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Cost-effectiveness microsimulation of catheter-directed thrombolysis in submassive pulmonary embolism using a right ventricular function model

Abstract

Approximately 30–50% of hemodynamically stable patients presenting with acute pulmonary embolism (PE) have evidence of right ventricular (RV) dysfunction. These patients are classified as submassive PE and the role of reperfusion therapy remains unclear. We sought to identify the circumstances under which catheter-directed thrombolysis (CDT) would represent high-value care for submassive PE. We used a computer-based, individual-level, state-transition model with one million simulated patients to perform a cost-effectiveness analysis comparing the treatment of submassive PE with CDT followed by anticoagulation to treatment with anticoagulation alone. Because RV function impacts prognosis and is commonly used in PE outcomes research, our model used RV dysfunction to differentiate health states. One-way, two-way, and probabilistic sensitivity analyses were used to quantify model uncertainty. Our base case analysis generated an incremental cost-effectiveness ratio (ICER) of $119,326 per quality adjusted life year. Sensitivity analyses resulted in ICERs consistent with high-value care when CDT conferred a reduction in the absolute probability of RV dysfunction of 3.5% or more. CDT yielded low-value ICERs if the absolute reduction was less than 1.56%. Our model suggests that catheter-directed thrombolytics represents high-value care compared to anticoagulation alone when CDT offers an absolute improvement in RV dysfunction of 3.5% or more, but there is substantial uncertainly around these results. We estimated the monetary value of clarifying the costs and consequences surrounding RV dysfunction after submassive PE to be approximately $268 million annually, suggesting further research in this area could be highly valuable.

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References

  1. White RH (2003) The epidemiology of venous thromboembolism. Circulation 107(23 Suppl 1):I4–8. https://doi.org/10.1161/01.CIR.0000078468.11849.66

    Article  PubMed  Google Scholar 

  2. Heit JA, Spencer FA, White RH (2016) The epidemiology of venous thromboembolism. J Thromb Thrombolysis 41(1):3–14. https://doi.org/10.1007/s11239-015-1311-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Kucher N, Rossi E, De Rosa M, Goldhaber SZ (2006) Massive pulmonary embolism. Circulation 113(4):577–582. https://doi.org/10.1161/CIRCULATIONAHA.105.592592

    Article  PubMed  Google Scholar 

  4. Kasper W, Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser KD, Rauber K, Iversen S, Redecker M, Kienast J (1997) Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol 30(5):1165–1171

    Article  CAS  Google Scholar 

  5. Aujesky D, Obrosky DS, Stone RA, Auble TE, Perrier A, Cornuz J, Roy PM, Fine MJ (2005) Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 172(8):1041–1046. https://doi.org/10.1164/rccm.200506-862OC

    Article  PubMed  PubMed Central  Google Scholar 

  6. Konstantinides SV, Barco S, Lankeit M, Meyer G (2016) Management of pulmonary embolism: an update. J Am Coll Cardiol 67(8):976–990. https://doi.org/10.1016/j.jacc.2015.11.061

    Article  PubMed  Google Scholar 

  7. Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ, Jenkins JS, Kline JA, Michaels AD, Thistlethwaite P, Vedantham S, White RJ, Zierler BK, American Heart Association Council on Cardiopulmonary CCP, Resuscitation, American Heart Association Council on Peripheral Vascular D, American Heart Association Council on Arteriosclerosis T, Vascular B (2011) 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 123(16):1788–1830. https://doi.org/10.1161/CIR.0b013e318214914f

    Article  PubMed  Google Scholar 

  8. Grifoni S, Olivotto I, Cecchini P, Pieralli F, Camaiti A, Santoro G, Conti A, Agnelli G, Berni G (2000) Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation 101(24):2817–2822

    Article  CAS  Google Scholar 

  9. Kreit JW (2004) The impact of right ventricular dysfunction on the prognosis and therapy of normotensive patients with pulmonary embolism. Chest 125(4):1539–1545

    Article  Google Scholar 

  10. Sista AK, Kearon C (2015) Catheter-directed thrombolysis for pulmonary embolism: where do we stand? JACC Cardiovasc Interv 8(10):1393–1395. https://doi.org/10.1016/j.jcin.2015.06.009

    Article  PubMed  Google Scholar 

  11. Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, Bluhmki E, Bouvaist H, Brenner B, Couturaud F, Dellas C, Empen K, Franca A, Galie N, Geibel A, Goldhaber SZ, Jimenez D, Kozak M, Kupatt C, Kucher N, Lang IM, Lankeit M, Meneveau N, Pacouret G, Palazzini M, Petris A, Pruszczyk P, Rugolotto M, Salvi A, Schellong S, Sebbane M, Sobkowicz B, Stefanovic BS, Thiele H, Torbicki A, Verschuren F, Konstantinides SV, Investigators P (2014) Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 370(15):1402–1411. https://doi.org/10.1056/NEJMoa1302097

