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Vizza carmine dario gli analoghi della prostaciclina nel trattamento dell’ipertensione polmonare-torino
 

Vizza carmine dario gli analoghi della prostaciclina nel trattamento dell’ipertensione polmonare-torino

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    Vizza carmine dario gli analoghi della prostaciclina nel trattamento dell’ipertensione polmonare-torino Vizza carmine dario gli analoghi della prostaciclina nel trattamento dell’ipertensione polmonare-torino Presentation Transcript

    • Gli analoghi della prostaciclina neltrattamento dell’ipertensionepolmonare Carmine Dario Vizza Centro Ipertensione Polmonare DAI Malattie Cardiovascolari e Respiratorie Universita’ Universita’ di Roma “La Sapienza” Sapienza” Direttore Prof Francesco Fedele dario.vizza@uniroma1.it Pulmonary Hypertension Unit La Sapienza University oi Rome
    • Rationale of specific PAH treatments PDE5-I Prostanoids ET-1 Antagonists Decreased production Increased production NO,PGI2 ET1 ⇓ Vasodilators anti-proliferative factors ⇑ Vasoconstrictor proliferative factors Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Meccanismo di Azione dei Prostanoidi Muscolo liscio Pulmonary Hypertension Unit La Sapienza University oi Rome
    • Epoprostenolo 1982: effetti emodinamici acuti (Rubin, Circulation) 1984: primo studio a lungo termine in PPH come ponte al tx polmonare (Higenbottam, Lancet) 1990: primo studio randomizzato (Rubin Ann Int Med) 1996: miglioramento della sopravvivenza in trial multicentrico (Barst NEJM) Pulmonary Hypertension UnitLa Sapienza University oi Rome Approvazione FDA 1996
    • Prospective, randomized, multicentric study Epoprostenol vs conventional therapy 81 PPH (NYHA III-IV) followed 12 weeks III- Improvement of all outcome variables Exercise tolerance Symptoms NYHA class Quality of life Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Epoprostenolo e sopravvivenza 100 80 Sopravvivenza (%) 60 Epoprostenolo migliora la sopravvivenza nei 40 pazienti con IP severa Prostaciclina (n=41) 20 Trattamento convenzionale (n=40) 0 0 2 4 6 8 10 12 Settimane Pulmonary Hypertension Unit Barst et al NEJM 1996La Sapienza University oi Rome
    • Epoprostenolo Risultati a lungo termineIpertensione Polmonare Primitiva 27 pazienti trattati con Epoprostenolo per un periodo >1 anno (12-36 mesi), III-IV classe NYHA Base Follow-up p< Pad, mmHg 15±6 9±7 0.001 Pap, mmHg 67±10 52±12 0,001 Pas, mmHg 102±18 87±10 0.001 PC, L/min 3.8±1.2 6.3±2 0.001 RVP, WU 16.7±5.4 12.1±4.5 0.001 RVS, WU 25.1±8.9 17.7±4.9 0.001 SvO2,% 53±8 64±10 0.001 Treadmill Tempo Exer 261±175 631±283 0.001 Pulmonary Hypertension UnitLa Sapienza University oi Rome McLaughlin, N Engl J Med 1998
    • PAH specific Drugs Half-life Route Dosage ProstanoidsEpopoprostenol 2-4 min i.v. max toleratedIloprost 20-40 min i.v./inhal 2.5-5 mcg x 6-9Treprostinil 4-6 ore s.c. max toleratedBeraprost 40-120 min os 480 mcg ET-1 AntagonistsBosentan 360-480 min os 125 mg bidSitaxentan 10 ore os 100 mgAmbrisentan 9-15 ore os 5-10 mg PDE-5 InhibitorsSildenafil 180-240 min os 20–80 mg tidTadalafil Pulmonary Hypertension Unit 36-40 ore os 10-40 mg tid La Sapienza University oi Rome
