The long-term effects of endothelin receptor antagonists on pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) are not well studied. This post hoc analysis examined changes in pulmonary hemodynamics in a cohort of patients with PAH who underwent follow-up right heart catheterization (RHC) in a long-term ambrisentan study (ARIES-E). A retrospective review was conducted of patients who underwent RHC after >3 months of ambrisentan therapy. Changes from baseline in mean PAP, mean right atrial pressure, cardiac index, and PVR were assessed and correlations between these hemodynamic changes and exercise capacity were examined. Sixty-eight patients who received ambrisentan in the ARIES studies had ≥1 follow-up RHC while receiving ambrisentan. Fifty-eight patients were on ambrisentan alone at the time of the first RHC. Median time from initiation of ambrisentan therapy to follow-up RHC was 60 weeks (range 14 to 158). Significant improvements compared to baseline were observed for mean PAP (−7.6 mm Hg, 95% confidence interval [CI] −10.0 to −5.1), PVR (−266 dyne × s/cm 5 , 95% CI −350 to −180), and cardiac index (0.4 L/min/m 2 , 95% CI 0.2 to 0.6 L/min/m 2 ); for patients on ambrisentan alone, changes in mean PAP and PVR were inversely correlated with change from baseline 6-minute walking distance (r = −0.41 and −0.43, respectively, p <0.001 for the 2 comparisons) at time of follow-up RHC. In conclusion, ambrisentan may provide sustained improvements in pulmonary hemodynamics in patients with PAH who receive long-term treatment and these changes correlate with improvements in exercise capacity.
Ambrisentan is an endothelin receptor antagonist that was shown to improve exercise capacity and delay clinical worsening in patients with pulmonary arterial hypertension (PAH) in 2 concurrently run, 12-week multicenter randomized controlled trials, i.e., Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies 1 and 2 (ARIES-1 and ARIES-2). Improvement in pulmonary hemodynamics was also demonstrated after 12 weeks of therapy in a previous dosing trial. Patients enrolled in ARIES-1 and ARIES-2 were eligible to be enrolled in a long-term open-label extension study (ARIES-E). Recently 2-year data from the ARIES-E trial were published and demonstrated that ambrisentan was associated with sustained improvement in 6-minute walking distance (6WMD) and low risk of clinical worsening, death, and liver function test abnormalities. Although repeat right heart catheterization (RHC) was not a requirement of the ARIES-E, it was performed in many patients at the discretion of their physicians at some point during the follow-up observation period. In the present study, we examined the long-term effect of ambrisentan on cardiopulmonary hemodynamics in all patients with PAH in the ARIES-E trial who underwent follow-up catheterization after ≥3 months of ambrisentan therapy.
Methods
Study subjects included patients with PAH who received ≥ 1 dose of ambrisentan in the ARIES-1, ARIES-2, or ARIES-E. ARIES-1 and ARIES-2 were 12-week randomized trials that compared the efficacy of ambrisentan (2.5, 5, or 10 mg 1 time/day) to placebo in patients with idiopathic PAH or PAH associated with connective tissue disease, human immunodeficiency virus infection, or anorexigen use. PAH was defined as mean pulmonary arterial pressure (PAP) ≥25 mm Hg at rest measured by RHC, pulmonary capillary wedge pressure <15 mm Hg, and pulmonary vascular resistance (PVR) >240 dyne × s/cm 5 . After 3 months of study drug, patients were eligible to participate in a long-term extension trial (ARIES-E). The analysis presented includes data collected through June 2008 ( http://www.Clinicaltrials.gov , identifier NCT00578786 ).
Right atrial pressure, PAP, and cardiac index were measured under conditions at rest by RHC. The most recent measurements obtained before initiation of ambrisentan therapy were used as baseline values. Follow-up RHC was not required as part of the ARIES-E but was performed at the discretion of the site investigator. The 6MWD performed closest to the time of follow-up RHC was used to assess correlations with hemodynamic parameters.
Baseline characteristics are presented using descriptive statistics. For patients who had >1 follow-up RHC, only the first catheterization obtained after initiation of ambrisentan was used for determination of change from baseline. For correlation analyses with 6MWD, all hemodynamic measurements obtained after >3 months of ambrisentan monotherapy were used. Hemodynamic data were expressed as mean ± SD and 95% confidence interval (CI), where appropriate. Because similar results were observed regardless of ambrisentan dose, data are presented as all doses of ambrisentan combined unless otherwise noted. Changes compared to baseline were considered significant if 95% CIs for the change excluded 0. Correlations between hemodynamic data and 6MWD were examined using Pearson correlation coefficient and were considered statistically significant at a p value <0.05.
