clinical challenges in pulmonary...
TRANSCRIPT
04/03/60
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Clinical Challenges in Pulmonary Hypertension
Nattapong Jaimchariyatam, MD, MS, FCCPAssociate Professpr of Medicine, Pulmonary Vascular and Transplantation,
Faculty of Medicine, Chulalongkorn University
Case 1
• ผู้ ป่วยเดก็หญิงไทยอาย ุ14 ปี
• 4 wks มีอาการเหนื�อยหลงัจากไปประเทศจีน ไปที�คนุหมงิ ต้าลี� ลี�เจียง แล้วสดุท้ายที� Shangri La
• เริ�มเหนื�อยเวียนศีรษะระหว่างการเดนิทางจาก ต้าลี� ไป ลี�เจียง (FCII -> IV) ที� Shangri La นอนราบไม่ได้ ไอ ไม่มีไข้ ตาบวม ขาบวม ไม่ได้ไปโรงพยาบาลทานยาจากคนที�ไปด้วย (ยา?) และ O2 supplement นอนพกั 2 คืน เดนิทางกลบั เหนื�อยดีขึ �น
• กลบัถึงเมืองไทยยงัเหนื�อย FCII ขาไม่บวมแล้ว นอนราบได้มากขึ �น
Shangri La
Heaven on Earth
4350 m above sea level
คุนหมิง
ต้าลี�2 คนื
ลี�เจยีง2 คนื
แชงกรีลา2 คนื
1891 m elevation
2007 m elevation
2560 m elevation
4350 m elevation
เริ�มเหนื�อย
นอนราบไม่ได้ คนื
แรก
เหนื�อยมาก บวม ได้
O2 ยา
Case 1
• เคยผ่าตดัตบัตั �งแตเ่ดก็ (ทอ่นํ �าดีอดุตนั) หลงัจากนั �นสบายดี (FCI) ขาดการตดิตามมาหลายปี
• ไม่สบูบหุรี� ไม่ดื�มสรุา ไม่ได้ใช้ยาอะไรเป็นประจํา
• ROS: ยงัเหนื�อยง่าย ไม่บวมแล้ว นอนใช้หมอนหนึ�งใบ ปัสสาวะอจุจาระปกต ิไม่ซีดไม่เหลือง
Physical Examination
• BT 36.5 PR 88/min RR 28/min BP 120/75
• Not pale, No jaundice
• No central cyanosis (O2sat 92% RA)
• Normal lung examination
• RV heaving and accentuated P2 present
• No liver stigmata
• No limb edema
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Problem lists
• Persistent dyspnea after high altitude climbing
• History of bile duct obstruction s/p surgery (3 month of age)
Annals of Internal Medicine 2004; 141: 789-800.
High Altitude related Medical Conditions
• High altitude illness/conditions– Acute mountain sickness (AMS)
– High-altitude pulmonary edema (HAPE)
– High-altitude cerebral edema (HACE)
– Periodic breathing
– Pulmonary hypertension
• Medical conditions exacerbated by high altitude
– Pulmonary hypertension, COPD, OSA
Lancet 2003; 361: 1967–74.
Risk Factors
• Physical exertion
• Age less than 50 years
• Residence at an altitude less than 900-1500 m
• Rapid rate of ascent
• Obesity (AMS??)
• Underlying cardiopulmonary disease
Lancet 2003; 361: 1967–74.
High Altitude Pulmonary Edema
• The 2nd night at a new altitude, rarely occurs after 4 d
• Risk factors: children, Hx of recurrent HAPE, rate of ascent, altitude reached, cold, exertion
• 50% have AMS, 14% have HACE
• Fever is common
Lancet 2003; 361: 1967–74.Ann Intern Med 2004; 141:789
High Altitude Pulmonary Edema
• Prevention:
– Slow ascent
– Nifedipine SR 20 mg BID (60 mg/d) prior to ascent and continue for 5 d at altitude
– Sidenafil 50 mg tid
• PH or intracardiac/pulmonary Shunt, VHD– consider when occurs at altitude < 8250 ft (2500 m)
Lancet 2003; 361: 1967–74Ann Intern Med 2004; 141:789N Engl J Med 2002 ; 346: 1606
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Problems list
• Disproportionate high altitude Pulmonary Edema
• Persistent dyspnea after high altitude climbing
Underlying Cardiopulmonary diseases ?
