OP0067 UTILITY OF RISK STRATIFICATION IN PREDICTING OUTCOMES OF INITIAL MONOTHERAPY VERSUS COMBINATION THERAPY IN PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH CONNECTIVE TISSUE DISEASE: A POST-HOC ANALYSIS OF THE AMBITION STUDY
Authors: Masataka Kuwana, Christiana Blair, Jonathan Langley, Tomohiko Takahashi, Gerry Coghlan
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The AMBITION study (NCT01178073, sponsored by GSK and Gilead) demonstrated a reduced risk of clinical failure event in patients receiving initial combination therapy of ambrisentan and tadalafil (COMB) compared with initial monotherapy of either agent (MONO) in treatment-naive patients with pulmonary arterial hypertension (PAH)<sup>1)</sup>. A similar treatment outcome was observed in connective tissue disease (CTD)-PAH or systemic sclerosis (SSc)-PAH subgroups in both the primary analysis set and modified intention to treat (mITT) population<sup>2,3)</sup>. The 2015 ESC/ERS guidelines<sup>4)</sup> and 2018 WSPH consensus recommended the use of risk assessment (classified as low, intermediate, and high risk) based on the variables to predict prognosis, but the clinical utility of risk stratification in patients with CTD- or SSc-PAH has not been established. <h3>Objectives:</h3> To evaluate utility of risk stratification strategy in predicting outcomes in CTD-PAH patients by post-hoc analysis of prospectively collected AMBITION data. <h3>Methods:</h3> This study examined 216 patients with CTD (COMB; n=117: MONO n=99) enrolled in the AMBITION study mITT population. The most common underlying CTD etiology was SSc (n=137). Abbreviated average risk score<sup>5)</sup> was determined at baseline and at 16 weeks based on 6-minute walking distance, NT-proBNP, and WHO-FC. Time to clinical failure (TtCF) was compared between groups stratified by the risk stratification and/or treatment assignment using the log-rank test. <h3>Results:</h3> At baseline, CTD patients were divided into low (n=27, 12.5%), intermediate (n=179, 82.9%), and high risk (n=10, 4.6%) and at Week 16, subjects were classified as low (n=55, 27.9%), intermediate (n=135, 68.5%), and high risk (n=7, 3.6%). Risk of clinical failure was lowest for subjects in the baseline low risk group and highest in the baseline high risk group. When TtCF was compared between COMB and MONO arms of CTD-PAH patients in individual risk groups at baseline, risk of clinical failure event was lower in COMB than in MONO in the low and the intermediate risk groups (P=0.05, hazard ratio [HR] NA due to no event in COMB, and P= 0.02, HR 0.519, 95%CI 0.297-0.905, respectively), however, no difference in the high risk group was observed. The same analysis was conducted using risk stratification at week 16, resulting in a 93% risk reduction in TtCF after Week 16 in COMB, compared with MONO in the low risk group (P&lt;0.001, HR 0.069, 95%CI 0.009-0.548), but no difference between COMB and MONO in the intermediate risk group (P=0.3). Risk of clinical failure event was comparable between patients with low and intermediate risk after 16 weeks of treatment with MONO. <h3>Conclusion:</h3> A simplified risk stratification at baseline and week 16 may be useful in predicting PAH related outcomes in patients with CTD-PAH. Among those achieving a low risk status at week 16, which could be considered a treatment goal, COMBO was associated with an improved outcome, when compared to MONO. <h3>References:</h3> [1] Galie N, et al. N Engl J Med2015; 373:834-44. [2] Kuwana M, et al. J Scleroderma Relat Disord2018 ;3: suppl. [3] Coghlan JG, et al. Ann Rheum Dis. 2017; 76:1219-27. [4] Galie N, et al. Eur Heart J. 2016; 37:67-119. [5] Kylhammar D, et al. Eur Heart J. 2017 (e-pub). <h3>Disclosure of Interests:</h3> Masataka Kuwana Grant/research support from: Actelion, Consultant for: Chugai, Reata, GlaxoSmithKline, Bayer, Boehringer-Ingelheim, Corpus, CSL-Berling, Mochida, Speakers bureau: Actelion, Pfizer, Bayer, Nippon Shinyaku, Chugai, Christiana Blair Employee of: Gilead Sciences, Jonathan Langley Employee of: GlaxoSmithKline, Tomohiko Takahashi Employee of: GlaxoSmithKline, Gerry Coghlan Grant/research support from: Actelion Pharmaceuticals, GlaxoSmithKline, Speakers bureau: Actelion Pharmaceuticals, GlaxoSmithKline, Bayer, Endotronix, Pfizer, United Therapeutics