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PRIORITY PRESS - 31st Annual Congress of the European Society of Cardiology

Barcelona, Spain / August 29-September 2, 2009

In a previously published report (Chest 2008;134:775-82), Benza et al. noted that despite “remarkable advances” made possible by novel therapeutic agents, prognosis for patients with pulmonary arterial hypertension (PAH) remains poor, with estimated median life expectancies of five to six years. Furthermore, most patients remain in World Health Organization (WHO) functional class III, with an “unacceptable” quality of life, despite therapy. The endothelin (ET)-receptor antagonists have earned a central place in the treatment of PAH, the first such antagonist being the non-selective ET_A/ET_B receptor antagonist bosentan.

STRIDE-2/2X Study Design

As Benza and colleagues pointed out, both ET_A and the ET_B receptors mediate pulmonary vascular smooth muscle constriction and proliferation. These actions, however, are normally counterbalanced by ET_B-mediated endothelial cell release of nitric oxide and prostacyclin. “There would therefore theoretically be interest in selective ET_A receptor antagonists in the treatment of PAH,” the authors indicated. The novel ET receptor antagonist sitaxsentan is highly selective for the A isoform.

From the original 18-week, phase III, multicentre STRIDE-2 trial (Sitaxsentan to Relieve Impaired Exercise) reported by Benza et al., 229 out of 246 patients in WHO functional class II-IV with idiopathic PAH or PAH associated with either connective tissue disease or with congenital heart defect were enrolled in the open-label extension trial, STRIDE-2X. All 125 patients randomized to 50 mg q.d. of the selective ET_A receptor antagonist in STRIDE-2 were uptitrated to 100 mg q.d. in STRIDE-2X. The cohort randomized to placebo in the original study was randomized again and subdivided into two groups: sitaxsentan 100 mg q.d. or bosentan 125 mg b.i.d. in STRIDE-2X. The final group that received only bosentan 125 mg b.i.d. in the first study received the same treatment in the extension trial.

As investigators reported, at one year in STRIDE-2X, 96% of patients on sitaxsentan and 88% of patients on bosentan were still alive. The estimated risk for a clinical worsening event at one year was lower in the selective ET_A arm at 34% vs. 40% in the non-selective ET_A/ET_B cohort. As they pointed out, the most commonly reported first clinical worsening events were initiation of new PAH treatment and hospitalization for PAH. Remaining patients in STRIDE-2X then entered a prolonged open-label extension study called STRIDE-3. All patients in this trial received sitaxsentan 100 mg q.d.

STRIDE-3 Study

At the European Society of Cardiology 2009 meeting, trialists under lead author Dr. Nazzareno Galiè, University of Bologna, Italy, reported three-year survival data of the remaining cohort. As the authors stated, the three-year analysis included all STRIDE-2 patients who were randomized to sitaxsentan 100 mg from study outset, patients who were switched to the same agent at the same dose in STRIDE-2X, and placebo patients who were switched to the same selective ETA receptor antagonist. Placebo patients who were randomized to bosentan in the open-label STRIDE-2X study were excluded in STRIDE-3. The cohort was predominantly women with WHO functional class II or III PAH. Some 61% of the cohort had idiopathic PAH, while 29% had PAH associated with connective tissue disease and 10% had PAH associated with congenital heart defect. During STRIDE-3, the addition of new concomitant medications for worsening PAH, such as calcium channel blockers, diuretics, anticoagulants, digitalis, prostacyclin/prostacyclin analogues, oxygen and chronic phosphodiesterase inhibitors, was allowed. The survival analysis at three years included 145 patients in total.

As the authors reported, 60% of the cohort still in the trial at three years (58 out of 97 in total) were still receiving sitaxsentan monotherapy. They added that the remaining patients were receiving combination therapy with sildenafil (26), prostacyclin/prostacyclin analogues (8), sildenafil and prostacyclins (4) or bosentan (1). At three years, 97 patients were still alive, 18 patients had been lost to follow-up and 30 had died, indicating that after three years of treatment, 77.5% of patients receiving the selective ETA antagonist were still alive.

