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PRIORITY PRESS - 20th Annual Congress of the European Respiratory Society

Barcelona, Spain / September 18-22, 2010

The need to improve treatment of pulmonary arterial hypertension (PAH) and the need for more new treatments were highlighted here at the ERS during a symposium focusing on application of the PAH guidelines issued jointly by the European Society of Cardiology (ESC) and the ERS (Galiè et al. Eur Heart J 2009;30:2493-537). Prof. Andrew Peacock, Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, UK, pointed to a recent lack of progress in treating PAH. “Before 1992, when we had no good treatments for this condition, the 2-year survival rate for PAH was <50%. This improved to 75% between 1992 and 1999, but since then, we have not seen any big increase,” he noted. “Clearly, we need to focus and try to improve the current situation.” He stressed the importance of early diagnosis of PAH for early therapeutic intervention and promotion of better quality of life, but he observed that first detection of symptoms is usually quite late. In 1987, the US National Institutes of Health (NIH) registry revealed that the mean interval between first symptoms and diagnosis of disease was 2 years (Rich et al. Ann Intern Med 1987;107:216-23). “Unfortunately we are still close to that now,” he told delegates.

Goal-oriented Approach

A goal-oriented approach to PAH therapy, in which treatment goals are established for individual patients, is recommended in the ESC-ERS guidelines. They should be non-invasive, easy to perform and repeat, and should be based on multiple parameters with prognostic significance, stated Dr. Iona Preston, Tufts Medical Center, Boston, Massachusetts, here at the ERS.

Functional class (FC) has been shown in many cohort studies to be a very powerful predictor for PAH, she noted. The latest (Humbert et al. Circulation 2010;122:156-63) found that at 36 months, patients in FC II had a survival rate of 80% compared with 60% in FC III and 40% in FC IV (Figure 1). The 6-minute walking distance (6MWD) test is noninvasive and easy to repeat in office visits. Patients who walk >350 m at baseline have much better long-term outcome than those who walk less, Dr. Preston noted. She stressed the importance of cardiopulmonary exercise testing, as peak VO2 (>10.4 mL/kg/min) and systolic blood pressure (SBP >120 mm Hg) during exercise is associated with better outcome (Wensel et al. Circulation 2002;106:319-24).

Figure 1.

Although no serological marker has been validated only for PAH, B-type natriuretic peptide (BNP) has been associated with hemodynamics and with 6MWD, and patients with higher BNP at baseline (=150 pg/mL) appear to have a worse prognosis than those with mildly elevated BNP (Nagaya et al. Circulation 2000;102:865-70). BNP <180 pg/mL after 3 months of therapy is associated with better survival at 2 years than BNP =180 pg/mL. N-terminal pro-brain natriuretic peptide (NT-proBNP) under1400 pg/mL is also associated with a better prognosis at 2 years (Fijalkowska et al. Circulation 2006;129:1312-21). Echocardiography parameters predict survival. Dr. Preston also stressed that continuous patient monitoring is an essential component of goal-oriented therapy.

Reaching WHO FC II Targets: Lessons from the EARLY Trial

Since there is no cure for PAH at present, the realistic objective of PAH treatment is to detect the disease in its early stages and promptly initiate therapy to maintain patients presenting with FC II, or even improve them to FC I, and improve patients in FC III/IV to FC II, noted Dr. Marius Hoeper, University of Hanover Medical School, Germany, during the ERS scientific sessions.

The importance of initiating therapy in FC II patients was demonstrated in EARLY (Endothelin Antagonist Trial in Mildly Symptomatic Pulmonary Arterial Hypertension Patients), to date the only randomized, placebo-controlled study dedicated to patients with FC II at baseline (Galiè et al. Lancet 2008;371:2093-100). These patients are mildly symptomatic and appear healthy, but their prognosis is quite poor if left untreated, Dr. Hoeper observed. In EARLY, 13% of the untreated patients had deteriorated within 6 months. One third of these cases will go on to have a clinical deterioration after one year, he added.

The ESC-ERS guidelines recommend (1A recommendation-evidence) initiating therapy in FC II patients with an endothelin receptor antagonist (ERA) (bosentan or ambrisentan) or a PDE-5 inhibitor (sildenafil). “The strongest evidence for any of drugs that they slow disease progression is for the ERAs,” Dr. Hoeper confirmed. In the EARLY study, bosentan treatment was associated with a significantly lower incidence of worsening FC compared with placebo and 97% of patients treated with bosentan stabilized or showed improved FC over the 6-month period, significant delay in PAH progression and a trend toward improved 6MWD.

For patients diagnosed in FC III or IV, the ESC-ERS treatment algorithm recommends an ERA, PDE-5 inhibitor or a prostanoid. Patients who do not improve with monotherapy should be escalated to combination therapy. An ERA plus a PDE-5 inhibitor, an ERA plus a prostanoid, and a prostanoid plus a PDE-5 inhibitor have all demonstrated benefit.

Dr. Hoeper suggested that in patients with inadequate response to double oral combination therapy, the best option might be the addition of i.v. epoprostenol. Early data from patients already on target-dose bosentan and high-dose sildenafil showed that the addition of i.v. epoprostenol substantially improved hemodynamics and in 6MWD from 375±113 m to 467±85 m (P<0.02) (Negro et al. Am J Respir Crit Care Med 2009;179:A3372). However, mean survival in these patients is still 2 to 3 years. This underscores the need to identify new therapies and for the ongoing trials of promising treatment strategies.

Effects of First-line Monotherapy

In a retrospective study presented here at the ERS by Dr. Wouter Jacobs, VU University Medical Centre, Amsterdam, The Netherlands, patients with idiopathic PAH given i.v. epoprostenol as initial therapy showed greater improvement in 6MWD compared with patients given first-line bosentan (Jacobs et al. J Heart Lung Transplant; epub ahead of print June 2010). However, survival and time to disease progression were similar in both treatments.

He and colleagues studied the long-term outcomes in PAH patients treated at his hospital between 1998 and 2006. Before 2003, patients were given i.v. epoprostenol as initial therapy, but after the introduction of bosentan in 2003, this was changed to oral bosentan. To control for disease severity, an analysis was performed on 2 cohorts of 16 pairs matched according to baseline cardiac output and 6MWD, irrespective of FC at baseline. Median (95% CI) improvements in 6MWD after 1, 2 and 3 years were +66 m (-9; 109), +78 m (-37; 161) and +98 m (-123; 182) with bosentan and +110 m (12; 265), +180 m (63; 327) and +142 m (116; 242) with i.v. epoprostenol. Kaplan-Meier estimates of patients without disease progression at 1, 2 and 3 years were 75%, 60% and 43%, respectively, with bosentan and 81%, 63% and 50% with i.v. epoprostenol. Survival at 1, 2 and 3 years was 100%, 92% and 92% with the ERA and 100%, 88% and 88% with epoprostenol.

“These results confirm the efficacy of first-line therapy, and that greater improvements in exercise capacity, as measured by 6MWD, should not be interpreted as an indication of achieving better survival,” Dr Jacobs remarked. However, “this was an observational study and we should be cautious about the conclusions we draw from these data,” he stated.