The 6MWT as a prognostic tool in pulmonary arterial hypertension: results from the COMPERA registry
In patients with pulmonary arterial hypertension, the 6-Minute Walk Test (6MWT) is recommended for risk stratification and follow-up by all guidelines. However, the prognostic value of the 6MWT has been discussed controversially. We sought to compare and validate all published 6MWT cut-off points.
From the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA)—registry we identified 2391 patients with pulmonary arterial hypertension who had at least one documented 6MWT measurement. A Medline search identified a total of 21 different threshold values for either single-point or change of 6MWT. All values were tested individually for prognostication of 1-year, 2-year and 3-year all-cause mortality.
The highest positive likelihood ratio was a cut-off value < 165 ms, whereas the best negative likelihood ratio was found to be a threshold of 440 ms. Furthermore, improvement in 6MWT had considerably less predictive value on mortality and survival than deterioration. Moreover, absolute single-point values outperformed change values for both improvement and worsening.
Our data confirmed the prognostic relevance of the 6MWT and support the cut-off values stated in most recent guidelines. Furthermore, these results explain why changes in 6MWT did not correlate consistently with prognosis in previous studies.
KeywordsPulmonary arterial hypertension PAH 6-Minute walk test Risk stratification Cut-off value
The authors are indebted to the COMPERA investigators.
This work was supported by the German Centre of Lung Research (DZL) and the Deutsche Forschungsgemeinschaft (Professor Hoeper, HO 1599/2-1). COMPERA is funded by unrestricted grants from Actelion Pharmaceuticals, Bayer and GSK. These companies were not involved in data analysis or the writing of this manuscript.
Compliance with ethical standards
Conflict of interest
Dr. Zelniker has nothing to disclose. Dr. Huscher reports personal fees from Actelion Pharmaceuticals, Switzerland outside the submitted work. AVN reports speakers fees from actelion, and Bayer outside the submitted work. Dr. Ewert has nothing to disclose. Dr. Lange reports other from Compera-Registry, during the conduct of the study; grants, personal fees and non-financial support from Actelion, grants, personal fees and non-financial support from Bayer, grants and personal fees from GlaxoSmithKline, personal fees from Pfizer, personal fees from MSD, grants and personal fees from United Therapeutics, outside the submitted work. Dr. Klose reports grants and personal fees from Actelion, grants and personal fees from GSK, personal fees from Pfizer, grants and personal fees from Bayer, personal fees from MSD, personal fees from United Therapeutics, personal fees from OMT, outside the submitted work. Dr. Dumitrescu reports other from COMPERA-Registry, during the conduct of the study; grants, personal fees and non-financial support from Actelion Pharmaceuticals, personal fees from Bayer, personal fees from GlaxoSmithKline, personal fees from Novartis, personal fees from Servier, outside the submitted work. Dr. Halank reports personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees and non-financial support from GlaxoSmithKline, personal fees from OMT, personal fees from MSD SHARP & DOHME, personal fees from Pfizer, outside the submitted work. Dr. Held reports grants from Actelion, honoraria for lectures from Actelion, Bayer Healthcare, Berlin Chemie, Boehringer Ingelheim, GSK, MSD, Novartis, Pfizer, honoraria for advisory board activities from Actelion, Bayer, Boehringer, GSK, MSD, outside the submitted work and partizipation in clinical trails of Actelion, Bayer, GSK, Pfizer, United Therapeutics. Dr. Gall has nothing to disclose. Dr. Pittrow reports personal fees from Actelion, personal fees from Bayer, personal fees from Pfizer, outside the submitted work. Dr. Hoeper reports personal fees from Actelion, personal fees from Bayer, personal fees from Gilead, personal fees from GSK, personal fees from MSD, personal fees from Pfizer, outside the submitted work. Dr. Frankenstein has nothing to disclose.
