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Leading with InnovationServing with Compassion ST. MICHAEL’S HOSPITALA teaching hospital affiliated with the University of Toronto l
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S T . M I C H A E L ’ S H O S P I T A L , U N I V E R S I T Y O F T O R O N T O , O N T A R I O
Scientific UpdateTM
NYHA Functional Class II: An Achievable Goal for All Patients
with Pulmonary Arterial Hypertension Receiving Treatment
Originally presented by: Simon Gibbs, MD, Jean-Luc Vachiéry, MD, Nazzareno Galiè, MD, and Vallerie McLaughlin, MD An educational report from a Satellite Session at the 2009 Congress of the European Society of Cardiology
Discussed by: JUAN CARLOS MONGE, MD, FACC, FRCPC eligible for treatment. Generally, at this point in the disease Pulmonary arterial hypertension (PAH) is a progressive disease
course even stabilization, which was often the most hopeful characterized by a poor prognosis with a median survival of
outcome, is not satisfactory. If supported by evidence, it would ~2.8 years in patients with untreated idiopathic PAH, and
be reasonable to initiate treatment when the patients are in func- only 1 year for patients with untreated PAH associated with
tional class II before serious right-ventricular dysfunction is systemic sclerosis (scleroderma).1-3 The prevalence of PAH
present. Stabilization at, or improvement, to a better functional ranges from 15 to 50 patients per 1 million population; for
class would be a more satisfactory outcome and could improve instance, in the United Kingdom the number of patients
receiving treatment for PAH is 27 patients /million popula-
In recent years, many important advances have been made tion. This issue of Cardiology Scientific Update discusses the
in the management of PAH. There are better tools for assessment identification of patients at an earlier functional stage and
and diagnosis in this disease, and targeted screening programs examines the concept of “treating to target,” ie, setting and
have been implemented. Additionally, the field has gained an achieving more aggressive goals in the management of patients
improved understanding of the pathophysiology of PAH, result- with PAH, including the use of combination therapy.
ing in the development of PAH-specific therapies and leading toimproved long-term outcomes.7 The combination of an earlier PAH is more prevalent in certain populations; eg, patients diagnosis, a more timely intervention earlier in the disease with connective tissue disease are particularly at risk, with pul- process, and a goal-oriented treatment strategy (“treating to monary hypertension found in ~7%-12% of patients hospital- target”) are all important steps towards achieving the ambitious ized for scleroderma.4-6 PAH is also seen in patients with human goal of improving outcomes in this serious disease.
immunodeficiency virus/acquired immunodeficiency syndrome, The diagnosis of PAH at an early stage can often be a chal- although the prevalence is probably lower than in scleroderma, lenging diagnostic problem; however, the identification of patients and it is an important problem for a significant proportion of in WHO/NYHA functional class II is a feasible objective. The tar- patients with congenital heart disease.
geted screening of high-risk groups, such as those with systemic In patients with World Health Organization (WHO) func- sclerosis, may assist in early-stage diagnosis. Annual echocar- tional class II symptoms, which are similar to New York Heart diographic screening is now recommended for scleroderma Association (NYHA) functional class II symptoms for heart failure, patients with symptoms compatible with PAH (Grade 1 recom- there is only a relatively short delay between these symptoms mendation, level of evidence C). A weaker recommendation is in and the progression to functional class III (Figure 1). Addition- place for asymptomatic patients (Grade IIb recommendation, ally, the evidence suggests that if treatment is initiated after the level of evidence C).8 A recent report also indicated that screen- onset of WHO class III symptoms the prognosis may be poorer, ing HIV patients leads to an earlier diagnosis.9 but treatment at an improved functional class has a beneficial After a definitive diagnosis of PAH is established, the initia- tion of effective and specific therapy is essential and should not PAH is a progressive disease that leads to right-ventricular be delayed. This extremely important point should be empha- dysfunction. Currently, there is no cure for PAH and, until very sized given the rapidly progressive nature of PAH and the bene- recently, only patients with class III or IV symptoms, well advanced fits of early therapeutic intervention in NYHA functional class I in the hemodynamic continuum of the disease, were considered or II over treatment initiated in the latter stages of the disease.10,11 Division of Cardiology
The opinions expressed in this publication do not necessarily represent those of the Division of Cardiology, St. Michael’s Hospital, the University of Toronto, the educational sponsor, or the publisher, but rather are those of the author based on the available scientific literature. The author has been required to disclose any potential conflicts of interest relative to the content of this publication. Cardiology Scientific St. Michael’s Hospital, 30 Bond St., Suite 7049, Queen Wing, Toronto, Ontario M5B 1W8 Fax: (416) 864-5941
Update is made possible by an unrestricted educational grant.
