Επιλζγοντασ κεραπεία για τθν πνευμονικι αρτθριακι υπζρταςθ: παρεντερικι, από του ςτόματοσ ι ειςπνεόμενθ;

Επιλζγοντασ κεραπεία για τθν πνευμονικι αρτθριακι υπζρταςθ: παρεντερικι, από του ςτόματοσ ι ειςπνεόμενθ; Ηρακλισ Τςαγκάρθσ, Επίκουροσ Κακθγθτισ Εντατικισ Θεραπείασ Διακλινικό Ιατρείο Πνευμονικισ Υπζρταςθσ Αττικό Νοςοκομείο

The kingdom of the near-dead. The shortened unnatural life history of primary pulmonary hypertension. Robin ED Chest 1987;92(2): 330-4

Endothelial Cell Dysfunction in PAH ET-1 is elevated (+) Vasoconstriction Cell proliferation / Hypertrophy NO and PGI 2 are reduced (-) Vasodilation Anti-proliferation Anti-inflammation Spieker LE et al. J Am Coll Cardiol. 2001;37:1493-1505. Luscher TF and Barton M. Circulation. 2000;102:2434-2440. Albrecht EW et al. J Pathol. 2003;199:8-17. Hankins SR and Horn EM. Curr Cardiol Rep. 2000;2:244-251.

ERS/ESC guidelines

ERS/ESC guidelines

ERS/ESC guidelines

Αναςτολείσ διαφλων αςβεςτίου-ccb Υψθλζσ θμεριςιεσ δόςεισ 120 240 nifedipine 240 720 diltiazem 10-20 mg for amlodipine Οι CCBs αρχίηουν από χαμθλι δόςθ και αυξάνονται προςεκτικά ςτθ μζγιςτθ επιτρεπόμενθ δόςθ Περιοριςτικοί παράγοντεσ: ςυςτθματικι υπόταςθ, οιδιματα

Αναςτολείσ διαφλων αςβεςτίου-ccb Προςοχι όταν o CI<1.5 L/min/m 2

ERS/ESC guidelines

Class IV

ERS/ESC guidelines

*

% Control Instability of epoprostenol 100 80 60 40 20 Tyrode s solution ph 7.7 Washed human platelets (2x10 8 ml -1 ) 10 20 30 Incubation time (min) Epoprostenol Unstable at physiological temperatures and ph 2 Light sensitive 2 Hydrolysed to 6-oxo-PGF 1α 2 Elimination half-life of approximately 3 minutes 2 Decay of prostacyclin at 37 C in vitro 1 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

I.V. Εποπροςτενόλθ

Adverse events with IV epoprostenol from SmPC Adverse event(s) 1 Sepsis, septicaemia* Headache Facial flushing Nausea, vomiting Jaw pain Decreased platelet count Anxiety, nervousness Tachycardia (at doses of 5 ng/kg/min and below) Abdominal colic/abdominal discomfort Dry mouth Local infection*, chest pain Reddening/pain at the infusion site*, occlusion of the IV catheter*, pain at infusion site*, lassitude, chest tightness Pallor Frequency Very common Very common Very common Very common Very common Common Common Common Common Uncommon Rare Very rare Very rare *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

What are the facts about practicalities of Short half-life (3-5 minutes) Flolan administration Practicalities 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/year 1 Catheter related sepsis: 0.1-0.4 per patient/year 2 1. Sitbon et al 2002 JACC 40:7807-88 2.Hoeper et al, Am J Respir Crit Care Med 165.:209 1216, 2002.

Εναλλακτικι λφςθ?

ERS/ESC guidelines

Treprostinil plasma concentration (pg/ml) 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 20,000 16,000 12,000 8,000 n=47 Route of treprostinil administration IV SC Conclusion: Treprostinil plasma concentrations follow predictable relationship to treprostinil dose 4,000 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Treprostinil dose (ng/kg/min) 130 IV, intravenous; PAH, pulmonary arterial hypertension; PK, pharmacokinetics; SC, subcutaneous McSwain et al. J Clin Pharmacol. 2008;48:19-25

