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MEDICAL OPTIONS - Respirology

February 2014

The 6-Minute Walk Test: Rethinking Outcome Measures in PAH

Editorial Review
Written by: Theodore Bosworth

Paul Hernandez, MDCM, FRCPC
Respirologist, QEII Health Sciences Centre
Professor, Department of Medicine
Dalhousie University
Halifax, Nova Scotia

The 6-minute walk test (6MWT) is a widely used, inexpensive, and easyto- administer field test of functional exercise capacity. In pulmonary arterial hypertension (PAH), the officebased 6MWT is used both to evaluate functional status and as a means to monitor response to therapy. The 6MWT has also been employed as the primary endpoint of clinical trials for more than 20 years, providing the basis for regulatory approval of most of the treatments currently available.1 In these placebo-controlled trials, the 6MWT provides an objective measure of change in a functional capacity. However, it is not proven that change in 6MWT distance is a sensitive predictor of long-term outcomes, which is an important limitation when comparing two active therapies with the potential to slow disease progression. It is due to this limitation that other endpoints, particularly survival or a composite endpoint that includes survival, are replacing 6MWT as a primary measure of benefit in trials of newer treatment strategies.

Background: 6MWT in Clinical Practice

Field and laboratory based exercise tests are practical methods with which to evaluate functional capacity. Although a variety of exercise tests have been employed, the 6MWT, which evaluates distance walked on a hard surface over 6 minutes and requires no special exercise equipment, is an indicator of ability to perform activities of daily living, and is easy to administer.2 In respiratory medicine, it is commonly used in the clinical evaluation of pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and other conditions in which lung function is moderately to severely impaired.3 In the 2002 American Thoracic Society (ATS) guidelines for practical evaluation of PAH in a clinical setting (See Table 1), it was suggested that the 6MWT may provide a better indication of change in quality of life and ability to perform activities of daily living than more specific measures of lung function like peak oxygen uptake.3 However, the guidelines cautioned that data supporting the use of the 6WMT as a single measure of functional status or as a predictor of long-term outcome in respiratory diseases is limited.

Table 1.

 

More than 10 years after publication of the ATS guidelines, the value of the 6MWT as a predictor of long-term outcome or surrogate marker of a change in the natural history of the disease, as opposed to a measure of symptomatic relief, remains unresolved. In COPD, for example, the discriminatory thresholds for predicting mortality with 6MWT over a 3-year period varied by patient characteristics, particularly age.4 The sensitivity of change in 6MWT distance to evaluate the benefit of bronchodilation in COPD has also been called into question.5 In ILD associated with scleroderma, the inability of 6MWT to predict outcome of the respiratory component was attributed to other physical impairments inhibiting functional capacity.6

Determining whether 6MWT is a useful predictor of outcome in PAH is critical because of a proliferation of new therapies that alone or in combination have the potential to slow disease progression. Symptom relief is important, but therapies have the potential to exert a favourable effect on the natural history of this disease, which makes it imperative to compare relative effects in order to define optimal care.

Measuring the Clinical Burden of PAH

Symptomatic improvement from treatment of PAH, a complex disorder with multiple etiologies and clinically relevant subclassifications,7,8 is not necessarily correlated with protection from the morbidity and mortality associated with its systemic complications. Due to a broad array of structural, mechanistic, and biochemical changes, a large number of variables are potentially useful for detecting and monitoring PAH.7 Of those variables with clinical relevance, it is useful to recognize that some variables may correlate with symptom expression, some with progression of the underlying pathophysiology, and others with both.

Clinically, an improvement in a functional classification, signifying a change in symptoms, is a valid measure of benefit from treatment even when these cannot be considered surrogates for an improvement in outcome. The functional classification from the World Health Organization (WHO), which ranges from I, signifying no impairments from symptoms on clinical activity, to IV, which signifies presence of PAH-related symptoms, such as dyspnea, at rest, provide ready evidence of the clinical burden of PAH, and it correlates with mortality;9 however, the evidence that a treatment-related change in functional class leads directly to improved survival is weaker. Similarly, relatively sophisticated tools for measuring exercise capacity, such as cardiopulmonary exercise testing (CPET), which measures metabolic gas exchange at rest and during exercise, is also prognostic,10 although a treatment-related improvement has not been definitively shown to alter long-term outcomes.

In the effort to measure benefit from treatment in PAH, both hard clinical endpoints, which relate to an objective reduction in hospitalizations and, ultimately, mortality, and softer patient-related endpoints, such as improvement in quality of life, should be considered. The debate regarding the optimal selection of endpoints for trials in PAH involves both. Controlling symptoms to permit patients to participate in activities of daily living is an important treatment goal, but optimal therapies will reduce both symptoms and slow disease progression, a benefit that must be demonstrated with a favourable effect on hard endpoints.

The 6MWT: Surrogate in PAH

The 6MWT was employed as the primary endpoint in initial pharmacological studies for several practical reasons, particularly the difficulty of showing a difference in survival over trials lasting typically 12 to 24 weeks,11 but 6MWT has never been shown to be a valid surrogate for a change in disease progression. Even though large clinical trials typically employed a broad array of other laboratory, radiologic, and clinical variables to monitor improvement in lung and cardiac function, the best explanation for the persistent use of 6MWT as a primary endpoint may simply be precedent. Even while several groups have argued in recent years that the primary endpoint in PAH trials should include survival because it provides perhaps the most convincing evidence of a relative advantage of one treatment strategy over another,11-13 there has also been increasing evidence, including analyses from the recently completed SERAPHIN trial, that change in the 6MWT is not an accurate predictor of this outcome.

