0
Editorials |

Has the 6-Min Walk Distance Run Its Course?Has the 6-Min Walk Distance Run Its Course? FREE TO VIEW

Vallerie V. McLaughlin, MD, FCCP
Author and Funding Information

From the Department of Medicine, Division of Cardiovascular Medicine, University of Michigan Health System.

Correspondence to: Vallerie V. McLaughlin, MD, FCCP, Department of Medicine, University of Michigan, 1500 E Medical Center Dr, SPC 5853, Ann Arbor, MI 48109; e-mail: vmclaugh@med.umich.edu


Financial/nonfinancial disclosures: The author has reported to CHEST the following potential conflicts of interest: Dr McLaughlin has received speaking and/or consulting fees from Actelion Pharmaceuticals, Ltd; Bayer; Gilead; and United Therapeutics Corp. The University of Michigan has received funding for multicentre clinical trials from Actelion Pharmaceuticals, Ltd; Bayer; Gilead; Novartis AG; and United Therapeutics Corp.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(6):1363-1364. doi:10.1378/chest.12-1110
Text Size: A A A
Published online

Therapeutic advances in the field of pulmonary arterial hypertension (PAH) have been considerable over the past 2 decades. We now have numerous US Food and Drug Administration-approved therapies that fall into three classes: the prostanoids, the endothelin receptor antagonists, and the phosphodiesterase type 5 inhibitors. Therapies in several novel therapeutic classes are being investigated.

The prostanoids are among the most effective therapies, particularly for patients with more advanced disease. They are, however, hindered by cumbersome delivery systems requiring continuous IV infusion (epoprosentol and treprostinil), continuous subcutaneous infusion (treprostinil), or frequent interment inhalation (iloprost and treprostinil). The “holy grail” of prostanoid therapy would be an effective, well-tolerated, oral form. Beraprost is an oral prostanoid that is currently approved only in Japan. Randomized controlled trial data with beraprost are contradictory, with one trial demonstrating an improvement in 6-min walk distance (6MWD) at 12 weeks and another establishing that beraprost failed to prevent disease progression at 1 year.1,2

In this issue of CHEST (see page 1383), Tapson et al3 report the results of the Oral Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Patients on Background Endothelin Receptor Antagonist and/or Phosphodiesterase Type 5 Inhibitor Therapy (FREEDOM-C) Study, a randomized, placebo-controlled trial of oral treprostinil for the treatment of patients with PAH on background therapy with endothelin receptor antagonists and/or phosphodiesterase type 5 inhibitors. In this trial, 350 patients with PAH were randomized to placebo or oral treprostinil and followed over 16 weeks with the primary end point being the 6MWD. The placebo-corrected median difference in change in 6MWD over the 16 weeks was not significant at 11 m (P = .07). There was also no change in the secondary end point of time to clinical worsening. There were clear limitations of the study that likely contributed to this neutral result, including the high dropout rate (22% subjects on active drug, 14% of subjects receiving placebo), high frequency of dual, background, oral therapy (45%), and difficulty with dose titration. Did the drug fail or did the study design fail?

Primary end points in randomized controlled trials must meet three criteria: They should be (1) clinically relevant, (2) sensitive to treatment effect, and (3) measurable and interpretable. Survival is the most robust end point that meets these criteria, but is impractical in a disease state such as PAH, in which trials enroll hundreds, rather than thousands, of patients, and for which there are currently multiple effective therapies. The surrogate end point most commonly used in PAH is the 6MWD.

Nearly 2 decades ago, IV epoprostenol was approved by the US Food and Drug Administration based on a 12-week randomized trial that demonstrated an improvement in the primary end point of 6MWD.4 Epoprostenol remains the only therapy for PAH that has established a survival benefit in the context of a randomized controlled trial. With the exception of iloprost, every other PAH therapy was approved based on trials in which the 6MWD was the primary end point. While there are many limitations of the 6MWD, it has been an effective surrogate end point for clinical trials in PAH. However, the landscape of PAH is now substantially different than when the epoprostenol trials commenced 2 decades ago.

Figure 1 emphasizes some of the changes in the PAH environment that have occurred over the past 20 years. When we embarked upon the initial epoprostenol trials, there were no specific therapies for PAH. Very ill, often incident/newly diagnosed patients were cared for in a handful of expert centers. Over time, circumstances have changed. Currently, patients are cared for at many centers and in the community and enjoy a longer (but far from ideal) survival. Patients enrolled in clinical trials tend to be prevalent patients (in some cases having been diagnosed years earlier) who are less ill and are frequently on background PAH-specific therapy. These factors potentially reduce the discriminatory ability of an end point such as the 6MWD. For example, incident patients are at higher risk for death and deterioration, and the results from several add-on therapy trials have suggested that improvements in 6MWD may be blunted in patients already on PAH-specific therapy.5-8 While there has been an abundance of change in the rest of the terrain, why are we still using the same end point for clinical trials in PAH?

