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18th Annual Congress of the European Respiratory Society

Berlin, Germany / October 4-8, 2008

Pulmonary arterial hypertension (PAH) is regarded as a very serious disease with a very poor prognosis. It can be classified as idiopathic, familial, or as being associated with other diseases such as connective tissue disease (scleroderma), congenital heart disease or HIV. Most patients present at an advanced stage, with less than 25% of patients being diagnosed in the early stages of PAH progression, i.e. World Health Organisation functional class (WHO FC) I-II. Even patients with mildly symptomatic PAH progress rapidly if left untreated. With better understanding of the pathobiology of the disease, advances in novel diagnostic procedures and the advent of screening programs, early-stage PAH is being identified in increasingly larger numbers of patients. Until recently, however, treatments for PAH were studied largely in patients with moderate to severe disease (WHO FC III and IV), despite observational data suggesting that initiation of treatment might be advantageous in patients with WHO FC II disease.

The Endothelin Antagonist tRial in mildLY Symptomatic Pulmonary Arterial Hypertension Patients (EARLY) was the first randomized, placebo-controlled clinical study carried out in patients with WHO FC II PAH. In the trial, the endothelin receptor antagonist (ERA) bosentan was associated with improvements in both the primary end points, with a significant reduction in pulmonary vascular resistance (PVR) and a trend toward an increase in six-minute walking distance (6MWD). Treatment also significantly improved time to clinical worsening in terms of time to symptomatic progression of disease and hospitalizations for PAH. Symptomatic disease progression occurred in 1.1% of the active treatment group and in 10% of patients receiving placebo. “The EARLY results emphasize the importance of early diagnosis and intervention in PAH,” indicated Prof. Marc Humbert, PhD, Université Paris-Sud 11, Centre National de Référence de l’Hypertension Artérielle Pulmonaire, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine-Béclère, Clamart, France. Prof. Humbert reviewed the EARLY data, which were also published recently (Galiè et al. Lancet 2008;371:2093-100).

The EARLY Trial

The EARLY trial enrolled patients with WHO FC II PAH aged 12 years or over with a 6MWD of <80% of the normal predicted value or <500 metres associated with a Borg dyspnea index of <u>></u>2 points. A total of 185 patients were randomly assigned to receive bosentan 62.5 mg b.i.d. for four weeks, then 125 mg b.i.d. or placebo for the six-month, double-blind treatment period. At six months, PVR was 83.2% of the baseline value in the ERA group vs. 107.5% in the placebo group, a highly significant treatment effect of -22.6% (95% CI: -33.5 to -10.0; P<0.0001). The 6MWD test had increased by 11.2 metres from baseline in the ERA group and decreased by 7.9 metres in the placebo group, a mean treatment effect of 19.1 metres (95% CI: -3.6 to 41.8; P=0.076). “There is evidence of a ceiling effect with the 6MWD test in patients with milder-stage PAH that would account for the trend seen even in these patients,” Prof. Humbert explained. With a mean 6MWD of approximately 431 metres at baseline, exercise capacity was relatively well preserved with little potential for significant improvement. “Nonetheless, it was a strong trend,” he commented (Figure 1 and 2).

Figure 1.

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Figure 2.

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Clinical Worsening

Clinical worsening, a secondary end point in the EARLY trial, was defined as death, hospitalization for PAH, or symptomatic progression of PAH, i.e. the appearance or worsening of right heart failure or a decrease in two 6MWD tests by <u>></u>10% from baseline or by <u>></u>5% with an increase in Borg dyspnea index by <u>></u>2 points. Few deaths were expected in these mildly symptomatic patients within six months. Time to clinical worsening was the most exciting part of the EARLY trial, according to Prof. Humbert, with a delay in the bosentan group compared with the placebo group (hazard ratio [HR] 0.227, 95% CI: 0.065 to 0.798; P=0.0114) (Figure 3). Fewer patients in the bosentan group reached one or more of the components of clinical worsening by six months than patients on placebo. Symptomatic progression or hospitalization related to PAH was more common in the placebo group. Neither of the two deaths in the trial was related to PAH. “These data are very valuable to have in the community,” Prof. Humbert remarked. “The time has come to have clinical worsening applied as a primary end point in clinical trials of PAH.”

The proportion of patients with worsening WHO FC III/IV was significantly reduced with bosentan compared with placebo (3.4% vs. 13.2%, respectively; P=0.0285). “We see that in patients with class II disease exposed to placebo, more than 10% progress to class III. This is an important take-home message,” Prof. Humbert told the audience. “The severity of some patients in WHO FC class II should not be overlooked.” Another indication of progression in the placebo group was an increase in levels of N-terminal-prohormone-brain natriuretic peptide (NT-proBNP) in the placebo group, whereas NT-proBNP was re
ean treatment effect, -471 ng/L; P=0.0003).

Figure 3.

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Quality of Life and Safety

Quality of life, assessed by the 36-item short-form health survey (SF-36), was considered to be improved by 57% of patients on bosentan compared with 38% of those on placebo (relative risk [RR] 1.50, 95% CI: 1.07 to 2.10; P=0.0244). “This result was particularly encouraging,” Prof. Humbert indicated. Bosentan was well tolerated, with a safety profile consistent with previous studies. The incidence of adverse events (AEs) was similar in the patients on bosentan or placebo (69.9% vs. 65.2%, respectively). Serious AEs occurred in 12 (13%) patients in the bosentan group and eight (9%) in the placebo group, the most common being syncope and right ventricular failure, respectively. Twelve (13%) patients on bosentan had elevations in aminotransferases three times the upper limit of normal. “This was not a surprise,” Prof. Humbert commented. “About 10% of patients exposed to endothelin antagonists as first-line experience elevations in liver transaminases and it should be remembered that the six-month exposure in the EARLY trial was longer than any other previous trial of ERAs,” he noted. All the increases seen in EARLY returned toward baseline without intervention, or after discontinuation or bosentan dose reduction. Monthly monitoring of liver transaminase levels is recommended in patients treated with all ERAs.

