Figures
- Figure 1.
Definition of the morbidity and mortality primary end-points used in the SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) trial. PAH: pulmonary arterial hypertension; 6MWD: 6-min walk distance; PDE-5: phosphodiesterase-5; ERA: endothelin receptor antagonist.
Tables
- Table 1. Number of deaths in randomised, placebo-controlled trials of pulmonary arterial hypertension-specific therapies
First author [ref.] Study acronym Patients n Study period weeks Primary end-point Deaths n Study drug Comparator Rubin [7] 23 8 Haemodynamics# Epoprostenol, n=1 Conventional therapy, n=3 Barst [8] 81 12 Survival and change in 6MWD# Epoprostenol, n=0 Conventional therapy, n=8 Badesch [9] 111 12 Change in 6MWD Epoprostenol, n=4 Conventional therapy, n=5 Simonneau [10] 470 12 Change in 6MWD Treprostinil, n=9 Placebo, n=10 Hiremath [11] TRUST 44 12 Change in 6MWD Treprostinil, n=3 Placebo, n=5 Galiè [12] ALPHABET 130 12 Change in 6MWD Beraprost, n=1 Placebo, n=1 Barst [13] 116 36 Disease progression: death, transplantation, epoprostenol rescue or 25% decrease in peak oxygen consumption Beraprost, n=1 Placebo, n=2 Olschewski [14] AIR 203 12 Improved by one NYHA FC and 10% increase in 6MWD Iloprost, n=1 Placebo, n=4 McLaughlin [15] STEP 67 12 Change in 6MWD, NHYA FC, Borg dyspnoea index# Iloprost/bosentan, n=0 Placebo/bosentan, n=0 Hoeper [16] COMBI 40 12 Change in 6MWD Iloprost/bosentan, n=0 Placebo/bosentan, n=0 Channick [17] 32 12 Change in 6MWD Bosentan, n=0 Placebo, n=0 Rubin [18] BREATHE-1 213 16 Change in 6MWD Bosentan, n=4¶ Placebo, n=2 Galiè [19] EARLY 185 24 Change in PVR and 6MWD Bosentan, n=1 Placebo, n=1 Galiè [20] BREATHE-5 54 16 Change in PVR Bosentan, n=0 Placebo, n=0 Humbert [21] BREATHE-2 33 16 Change in total pulmonary resistance Epoprostenol plus bosentan, n=3+ Epoprostenol plus placebo, n=0 Wilkins [22] SERAPH 26 16 Changes in right ventricular mass Bosentan, n=0 Sildenafil, n=1 Galiè [23] ARIES 394 12 Change in 6MWD Ambrisentan, n=4 Placebo, n=6 Barst [24] STRIDE-1 178 12 Change in peak oxygen consumption Sitaxentan, n=1 Placebo, n=0 Barst [25] STRIDE-2 247 18 Change in 6MWD Sitaxentan, n=0 Placebo, n=2 Bosentan, n=0 Sandoval [26] STRIDE-4 98 18 Change in 6MWD Sitaxentan, n=0 Placebo, n=0 Sastry [27] 22 12 Change in 6MWD Sildenafil, n=0 Placebo, n=1 Galiè [28] SUPER-1 278 12 Change in 6MWD Sildenafil, n=3 Placebo, n=1 Singh [29] 20 8 Change in 6MWD Sildenafil, n=0 Placebo, n=0 Simonneau [30] PACES 267 16 Change in 6MWD Sildenafil, n=0 Placebo, n=7 Galiè [31] PHIRST 405 16 Change in 6MWD Tadalafil, n=2 Placebo, n=1 Jing [32] EVALUATION 66 12 (+12 open label) Change in 6MWD Vardenafil, n=1 Placebo, n=2 Langleben [33] 71 12 Change in 6MWD Terbogrel, n=1 Placebo, n=0 Ghofrani [34] 59 24 Change in 6MWD Imatinib, n=3 Placebo, n=3 Hoeper [35] IMPRES 202 24 Change in 6MWD Imatinib, n=5 Placebo, n=5 6MWD: 6-min walk distance; NYHA FC: New York Heart Association functional class; PVR: pulmonary vascular resistance. #: primary end-point not specified; ¶: three patients were in the post 12-week treatment period; +: there was one death after withdrawal from study.