Figure 2: Improvement of FC affects prognosis23
Figure 1: NYHA FC II patients can deteriorate quickly if
Adapted from Galiè N et al. Lancet. 2008;371(9630):2093-2100, copyright 2008, Reproduced from Sitbon O, et al. J Am Coll Cardiol. 2002;40(4):780-788, with with permission from Elsevier. NYHA FC = New York Heart Association functional class.
permission from Elsevier. Copyright 2002 American College of Cardiology Foundation.
In addition to earlier initiation of effective therapy, a goal- Other significant improvements in bosentan-treated patients oriented approach is gaining acceptance for the management of were found in the levels of the cardiac biomarker N-terminal PAH. This approach includes considering the use of agents with pro-brain natriuretic peptide (NT-proBNP) and in the Short Form potential complementarities and synergistic mechanisms of action, (SF)-36 Health Survey results, compared with placebo. Addition- not only in patients with advanced disease who are not ally, in the subgroup of patients who remained concomitantly on responding to monotherapy, but also in less-stable functional sildenafil, there were also improvements in line with the overall class II patients. More clinical studies are needed to determine results of the trial. Bosentan exhibited a safety and tolerability the best approach in the treat-to-target strategy. For now, it is profile that was consistent with previous placebo-controlled crucially important to assess the efficacy of treatment by combi- clinical trials.14,15 Based on the results of EARLY, bosentan is now nations of methods such as exercise capacity, echocardiography, approved in Europe, the United States, and Canada for the treat- cardiac biomarkers, and right heart catheterization.
ment of PAH in patients with WHO/NYHA functional class II.
Although EARLY is the only trial to date examining a func- Early detection and intervention in PAH
tional class II patient population exclusively, other studies have The Endothelin Antagonist tRial in mildLY symptomatic included some patients with NYHA functional class II PAH.
PAH patients (EARLY) study12 demonstrated the value of early These studies include the Sildenafil Use in Pulmonary Arterial therapeutic intervention in PAH. EARLY is the only randomized, Hypertension (SUPER) study,16,17 the Safety and Efficacy Study of placebo-controlled trial to exclusively enroll a WHO functional Sitaxentan Sodium in Patients With Pulmonary Arterial Hyper- class II patient population; it was designed to evaluate the effects tension (STRIDE)-1 and STRIDE-2 with a selective ERA,18,19 and of the dual endothelin receptor antagonist (ERA), bosentan, the Ambrisentan in Patients With Moderate to Severe Pulmonary while providing insight into the natural history of PAH, specifically, Arterial Hypertension (PAH), ARIES-1 and ARIES-2 studies with at the earlier stages. EARLY involved 185 patients who received 6 another selective ERA.20 Unlike EARLY, however, these studies months of either placebo or bosentan; 29 patients were taking included <40% NYHA functional class II patients and the base- sildenafil at study entry and were permitted to stay on the drug line 6-MWD was on average <400 m revealing that, overall, the during the trial with assignment in nearly equal numbers to the patients were in a later disease stage than the patients enrolled in placebo and bosentan groups. An analysis of baseline character- istics demonstrated that the study patient population was com- The EARLY study reinforces the importance of the early patible with a functional class II population, since the mean diagnosis and initiation of therapy in PAH; it is the first clinical 6-minute walk distance (6-MWD) was 436 m, consistent with trial to demonstrate that clinical worsening can be delayed in data from the French National Registry.13 mildly symptomatic (NYHA II) PAH patients. Because EARLY The EARLY trial demonstrated a highly significant reduction was a placebo-controlled trial, it also provided important infor- in pulmonary vascular resistance (P< 0.0001), a co-primary end- mation about the natural history and the progressive nature of point. There was no statistically significant difference in the other PAH even in minimally symptomatic patients, strongly endorsing co-primary endpoint, the 6-MWD (P= 0.076), which may be a early intervention and screening programs in high-risk groups.
reflection of the relatively well-preserved baseline exercise capacity.
