Acknowledgements. PAH in Children: Natural History. The Sildenafil Saga

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1 The Sildenafil Saga David L. Wessel, MD Executive Vice President Chief Medical Officer Ikaria Distinguished Professor of Critical Care Children s National Medical Center Washington, DC, USA Acknowledgements Steve Abman, MD Dunbar Ivy. MD Robyn Barst, MD For their help in original concepts sharing of slides and information in the public domain tireless efforts to get clinical trial data published PAH in Children: Natural History Survival (n=27) (n=8) (n=3) P=0.002 (n=14) (n=9) (n=5) PGI 2 given (n=31) PGI 2 indicated but not given (n=28) Barst, et al. Circ

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3 NO Plus Oxygen Methods Baseline (RA) 100% Oxygen NO (80 ppm) with oxygen Pulmonary Hypertension Treatment Limitations of inhaled NO: Incomplete response Withdrawal response (rebound) High doses limited by methgb Administration as a gas is awkward Expensive 3

4 Abman and Ivy JTCVS 1998 Dipyridamole in rebound PH Atz and Wessel 1999 Pulmonary Hypertension Sildenafil blunts rebound PH during withdrawal from NO Namachivayam et al Am Rev Resp Crit Care Med

5 SUPER-1 SM Improvements in 6-Minute Walk Distance Change from baseline (m) *p< Week 4 Week 8 Week 12 * * * 45 m 46 m 50 m placebo sildenafil 20mg sildenafil 40mg sildenafil 80mg SUPER-1 SM 238 Adult Patients with PAH SUPER-1 SM Reductions in Mean PAP Change from baseline (mmhg) Week placebo sildenafil 20mg sildenafil 40mg -2.7 mmhg -3.0 mmhg P=0.04 P=0.01 sildenafil 80mg -5.1 mmhg p<0.001 SUPER-1 SM 5

6 Intravenous Sildenafil Trial for PPHN Dose escalation trial for safety N=30 neonates with PPHN, OI>15 Marked improvement in OI over 4 hours Only 1/7 patients required ino No adverse effects on BP or oxygenation at highest doses Intravenous Sildenafil Trial for PPHN: OI over time Oxygenation Index Time (Hours) Cardiac Intensive Care Postop Cardiac Intravenous Sildenafil Trial Randomized, double blinded, placebo controlled, multicenter trial in postop pts with PAP > ½ systemic 3 dose regimen to achieve plasma 40, 120 and 360 ng/ml 18 (21%) had PH; Median age 5 months (3mo- 14 yo) Fraisse, Butrous, Taylor, Oakes, Dilleen and Wessel Intensive Care Medicine

7 (STARTS-1) Prospective, randomized, placebo controlled, multinational trial of oral sildenafil in children 1-17 years with PAH Included idiopathic PAH and APAH-CHD Primary outcome was peak VO2 (CPET) at 16 weeks Secondary outcomes included pulmonary hemodynamics and WHO functional class 7

8 (STARTS-1) Etiology of PAH Primary Diagnosis Placebo Sildenafil All subjects (N=234) IPAH 35% 33% APAH-CHD* 65% 67% Developmentally able subjects (N=115) IPAH 33% 36% APAH-CHD* 67% 64% *includes inoperable if O 2Sat>88%; APAH-CHD if more than 6 months post-op (STARTS-1) Dosing Dose (mg) Body Weight(kg) Low Dose Medium Dose High Dose 8-20* > > * In the 8 20kg weight group the treatment allocation was 1:1:2 to the Placebo:Medium:High Dose groups, respectively. Subject Accountability Oral Sildenfil 324 Screened 235 Randomised 234 Treated Placebo Low Dose Medium Dose High Dose 60 Randomised 60 Treated 42 Randomised 42 Treated 56 Randomised 55 Treated 77 Randomised 77 Treated 30 (50%) Dev Ab 29 Analysed 28 (67%) Dev Ab 24 Analysed 28 (50%) Dev Ab 26 Analysed 29 (38%) Dev Ab 27 Analysed 8

9 (STARTS-1) Results N=234, 115 performed CPET (106 evaluable) Peak VO 2 marginally improved in sildenafil group compared with placebo (p=.056) Mean PA pressure decreased by 7mmHg compared with placebo WHO functional class improved Safety, tolerability, PK established for short term Barst RJ, Ivy DD, Gaitan G, Szatmari A, Rudzinski A, Garcia A, Sastry BKS, Pulido T, Layton GR, Serdarevic- Pehar M, Wessel DL. A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial Hypertension. Circulation Jan 17;125(2): Evidence that Sildenafil Treatment is Associated with Improvement in Exercise Capacity (Primary Analysis, ITT Population) Low (n=24) Medium (n=26) High (n=27) Combined (n=77) p = Comparison to Placebo (n=29) with 95% CIs ANCOVA model allowed for variation due to baseline Peak VO 2, etiology, weight group, and treatment Evidence that Sildenafil Treatment is Associated with Improvement in Exercise Capacity % Change in Peak VO Low Dose Medium Dose High Dose Combined Doses Treatment Group Placebo Mean % Change in Peak VO2 from Baseline to Week 16 with 95% Confidence Intervals 9

