Intravenous Therapies for Pulmonary Hypertensive Vascular Disease. Intravenous Treatment for PAH: Past, Present and Future 3/10/2012

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1 Intravenous Therapies for Pulmonary Hypertensive Vascular Disease Robyn J Barst MD Professor Emeritus Columbia University New York, NY March 1 th 212 Presented By: Erika Berman Rosenzweig, MD Dr. Robyn J Barst Disclosures: Consultant: Actelion, Eli Lilly, Gilead, Ikaria, Novartis, Pfizer, VentriPoint Stock Options: VentriPoint Dr. Erika Berman Rosenzweig Disclosures Has received grant/research support from Actelion, Bayer AG, Eli Lily, Gilead Sciences, GSK, Novartis AG, Pfizer, and United Therapeutics Corporation Has served as a consultant for Actelion, GIlead and United Therapeutics. Intravenous Treatment for PAH: Past, Present and Future Why Treat Pulmonary Arterial Hypertension? Percentage Surviving Idiopathic PAH: PPH NIH Registry Data ( ) Median survival 2.8 years NIH = National Institutes of Health Years of Follow-up Median survival 1 months in children D Alonzo, Barst et al. Ann Int Med 1991 D4_SHOW_FILE_PM_V1.ppt 1

2 Treatment Algorithm in 199 Why Diagnose Pulmonary Arterial Hypertension? No Treatment. Sir John R. Vane: 1976 Discovery of Prostacyclin (Nobel Prize) Sir John R. Vane ( ), Nobel Prize 1982: discovery prostacyclin (PGI 2 ) 1976 Prostacyclin: Mechanisms of Action Vasodilation Prevents and reverses platelet aggregation Antiproliferative Inhibits vascular cell migration Improves endothelial dysfunction Improves ET-1 clearance Cardiac inotrope PAH: Prostacyclin Synthase Expression is Decreased in the Lung Tuder et al. Am J Respir Crit Care Med 1999 D4_SHOW_FILE_PM_V1.ppt 2

3 Vasoactive Mediators: Imbalance in PAH Effects of IV Prostacyclin Infusion Vasoconstriction Thrombosis Inflammation Proliferation Prostacyclin and NO Reduced Activity Acute vasodilator testing with iv prostacyclin (epoprostenol sodium) in PAH (n=7): Increase cardiac output Decrease pulmonary resistance Increased Activity Endothelin-1 and Thromboxane A 2 Vasodilation Anti-thrombosis Anti-inflammation Anti-proliferation Rubin et al. Circ 1982 Continuous IV Prostacylin Produces Sustained Decrease In Pulmonary Resistance (n=3; hr Infusion) Long-Term Treatment of PAH with Continuous IV Epoprostenol: Maintenance Effect? Palliative Bridge to Transplantation infusion infusion stopped Rubin et al. Circ 1982 Lancet D4_SHOW_FILE_PM_V1.ppt 3

4 Administration of Chronic IV Epoprostenol (Flolan ) Rapidly (t 1 / 2 = 3 min) hydrolyzed in circulation to 6-keto-PGF 1α No oral preparation Must be given via continuous intravenous infusion to achieve sustained pharmacologic effect Flolan (epoprostenol sodium) Therapy for PAH: Clinical Development Program Objectives: To assess the safety and efficacy of iv epoprostenol in PPH Design: 8 week phase III open-label, randomized prospective trial 1 12 week phase III open-label, randomized prospective trial 2 Treatment: Epoprostenol plus Conventional Therapy* compared with Conventional Therapy alone * anticoagulants, diuretics and oxygen 1 Rubin et al. Ann Int Med 199; 2 Barst et al. NEJM 1996 IV Epoprostenol in IPAH: Change in 6MWD at 8 and 12 Weeks IV Epoprostenol: Effect on Survival in IPAH 8 1 Change in 6MW distance (m) Week 4 Weeks 8 and 12 (Mean) Epoprostenol (11; 41) Conventional Therapy (14; 4) Survival (%) p= Weeks Epoprostenol (n=41) Conventional Therapy (n=4) Rubin et al. Ann Intern Med 199; Barst et al. NEJM 1996 Barst et al. NEJM 1996 D4_SHOW_FILE_PM_V1.ppt 4

