ΠΡΟΣΤΑΝΟΕΙΔΗ: ΕΦΑΡΜΟΓΗ ΚΑΙ ΡΟΛΟΣ ΣΤΗΝ ΠΝΕΥΜΟΝΙΚΗ ΥΠΕΡΤΑΣΗ ΣΗΜΕΡΑ Γεωργία Γ. Πίτσιου, MD, PhD Πνευμονολόγος- Εντατικολόγος Μονάδα Αναπνευστικής Ανεπάρκειας ΑΠΘ

ACCF/AHA 2009 EXPERT CONSENSUS DOCUMENT ON PULMONARY HYPERTENSION JACC April 2009

J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl)

The discovery of prostacyclin (1976) An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation Nature, 1976 A young woman, bedbound with severe PH, responded to intravenous epoprostenol with a fail in pulmonary vascular resistance, improved oxygenation, and a rise in exercise tolerance. For 13 months, continuous infusion of epoprostenol has enabled her to live independently at home Higenbottam et al. Lancet 1984; 1(8385):1046-7

Prostacyclin analogues: Chemical structures and plasma half-lives OH COOH O PGI2 (t½= 2 min)1 COOH OH Iloprost (t½= ~30 min)2 CH3 Beraprost (t½= ~30 min)2 COO* Na+ O CH3 HO OH OH COOH O Treprostinil (t½= ~240 min)3 PGI2, prostacyclin; t1/2, half-life 1. Clapp et al. Am J Respir Cell Mol Biol. 2002;26:194-201; 2. Gomberg-Maitland et al. Eur Respir J. 2008;31:891-901; 3. Remodulin® (treprostinil) US prescribing information; United Therapeutics Corp. January 2010

Importance of prostacyclin in PAH pathophysiology Anti-proliferation Vasodilatation Anti-thrombosis AC, adenylyl cyclase; AMP, adenosine monophosphate; cAMP, cyclic adenosine monophosphate; IP; prostaglandin receptor; P, arachidonic acid; PAH, pulmonary arterial hypertension; PDE, phosphodiesterase; PGH2, prostaglandin H2; PGI2, prostacyclin; PPAR, peroxisome proliferator-activated receptor 1. Humbert et al. N Engl J Med. 2004;351:1425-1436; 2. Ghofrani et al. J Am Coll Cardiol. 2004;43:68S-72S; 3. Mitchell et al. Exp Physiol. 2007;93:141-147

Mubarak KK. Respir Med 2010

Prostacyclin Analogues: Intravenous, Subcutaneous, or Inhaled Epoprostenol (Flolan®) Treprostinil (Remodulin®) Treprostinil (Remodulin®) Iloprost (Ventavis®) Prostacyclin and prostacyclin analogues are available in intravenous (IV), subcutaneous (SC), and inhaled formulations. These drug delivery systems are complex. IV epoprostenol and treprostinil require a chronic indwelling central venous catheter, usually a tunneled catheter exiting the left upper or right upper chest wall. Potential complications: infection (blood stream, tunnel, or exit site infection), thrombosis, accidental removal, device malfunction. SQ trepostinil Treprostinil, a prostacyclin analogue, has a longer half-life (approximately 4.5 hr) than epo (≤6 min), and can be administered SC. Potential complications: 85% of patients reported incidence of infusion pain and/or site reaction (redness and swelling, not dose related), leading to discontinuation in 8%. Significant infection is rare. Iloprost is administered via iNeb device (hand-held portable device). Takes approx 6-10 min to deliver the total dose, depending on the patient’s breathing pattern, plus up to 10 min per session for device cleaning (time reduced recently with new cleaning system) Since the dose frequency is 6-9 times per day (every 2 hours while awake), it can be cumbersome.

