Edema is a common side effect of endothelin receptor antagonists. Ambrisentan is an endothelin type A-selective endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension. We examined the clinical outcomes of patients who developed edema with and without ambrisentan treatment in 2 phase III, randomized placebo-controlled trials, ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2 (ARIES-1 and ARIES-2) (n = 393). Edema-related adverse events were extracted using broad adverse event search terms. The present post hoc analysis included 132 placebo patients and 261 ambrisentan patients. Of these patients, 14% of the placebo patients and 23% of the ambrisentan patients experienced edema-related adverse events. Overall, the patients who experienced edema tended to have a worse baseline World Health Organization (WHO) functional class (edema 76%, WHO functional class III-IV; no edema 56%, WHO functional class III-IV). In the ambrisentan patients, those with edema were older (mean age 58 ± 13 years) and heavier (mean weight 75 ± 19 kg) than those without edema (mean age 49 ± 15 years; mean weight 70 ± 17 kg). At week 12 of treatment, the ambrisentan patients had significantly increased their 6-minute walk distance (6MWD) by 34.4 m compared to the placebo patients in whom the 6MWD had deteriorated by −9.0 m (p <0.001). Among the ambrisentan patients, those without edema had a 6MWD increase of 38.9 m and those with edema had a 6MWD increase of 19.4 m. Ambrisentan significantly improved the brain natriuretic peptide levels by −34% compared to the brain natriuretic peptide levels in the placebo group that had worsened by +11% (p <0.001). Ambrisentan reduced the brain natriuretic peptide concentrations similarly in patients with and without edema. In conclusion, the present subanalysis of patients with pulmonary arterial hypertension has revealed that ambrisentan therapy provides clinical benefit compared to placebo, even in the presence of edema.
Pulmonary arterial hypertension (PAH) is a chronic, progressive disease resulting in changes in pulmonary hemodynamics leading to increased vascular resistance and subsequent right-sided heart failure. Ambrisentan is a selective type A endothelin (ET) receptor antagonist (ERA) approved for the treatment of PAH. Edema is a common side effect of ERAs. The development of edema during ERA therapy might limit its use and effectiveness; therefore, we analyzed data from 2 phase III, randomized, placebo-controlled trials, ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2 (ARIES-1 and ARIES-2) (n = 393) to help understand the potential risk factors for developing edema and the effect of edema on the clinical outcomes with ambrisentan treatment. The combined ARIES-1 and ARIES-2 published clinical data have shown an overall rate of peripheral edema of 17% in ambrisentan-treated patients (n = 261) compared with 11% in placebo patients (n = 132). In the present subanalysis, we examined the baseline characteristics and clinical outcomes of the patients who developed edema, characterized by a broader definition, with and without ambrisentan treatment in the ARIES-1 and ARIES-2 studies.
Methods
We randomized patients with World Health Organization group I PAH and who had received treatment in 2 concurrent placebo-controlled phase III trials: ARIES-1 (n = 201) and ARIES-2 (n = 192). The full methods and results for both of these studies have been previously published. Patients received either placebo or ambrisentan at oral doses ranging from 2.5 to 10 mg/day for 12 weeks. The primary end point for both studies was the change from baseline in the 6-minute walk distance (6MWD) at week 12. The secondary end points included in this study and relevant to the present subanalysis included brain natriuretic peptide (BNP), the Borg Dyspnea Index (BDI), and World Health Organization (WHO) functional class.
To retrospectively capture and quantify those subjects who experienced any form of edema in the combined trial data, we queried the databases using adverse event search terms related to edema, including peripheral edema, edema, pitting edema, gravitational edema, localized edema, anasarca, fluid retention, and fluid overload. The edema search terms used in the present analysis varied from the original published clinical trial results in which peripheral edema was the only search term used for edema adverse event rates.
