Introduction and The EARLY Trial

Introduction

Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary arterial vasoconstriction and remodeling, leading to a marked rise in pulmonary vascular resistance (PVR), pulmonary hypertension, right ventricular dysfunction, functional limitation, and eventually, right heart failure and death.^[1] PAH may be idiopathic, familial, or associated with certain predisposing conditions such as connective tissue disease(s) (ie, scleroderma), HIV infection, prior anorexigen use, cirrhosis with portal hypertension, or congenital heart disease with left-to-right shunting.

Perturbations in 3 main pathobiologic pathways have been shown to play a role in disease progression, notably, relative prostacylin deficiency; impairment of cyclic guanosine monophosphate (cGMP)-mediated (nitric oxide, natiuretic peptides) signaling; and an excess of endothelin, a potent vasoconstrictor and mitogen in the pulmonary vasculature. As such, exogenous prostacyclin therapy, phosphodiesterase 5 inhibition, and endothelin receptor antagonism have been shown to modify disease progression in PAH. However, studies have focused primarily on patients with PAH who are in the latter stages of their disease process, with 60% to 100% of patients being World Health Organization (WHO) functional class (FC) 3 or 4 at study enrollment.^[2-4] Thus, the ability of pharmacotherapy to modify disease progression at an earlier stage (ie, FC 2) of PAH has been largely unexplored.

The EARLY Trial

The Endothelin Antagonist Trial in Mildly Symptomatic Pulmonary Arterial Hypertension Patients (EARLY) study is the first randomized, double-blind, multicentre, placebo-controlled clinical trial designed to examine the role of pharmacotherapy, and specifically endothelin receptor antagonism, on disease progression in patients with PAH who were FC 2 at enrollment.^[5] Patients (n = 185) were randomly assigned to receive either bosentan at an initial dose of 62.5 mg twice daily, increasing to 125 mg twice daily after 4 weeks, or placebo for 6 months.

The co-primary endpoints were percent change from baseline PVR and change from baseline 6-minute walk distance (6MWD). Secondary endpoints included time to clinical worsening (defined as death from any cause during the study period), PAH-related hospitalization, and symptomatic progression of PAH. Symptomatic progression was defined as the appearance or worsening of clinical right heart failure, a ≥ 10% decrease in the 6MWD from baseline on 2 tests done 2 or more weeks apart, or ≥ 5% drop in the 6MWD with a ≥ 2-point increase in the Borg dyspnea index. Other secondary endpoints included change from baseline to WHO FC at 6 months, mean pulmonary artery pressure, cardiac index, and mixed-venous oxygen saturation. Other endpoints included change from baseline N-terminal-pro-B-type natriuretic peptide (NT-proBNP) level at 6 months and quality of life as measured by the SF-36 questionnaire.

The majority (approximately 60%) of patients had either idiopathic PAH or PAH associated with connective tissue disease (approximately 18%). Baseline hemodynamics in this PAH cohort were similar to those in prior studies done in more functionally impaired patients in terms of the mean right atrial pressure (7 mm Hg), mean pulmonary artery pressure (53 mm Hg), cardiac index (2.7 L/min/m²), and PVR (10.3 mm Hg/L/min). By contrast, the baseline 6MWD in the EARLY cohort was 435 meters (compared with baseline 6MWD of 314-398 meters in previous studies), reflecting patients' relatively well preserved functional status.

At 6 months, the mean PVR was 83.2% of baseline in the bosentan-treated group and 107.5% of baseline in the placebo group (treatment effect 22.6% reduction in PVR; P < .0001). Reduction in PVR was also observed in the subgroup of patients receiving concomitant treatment with sildenafil. The mean 6MWD increased 11.2 meters in the bosentan-treated group and decreased 7.9 meters in the placebo group; the treatment effect (+19.1 meters) fell short of statistical significance (P = .0758). Consistent with the decrease in PVR, bosentan treatment led to a modest increase in the cardiac index and decrease in the mean pulmonary artery pressure.

There was a significant delay in time to clinical worsening in the bosentan-treated group (hazard ratio 0.227, P = .0114) as shown in the Figure, a finding largely driven by a reduction in progression of symptomatic PAH in the bosentan-treated group (1%) vs the placebo group (10%).

There were no differences in mortality rates (1%) between treatment groups. In addition, bosentan-treated patients were less likely to experience deterioration in their functional class (bosentan-treated group 3.4% vs placebo group 13.2%). Further analysis revealed that bosentan treatment led to a significant reduction in the NT-proBNP level vs placebo (treatment effect -471 ng/mL, P = .003).

The number of adverse events was similar between groups, with bosentan-treated patients more commonly experiencing nasopharyngitis and an asymptomatic rise in liver aminotransferase levels to more than 3 times the upper limit of normal (13% in bosentan-treated group vs 2% in placebo group). Aminotransferase levels returned toward baseline values in all patients either spontaneously or with dose reduction or discontinuation of bosentan.

The Benefit of Early Intervention

Thus, the EARLY study demonstrates that even in patients with PAH who have relatively preserved baseline functional capacity, pharmacologic intervention with the endothelin receptor antagonist bosentan over a 6-month period is associated with improved cardiopulmonary hemodynamics, neurohormonal evidence of right ventricular unloading, and delayed clinical progression. That the change in 6MWD fell short of statistical significance is not surprising, given subjects' relative achievement on the baseline walk test, often referred to as the "ceiling effect." Taken together, these findings also underscore the limitations of the 6MWD test as a singular surrogate endpoint and reinforce the importance of employing more integrated metrics of clinical disease progression both clinically and for the purpose of clinical research.

Likewise, the EARLY trial results clearly demonstrate that patients at a relatively early stage of PAH are subject to hemodynamic and clinical deterioration over a relatively short time frame. These findings provide important insight into the tempo of disease progression in PAH, confirming the suspicions of many clinicians experienced at treating PAH, that once diagnosed, PAH should be aggressively treated because relative preservation of FC can provide false reassurance. The EARLY study shows that relative FC preservation in PAH should be viewed by clinicians as an opportunity to modify, not observe, the natural history of PAH.

This activity is supported by an independent educational grant from Actelion.

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3. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903. Abstract
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5. Galie N, Rubin LJ, 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;371:2093-2100. Abstract