10 Changes in Pulmonary Hemodynamics: Dose Response Observed* PVRI (Wood m 2 ) Low (n=36) Medium (n=49) High (n=67) mpap (mmhg) Low (n=39) Medium (n=55) High (n=71) Comparison to Placebo with 95% CIs *From Baseline to Week 16 Changes in Pulmonary Hemodynamics: Dose Response Observed* PVRI (Wood m 2 ) Low (n=36) Medium (n=49) High (n=67) mpap (mmhg) Low (n=39) Medium (n=55) High (n=71) Comparison to Placebo with 95% CIs *From Baseline to Week 16 (STARTS-1) Summary In a double blind, placebo controlled dose ranging study in children with PAH, sildenafil marginally improved exercise capacity and hemodynamics in a dose dependent manner The effect was amplified in the medium and high dose groups Improvements in exercise capacity and hemodynamics were similar to those seen in the adult population Functional class improved in patients treated with sildenafil 10

11 Long Term Extension Trial STARTS-2 After 16 weeks, 228 completed STARTS entered STARTS-2 Placebo treated patients were randomized to low, medium or high dose sildenafil No placebo group Unblinded after STARTS-1 closed Up-titration permitted Long Term Extension Trial STARTS-2 Median treatment exposure was 3.8 years 35 patients died (June, 2011). All deaths were attributable to progression of disease. Survival rates for all groups were better than historical controls and as good or better than current era survival reports The percentage of deaths was higher in the high dose group vs medium or low dose groups. The hazard ratio for high dose compared to low dose was 3.5, p=0.015 Mortality for PAH Patients on Sildenafil 11

12 Recommendations from FDA Use of Revatio, particularly chronic use, is not recommended in children. Patients should not discontinue sildenafil before talking to their medical provider Warning! (FDA web page) Revatio (sildenafil): Drug Safety Communication - Recommendation Against Use in Children [Posted 08/30/2012] AUDIENCE: Pediatrics, Cardiology, Pulmonology ISSUE: FDA notified healthcare professionals and their medical care organizations that Revatio (sildenafil) should not be prescribed to children (ages 1 through 17) for pulmonary arterial hypertension (PAH). Revatio shown to be fatal in kids 12

13 from John Berger: We need to talk. A mother called me today to say that she was unable to refill her sildenafil prescription because her insurance company would no longer pay for it. Criticisms of the study: Numbers for primary endpoint are small The outcome measure was not previously validated for adult with PH The overall effect was not statistically significant The long term outcome is worse for higher doses of this drug and.. The lower dose in the short term trial was ineffective. So why give a drug to a kid where the low dose doesn t work and the high dose kills? 13

14 Mortality for PAH Patients on Sildenafil Knowns, unknowns and inconsistencies in the long term data: The adverse effect of high dose not observed for three years High dose sildenafil did not correlate with high blood levels of sildenafil Long term analysis did not account for low dose patients who were up-titrated to higher doses The hazard ratio for mortality in high dose patients was diminished after adjusting for risk factors (RAp and PVRI) at baseline Knowns, unknowns and inconsistencies in the long term data (continued): Increased mortality at high dose was NOT observed for patients <20 kg. Increased mortality at high dose was NOT observed for patients with APAH-CHD (2/3rds of patients) Sildenafil was not studied in newborns or infants or children with chronic lung disease 14

15 Knowns, unknowns and inconsistencies in the long term data (continued): The European regulatory agency (EMA) reviewed the same data and reached the following conclusion and recommendations: The labeling includes a new indication in paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Recommended dose for patients<20 kg is 10 mg TID and for patients >20 kg is 20 mg TID 15

16 The European regulatory agency (EMA) reviewed the same data and reached the following conclusion and recommendations: the overall efficacy data generated from studies show that administration of sildenafil is associated with improvements in clinical endpoints that are relevant to the treatment of PAH, including exercise capacity, pulmonary hemodynamics and WHO functional class. After careful clinical review of the disease courses and causes for death, no biologically plausible explanation for the observed imbalance of deaths related to sildenafil dose has been found. As a precautionary measure, the higher sildenafil doses are not recommended in paediatrics with PAH. Recommendations from Pediatric Pulmonary Hypertension Network (PPHNet): Families should be notified if children are on sildenafil Patients should not discontinue sildenafil before talking to their medical provider Strongly recommend avoiding high dose (>1 mg/kg/dose) sildenafil chronic administration Continue sildenafil cautiously at lower doses among broad categories of patients after discussion with family Consider additional therapies for those on sildenafil treatment only Pulmonary Hypertension Keys to future progress Early intervention in CHD Biologic discovery and new drug development Better, cheaper, easier drugs, especially for chronic therapy Collaborative research programs in Asia, USA, Europe, SA Biomarkers of disease severity Genetic markers of risk and tailored therapy 16