Figures 1a and 1b

In a meta-analysis of 22 randomized trials, active treatments, relative to placebo, provided significant reductions in all-cause mortality (P<0.01) and a composite of hospitalization for PAH and lung transplantation (P<0.01), but no significant relationship was found between change in 6-minute outcome with hospitalization, or all-cause death (See Figures 1a and 1b).14 In another meta-analysis of 10 studies, active treatment was associated with a greater than 50% reduction in the odds ratio (OR) of a clinical event, but a meta-regression found that change in 6MWT explained only 22% of this treatment effect and was a weak surrogate for detecting the reduction in events.15

Rather than 6MWT as a single baseline measure, which does correlate with functional status and may be prognostic, it is change in 6MWT as a result of treatment that is being challenged as an outcome predictor. In a study that evaluated prognostic factors in patients treated with epoprostenol, low baseline 6MWT, along with other evidence of advanced disease, was a prognostic factor, but change in 6MWT, unlike improvement in some other measures, such as New York Heart Association (NYHA) functional class, was not.16 In that study, mortality curves were superimposable when those with equal or greater than 112 m improvement were compared to those with less (See Figure 2). More recently, baseline 6MWT was a predictor of 2-year mortality in two randomized trials of ambrisentan, but change in 6MWT at 12 weeks was not.17

Figure 2.

Changing the Treatment Paradigm

In the era prior to the introduction of vasoactive therapies, PAH was frequently detected at advanced stages when the functional limitations imposed by the disease were substantial and the 5-year survival rates were low.18 In the modern era, PAH is more often detected relatively early, and treatments, judging from a meta-analysis, are providing a survival benefit.19 While many forms of PAH remain progressive and ultimately fatal,20 the growing array of treatment strategies with the potential to prolong life suggests that trials should employ a primary endpoint that will show differences in effect on hard outcomes, particularly survival.

A task force convened to address trial design and endpoints, drew a similar conclusion.11 While acknowledging the value of a large host of endpoints designed to demonstrate change in lung and vascular function as well as improvements in quality of life, the members of this task force recommended that pivotal treatment trials employ a composite endpoint of time to clinical worsening with a uniform definition. Their proposed definition includes 6MWT when strictly defined and correlated with change in functional class, but it also includes all-cause mortality and PAH-related hospitalization. Adjudication of these endpoints was further recommended.

These principles have already been incorporated into trials, including the recently completed SERAPHIN study of the endothelin-receptor antagonist macitentan.21 Such endpoints are expected to provide a better indication of the relative utility of available options.

Summary

In selecting therapies for PAH, it is important to consider etiologies, functional class, and treatment goals. The 6MWT has been and remains a simple and useful measure of functional capacity, but it appears to have limited value as a surrogate for the efficacy of PAH therapy on disease progression when two strategies are being compared. In clinical trial design, more comprehensive composite endpoints that include hard clinical outcomes are expected to better capture the relative merits of emerging therapeutic options.

 

References

1. Rubin LJ. The 6-minute walk test in pulmonary arterial hypertension: how far is enough? Am J Respir Crit Care Med 2012;186:396-7.
2. Solway S, Brooks D, Lacasse Y, Thomas S. A qualitative systematic overview of the measurement properties of functional walk tests used in the cardiorespiratory domain. Chest 2001;119:256-70.
3. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111-7.
4. Spruit MA, Polkey MI, Celli B, et al. Predicting outcomes from 6-minute walk distance in chronic obstructive pulmonary disease. J Am Med Dir Assoc 2012;13:291-7.
5. Borel B, Provencher S, Saey D, Maltais F. Responsiveness of Various Exercise-Testing Protocols to Therapeutic Interventions in COPD. Pulmonary Medicine 2013;2013:410748.
6. Schoindre Y, Meune C, Dinh-Xuan AT, Avouac J, Kahan A, Allanore Y. Lack of specificity of the 6-minute walk test as an outcome measure for patients with systemic sclerosis. J Rheumatol 2009;36:1481-5.
7. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006;114:1417-31.
8. Simonneau G, Galiè N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5S-12S.
9. McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:78S-92S.
10. Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Exercise pathophysiology in patients with primary pulmonary hypertension. Circulation 2001;104:429-35.
11. McLaughlin VV, Badesch DB, Delcroix M, et al. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S97-107.
12. Committee for Medicinal Products for Human Use: Guidelines on the clinical investigations of medicinal products for the treatment of pulmonary arterial hypertension. EMA, 2009. (Accessed August 29, 2013, at http://www.emea.europa.eu/guideline/2009/12/ WC500016686.pdf.).
13. Galiè N, Simonneau G, Barst RJ, Badesch D, Rubin L. Clinical worsening in trials of pulmonary arterial hypertension: results and implications. Curr Opin Pulm Med 2010;16 Suppl 1:S11-9.
14. Savarese G, Paolillo S, Costanzo P, et al. 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 2012;60: 1192-201.
15. Gabler NB, French B, Strom BL, et al. Validation of  6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation 2012;126:349-56.
16. 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;40:780-8.
17. Fritz JS, Blair C, Oudiz RJ, et al. Baseline and follow-up 6-min walk distance and brain natriuretic peptide predict 2-year mortality in pulmonary arterial hypertension. Chest 2013;143:315-23.
18. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343-9.
19. Galiè N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403.
20. Humbert M. Impression, sunset. Circulation 2013;127:1098-100.
21. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369:809-18.


Time to Clinical Worsening: Defining an Endpoint

David Langleben, MD, FRCPC
Director, Centre for Pulmonary Vascular Disease
Jewish General Hospital
Professor of Medicine
McGill University
Montreal, Quebec

In the phase 3 trials that have studied current therapies for pulmonary arterial hypertension (PAH) for efficacy, time to clinical worsening (TTCW) has been a common secondary endpoint. Unlike the 6-minute walk test (6MWT), which reflects symptomatic change, TTCW has the potential to reflect the impact of treatment on a much broader range of outcomes, particularly protection against the events, like hospitalizations or death, that characterize PAH progression.In the absence of curative therapies, it is appropriate to consider the effects of therapies on harder endpoints, like mortality or PAH-related hospitalizations, as well as measures of quality of life and functional capacity. As a primary endpoint, TTCW has the potential to capture the effects of therapy across multiple relevant outcomes, but consistent and reproducible definitions of TTCW are needed. As therapies improve, it will be increasingly important to evaluate whether milestones of disease progression can be attenuated, particularly when two treatment strategies are compared.

