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Boston, MA
Drs. Roberts, Preston, and Hill are affiliated with the Division of Pulmonary, Critical Care, and Sleep Medicine, Tufts-New England Medical Center.
Correspondence to: Nicholas S. Hill, MD, FCCP, Division of Pulmonary, Critical Care and Sleep Medicine, Tufts-New England Medical Center, 750 Washington St, No. 257, Boston, MA 02111; e-mail: Nhill{at}tufts-nemc.org
In the 10 years since the approval of epoprostenol by the US Food and Drug Administration, impressive progress has been made in understanding the pathogenesis, diagnostic evaluation, and therapy of pulmonary arterial hypertension (PAH).1 In this issue of CHEST (see page 1198), Stuart Rich, a leading figure in the field for > 2 decades, offers a thoughtful and provocative critique of this progress.2 He argues that our therapeutic end points are inadequate and that, with the exception of therapy with IV epoprostenol, none of the newer approved therapies have any proven benefits beyond short-term effects on functional capacity. He calls for a reassessment of end points and calls on us to "demand" that clinical trials "address the mechanism of action, define the population in whom the drug may benefit and ... characterize how it has affected the status of the disease."
There is no arguing against Dr. Rich’s basic premise. The currently used end points are unquestionably flawed. The 6-min walk distance, which is the major outcome variable in most of the more recent clinical trials, is "affected by a multitude of factors, including age, gender, height, and weight." Dr. Rich could also have mentioned that it is influenced by patient effort and musculoskeletal conditions, and has a ceiling effect.3 The World Health Organization functional class is no better; it is a blunt instrument that relies on subjective interpretation by both the patient and caregiver. Hemodynamic responses to therapy in the clinical trials have been, in Dr. Rich’s view, "unimpressive," and the trials much too short. He bemoans the lack of any end points that reflect the true status of the disease such as assessments of vessel or cardiac structure, or molecular markers of the biological state of the disease. These are valid points.
Dr. Rich proposes that, going forward, trials should be long term (without specifying how long) and randomized, and should include robust end points. He advocates an exercise end point and suggests that cardiopulmonary exercise testing or the shuttle walk test may have advantages over the 6-min walk test. Although the cardiopulmonary exercise testing may be more "representative," it requires more technical expertise and expense than the 6-min walk and is not as practical when used for frequent monitoring. The shuttle walk test, on the other hand, deserves more investigation. While only slightly more costly or technically demanding than the 6-min walk test, it detected a 92% improvement in a recent study4 in COPD patients undergoing pulmonary rehabilitation, whereas the 6-min walk test found only a 17% improvement.
Dr. Rich also recommends invasive central hemodynamic analysis for all clinical trials. This is unquestionably a desirable goal but may not be practical for repeated monitoring. Clearly, right heart catheterization must be performed to confirm the diagnosis of PAH, but how often it is necessary in making subsequent treatment decisions is controversial. It is surprising that he does not mention the promise of noninvasive techniques to provide surrogate information for hemodynamics such as increasingly sophisticated echocardiographic-Doppler techniques and cardiac MRI.56 These have not yet been adequately tested, but hold promise for the future.
Dr. Rich’s next two suggested end points, anatomic and biological, have great appeal, but there are currently no methods for accurately assessing them short of lung biopsy. He refers to some promising techniques, such as intravascular ultrasound7 and micro-CT scanning,8 but these are presently investigational. Likewise, biological markers have great potential, but none, not even brain natriuretic peptide, has yet been shown to be a reliable therapeutic end point.
The last of Dr. Rich’s suggestions, that we need a survival end point, is the most provocative. He is unquestionably correct that we do not know whether the approved PAH therapies have any effect on long-term survival. The multiple long-term, open-label trials that have reported favorable survival times910 have been uncontrolled and not definitive. Furthermore, the trials on patients with arrhythmias or congestive heart failure that showed excess mortality rates in the treatment groups1112 are sobering reminders of the necessity to do controlled trials to prove efficacy. But what fully informed patient would enroll in a year-long (or longer), placebo-controlled survival trial when medications with proven efficacy (for functional status) are already available. Would we put a loved one in such a trial? To make it ethical, there would have to be stopping rules for patients whose conditions were deteriorating. But if too many patients stopped and crossed over (which is likely), then survival could not be assessed. Furthermore, who would pay for such a trial? The risk of showing lack of efficacy in the long term (as with the beraprost trial) would likely stem the enthusiasm of industry.
We commend Dr. Rich for making his plea, but our current end points are unlikely to be jettisoned anytime soon. We are reminded of Winston Churchill’s statement "Democracy is the worst form of government, except for all the others." We cannot reject our current end points until we develop better ones. We will continue to need subjective outcome measures of dyspnea and functional status because improving our patients’ sense of well being remains an important goal of therapy. Dr. Rich’s suggestions about exercise, anatomic, and biological end points will hopefully stimulate further investigation. The emerging technologies in proteomics and genomics to identify novel biomarkers are generating excitement in this regard. Understanding the long-term efficacy of our therapies is critically important, but long-term placebo-controlled survival trials are unlikely to be performed. Properly designed long-term observational trials may be worth contemplating, however.13 Complex phenotypes and low disease prevalence require that the PAH community intensify collaborative clinical and translational research efforts in order to address the important issues that Dr. Rich raises.
Footnotes
Dr. Roberts has no conflicts of interest. Drs. Preston and Hill have received honoraria from and Dr. Hill has served as a consultant for Actelion, Inc, Encysive, Cotherix, and Pfizer, Inc. Dr. Hill has received research grants from Actelion, Encysive, Cotherix, ICOS, Myogen, United Therapeutics, and Pfizer, Inc.
References
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