Background/Purpose: The 6MWD is a valuable tool for evaluating response to therapy in patients with pulmonary arterial hypertension and may be considered a surrogate measure for survival in PAH.  However, due to musculoskeletal and other non-PAH related factors, there has been a less robust effect on 6MWD in patients with CTD-PAH.  We analyzed the ARIES database to determine the percentage of CTD-PAH patients who have achieved categorical changes in 6MWD while receiving ambrisentan.  

Methods: Data from the combined ARIES 1 & 2 placebo controlled studies (ARIES-C) as well as the extension study (ARIES-E) were used. Based upon the previously determined MID of 26m in the overall PAH population participating in the ARIES clinical trials (Minnai, ATS 2014), we chose to evaluate the number of patients achieving changes from their baseline 6MWD in 30m intervals.  Analysis was broken down by 6MWD at the end of each year through year 3 and observed cases are reported.  Patients who discontinued participation prior to completing year three continued to have survival status evaluated and overall survival status is reported.  Adverse events over three years are also reported.

Results: There were 124 CTD-PAH patients who participated in the ARIES clinical trials.  At the end of year 3, 6MWD data was available for 55 patients and was unavailable for 69 patients (died = 29, missing 6MWD, alive = 29, and missing 6MWD with survival status unknown = 11).  Of patients with an evaluable 6MWD at each yearly interval, the majority [57/91 (63%) at year 1, 43/75 (57%) at year 2, and 32/55 (58%) at year 3] demonstrated improvement from baseline and this was maintained throughout the three years.  Additionally, of the patients demonstrating improvement in 6MWD, most were categorized as demonstrating an improvement of at least +60m over baseline which is well above the MID. At the completion of 3 years, survival status is unknown for 11 of the 124 CTD-PAH patients participating.  Of the 113 patients where survival status is known, 84 (74.3%) were alive at three years.   Adverse events occurring over 3 years were consistent with observed AEs in both PAH and CTD, and were consistent with the known profile of ambrisentan. 

Table 1.

	Year 1	Year 2	Year 3
CTD-PAH patients with evaluable 6MWD	n = 91	n = 75	n = 55
≥60m improvement	25 (27.5%)	23 (30.7%)	14 (25.5%)
≥30 – 60m improvement	17 (18.7%)	12 (16%)	6 (10.9%)
0 – 30m improvement	15 (16.5%)	8 (10.7%)	12 (21.8%)
0 – 30m worsening	18 (19.8)	11 (14.7%)	5 (9.1%)
>30m – 60m worsening	5 (5.5%)	9 (12%)	8 (14.5%)
> 60m worsening	11 (12.1%)	12 (16%)	10 (18.2%)
Overall improved	57 (62.6%)	43 (57.3%)	32 (58.2%)
Overall worsening	34 (37.4%)	32 (42.7%)	23 (41.8%)

Conclusion: Although CTD-PAH patients often do not have a robust improvement in 6MWD, among patients with CTD-PAH who received ambrisentan and had evaluable 6MWD, the majority demonstrated increases in 6MWD over 3 years  with 58.2% maintaining improvement by the end of year 3.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/categorical-change-in-6mwd-in-patients-with-connective-tissue-disease-associated-pulmonary-arterial-hypertension-receiving-ambrisentan-over-3-years/