Current Targets of Therapy

PAH is one of five classes of pulmonary hypertension (PH), a hemodynamically defined term that encompasses a broad array of pathophysiologies.1 PAH may develop in association with a number of precipitating conditions, like congenital cardiac shunts, HIV, portal hypertension and connective tissue diseases, and other causes. Idiopathic PAH has an incidence of 1 or 2 per million.2 In PAH, genetic susceptibility may play a significant role although the interplay between specific mutations and environmental triggers is not fully understood.3 It is possible if not likely that the different etiologies that produce PAH drive similar pathophysiological processes, resulting in remodeling and narrowing of the pulmonary microvasculature.

Differences in the relative activation or deactivation of the multiple biochemical pathways implicated in the steps leading to tissue remodeling in PAH may explain differences in the speed at which it progresses. While all of the available therapies for PAH have similar hemodynamic effects, the different pathways with which this is achieved may affect other molecular signaling. For example, epoprostenol, as well as other prostacyclin and prostacyclin analogues, bind to the prostacyclin receptor to initiate a series of molecular steps leading to vasodilation through activation of G protein and upregulation of cAMP.4 However, these agents have other actions, particularly anti-platelet effects that may also be relevant to control of PAH, and they can alter the pulmonary production of endothelin-1.5,6

Similarly, endothelin receptor antagonists (ERA) block the receptor on endothelial cells responsible for release of endothelin, a potent vasoconstrictor and mitogen, but this receptor system appears to be interlinked with pressure-independent molecular pathways that may contribute to PAH progression.7 This includes pro-inflammatory activation of cytokines and pro-proliferative mechanisms such as anti-apoptotic activity.8 The relative effects of different ERA agents may differ according to their inhibition of endothelin receptor subtype A (ETA), which appears to be primarily involved in proliferative activity, and subtype B (ETB), which appears to primarily mediate vasodilatory and endothelin-clearance activity.7 The clinical differences between nonselective versus selective receptor blockade have not been thoroughly studied.9

Table 1

Phosphodiesterase-5 (PDE-5) inhibitors produce vasodilation by blocking hydrolysis of cyclic guanylate monophosphate (cGMP), which relaxes smooth muscle cells.10 The first clinically approved soluble guanylate cyclase stimulator, riociguat, directly stimulates cGMP production,11 The association between increased cGMP activity and anti-proliferative effects is again potentially relevant to inhibition of remodeling in the pulmonary arteries.12

Most of the current therapies for PAH were approved on the basis of improvements in 6MWT relative to placebo. It is likely that each of these agents acts on many pathways that may be relevant to disease progression. Relative to a single hard endpoint, such as mortality, which is likely to require large trials with extensive follow-up, the advantage of a composite TTCW endpoint that encompasses both functional capacity and event-free survival is its feasibility as an endpoint in smaller, shorter trials. Both outcomes are relevant to patient well-being.

TTCW as Clinical Endpoint

TTCW has been included among secondary endpoints in clinical trials for PAH for more than 10 years. In BREATHE-1, a placebocontrolled trial that led to regulatory approval of bosentan, TTCW was defined as the combined endpoint of death, lung transplantation, hospitalization for pulmonary hypertension, lack of clinical improvement or worsening leading to discontinuation, need for epoprostenol therapy, or atrial septostomy.13 In ARIES-1, a placebo-controlled trial that led to regulatory approval of ambrisentan, the definition of TTCW was similar, but patients who required additional PAH medications for clinical worsening were withdrawn.14 Other studies, such as EARLY, which evaluated bosentan in early stage PAH, PACES, which tested the combination of sildenafil and epoprostenol, and PATENT-1, which tested the efficacy of riociguat, have also employed TTCW as a secondary endpoint with slight variations in how it was defined15-17 (See Table 1).

Relative to a single endpoint, whether exercise capacity or a specific event, such as death, the composite TTCW endpoint has the advantage of providing a more comprehensive assessment of the impact of treatment. However, one disadvantage of a mix of hard endpoints, such as death or hospitalization, with softer endpoints, such as a degree of worsening that warrants additional therapy, is the potential for unequal rigor in how they are defined and adjudicated. In addition, the value of therapy against a specific endpoint within the composite outcome may be obscured when the analysis is powered for the composite outcome as a whole. However, like an intent-to-treat analysis designed to eliminate any prejudice after treatment has been assigned, TTCW can provide a global indication of effect on clinical course in a given population.

Timeframe is important. PAH efficacy studies often evaluate improvements in exercise capacity over limited periods, typically less than 6 months. With an increasing array of effective oral therapies that can be initiated at an earlier stage of disease, the effort to evaluate an effect on disease progression becomes more attractive even if the ability to show an effect requires longer periods of follow-up (See Table 2). Whereas early trials with intravenous prostacyclin therapies were conducted in patients with advanced PAH for whom symptom control was an urgent priority, the opportunity to interrupt the pathophysiology of PAH before structural damage is extensive may eventually lead to therapies that control the underlying disease process.

Table 2.

 

Clinical Endpoint Trials

Several trials have been launched and one trial completed in which TTCW has been elevated to the primary endpoint. In the first of these, called SERAPHIN, TTCW was defined as a composite of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of PAH.18 Patients, of which about half were in World Health Organization (WHO) functional class II at the time of treatment initiations, were randomized to one of two doses of the ERA macitentan or placebo. Over a mean follow-up of approximately 2 years, the 10 mg dose of macitentan was associated with a 45% improvement (P<0.001) in the TTCW endpoint relative to placebo.

