Πνευμονική Υπέρταση: Μια ΚΡΙΤΙΚΗ ματιά στις κλινικές μελέτες - AMBITION. Αναστασία Ανθη

Πανελλήνια Σεμινάρια Ομάδων Εργασίας 2017 k Πνευμονική Υπέρταση: Μια ΚΡΙΤΙΚΗ ματιά στις κλινικές μελέτες - AMBITION Αναστασία Ανθη Β Κλιν. Εντατικής Θεραπείας & Διακλινικό Ιατρείο Πνευμ. Υπέρτασης Π.Γ.Ν. «ΑΤΤΙΚΟΝ»

Disclosures Sponsored to attend scientific meetings, or honoraria by: Actelion Bayer MSD Galenica GSK Pfizer

Ambition study August 27, 2015

JACC, June 2009 PAH Evidence-Based Algorithm

AMBITION A Randomised, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension

AMBITION A Randomised, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension The study was aimed to answer the question: starting PAH treatment with a combination of an ERA and a PDE5 inhibitor is better than starting on a single specific therapy (ERA or PDE5 inhibitor alone) in relationship with clinical outcome?

AMBITION A Randomised, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension Combination therapy with Tadalafil /Ambrisentan was selected because both medicines do not have clinically relevant drug-drug interactions when co-administered have once a day dosing & target separate pathways implicated in the pathobiology of PAH

Study Enrollment Criteria Key enrollment criteria: WHO Group 1 Pulmonary Arterial Hypertension (PAH) IPAH/HPAH; APAH (HIV, CTD, Drugs and Toxins, repaired simple CHD) Functional Class II or III Treatment naïve Age 18-75 Baseline 6MWD 125-500m Original Protocol Criteria (Intent to Treat (ITT)) PVR 240 dyn s/cm 5 PCWP or LVEDP 15 mmhg No exclusion of subjects with risk factors for left ventricular disease N. Galiè, et al. N Engl J Med 2015;373:834-44

Study Enrollment Criteria Key enrollment criteria: WHO Group 1 Pulmonary Arterial Hypertension (PAH) IPAH/HPAH; APAH (HIV, CTD, Drugs and Toxins, repaired simple CHD) Functional Class II or III Treatment naïve Age 18-75 Baseline 6MWD 125-500m Amendment 2: To reduce likelihood of enrolling subjects with PH due to covert diastolic dysfunction Original Protocol Criteria (Intent to Treat (ITT)) PVR 240 dyn s/cm 5 PCWP or LVEDP 15 mmhg No exclusion of subjects with risk factors for left ventricular disease Amendment 2 Changes (Primary Analysis Set (PAS)) PVR 300 dyn s/cm 5 PCWP a lowered to 12 mmhg in subjects with PVR 300 but < 500 dyn s/cm5 Exclusion of subjects with 3 of the following risk factors for left ventricular disease: BMI 30 History of essential hypertension Diabetes mellitus (any type) History of significant CAD N. Galiè, et al. N Engl J Med 2015;373:834-44 a PCWP requirement maintained at 15 mmhg In subjects with PVR 500 dyn s/cm 5

AMBITION: An Event Driven Trial with Time to First Clinical Failure Event as Primary Endpoint Combination arm: Ambrisentan + Tadalafil PAH Patients N = 610 (n=500 PAS) Randomized 2:1:1 to Combination arm or Monotherapy arm Monotherapy Arm: Ambrisentan + Placebo OR Monotherapy Arm: Tadalafil + Placebo 105 events in PAS: primary endpoint N. Galiè, et al. N Engl J Med 2015;373:834-44

Primary End Point: Clinical Failure Event Time (days) to first clinical failure event of PAH, defined as: Death (all-cause) or Hospitalization for worsening PAH* >15% decrease from baseline in 6MWD # and WHO functional class III or IV symptoms # or Disease progression* or Unsatisfactory long-term clinical response* * CEAC adjudicated Receiving 1 dose of treatment and being in the study 6 months and A decrease from baseline in 6MWD # and WHO functional class III symptoms for 6 months or longer At 2 clinic visits separated by 6 months # At 2 consecutive post-baseline visits separated by 14 days N. Galiè, et al. N Engl J Med 2015;373:834-44