Prominent central PAEnlarged rt descending PA
Peripheral hypovascularity
RV Enlargement
RA Enlargement
Diagnostic dilemma
Confirmation of PH
Identification of PH classIdentification of PH class
Evaluation of severityEvaluation of severity
Hx, PE, CXR, EKG, Echo, ± RHC
V/Q scan, CTPA, HRCTSerology, LFT, PFT, Genetic assessment
BNPWHO-FC6MWTCPET
Echo criteria for estimation of PH
ESC guideline 2015. EHJ 2015.
RVSP
Complete RHC
(+/- LHC)
การตรวจ echocardiogram เพื�อ ให้วินิจฉัยแยกโรคเช่น left sided heart disease, congenital heart disease, AV fistula, thrombus ใน atrium หรือ pulmonary
artery เป็นต้น ก่อนจงึจะพิจารณาใช้ค่า RVSP
RVSP 36- 50 mmHgRVSP < 36 mmHg RVSP ≥ 50 mmHg
No PAH
Diagnosis PAH
- E/e’ < 8 and
- LA Vol index ≤ 28 ml/m2
- mPAP ≥ 25 mmHg
- PVR ≥ 3 WU
- E/e’ < 8 and
- LA Vol index ≤ 28 ml/m2
yesNot sure
Thai PH Guideline 2013
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Echocardiography
• D-shaped LV, LVEF 65%, LA 28 mm, Mitral e/e’ 8
• Dilated RV (44 mm), PA (41 mm), TAPSE 15 mm
• TRV 4.31, est RA 15, RVSP 89.3
• No intracardiac shunt
1. Pulmonary arterial hypertension1.1 Idiopathic PAH
1.2 Heritable PAH
1.2.1 BMPR2
1.2.2 ALK1, ENG, SMAD9, CAV1, KCNK3
1.2.3 Unknown
1.3 Drug- and toxin-induced
1.4 Associated with
1.4.1 Connective tissue diseases
1.4.2 HIV infection
1.4.3 Portal hypertension
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis
1’ Pulmonary veno-occlusive disease and/orpulmonary capillary haemangiomatosis
1’’ Persistent PH of the newborn (PPHN)
2. PH due to LHD2.1 LV systolic dysfunction
2.2 LV diastolic dysfunction
2.3 Valvular disease
2.4 Congenital/acquired left heart inflow/outflow obstruction
3. PH due to lung diseases and/or hypoxia3.1 COPD
3.2 Interstitial lung disease
3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental lung diseases
4. CTEPH and PA obstruction
5. PH with unclear multifactorial mechanisms5.1 Haematological disorders: chronic haemolytic anaemia,
myeloproliferative disorders, splenectomy
5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
5th World Symposium and 2015 ESC Guideline on PH :
Modified classification of PH
Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34-41ESC guideline 2015. EHJ 2015.
COPD: chronic obstructive pulmonary disease; CTEPH: chronic thromboembolic pulmonary hypertension; LHD: left heart disease; LV: left ventricular
VC RA RV PA PVPC
LA LV Ao
Post-Capillary PH (PCWP>15 mmHg; PVR nl)
Systemic HTNAoV Disease
Myocardial DiseaseDilated CMP-ischemic/non-isch.