    Article  PubMed  CAS  Google Scholar 

  12. Chatterjee S, Chakraborty A, Weinberg I, Kadakia M, Wilensky RL, Sardar P, Kumbhani DJ, Mukherjee D, Jaff MR, Giri J (2014) Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA 311(23):2414–2421. https://doi.org/10.1001/jama.2014.5990

    Article  PubMed  CAS  Google Scholar 

  13. Konstantinides SV, Meyer G (2019) The 2019 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 40(42):3453–3455. https://doi.org/10.1093/eurheartj/ehz726

    Article  PubMed  Google Scholar 

  14. Piazza G, Hohlfelder B, Jaff MR, Ouriel K, Engelhardt TC, Sterling KM, Jones NJ, Gurley JC, Bhatheja R, Kennedy RJ, Goswami N, Natarajan K, Rundback J, Sadiq IR, Liu SK, Bhalla N, Raja ML, Weinstock BS, Cynamon J, Elmasri FF, Garcia MJ, Kumar M, Ayerdi J, Soukas P, Kuo W, Liu PY, Goldhaber SZ, Investigators SI (2015) A prospective, single-arm, multicenter trial of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute massive and submassive pulmonary embolism: the SEATTLE II study. JACC Cardiovasc Interv 8(10):1382–1392. https://doi.org/10.1016/j.jcin.2015.04.020

    Article  PubMed  Google Scholar 

  15. Kucher N, Boekstegers P, Muller OJ, Kupatt C, Beyer-Westendorf J, Heitzer T, Tebbe U, Horstkotte J, Muller R, Blessing E, Greif M, Lange P, Hoffmann RT, Werth S, Barmeyer A, Hartel D, Grunwald H, Empen K, Baumgartner I (2014) Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 129(4):479–486. https://doi.org/10.1161/CIRCULATIONAHA.113.005544

    Article  PubMed  Google Scholar 

  16. Kuo WT, Banerjee A, Kim PS, DeMarco FJ, Levy JR, Facchini FR, Unver K, Bertini MJ, Sista AK, Hall MJ, Rosenberg JK, De Gregorio MA (2015) Pulmonary embolism response to fragmentation, embolectomy, and catheter thrombolysis (PERFECT). Chest 148(3):667–673. https://doi.org/10.1378/chest.15-0119

    Article  PubMed  Google Scholar 

  17. Anderson JL, Heidenreich PA, Barnett PG, Creager MA, Fonarow GC, Gibbons RJ, Halperin JL, Hlatky MA, Jacobs AK, Mark DB, Masoudi FA, Peterson ED, Shaw LJ, Measures AATFoP, Guidelines AATFoP (2014) ACC/AHA statement on cost/value methodology in clinical practice guidelines and performance measures: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and Task Force on Practice Guidelines. Circulation 129(22):2329–2345. https://doi.org/10.1161/CIR.0000000000000042

    Article  PubMed  Google Scholar 

  18. Arora S, Panaich SS, Ainani N, Kumar V, Patel NJ, Tripathi B, Shah P, Patel N, Lahewala S, Deshmukh A, Badheka A, Grines C (2017) Comparison of in-hospital outcomes and readmission rates in acute pulmonary embolism between systemic and catheter-directed thrombolysis (from the National Readmission Database). Am J Cardiol 120(9):1653–1661. https://doi.org/10.1016/j.amjcard.2017.07.066

    Article  PubMed  Google Scholar 

  19. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG (1995) Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implication. Arch Intern Med 155(5):469–473

    Article  CAS  Google Scholar 

  20. Arias E, Heron M, Xu J (2017) United States Life Tables, 2014. Natl Vital Stat Rep 66(4):1–64

    PubMed  Google Scholar 

  21. Kline JA, Steuerwald MT, Marchick MR, Hernandez-Nino J, Rose GA (2009) 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 136(5):1202–1210. https://doi.org/10.1378/chest.08-2988

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Hokusai VTEI, Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369(15):1406–1415. https://doi.org/10.1056/NEJMoa1306638

    Article  CAS  Google Scholar 

  23. Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F, Albanese P, Biasiolo A, Pegoraro C, Iliceto S, Prandoni P, Thromboembolic Pulmonary Hypertension Study G (2004) Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 350(22):2257–2264. https://doi.org/10.1056/NEJMoa032274

    Article  PubMed  CAS  Google Scholar 

  24. Coyle K, Coyle D, Blouin J, Lee K, Jabr MF, Tran K, Mielniczuk L, Swiston J, Innes M (2016) Cost effectiveness of first-line oral therapies for pulmonary arterial hypertension: a modelling study. Pharmacoeconomics 34(5):509–520. https://doi.org/10.1007/s40273-015-0366-8

