Presentation on theme: "Marius M Hoeper The use of ERA after SERAPHIN, COMPASS-2 and AMBITION."— Presentation transcript:
Marius M Hoeper The use of ERA after SERAPHIN, COMPASS-2 and AMBITION
Galie N et al. J Am Coll Cardiol 2013;62:D60-72 Grade I recommendation and high level of evidence only for initial mono-therapy
The future of combination therapy 1. Is monotherapy still adequate? 2. Sequential or up-front? 3. Are all drugs the same?
Is monotherapy still adequate?
Macitentan reduced morbidity/mortality events in treatment-naive patients Macitentan 10 mg: 55% Patients without the event (%) Macitentan 10 mg Macitentan 3 mg Placebo Treatment difference3 mg10 mg Hazard ratio (HR) Log-rank p-value0.007<0.001 Risk reduction of primary endpoint event vs placebo Macitentan 3 mg: 47% Patients at risk Macitentan 10 mg Macitentan 3 mg Placebo Time from treatment start (months) Pulido T, et al. N Engl J Med 2013; 369:
SERAPHIN: Adding macitentan to pre-treated, stable FC II/III patients improved outcome Pulido T, et al. N Engl J Med 2013; 369: Macitentan 10 mg: 38% Patients without the event (%) Macitentan 10 mg Placebo Treatment difference10 mg Hazard ratio (HR)0.62 Log-rank p-value0.009 Risk reduction of primary endpoint event vs placebo Patients at risk Macitentan 10 mg Placebo Time from treatment start (months) Pulido T et al. N Engl J Med 2013;369:809-18
SERAPHIN – Patient characteristics All patients n = 742 Placebo n = 250 Macitentan 3 mg n = 250 Macitentan 10 mg n = 242 Female sex, % Age, years, mean ± SD 45.6 ± ± ± ± MWD, m, mean ± SD 360 ± ± ± ± 93 PVR, dyn. sec/cm ± ± ± ± WHO FC, % I/II III/IV Background PAH therapy, % PDE-5 inhibitors Oral/inhaled prostanoids Pulido T et al. N Engl J Med 2013;369:809-18
SERAPHIN – primary endpoint Pulido T et al. N Engl J Med 2013;369: OR All events adjudicated by a blinded clinical events committee AND OR
Conclusions from SERAPHIN Patients with PAH presenting in FC II/III benefit from macitentan, regardless of them being treatment-naïve or pre- treated with a PDE5i Monotherapy with PDE5i may no longer be appropriate for patients with PAH
Up-front or sequential?
AMBITION – Objective “The primary objective of this study is to compare the difference between two treatment strategies; first-line combination therapy (with ambrisentan 10mg od and tadalafil 40mg od) vs. monotherapy (with ambrisentan 10 mg od or tadalafil 40 mg od) in subjects with PAH. This will be assessed by time to first clinical failure (TtCF) event.”
AMBITION – Study design Combination arm: AMB + TAD Monotherapy arm: AMB + PBO Group Randomized 2:1:1 to Combination arm or Monotherapy arm Monotherapy arm: TAD + PBO Group 105 events in PAS: primary endpoint PAH Patients N = 610 (n=500 PAS) OR AMB: ambrisentan TAD: tadalafil PBO: placebo
AMBITION – Dose titration 610 PAH Subjects Randomized 2:1:1 Combination or Monotherapy 5 mg ABS 20 mg TAD 5 mg ABS 40 mg TAD (n=302) 5 mg ABS PBO TAD 10 mg ABS PBO TAD 20 mg TAD PBO ABS 40 mg TAD PBO ABS Sham (PBO) Up-titration Sham (PBO) Up-titration Peak/trough Evaluation (6MWD) Evaluation of Secondary Efficacy Endpoints Week 16 Week 24 Visit: Week - 4 Week 0 (Randomization) Week 4Week Clinical Failure Events: Primary Endpoint Safety Visits Every 4 Weeks EOS (~4 weeks after 1st dB lock) FAV (~28 days after 105 Clinical Failure Events Reached) Clinic Visits Every 12 Weeks 10 mg ABS 40 mg TAD (n=152) (n=151) Ambrisentan (ABS) Tadalafil (TAD) Placebo (PBO) Screening FAV: Final Assessment Visit EOS: End of Study