Hypertrophic CMPRestrictive/infiltrative CMP
Obesity and others
Atrial MyxomaCor Triatriatum
PV compression
PVOD
PAHRespiratory
DiseasesPE
Pulmonary Hypertension: Define Lesion
MV Disease
LVEDP
Mixed PHPre-capillary
PH(PCWP<15 mmHg
PVR > 3 Wu) 23; 6 April 2014
Characteristic features of PH associated with LV diastolic dysfunction
Factors favouring diagnosis of LV diastolic dysfunction in the presence of PH as assessed by Doppler echocardiography
1. Clinical featuresAge > 65 yearsElevated systolic BPElevated pulse pressureObesity, metabolic syndromeHypertensionCoronary artery diseaseDiabetes mellitusAtrial fibrillation
2. EchocardiographyLA enlargementConcentric remodelling of the LV (relative wall thickness > 0.45)LV hypertrophyPresence of echocardiographic indicators of elevated LV filing pressure
3. Interim evaluation (after echocardiography)Symptomatic response to diureticsExaggerated increase in systolic BP with exerciseRe-evaluation of chest radiograph consistent with HF
Adapted from Galiè N, et al. Eur Heart J 2009; 30:2493-537.ESC guideline 2015. EHJ 2015
BP: blood pressure; HF: heart failure; LA: left atrium; LV: left ventricle/ventricular
5th World Symposium and 2015 ESC Guideline on PH: New proposed definition and classification of PH-LHD
Terminology PAWP Diastolic PAP – PAWP
Isolated post-capillary PH > 15 mmHg < 7 mmHg
Combined post-capillary and pre-capillary PH
> 15 mmHg ≥ 7 mmHg
2 types of PH-LHD have been proposed on the basis of the level of the diastolic pressure difference
The term “out-of-proportion” PH should be abandoned
LHD: left heart disease; PAP: pulmonary arterial pressure; PAWP: pulmonary artery wedge pressure
Vachiéry JL, et al. J Am Coll Cardiol 2013; 62:D100-8.ESC guideline 2015. EHJ 2015
Yes Yes
5th World Symposium and 2015 ESC Guideline on PH : Diagnosis of PH
Hoeper MM, et al. J Am Coll Cardiol 2013; 62:D42-50.ESC guideline 2015. EHJ 2015
Symptoms, signs, history suggestive of PH
Consider most common causes of PH (i.e, left heart disease, lung disease)
Echocardiography compatible with PH?
PH unlikely
History, signs, risk factors, ECG, X-ray, pulmonary function test incl. DLCO,
consider blood gas analysis, HR-CT
Consider other causes or recheck
Diagnosis of heart disease or lung disease confirmed?
No signs of severe PH/RV dysfunction
Signs of severe PH/RV dysfunction
V/Q scintigraphyUnmatched perfusion defects?
Treat underlying disease Refer to PH expert centre
CTEPH likelyCT angiography, RHC plus PA
(PEA expert centre)
RHCmPAP ≥ 25 mmHg, PAWP
≤ 15 mmHg, PVR > 3 Wood units
PAH likelySpecific diagnostic tests
Consider other causes
Yes No
No
Yes No
Yes No
CTEPH: chronic thromboembolic pulmonary hypertension; DLCO: carbon monoxide diffusing capacity; ECG: electrocardiogram; HR-CT: high resolution CT; mPAP: mean pulmonary arterial pressure; PA: pulmonary angiography; PAWP: pulmonary artery wedge pressure; PEA: pulmonary endarterectomy; PVR: pulmonary vascular resistance; RHC: right heart catheterisation; RV: right ventricular; V/Q: ventilation/perfusion
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CO = 4.52Qp:Qs = 1PVR = 902
55
4
6
5
HVPG = 17-7= 10 mmHg
CO = 4.52Qp:Qs = 1PVR = 902
55
4
6
5
Lab
• CBC: Hct 39 WBC 4800 (N59 L31) Plt 84000
• BUN/Cr 8/06
• Na 138 K 4 Cl 110 CO2 21
• LFT: Alb 4 Glob 2.3 TB/DB 1.78/1.39 AST/ALT 129/136 AP 374 GGT 252
• INR 1.2
• ANA neg AntiHIV neg
5th World Symposium and 2015 ESC Guideline on PH: Drug and Toxin-induced PAH
Hoeper MM, et al. J Am Coll Cardiol 2013; 62:D42-50.ESC guideline 2015. EHJ 2015
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Ultrasonography
• Liver: small size with nodular surface
• Small bowel at CBD
–post Kasai operation? (BA)
• No ascites
• Normal KUB
CirrhosisCirrhosis Cardiac cirrhosis ? Cardiac cirrhosis ?
