ΣΥΝΟΠΤΙΚΗ ΔΙΑΓΝΩΣΤΙΚΗ ΚΑΙ ΘΕΡΑΠΕΥΤΙΚΗ ΠΡΟΣΕΓΓΙΣΗ ΚΑΡΔΙΑΓΕΙΑΚΩΝ ΠΑΘΗΣΕΩΝ ΠΝΕΥΜΟΝΙΚΗ ΥΠΕΡΤΑΣΗ

Transcript

1 Περιφερικό Καρδιολογικό Συνέδριο ΕΚΕ Κοζάνη 2012 ΣΥΝΟΠΤΙΚΗ ΔΙΑΓΝΩΣΤΙΚΗ ΚΑΙ ΘΕΡΑΠΕΥΤΙΚΗ ΠΡΟΣΕΓΓΙΣΗ ΚΑΡΔΙΑΓΕΙΑΚΩΝ ΠΑΘΗΣΕΩΝ ΠΝΕΥΜΟΝΙΚΗ ΥΠΕΡΤΑΣΗ George Giannakoulas, MD Pulmonary Hypertension Clinic AHEPA University Hospital

2 Available on

3 What is Pulmonary Hypertension? An haemodynamic definition Pressure Mean PAP > 25 mmhg (rest) or > 30 mmhg (exercise) Extensive literature search* found N= mmhg upper limit 20+2 mmhg mpap < 20 mmhg Normal mpap mmhg Borderline mpap > 25 mmhg Pulmonary hypertension * Olschewski et al. 4th World Congress on PAH, Dana Point Ca, Feb 2008

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5 Updated clinical classification of pulmonary hypertension (Dana Point 2008)

6 PH diagnosis

7 Referral to Specialist centre London Royal Free Hammersmith Royal Brompton Great Ormond Street Glasgow Sheffield Cambridgeshire Republic of Ireland Newcastle Upon Tyne

8 Class NYHA Functional Class Pa6ent Symptoms Class I (Mild) No limita1on of physical ac1vity. Ordinary physical ac1vity does not cause undue symptoms Class II (Mild) Slight limita1on of physical ac1vity. Comfortable at rest, ordinary physical ac1vity results in symptoms. Class III (Moderate) Marked limita1on of physical ac1vity. Comfortable at rest, but less than ordinary ac1vity causes symptoms. Class IV (Severe) Symptoms of cardiac insufficiency at rest. If any physical ac1vity is undertaken, discomfort is increased.

9 Increased awareness of PAH may lead to earlier patient diagnosis Patients (%) French registry ( ): 75% of patients diagnosed in late-stage disease Patients (%) More recent findings from the REVEAL registry ( ) suggest that increased disease awareness is leading to earlier patient referral in the symptomatic stages of the disease FC I FC II FC III FC IV FC I FC II FC III FC IV FC = functional class; PAH = pulmonary arterial hypertension; REVEAL = Registry to Evaluate Early and Long-term PAH Disease Management 1. Humbert M, et al. Am J Respir Crit Care Med 2006;173: ; 2. Badesch DB, et al. Chest 2007;132 (Suppl):473.

10 PH etiology 3,5% 10% 1,5% 78% 7% Adapted from Galiè N. ESC 2009 Gabbay et al. ATS 2007

11 Differential diagnosis of PH Diagnosis is based on echocardiographic suspicion and initial exclusion of the most common causes of PH Galiè et al. Eur Heart J 2009

12 Doppler echocadiography-based criteria for Pulmonary Hypertension Level of suspicion TR max Velocity Estimated RVSP (mmhg) Other DE findings Class/ Level Unlikely < 2.8 m/s < 36 mmhg No I/B Possible < 2.8 m/s < 36 mmhg Yes IIa/C m/s mmhg No Likely > 3.4 m/s > 50 mmhg Yes/No I/B Galiè et al. Eur Heart J 2009