In this study, there was a non-significant trend for a reduction in PAH-related mortality on the higher dose of macitentan relative to placebo, but the treatment effect was largely driven by a reduced rate of worsening of PAH. Not surprising in a trial that enrolled a large proportion of patients with mild-tomoderate disease, death was rarely the first event (See Figure 1). While this is the first event-driven study to show benefit with a PAH treatment relative to placebo, it is not known whether other PAH therapies would perform the same. With a large number of therapies now available for PAH, these data are needed to develop rational algorithms. One step in this direction may be provided by COMPASS-2, another event driven study in which patients were randomized to the ERA bosentan plus the PDE-5 inhibitor sildenafil or sildenafil alone.19

Standard definitions of TTCW will be useful in trials attempting to compare one treatment strategy to another, although the comparisons between agents should always be intra-trial and never inter-trial. Such standard definitions were envisioned by a WHO working group, which first addressed this issue in 2008.20 They specifically recommended that mortality, non-elective hospital stay, and rigorously confirmed decline in exercise capacity be included in TTCW, but conceded that other measures of clinical benefit, particularly change in quality of life, are important (See Figure 1). While such steps as adjudication of endpoints were further recommended to improve the integrity of the data, the working group acknowledged that PAH is a complex disease for which relative benefits of therapy may differ in early- versus late-stage disease.

Figure 1

Although PAH is characterized by elevated pulmonary artery pressure, the structural changes produced in the lungs and the severity of cardiac dysfunction drive risk of events. The relative importance of the interrelated molecular processes implicated in these structural changes may differ by the etiology of the PAH or vary by individual patient. To the extent that available therapies may affect these processes differently, agents that are equally effective for improving exercise capacity may not necessarily provide the same relative protection against disease progression as expressed by events or the underlying processes, such as tissue remodeling. Indeed, even our most potent therapies may not alter the pulmonary microvascular remodeling.21 In such a case, delaying clinical events may be paramount.

Summary

PAH is a progressive disease that cannot be reversed with current therapies, but there is evidence that the clinical course can be stabilized for many patients for at least several years. This includes favourable results from a phase 3 trial in which TTCW was employed as the primary endpoint. Relative to exercise capacity as measured with the 6MWT, the TTCW endpoint addresses the potential for current therapies to either slow or protect against the progression of PAH, as well as improve symptoms. The value of TTCW as a trial endpoint has increased with appreciation that, short of cure, clinical stability or improvement in lung and cardiac function are the ultimate goals. TTCW has been variably defined whether as a secondary or primary endpoint in trials conducted to date, but a uniform definition would be useful for the rigorous efforts needed to establish a hierarchy of interventions.

 

References

1. Galiè N, Hoeper MM, Humbert M, et al. 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 2009;30: 2493-537.
2. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006;173:1023-30.
3. Yuan JX, Rubin LJ. Pathogenesis of pulmonary arterial hypertension: the need for multiple hits. Circulation 2005;111:534-8.
4. Ruan CH, Dixon RA, Willerson JT, Ruan KH. Prostacyclin therapy for pulmonary arterial hypertension. Texas Heart Institute Journal / from the Texas Heart Institute of St Luke’s Episcopal Hospital, Texas Children’s Hospital 2010;37:391-9.
5. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:1477-82.
6. Langleben D, Barst RJ, Badesch D, et al. Continuous infusion of epoprostenol improves the net balance between pulmonary endothelin-1 clearance and release in primary pulmonary hypertension. Circulation 1999;99:3266-71.
7. Luscher TF, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation 2000;102:2434-40.
8. Shichiri M, Kato H, Marumo F, Hirata Y. Endothelin-1 as an autocrine/paracrine apoptosis survival factor for endothelial cells. Hypertension 1997;30:1198-203.
9. Gatfield J, Mueller Grandjean C, Sasse T, Clozel M, Nayler O. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PloS one 2012;7:e47662.
10. Wilkins MR, Wharton J, Grimminger F, Ghofrani HA. Phosphodiesterase inhibitors for the treatment of pulmonary hypertension. Eur Resp J 2008;32:198-209.
11. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 2011;123: 2263-73.
12.Wharton J, Strange JW, Moller GM, et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med 2005;172:105-13.
13. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903.
14. Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebocontrolled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008;117:3010-9.
15. Galiè N, Rubin L, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008;371:2093-100.
16. Simonneau G, Rubin LJ, Galiè N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med 2008;149:521-30.
17. Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330-40.
18. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369:809-18.
19. clinicaltrials.gov. Effects of the combination of bosentan and sildenafil versus sildenafil monotherapy on pulmonary afterial hypertension (PAH) (COMPASS-2). http://clinicaltrialsgov/show/ NCT003034592006.
20. McLaughlin VV, Badesch DB, Delcroix M, et al. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S97-107.
21. Rich S, Pogoriler J, Husain AN, Toth PT, Gomberg- Maitland M, Archer SL. Long-term effects of epoprostenol on the pulmonary vasculature in idiopathic pulmonary arterial hypertension. Chest 2010;138:1234-9.


Monotherapy Vs. Combination Therapy: Efficacy in Improving Outcomes in PAH

Robert D. Levy, MD, FRCPC
Associate Director, Pulmonary Hypertension Program
Vancouver General Hospital
Professor of Medicine, Respiratory Division
University of British Columbia
Vancouver, British Columbia

 

In pulmonary arterial hypertension (PAH), it is logical to expect greater clinical benefit from combining two effective agents with independent mechanisms of action relative to one alone. In many published guidelines, the use of combination therapy in individuals with an inadequate response to a single agent is accepted despite caution that the practice is not evidence-based. The limitations of the evidence do not stem only from an absence of trials but from inconsistent findings generated by small studies. The inconsistency may be driven by one or more factors, including unequal efficacy among different combinations, heterogeneity amongst patient populations, the severity of disease at the time combination therapy is being tested, or differences in how clinical benefit is evaluated. In the absence of a cure, a combination of treatments acting on different pathophysiological mechanisms of PAH may provide the best opportunity for delaying progression, but data are needed to substantiate this premise.