AMBITION – Primary endpoint („time to clinical failure“) Adapted to reflect current clinical practice Time to clinical failure is defined as the time from randomization to the first occurrence of: Death (all-cause) Hospitalization for worsening PAH (adjudicated) Non-elective hospitalization for worsening PAH Lung or heart/lung transplant Atrial septostomy Initiation of parenteral prostanoid therapy Disease progression (adjudicated) >15% decrease from baseline in 6MWD combined with WHO class III or IV symptoms (at two consecutive post-baseline clinic visits separated by ≥14 days) Unsatisfactory long-term clinical response (adjudicated, all criteria required) Receiving randomized treatment for at least 6 months A decrease from baseline in 6MWD at two consecutive post-baseline clinic visits separated by ≥14 days Sustained WHO class III or IV symptoms for ≥6 months These events trigger combination therapy according to the goal-oriented approach recommended in current guidelines These events trigger combination therapy according to the goal-oriented approach recommended in current guidelines The monotherapy arms in AMBITION represent standard of care, i.e. sequential combination therapy if treatment goals are not met The monotherapy arms in AMBITION represent standard of care, i.e. sequential combination therapy if treatment goals are not met
GSK Press release
AMBITION did show improved outcome (TTCF) with upfront combination therapy Galie N et al. ERS 2014 Combination vs pooled monotherapy
The implications of SERAPHIN and AMBITION Combination therapy with an ERA and a PDE-5i is probably going to become standard of care for patients with newly diagnosed PAH presenting in functional class II or III Evidence to support this concept has been generated by both the SERAPHIN and AMBITION study Both trials suggest that the concept of goal-oriented therapy may no longer valid for the initial PAH therapy (but continues to be relevant for further treatment decisions)
Are all drugs the same? ERA
Macitentan reduced the number of morbidity/mortality events Pulido T et al. N Engl J Med 2013;369: Months HR 0.7, p=0.01 HR 0.55, p< MWD 10 mg vs placebo +22 m (p=0.008)
COMPASS-II: Adding bosentan to sildenafil did not improve outcome
Sildenafil plasma concentrations are reduced by bosentan therapy Paul GA et al. Br J Pharmacol 2005;60: X Sildenafil 100 mg alone 4 weeks bosentan 62.5 mg bid 4 weeks bosentan 125 mg bid Sildenafil AUC dropped by 69% when bosentan was co-administered at 125 mg bid for 4 weeks
Which ERAs will be used in the future? Long-term efficacy has been demonstrated for ambrisentan (in combination with tadalafil) and macitentan, but not for bosentan Where available and reimbursed, ambrisentan or macitentan are expected to become the preferred ERAs for treatment-naïve patients Based on previous studies (BREATHE-I, EARLY), bosentan is still a valuable option when other ERAs are not available/not reimbursed, as well as in bosentan pre-treated patients with a satisfying clinical response
Functional class IV
Sitbon O, et al. Eur Respir J. 2014; 43: Upfront triple combo therapy: i.v. epoprostenol + bosentan + sildenafil 19 incident (i.e. newly diagnosed) patients with Idiopathic (n=9) or heritable (n=10) PAH Mean age 39 ± 14 years (18 – 63) NYHA FC III (n=8) or IV (n=11) Severe haemodynamics: CI 1000 d.s.cm -5
Upfront triple combination therapy: Effect on haemodynamics Prospective, observational analysis of idiopathic or heritable PAH patients (n = 19) treated with upfront combination therapy (epoprostenol, bosentan and sildenafil) Baseline4-month Last visit (32 ± 19 months) RAP (mmHg)11.9 ± ± 4.9*5.2 ± 3.5* mPAP (mmHg)65.8 ± ± 14.0*44.4 ± 13.4* PCWP (mmHg)8.4 ± ± ± 2.8 CI (l/min/m 2 )1.66 ± ± 0.69*3.64 ± 0.65* PVR (d.s.cm -5 )1718 ± ± 260*492 ± 209* Heart rate (bpm)92.3 ± ± 9.8*79.9 ± 13.4* Mean BP (mmHg)92.1 ± ± 11.7*84.9 ± 19.4 SvO 2 (%)51.0 ± ± 5.2*72.2 ± 4.0* *p < 0.01 versus baseline n = 18 Sitbon O, et al. Eur Respir J. 2014; Epub ahead of print.
Sitbon O, et al. Eur Respir J. 2014; 43:1691-7
Despite lack of robust evidence, up-front triple combination therapy (ERA + PDEi or sGC + IV PCA) may be the best approach to FC IV patients (and FC III patients with severe haemodynamic impairment) Initial therapy for WHO-FC IV
Conclusions Up-front or early combination therapy is expected to become standard of care for patients with PAH ERA + PDE5i for patients in FC II/III ERA + PDE5i + IV/SC PCA in FC IV (or severe FC III) The future role of new drugs such as Riociguat or Selexipag in PAH still needs to be defined