Figure Jump LinkFigure 1. Given the changes in PAH treatment, short-term assessment of 6MWD may not be the best PAH trial end point in 2012. 6MWD =6-min walk distance; EU = European Union; FC = functional class; PAH = pulmonary arterial hypertension; Pts = patients; Tx = therapy; US = United States.Grahic Jump Location

Given the evolution of PAH care and eligible clinical trial subjects, it is imperative that clinical trial design and end points evolve as well. To advance the field, we should move toward longer term time-to-clinical-worsening trials, potentially even event-driven morbidity/mortality trials. This type of trial design was proposed at the 4th World Symposium on Pulmonary Hypertension and advocates a clinically relevant end point that is sensitive to treatment effect and is measurable and interpretable.9 The components of this composite end point should be standardized for future trials. While hard events, such as death and hospitalization for PAH, are clear; softer events, such as disease progression and the need for additional therapy, require clarification and standardization. It is critical that events be adjudicated by a blinded committee. Several ongoing PAH trials have adopted such a design and are likely to make meaningful contributions to the PAH field.

So, is oral treprostinil an effective therapy for PAH? All we can say from the current study is that, in a population of previously diagnosed patients on background PAH-specific therapy, oral treprostinil did not improve exercise capacity as measured by 6MWD at 16 weeks. As in previous studies of treprostinil, there was a dose response to therapy. Whether higher doses of oral treprostinil, if tolerated, given over a longer duration would result in clinically meaningful improvements is unknown. Perhaps we have also learned that the 6MWD has run its course as a primary end point in PAH clinical trials.

References

Galiè N, Humbert M, Vachiéry JL, et al Arterial Pulmonary Hypertension and Beraprost European (ALPHABET) Study Group Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002;39(9):1496-1502. [CrossRef] [PubMed]
 
Barst RJ, McGoon M, McLaughlin V, et al Beraprost Study Group Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41(12):2119-2125. [CrossRef] [PubMed]
 
Tapson VF, Torres F, Kermeen F, et al Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest. 2012;142(6):1383-1390.
 
Barst RJ, Rubin LJ, Long WA, et al The Primary Pulmonary Hypertension Study Group A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5):296-302. [CrossRef] [PubMed]
 
Humbert M, Sitbon O, Yaïci A, et al French Pulmonary Arterial Hypertension Network Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J. 2010;36(3):549-555. [CrossRef] [PubMed]
 
Simonneau G, Rubin LJ, Galiè N, et al PACES Study Group Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008;149(8):521-530. [PubMed]
 
McLaughlin VV, Oudiz RJ, Frost A, et al Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174(11):1257-1263. [CrossRef] [PubMed]
 
McLaughlin VV, Benza RL, Rubin LJ, et al Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55(18):1915-1922. [CrossRef] [PubMed]
 
McLaughlin VV, Badesch DB, Delcroix M, et al End points and clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1)(suppl):S97-S107. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Given the changes in PAH treatment, short-term assessment of 6MWD may not be the best PAH trial end point in 2012. 6MWD =6-min walk distance; EU = European Union; FC = functional class; PAH = pulmonary arterial hypertension; Pts = patients; Tx = therapy; US = United States.Grahic Jump Location

Tables

References

Galiè N, Humbert M, Vachiéry JL, et al Arterial Pulmonary Hypertension and Beraprost European (ALPHABET) Study Group Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002;39(9):1496-1502. [CrossRef] [PubMed]
 
Barst RJ, McGoon M, McLaughlin V, et al Beraprost Study Group Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41(12):2119-2125. [CrossRef] [PubMed]
 
Tapson VF, Torres F, Kermeen F, et al Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest. 2012;142(6):1383-1390.
 
Barst RJ, Rubin LJ, Long WA, et al The Primary Pulmonary Hypertension Study Group A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5):296-302. [CrossRef] [PubMed]
 
Humbert M, Sitbon O, Yaïci A, et al French Pulmonary Arterial Hypertension Network Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J. 2010;36(3):549-555. [CrossRef] [PubMed]
 
Simonneau G, Rubin LJ, Galiè N, et al PACES Study Group Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008;149(8):521-530. [PubMed]
 
McLaughlin VV, Oudiz RJ, Frost A, et al Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174(11):1257-1263. [CrossRef] [PubMed]
 
McLaughlin VV, Benza RL, Rubin LJ, et al Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55(18):1915-1922. [CrossRef] [PubMed]
 
McLaughlin VV, Badesch DB, Delcroix M, et al End points and clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1)(suppl):S97-S107. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

CHEST Journal Articles
CHEST Collections
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543