Baseline Characteristics Characteristic Combination Therapy (n=253) Pooled Monotherapy Ambrisentan monotherapy (n=126) Tadalafil Monotherapy (n=121) (n=247) Age, y, mean ± SD 54.5 ±14.3 54.2 ± 14.9 53.9 ± 14.7 54.5 ±15.2 Female sex, n (%) 188 (74) 200 (81) 100 (79) 100 (83) Race/Race combinations, n (%) White 232 (92) 212 (86) 106 (85) 106 (88) African American / African Heritage 10 (4) 24 (10) 13 (10) 11 (9) Asian 5 (2) 7 (3) 4 (3) 3 (2) Other 6 (2) 3 (1) 3 (2) 1 (1) Region, n (%) North America 116 (46) 112 (45) 51 (41) 61 (50) Europe 129 (51) 128 (52) 72 (57) 56 (46) Asia Pacific 8 (3) 7 (3) 3 (2) 4 (3) N. Galiè, et al. N Engl J Med 2015;373:834-44

Baseline Characteristics Characteristic Combination Therapy (n=253) Pooled Monotherapy (n=247) Ambrisentan Monotherapy (n=126) Tadalafil Monotherapy (n=121) PAH classification, n (%) Idiopathic Heritable Associated with CTD Associated with CHD Associated with HIV Associated with drug use or toxin 127 (50) 7 (3) 103 (41) 5 (2) 5 (2) 6 (2) 138 (56) 7 (3) 84 (34) 4 (2) 4 (2) 10 (4) 72 (57) 3 (2) 44 (35) 1 (1) 2 (2) 4 (3) 66 (55) 4 (3) 40 (33) 3 (3) 2 (2) 6 (5) exposure Concomitant calcium channel 77 (30) 79 (32) 37 (29) 42 (35) blockers, n (%) No history of PAH therapy, n (%) 242 (96) 235 (96) 120 (97) 115 (95) Time from diagnosis to first study drug administration, days, median 20.0 25.0 20.5 29.0 N. Galiè, et al. N Engl J Med 2015;373:834-44

Baseline Characteristics Characteristic Combination Therapy (n=253) Pooled Monotherapy (n=247) Ambrisentan monotherapy (n=126) Tadalafil Monotherapy (n=121) Baseline Who Functional Class II 76 (30%) 79 (32%) 38 (30%) 41 (34%) III 177 (70%) 168 (68%) 88 (70%) 80 (66%) Baseline 6MWD (m) ± SD 353.5 (87.9) 351.7 (91.8) 354.2 (92.3) 349.2 (91.6) Hemodynamic variables RAP, mm Hg, mean ± SD 7.7 ± 4.5 7.9 ± 4.7 7.4 ± 4.6 8.4 ± 4.8 PAP, mm Hg, mean ± SD 48.1 ± 12.4 49.3 ± 12.6 50.4 ± 12.5 48.1 ± 12.6 PCWP, mm Hg, mean ± SD 8.4 ± 3.1 8.9 ± 3.4 8.6 ± 3.3 9.3 ± 3.5 CI, L/min/m 2, mean ± SD 2.41 ± 0.64 2.43 ± 0.71 2.41 ± 0.66 2.45 ± 0.77 PVR, dyne.sec/cm 5, mean ± SD 824.1 ± 467.0 825.7 ± 402.1 852.4 ± 394.7 798.0 ± 409.4 Time on study medication to FAV, 550.0 ± 340.8 NA 466.5 ± 341.4 501.2 ± 328.7 days, mean ± SD N. Galiè, et al. N Engl J Med 2015;373:834-44

Upfront combination therapy with ambrisentan/tadalafil reduced the risk of clinical failure Primary Endpoint: Time to First Clinical Failure Event (PrimaryAnalysis Set) 50% Risk Reduction 95% CIs (using log-log transform method) are presented for each treatment group at weeks 4, 8, 16, 24, and then every 12 weeks up to week 96. N. Galiè, et al. N Engl J Med 2015;373:834-44

First Adjudicated Clinical Failure by Subgroups Pooled Monotherapy CONFIDENTIAL N. Galiè, et al. N Engl J Med 2015;373:834-44