    • ProstanoidiEpoprostenolo Treprostinil IloprostEffetti sistemici Infezioni Frequenti- Dolori muscolari Inalazioni- Diarrea Broncospasmo- Flush cutaneo Pulmonary Hypertension Unit La Sapienza University oi Rome
    • Short-term Efficacy on 6-min walk distance Epoprostenol PPH SSc 81 pts 111 pts 80 Mean change in the 6 ’WD (m) 60 Active Tx 40 20 0 -20 Control -40 Tx effect + 47 m + 108 m + 18 m + 36 m P value < 0.003 < 0.001 0.005 0.004 Pulmonary Hypertension Unit Open trials Double-blind trials La Sapienza University oi Rome
    • Short-term Efficacy on Pulmonary Vascular Resistance Epoprostenol 8 Mean change in PVR (mmHg/L) 6 Control 4 2 0 -2 Active Tx -4 Tx effect - 4.9 - 5.5 -4.7 -4/-1.1 P value <0.001 < 0.001 0.001 0.01 / ns Pulmonary Hypertension Unit Open trials Double-blind trials La Sapienza University oi Rome
    • Short-term Efficacy on Cardiac Index Mean change in Cardiac Index (L/min/m2) Epoprostenol (PPH) (Scl) 0,8 0,6 Control (CO) 0,4 0,2 0 -0,2 Active Tx -0,4 Tx effect +0.5 + 0.6 +0.18 +0.75/0.25 P value 0.01 0.01 0.003 0.001 Pulmonary Hypertension Unit Open trials Double-blind trials La Sapienza University oi Rome
    • Quale impatto sulla sopravvivenza ? Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Epoprostenolo epoprostenol 67% 62% epoprostenol 36% 38% Pulmonary Hypertension UnitSitbon O. et al. JACC 2002;40:780-788 Mc Laughlin VV. et al. Circulation 2002;106:1477-82 La Sapienza University oi Rome
    • Long-term Epoprostenol&Treprostinil (iPAH) Treprostinil Epoprostenol NIH formula Pulmonary Hypertension Unit Lang I. Chest 2006;129:1636-1643 La Sapienza University oi Rome
    • Long-Long-Term Outcome in IPAH With Treprostinil 100 91% 90 82% 76% 80 72% 69% 70 56% % Survival 60 50 46% 38% 40 30 20 10 0 0 1 year 2 years 3 years 4 years n at risk 332 231 149 82 10 Pulmonary Hypertension Unit La Sapienza University oi Rome Barst et al. Eur Respir J. 2006;28:1195-1203.
    • Long-term IloprostOpitz C. Eur Heart J 2005; 26: 1895–1902 Pulmonary Hypertension Unit La Sapienza University oi Rome
    • Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Quando utilizzare i Prostanoidi ? Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Prostanoidi come prima linea• Pazienti con rapida progressione in NYHA III & emodinamica compromessa (PAD > 15 mmHg; IC < 2.0 L/min/m2):• IV classe funzionale (solo EPO) Prostanoidi come 2/3°linea• Pazienti in NYHA III in terapia di combinazione & emodinamica compromessa (PAD > 10 mmHg; IC < 2.2 L/min/m2):• IV classe funzionale (solo EPO) Pulmonary Hypertension Unit La Sapienza University oi Rome
    • Quale Prostanoide ?a) Se il paziente è in NYHA IV Epoprostenolob) In NYHA III considerare la situazione del singolo soggetto: - Rapidità di risposta terapeutica - Capacità del paziente di adattarsi alla terapia cronica - Capacità della famiglia di supportare il malato - Esperienza personale - Costi Pulmonary Hypertension Unit La Sapienza University oi Rome