13 When to proceed to RHC? Level of probability DE criteria Symptoms Risk factors RHC Class/ Level Low Unlikely No No No I/C Yes Yes No Yes No Yes Intermediate Possible No No No I/C No Yes Yes Yes? Yes IIb/C IIb/C High Likely Yes Y/N Yes I/C No Yes IIa/C RHC indicated in high and intermediate probability with symptoms and risk factors for PAH Galiè et al. Eur Heart J 2009

14 Favorable vasodilator response Drop in mean PAP of 10 mm Hg to a value <40 mm Hg with an unchanged or increased cardiac output

15 Vasoreactivity testing Base NO 20 ppm mpap 45 mmhg mpap 28 mmhg

16 Other imaging modalities Echocardiographic Measurements Male Age 25 Years mpap = 56 mmhg Female Age 24 Years mpap = 53 mmhg

17 Echocardiographic Measurements Male Age 25 Years mpap = 56 mmhg Female Age 24 Years mpap = 53 mmhg SV = 90 ml, 6MWD = 500 m SV = 30 ml, 6MWD = 300 m

18 PH treatment

20 Percentage Surviving 100 IPAH/FPAH (PPH): Progressive disorder associated with high mortality rate best! PAH Survival-NIH registry data 1980 s 80 The earliest the 60 68% 50% mortality at 2.5 years if left untreated Time from sx to dx: 2.5 yrs Median: 2.8 yrs 50% survival at 2.5 yrs 48% 34% Years of Followup D Alonzo GE, Barst RJ, Ayres SM. Survival in patients with PPH: Results from a National Prospective Registry. Ann Internal Med. 1991; 115:

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22 BREATHE-1:Time to Clinical Worsening Event-Free (%) % 89% p = % p = % Bosentan (n = 144) Bosentan (n = 35) Placebo (n = 69) Placebo (n = 13) Time (weeks) * Time to clinical worsening = Shortest time to either death, premature withdrawal or hospitalization due to PHT worsening, or initiation of epoprostenol therapy

23 ARIES Study ARIES-E: Long term effects of ambrisentan Improvement Change in 6MWD (m) Years 5 mg, n = mg, n = Change from baseline data presented Mean ± 95% confidence interval Last observation carried forward for missing data Data on File Presentation by Ron Oudiz CHEST 2008

24 Sildenafil: Outcomes

25 I.V. Flolan

26 Advanced therapies for PAH Survival benefits Overall RR 0.57, 95% CI 0.35, 0.93 Reduce in mortality by 43%, p = BUT Advanced therapies have improved survival Mortality remains high We need further progress Galiè N, et al. Eur Heart J 2009; 30:

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29 Group 2

30 PDE- 5 Inhibi6on to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure: the RELAX trial A large NIH- funded, randomized, placebo- controlled trial that is currently ongoing in pa1ents with HF and preserved LV func1on. Preliminary results show: - Increase in exercise capacity - Improvement in arterial s1ffness - Improvement in arterioventricular coupling in the sildenafil group

32 Group 3

34 Group 4

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40 Thank you

42 Targets for Therapy in PAH mbert et al. New Engl J Med 2004

43 Some RV actions of Current Stimulate s Therapies ETRA PDE5i Inhibits PDE5i PGI 2 ETRA PGI 2 PDE5i? ETRA? PGI 2 PDE5i PDE5i ETRA

44 Time-course of 25 published randomized controlled studies (identified by acronyms, if any, or drug and year of publication) in pulmonary arterial hypertension as of May Galiè N et al. Eur Heart J 2010;31:

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46 Prostacyclin Analogues: Intravenous, Subcutaneous, or Inhaled Epoprostenol (Flolan ) Treprostinil (Remodulin ) Treprostinil (Remodulin ) Iloprost (Ventavis )

