Key Point

In a pro/con presentation, speakers debated the issue of whether traditional end points should remain the standard of care for patients with PAH.

SAN DIEGO—The six-minute walk test, NYHA functional class, and other traditional end points should remain the standard of care for following patients with pulmonary arterial hypertension (PAH), stated David B. Badesch, MD, during a pro-con debate at the annual meeting of the American Thoracic Society.¹

“There are a lot of data that support using traditional end points,” pointed out Dr. Badesch, Professor in the Department of Pulmonary Sciences and Critical Care Medicine at the University of Colorado Health Sciences Center in Denver. “Traditional end points are of functional significance, and they translate well to clinical practice and follow-up.”

Some of the strongest data favoring traditional end points are from a pivotal trial of epoprostenol for NYHA functional class III or IV primary PAH. In that trial, Sitbon and colleagues found that the baseline six-minute walk distance independently predicted survival.² In other high-quality research, a six-minute walk distance of less than 250 meters was associated with significantly increased mortality in PAH.

It has long been known that functional class correlates closely with survival in untreated PAH patients, said Dr. Badesch. Increased right atrial pressure, depressed cardiac output, and additional undesirable hemodynamic changes have shown a negative association with survival in several PAH trials.

Dr. Badesch stressed that feasibility trials can be done only with traditional end points because no others have been adequately investigated and validated. He added that traditional end points are firmly entrenched; the FDA and other regulatory agencies tend to rely heavily on them, and they have been used in most of the clinical trials involving patients with PAH.

However, Dr. Badesch acknowledged that PAH is not characterized only by vasoconstriction and that end points addressing the structural component of the disease are needed. “If we could come up with sensitive markers that reflect the underlying pathology, I think that would be a significant advance,” he concluded.

THE OPPOSING VIEWPOINT

Taking the con side in the debate, Keith D. McNeil, MBBS, said that traditional end points should not remain the standard of care for following PAH patients. He referred to these end points as merely descriptors of a patient’s state at one point in time and claimed that the data needed to determine their optimal values do not exist.

Moreover, there are many unanswered questions about exactly what traditional end points mean and how relevant they are clinically. “We are largely ignoring the needs of our patients by looking at these parameters,” asserted Dr. McNeil, Head of Transplant Services at Prince Charles Hospital in Chermside, Australia.

He was especially skeptical of the six-minute walk test. “How relevant is it to be able to walk an additional 36 meters?” he asked, referring to the BREATHE-1 trial in which bosentan produced approximately that measure of improvement.³

The test is less reliable in practice than in trials, he added. Whether an improvement indicates a positive treatment response, the amount of change that would be needed to confirm such a response, and if there is a correlation with survival are all unknown. “If we are going to set something up as a standard, we should know a lot more about it than this,” Dr. McNeil remarked.

No single hemodynamic variable is adequate for evaluating PAH patients—which is why so many are used, he said. Although some of these variables do correlate with survival, the correlations reveal nothing about the length of survival, degree of treatment response, or quality of life.

NYHA functional class “is an incredibly subjective parameter, both from the patient’s and physician’s point of view,” Dr. McNeil maintained. Moreover, he said, the differences between NYHA class II and early class III patients are blurred; thus, functional class is not an effective end point in PAH.

Because the aim of PAH treatment is to improve right ventricular performance, end points that accurately reflect that performance should be used, suggested Dr. McNeil. The B-type natriuretic peptide level is one promising option, he said. Other biologic markers that may closely reflect right ventricular performance include serotonin, prostanes, endothelin-1, C-reactive protein, and D-dimer.

—Timothy Begany

Reference
1. McLaughlin VV, Tapson VF, Robbins IM, et al. Pro-con debates in pulmonary arterial hypertension: traditional endpoints of six-minute walk and hemodynamics remain the standard of care by which to follow PAH patients. Presented at: annual meeting of the American Thoracic Society; May 24, 2005; San Diego, Calif.
2. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40:780-788.
3. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903.

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