    • L’esperienza di un Centro di Riferimento Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Methods• 57 patients (5M/10F, 49±11) with severe precapillary PH, treated with parenteral prostanoids, have been followed for a mean of 1084 ±1114 days.• Data collected at baseline and during follow-up: – Medical history – NYHA functional class – 6 MWT – Ecocardiography – Right heart catheterization• Parenteral prostanoids: – Epoprostenol (Flolan) – Treprostinil (Remodulin) Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Results # p<0,05 Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Results # p<0,05 Clinical, echocardiographic and hemodynamic data are considered before prostanoid initiation. Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Results Survival in 57 patients with pulmonary hypertension from first evaluation at our center. 85% 67% 51% 43% Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Results Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Results Univariate analysis of clinical, echocardiographic and hemodynamic variables associated with mortality Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Results Multivariate analysis of clinical, echocardiographic and hemodynamic variables associated with mortality (χ2 = 24; df = 3; p = 0,00002) Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Conclusioni I • Quando si inizia a trattare un paziente con terapia orale si deve programmare un attento follow-up per decidere quando iniziare terapie più complesse ! • Spesso i pazienti vengono inviati ad un centro che offre la terapia con prostanoidi troppo tardivamente Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • 1,0 Breath-1 NEJM 2002 0,9 0,8 Mc Laughlin ERJ 2005 0,7 0,6 0,5 no CW 0,4 0,3 Provencher Thorax 2005 0,2 0,1 Cumulative Pro 0,0 0 180 360 540 720 900 1080 1260 1440 Time, days Pulmonary Hypertension Unit Vizza CD, Annual Chest meeting 2008La Sapienza University oi Rome
    • Epoprostenolo: sopravvivenza & NYHA 1 0.8 Cumulative survival NYHA FC III (n = 120) 0.6 0.4 p < 0.001 0.2 NYHA FC IV (n = 58) 0 0 12 24 36 48 60 72 84 96 108 Time (months) Pulmonary Hypertension Unit Sitbon O, et al. J Am Coll Cardiol 2002; 40:780-8.La Sapienza University oi Rome
    • Conclusioni II• L’efficacia terapeutica dei prostanoidi parenterali (EPO- TREP) è strettamente dipendente dal dosaggio che è possibile raggiungere con farmaco (effetti collaterali)• La dose di TREP non è equipollente a quella dell’EPO (è necessario arrivare a dosi 1.3-1.5 volte di TREP per lo stesso effetto clinico ed emodinamico)• L’EPOPROSTENOLO è l’unico farmaco che ha l’indicazione per la classe NYHA IV• L’ILOPROST inalatorio non sembra essere un farmaco ottimale per la monoterapia Pulmonary Hypertension Unit La Sapienza University oi Rome
    • Centro Ipertensione Polmonare Primitiva e Forme Associate Responsabile: Carmine Dario VizzaUn. La Sapienza Az. Policlinico Roma Umberto I PH clinicians (Cardiology ward, CCU, consultation & outpatients management): Senior Cardiologists Dr. Vizza, Dr Badagliacca, Dr Poscia Fellows: Dr. Nona, Dr. Gambardella In Training: Dr. Pezzuto, Dr Papa, Dr Scarton Echo Lab Right Cath Lab Dr. Sciomer PFTs-CPX Lab CT & RNM Lab Dott. Mancone Dr. Badagliacca Prof. Palange Dott. Carbone Dott. Colantoni Dott.Valli Dott. Francone Reumathologists Liver Transplant Unit HIV outpatients clinic Pulmonary Ward Lung Transplant Program Prof. Parola http://w3.uniroma1.it/cardiore/iperpolm/iperpolm.htm http://www.ipertensionepolmonare.it Pulmonary Hypertension Unit La Sapienza University oi Rome
    • Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Switching prostanoids• One from epoprostenol to IV iloprost – Higenbottam et al HEART (1998)• Four from epoprostenol to treprostinil – Vachiéry et al CHEST (2002) IV EPO to SC TRE – Gomberg-Maitland et al Am J Crit Care Med (2005) IV EPO to IV TRE – Sitbon et al J Cardiovasc Pharmacol (2007) IV EPO to IV TRE – Rubenfire et al CHEST (2007) IV EPO to SC TRE (RCT)All transitions were successfulDose to maintain equal efficacy ranges from 1:1 to 1:3Two studies on bio-equivalence between SC & IV TRE bio- Laliberte et al J Cardiovasc Pharmacol 2004 (10ng/kg/min in healthy volunteers) McSwain et al J Cardiovasc Pharmacol 2008 (up to 125ng/kg in PAH courtesy JL Vachiery Pulmonary Hypertension Unit La Sapienza University oi Rome
    • Sc Treprostinil Dose in De NovoPatients Treprostinil dose, ng/kg/min Study Year Discharge Week 12 1 year Simonneau1 2002 NA 9 NA Barst2 2006 NA NA 26 Lang3 2006 NA ≥20 26 Soto4-6 2006/7 14 ≥40 44 Dose range: 5-14 9-40 26-441. Simonneau et al. Am J Respir Crit Care Med. 2002;165(6):800-804. 2. Barst et al. Eur Respir J.2006;28(6):1195-1203. 3.. Lang et al. Chest. 2006;129(6):1636-1643. 4. Soto et al. Chest. 2006;120S. 5. Soto et Pulmonary Hypertension Unital. PosterSapienza University oi Rome18-23, 2007; San Francisco, CA. 6. Soto. Chest. 2007;132(suppl):634S. La presented at: ATS; May 37
    • Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Overview of clinical trials – Issues to considerNo RCT provides blinded head-to-head comparison head-to-between different drugs, excepted for a small study*Consistent study design, although differences in Population (etiology, NYHA class) Secondary EP (HD, time to worsening, QOL) Duration (12-18 weeks, up to 12 months) (12-The most common primary EP was exercise capacityby the 6-minute walking distance (6MWD) 6-Survival has been assessed in 2 RCTs as primary EPbut events were reported in all trials and assessedin long term observations Pulmonary Hypertension UnitLa Sapienza University oi Rome * (SERAPH) Wilkins et al Am J Respir Crit Care Med 2005
    • Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • RCT’ RCT’s with prostanoids in PAH (1) EPOPROSTENOL Rubin Ann Intern Med 1990;112:485 Barst NEJM 1996;334:296 Badesch Ann Intern Med 2000;132:425 TREPROSTINIL Simonneau AJRCCM 2002;165:800 ILOPROST Olschewski N Engl J Med 2002;347:322 BERAPROST Galié et al J Am Coll Cardiol 2002;39:1496 Barst J Am Coll Cardiol 2003;41:2119 courtesy JL Vachiery Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • RCT’ RCT’s with prostanoids in PAH (2) Epoprostenol Treprostinil Beraprost Iloprost (3) (1) (2) (1)n included 215 469 246 203WHO class (%) II 4 11 61 0 III 73 82 49 59 IV 23 7 0 41Etiology (%) iPAH 48,4 58,1 60,5 50,2 CTD 51,6 18,7 10,2 17,2 CHD 0 23,2 29,3 0 Other 0 0 0 28 courtesy JL Vachiery Pulmonary Hypertension Unit (CTEPH) La Sapienza University oi Rome
    • RCT’ RCT’s with prostanoids in PAH (3) Epoprostenol Treprostinil Beraprost Iloprost (3) (1) (2) (1)n included 215 469 246 203SMWT ↑ ↑ ↑ ↑HDynamics ↓ ↓ No change ↓Clin events ↓ (iPAH) ↓ ↓ ↓ ↑ (iPAH) NA NA NASurvival ↑ ↑ No change ↑QOL NA NA No change NAPeak VO2 (US study) Drawback Central cath JLPain GI disorder Dosing courtesy Vachiery Pulmonary Hypertension Unit La Sapienza University oi Rome
