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Would long-term outcome data impact how we interpret current treatment goals to manage PAH?

Treatment goals are employed in pulmonary arterial hypertension (PAH) to monitor a patient’s response to therapy and to ensure the best possible outcome for the patient1. As such, the variables utilised as treatment goals should have established prognostic relevance2,3.

Although the change in haemodynamic and cardiac function parameters, such as cardiac index (CI)4, right atrial pressure (RAP)4 and brain natriuretic peptide (BNP)5, as well as
6-minute walk distance (6MWD)5-9, during therapy, do not correlate with long-term outcome, the absolute values of these parameters do5,9,10. Consequently, the ambitious treatment goals proposed at the 5th World Symposium on PH are based on absolute values of prognostic indicators assessed while the patient is on treatment11 (see slide 1).

It is difficult for patients on monotherapy to reach the ambitious treatment goals recommended by experts, and even patients on dual therapy often fail to meet these12-14 (see slide 2).

In addition, therapies currently used to treat PAH have been approved on the basis of short-term studies15 investigating change in 6MWD16, which do not provide data on the effect of these treatments on long-term, patient outcomes.

The SERAPHIN study was the first study in PAH to assess the long-term benefits of a therapy on direct measures of disease progression, using a composite morbidity and mortality primary endpoint. Results from the SERAPHIN study demonstrated a significant reduction in morbidity-mortality events, as measured by a composite endpoint, independent of treatment goals17.

Experts at the 5th World Symposium on PH recently proposed updates to the treatment algorithm. A 4-level hierarchy for endpoints in RCTs was proposed, according to the strength in which they reflect true clinical benefit to patients18 (see slide 3). Consequently, two of the approved drugs recommended for the initial treatment of PAH, macitentan and epoprostenol i.v., have been highlighted as they are the only drugs with a prospectively defined, proven effect on morbidity and mortality, and all-cause mortality, respectively (see slide 4). These two endpoints have been categorised as level 1: a true clinical efficacy measure18.

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Show References

1. Sitbon O, Galiè N. Treat-to-target strategies in pulmonary arterial hypertension: the importance of using multiple goals. Eur Respir Rev 2010; 19:272-78.

2. Galiè N, Hoeper MM, Humbert M et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30:2493-537.

3. Galiè N, Hoeper MM, Humbert M et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009; 34:1219-63.

4. Savarese G, Musella F, D'Amore C et al. Hemodynamics, exercise capacity and clinical events in pulmonary arterial hypertension. Eur Respir J 2013; 42:414-24.

5. Fritz JS, Blair C, Oudiz RJ et al. Baseline and follow-up six minute walk distance and BNP predict 2-year mortality in pulmonary arterial hypertension. Chest 2013; 143:315-23.

6. Farber HW. Validation of the 6-minute walk in patients with pulmonary arterial hypertension: trying to fit a square PEG into a round hole? Circulation 2012; 126:258-60.

7. Savarese G, Paolillo S, Costanzo P et al. Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension?: a meta-analysis of 22 randomized trials. J Am Coll Cardiol 2012; 60:1192-201.

8. Gabler NB, French B, Strom BL et al. Validation of six-minute-walk distance as a surrogate endpoint in pulmonary arterial hypertension trials. Circulation 2012; 126:349-56.

9. Sitbon O, Humbert M, Nunes H et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002; 40:780-88.

10. Launay D, Sitbon O, Le PJ et al. Long-term outcome of systemic sclerosis-associated pulmonary arterial hypertension treated with bosentan as first-line monotherapy followed or not by the addition of prostanoids or sildenafil. Rheumatology (Oxford) 2010; 49:490-500.

11. McLaughlin V, Gaine S, Howard LS. Treatment goals of pulmonary hypertension. J Am Coll Cardiol 2013; 62:D73-81.

12. Barst RJ, Chung L, Zamanian RT et al. Functional Class Improvement and Three-Year Survival Outcomes in Patients With Pulmonary Arterial Hypertension in the REVEAL Registry. Chest 2013; 144:160-8.

13. Hoeper MM, Markevych I, Spiekerkoetter E et al. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 2005; 26:858-63.

14. Nickel N, Golpon H, Greer M et al. The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2012; 39:589-96.

15. Galiè N, Manes A, Negro L et al. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009; 30:394-403.

16. Rubin LJ. The 6-minute walk test in pulmonary arterial hypertension: how far is enough? Am J Respir Crit Care Med 2012; 186:396-7.

17. Pulido T, Adzerikho I, Channick R et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369:809-18.

18. Galiè N, Corris PA, Frost A et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol 2013; 62:D60-72.

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