Pharmacological effects of prostacyclin Anti-inflammatory Anti-thrombotic Vasodilatation Anti-proliferative Pharmacological effects of prostacyclin O OH HOOC Prostacyclin Gomberg-Maitland et al. Eur Respir J. 2008;31:891-901; Zardi et al. Int Immunopharmacol. 2005;5:437-459; Ghofrani et al. J Am Coll Cardiol. 2004;43:68S-72S; Humbert et al. J Am Coll Cardiol. 2004;43:13S-24S

Haemodynamic effects of systemically applied prostanoids Prostacyclin Pulmonary vasodilatation (weeks) Neurohormonal activation (weeks) Pulmonary vasodilatation (mins) Systemic vasodilatation Positive inotropic effects + PVR  SAP  - - Arterial baroreflex (mins) - Cardiac output  PVR, pulmonary vascular resistance; SAP, systemic arterial pressure as measured with the method of Riva Rocci. +: positive effect; –: negative effect Adapted from Gomberg-Maitland M. Eur Respir J 2008;31:891-901

Instability of epoprostenol 100 Epoprostenol Tyrode’s solution pH 7.7 80 Washed human platelets (2x108 ml-1) Unstable at physiological temperatures and pH2 Light sensitive2 Hydrolysed to 6-oxo-PGF1α2 Elimination half-life of approximately 3 minutes2 60 % Control 40 20 10 20 30 Incubation time (min) Decay of prostacyclin at 37°C in vitro1 Data are mean ±standard error PGF, prostaglandin F 1. Adapted from Whittle BJR; 1983. Actions of prostacyclin and thromboxanes: Products of the arachidonic acid cascade. In: Hormones and cell regulation, Volume 7. Eds Dumont, J.E., Nunez, J., Denton, R.M. Elsevier Biomedical Press; Amsterdam, pp 3-23; 2. Flolan® (epoprostenol sodium) Summary of Product Characteristics, GlaxoSmithKline. March 2006

What are the facts about practicalities of Flolan administration Short half-life (3-5 minutes) Continuous IV infusion - Permanent tunneled subclavian catheter Drug preparation and change-over crucial Mixed with buffer Drug must be stored refrigerated Post change flushing 12hour dosing un-cooled, 24 hour dosing if cooled Continuous infusion Patient education / Specialized nurses Complications Total infections: 0.19 patients/year1 Catheter related sepsis: 0.1-0.4 per patient/year2 1. Sitbon et al 2002 JACC 40:7807-88 2.Hoeper et al, Am J Respir Crit Care Med 165.:209–1216, 2002.

I.V. Εποπροστενόλη

* Conventional treatment consisted of oral anticoagulants, oral vasodilators, diuretic agents, cardiac glycosides, and supplemental oxygen. All patients received anticoagulants except for one in the treatment group

IV epoprostenol long-term observational study: Survival rates Mc Laughlin1 Sitbon2 100 1.0 0.8 IV epoprostenol (n=178) 80 (n=162) 0.6 Survival (%) 60 Cumulative survival 0.4 40 Historical controls** (n=135) 0.2 Predicted survival (NIH)* 20 0.0 6 12 18 24 30 36 12 24 36 48 60 72 84 96 108 120 Time (months) Time (months) 178 129 85 57 36 21 7 3 1 n 135 59 34 20 11 4 2 2 1 * Survival was predicted according to the equation derived from NIH registry 3 ** Historical control: patients were followed up at the centre Similar survival rates (%) 1 year 2 years 3 years 5 years Mc Laughlin 87.3 76.3 62 - Sitbon 70 63 55 1. McLaughlin W et al Circulation 2002; 106: 1477–1482 2. Sitbon O et al J Am Coll Cardiol 2002; 40: 780–799 NIH: National Institutes for Health

IV epoprostenol: NYHA FC is predictive of survival PAH patients in NYHA FC III at baseline have a higher survival rate when treated with IV epoprostenol compared with those in NYHA FC IV at baseline McLaughlin 20021 Sitbon 20022 100 12 36 24 48 60 72 84 96 108 80 40 20 100 80 NYHA FC III NYHA FC III 60 Survival (%) 40 NYHA FC IV p=0.001 20 NYHA FC IV 12 24 36 48 60 72 84 Time on epoprostenol (months) Time on epoprostenol (months) 120 92 65 46 31 17 6 2 1 N n 162 33 95 70 48 30 20 10 58 37 20 11 5 4 1 1 1. McLaughlin W et al Circulation 2002; 106: 1477–1482 2. Sitbon O et al J Am Coll Cardiol 2002; 40: 780–799