A program called ItinérAIR-Sclérodermie has been implemented However, there was a significant delay in the time to clinical wors- for screening throughout France, revealing the effectiveness of ening (P= 0.0114) in the bosentan-treated group compared with placebo. Moreover, only 3% of the patients treated with bosentanexperienced clinical worsening compared with 14% of the patients Achieving treatment goals in PAH
on placebo (Figure 3). The stabilization of WHO functional class PAH is a complex disease, but after the fruitful research of in the bosentan group also supports the conclusion that a delay recent years, the pathophysiology is much clearer. The prosta- in disease progression is associated with this ERA treatment.
cyclin, endothelin, and nitric oxide pathways are implicated in Scientific Update
Figure 3: EARLY: Effect of bosentan on time to clinical
Figure 4: Pivotal RCTs in PAH with oral drugs:
Hazard ratio = 0.227
Patients are censored at the end of the study RCT = randomized, controlled trial; 6-MWD = 6-minute walking distance.
Reproduced from Galiè N et al. Lancet. 2008;371(9630):2093-2100, copyright 2008, dynamics. Combination therapy is initiated if the patient does with permission from Elsevier. PVR = pulmonary vascular resistance; not meet the following criteria: improvement or maintenance of functional capacity to NYHA II, 6-MWD >500 m in patients < 55 the pathogenesis of PAH and therapies specifically targeting these years of age, cardiac index >2.4 L / min/m2, and mean right-atrial aspects are the usual first-line treatments for this condition. The pressure <10 mm Hg. Based on this strategy, >40% of the dual ERA, bosentan, is indicated as a first-line therapy for NYHA patients treated at this centre are receiving combination therapy.
functional class III patients and, following the EARLY trial, the A German centre found that therapy with combinations of indication was extended to functional class II patients.8 Other bosentan, sildenafil, and iloprost reduced the need for intra- approved PAH therapies in Canada include the ERAs, ambrisen- venous prostanoids and lung transplantation in NYHA func- tan and sitaxsentan, the phosphodiesterase (PDE)-5 inhibitor, sildenafil, and the prostanoids, epoprostenol, and treprostinil.
The aggressive and unrelenting nature of PAH and the Exploring the evidence for combination therapy
involvement of multiple pathways in its pathogenesis provide a Data from the Registry to Evaluate Early and Long-term PAH strong rationale for the use of combination therapy involving Disease Management (REVEAL) indicate that bosentan and agents with complementary and synergistic mechanisms of action.21 sildenafil are the most commonly used combination regimen for Escalating therapy by combining agents is now considered an PAH management.24 Both drugs are administered orally, avoiding appropriate option in most patients who continue to exhibit the obvious problems and limitations of intravenous drugs.
disease progression on monotherapy. The selection of a drug Additionally, both agents are generally well tolerated and target combination must take into account the evidence for the indi- different pathways. A recent retrospective analysis25 of PAH vidual agents, including their safety and efficacy. Although com- patients, who were deteriorating on monotherapy, demonstrated bination therapy data are now reported more frequently, further that sequential dual therapy (bosentan + sildenafil in 74%) led clinical trials are necessary to evaluate the most effective combi- to improvements in the 6-MWD, the NYHA functional class, and nations in specific patient populations and to address important cardiac hemodynamics after the addition of the second agent.
issues such as the use of drugs simultaneously or sequentially.22 Moreover, these beneficial effects were maintained for 12 months.