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48 Effects of the Combina6on of Bosentan and Sildenafil Versus Sildenafil Monotherapy on PAH the Compass 2 trial This study will investigate the effects of the combination of bosentan and sildenafil. Patients with symptomatic PAH treated with a stable dose of sildenafil equal to or greater tha 20 mg t.i.d. for at least 12 weeks will be randomized to placebo or bosentan 125 mg b.i.d. All randomized patients will be treated with study drug until the predefined target number of morbidity/mortality events is reached Estimated Enrollment: 250 Study Start Date: April 2006 Estimated Study Completion Date: June 2012 Estimated Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)

49 A Study of First- Line Ambrisentan and Tadalafil Combina6on Therapy in Subjects With PAH the AMBITION trial The purpose of this study is to compare the two treatment strategies; first-line combination therapy (ambrisentan and tadalafil) versus first-line monotherapy (ambrisentan or tadalafil) in subjects with PAH. This will be assessed by time to the first clinical failure event. Estimated Enrollment: 352 Study Start Date: October 2010

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51 Meta-analysis of PAH trials by pump function Handoko ML, et al. Eur Resp Rev 2010

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54 Prevention of pulmonary vascular remodeling with losartan Rondelet B. Am J Physiol Heart Circ Physiol 2005

55 RV pacing Handoko ML. Am J Physiol Heart Circ Physiol 2009

56 IPAH patients are particularly susceptible to amiodarone-induced thyroid dysfunction, with potentially life-threatening consequences Prolonged exposure increases the risk

57 There has been progress The disease has remained incurable and median survival is still limited to,5 6 yrs, with insufficient functional improvement in many of the survivors

58 Γεώργιος Γιαννακούλας, MD, PhD, FESC Ιατρείο Συγγενών Καρδιοπαθειών και Πνευμονικής Υπέρτασης Α Καρδιολογική Κλινική ΑΧΕΠΑ

59 Diagnosis and assessment of PAH Patients are likely best assessed in a specialised referral centre An organised approach to the diagnostic evaluation is necessary To monitor patients status and response to management, using multiple assessment techniques is probably preferred over any single test. Such an evaluation should include assessment of: History and physical examination Exercise capacity (6MWT, CPET) Non-invasive imaging (ECHO, MRI, etc) Hemodynamics

60 Signs and symptoms of PAH Dyspnoea on exertion* Fatigue* Weakness* Syncope/pre-syncope* Chest pain* Abdominal bloating Cough Haemoptysis Raynaud's phenomenon Poor appetite Nausea Peripheral oedema Hoarseness *Typical early symptoms PAH = pulmonary arterial hypertension 1. McGoon M, et al. Chest 2004;126 (Suppl 1):14 34; 2. Rich S, et al. Ann Intern Med 1987;107:216 23; 3. Rubin LJ. Chest 2004;126 (Suppl 1):7 10.

61 PAH: physical examination Loud pulmonary valve closure sound (P2)* Early systolic pulmonary valve ejection click* Midsystolic pulmonary ejection murmur* Prominent jugular a wave* Left parasternal lift* Tachycardia: right ventricular S4 gallop* right ventricular S3 gallop Tachypnoea Diaphoresis Pallor/acrocyanosis/cyanosis Elevated jugular venous pressure Systolic murmur (TR) Diastolic murmur (PI) Hepatomegaly, frequently pulsatile Oedema Ascites Failure to thrive *Typical early signs P2 = pulmonic valve closure; PAH = pulmonary arterial hypertension; PI = pulmonary insufficiency; TR = tricuspid regurgitation 1. Bossone E, et al. Chest 2007;131:339 41; 2. McGoon M, et al. Chest 2004;126 (Suppl 1):14 34; 3. Rich S, et al. Ann Intern Med 1987;107:

62 PAH ASD

63 mpap 50 mmhg CI 2.4 l/sec/m² PVR 8.9 WU

64 When things are obvious!

65 But not always

66 Cardiopulmonary Haemodynamics CO = (LVOTd) 2. VTI LVOT. HR

67 Cardiopulmonary Haemodynamics 4 CO Adapted from: Fisher MR et al. AJRCCM 2009; 179:

68 Factors associated with a higher probability of PH due to LHD Clinical features Echocardiography Interim evaluation Age > 65 Elevated systolic BP Elevated pulse pressure Obesity, metabolic syndrome Coronary artery disease Diabetes mellitus Atrial fibrillation Left atrial enlargement Concentric remodelling of the LV Echocardiographic indicators of elevated LV filling pressure Symptomatic response to diuretics Exaggerated increase in BP during exercise Chest X-ray consistent with HF Galiè et al. Eur Heart J 2009