Adverse events with IV epoprostenol from SmPC Frequency Sepsis, septicaemia* Very common Headache Facial flushing Nausea, vomiting Jaw pain Decreased platelet count Common Anxiety, nervousness Tachycardia (at doses of 5 ng/kg/min and below) Abdominal colic/abdominal discomfort Dry mouth Uncommon Local infection*, chest pain Rare Reddening/pain at the infusion site*, occlusion of the IV catheter*, pain at infusion site*, lassitude, chest tightness Very rare Pallor From Flolan SPC *Associated with the delivery system for epoprostenol Very common – 10%; common – 1% and <10%; uncommon – 0.1% and <1%; rare – 0.01% and <0.1%; very rare –<0.01% 1. Flolan® Summary of Product Characteristics

Ενημέρωση ασθενή Αναλυτική ενημέρωση για στάδιο της νόσου και εξελικτική πορεία Περιγραφή θεραπείας-Προετοιμασίας (καθετήρας, φορητή αντλία, φάρμακο, παρενέργειες) Απόλυτη συναίνεση, Διάθεση και πιστή τήρηση οδηγιών Ψυχολογική Υποστήριξη

FLOLAN administration FLOLAN : IV infusion 24 hours, daily. A central line & a PUMP (200g) 20

Εκπαίδευση στο χειρισμό του κεντρικού φλεβικού καθετήρα ντρικοί Φλεβικοί καθετήρες

Φορητή αντλία χορήγησης Εκπαίδευση Φορητή αντλία χορήγησης

Initiation and long-term dose adaptation1 of IV Flolan infusion Initiation: Flow rate is adjusted under medical supervision1 Begin treatment at 1 ng/kg/min Increase by increments of 1 ng/kg/min every 12 to 24 hours up to 10 ng/kg Increase by increments of 1 ng/kg/min every 15 days up to 16 ng/kg Dose increase According to PAH symptom exacerbation in trials, mean monthly increase is 1 ng/kg/min However, increase must be tailored to each individual Dose reduction Reduce when clinical signs of overdose or excessive elevation of cardiac output are evident Decrease gradually in stages of 2 ng/kg/min Patient follow up should be assessed early, within 3 months of therapy initiation,8 regularly and systematically 1. Flolan SpC. 8. Sitbon et al. J American Coll Cardiol 2002. 23

Prostacyclin analogues: Chemical structures and plasma half-lives OH COOH O PGI2 (t½= 2 min)1 COOH OH Iloprost (t½= ~30 min)2 CH3 Beraprost (t½= ~30 min)2 COO* Na+ O CH3 HO OH OH COOH O Treprostinil (t½= ~240 min)3 PGI2, prostacyclin; t1/2, half-life 1. Clapp et al. Am J Respir Cell Mol Biol. 2002;26:194-201; 2. Gomberg-Maitland et al. Eur Respir J. 2008;31:891-901; 3. Remodulin® (treprostinil) US prescribing information; United Therapeutics Corp. January 2010

Modifications to the prostacyclin side chain for increased stability Treprostinil O COOH Beraprost OH CH3 Stability HOOC O OH OH CH3 Iloprost Prostacyclin CH3 OH

Treprostinil background Prostacyclin analogue Pharmacology: vasodilatation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation1 Approved for SC infusion for idiopathic and heritable PAH in patients with NYHA class III severity of disease to improve exercise tolerance and symptoms of the disease1 Metabolised by the liver2 Treprostinil metabolites mainly excreted via kidneys1 IPAH, idiopathic pulmonary arterial hypertension; NYHA, New York Heart Association; SC, subcutaneous 1. Remodulin® (treprostinil sodium) Summary of Product Characteristics, United Therapeutics Europe Ltd. April 2010; 2. Skoro-Sajer et al. Vasc Health Risk Manag. 2008;4:507-513