In the management of PAH, a treat-to-target approach for The Combination Therapy in Pulmonary Arterial Hyper- combination therapy is effective and used in many specialized tension (COMPASS) program is a series of studies initiated in PAH centres. These centres apply goal-oriented algorithms with 2006 that was designed to specifically evaluate the safety and predefined follow-up parameters to evaluate patient response to efficacy of bosentan in combination with sildenafil. COMPASS- therapy and to determine the most appropriate treatment. With 126 was a multicentre, open-label, prospective study demonstrat- an improved understanding of PAH natural history, the impact ing that a single dose of sildenafil in PAH patients receiving of functional capacity on survival, and the possible prognostic long-term bosentan led to significant improvements in pulmo- improvements with current therapies, treatment goals have nary vascular resistance (PVR; 15.2 % reduction observed 60 become more ambitious. Previously, step-up therapy was con- minutes after a 25-mg dose) and total pulmonary resistance sidered only in PAH patients with evident clinical deterioration, (13.3% reduction). COMPASS-2 is a double-blind, placebo- but now the focus is shifting towards achieving and maintaining controlled study evaluating the effect on morbidity and mortality of adding bosentan to sildenafil compared with sildenafil alone.
One example, among several others, of a centre utilizing This study is the first event-driven trial in PAH with morbidity a goal-oriented treatment algorithm is the Pulmonary Vascular and mortality as the primary endpoint; recruitment for Disease Center at the University of Bologna, Italy. In this centre, patients are assessed prior to the initiation of a new treatment COMPASS-3 is an open-label Phase IV study designed to and 3 to 4 months later, using such parameters as predefined assess whether treatment with bosentan, either as monotherapy goals for functional capacity, exercise tolerance, and hemo- or with the addition of sildenafil, improves the 6-MWD after Scientific Update
28 weeks of therapy. This study is also evaluating the utility of 10. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106(12):1477-1482.
magnetic-resonance imaging to assess cardiac remodeling in PAH 11. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in patients and correlating any improved functional capacity with primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40(4):780-788.
other parameters. Interestingly, in the subgroup of patients in the 12. Galiè N, Rubin Lj, Hoeper M, et al. Treatment of patients with mildly symptomatic pul- EARLY trial who received bosentan in combination with silde- monary arterial hypertension with bosentan (EARLY study): a double-blind, randomisedcontrolled trial. Lancet. 2008;371(9630):2093-2100.
nafil there were improvements in PVR similar to those seen in 13. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results COMPASS-1;12 in addition, time to clinical worsening exhibited from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023-1030.
14. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antag- a trend towards improvement compared with patients on silde- onist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358(9288):1119-1123.
15. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension.
Part of another trial, the Pulmonary Arterial Hypertension N Engl J Med. 2002;346(12):896-903.
16. Galiè N, Ghofrani HA, Torbicki A, et al; Sildenafil Use in Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST)27 investigated the effects of (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl combining bosentan with the PDE-5 inhibitor, tadalafil, over 16 J Med. 2005;353(20):2148-2157.
17. Badesch DB, Hill NS, Burgess G, et al; SUPER Study Group. Sildenafil for pulmonary arterial weeks. In patients receiving first-line bosentan, the addition of hypertension associated with connective tissue disease. J Rheumatol. 2007;34(12):2417-2422.
tadalafil 40 mg resulted in a 23 m increase in the 6-minute walk 18. Barst RJ, Langleben D, Frost A, et al; STRIDE-1 Study Group. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;169(4):441-447.
distance compared with the addition of placebo, although this 19. Barst RJ, Langleben D, Badesch D, et al; STRIDE-2 Study Group. Treatment of pulmonary failed to achieve statistical significance.
arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am CollCardiol. 2006;47(10):2049-2056.
The combination of bosentan28-31 or sildenafil31,32 with prosta- 20. Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial noids has also been evaluated. In the placebo-controlled Safety hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized,double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. and Pilot Efficacy Trial of Iloprost Inhaled Solution as Add-On Therapy With Bosentan in Subjects With PAH (STEP) trial,30 21. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351(14):1425-1436.
the combination resulted in significant improvements in NYHA 22. O’Callaghan DS, Gaine SP. Combination therapy and new types of agents for pulmonary functional class, mean pulmonary arterial pressure, PVR, and arterial hypertension. Clin Chest Med. 2007;28(1):169-185, ix.
23. Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treat- time to clinical worsening. In an open-label extension of STEP, ment and combination therapy for pulmonary arterial hypertension. Eur Respir J. 2005; the combination continued to be well tolerated and survival was 24. Barst RJ, McGoon M, Benza R, et al. The REVEAL registry: a tool for the evaluation of PAH disease management. Paper presented at: The European Respiratory Society AnnualCongress. October 4-8, 2008; Berlin, Germany. Abstract 1415.
25. Keogh A, Kotlyar E, Macdonald P, et al. Sequential combination therapy in pulmonary arte- rial hypertension. Paper presented at: The American Thoracic Society Meeting. May 18-23,2007; San Francisco, California. Abstract A30.
It is clear that increasing evidence from clinical trials, reg- 26. Gruenig E, Michelakis E, Vachiéry JL, et al. Acute hemodynamic effects of single-dose silde- istries, and clinical practice in specialized centres support the nafil when added to established bosentan therapy in patients with pulmonary arterial hyper-tension: Results of the COMPASS-1 Study. J Clin Pharmacol. 2009; September 15 [Epub ahead use of combination therapy in PAH; as a result, it will probably play an increasingly important role in the management of this 27. Galiè N, Brundage BH, Ghofrani HA, et al; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension.
serious disease and is likely to be reflected in future international Circulation. 2009;119(22):2894-2903.
treatment recommendations. A goal-driven approach (treating to 28. Frost AE, et al; The Step Investigators. Step-Open Label Extension: long-term benefits of inhaled iloprost (ILO) addition to bosentan for treatment of PAH. Paper presented at: The target) and the use of combination therapy will also increase the American Thoracic Society Meeting. May 18-23, 2007; San Francisco, California. Abstract likelihood that reaching or maintaining NYHA functional class II 29. Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pul- becomes an achievable goal for many patients with PAH.
monary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24(3):353-359.
30. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to exist- ing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174(11): References
1. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hyper- 31. McLaughlin V, Rubin L, Benza R, et al. TRIUMPH I: Efficacy and safety of inhaled trepros- tension. Results from a national prospective registry. Ann Intern Med. 1991;115(5):343-349.
tinil sodium in patients with PAH. Paper presented at: The American Thoracic Society Inter- 2. Kawut SM, Taichman DB, Archer-Chicko CL, Palevsky HI, Kimmel SE. Hemodynamics and national Conference. May 16-21, 2008. Toronto, Ontario. Abstract A965.
survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest. 32. 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: 3. Koh ET, Lee P, Gladman DD, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: a randomized trial. Ann Intern Med. 2008;149(8):521-530.
an analysis of 17 patients. Br J Rheumatol. 1996;35(10):989-993.
4. Hachulla E, Gressin V, Guillevin L, et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum. Dr. Monge has no disclosures to announce in association with the contents 5. Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis asso- ciated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis.
2003; 62(11):1088-1093.
6. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary SNELL Medical Communication acknowledges that it has received hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S43-S54.
an unrestricted educational grant from Actelion to support the 7. Galiè N, Torbicki A, Barst R, et al. Guidelines on diagnosis and treatment of pulmonary arte- distribution of this issue of Cardiology Scientific Update. Acceptance of rial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hyper-tension of the European Society of Cardiology. Eur Heart J. 2004;25(24):2243-2278.
this grant was conditional upon the sponsors’ acceptance of the policy 8. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pul- established by the Division of Cardiology, St. Michael’s Hospital, monary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hyper- and SNELL Medical Communication guaranteeing the educational tension 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 integrity of the publication. This policy ensures that the author and Heart J. 2009; August 27 [Epub ahead of print].
editor will at all times exercise unrestricted, rigorous, scientific inde- 9. Sitbon O, Lascoux-Combe C, Delfraissy JF,et al. Prevalence of HIV-related pulmonary arterial pendence free of interference from any other party.
hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med. 2008;177(1):108-113.
2009 Division of Cardiology, St. Michael’s Hospital, University of Toronto, which is solely responsible for the contents. Publisher: SNELL Medical Communication Inc. in cooperation with the Division of Cardiology,
St. Michael’s Hospital, University of Toronto. ™Cardiology Scientific Update is a Trade Mark of SNELL Medical Communication Inc. All rights reserved. The administration of any therapies discussed or referred to
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