5 Survival in IPAH with Long-Term Continuous IV Epoprostenol IV Flolan Approved 1995 Survival at 1, 2 and 3 years: 87%, 72% and 63% vs. historical controls 77%, 52% and 41%, respectively PPH and PAH associated with Scleroderma - NYHA Class III/IV with inadequate response to conventional therapy ph ; increasingly unstable at lower ph Unstable at RT; requires cold packs Rapidly hydrolyzed at neutral ph in blood Half life 3 minutes Continuous IV infusion via CVL and battery-operated pump Reconstituted with Sterile Diluent (Glycine Buffer) for Flolan Barst et al. Annals 1994 IV Epoprostenol: Long-term Outcome in IPAH IV Epoprostenol: Long-term Outcome in IPAH Survival (%) * At 1, 2, 3 years: 88%, 76%, 63% At 1, 2, 3 years: 59%, 46%, 35% *P<.1. 2 n= Median follow-up 31 months Months * Observed Expected (NIH Registry) * Survival % IV epoprostenol Historical control No. at risk IV epo: Months Hist. control: at 1, 2, 3, 5 years: 85%, 7%, 63%, 55% at 1, 2, 3, 5 years: 58%, 43%, 33%, 28% McLaughlin et al. Circulation 22 Sitbon et al. JACC 22 D4_SHOW_FILE_PM_V1.ppt 5

6 IV Epoprostenol: Effect on Survival in Children with IPAH Functional Improvement with Chronic IV Epoprostenol Survival (n=27) (n=8) (n=3) p=.2 (n=14) (n=9) (n=5) (n=7) Years PGI 2 given (n=31) PGI 2 indicated but not given (n=28) Distance (m) n= ± 93 Baseline p< ± 15 Follow-up 11.4 ± 7.1 months Improved 6-MWD Total: 39 children (25 IPAH, 14 APAH) Percentage WHO IV WHO III WHO II WHO I Baseline n=39 <1 year n= yrs n= yrs n=16 Follow-up Improved WHO functional class Barst, et al. Circ 1999 Lammers. Heart 27. Chronic IV Epoprostenol for PAH Associated with Congenital Heart Disease IV Epoprostenol: Tolerability and Safety % Change from baseline 8% 6% 4% 2% % -2% -4% * CI PAPm * PVR RAPm Jaw pain Headache Diarrhea, Nausea Rash Leg and foot pain Impotence Weight loss Infection, Sepsis Thromboemboli events Systemic hypotension Increased ascites Coronary steal Rebound PH (interrupt infusion) Thrombocytopenia N=2-6% *p<.1 vs baseline. N=16 * Rosenzweig EB et al. Circulation. 1999;99: D4_SHOW_FILE_PM_V1.ppt 6

7 IV Epoprostenol as a Bridge to Transplant With the availability of IV epoprostenol.. Patients began to defer transplant Some patients even took themselves off the transplant list WHY? 1993 Cold Packs Mixing Cold Packs D4_SHOW_FILE_PM_V1.ppt 7

8 Goals of PAH Treatment Goals of PAH Treatment Improve Overall Quality of Life Increase Stability epoprostenol stable at room temperature 8 hrs or 24 hrs with ice packs Half-Life epoprostenol 3 minutes Decrease SAEs and AEs delivery system; epoprostenol Improve Survival Epoprostenol (Flolan ) Injection Alternative IV Prostacyclin Analogues IV Treprostinil (Remodulin ) Prostacyclin analog - stable at room temperature; longer half-life IV Epoprostenol (Veletri ) A new formulation of intravenous epoprostenol with improved stability for the treatment of PAH Treprostinil (treprostinil sodium) Injection Prostacyclin analogue Stable at room temperature Half-life: 4.5 hours Cutaneous administration 24/7 subcutaneous or intravenous D4_SHOW_FILE_PM_V1.ppt 8