Dose Escalation Strategies

In EARLY, 28 patients (15 in the placebo group and 13 on bosentan), were receiving concomitant treatment with the phosphodiesterase-5 inhibitor sildenafil. Similar effects of treatment to those seen overall were reported for both primary end points in these patients, with PVR -20.4% of baseline at month 6 (95% CI: -43.9 to 13.0; P=0.0478) and 6MWD increased by a median of 15 metres (95% CI: -43.1 to 53.9). Principal investigator of the EARLY trial, Prof.Nazzareno Galiè, Head, Pulmonary Hypertension Centre, Institute of Cardiology, and Associate Professor of Cardiology, University of Bologna, Italy, noted that bosentan in combination with sildenafil is currently the most commonly used combination regimen for the treatment of PAH, according to the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) (Badesch et al. Chest 2007;132(4 suppl):473S).

There is growing evidence that combination therapy in PAH is effective and well tolerated, he noted. Dr. Galiè cautioned, however, that although combination therapy for PAH is already being widely used in daily clinical practice, some issues remain to be addressed, especially the most important pathways to target, the optimum time to initiate combination therapy and optimal doses of combination therapies. Since both agents target different pathways implicated in the pathogenesis of PAH and both are administered orally, greater improvements might be expected in some patients, he suggested.

The COMPASS Program

An ongoing series of clinical trials known as the COMPASS program (Effects of Combination of Bosentan and Sildenafil vs. Sildenafil Monotherapy on Morbidity and Mortality in Symptomatic Patients with Pulmonary Arterial Hypertension) is currently investigating the safety and efficacy of combination bosentan/sildenafil. COMPASS-1, carried out in Europe and Canada, evaluated the acute hemodynamic effects of sildenafil when added to chronic bosentan treatment. The results demonstrated that there was no clinically relevant interaction between the two agents (Gruenig et al. Eur Heart J 2007;28(suppl 140):Abstract 1012).

Significant improvements were seen in PVR, the primary end point, and in total peripheral resistance. “These results cannot predict the chronic effect, but they are encouraging,” commented Dr. Galiè. COMPASS-3 is employing a treating-to-target strategy comparing combination bosentan/sildenafil with bosentan monotherapy in 100 patients. The results of this US trial are expected in 2009. COMPASS-2 is comparing the effects of the combination vs. sildenafil monotherapy on morbidity/mortality outcome in 250 patients recruited worldwide.The primary end point is time to the first morbidity/mortality event. The trial is incorporating a patient self-assessment tool corroborated by a 6MWD test, and all morbidity/mortality events will be adjudicated by a blinded, independent adjudication committee. The results of COMPASS-2 are expected in 2011.

HIV-associated PAH

An analysis of a series of patients with HIV associated with PAH treated with first-line bosentan over a long-term period was presented by Dr. Bruno Degano, Centre National de Référence de l’Hypertension Artérielle Pulmonaire, Hôpital Antoine-Béclère, Clamart, France (Degano et al. ERS 2008, Abstract 1583). The study confirmed improvements in symptoms, 6MWD and hemodynamics. The results also suggest that first-line bosentan therapy might have a positive impact on long-term survival in these patients. It appeared safe in combination with highly-active antiretroviral therapy (HAART) and had no negative impact on the control of HIV infection. The findings have also been published (Degano et al. Eur Respir J 2008 Sep 17; Epub ahead of print) (Figure 4).

Data were analyzed for 59 patients (mean age 40±15 years, 63% male) with WHO FC II-IV treated between May 2002 and July 2007 at two PAH centers in France. Sixty-one per cent of patients had symptomatic AIDS and 83% were taking HAART. Bosentan was prescribed at 62.5 mg b.i.d. for four weeks, followed by 125 mg b.i.d. thereafter. Additional therapy was permitted according to set criteria. At four months, PVR had decreased from 737±328 to 476±302 dyn.s/cm-5 (P<0.05) and 6MWD had increased from 358±98 metres to 435±89 metres (P<0.05). Long-term evaluation after a mean of 29±18 months’ follow-up in 38 patients revealed a further decrease in PVR to 444±356 dyn.s/cm-5 (P<0.05 vs. baseline; P<0.05 vs. four months); 6MWD remained constant. Of considerable interest, noted Dr. Degano, was that hemodynamics were normalized in 10 patients on ERA monotherapy. At their last evaluation, these patients were WHO FC I with a 6MWD of 532±52 metres. This was a surprising finding, Dr. Degano admitted, because complete normalization of hemodynamic parameters is exceptional with PAH-specific therapy in PAH patients with concomitant disease. Overall survival rates were 93%, 86% and 66% and event-free survival 82%, 73%, an
three years, respectively, better than previously reported in a series of patients with PAH/HIV.

Figure 4.

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History of right heart failure and WHO FC class IV were significantly related to poor overall survival. “This highlights the importance of screening patients with HIV infection and unexplained dyspnea in order to start PAH-specific therapy early in the course of the disease before the occurrence of right heart failure,” Dr. Degano stated.