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sullivan PW, Lawrence WF, Ghushchyan V (2005) A national catalog of preference-based scores for chronic conditions in the United States. Med Care 43(7):736–749

    Article  Google Scholar 

  26. Dasta JF, Pilon D, Mody SH, Lopatto J, Laliberte F, Germain G, Bookhart BK, Lefebvre P, Nutescu EA (2015) Daily hospitalization costs in patients with deep vein thrombosis or pulmonary embolism treated with anticoagulant therapy. Thromb Res 135(2):303–310. https://doi.org/10.1016/j.thromres.2014.11.024

    Article  PubMed  CAS  Google Scholar 

  27. Wells PS, Prins MH, Beyer-Westendorf J, Lensing AWA, Haskell L, Levitan B, Laliberte F, Ashton V, Xiao Y, Lejeune D, Crivera C, Lefebvre P, Zhao Q, Yuan Z, Schein J, Prandoni P (2018) Health-care cost impact of continued anticoagulation with rivaroxaban vs aspirin for prevention of recurrent symptomatic VTE in the EINSTEIN-CHOICE trial population. Chest 154(6):1371–1378. https://doi.org/10.1016/j.chest.2018.08.1059

    Article  PubMed  Google Scholar 

  28. Lin J, Lingohr-Smith M, Kwong WJ (2014) Incremental health care resource utilization and economic burden of venous thromboembolism recurrence from a US payer perspective. J Manag Care Pharm 20(2):174–186. https://doi.org/10.18553/jmcp.2014.20.2.174

    Article  PubMed  CAS  Google Scholar 

  29. Ziaeian B, Heidenreich PA, Xu H, DeVore AD, Matsouaka RA, Hernandez AF, Bhatt DL, Yancy CW, Fonarow GC (2018) Medicare expenditures by race/ethnicity after hospitalization for heart failure with preserved ejection fraction. JACC Heart Fail 6(5):388–397. https://doi.org/10.1016/j.jchf.2017.12.007

    Article  PubMed  Google Scholar 

  30. Kirson NY, Birnbaum HG, Ivanova JI, Waldman T, Joish V, Williamson T (2011) Excess costs associated with patients with chronic thromboembolic pulmonary hypertension in a US privately insured population. Appl Health Econ Health Policy 9(6):377–387. https://doi.org/10.2165/11592440-000000000-00000

    Article  PubMed  Google Scholar 

  31. Said Q, Martin BC, Joish VN, Kreilick C, Mathai SC (2012) The cost to managed care of managing pulmonary hypertension. J Med Econ 15(3):500–508. https://doi.org/10.3111/13696998.2012.665109

    Article  PubMed  Google Scholar 

  32. Konstantinides SV, Vicaut E, Danays T, Becattini C, Bertoletti L, Beyer-Westendorf J, Bouvaist H, Couturaud F, Dellas C, Duerschmied D, Empen K, Ferrari E, Galie N, Jimenez D, Kostrubiec M, Kozak M, Kupatt C, Lang IM, Lankeit M, Meneveau N, Palazzini M, Pruszczyk P, Rugolotto M, Salvi A, Sanchez O, Schellong S, Sobkowicz B, Meyer G (2017) Impact of thrombolytic therapy on the long-term outcome of intermediate-risk pulmonary embolism. J Am Coll Cardiol 69(12):1536–1544. https://doi.org/10.1016/j.jacc.2016.12.039

    Article  PubMed  CAS  Google Scholar 

  33. Fasullo S, Scalzo S, Maringhini G, Ganci F, Cannizzaro S, Basile I, Cangemi D, Terrazzino G, Parrinello G, Sarullo FM, Baglini R, Paterna S, Di Pasquale P (2011) Six-month echocardiographic study in patients with submassive pulmonary embolism and right ventricle dysfunction: comparison of thrombolysis with heparin. Am J Med Sci 341(1):33–39. https://doi.org/10.1097/MAJ.0b013e3181f1fc3e

    Article  PubMed  Google Scholar 

  34. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M, Investigators M (2013) Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" trial). Am J Cardiol 111(2):273–277. https://doi.org/10.1016/j.amjcard.2012.09.027

    Article  PubMed  Google Scholar 

  35. Meneveau N, Ider O, Seronde MF, Chopard R, Davani S, Bernard Y, Schiele F (2013) Long-term prognostic value of residual pulmonary vascular obstruction at discharge in patients with intermediate- to high-risk pulmonary embolism. Eur Heart J 34(9):693–701. https://doi.org/10.1093/eurheartj/ehs365

    Article  PubMed  CAS  Google Scholar 

  36. Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH (1996) The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 125(1):1–7