9 Long-term Treatment with IV Treprostinil Completers n= 11 De novo n=16 AEs n=2 Premature discontinuation n= 5 Deaths n=3 Completed 48 weeks n=34 Patients Enrolled n= 47 Lost to Follow-up n= AEs 7 Transition n=31 Completers n= 23 Premature discontinuation n=13 Deaths 5 AEs n=5 Deaths n=2 Lost to Follow-up 1 Premature discontinuation n=8 Lost to Follow-up n=1 Six Minute Walk Distance (meters) Change in 6MWD from Baseline to Week 48 in the De Novo Patients Baseline (n=14) 4 Wk 12 (n=14) 332 Baseline (n=11) 457 Wk 48 (n=11) Mean Change +81m +125m Week 12 Week 48 (n=14) (n=11) Change in 6MWD from Baseline to Week 48 for the Transition Patients Hemodynamic Parameters: Baseline and One Year Six Minute Walk Distance (meters) Baseline Wk 12 (n=27) (n=27) Baseline Wk 48 (n=23) (n=23) Mean Change +1m -1m Week 12 Week 48 (n=27) (n=23) Hemodynamic Parameter De Novo N=11 Transition N=22* Baseline One Year Baseline One Year RAPm (mmhg) 12 ± 1 8 ± 1 5 ± 1 6 ± 1 PAPm (mmhg) 58 ± 5 48 ± 4 45 ± 3 48 ± 3 CI (L/min/m 2 ) 1.6 ± ± ± ±.2 PVRI (mmhg/l/min/m 2 ) 32 ± 3 16 ± 2 13 ± 1 13 ± 1 Mean ± SE De Novo Changes P<.5 *Catheterization was not performed on one patient due to patient refusal Transition changes NS D4_SHOW_FILE_PM_V1.ppt 9

10 K-M Estimates of Treatment Success for the De Novo and Transition Patients K-M Estimates of Survival for the De Novo and Transition Patients IV Treprostinil Administration Requires higher dose (~ 2-3 times) compared with Flolan Half life: 3-4 hours Stable at room temp for 48 hrs for IV No Ice Packs Every other day mixing Drug stability and half-life allow for slow infusions with smaller pumps (3ml/24 hrs) Slide courtesy of DD Ivy Transition IV Epoprostenol to IV Treprostinil 13 pediatric PAH - IV epo to IV treprostinil 2 deaths, 2 transitions to other therapies Transitioned in hospital over 24 hrs (rapid or slow) Patients maintained exercise capacity Higher dose yet fewer side effects Several blood stream infections - however, reported before current recommendations for treprostinil line care were implemented Ivy, et al. Am J Cardiol. 27:99(5): D4_SHOW_FILE_PM_V1.ppt 1

11 Fewer Side Effects Following Transition from IV Epoprostenol to IV Treprostinil Miniaturization with Treprostinil Mean severity score BL 6 mo 12 mo Headache Rash Diarrhea Jaw Pain Leg Pain GI CADD MS-3 CRONO Five Ivy, et al. Am J Cardiol. 27:99(5): Higher Incidence of Gram Negative BSIs with IV Treprostinil vs IV Epoprostenol Remodulin Flolan Remodulin Overall BSI Range (per 1 medicine days) Overall gram negative BSI Range (per 1 medicine days) Flolan IV Prostanoids: Minimizing Risk for Catheter Related- Blood Stream Infections (CR-BSI) Single center - closed-hub system and waterproofing precautions during showering with IV prostanoids in children to minimize CR- BSI 5 patients receiving prostanoids Closed-hub system and maintenance of dry catheter hub connections significantly reduced the incidence of CR-BSI (particularly infections caused by gram-negative pathogens) in patients receiving IV treprostinil *Morbidity and Mortality Weekly Report, March 2, 27, Volume 56, No 8, pp Ivy, et al, Infect Control Hosp Epidemiol 29; 3: D4_SHOW_FILE_PM_V1.ppt 11