The demographic and baseline characteristics were summarized by treatment group and by subjects with or without edema adverse events within the treatment groups. Differences between treatment groups in the change from baseline at week 12 in 6MWD, BNP, and BDI were analyzed using the Wilcoxon rank-sum test stratified by disease etiology (idiopathic PAH vs nonidiopathic PAH) and study (ARIES-1 vs ARIES-2). Prespecified comparisons were made between the combined ambrisentan group and placebo group. Post hoc comparisons were made between (1) the combined ambrisentan group and the placebo group within the subset of subjects with edema, (2) the combined ambrisentan group and the placebo group within the subset of subjects without edema, and (3) the combined ambrisentan subjects with edema and all placebo subjects (with or without edema). For 6MWD and BDI, point estimates and 95% confidence intervals for change from baseline to week 12 were estimated using least squares means and standard errors from 1-way analysis of variance. For BNP, the geometric mean and 95% confidence intervals for baseline and week 12 and the geometric mean ratios and 95% confidence intervals for the change from baseline to week 12 were constructed using the mean and standard errors based on the log values and log change values, respectively. The change from baseline in WHO functional class is presented categorically and was analyzed with a 7-point scale: −3, −2, −1 (improved), 0 (no change), 1, 2, and 3 (deteriorated) using the Wilcoxon rank-sum test. The risk of edema by dose group was evaluated by the baseline estimated glomerular filtration rate quartiles.
Results
Using the newer broadened search terms for edema, fewer placebo patients (14.4%) compared to ambrisentan patients (23.0%) experienced edema as an adverse event in the combined ARIES-1 and ARIES-2 trials (n = 393; Table 1 ). Serious adverse events of edema were reported by 2 (0.8%) of 261 subjects in the ambrisentan group and 1 (0.8%) of 132 subjects in the placebo group. Edema adverse events leading to study drug or study discontinuation were reported by 1 (0.4%) of 261 subjects in the ambrisentan group and 3 (2.3%) 132 subjects in the placebo group. Most adverse events of edema were graded as mild to moderate in severity, with a similar incidence between treatment groups (ambrisentan 93% and placebo 95%). At baseline, regardless of the treatment assignment, the patients who experienced edema tended to be women (86%) and to have worse WHO functional class (75% WHO functional class III-IV) compared to patients who did not experience adverse events of edema (77% women and 56% WHO functional class III-IV). In patients taking ambrisentan, those who reported edema were older (mean age 58 ± 13 years) and heavier (mean weight 75 ± 19 kg) than those without edema (mean age 49 ± 15 years; mean weight 70 ± 17 kg). Elderly patients (age ≥65 years) taking ambrisentan had a heightened risk of edema ( Table 1 ). Also, 50% of patients were taking diuretics at baseline and 55% of patients had received diuretics as concomitant medication at some point after baseline through week 12. No obvious relation was found between diuretic use before or during the trial and the development of edema.
| Demographics and Baseline Characteristic | Overall Placebo (n = 132) | Overall Ambrisentan (n = 261) | Placebo (n = 132) | Ambrisentan (n = 261) | ||
|---|---|---|---|---|---|---|
| Edema ⁎ Subgroup (n = 19; 14.4%) | No Edema Subgroup (n = 113; 86.6%) | Edema Subgroup (n = 60; 23.0%) | No Edema Subgroup (n = 201; 77.0%) | |||
| Women | 78% | 80% | 89% | 76% | 85% | 78% |
| White | 76% | 77% | 79% | 75% | 83% | 76% |
| Idiopathic pulmonary arterial hypertension | 64% | 64% | 63% | 65% | 58% | 65% |
| Pulmonary arterial hypertension associated with connective tissue disease | 33% | 31% | 37% | 32% | 35% | 30% |
| World Health Organization functional class III-IV | 61% | 59% | 79% | 58% | 73% | 54% |
| Age (years) | 49 ± 15 | 51 ± 15 | 49 ± 12 | 49 ± 16 | 58 ± 13 | 49 ± 15 |
| <65 | 79% | 79% | 84% | 78% | 65% | 83% |
| ≥65 | 21% | 21% | 16% | 22% | 35% | 17% |
| Weight (kg) | 74 ± 20 | 71 ± 18 | 74 ± 16 | 74 ± 20 | 75 ± 19 | 70 ± 17 |
| 6-Minute walk distance (m) | 342 ± 80 | 346 ± 81 | 346 ± 65 | 342 ± 82 | 323 ± 79 | 353 ± 80 |
| Borg Dyspnea Index score | 3.8 ± 2.2 | 3.8 ± 2.3 | 3.3 ± 1.7 | 3.9 ± 2.2 | 3.7 ± 1.9 | 3.9 ± 2.4 |
| Brain natriuretic peptide concentration (geometric mean, ng/L) | 264 ± 279 | 262 ± 375 | 284 ± 275 | 235 ± 281 | 287 ± 402 | 250 ± 347 |
⁎ Edema included the following adverse events terms: peripheral edema, edema, pitting edema, gravitational edema, localized edema, anasarca, fluid retention, and fluid overload.