69 Out of proportion PH: TPG (mean PAP mean PWP) >12 mmhg or mpap >35-40mmHg Introduction of the concept of «out of proportion PH» Exclusion or confirmation of CTEPH Galiè et al. Eur Heart J 2009

70 Galiè et al. Eur Heart J 2009

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72 Typical features of CTEPH Fedullo et al. N Engl J Med 2001 Hoeper M. Circulation 2006

73 High probability V/Q scan in Pulmonary Venoocclusive disease Bailey C et al. Am J Respir Crit Care Med Vol 162. pp , 2000

74 Galiè et al. Eur Heart J 2009

75 Why do we need RHC?

76 Bernoulli mod. equation RV-RA ΔP = 4. (TRV) 2 RV pressure = 4. (TRV) 2 + RAP RV pressure = Systolic PAP Yock PG, Popp RL. Circulation 1984;70: Sensitivity: Specificity: Diameter Collapse RAP < 2 50% 0-5 < cm2 < 50% mmhg 6-10 cm2 50% mmhg cm2 0% mmhg >15

77 Pulmonary Pressures PAPs 29% (9%) 48% 23% (15%) Good Doppler signals Poor Doppler signals (31%) Adapted from: Fisher MR et al. AJRCCM 2009; 179:

78 Pulmonary Pressures RAP RCH measurement % Echocardiographic Estimate 39% Adapted from: Fisher MR et al. AJRCCM 2009; 179:

79 Right heart catheterization RV, PA, PCWP, and LV pressures be measured at end expiration (esp in obese and pts with lung disease) For the measurement of cardiac output, both thermodilution and Fick methods are reliable in PAH patients, except severe TR and cardiogenic shock. The Fick method is mandatory in the presence of an intracardiac shunt. Vasodilator challenges with inhaled NO or intravenous epoprostenol or adenosine are encouraged in most patients

80 Exercise RHC An increase in PCWP to >15 mm Hg in response to exercise or fluid challenge suggests the presence of pulmonary venous hypertension Johns Hopkins University protocol for exercise RHC

81 Novel Techniques PVR is a simple measure of the opposition to the mean component of flow Pulmonary circulation is pulsatile with multiple bifurcations, and wave reflection is an inevitable consequence Impedance, the opposition to blood flow by the pulmonary circulation, is frequency dependent on and modulated by heart rate, vessel dimensions, vessel stiffness, and wave reflections Champion et al. Circulation 2009

82 Champion et al. Circulation 2009

83 RV-pulmonary circulation unit Champion et al. Circulation 2009

84 The effect of PH on the RV

85 RV is more sensitive to afterload changes Right Ventricle Stroke volume Left Ventricle % change in vascular resistance

86 MRI Gold standard for RV size and function Pulmonary angiography

87 Effect of advanced therapies

88 novel uses of MRI Using standard 1.5- T machines, pulses, and a single gadolinium injection as low as 2 to 5 cm 3 images were obtained without a breath hold

89 CT Normal

90 PET imaging

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93 ESC/ERS 2009 PAH guidelines Galie N et al, Eur Heart J 2009

94 Mortality of PAH-SSc is elevated 1.0 Cumulative survival Isolated PAH (n=259) 0.0 P=0.02 Respiratory disease (n=56) Years from diagnosis In the UK registry, 3-y survival of PAH-SScl = 47% Condliffe R et al. Am J Respir Crit Care Med 2009