Current Targets of Therapy

The current options for treatment of pulmonary hypertension include prostanoids, endothelin-receptor antagonists (ERA), phosphodiesterase-5 (PDE-5) inhibitors, calcium channel blockers, and, most recently, soluble guanylate cyclase (sGC) stimulators. Until recently, the efficacy of approved agents within these classes was most commonly evaluated with the 6-minute walk test (6MWT).1 Most trials of combinations have employed this same primary endpoint.2 In a disease characterized by progressive structural blood vessel and heart disease leading to irreversible deterioration in cardioplumonary function,3 hard primary clinical endpoints, such as PAH-related hospitalization and death, have now been advocated for in all drug efficacy trials.4 They may be particularly important for demonstrating a relative advantage for combination therapy. In patients with advanced disease for whom combination therapy is arguably most attractive, an improvement in exercise capacity may be an insensitive measure of clinically meaningful benefit.

While the pathobiology of PAH is incompletely understood, all of the available therapies target vasoactive mediators to promote vasodilation (as well as possibly antiproliferation), which, in turn, inhibits the adverse structural changes in the pulmonary vasculature.5 However, each of the available classes addresses different pathways to achieve this result (See Figure 1). Prostanoids are potent vasodilators which are provided to supplement endogenous prostacyclin, relatively suppressed in patients with PAH.6 Agents in the ERA class prevent the binding of endothelin-1, a potent vasoconstrictor that is upregulated in patients with PAH.7 PDE-5 inhibitors block the activity of an enzyme that inhibits cyclic guanosine monophosphate (cGMP), an important mediator of the vasodilator nitric oxide (NO).8 The sGC stimulators also raise levels of cGMP to increase vasorelaxation but by a mechanism independent of NO activity.9 In all cases, the reduction in pulmonary vasoconstriction has been linked to antiproliferative effects fundamental to slowing or preventing tissue remodeling that characterizes disease progression.

Figure 1.

 

The evidence that current therapies when employed as single agents can slow disease progression can be derived from several sources, including a meta-analysis of controlled trials in which a survival benefit was observed.10 In addition, favourable effects from therapy on prognostic secondary endpoints in controlled trials, such as increased cardiac index, reduced serum levels of brain natriuretic peptide (BNP), and sustained reductions in pulmonary vascular resistance (PVR), have been common. More recently, the first phase 3 trial in PAH to employ clinical events as the primary endpoint demonstrated a favourable outcome. In that study, called SERAPHIN, a novel dual ERA called macitentan was associated with 45% reduction relative to placebo in the composite endpoint of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of PAH after a mean treatment period of two years.11 As an isolated endpoint, mortality rates did not differ significantly.

If drugs within each of the classes of treatment for PAH act on different pathways to slow disease progression, it is reasonable to expect that a combination of agents would have additive or even potentially synergistic effects. This expectation is widely shared despite limited evidence. In a survey of 2438 patients who were taking a PAH-specific medication from the largest U.S. PAH registry, 46% were on two agents and 9% were on three (See Figure 2).12 Several guidelines cite the potential for benefit in accepting the use of combination therapy in individuals with inadequate response to single agents while acknowledging the limitations of the data.13,14

Figure 2.

 

Combination Therapy: Clinical Trials

The trials of combination therapy have ranged in size from 33 to 405 patients, have employed different combinations in different sequences, and have been largely short-term (See Table 1). Although many of the studies have been conducted in patients with advanced disease, characterized by WHO class III or higher, the EARLY trial showed an improvement in exercise capacity in WHO functional class II patients already taking sildenafil when bosentan rather than placebo was added.15 Most studies have employed 6MWT as the primary efficacy endpoint, but many of these studies have placed equal emphasis on safety endpoints including attention to pharmacokinetic interactions.

Table 1

 

Since anecdotal reports of benefit from combination therapy seemed promising, the first double-blind, placebo-controlled trial, called BREATHE-2, was modest in scope.16 In this study, 33 PAH patients in WHO functional class of III or IV were initiated on the prostanoid epoprostenol and then randomized at 16 weeks to receive the addition of the ERA bosentan versus placebo. At the end of 16 weeks, there was a trend toward an improvement in hemodynamics and exercise capacity, but differences did not reach statistical significance.

Considered inconclusive rather than negative, the BREATHE-2 study encouraged the series of studies that followed, including STEP,17 COMBI,18 and TRIUMPH,19 all of which included a prostanoid. Results have continued to be mixed. In STEP, 67 PAH patients in WHO functional class III were initiated on bosentan before being randomized to inhaled iloprost or placebo. At 12 weeks, those randomized to receive iloprost in addition to bosentan had significant improvements in 6MWT distance relative to those randomized to receive placebo with bosentan.17 Patients on the active combination were also significantly more likely to improve in functional class, and there were favourable changes in hemodynamic measures, such as mean pulmonary arterial resistance (mPAP) and pulmonary vascular resistance (PVR), that  were statistically superior to placebo. In contrast, the COMBI trial,18 which evaluated the same combination, was terminated at an interim analysis after enrolling only 40 patients when there was no significant advantage for the addition of inhaled iloprost relative to bosentan alone for the primary endpoint of 6MWT.

The primary endpoint of 6MWT was met in the much larger TRIUMPH study. However, a lack of significant benefit on several secondary endpoints important to patients including change in functional class, time to clinical worsening, and signs and symptoms of PAH, complicated the interpretation of the finding. In this study, 235 PAH patients in WHO functional class III or IV who were taking either bosentan or the PDE-5 inhibitor sildenafil were randomized to treprostinil or placebo and evaluated after 12 weeks.