12 The Children s Hospital, Denver BSI Incidence Pre and Post Hub Protection Treprostinil Epoprostenol Closed-Hub System for Reducing Risk of BSI 1,2 Split-septum cap CVC line Decreased exposure of CVC hub; changed weekly Split-septum devices: Q- Syte TM, Interlink.22-micron filter Direct connect BSI rates per 1 catheter days Ivy, et al, Infect Control Hosp Epidemiol 29; 3: Akagi et al. Circ J. 27;71: Do et al. J Infect Dis. 1999;179: Effect of Increasing Diluent ph on BSI rate with IV Treprostinil Improve Risk-Benefit Profile Parenteral IV Treprostinil Therapy: Implantable Pump System Patient QoL Issues Treatment-related symptoms Compromised personal freedom Interactions with treatment and healthcare system; disease always on mind Clinical Issues Catheter-related infections Catheter-related complications Patients discontinuing SC therapy Rich et al. Poster presented at: ERS Sept 21; Barcelona, Spain. D4_SHOW_FILE_PM_V1.ppt 12

13 Implantable Pump System - Delivery of IV Treprostinil SynchroMed III Pump Programmable rate pump Two sizes available 4 ml reservoir 2 ml reservoir Size 2 ml 4 ml Pump Thickness (including septum) 19.5 mm 26. mm Weight (empty/full) 165/ 185 g 175/ 215 g Displacement volume 91 ml 121 ml Diameter (including CAP) 87.5 mm 87.5 mm Pump reservoir Volume 2. ml 4. ml SynchroMed III Implantable Drug Infusion Pump 888 Clinician Programmer Implantable Intravascular 821 Catheter Treprostinil Residual volume 1.4 ml 1.4 ml Fill volume at shipping 17.5 ml 37.5 ml Flow Rate Maximum programmable 24 ml/ day 24 ml/ day Minimum programmable.48 ml/ day.48 ml/ day Implantable Intravascular Catheter Silicone catheter Coil Reinforced Catheter Body Sleeve Valve Flow out when: PSVC PCatheter - Pcatheter > PSVC P, pressure; SVC, superior vena cava. Implant: Procedure Overview Obtain venous access Flush, implant, and anchor catheter Make pump incision and create pocket Tunnel subcutaneously Connect pump and catheter Place pump in pocket, anchor, close incisions Program pump Transition off temporary line once priming bolus is complete D4_SHOW_FILE_PM_V1.ppt 13

14 Pump Refill Refill Frequency: approximately every 4 12 weeks Refill kit is used to access the reservoir fill port of the pump Remaining drug is aspirated Pump is filled with treprostinil Pump is programmed Potential Benefits for Patients Eliminate external drug pump, catheter care, drug mixing (IV only) Reduce interference with daily activities; catheter infections and complications due to exposure to external environment Enhance patient convenience and ease of use Create hands-free safe and effective delivery of IV treprostinil therapy Combination Therapy? Improve Efficacy over Monotherapy? Sildenafil as add-on to Background IV Epoprostenol Addition of Sildenafil to IV Epoprostinil: Change From Baseline to Week 16 in 6MWD (PACES-1) Change in 6MWD from baseline (m) MWD, 6-minute walk distance. -2 Placebo + epoprostenol P<.1 Baseline Week 4 Week 8 Week 12 Week 16 Sildenafil + epoprostenol 3 4 N= m Simonneau et al. Ann Intern Med. 28;149: D4_SHOW_FILE_PM_V1.ppt 14