Provisional Diagnosis
• Pulmonary hypertension (likely precap-PH)
• Cirrhosis (BA post Kasai operation OR Cardiac cirrhosis)
Pulmonary Hemodynamics Associated with Liver Disease
mPAP PVR CO PCWP
Hyperdynamiccirculatory state
Excess volume
Portopulmonaryhypertension
Final Diagnosis
HAPE in patient with POPH (?)
BA with cirrhosis s/p Kasai operation
Portopulmonary hypertension exacerbated by high altitude
Portopulmonary hypertension
• 6-9% of OLT candidate
• Neither severity of liver disease or degree of portal HT predict POPH
• Female gender, autoimmune hepatitis: independent risk factors
• Less severely impaired hemodynamics compared to IPAH (lower PVR, higher CO)
Fritz JS, et al. Am J Respir Crit Care Med 2013;187:133-43
Portopulmonary hypertension
• Diagnostic criteria
–Clinical portal hypertension
–mPAP > 25 mmHg
–PCWP < 15 mmHg (TPG > 12 mmHg)
–PVR > 240 dyn s cm-5
Roisin RR, et al. Eur Respir J 2004;24:861-80
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Survival from time of diagnostic RHC
Benza RL, et al. Chest 2012;142(2):448-56.
REVEAL study
Pavec JL, et al. Am J Respir Crit Care Med 2008;178:637-43
NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE
Pathogenesis of PAH
Dilated RV- Intact pericardium RAP
Intrapericardial pressure (IPP)
LV transmural filling pressure
LVEDP-IPP+
Shift of IV septum toward LV
LV preload and LV distensibility
Systemic Cardiac Output
Pulmpnary hypertension
Pressure overload
RV hypertrophyDec. wall stress
RV failureRV ischemiaTVRInc. wall stressPre&afterload mismatchDecrease LV compliance
Compensatory phaseNormal CO, RAP
Decompensatory phaseCO, RAP, PcWP
Hypoxia, AcidosisArrhythmias
Pathophysiology
43; 6 April 2014
RV anatomy: Normal versus PAH
Normal PAH
Chin KM, et al. Coron Artery Dis 2005; 16:13-8.
LV120 mmHg
RV LV PRV
Thickness
Stress
Coronary perfusion pressure + O2 demand = Supply/Demand
RV distension & LV filling = Cardiac output20 mmHg
LV: left ventricle/ventricular; RV: right ventricle/ventricular
Minai OA, et al. Cleveland Clincal J Med 2007;74:737-47
Asymptomatic compensated
Symptomatic decompensating
Advanced decompensated
Subtle Overt
S&S None SOB, Fatigue SOB, edema RVF, syncope, death
FC I II III IV
Hemodynamic trends
Pathologic appearance
CO
PAP PVR
RAP
PAH: Clinical course and progressionPAH: Clinical course and progression
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PAH is a malignant disease
0 1 2 3 4 5 6
Advanced lung cancer
WHO Class IV PAH
Advanced colorectal cancer
Advanced breast cancer
Advanced prostate cancer
WHO Class III PAH
Median survival (years) compared to advanced cancers
D’Alonzo GE, et al. Annals of Internal Medicine; 1991; 115(5): 343-9Kato I, et al. Cancer; 2001; 92: 2211-9
POPH: Management
• B-blocker and TIPS may be harmful
• Pulmonary vasodilators
– Prostacyclins
– Endothelin receptor antagonists
– Phosphodiesterase inhibitors
Fritz JS, et al. Am J Respir Crit Care Med 2013;187:133-43
Therapeutic Targets in Pulmonary Hypertension
Humbert M, et al. N Engl J Med 2004; 351:1425-36.