95 Outcome of PAH-SSc is worse than IPAH % survival Logrank p-value= IPAH (n=41) PAH-SScl (n=50) Time (years) despite a less severe state of diagnosis, (Ppa 46 vs 54 mmhg) Fisher M et al. ARTHRITIS & RHEUMATISM 2006; 54:

96 SSc Other CTD (ie SLE) Asymptomatic or Decline in DLCO Echocardiography (yearly in asymptomatic SSc) Symptomatic TRV < 2.8 m/sec No other sign of PH TRV m/s TRV > 3.4m/s With or without signs of PH No other sign of PH Other signs of PH PH unlikely PH possible PH likely PH highly likely - Biomarkers NI workup + Perform non invasive workup (Biomarker, V/Q scan, HRCT ) to exclude non PAH PH Consider Follow up echo (3-6 mo) In symptomatic patients RHC indicated For PAH diagnosis Vachiery JL, Coghlan G Eur Respir Review 2009

97 Which prognostic indicators? Clinical assessment Symptoms Clinical Signs Rate of progression NYHA/WHO FC Signs of RV failure Distance walked Peak VO 2 VE/VCO 2 slope Exercise capacity 6 minute walking test CP exercise test Evaluation of RV (dys)function Biomarkers Echocardiographic variables Invasive haemodynamics baseline and follow up Changes in BP BNP/NT-ProBNP Troponin Uric acid Others (NA, Hb) TAPSE Tei index Pericardial effusion RAP Cardiac index

98 Problems and controversies The degree of PH (PAP) does not strongly correlate with symptoms or survival, whereas RV size and right atrial pressure reflect functional status and are strong predictors of survival Μeasurement of PAP is not necessarily a sensitive index of the condition of the pulmonary vasculature. PAP might drop as the RV function deteriorates The interobserver variability in interpreting a PCWP waveform is extremely large, with variations of as much as 23 mm Hg

99 Take home messages PAH should be considered in the differential diagnosis of exertional dyspnoea, syncope, angina, and/or progressive limitation of exercise capacity, particularly in patients without apparent risk factors, symptoms or signs of common cardiovascular and respiratory disorders Special awareness should be directed towards patients with associated conditions and/or risk factors for development of PAH, such as family history, CTD, CHD, HIV infection, portal hypertension, haemolytic anaemia, or a history of intake of drugs and toxins known to induce PAH Echocardiography is a first line noninvasive tool and should always be performed in the case of suspected PH. However, decisions on initiating treatment or risk stratification should be based on multiple diagnostic tests, especially RHC

100 Thank you for your attention

101 PAH in CHD

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103 1 HIV 6.2% ipah 39.2% PoHT 10.4% CHD 11.3% CTD 15.3% Anorex 9.5% FPAH 3.9% 52.6% PPH 4.3% had at least 2 coexisting factors Minimal incidence 2.4/million (n=121) Minimal prevalence 15/million (n=553) Large regional differences up to 25/million 1. Humbert AJRCCM 2006;173:1023

104 All hospital activities captured Based on the Scottish Morbidity Record Scheme years with ipah, PAH-CHD or PAH-CTD Scottish Pulmonary Vascular Unit UK referral centre for Scotland Equivalent to french national reference centre Prevalence (cases/m) SMR SPVU Incidence (cases/m/year)

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106 American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association, et al. J Am Coll Cardiol 2009;0:j.jacc v

107 Inherited PAH Περιλαµβάνονται ασθενείς µε οικογενειακό ιστορικό ή ασθενείς µε IPAH και αναγνωρισµένες µεταλλάξεις Γονιδιακός έλεγχος δεν είναι απαραίτητος

108 Απώλεια της ανασταλτικής δράσης της ΒΜP στον πολ/σµό ΛΜΙ Προαγωγή της απόπτωσης του ενδοθηλίου

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112 Mitral E/Em=7.8

113 LV Eccentricity index D2 D1 LVEI = D2/D1

114 RV systolic function

115 RV systolic function RV function Cut-off value = 10.5 cm. S -1 Sensitivity : 90% Specificity : 85% Meluzin J et al. Eur Heart J 2001; 22:340-48