In the still larger PACES study, 267 patients with advanced PAH on stable doses of epoprostenol were randomized to the PDE-5 inhibitor sildenafil or placebo.20 Relative to placebo, the combination significantly improved 6MWT, the primary endpoint, and exerted a favourable effect on several clinically meaningful secondary endpoints, including time to clinical worsening and health-related quality of life. There was also a favourable effect on several hemodynamic measures, but the authors noted that relative benefit was greatest in those with the best baseline exercise capacity.

In the largest of the combination trials, called PHIRST, 405 PAH patients who were not already on background bosentan were initiated on this therapy before being randomized to one of several doses of the PDE-5 inhibitor tadalafil or placebo.21 Relative to placebo, tadalafil significantly improved 6MWT, the primary endpoint, in a dose-dependent fashion. In addition, the combination delayed time to clinical worsening and improved health-related quality of life relative to placebo. Although the majority of patients in this study, like previous studies, were in WHO functional class III or above, about one-third of patients were in functional class II.

Following favourable hemodynamic improvements with the combination of bosentan and sildenafil in the open-label COMPASS-1 trial,22 the COMPASS-2 trial was launched and is nearing completion. In this doubleblind, placebo-controlled trial, 330 PAH patients were randomized to bosentan alone, sildenafil alone, or the combination. The primary endpoint is a composite of clinical events.

The recently completed IMPRES study evaluated imatinib, an inhibitor of platelet derived growth factor (PDGF) signaling in patients with PAH already receiving at least two other agents for PAH.23 Despite a high rate of serious adverse events, leading to discontinuation in 44% of patients, hemodynamics and exercise capacity were improved relative to placebo at the end of 24 weeks. There were no differences in functional class, time to clinical worsening, or death. After more data was requested from regulatory agencies regarding the efficacy and safety of imatinib in PAH, the sponsoring company recently withdrew its application for this indication in both the U.S. and the European Union.

Combination Therapy: Current Status

Combination therapies remain promising, if incompletely validated, within the context of treatment algorithms designed to improve relevant clinical endpoints. In a meta-analysis, combination therapy was associated with a modest improvement in exercise capacity relative to single agents but did not provide compelling evidence of an improvement in outcome.24 However, the theoretical benefits of intensifying therapy through a combination of drugs remain compelling. Event-driven, multicentre trials conducted in well-defined populations are needed in early and late stage disease. While the most urgent need for more effective therapies is in advanced disease when the efficacy of conventional therapies is diminishing, it is equally important to explore the possibility that early use of combination therapy slows disease progression. Studies are needed to determine whether tight earlier control with up-front combination therapy is preferable to sequential intensification of treatment when therapeutic goals are not met, although a treat-to-target approach with close monitoring and prompt escalation of therapy in those not achieving improvements on treatment has been advocated.25

The decision to use combination therapy in the absence of these data is complex and requires a careful estimate of an expected benefit-to-risk. Guidelines do accept the use of combination therapy in patients with diminishing response to single agents, but the specific recommendations regarding which combinations to use and under what circumstances remain vague. The potential for improvement in symptoms deserves to be balanced against the potential for increased adverse events, but the limited availability of controlled data is an obstacle to an objective, conclusive approach.

Summary

PAH is an incurable condition progressing to right heart failure and death. The first eventdriven trial corroborates other evidence that currently available therapies slow progression, but morbidity and mortality rates remain high. The potential to improve outcomes by combining two or more active agents with independent mechanisms of action is appealing but inconsistently supported in randomized and controlled trials. Event-driven studies are essential, not only to validate combination therapy, but also to better understand when these therapies are most appropriately applied to favourably affect the natural history of this condition.

References

1. Rich S. The 6-minute walk test as a primary endpoint in clinical trials for pulmonary hypertension. J Am Coll Cardiol 2012;60:1202-3.
2. Galiè N, Negro L, Simonneau G. The use of combination therapy in pulmonary arterial hypertension: new developments. European Respiratory Review: An official Journal of the European Respiratory Society 2009;18: 148-53.
3. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004;351:1655-65.
4. McLaughlin VV, Badesch DB, Delcroix M, et al. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S97-107.
5. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004;109:159-65.
6. Galiè N, Manes A, Branzi A. Prostanoids for pulmonary arterial hypertension. American Journal of Respiratory Medicine: Drugs, Devices and Other Interventions 2003;2:123-37.
7. Galiè N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovascular Research 2004;61:227-37.
8. Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-57.
9. Schermuly RT, Janssen W, Weissmann N, Stasch JP, Grimminger F, Ghofrani HA. Riociguat for the treatment of pulmonary hypertension. Expert Opinion on Investigational Drugs 2011;20:567-76.
10. Galiè N, Manes A, Negro L, Palazzini M, Bacchi- Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403.
11. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369:809-18.
12. McGoon MD, Miller DP. REVEAL: a contemporary US pulmonary arterial hypertension registry. European Respiratory Review: An official Journal of the European Respiratory Society 2012;21:8-18.
13. McLaughlin VV, Archer SL, Badesch DB, et al. 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. Circulation 2009;119:2250-94.
14. Galiè N, Hoeper MM, Humbert M, et al. 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 2009;30:2493-537.
15. Galiè N, Rubin LJ, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomized controlled trial. Lancet 2008;371:2093-2100.
16. Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Resp J 2004;24:353-9.
17. 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;174:1257-63.
18. Hoeper MM, Leuchte H, Halank M, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Resp J 2006;28:691-4.
19. 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;55:1915-22.
20. Simonneau G, Rubin LJ, Galiè N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med 2008;149:521-30.
21. Galiè N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894-903.
22. Greunig M, Michelakis A, Vachiery JL. Eur Heart J 2007;28:140.
23. Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary hypertension: results of the randomized IMPRES study. Circulation 2013;127:1128-38.
24. Fox BD, Shimony A, Langleben D. Meta-analysis of monotherapy versus combination therapy for pulmonary arterial hypertension. American Journal of Cardiology 2011;108:1177-82.
25. Hoeper MM. “Treat-to-target” in pulmonary arterial hypertension and the use of extracorporeal membrane oxygenation as a bridge to transplantation. Eur Respir Rev 2011;20:297-300.

