Galie N, Benza R, Rubin LJ, Hoeper MM, Jansa P, Kusic-Pajic A, Simonneau G

Transcription

1 Bosentan improves hemodynamics and delays time to clinical worsening in patients with mildly symptomatic pulmonary arterial hypertension: Results of the EARLY study Galie N, Benza R, Rubin LJ, Hoeper MM, Jansa P, Kusic-Pajic A, Simonneau G

2 Disclosure of Commercial Interest Dr. Benza has received grants/research support from Actelion, Encysive, Lung RX, Inc., Gilead, Inc., Pfizer Inc, and United Therapeutics. Dr. Benza has served as a steering committee member, and/or speaker s bureau member for Actelion, Gilead, Pfizer Inc, and United Therapeutics. Dr. Benza has received honoraria for speaking from Actelion, Encysive, and Pfizer.

3 The Truth about Pulmonary Arterial Hypertension (PAH) PAH is a deadly disease Insidious in onset Once symptomatic, progresses rapidly without treatment Medical therapies exist, but most tested in patients with advanced disease

4 ACE Inhibitors Improve Survival in Minimally symptomatic CHF Mortality (%) Placebo (n=126) CONSENSUS NYHA Class IV Risk reduction 40% (p=0.003) Enalapril (n=126) Placebo (n=1284) SOLVD NYHA Class II-III Risk reduction 16% (p=0.0036) Enalapril (n=1285) Months CONSENSUS Trial Study Group. N Engl J Med. 1987:316: The SOLVD Investigators. N Engl J Med. 1991;325:

5 EARLY: Study rationale EARLY designed to demonstrate efficacy and safety of bosentan in mildly symptomatic (WHO functional class II) PAH patients

6 EARLY: Study design Prospective, randomized, double-bind, placebocontrolled, parallel-group Screening Bosentan 62.5 mg bid Bosentan 125 mg bid Placebo Placebo 4 weeks 4 weeks 20 weeks Baseline randomisation 6 months

7 EARLY: Main inclusion criteria Patients 12 years of age WHO functional class II PAH due to idiopathic/familial associated with HIV, anorexigens, atrial septal defect (ASD) < 2 cm, ventricular septal defect (VSD) < 1 cm or patent ductus arteriosus (PDA), connective tissue or auto-immune diseases Pulmonary vascular resistance (PVR) 320 dyn sec cm 5 (4 WOOD units) 6-minute walk distance (6MWD) < 80% of normal predicted value or < 500 m associated with a Borg dyspnea index of 2

8 EARLY: Main exclusion criteria Severe obstructive lung disease: FEV 1 /FVC < 0.5 Total lung capacity < 80% of normal predicted value Symptomatic lower limb vascular disease PAH-specific treatment Exception: protocol amendment allowed sildenafil use, as it was approved for PAH treatment during conduct of the study Sildenafil-treated patients were stratified at enrolment into the two treatment groups

9 EARLY: Study endpoints Co-primary endpoints: PVR at rest at month 6, expressed as percent of baseline value Change in 6MWD from baseline to month 6 Secondary endpoints: Time to clinical worsening Change from baseline to month 6 in WHO functional class Quality of life (SF-36) TPR, mrap, mpap, CI, SVO 2 at rest Exploratory endpoint: Change in N-terminal-proB-type natriuretic peptide (NT-proBNP) concentration

10 EARLY: Definition of clinical worsening Death during treatment period or as outcome of adverse event leading to discontinuation Hospitalization for PAH Symptomatic progression of PAH Appearance or worsening of right heart failure Decrease in two 6MWT by at least 10% from baseline or by at least 5% with an increase in Borg dyspnea index by > 2 6MWT performed at least 2 weeks apart second 6MWT not mandatory if signs of right heart failure overt

11 EARLY: Patient disposition Patients enrolled n = 185 Randomized and treated Placebo n = 92 Bosentan n = 93 Concomitant sildenafil Yes n = 15 No n = 77 Yes n = 14 No n = 79 Premature discontinuations Completed study n = 10 (9 due to AEs 1 withdrew consent) n = 82 n = 12 (9 due to AEs, 1 withdrew consent, 2 protocol violations) n = 81 AE = Adverse event

12 EARLY: Patient demographics and baseline characteristics Placebo (n = 92) Bosentan (n = 93) Gender (% females) Age (mean SD, years) Weight (mean SD, kg) Race (% White:Black:Asian) 88:3:9 94:2:4 Time from diagnosis (mean SD, years) Etiology, n (%) IPAH CHD CTD HIV Other * ** 58 (63) 16 (17) 15 (16) 2 (2) 1 (1) 54 (58) 16 (17) 18 (19) 5 (5) 0 (0) *n = 91; **n = 92

13 EARLY: Baseline characteristics Variable (mean SD) Placebo (n = 92) Bosentan (n = 93) 6MWD, m PVR, dyn sec cm # mrap, mmhg * mpap, mmhg TPR, dyn sec cm # Cardiac index, L min 1 m # SVO 2, % NT-proBNP conc., ng/l & * n = 91; # n = 92; n = 83; n = 84; n = 71; & n = 65