    Article  CAS  Google Scholar 

  37. Khan F, Rahman A, Carrier M, Kearon C, Weitz JI, Schulman S, Couturaud F, Eichinger S, Kyrle PA, Becattini C, Agnelli G, Brighton TA, Lensing AWA, Prins MH, Sabri E, Hutton B, Pinede L, Cushman M, Palareti G, Wells GA, Prandoni P, Buller HR, Rodger MA, Collaborators M (2019) Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis. BMJ 366:l4363. https://doi.org/10.1136/bmj.l4363

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kabrhel C, Ali A, Choi JG, Hur C (2017) Systemic thrombolysis, catheter-directed thrombolysis, and anticoagulation for intermediate-risk pulmonary embolism: a simulation modeling analysis. Acad Emerg Med 24(10):1235–1243. https://doi.org/10.1111/acem.13242

    Article  PubMed  Google Scholar 

  39. Perlroth DJ, Sanders GD, Gould MK (2007) Effectiveness and cost-effectiveness of thrombolysis in submassive pulmonary embolism. Arch Intern Med 167(1):74–80. https://doi.org/10.1001/archinte.167.1.74

    Article  PubMed  Google Scholar 

  40. Kaymaz C, Akbal OY, Tanboga IH, Hakgor A, Yilmaz F, Ozturk S, Poci N, Turkday S, Ozdemir N, Konstantinides S (2018) Ultrasound-assisted catheter-directed thrombolysis in high-risk and intermediate-high-risk pulmonary embolism: a meta-analysis. Curr Vasc Pharmacol 16(2):179–189. https://doi.org/10.2174/1570161115666170404122535

    Article  PubMed  CAS  Google Scholar 

  41. Bloomer TL, El-Hayek GE, McDaniel MC, Sandvall BC, Liberman HA, Devireddy CM, Kumar G, Fong PP, Jaber WA (2017) Safety of catheter-directed thrombolysis for massive and submassive pulmonary embolism: results of a multicenter registry and meta-analysis. Catheter Cardiovasc Interv 89(4):754–760. https://doi.org/10.1002/ccd.26900

    Article  PubMed  Google Scholar 

  42. Rali PM, Criner GJ (2018) Submassive pulmonary embolism. Am J Respir Crit Care Med 198(5):588–598. https://doi.org/10.1164/rccm.201711-2302CI

    Article  PubMed  Google Scholar 

  43. Goldhaber SZ, Agnelli G, Levine MN (1994) Reduced dose bolus alteplase vs conventional alteplase infusion for pulmonary embolism thrombolysis. An international multicenter randomized trial. The Bolus Alteplase Pulmonary Embolism Group. Chest 106(3):718–724. https://doi.org/10.1378/chest.106.3.718

    Article  PubMed  CAS  Google Scholar 

  44. Kiser TH, Burnham EL, Clark B, Ho PM, Allen RR, Moss M, Vandivier RW (2018) Half-dose versus full-dose alteplase for treatment of pulmonary embolism. Crit Care Med 46(10):1617–1625. https://doi.org/10.1097/CCM.0000000000003288

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. FlowTriever Pulmonary Embolectomy Clinical Study (FLARE). https://clinicaltrials.gov/ct2/show/NCT02692586.

  46. Dudzinski DM, Giri J, Rosenfield K (2017) Interventional Treatment of Pulmonary Embolism. Circ Cardiovasc Interv. https://doi.org/10.1161/CIRCINTERVENTIONS.116.004345

    Article  PubMed  Google Scholar 

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Funding

SM was supported by Grant T32: 5T32HL007633 from the National Heart Lung and Blood Institute (NHLBI).

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SEM and JZ developed the model, interpreted and analyzed the data, and wrote the manuscript. AP contributed to model design, data interpretation and manuscript editing. FR and GW contributed to data interpretation and the editing of the manuscript.

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Correspondence to Stefanie E. Mason.

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SM was funded by the NHLBI (as stated above). GW has received grants from BTG Interventional Medicine to analyze images related to catheter-directed therapy. JZ, FR, and AP have no conflicts of interest to disclose. Neither the NHLBI nor BTG had any involvement in model design, analysis or interpretation of model data, preparation, review, or approval of the manuscript, or the decision to submit the manuscript for publication.

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Mason, S.E., Zhu, J., Rahaghi, F.N. et al. Cost-effectiveness microsimulation of catheter-directed thrombolysis in submassive pulmonary embolism using a right ventricular function model. J Thromb Thrombolysis 49, 673–680 (2020). https://doi.org/10.1007/s11239-020-02058-y

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Keywords

  • Pulmonary embolism
  • Thrombolytic therapy
  • Right ventricle
  • Pulmonary embolism therapy
  • Fibrinolytic agents