Treprostinil PK data: Dose proportionality In patients with PAH, increasing SC or IV treprostinil dose increases plasma concentrations in linear fashion, irrespective of route of administration Conclusion: Treprostinil plasma concentrations follow predictable relationship to treprostinil dose Route of treprostinil administration IV SC 20,000 16,000 n=47 12,000 Treprostinil plasma concentration (pg/ml) 8,000 4,000 10 20 30 40 50 60 70 80 90 100 110 120 130 Treprostinil dose (ng/kg/min) IV, intravenous; PAH, pulmonary arterial hypertension; PK, pharmacokinetics; SC, subcutaneous McSwain et al. J Clin Pharmacol. 2008;48:19-25

Simonneau et al. Am J Respir Crit Care Med. 2002;165:800–804 Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension A double-blind, randomized, placebo-controlled trial Simonneau et al. Am J Respir Crit Care Med. 2002;165:800–804

Safety profile and tolerability Event (≥10% in SC treprostinil group) SC treprostinil (n=233; n [%]) Placebo (n=236; n [%]) p value Infusion site pain 200 (85) 62 (27) <0.0001 Infusion site reaction 196 (83) Infusion site bleeding / bruising 79 (34) 102 (44) ns Headache 64 (27) 54 (23) Diarrhoea 58 (25) 36 (16) 0.009 Nausea 52 (22) 41 (18) Rash 32 (14) 26 (11) Jaw pain 31 (13) 11 (5) 0.001 Vasodilatation 25 (11) 0.01 18 patients (8%) in treprostinil group discontinued treatment due to intolerable abdominal infusion site pain vs 1 patient in placebo group ns, non-significant; SC, subcutaneous Adapted from Simonneau et al. Am J Respir Crit Care Med. 2002;165:800-804

Long-term survival profile in IPAH patients Observed vs predicted survival 91% 82% 76% 72% 69% 56% 46% 38% Observed survival Predicted survival Survival (%) 10 20 30 40 50 60 70 80 90 100 0.0 Time (years) 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 At risk (n) 332 231 149 82 10 Observed survival in 332 SC treprostinil-treated IPAH patients (with baseline haemodynamic parameters available) vs predicted survival by the National Institutes of Health equation IPAH, idiopathic pulmonary arterial hypertension; SC, subcutaneous Adapted from Barst et al. Eur Respir J. 2006;28:1195-1203

Πολλαπλές συγκεντρώσεις Tailoring dose /συμπτωματολογία REMODULIN®  Μορφή / Περιεκτικότητα Διάλυμα για έγχυση 1 mg/ml (φιαλίδιο 20ml) Διάλυμα για έγχυση 2.5 mg/ml (φιαλίδιο 20ml) Διάλυμα για έγχυση 5 mg/ml (φιαλίδιο 20ml) Διάλυμα για έγχυση 10 mg/ml (φιαλίδιο 20ml) Πολλαπλές συγκεντρώσεις Tailoring dose /συμπτωματολογία Εξατομικευμένη χορήγηση

Infusion pump comparison CADD-MS™ 31 CADD-Legacy™2,3 Canè Crono Five4 Administration SC and IV use (treprostinil) IV use (epoprostenol or treprostinil) Reservoir 3 ml syringe 50–100 ml 10–20 ml Dimensions 80 x 47 x 24 mm 41 x 97 x 112 mm 77 x 47 x 29 mm Weight 90 g 391 g 115 g Treprostinil reservoir should be changed at least every 72 hours5 Change of reservoir is not associated with change of site. IV, intravenous; SC, subcutaneous CADD-MS is a trademark and CADD-Legacy is a registered trademark of Smiths Medical System 1. http://www.smiths-medical.com/catalog/ambulatory-pumps-sets/cadd-ambulatory-infusion-pumps/cadd-ms/cadd-ms-3-ambulatory.html. Accessed May 2010; 2; http://www.smiths-medical.com/catalog/ambulatory-pumps-sets/cadd-ambulatory-infusion-pumps/cadd-legacy/cadd-legacy-1-pump.html. Accessed May 2010; 3. http://www.firstbiomed.com/catalog_page_print.aspx?equip_id=77&id=13&key=equip_mfg_id&link=c. Accessed May 2010; 4. http://www.infucare.ch/cronoFIVE.htm. Accessed May 2010; 5. Treprostinil Summary of Product Characteristics. United Therapeutics, April 2010

