JL. , et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015; 46 (04) 903-975
• 21 Miller GA, Sutton GC, Kerr IH, Gibson RV, Honey M. Comparison of streptokinase and heparin in treatment of isolated acute massive pulmonary embolism. BMJ 1971; 2 (5763): 681-684
• 22 Meyer G, Collignon MA, Guinet F, Jeffrey AA, Barritault L, Sors H. Comparison of perfusion lung scanning and angiography in the estimation of vascular obstruction in acute pulmonary embolism. Eur J Nucl Med 1990; 17 (6-8): 315-319
• 23 Qanadli SD, El Hajjam M, Vieillard-Baron A. , et al. New CT index to quantify arterial obstruction in pulmonary embolism: comparison with angiographic index and echocardiography. Am J Roentgenol 2001; 176 (06) 1415-1420
• 24 van Es J, Douma RA, Kamphuisen PW. , et al. Clot resolution after 3 weeks of anticoagulant treatment for pulmonary embolism: comparison of computed tomography and perfusion scintigraphy. J Thromb Haemost 2013; 11 (04) 679-685
• 25 Worsley DF, Alavi A. ; Prospective Investigation of Pulmonary Embolism Diagnosis Study. Comprehensive analysis of the results of the PIOPED Study. J Nucl Med 1995; 36 (12) 2380-2387
• 26 Meneveau N, Ider O, Seronde MF. , et al. Long-term prognostic value of residual pulmonary vascular obstruction at discharge in patients with intermediate- to high-risk pulmonary embolism. Eur Heart J 2013; 34 (09) 693-701
• 27 van der Meer RW, Pattynama PM, van Strijen MJ. , et al. Right ventricular dysfunction and pulmonary obstruction index at helical CT: prediction of clinical outcome during 3-month follow-up in patients with acute pulmonary embolism. Radiology 2005; 235 (03) 798-803
• 28 Lowery EM, Brubaker AL, Kuhlmann E, Kovacs EJ. The aging lung. Clin Interv Aging 2013; 8: 1489-1496
• 29 Fleg JL, Strait J. Age-associated changes in cardiovascular structure and function: a fertile milieu for future disease. Heart Fail Rev 2012; 17 (4-5): 545-554
• 30 Bertoletti L, Quenet S, Mismetti P. , et al; RIETE Investigators. Clinical presentation and outcome of venous thromboembolism in COPD. Eur Respir J 2012; 39 (04) 862-868
• 31 Lewczuk J, Piszko P, Jagas J. , et al. Prognostic factors in medically treated patients with chronic pulmonary embolism. Chest 2001; 119 (03) 818-823
• 32 Voelkel NF, Cool CD. Pulmonary vascular involvement in chronic obstructive pulmonary disease. Eur Respiratory J 2003; 22: 28s-32s
• 33 Vaidyula VR, Criner GJ, Grabianowski C, Rao AK. Circulating tissue factor procoagulant activity is elevated in stable moderate to severe chronic obstructive pulmonary disease. Thromb Res 2009; 124 (03) 259-261
• 34 Jankowski M, Undas A, Kaczmarek P, Butenas S. Activated factor XI and tissue factor in chronic obstructive pulmonary disease: links with inflammation and thrombin generation. Thromb Res 2011; 127 (03) 242-246
• 35 Steffel J, Lüscher TF, Tanner FC. Tissue factor in cardiovascular diseases: molecular mechanisms and clinical implications. Circulation 2006; 113 (05) 722-731
• 36 Bhopale GM, Nanda RK. Blood coagulation factor VIII: an overview. J Biosci 2003; 28 (06) 783-789
• 37 Kyrle PA, Minar E, Hirschl M. , et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343 (07) 457-462
• 38 Bonderman D, Turecek PL, Jakowitsch J. , et al. High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension. Thromb Haemost 2003; 90 (03) 372-376
• 39 Murin S, Marelich GP, Arroliga AC, Matthay RA. Hereditary thrombophilia and venous thromboembolism. Am J Respir. Crit Care Med 1998; 158 (05) 1369-1373
• 40 Ho WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med 2006; 166 (07) 729-736