 

Redefining Valid Goals in PAH: Survival and Quality of Life

Sanjay Mehta, MD, FRCPC, FCCP
Chair, Board of Directors, Pulmonary Hypertension Association (PHA) Canada
Director, Southwestern Ontario Pulmonary Hypertension Clinic
Professor of Medicine
Respirology Division / Department of Medicine
Schulich School of Medicine & Dentistry
Western University
London, Ontario

Pulmonary arterial hypertension (PAH) is a serious, usually progressive, and often fatal disease. Prior to the development of therapies approved specifically for the treatment of PAH, patients remained extremely limited and often disabled by symptoms such as dyspnea, and typically had a very high risk of death within a few years of diagnosis. For example, the median survival for primary PAH was 2.8 years from diagnosis,1 and less than one-third of patients were still alive after 5 years. In the modern era of PAH management, we believe that survival has improved to a modest degree.2,3 This has implications for treatment goals. Although PAH remains a progressive and incurable process, the relative ability of available therapeutic strategies to attenuate this progression deserves to be evaluated independent of the relative ability to control symptoms. Prolonged survival also offers the opportunity to specifically consider the impact of one treatment strategy relative to another on a patient’s quality of life over a longer period of extended survival. In evaluating novel PAH therapies, placebo-controlled trials have typically included a broad array of exploratory secondary endpoints to gauge treatment effects. With the current opportunity to select among therapeutic strategies with activity against PAH, relative effect on survival and morbidity is assuming increasing importance.

Current Goals of Therapy

Pulmonary arterial hypertension (PAH) has multiple etiologies, including congenital heart abnormalities, connective tissue disease, and human immunodeficiency virus (HIV) infection, but the largest subgroup, representing nearly 50% of patients in clinical trials and in clinical practice, remains idiopathic PAH.3 Regardless of etiology, the complex pathophysiology of pulmonary vascular obstruction due to vasoconstriction, smooth muscle cell hypertrophy and proliferation, intimal and medial fibrosis, and microvascular thrombosis all result in impaired pulmonary blood flow, and increased workload on the right ventricle (RV), leading to eventual RV failure and death. All of the approved PAH treatments have demonstrated improved symptoms, presumably through reducing pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), and thus, improving RV function and pulmonary vascular blood flow4 (See Table 1).

Table 1.

According to World Health Organization criteria, PAH is one of the five major categories of pulmonary hypertension. All produce an elevated pulmonary arterial pressure that leads to structural alterations in the lung and heart. From the perspective of clinical impact, the symptoms that develop from these structural changes are captured through assessment using the modified NYHA functional classes, ranging from I to IV, which describe a patient’s limitations during everyday activity.

In the trial that led to regulatory approval of the prostanoid epoprostenol, which was the first therapeutic agent specific for PAH, the goal was to demonstrate functional improvement, measured with the 6-minute walk test (6MWT) over 12 weeks.5 Until recently, most trials employed the same primary endpoint over a similar short time period of 12-16 weeks, but a growing array of treatment options has increased the need to consider treatment choice on broader clinically-relevant outcomes, including disease progression.

These options now include, in addition to prostanoids, calcium channel blockers, endothelin receptor antagonists (ERA), phosphodiesterase-5 (PDE-5) inhibitors, and, most recently, a soluble guanylate cyclase (sGC) stimulator. All these PAH medications share the ability to reduce pulmonary vascular resistance (PVR) but do so through different pathways.

Due in particular to the irreversible structural changes characteristic of advanced PAH, it is appropriate to seek different treatment goals for different disease stages. In advanced PAH, which was representative of the types of patients enrolled in initial trials, an improvement in functional capacity was perhaps a reasonable endpoint for an endstage process. In earlier stages, the potential for the therapeutic effect to slow or halt the disease process may be poorly reflected by functional capacity alone. Attenuated progression is best reflected by reduced clinical events over sufficient follow-up, but molecular, hemodynamic or structural measures may be useful for a better understanding of how or whether treatment choices exert different effects on the underlying pathophysiology.

Clinical Trials: Establishing Benefit in PAH

The need for trials to provide a more comprehensive evaluation of symptom control and improved quality of life was recognized in a consensus panel recommendation several years ago.6 The first phase 3 study to employ a composite endpoint capturing morbidity and mortality, conducted with the novel ERA macitentan, was recently published.7 Although 48.2% were in WHO functional class III or higher, slightly more than half were in functional class II, which identifies a population with only modest limitations on activity. On the composite endpoint, the higher dose of macitentan reduced the hazard ratio of a composite morbidity and mortality endpoint by 45% (P<0.001). The 50% reduction (P<0.001) relative to placebo in the combined secondary endpoint of death due to PAH or PAH-related hospitalization also implies a reduction in the pace of progression even if benefit relative to another active therapy is unknown (See Figure 1).

Figure 1.

 

Due to progressive and irreversible structural changes that characterize PAH, opportunities for clinical benefit from therapy may be different in late relative to early stage disease. Specifically, the greatest opportunity for treatment to alter the trajectory of disease may occur in advance of significant structural changes. In those with preserved lung and cardiac function, effective treatment may slow the disease process to a degree no longer possible when these organs have been compromised. In a registry, improvement in functional class, a potential marker of disease reversibility, predicted 3-year survival.8 Although an improvement in functional class was only achieved in 27% of those in the registry, survival at 3 years climbed from 66% to 84% (P<0.001) in those improved from class III to II when initiated on therapy (See Figure 2).

Figure 2.