NT-proBNP: change from baseline to week 24 and treatment differences Ratio of NT-proBNP (pg/ml) to BASELINE Treatment ratios to COMBO Week 24 Combo vs pooled mono p<0.0001 Combo vs ambrisentan mono p=0.0070 Combo vs tadalafil mono p<0.0001 Vertical bars represent 95% CIs. Graph is a mixed models repeated measures (MMRM) analysis adjusted for baseline aetiology of PAH (IPAH/HPAH vs non-ipah), WHO FC (II vs III) and baseline, with no imputation for missing data. N. Galiè, et al. N Engl J Med 2015;373:834-44

6MWD: change from baseline to week 24 and treatment differences Median change in 6MWD (m) from baseline Median treatment difference with COMBO (m) Week 24 Combination: +49.0m Pooled mono: +23.8m Ambrisentan mono: +27.0m Tadalafil mono: +22.7m Vertical bars represent 95% CIs. Stratified Wilcoxon Rank Sum analysis. Worst rank scores were used for missing data following death or adjudicated hospitalisation; otherwise, LOCF imputation was used. N. Galiè, et al. N Engl J Med 2015;373:834-44

WHO FC change at week 24 Combination therapy (n=253) Pooled monotherapy (n=247) Ambrisentan monotherapy (n=126) Tadalafil monotherapy (n=121) Baseline WHO FC, observed, n 253 247 126 121 II 76 (30%) 79 (32%) 38 (30%) 41 (34%) III 177 (70%) 168 (68%) 88 (70%) 80 (66%) Week 24 WHO FC, observed, n 233 220 109 111 Improved 89 (38%) 80 (36%) 41 (38%) 39 (35%) No change 138 (59%) 133 ( 60%) 63 (58%) 70 (63%) Deteriorated 6 (3%) 7 (3%) 5 (5%) 2 (2%) Week 24 WHO FC, imputed*, n 252 244 124 120 Improved 94 (37%) 81 (33%) 42 (34%) 39 (33%) No change 146 (58%) 147 (60%) 73 (59%) 74 (62%) Deteriorated 12 (5%) 16 (7%) 9 (7%) 7 (6%) p value 0.2375 0.3011 0.3641 *Worst case imputation (0) was used for missing data following death or adjudicated hospitalisation; otherwise, LOCF imputation was used. Baseline data have not been used for imputation. p value from CMH tests stratified by baseline aetiology of PAH (IPAH/HPAH vs non-ipah) and WHO FC (II vs III). N. Galiè, et al. N Engl J Med 2015;373:834-44

Only adverse events on randomised treatment, with onset between first dose of study drug and last dose+30 days are shown Adverse Events ( 15% in COMB) AE Term n, (%) COMB (n=253) AMB Mono (n=126) TAD Mono (n=121) Any AE 247 (98%) 120 (95%) 114 (94%) Oedema peripheral 115 (45%) 41 (33%) 34 (28%) Headache 107 (42%) 41 (33%) 42 (35%) Nasal congestion 54 (21%) 19 (15%) 15 (12%) Diarrhoea 50 (20%) 29 (23%) 23 (19%) Dizziness 50 (20%) 24 (19%) 14 (12%) Dyspnoea 44 (17%) 22 (17%) 20 (17%) Nausea 43 (17%) 18 (14%) 20 (17%) Cough 40 (16%) 14 (11%) 21 (17%) Flushing 38 (15%) 18 (14%) 11 (9%) Anemia 37 (15%) 8 (6%) 14 (12%) Nasopharyngitis 37 (15%) 26 (21%) 18 (15%) Pain in extremity 37 (15%) 14 (11%) 18 (15%) Syncope 13 (5%) 7 (6%) 10 (8%)

Initial combination therapy with ambrisentan & tadalafil in CTD-PAH: subgroup analysis from the AMBITION trial Coghlan JG, et al. Ann Rheum Dis 2016;0:1 9.

Initial combination therapy with ambrisentan & tadalafil and mortality in pts with PAH: a secondary analysis of the results from the AMBITION study Hoeper MM et al. Lancet Respir Med 2016

Initial combination therapy with ambrisentan & tadalafil and mortality in pts with PAH: a secondary analysis of the results from the AMBITION study Initial combination therapy might be associated with a survival advantage compared with initial monotherapy in pts with newly diagnosed PAH This hypothesis needs to be addressed in future studies Hoeper MM et al. Lancet Respir Med 2016

Evidence based treatment algorithm for PAH patients PH guidelines 2015

Evidence based treatment algorithm for PAH patients Initial monotherapy Initial oral combination PH guidelines 2015