116 RV systolic function RV systolic function Normal value: 0.28 ± 0.04 a b

117 RV systolic function RV systolic function c a b Adapted from Huez S. Index = (a + c)/b Harada K et al. Am J Card 2002; 90: 566-9

118 Noninvasive echo measurements mean PAP=90 (0.45 x PAAT) valid when PAAT<120ms Dabestani A et al. Am J Cardiol PVR = TRV/TVI RVOT x PVR ECHO =(3.64/6.5)x =5.76 WU PVR CATH= 6.0 WU Abbas AE et al. JACC 2003

119 Progression of PAH role of haemodynamics Asymptomatic Symptomatic/ Stable Progressive/ Declining Level RV function Cardiac output at exercise Cardiac output at rest Mean PAP Increasing PVR Time Adapted from Rich et al. In: Harrison s Principles of Internal Medicine. 15th ed. 2001:

120 Definition of inadequate response to PAH treatments Inadequate clinical response for patients who were initially in WHO-FC II or III: Resulting clinical status defined as stable and not satisfactory. Resulting clinical status defined as unstable and deteriorating. Inadequate clinical response for patients who were initially in WHO- FC IV: No rapid improvement to WHO-FC III or better. Resulting clinical status defined as stable and not satisfactory.

121 Risk assessment

122 PAH follow up

123 Αναδροµική µελέτη σε πληθυσµό 557 ασθενών µε IPAH Responders :12.6% (n=70) Μακροπρόθεσµη ανταπόκριση στους CCB: παραµονή σε στάδιο NYHA I/II µε παράλληλη βελτίωση των αιµοδυναµικών µετρήσεων, σε σχεδόν φυσιολογικές τιµές, υπό µονοθεραπεία µε CCB για τουλάχιστον 1 έτος Μακροπρόθεσµη ανταπόκριση: <10% ασθενών µε IPAH Circulation 2005;111:

124 ERAs J Am Coll Cardiol Jun 30;54(1 Suppl):S78-84

125 ΕΝΔΟΦΛΕΒΙΑ ΕΠΟΠΡΟΣΤΕΝΟΛΗ Χρόνος ηµίσειας ζωής <6min, ασταθές σε θερµοκρασία δωµατίου συνεχής ενδοφλέβια έγχυση µε µόνιµο καθετήρα Ανεπιθύµητες ενέργειες κεφαλαλγία, πόνος στη γνάθο, έξαψη, ναυτία, διάρροια, µυοσκελετικά άλγη σχετιζόµενες µε τον καθετήρα: λοίµωξη /σήψη, θρόµβωση διακοπή της λειτουργίας της αντλίας Αντενδείξεις Αριστερή καρδιακή ανεπάρκεια Πνευµονική φλεβοαποφρακτική νόσος Υψηλό κόστος

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127 ΥΠΟΔΟΡΙΑ ΤΡΕΠΡΟΣΤΙΝΙΛΗ (sc TREPROSTINIL) Σταθερό ανάλογο προστακυκλίνης µε χρόνο ηµίσειας ζωής 4.5 ώρες Συνεχής υποδόρια έγχυση µε ειδική αντλία Ανεπιθύµητες δράσεις συστηµατικές πόνος στο σηµείο της έγχυσης τοπική αντίδραση Υψηλό κόστος Simonneau G,Barst RJ,Galie N et al. Am J Respir Crit Care Med 2002

128 Επίπτωση της θεραπείας πρώτηςγραμμής με προστακυκλίνη στην επιβίωση ασθενών με ΙΠΑΥ % % Survival in IPAH (%) Sc Treprostinil (Lang et al. CHEST 2006) Expected (after D Alonzo et al. Ann Intern Med 1991) IV epoprostenol (Mc Laughlin et al. Circulation 2002) At risk (n) Time (weeks)

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130 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) Olschewski H, Simonneau G,Galie N et al. AIR study N Engl J Med 2002 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