 

While clinical endpoint trials are essential for comparing treatment strategies, the complexity of PAH may limit the value of adjunctive measures for revealing how different therapeutic options affect disease progression. Short-term functional improvements in WHO functional class and 6MWT distance used to demonstrate efficacy of most current PAH therapies do not address or reveal the impact of PAH therapy on long-term outcomes, such as hospitalization for PAH-related causes. Moreover, assessment of such endpoints over the short-term is a poor surrogate for testing the ability of treatment to prevent or slow progressive structural changes of PAH. Similarly, improvements in other surrogate endpoints, such as biomarkers, or changes in PAH-relevant biologic measures, such as hemodynamics or protection from progressive structural changes have limited value for judging relative clinical benefits of available therapies, although such endpoints may play an important role for advancing insight into how different agents or different combinations of agents affect the underlying pathophysiology of PAH.

In PAH, clinical trial design has been largely directed by therapeutic goals. Initially, identifying treatments capable of controlling symptoms in the form of improved functional capacity was the priority. More recently, trials are being designed to demonstrate a reduction in clinically relevant events, reflected in composite endpoints that include mortality and morbidity, such as PAH-related hospitalizations. As future clinical trials may directly compare two treatment strategies, rather than a single active agent to placebo, hard endpoints will remain important, but such surrogate endpoints as relative protection from tissue remodeling will be useful in learning how treatments may be best applied to prevent disease progression, particularly at early stages of disease.

Optimization of Therapy

Functional class is a criterion for selection of first-line PAH therapies in evidence-based guidelines, such as those from the European Respiratory Society (ERS).9 Due to the limited number of studies comparing treatment options, these recommendations owe more to how trials were conducted than to evidence that one therapy is more effective than another in these populations. For example, significant acute vasoreactivity during direct hemodynamic testing is a criterion for initiating therapy with a calcium channel blocker (CCB) in preference to an agent from one of the other drug classes, but in those without acute vasoreactivity or an inadequate response to CCB, the guidelines acknowledge that there is no evidence basis for selecting among the other treatment options.

Regular evaluation of disease progression in patients on treatment is recommended in guidelines, but there is limited guidance from treatment algorithms in regard to how advancing disease should affect treatment choices. While clinical assessments, such as the 6MWT, are recommended every 3 to 6 months, tests more sensitive to underlying PAH disease progression, such as echocardiography and right heart catheterization, are recommended with clinical worsening or within 6 months of a change in therapy. Combination therapy with ERA, PDE-5 inhibitors, or prostanoids is recommended in the event of inadequate treatment response to one of these agents used alone, but supportive data for any specific combination or, in particular, for one combination relative to another, is not provided from prospective, controlled trials.

For practical purposes, oral therapies are considered preferable to prostanoids that require continuous infusion or injection. This is recognized in many guidelines, including those from the ERS, which confer the highest designation (evidence 1-A) to bosentan, ambrisentan, and sildenafil for those in WHO functional class II. For functional class III, these agents are joined by inhaled iloprost, and intravenous (IV) epoprostenol. Only IV epoprostenol is given a 1-A classification for treatment of functional class IV. While tadalafil is the only agent given a 1-B classification for functional class II and III, all of the oral agents alone or in combination receive IIa-C classification for functional class IV patients, in whom there is limited assessment of the treatment benefits of these medications, which have been modest in clinical experience.

However, ERS and other guidelines appropriately emphasize that management of PAH cannot be reduced to the prescription of therapies that reduce pulmonary vascular pressure. The value of supportive care, such as psychosocial support, prevention of infection, diuretics, and oral anticoagulants play an invaluable role in sustaining an optimal quality of life as the burden of disease advances. Multidisciplinary care can be helpful in coordinating a comprehensive treatment plan to control complications and address obstacles to activities of daily living. For example, rehabilitative exercise, which is logically appealing to improve functional capacity even if it has an unproven role in improving outcomes, must be tailored to the capabilities of the patient.

The expansion of treatment options and efforts to detect PAH at early stages provides an opportunity to reconsider treatment goals. There is no immediate prospect for therapies to cure PAH, but studies designed to compare strategies for their impact on clinical events rather than functional capacity may establish which therapies provide the incremental improvements in outcomes that will lead clinical practice forward. As current therapies control pulmonary hypertension with different mechanisms, it is important to consider their relative efficacy at different stages of disease in the context of goals that may include attenuation of the underlying pathophysiological process.

Summary

PAH is a complex, heterogeneous, and multifactorial disease. While PAH remains progressive and incurable, there is at least indirect evidence that outcomes are improving with current therapies. Although improvement in the severity of pulmonary hypertension and RV failure is the shared mechanism of benefit for available treatments for PAH, these therapies act on different pathways. It is therefore important to consider the relative effects of available therapies on clinical or surrogate measures of progression. Although efforts to identify relative benefits on the underlying pathophysiology of PAH does not diminish the immediate importance of improving quality of life and relieving the burden of illness on daily activities, particularly in late stages of disease, expanding clinical trial designs to explore endpoints beyond stabilization of functional capacities may be useful to the effort to advance toward treatments capable of exerting a favourable change on the natural history of PAH.

References

1. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343-9.
2. Galiè N, Manes A, Negro L, Palazzini M, Bacchi- Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403.
3. Thenappan T, Shah SJ, Rich S, Tian L, Archer SL, Gomberg-Maitland M. Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation. European Respiratory Journal 2010;35: 1079-87.
4. McGoon MD, Kane GC. Pulmonary hypertension: diagnosis and management. Mayo Clinic proceedings Mayo Clinic 2009;84:191-207.
5. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-301.
6. McLaughlin VV, Badesch DB, Delcroix M, et al. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S97-107.
7. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369:809-18.
8. Barst RJ, Chung L, Zamanian RT, Turner M, McGoon MD. Functional class improvement and 3-year survival outcomes in patients with pulmonary arterial hypertension in the REVEAL Registry. Chest 2013;144:160-8.
9. Galiè N, Hoeper MM, Humbert M, et al. 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 2009;30:2493-537.

 

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