Subgroup Analysis by Etiology

In their analysis of treatment response at one year in STRIDE-2X, investigators carried out a subgroup analysis looking at treatment response based on etiology. Results of this analysis suggested that PAH patients with connective tissue disease responded differently to selective ET_A antagonism than they did to non-selective ETA/ETB antagonism. For example, at one year, 24% of patients on sitaxsentan monotherapy vs. 57% those on bosentan monotherapy had discontinued treatment (Benza et al. Chest 2008). Correspondingly, discontinuation rates in PAH patients with no connective tissues disease were 32% and 37%, respectively. Rates of clinical worsening events for the connective tissue disease subgroup were also substantively different at 27% for the selective ET_A group and 56% for the non-selective ET_A/ET_B group. Again, rates of clinical worsening events at between 27% and 28% were very similar for PAH patients without connective tissue disease. Survival rates at one year for those with connective tissues disease were 96% for the selective ET_A antagonist group vs. 80% for the non-selective ET_A/ET_B antagonist group, whereas at 95% and 91%, respectively, there was very little difference in survival in PAH patients without connective tissue disease.

In the STRIDE investigators’ subgroup analysis at three years, 67% of PAH patients with connective tissue disease were still alive compared with 78% of the cohort overall.

Commenting on STRIDE-3, co-investigator Dr. Robert Naeije, Professor of Medicine and Physiology, Erasmus University Hospital, Brussels, Belgium, noted that scleroderma-associated PAH has a worse prognosis compared with PAH of other etiologies and the mortality is indeed higher for PAH-associated connective tissue disease. Still, he deemed it encouraging that the trends seen during STRIDE-2X persisted out to year 3 in STRIDE-3. “I think this drug shows up favourably and that it is an effective therapy and a good antagonist for PAH,” he said in an interview. Hepatic transaminase (both AST and ALT) elevations are a known class effect of ET-receptor antagonists, Dr. Naeije pointed out. Elevations in liver enzymes were not reported by STRIDE-3 investigators but in STRIDE-2X, 6% for the selective ET_A receptor antagonist group and 14% for the non-selective ET_A/ET_B receptor antagonist group had elevations in liver enzymes greater than 3 times the upper limit of normal.

STRIDE Outcomes and Functional Class

In a related report also presented here at the ESC, data from the STRIDE trials and subsequent extension studies were again evaluated to compare outcomes based on baseline functional class. A total of 87 patients in functional class II and 175 in functional class III were included in this analysis, all of whom received the selective ET_A receptor antagonist. As reported by lead author Dr. Galiè, compared with placebo, median six-minute walking distance improved by 20 m and 6 m at week 12 in functional class II patients, and by 41 and 37 m in functional class III patients in STRIDE-1 and STRIDE-2, respectively.

Median differences in change from baseline at week 12 were significant compared with placebo for pulmonary vascular resistance, the pulmonary vascular resistance index and the cardiac index for both classes of patients on active therapy. In STRIDE-1, change in the pulmonary vascular resistance index significantly correlated with change in functional class. Survival at three years among the 43 remaining patients in functional class II was 83% compared with 75% among the remaining 53 patients with functional class III at baseline.

Dr. Galiè et al. concluded that the observed hemodynamic improvement seen in functional class II patients in this analysis and its correlation with functional class changes suggest that earlier treatment with a selective ET_A receptor antagonist might prevent or delay deterioration.

Study Patient Characteristics

In a comparison of PAH patients who were involved in randomized control trials (RCTs) and those included in multicentre registries, Italian investigators under lead author Dr. Alessandra Manes, Institute of Cardiology, Bologna, found that the average age of RCT patients was 47.5 years and 77% were women. The average age of patients included in registries was 51 years and 74% of them were female. Idiopathic PAH was the most frequent etiology in RCTs at 63% compared with 53% of patients enrolled in registries. PAH associated with connective tissue disease was the second most frequent etiology in RCTs at 22% compared with 23% of patients enrolled in registries.

The authors concluded that patients enrolled in RCTs tended to be younger, more likely to have idiopathic PAH and be in functional class III and IV compared with patients included in registries. Baseline hemodynamics between the two groups were, however, “remarkably similar.”