Subcutaneous treprostinil is advantageous compared to intravenous epoprostenol because of a less cumbersome delivery system and no need for a surgically implanted central venous line. Epoprostenol requires sterile daily or twice daily reconstitution with ice packing, and is admin- istered with a variety of more or less bulky portable pump systems. In contrast, treprostinil is supplied in 20 mL vials containing either 1, 2.5, 5, or 10 mg/mL that may be stored at room temperature. In addition, treprostinil is delivered via a mini-infusion pump, which is of the size of a small cell phone. The injection site is changed approximately every 3 days. However, while this is not recommended, many patients ﬁnd it less painful to leave the subcutaneous catheter in place for longer periods of time, up to 2–3 weeks, and this seems to be generally well tolerated (Vachiery and Naeije 2004). The pivotal treprostinil trial The pivotal 12-week trial included 2 parallel North American and European international, multicenter, double-blind, randomized, parallel, placebo-controlled studies in a total of 470 patients aged 8–75 years with PAH (Simmoneau et al 2002). This has been until now the largest random- ized controlled trial ever performed in PAH. The primary endpoint was exercise capacity as assessed by the 6-min walk distance. Principal reinforcing endopoints were a dys- pnea-fatigue rating and a clinical score. The clinical score included a speciﬁed list of symptoms (dyspnea, orthopnea, fatigue, chest pain, dizziness, syncope, palpitations, and edema) and signs (loud pulmonic sound, right ventricular third sound, right ventricular fourth sound, right ventricular heave, tricuspid insufﬁciency murmur, pulmonic regurgita- tion murmur, hepatomegaly, and jugular vein distension at 45°). A simpliﬁed clinical score of only 5 of these items, ie, dyspnea, fatigue, chest pain, dizziness, syncope, was also used and proved equally sensitive to therapy. The second- ary endpoints were the Borg score and hemodynamics (right atrial pressure, Ppa, Ppw, cardiac output heart rate, and mixed venous oxygenation saturation). Quality of life (QOL) was assessed using the Minnesota Living with Heart Failure questionnaire. Six-min walk test, Borg score, dyspnea-fatigue rating, clinical score, and QOL were obtained at baseline and 1, 6, and 12 weeks after randomization. The hemodynamic measurements were obtained at baseline and 12 weeks after randomization. The two studies were analyzed individually as well as together. Treprostinil was initiated at a ﬁxed dose of 1.25 ng/kg/min (or half this dose if not tolerated), and then progressively Vascular Health and Risk Management 2008:4(3) Treprostinil for pulmonary hypertension increased if tolerated by 1.25 ng/kg/min during the ﬁrst 4 weeks, then by 2.5 ng/kg/min per week until a maximum of 22.5 ng/kg/min at week 12. In fact, the ﬁnal doses achieved remained below these target doses, at 9.3 ± 0.4 ng/kg/min in the treprostinil group, and 19.1 ± 0.3 ng/kg/min in the placebo group. This was explained by slowing of dose escalation because of infusion site pain. The two study groups were comparable in age, gender distribution, and severity of pulmonary hypertension, with 82% of the patients in NYHA functional class III, 11% in NYHA class II, and 7% in NYHA class IV, and an average baseline 6-min walk distance of 326 m. Subsets of PAH were IPAH in 58% of the patients, CTD-PAH in 19%, and CHD-PAH in 23%. In analyzing both studies together, the overall median 6-min walk increased by 10 m in the treprostinil group, and did not change in the placebo group, with a between-group effect of 16 m (p = 0.0064). It is interesting that the two studies did not reach a p 0.05 level of signiﬁcance on the placebo-substracted change in the 6-min walk distance (p = 0.0607 and 0.055, respectively). The pre-speciﬁed cri- teria, ie, pooled p 0.01 with one of the two trials with a p 0.05, were not achieved, but it appeared reasonable to conclude that the results showed a treatment effect of trepro- stinil in PAH, because of signiﬁcant directional changes in all the reinforcing and secondary endpoints. As in other prostacyclin trials in IPAH or CTD-PAH, hemodynamic changes after 12 weeks of treatment, though signiﬁcant, were relatively minor: in the treprostinil and placebo groups, respectively, Ppa +2.3 vs –0.7 mmHg and cardiac output +0.12 vs –0.06 L/min/m2. On the other hand, both the 6-min walk distance and the clinical score was already signiﬁcantly improved by treprostinil after 6 weeks of treatment, illustrat- ing the relevance of the 6-min walk distance to detect clinical changes in PAH patients. A covariate analysis showed no interactions between treprostinil treatment effect and age, gender, race, or diag- nostic category. However, an a posteriori subgroup analysis showed similar responses to treprostinil in IPAH and CTD- PAH, but no signiﬁcant change in 6-min walk distance in CHD-PAH. This difference was explained by the inhomo- geneous character of that subgroup, and also by the fact that CHD-PAH tends to be stable for much longer periods of time than other PAH categories. On the other hand, there were signiﬁcant interactions between treprostinil treatment effect and NYHA functional class, baseline 6-min walk distance, and SvO2. The 6-min walk distance was improved by 54 m in the 34 patients in NYHA class IV, 17 m in the 382 patients 509