    • Centro Ipertensione Polmonare Primitiva e Forme Associate Responsabile: Carmine Dario VizzaUn. La Sapienza Az. Policlinico Roma Umberto I PH clinicians (Cardiology ward, CCU, consultation & outpatients management): Senior Cardiologists Dr. Vizza, Dr Badagliacca Fellows: Dr. Poscia In Training: Dr. Nona, Dr. Crescenzi Echo Lab Right Cath Lab Dr. Sciomer PFTs-CPX Lab CT & RNM Lab Dott. Mancone Dr. Badagliacca Prof. Palange Dott. Carbone Dott. Colantoni Dott.Valli Dott. Francone Reumathologists Liver Transplant Unit HIV outpatients clinic Pulmonary Ward Lung Transplant Program Prof. Parola http://w3.uniroma1.it/cardiore/iperpolm/iperpolm.htm Pulmonary Hypertension Unit La Sapienza University oi http://www.ipertensionepolmonare.it Rome
    • Terapie di associazione Pulmonary Hypertension UnitLa Sapienza University oi Rome
    • Patient disposition Substitution rules for missing values Patients randomized (n=33) After epoprostenol IV 2 ng/kg/min during 48 hours Epoprostenol + Epoprostenol +Randomization Bosentan (n=22) Placebo (n=11) Premature 1 abnormal LFT*discontinuation 1 deterioration 1 abnormal LFT* 2 deaths† *Last value carried forward for calculation of hemodynamic variables † “worst”value assigned for analysis of hemodynamic variables, zero attributed to the walk test and Class IV for FC at endpoint Pulmonary Hypertension Unit La Sapienza University oi Rome Humbert et al. Eur Respir J 2004;24:353
    • Patient demographics Placebo + Bosentan + Epoprostenol (n=11) Epoprostenol (n=22) Gender M:F 45%:55% 23%:77% Mean age (years) 47 45 Etiology of PAH: Idiopathic 10 (91%) 17 (77%) Systemic sclerosis 1 (9%) 4 (18%) Other * 0 1 (5%) * Other: Lupus Pulmonary Hypertension UnitLa Sapienza University oi Rome Humbert et al. Eur Respir J 2004;24:353
    • Baseline characteristics Placebo + Bosentan + Epoprostenol (n=11) Epoprostenol (n=22) TPR (dyn.sec.cm-5) 1628 ± 154 1697 ± 142 CI (L/min/m2) 1.7 ± 0.2 1.7 ± 0.1 mPAP (mm Hg) 60.9 ± 2.9 59.2 ± 4.0 mRAP (mm Hg) 11.9 ± 2.2 11.9 ± 1.1 6 MW test (meters) 305 ± 31 286 ± 24 NYHA Class III:IV 8:3 (73%:27%) 17:5 (77%:23%)Mean ± SEM Pulmonary Hypertension Unit La Sapienza University oi Rome Humbert et al. Eur Respir J 2004;24:353
    • Mean change in hemodynamics from baseline to week 16 Placebo + Epoprostenol Bosentan + Epoprostenol p-value Baseline Week 16 Change Baseline Week 16 ChangeTPR dyn*sec/cm5 1628 1242 -22.6%* 1697 1016 -36.3 %* NS†CI L/ mn/m2 1.7 2.3 37.9 %* 1.7 2.5 48.7 %* NSmPAP mmHg 60.9 59.2 -2.2 % 59.2 52.5 -9.0 %* NSmRAP mmHg 11.9 12.2 0.3 mmHg 11.9 10.0 -1.9 mmHg NS(absolute change) * p < 0.05 compared to baseline † p=0.08 for the difference in the % change Pulmonary Hypertension Unit La Sapienza University oi Rome Humbert et al. Eur Respir J 2004;24:353
    • TPR % change from baseline in completers Placebo + Bosentan + epoprostenol (n=10) epoprostenol (n=19) 0 0 -20 -20% change -40 -40 -60 -60 -80 -80 Baseline Week 16 Baseline Week 1629 of 32 patients completed Pulmonary Hypertension Unit Humbert et al. Eur Respir J 2004;24:353 La Sapienza University oi Rome