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133 ΑΝΤΑΓΩΝΙΣΤΕΣ ΥΠΟΔΟΧΕΩΝ ΕΝΔΟΘΗΛΙΝΗΣ ERAs Ambrisentan Bosentan Sitaxentan Εκλεκτικότητα ΕΤ Α :ΕΤ Β 30:1 6500:1 4000:1 Δοσολογία mg 100mg 5-10mg Αλληλεπιδράσεις sildenafil αντιπηκτικά κυκλοσπορίνη Α Ανεπιθύμητες ενέργειες γλιβενκλαμίδη κυκλοσπορίνη Α, αντισυλληπτικά Ηπατοτοξικότητα (ALT/AST>3φορές) 0.8-3% κυκλοσπορίνη Α 11% 3-5% Περιφερικό οίδημα 4.7% 9%

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136 IV sildenafil 10 mg (12.5ml) = 20 mg oral dose European Heart Journal (2004) 25,

137 Effect of Tadalafil* on 6MWD (PHIRST) Change in 6MWD (m) Placebo Tadalafil 2.5 mg Tadalafil 10 mg Tadalafil 20 mg Tadalafil 40 mg p<0.001 p<0.05 p< Weeks *Adcirca Galiè N et al. Circulation. 2009;119;

138 Ευεργετικά αποτελέσµατα των νεότερων θεραπειών της ΠΑΥ

139 Chest 1987;92; D Alonzo et al. Ann Intern Med 1991;115:343-9 NIH Registry : Επιβίωση 1 yr 3 yr 5 yr 68% 48% 34%

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141 NYHA I,II NYHA III NYHA IV

142 Συνδυασμοί φαρμάκων Προστανοειδή (iv, sc,inh) Ανταγωνιστές υποδοχέων ενδοθηλίνης Αναστολείς φωσφοδιεστεράσης-5 BREATHE 2 STEP PACES-1 TRIUMPH PHIRST IV epoprostenol + bosentan (as 1 st line Tx) Bosentan + inhaled iloprost IV epoprostenol + sildenafil Bosentan or sildenafil + inhaled treprostinil Bosentan + tadalafil

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144 Dromparis P, Sutendra G, Michelakis ED. J Mol Med Aug 24.

145 Michelakis ED, Sutendra G, Dromparis P, et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2010 ;2:31ra34 McMurtry MS, Bonnet S, Wu X, Michelakis ED. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 2004;95:

146 ΣΧΟΛΙΑ - ΣΥΜΠΕΡΑΣΜΑΤΑ Η πρόγνωση των ασθενών µε ΠΑΥ βελτιώνεται Η θνητότητα παραµένει υψηλή Η βέλτιστη αντιµετώπιση των ασθενών απαιτεί: Συνεργασία µε εξειδικευµένο κέντρο Στενή παρακολούθηση των ασθενών Λογική χρήση των φαρµάκων και των συνδυασµών αυτών

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148 ERAs J Am Coll Cardiol Jun 30;54(1 Suppl):S78-84

149 Metaanalysis of randomised controlled trials in PAH (Galie N. et al. Eur Heart J Feb 2009)

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155 Strategies to Prevent and Treat Right Heart Failure Reduce RV wall stress ( MVO 2, ischemia) Reduce RV afterload Pulmonary vasodilators (O 2, CCB, ERA s, prostanoids, nitric oxide) Anticoagulation to prevent thrombosis Reduce RV preload and TR (diuretics: loop, aldosterone antagonists) Improve RV inotropy Chronically: digoxin Acutely: IV epoprostenol, IV treprostinil low dose IV dobutamine or dopamine at 1-2 mcg/kg/

156 Invasive Treatment of Advanced RV Failure Atrial septostomy +/- ECMO Improve LV filling and systemic cardiac output Transplantation - lung / heart-lung Reserved for patients who continue to deteriorate with poor QOL despite aggressive pharmacologic therapy 1 year survival % 5 year survival %