ΤΟΠΟΘΕΤΗΣΗ ΑΝΤΛΙΑΣ Το REMODULIN χορηγείται μέσω συνεχούς υποδόριας έγχυσης Διαμέσου ενός υποδόριου καθετήρα, με χρήση μιας μικρής φορητής αντλίας 24ωρης έγχυσης Πολλαπλές επιλογές σημείων έγχυσης Για περιπατητικούς ασθενείς Χωρίς να απαιτούνται άσηπτες συνθήκες Σέβεται την αυτονομία του ασθενή

ΒΗΜΑΤΑ ΧΟΡΗΓΗΣΗΣ 2 1 3 4

Infusion site reaction and pain In the pivotal study and long-term follow up: 83%1 and 81%2 of patients experienced some level of infusion site reaction 85%1 and 92%2 of patients reported some degree of infusion site pain 8%1 and 23%2 of patients discontinued therapy because of site pain (70% of these within the first year)2 Rate of discontinuation due to infusion site pain markedly reduced through education, strong nursing support and proactive pain management3 1. Simonneau et al. Am J Respir Crit Care Med. 2002;165:800-804; 2. Barst et al. Eur Respir J. 2006;28:1195-1203; 3. Lang et al. Chest. 2006;129:1636-1643

Πόνος στο σημείο της έγχυσης Συνήθως υποχωρεί μετά από 3-5 ημέρες Μπορεί να διαχειριστεί αποτελεσματικά και μπορεί να μειωθεί με τη μακροχρόνια θεραπεία Το σημείο της έγχυσης να αλλάζει μια φορά κάθε 3-4 εβδομάδες: γεγονός το οποίο μπορεί να βοηθήσει στην ελαχιστοποίηση εμφάνισης του πόνου

Site pain care: Possible pharmacological approaches Hot / cold packs Oral and topical analgesics Anti-inflammatory creams Oral and topical antihistamines Corticosteroids Anti-depressants Systemic analgesics (eg NSAIDs, GABA analogues or opioids) GABA, gamma-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drug

Recommended dosing for treprostinil Initial infusion rate: 1.25 ng/kg/min (0.625 ng/kg/min if poorly tolerated) Increase infusion rate in increments of 1.25 ng/kg/min per week for first 4 weeks and then 2.5 ng/kg/min per week Adjust dose on individual basis in order to achieve maintenance dose at which symptoms improve and which is tolerated by the patient Efficacy only maintained in pivotal 12-week trials with dose increases on average of 3–4 times/month Aim of treatment: Establish dose at which PAH symptoms are improved, whilst minimising excessive pharmacological effects of treprostinil Adverse events (eg flushing, headache, jaw pain, hypotension, nausea, vomiting and diarrhoea) are generally dose-dependent They may disappear with continued treatment Infusion rate may be reduced to diminish intensity if persistent / intolerable PAH, pulmonary arterial hypertension United Therapeutics Europe Ltd. Remodulin (treprostinil) summary of product characteristics. April 2010

Relationship between rate of dose titration and incidence of site pain Study assessed effect of treprostinil infusion rate on incidence of site pain 23 patients with PAH randomised to slow or fast dose escalation groups Treprostinil dose at week 12 Slow escalation group: 12.9 ±2.7 ng/kg/min Rapid escalation group: 20.3 ±5.8 ng/kg/min 25 58% experienced site pain 20 p=0.04 15 Dose (ng/kg/min) 82% experienced site pain 10 5 Rapid dose escalation Slow dose escalation 2 4 6 8 10 12 Time (week) Rapid titration associated with lower incidence of infusion site pain Lack of treprostinil dose dependence of infusion site pain PAH, pulmonary arterial hypertension Skoro-Sajer et al. Clin Pharmacokinet. 2008;47:611-618