- 1.Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M (2004) Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43(12 Suppl S):13S-24S. https://doi.org/10.1016/j.jacc.2004.02.029 PubMedGoogle Scholar
- 2.Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitland ML, Michelakis ED, Morrell NW, Newman JH, Rabinovitch M, Schermuly R, Stenmark KR, Voelkel NF, Yuan JX, Humbert M (2009) Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 54(1 Suppl):S10-19. https://doi.org/10.1016/j.jacc.2009.04.006 Google Scholar
- 3.Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M (2015) 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 46(4):903–975. https://doi.org/10.1183/13993003.01032-2015 CrossRefPubMedGoogle Scholar
- 4.Ewert R, Richter MJ, Steringer-Mascherbauer R, Grunig E, Lange TJ, Opitz CF, Warnke C, Ghofrani HA (2017) Intravenous treprostinil infusion via a fully implantable pump for pulmonary arterial hypertension. Clin Res Cardiol 106(10):776–783. https://doi.org/10.1007/s00392-017-1114-1 CrossRefPubMedGoogle Scholar
- 6.Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G, Guidelines ESCCfP (2009) Guidelines for the diagnosis and treatment of pulmonary hypertension: the 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 the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 30(20):2493–2537. https://doi.org/10.1093/eurheartj/ehp297 CrossRefPubMedGoogle Scholar
- 7.McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, American College of Cardiology Foundation Task Force on Expert Consensus D, American Heart A, American College of Chest P, American Thoracic Society I, Pulmonary Hypertension A (2009) ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 53 (17):1573–1619. https://doi.org/10.1016/j.jacc.2009.01.004 CrossRefPubMedGoogle Scholar
- 8.Galie N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, Shapiro S, White RJ, Chan M, Beardsworth A, Frumkin L, Barst RJ, Pulmonary Arterial H, Response to Tadalafil Study G (2009) Tadalafil therapy for pulmonary arterial hypertension. Circulation 119(22):2894–2903. https://doi.org/10.1161/CIRCULATIONAHA.108.839274 CrossRefPubMedGoogle Scholar
- 10.Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G, Sildenafil Use in Pulmonary Arterial Hypertension Study G (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353 (20):2148–2157. https://doi.org/10.1056/NEJMoa050010 CrossRefPubMedGoogle Scholar
- 12.Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ, Group P-S (2013) Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 369(4):330–340. https://doi.org/10.1056/NEJMoa1209655 CrossRefPubMedGoogle Scholar
- 13.Fritz JS, Blair C, Oudiz RJ, Dufton C, Olschewski H, Despain D, Gillies H, Kawut SM (2013) Baseline and follow-up 6-min walk distance and brain natriuretic peptide predict 2-year mortality in pulmonary arterial hypertension. Chest 143(2):315–323. https://doi.org/10.1378/chest.12-0270 CrossRefPubMedGoogle Scholar
- 15.McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galie N, Gibbs JS, Kim NH, Oudiz RJ, Peacock A, Provencher S, Sitbon O, Tapson VF, Seeger W (2009) End points and clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol 54(1 Suppl):S97-107. https://doi.org/10.1016/j.jacc.2009.04.007 PubMedGoogle Scholar
- 16.Savarese G, Paolillo S, Costanzo P, D’Amore C, Cecere M, Losco T, Musella F, Gargiulo P, Marciano C, Perrone-Filardi P (2012) Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J Am Coll Cardiol 60(13):1192–1201. https://doi.org/10.1016/j.jacc.2012.01.083 CrossRefPubMedGoogle Scholar
- 17.Olsson KM, Delcroix M, Ghofrani HA, Tiede H, Huscher D, Speich R, Grunig E, Staehler G, Rosenkranz S, Halank M, Held M, Lange TJ, Behr J, Klose H, Claussen M, Ewert R, Opitz CF, Vizza CD, Scelsi L, Vonk-Noordegraaf A, Kaemmerer H, Gibbs JS, Coghlan G, Pepke-Zaba J, Schulz U, Gorenflo M, Pittrow D, Hoeper MM (2014) Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation 129(1):57–65. https://doi.org/10.1161/CIRCULATIONAHA.113.004526 CrossRefPubMedGoogle Scholar