14 % of baseline PVR at month 6 (geometric means) EARLY: Co-primary endpoint: Bosentan significantly reduced PVR Placebo n = 88 Bosentan n = p < ; Wilcoxon 80 Treatment effect:* 22.6% 95% CL: 33.5, 10.0 *(ratio of geometric means 1) x 100

15 Mean (± SE) change in 6MWD* (m) EARLY: Co-primary endpoint: 6MWD from baseline to month Placebo (n = 91) Bosentan (n = 86) Weeks 15 p = 0.076; Wilcoxon 20 Mean treatment effect:* m 95% CL: 3.6, 41.8 *from baseline to month 6

16 Patients without the event (%) EARLY: Effect of bosentan on time to clinical worsening Placebo Bosentan 77% relative risk reduction Hazard ratio = % CL: 0.065, Patients are censored at the end of the study p = ; log rank Weeks from treatment start Patients at risk

17 EARLY: Components of clinical worsening Total pts with at least one cause, n (%) Placebo Bosentan (n = 92) (n = 93) 13 (14.1%) 3 (3.2%) Symptomatic progression of PAH (excl. hospitalization) 9 (9.8%) 1 (1.1%) Hospitalization for PAH 3 (3.3%) 1 (1.1%) Death 1 (1.1%) 1 (1.1%)

18 Patients (%) EARLY: Effect of bosentan on WHO functional class 14 Placebo (n = 91) 12 Bosentan (n = 87) Relative risk = 1.26 (95% CI: 0.40, 3.96) p = Relative risk = 0.26 (95% CI: 0.08, 0.90) p = Proportion of patients improved* (II I) Proportion of patients worsened* (II III or IV) *from baseline to month 6

19 Patients (%) EARLY: Effect of bosentan on Quality of Life SF-36 Health Transition Item Placebo (n = 81) Bosentan (n = 75) Relative risk = 1.50 (95% CI: 1.07, 2.10) p = Proportion of patients improved* Proportion of patients worsened* Relative risk = 1.01 (95% CI: 0.52, 1.94) p = *from baseline to month 6

20 Change in CI* (l.min -1.m -2 ) (mean, 95% CL) Change in SVO 2 * (%) (mean, 95% CL) Change in mrap* (mmhg) (mean, 95% CL) Change in mpap* (mmhg) (mean, 95% CL) EARLY: Consistent improvements in hemodynamics with bosentan mrap -4-6 mpap CI SVO *from baseline to Month 6 Placebo Bosentan

21 Mean ( SE) change in NT-proBNP concentration* (ng/l) EARLY: Effect of bosentan on NT-proBNP concentration Placebo n = 71 Bosentan n = 65 p = ; Wilcoxon 400 Mean treatment effect:* 471 ng/l 95% CL: 749, 192 Mean baseline values: Placebo = 844 ng/l; Bosentan = 706 ng/l Normal values of central lab: < 125 ng/l *from baseline to month 6

22 EARLY: Adverse event profile was similar to that reported previously Number of patients (%) Placebo (n = 92) Bosentan (n = 93) Nasopharyngitis 8 (9%) 7 (8%) Abnormal LFTs 3 (3%) 7 (8%) Edema (peripheral) 7 (8%) 6 (6%) Nausea 8 (9%) 5 (5%) Dizziness 5 (5%) 5 (5%)

23 EARLY: Discontinuations of study treatment Total patients with at least one reason, n (%) Death PH aggravated Adverse event (other than PH aggravated) Administrative / other Placebo (n = 92) Bosentan (n = 93) 10 (10.9) 12 (12.9) 1 (1.1) 6 (6.5) 2 (2.2) 1 (1.1) 1 (1.1) 2 (2.2) 6 (6.5) 3 (3.2)

24 EARLY: Summary of the EARLY results Untreated, WHO FC II PAH will continue to progress When compared to placebo, bosentan: significantly improved hemodynamics 6MWD increased but did not reach statistical significance significantly delayed time to clinical worsening had a significant effect on preservation of WHO FC significantly reduced NT-proBNP plasma levels Bosentan was well tolerated, with a safety profile consistent with previous RCTs

25 EARLY: Authors conclusions EARLY study demonstrates that mildly symptomatic PAH patients progress hemodynamically and clinically, despite the maintenance of exercise capacity Bosentan treatment in this patient population is associated with improvements in hemodynamics and ameliorates clinical deterioration These findings indicate that treatment with bosentan may be beneficial for WHO FC II PAH patients

26 EARLY: Summary for patients Symptoms and level of function in PAH patients are measured using the World Health Organization functional class (WHO FC) system Patients in WHO FC I and II are mildly symptomatic; WHO FC III and IV are the most severely affected The effect of PAH treatments has not previously been explored in patients with mildly symptomatic PAH (FC I and II) The results of this 6-month study showed that in patients with PAH in WHO functional class II, bosentan treatment: was not associated with an increased walking distance improved pressures in the pulmonary vessels and made clinical deterioration less likely