ΓΡΗΓΟΡΗ ΤΙΤΛΟΠΟΙΗΣΗ ΤΗΣ ΔΟΣΗΣ Day 1 2 ng/kg/min Day 2 +2 ng/kg/min Day 4 Day 5 Day 6 Day 7 1η εβδομαδα ΓΡΗΓΟΡΗ ΤΙΤΛΟΠΟΙΗΣΗ ΤΗΣ ΔΟΣΗΣ 14 ng/kg/min 1ος μήνας Week 2 +2 ng/kg/min Week 3 Week 4 Week 5 22 ng/kg/min Month 2 +2 ng/kg/min Month 3 Month 4 28 ng/kg/min

Περιστατικό Γυναίκα 54 ετών, ΙΠΑΥ Σε τριπλή θεραπεία με συνδυασμό Tb Sildenafil 25 mg(1X3), tb Tracleer 125 mg(1X2), amp Ventavis (1X6), tb Lasix 40 (1X2), LTOT (3lit/min) Επανειλημμένες εισαγωγές με δεξιά καρδιακή ανεπάρκεια 6MWT: 100m NYHA IV RHC: mPAP 54mmHg, CI 2 Lt/min/m2, RAP 15mmHg

A/α θώρακος

Έναρξη τρεπροστινίλης sc(Remodulin) Σταδιακή ↑ της δόσης κατά 1,25 ng/kg/min έως 30 ng/kg/min

6 μήνες μετά Υπό tb Tracleer 125 (1X2), tb Viagra 25(1X3) και Remodulin (30ng/kg/min ) Σε 6ΜWΤ: 386 m SpO2: 94%→87% (υπό ρινική κάνουλα 3lit/min) NHYA III Τελική έκβαση: Η ασθενής κατέληξε περίπου 18 μήνες μετά την έναρξη τρεπροστινίλης από συγκοπικό επεισόδιο

Aιμοδυναμική επίδραση της εισπνεόμενης ιλοπρόστης σε σοβαρή πνευμονική υπέρταση Olschewski et al. Ann Intern Med 1996

ΕΙΣΠΝΕΟΜΕΝΗ ΙΛΟΠΡΟΣΤΗ (ILOPROST) PPH-CTD-CTEPH N = 203 NYHA : III-IV Iloprost = 2.5 or 5 µg 6-9/d Combined primary end-point (NYHA FC + 6MWT) Εκλεκτική αγγειοδιαστολή της πνευμονικής κυκλοφορίας Ανεπιθύμητες δράσεις ξηρός βήχας ήπιες συστηματικές Χρήση ειδικού νεφελοποιητή Βραχεία διάρκεια δράσης 6-9 (- 12) εισπνοές /ημέρα Διακοπή κατά τη διάρκεια της νύχτας Olschewski H, Simonneau G,Galie N et al. AIR study N Engl J Med 2002

Σχόλια-Συμπεράσματα Η θεραπεία με παρεντερικά προστανοειδή απαιτεί προσεκτικό σχεδιασμό Καλή επιλογή ασθενή - σωστή ψυχολογική προετοιμασία Υποστήριξη από πολυδύναμη ομάδα Εκπαίδευση ασθενή: Κεντρικός ο ρόλος του νοσηλευτή Διαθέσιμη 24ωρη γραμμή επικοινωνίας Στενή παρακολούθηση από εξειδικευμένο κέντρο για την έγκαιρη αναγνώριση και αντιμετώπιση ανεπιθύμητων ενεργειών

Majority of patients die before receiving prostanoids Retrospective review of all incident cases of idiopathic, heritable and anorexigen-associated PAH (between 1 Jan 2001 and 31 Dec 2009) in Scottish Pulmonary Vascular Unit, Glasgow, UK 94 incident cases (62% female) 36% (n=34) on combination therapy Median time from initiation of monotherapy to introduction of second agent: 244 days Only 25% (n=8) of patients who died (n=28) were receiving prostanoids at time of death Escalated to prostanoid therapy, 25% No prostanoids, 75% n=28 PAH, pulmonary arterial hypertension Ling et al. Thorax. 2010;65:A89-A90. Abstract