    • Change in walk distance from baseline to week 16 Meters -60 -40 -20 0 20 40 60 80 100 120 140 Mean and 95% CI Placebo + epoprostenol Bosentan + epoprostenol Median and 95% CI Placebo + epoprostenol Bosentan + epoprostenol -60 -40 -20 0 20 40 60 80 100 120 140 Pulmonary Hypertension UnitLa Sapienza University oi Rome Humbert et al. Eur Respir J 2004;24:353
    • Combination Therapy for PAH• Three separate therapeutic pathways available Potential to increase efficacy by combining agents targeting different pathways• Potential to reduce need for invasive therapyControversies/precautions• Virtually all data are from uncontrolled trials with small numbers of patients• Combination therapy most often studied as add-on treatment to existing monotherapy• No prospective clinical trial data available on use of triple-class combination therapy Pulmonary Hypertension Unit La Sapienza University oi Rome
    • STEP: Inhaled Iloprost added to bosentan Post-inhalation change in 6-MWD (Week 12) Iloprost Placebo ________________________ ______________________ Meters Change Meters Change Walked from Baseline Walked from Baseline___________________________________________________________________________•Baseline (m) Mean 336 + 61 340 + 73•Week 12 (m) Mean 367 + 84 30 m 343 + 99 4m p-value 0.001 0.69(vs. baseline)Placebo-adjusted Difference: Pulmonary Hypertension Unit +26 m p = 0.051 La Sapienza University oi Rome
    • Sildenafil Add-On to Stable Epoprostenol Therapy Clinical Worsening Event at 16 Weeks• 16-week study (n=267) Patients on stable epoprostenol for >3 months Patients (%) 80% of patients provided with sildenafil 80 mg tid• Deaths at 16 weeks Placebo (n=7) Sildenafil (n=0) Placebo Sildenafil Simonneau G, Rubin L, Gaile N, et al. Ann Intern Med. 2008 Pulmonary Hypertension Unit . La Sapienza University oi Rome
    • Sildenafil Added to Epoprostenol: Change from Baseline in 6-Minute Walk Distance 50 From Baseline (m) Sildenafil * 40 Mean Change 30 20 10 Placebo 0 -10 0 4 8 12 16 WeeksSimonneau G, Rubin L, Gaile N, et al.Ann Intern Med. 2008 Oct 21;149(8):521-30 Pulmonary Hypertension Unit . La Sapienza University oi Rome
    • Inhaled Treprostinil•Battery operated(rechargeable)•Single breath technology•Each treatment completedin less than one minute Pulmonary Hypertension Unit La Sapienza University oi Rome
    • Inhaled Treprostinil Hemodynamics at Week 12 (post-inhalation) (n = 11) PercentMean ± SD Baseline 12 weeks change p-value______________________________________________________________PAPm 49 ± 10 44 ± 12 - 10% 0.041mmHgPVR 9.3 ± 4.9 6.9 ± 3.5 - 26% 0.052Wood unitsCI 2.6 ± 1 3.0 ± 0.9 + 15% 0.058Liters/min/m2SAPm 85 ± 15 86 ± 14 + 1% 0.83mmHgChannickHypertensionJACC 2006 Pulmonary et al, Unit La Sapienza University oi Rome
    • TRIUMPH – 6MWD Median Change Peak = between 10 and 60 minutes after dose Trough = 4 hours or greater after dose P < 0.0006 P < 0.00026MWD Median Change from Baseline (m) P < 0.007 P = NS Hodges- Hodges-Lehmann Estimate of median change from baselineMcLaughlin V, HypertensionRespir Crit Care Med. 2008;177:A965. Pulmonary et al. Am J Unit La Sapienza University oi Rome
    • 6 MWD as an Endpoint: Diminishing ReturnsChange from Baseline (m)6MWD Placebo Corrected Treprostinil – median; Others - Mean Week Pulmonary Hypertension Unit La Sapienza University oi Rome