- Table 2. Definitions of time to clinical worsening used as secondary end-points in short-term, fixed-duration randomised controlled trials and number of events
First author [ref.] Study acronym Patients n Study period weeks Definition of time to clinical worsening Events n Study drug Comparator Galiè [12] ALPHABET 130 12 All-cause mortality Hospitalisation for worsening of PH symptoms Beraprost, n=4 Placebo, n=3 Olschewski [14] AIR 203 12 Clinical deterioration Death Need for transplantation Iloprost, n=6 Placebo, n=13 Hoeper [16] COMBI 40 12 Death Hospitalisation for right heart failure Deterioration in FC Decrease in 6MWD by 20% from baseline or <150 m Iloprost/bosentan, n=3 Placebo/bosentan, n=4 Channick [17] 32 12 Right ventricular heart failure Aggravated pulmonary hypertension Bosentan, n=0 Placebo, n=3 Rubin [18] BREATHE-1 213 16 Death Lung transplantation Atrial septostomy Hospitalisation for PH Lack of clinical improvement or worsening leading to discontinuation Need for epoprostenol therapy Bosentan, n=25 Placebo, n=34 Galiè [19] EARLY 185 24 Death Hospitalisation due to PAH Progression of PAH Bosentan, n=3 Placebo, n=13 Galiè [23] ARIES 394 12 Death Lung transplantation Atrial septostomy Hospitalisation for PAH Study withdrawal because of the addition of other PAH medications, or early escape criteria Ambrisentan, n=12 Placebo, n=20 Barst [24] STRIDE-1 178 12 Death Transplantation Atrial septostomy Epoprostenol use Sitaxentan, n=1 Placebo, n=3 Barst [25] STRIDE-2 247 18 Death Atrial septostomy Transplantation Hospitalisation for PAH Initiation of new chronic PAH treatment Combined WHO FC deterioration and 15% decrease in 6MWD from baseline Sitaxentan, n=10 Placebo, n=10 Bosentan, n=9 Sandoval [26] STRIDE-4 98 18 Hospitalisation for worsening PAH Death Need for heart–lung or lung transplantation Atrial septostomy Addition of any new type of chronic treatment for PAH A combination of deterioration in WHO FC and 15% decrease in 6MWD from baseline Sitaxentan, n=1 Placebo, n=3 Galiè [28] SUPER-1 278 12 Death Transplantation Hospitalisation for PAH Initiation of additional therapies for PAH Sildenafil, n=10 Placebo, n=7 Simonneau [30] PACES 267 16 Death Lung transplantation Hospitalisation due to PAH Initiation of bosentan therapy Change in epoprostenol dose of 10% due to clinical deterioration Sildenafil, n=8 Placebo, n=24 Galiè [31] PHIRST 405 16 Death Lung or heart–lung transplantation Atrial septostomy Hospitalisation due to worsening PAH Initiation of new PAH approved therapy Worsening WHO FC Tadalafil, n=30 Placebo, n=13 Jing [32] EVALUATION 66 12 (+12 open label) Death Hospitalisation for PAH progression Vardenafil, n=1 Placebo, n=4 Hoeper [35] IMPRES 202 24 Death Hospitalisation for worsening of PAH Worsening of WHO FC by at least one level or a 15% decrease from baseline in 6MWD Imatinib, n=37 Placebo, n=32 PH: pulmonary hypertension; FC: functional class; 6MWD: 6-min walk distance; PAH: pulmonary arterial hypertension; WHO: World Health Organization.
Disclosures
Files in this Data Supplement:
Vol 22 Issue 130
Table of Contents
New perspectives in long-term outcomes in clinical trials of pulmonary arterial hypertension