27 EARLY investigators Australia: E Gabbay, A Keogh, K McNeil, S Proudman, T Willimans, P Youssef Austria: I Lang, H Olschewski Belgium: M Delcroix, R Naeije Brazil: JSO Arakaki, GM Bohns Meyer, AMP Bandeira de Oliveira, MV Tavares Santana, D Waetge Canada: C Bradley, J Granton, D Helmersen, P Hernandez, DC Lien, S Martel, S Mehta, Czech Republic: H Al-Hiti, P Jansa Denmark: J Carlsen France: A Chaouat, G Habib, C Pison, G Simonneau Germany: R Ewert, M Hoeper, H Klose, JPM Meyer, M Pfeifer, HRW Wirtz Greece: A Manginas, G Parharidis, I Nanas Hongkong: S Lee Wai Luen, E Li Ireland: S Gaine Israel: MR Kramer, M Yigla Italy: N Galiè, A Gavazzi, S Harari, DC Vizza Netherlands: KA Boomars, A Boonstra, RJ Snijder, FHJ van den Hoogen Norway: D Atar Singapore: ST Lim, J Raghuram, J Yip Spain: JA Barberá, A Roman, MA Gómez-Sánchez Sweden: B Ekmehag, G Wikström Switzerland: L Nicod, R Speich UK: G Coghlan, P Corris, D Kiely, J Pepke-Zaba USA: D Badesch, R Barst, RL Benza, C Daniels, B DeBoisblanc, S Eaton, A Frost, M Gomberg- Maitland, H Kim, V McLaughlin, O Minai, M Park, I Preston, R Oudiz, D Ross, R Solica, F Torres

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29 Back-up slides

30 EARLY: Clinical worsening: individual data in the placebo group (pts 1 to 5) At EoS* Patient First event of clinical worsening Symptomatic progression Day 108 Symptomatic progression Day 51 Symptomatic progression Day 77 Symptomatic progression Day 181 Symptomatic progression Day 113 Hospit. / PD ** Δ PVR (dyn s cm 5 ) PD Day 122 PD Day 51 Δ 6MWD (m) Δ Borg dyspnea index WHO FC III ND ND ND ND III PD Day III III * EoS corresponds to either premature discontinuation or study completion. ** PD = premature discontinuation. All discontinuations due to worsening PAH

31 EARLY: Clinical worsening: individual data in the placebo group (pts 6 to 9) Patient First event of clinical worsening Symptomatic progression Day 22 Symptomatic progression Day 177 Symptomatic progression Day 161 Symptomatic progression Day 189 Hospit. / PD ** Δ PVR (dyn s cm 5 ) PD Day 50 PD Day 177 At EoS* Δ 6MWD (m) Δ Borg dyspnea index WHO FC II III ND ND II III * EoS corresponds to either premature discontinuation or study completion. ** PD = premature discontinuation. All discontinuations due to worsening PAH

32 EARLY: Clinical worsening: individual data in the placebo group (pts 10 to 13) At EoS* Patient First event of clinical worsening Symptomatic progression Day 141 Symptomatic progression Day 155 Hospit. / PD ** Δ PVR (dyn s cm 5 ) Hospit. Day 149 Hospit. Day 171 Δ 6MWD (m) Δ Borg dyspnea index WHO FC ND ND III II 12 Hospitalization Day 57 PD Day III 13 Death Day 31 # - ND ND ND ND * EoS corresponds to either premature discontinuation or study completion. ** PD = premature discontinuation. All discontinuations due to worsening PAH # Patient with SLE: spinal cord hemorrhage, respiratory failure post surgery, no autopsy

33 EARLY: Clinical worsening: individual data in the bosentan group (pts 1 to 3) At EoS* Patient 1 First event of clinical worsening Symptomatic progression Day 42 Hospit. / PD ** Δ PVR (dyn s cm 5 ) PD Day 151 Δ 6MWD (m) Δ Borg dyspnea index WHO FC ND 1 2 III 2 Hospitalization Day 84 PD Day 86 ND ND ND IV 3 Death # Day ND ND ND ND *EoS corresponds to either premature discontinuation or study completion ** PD = premature discontinuation. All discontinuations due to worsening PAH # Patient with SLE: fall, headache, rapid death, no autopsy

34 Mean (95% CL) change in Borg dyspnea index* EARLY: Effect of bosentan on Borg dyspnea index Bosentan n = Placebo n = 89 Mean treatment effect:* % CL: 1.0, 0.1 p = ; Wilcoxon *from baseline to Month 6

35 EARLY: Overview of adverse events Number of patients (%) Placebo (n = 92) Bosentan (n = 93) Adverse event (AE) 60 (65.2) 65 (69.9) Severe AE 13 (14.1) 10 (10.8) Treatment-related AE 26 (28.3) 31 (33.3) Serious AE 8 (8.7) 12 (12.9) Deaths 1 (1.1) 1 (1.1) AE leading to discontinuation 9 (9.8) 9 (9.7)