For the combined ARIES trials, the baseline 6MWD for the placebo- and ambrisentan-treated patients was comparable ( Table 1 ). The changes from baseline at week 12 in outcomes by the presence or absence of edema are listed in Table 2 . Patients receiving ambrisentan significantly increased their 6MWD compared to those taking placebo (p <0.001). Ambrisentan patients who experienced edema improved their 6MWD at week 12 despite the lower baseline 6MWD values compared to those who did not experience edema (323 ± 79 m vs 353 ± 80 m, respectively). However, ambrisentan patients who did not experience edema had a greater increase in the 6MWD. The baseline plasma BNP concentrations were comparable between the placebo and ambrisentan groups ( Table 1 ). At week 12, patients receiving ambrisentan had significantly improved BNP levels compared to patients taking placebo, whose levels had deteriorated (p <0.001). Among the ambrisentan patients, a reduction in BNP concentrations was observed in both patients with edema (p = 0.058) and without edema (p <0.001) compared to the placebo patients. An improvement was still seen in the 6MWD (p = 0.032) and BNP levels (p = 0.013) in the ambrisentan patients with edema compared to the overall placebo patients ( Table 2 ). In addition, the WHO functional class deteriorated for 14% more placebo patients at week 12 compared to the ambrisentan patients. In the ambrisentan group, 4.5% more patients with edema had a deterioration in WHO functional class compared to those without edema.
| Variable | Overall Placebo (n = 132) | Overall Ambrisentan (n = 261) | Placebo (n = 132) | Ambrisentan (n = 261) | ||
|---|---|---|---|---|---|---|
| Edema ⁎ Subgroup (n = 19; 14.4%) | No Edema Subgroup (n = 113; 86.6%) | Edema Subgroup (n = 60; 23.0%) | No Edema Subgroup (n = 201; 77.0%) | |||
| Δ 6-Minute walk distance (m) | ||||||
| Mean | −9.0 | 34.4 | −54.8 | −1.2 | 19.4 | 38.9 |
| 95% Confidence interval | −24, 5.9 | 25, 44 | −106.3, −3.4 | −16.2, 13.7 | 6.3, 32.5 | 27.3, 50.5 |
| p Value 1 | — | <0.001 | — | — | 0.002 | <0.001 |
| p Value 2 | — | — | — | — | 0.032 | — |
| Δ Borg dyspnea index score | ||||||
| Mean | 0.40 | −0.45 | 1.2 | 0.3 | −0.4 | −0.5 |
| 95% Confidence interval | −0.02, 0.82 | −0.69, −0.20 | 0.05, 2.38 | −0.19, 0.72 | −0.88, 0.18 | −0.75, −0.19 |
| p Value 1 | — | <0.001 | — | — | 0.07 | 0.005 |
| p Value 2 | — | — | — | — | 0.142 | — |
| Δ Brain natriuretic peptide concentration (ng/L) | ||||||
| % Geometric mean ratio | 11 | −34 | 47 | 7 | −28 | −35 |
| 95% Confidence interval | −6, 31 | −25, −41 | 0, 115 | −11, 27 | −42, −10 | −44, −25 |
| p Value 1 | — | <0.001 | — | — | 0.058 | <0.001 |
| p Value 2 | — | — | — | — | 0.013 | — |
| Δ World Health Organization functional class | ||||||
| Improved | 21% | 22% | 0% | 24% | 20% | 23% |
| No change | 62% | 74% | 63% | 62% | 73% | 75% |
| Deteriorated | 17% | 3% | 37% | 14% | 7% | 2.5% |
| p Value 1 | — | 0.011 | — | — | <0.001 | 0.104 |
| p Value 2 | — | — | — | — | 0.419 | — |
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