REMODULIN Μορφή / Περιεκτικότητα Διάλυμα για ζγχυςη 1 mg/ml (φιαλίδιο 20ml) Διάλυμα για ζγχυςη 2.5 mg/ml (φιαλίδιο 20ml) Διάλυμα για ζγχυςη 5 mg/ml (φιαλίδιο 20ml) Διάλυμα για ζγχυςη 10 mg/ml (φιαλίδιο 20ml) Πολλαπλζσ ςυγκεντρώςεισ Tailoring dose /ςυμπτωματολογία Εξατομικευμζνη χορήγηςη

Infusion pump comparison CADD-MS 3 1 CADD-Legacy 2,3 Canè Crono Five 4 Administration SC and IV use (treprostinil) IV use (epoprostenol or treprostinil) SC and IV use (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 hours 5 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

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) 62 (27) <0.0001 Infusion site bleeding / bruising 79 (34) 102 (44) ns Headache 64 (27) 54 (23) ns Diarrhoea 58 (25) 36 (16) 0.009 Nausea 52 (22) 41 (18) ns Rash 32 (14) 26 (11) ns Jaw pain 31 (13) 11 (5) 0.001 Vasodilatation 25 (11) 11 (5) 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

Πόνοσ ςτο ςθμείο τθσ ζγχυςθσ Συνικωσ υποχωρεί μετά από 3-5 θμζρεσ Μπορεί να διαχειριςτεί αποτελεςματικά και μπορεί να μειωκεί με τθ μακροχρόνια κεραπεία Το ςθμείο τθσ ζγχυςθσ να αλλάηει μια φορά κάκε 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

Class III

ERS/ESC guidelines

McLaughlin & McGoon Circulation 2006, 114:1417-1431

mm Hg Hemodynamics Change from baseline to week 12 Cardiac index Mean pulmonary arterial pressure Pulmonary vascular resistance L/min/m 2 0.8 0.4 0-0.4 P < 0.0001 10 5 0 P = 0.013 Dyn.sec.cm -5 400 200 0-200 P = 0.0001-0.8 Week 12-5 Week 12-400 Week 12 Placebo (n = 10) Bosentan (n = 20) Channick et al. Lancet 2001;358:1119

AIR-Study Results 20,0% 17% 15,0% 10,0% 5,0% 5% p = 0,007 Iloprost Placebo 0,0% Patients in % Combined clinical end point: Improvement in NYHA Stadium (at least one class) AND improvement of 6 min walk test for at least 10% AND no deterioration or death Source: Olschewski et al, New England Journal of Medicine 2002;347:322-9

McLaughlin and McGoon, 2006

NYHA III Cardiac index < 2.0 L/min/m 2 mrap <12 mm Hg, Mixed venous oxygen saturation <55%, 6MWD<300 m.

PO IV/Sc

Class II

ERS/ESC guidelines

Bosentan: EARLY study So far only bosentan has been investigated in a RCT with patients in functional stage II only, and demonstrated significant improvement of hemodynamics as well as a reduced rate of clinical events even though it did not achieve one of the predefined primary endpoints, the improvement of the 6-MWT. EMA evaluated the data as solid to issue an indication for bosentan for the treatment of PAH patients in functional class II.

Ambrisentan: ARIES study Even if there is no such specific study for ambrisentan, the EMA decided on the basis of subgroup analyses of class II patients from the ARIES studies of ambrisentan, to initially issue approval also for functional class II patients

Easy to use - Toxicity Data from a postmarketing surveillance in the US showed no evidence of hepatotoxicity with the use of ambrisentan. Accordingly, the FDA has removed the recommendation to perform monthly transaminase controls in patients with ambrisentan therapy.

Αλλθλεπιδράςεισ

Αλλθλεπιδράςεισ

Ειδικζσ ομάδεσ

In light of the high costs of targeted PAH therapies, the consideration of cost efficacy is of relevance.

In light of the high costs of targeted PAH therapies, the consideration of cost efficacy is of relevance. However, when treating patients with a lifethreatening disease, medical necessities must always be paramount.

In light of the high costs of targeted PAH therapies, the consideration of cost efficacy is of relevance. However, when treating patients with a lifethreatening disease, medical necessities must always be paramount.

In this context, it is crucial to ensure a proper diagnostic work-up and classification, and to prescribe targeted PAH therapies within the approved indication and meet the requirements of each individual patient.

In this context, it is crucial to ensure a proper diagnostic work-up and classification, and to prescribe targeted PAH therapies within the approved indication and meet the requirements of each individual patient. It is the responsibility of PH expert centers to ensure this.