15 Addition of Sildenafil to IV Epoprostenol: Delayed Clinical Worsening and Decreased Mortality (PACES-1) REVEAL Registry: Treatment of FC IV Patients Enrolled in REVEAL No clinical worsening event (%) Baseline P=.2 Placebo Sildenafil Time from randomization (d) Treatment Persons at risk (censored), n Baseline Day 28 a Day 56 b Day 84 c Day 112 d Epoprostenol + placebo (1) 116 () 111 (2) 7 (36) Epoprostenol + sildenafil () 128 (2) 125 (2) 78 (44) a The number censored between days and 27 b The number censored between days 28 and 55 c The number censored between days 56 and 83 7 deaths, all in the placebo group d The number censored between days 84 and 111 FC, functional class; PAH, pulmonary arterial hypertension. 63% on oral therapy only Simonneau et al. Ann Intern Med. 28;149: Badesch et al. Poster presented at: ATS 28; May 16-21, 28; Toronto, Canada. Time to Initiation of Prostanoid Therapy Mayo Clinic: Versus patients; 77% female; mean age, 54 y; mean disease duration, 1.9 y Prior to 2, up to 5% of patients received prostanoids within the first year of diagnosis, which declined to 25% after 2 Higher FC, mrap, and mpap were associated with initiation of prostanoids Medication use Time to medication (years) Diagnosis year group: Are Parenteral Prostanoids Under-utilized? REVEAL Mortality Data Therapy at Time of Death IV/SC prostanoid therapy 43% 16% 14.1% 15% 12% 11.7% 12.1% 1.3% 8% 4% 8.4% 8.4% 5.9% 4.7% 3.2% 1.1% % 4.9% mpap, mean pulmonary arterial pressure; mrap, mean right atrial pressure. N=793. Deaths in REVEAL registry. Maradit-Kremers, et al. Poster presented at: PHA 28; June 2-22, 28; Houston, TX Farber H, et al. Chest. 211;14:93A D4_SHOW_FILE_PM_V1.ppt 15

16 Abstract Pediatric PAH: Treatment Regimens at the Time of Death 11% Deaths After 211 1% Monotherapy Oral + IV 2 oral 2 oral + IV Why Diagnose Pulmonary Arterial Hypertension? 17% 62% Why Treat Pulmonary Arterial Hypertension? N=24 deaths reported to FDA adverse event reporting system after availability of combination therapy Maxey D, et al. Am J Respir Crit Care Med. 211;183:A5891. D4_SHOW_FILE_PM_V1.ppt 16

17 Transition off IV Epoprostenol To Oral/Inhaled Therapies Age Dx EPO Bosentan Before After Yrs Duration M IPAH F IPAH M IPAH M IPAH F IPAH M IPAH F IPAH F IPAH Transition from IV Epoprostenol to Oral/Inhaled Targeted PAH Therapy in Pediatric IPAH n=13 Baseline Peak EPO Post EPO d/c p value* PAPm (mmhg) PVRi (u*m2) <.24 PVRi/SVRi <.84 C.I. (L/min/m2) <.8 SVO2 (%) <.38 n=14 (13) Ivy D, et al. Am J Cardiol 93: , 24 Melnick, et al. Am J Card 211 Transition from IV Epoprostenol to Oral/Inhaled Targeted PAH Therapy in Pediatric IPAH Transition from IV Epoprostenol to Oral/Inhaled Targeted PAH Therapy in Pediatric IPAH Pts (n) p<.3* I II III IV Transition appears safe with efficacy maintained in select pediatric IPAH patients Whether early initiation of IV epoprostenol improves long-term outcome vs deferral of IV epoprostenol until oral/inh therapy fails remains unclear B/L peak EPO OFF EPO *p value OFF EPO vs. peak EPO n=14 (13) Melnick, et al. Am J Card 211 Melnick, et al. Am J Card 211 D4_SHOW_FILE_PM_V1.ppt 17

18 In Summary, Treatment Goals for the Future.. Further improvement in overall quality of life Maintain or further improvement in outcome McLaughlin et al, JACC 29 Therapeutic Strategies Least invasive to most invasive Need to follow closely for deterioration or inadequate efficacy Most invasive up front therapy Similar paradigm to oncologic therapy (up-front invasive therapy) Possibility of transition off to less invasive therapies Summary: IV Prostanoids for the Treatment of PAH IV epoprostenol still remains the gold standard for the treatment of advanced pediatric PAH Combination therapy (including triple) appears to be efficacious when monotherapy or dual therapy is inadequate Does the delay in using aggressive PAH therapy worsen long term outcome in children? D4_SHOW_FILE_PM_V1.ppt 18