Results
Of the 383 patients who received ambrisentan in the ARIESs, 68 patients had ≥1 follow-up RHC by the end of the data collection period (June 2008). Ten of these patients had initiated additional PAH-directed therapies such as a phosphodiesterase type 5 inhibitor or a prostacyclin derivative before follow-up RHC was performed. The other 58 patients underwent repeat RHC on ambrisentan monotherapy.
Mean time from baseline RHC to initiation of ambrisentan therapy was 14 ± 24 weeks (median 8.5). Median time from initiation of ambrisentan therapy to first follow-up RHC was 60 weeks (range 14 to 158; Figure 1 ). At time of randomization, distributions of doses were 2.5 mg (n = 15), 5 mg (n = 37), and 10 mg (n = 16). At time of first follow-up RHC, distributions of ambrisentan doses were 2.5 mg (n = 3), 5 mg (n = 35), and 10 mg (n = 30). Thus, only 4% of patients were receiving less than the lowest Food and Drug Administration–approved dose of 5 mg/day by the time follow-up RHC was performed.
At time of study entry, patient age, gender, body mass index, 6MWD, Borg dyspnea index, and PAH cause were similar between patients who did and did not undergo follow-up RHC ( Table 1 ). About 3/4 of patients in the follow-up RHC group were in World Health Organization functional class III or IV at study entry compared to about 1/2 of patients in the no–follow-up RHC group. Patients who had follow-up RHC had a lower rate of death and study discontinuations than the no-RHC group, particularly during the first year of follow-up ( Table 2 ). However, patients in the follow-up RHC group had less of an increase in 6MWD and a smaller percentage was on ambrisentan monotherapy at 1 year and 2 years than patients in the no-RHC group ( Table 2 ). The annualized incidence of adverse events reported by the site investigator including peripheral edema, exacerbated dyspnea, right heart failure, and worsening of pulmonary hypertension was also greater in the follow-up RHC group ( Table 2 ).
| Characteristic | No RHC Follow-Up | RHC Follow-Up |
|---|---|---|
| (n = 315) | (n = 68) | |
| Women | 81% | 71% |
| Age (years) | 50 ± 15 | 55 ± 15 |
| Body mass index (kg/m 2 ) | 27 ± 6 | 28 ± 6 |
| Region | ||
| North America/Australia | 37% | 50% |
| Western Europe/Israel | 27% | 50% |
| Latin America | 23% | 0% |
| Eastern Europe | 13% | 0% |
| Idiopathic pulmonary arterial hypertension | 63% | 65% |
| 6-minute walk distance (meters) | 344 ± 88 | 362 ± 72 |
| Borg dyspnea index | 3.9 ± 2.4 | 3.6 ± 2.2 |
| World Health Organization class I/II | 50% | 25% |
| World Health Organization class III/IV | 50% | 75% |
| Characteristic | No RHC Follow-Up (n = 315) | RHC Follow-Up (n = 68) | ||
|---|---|---|---|---|
| 1 Year | 2 Years | 1 Year | 2 Years | |
| Change from baseline 6-minute walk distance (meters) ⁎ | 44 ± 92 | 42 ± 92 | 24 ± 73 | 24 ± 81 |
| Ambrisentan monotherapy ⁎ | 94.4% | 86.1% | 80.0% | 67.9% |
| Discontinuations | ||||
| Death | 5.7% | 11.4% | 2.9% | 8.8% |
| Adverse event † | 8.3% | 9.2% | 1.5% | 2.9% |
| Other ‡ | 6.6% | 8.6% | 0.0% | 1.5% |
| Adverse events (number of patients per patient-year of ambrisentan exposure) | ||||
| Peripheral edema | 0.291 | 0.617 | ||
| Headache | 0.161 | 0.226 | ||
| Upper respiratory tract infection | 0.110 | 0.106 | ||
| Dizziness | 0.106 | 0.110 | ||
| Right ventricular failure | 0.086 | 0.122 | ||
| Anemia | 0.084 | 0.049 | ||
| Cough | 0.085 | 0.172 | ||
| Worsening pulmonary hypertension | 0.082 | 0.124 | ||
| Exacerbated dyspnea | 0.082 | 0.127 | ||
| Nasal congestion | 0.077 | 0.068 | ||
| Nasopharyngitis | 0.078 | 0.077 | ||
| Palpitations | 0.056 | 0.173 | ||
† Includes no improvement or deterioration in clinical status or deteriorated and early escape.