- 20.Pittrow D, Ghofrani HA, Opitz CF, Huscher D, Hoeper MM (2009) [International, prospective register for the documentation of first-line and maintenance therapy in patients with pulmonary hypertension (CompERA-XL)]. Dtsch Med Wochenschr 134(Suppl 5):S173–S175. https://doi.org/10.1055/s-0029-1225318 CrossRefPubMedGoogle Scholar
- 22.Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD (2010) Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 122(2):164–172. https://doi.org/10.1161/CIRCULATIONAHA.109.898122 CrossRefPubMedGoogle Scholar
- 24.Gabler NB, French B, Strom BL, Palevsky HI, Taichman DB, Kawut SM, Halpern SD (2012) Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation 126(3):349–356. https://doi.org/10.1161/CIRCULATIONAHA.112.105890 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Frost AE, Badesch DB, Miller DP, Benza RL, Meltzer LA, McGoon MD (2013) Evaluation of the predictive value of a clinical worsening definition using 2-year outcomes in patients with pulmonary arterial hypertension: a REVEAL Registry analysis. Chest 144(5):1521–1529. https://doi.org/10.1378/chest.12-3023 CrossRefPubMedGoogle Scholar
- 28.Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Gerber MJ, Dufton C, Wiens BL, Rubin LJ, Ambrisentan in Pulmonary Arterial Hypertension RD-BP-CMESG (2008) Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 117 (23):3010–3019. https://doi.org/10.1161/CIRCULATIONAHA.107.742510 CrossRefPubMedGoogle Scholar
- 29.Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S, McLaughlin V, Hill N, Tapson VF, Robbins IM, Zwicke D, Duncan B, Dixon RA, Frumkin LR, Group S-S (2004) Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 169(4):441–447. https://doi.org/10.1164/rccm.200307-957OC CrossRefPubMedGoogle Scholar
- 31.Benza RL, Miller DP, Foreman AJ, Frost AE, Badesch DB, Benton WW, McGoon MD (2015) Prognostic implications of serial risk score assessments in patients with pulmonary arterial hypertension: a Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) analysis. J Heart Lung Transplant 34(3):356–361. https://doi.org/10.1016/j.healun.2014.09.016 CrossRefPubMedGoogle Scholar
- 32.Tyndall AJ, Bannert B, Vonk M, Airo P, Cozzi F, Carreira PE, Bancel DF, Allanore Y, Muller-Ladner U, Distler O, Iannone F, Pellerito R, Pileckyte M, Miniati I, Ananieva L, Gurman AB, Damjanov N, Mueller A, Valentini G, Riemekasten G, Tikly M, Hummers L, Henriques MJ, Caramaschi P, Scheja A, Rozman B, Ton E, Kumanovics G, Coleiro B, Feierl E, Szucs G, Von Muhlen CA, Riccieri V, Novak S, Chizzolini C, Kotulska A, Denton C, Coelho PC, Kotter I, Simsek I, de la Pena Lefebvre PG, Hachulla E, Seibold JR, Rednic S, Stork J, Morovic-Vergles J, Walker UA (2010) Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 69(10):1809–1815. https://doi.org/10.1136/ard.2009.114264 CrossRefPubMedGoogle Scholar
- 33.Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Cottin V, Degano B, Jais X, Montani D, Souza R, Simonneau G (2010) Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 122(2):156–163. https://doi.org/10.1161/CIRCULATIONAHA.109.911818 CrossRefPubMedGoogle Scholar
- 35.Frankenstein L, Remppis A, Graham J, Schellberg D, Sigg C, Nelles M, Katus HA, Zugck C (2008) Gender and age related predictive value of walk test in heart failure: do anthropometrics matter in clinical practice? Int J Cardiol 127(3):331–336. https://doi.org/10.1016/j.ijcard.2007.04.087 CrossRefPubMedGoogle Scholar
- 36.Frankenstein L, Zugck C, Nelles M, Schellberg D, Katus H, Remppis A (2008) Sex-specific predictive power of 6-minute walk test in chronic heart failure is not enhanced using percent achieved of published reference equations. J Heart Lung Transplant 27(4):427–434. https://doi.org/10.1016/j.healun.2008.01.010 CrossRefPubMedGoogle Scholar