‡ Includes withdrawal of consent, noncompliance, discretion of investigator, lost to follow-up, subject did not enroll in extension, and other.
No differences in baseline pulmonary hemodynamic measurements were seen between patients in the no-RHC and follow-up RHC groups at study entry ( Table 3 ). In patients who had repeat RHC, significant decreases were observed in mean PAP (−7.6 mm Hg, 95% CI −10.0 to −5.1) and PVR (−266 dyn/s/cm 5 , 95% CI −350 to −180) at time of follow-up assessment (median 60 weeks) and a significant increase in mean cardiac index (0.4 L/min/m 2 , 95% CI 0.2 to 0.6 L/min/m 2 ). Mean right atrial pressure (0.3 mm Hg, 95% CI −1.1 to 1.6) and pulmonary capillary wedge pressure (0.8 mm Hg, 95% CI −0.1 to 1.7) were unchanged with long-term treatment. Improvements in mean PAP, PVR, and cardiac index were similar in patients taking ambrisentan 5 compared to 10 mg at time of follow-up RHC ( Table 3 ).
| Ambrisentan Group | Ambrisentan Dose | Patients | Assessment | Mean PAP (mm Hg) | mRAP (mm Hg) | CI (L/min/m 2 ) | PCWP (mm Hg) | PVR (dyne × s/cm 5 ) |
|---|---|---|---|---|---|---|---|---|
| No right heart catheterization follow-up | all | 315 | baseline | 49 ± 15 | 8.3 ± 5.2 | 2.5 ± 0.8 | 9.6 ± 3.3 | 880 ± 528 |
| Right heart catheterization follow-up | all | 68 | baseline | 51 ± 13 | 7.6 ± 4.6 | 2.5 ± 0.8 | 8.7 ± 3.5 | 856 ± 474 |
| change from baseline | −7.6 (−10.0 to −5.1) | −0.3 (−1.1 to 1.6) | 0.4 (0.2 to 0.6) | 0.8 (−0.1 to 1.7) | −266 (−350 to −180) | |||
| 5 mg | 35 | baseline | 52 ± 12 | 8.0 ± 4.8 | 2.5 ± 0.7 | 8.8 ± 3.8 | 810 ± 432 | |
| change from baseline | −9.2 (−12.7 to −5.7) | −0.4 (−2.3 to 1.4) | 0.4 (0.2 to 0.6) | 1.1 (−0.2 to 2.5) | −257 (−354 to −159) | |||
| 10 mg | 30 | baseline | 49 ± 13 | 7.3 ± 4.7 | 2.4 ± 0.8 | 8.5 ± 3.3 | 932 ± 530 | |
| change from baseline | −6.2 (−10.0 to −2.3) | 1.0 (−1.3 to 3.2) | 0.4 (0.0 to 0.8) | 0.7 (−0.6 to 2.0) | −300 (−460 to −140) | |||
| Right heart catheterization follow-up Ambrisentan monotherapy ⁎ | all | 58 | baseline | 51 ± 13 | 7.7 ± 4.8 | 2.5 ± 0.7 | 8.8 ± 3.1 | 856 ± 480 |
| change from baseline | −8.2 (−11.0 to −5.5) | −0.1 (−1.6 to 1.4) | 0.5 (0.3 to 0.7) | 0.4 (−0.5 to 1.4) | −295 (−388 to −202) |
⁎ Monotherapy data for ambrisentan 2.5-mg dose not shown due to small sample (n = 3).
To exclude the possibility that improvement in pulmonary hemodynamics was not influenced by addition of prostacyclin or phosphodiesterase inhibitors in 10 patients who received additional PAH therapies, changes from baseline in hemodynamic parameters were examined for the 58 patients receiving ambrisentan monotherapy at the time of repeat catheterization. Similar to the overall RHC population, significant improvements were seen in pulmonary hemodynamics ( Table 3 ). On average, mean PAP decreased 15%, cardiac index increased 25% and PVR decreased 30% ( Figure 2 ). No changes were observed in mean right atrial pressure and pulmonary capillary wedge pressure ( Table 3 ). Changes in pulmonary hemodynamics in patients who had their initial follow-up RHC during the first year of therapy were similar to those who had their first follow-up catheterization during the second year of therapy ( Table 4 ).