Mechanisms of action of prostacyclin
• Relax vss. smooth muscle
• Inhibit Platelet aggregation
• Inhibit vss. cell migration and proliferation
• Improve clearance of endothelin-1
• Reverse remodeling of pulmonary vascular changes
• Improve peripheral O2 use by skeletal M.
49; 6 April 2014
Epoprostenol I.V. (Flolan®)Subcutaneous Treprostinil (Remodulin®)
•SQ administration•Longer half-life than epoprostenol•Pre-mixed•Stable at room temperature
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Ventavis® (iloprost) Inhalation Solution: Dosage and Administration
Indicated for inhalation via • Indicated for inhalation via the Prodose® AAD® system only
• 2.5 mcg initial dose– increase to 5 mcg if 2.5 mcg
dose is tolerated
– maintain at maximum tolerable dose (2.5 mcg or 5 mcg)
• 6-9 inhalations daily during waking hours; 8-10 minutes each
Beraprost (Dorner® ; Procyclin®)
• First stable Prostacyclin Analog (oral)
• Approval for PPH and SPH (Japan+Korea)
• RCT (NYHA II +III, 3 mon (ALPHABET) (Galie, N. et al. JACC 2002)
– 6-min walk improvement : 25 m (only PPH)
– Dose limitation due to side effects (pain, nausea)
• RCT (1 yr, NYHA II), USA, 12 months, negative (Barst et al. JACC, 2003)
• Approved for PAH in Japan, Korea, Thai
Endothelin Signal Transduction
ET-1
Vasoconstriction Vasodilatation
NO, PGI1
Endothelial cellETB
ETBETA
& Proliferation
Recommended Laboratory Monitoring with Bosentan
Liver function testing
• Prior to initiation of treatment
• Monthly
Hemoglobin
• Prior to initiation of treatment
• After 1 month, then every 3 months
HCG
• Prior to initiation of treatment
• Monthly
ETA Specific Endothelin-Receptor-Antagonists
ETA Specific Endothelin-Receptor-Antagonists
• Sitaxsentan– Pilotstudie I, Barst et al; Chest 2002
• OL, 20 PAH-Patienten
– Pilotstudie II, Barst et al; AJRCCM 2003
• RPCT, 178 PAH-Patienten
– STRIDE-1,-2
– 100 mg/day, less hepatitis
– Drug interaction with coumadin
• Ambrisentan
– Pilotstudie Galie et al. JACC 2005
• RCT (multiple Dosen), 64 PAH-Patienten
– iPAH, HIV,CTD
– 5-10 mg/day
– ARIES-1, ARIES-2Olschewski et al. ERS 2005
Barst et al. 2004
56; 6 April 2014
cAMP
cGMP
5´-AMP
PDE 1 2 3 4 5
5´-GMP
PKG
PKA
Vasodilatation
Prostanoids
Olschewski H. et al. J Lab Clin Med, 2001
cGMP
PKG
cAMP
PKA
Vasodilatation
Sildenafil
PCI2
NOOlschewski H. et al. J Lab Clin Med, 2001
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RCTs in PAH approved: Oral drugs
Drugs Study Background Primary endpoint
2nd
endpointDuration No. of
subjects
Bosentan Study-351BREATHE-1Early
BREATHE-5
NoNoNoSildenafil (16%)No
6 MWD6 MWDPVR, 6 MWD
SaO2, PVR
TTCWTTCWTTCW
-
12 wks16 wks24 wks
12 wks
32213185
54
Ambrisentan ARIES-1ARIES-2
NoNo
6 MWD6 MWD
-TTCW
12 wks12 wks
202192
Sildenafil SUPER-1SastryPACES
NoNoEpoprostenol
6 MWDTTCW6 MWD
--TTCW
12 wks12 wks16 wks
27722264
Tadalafil PHIRST NoBosentan (54%)
6 MWD TTCW 16 wks 405
Beraprost ALPHABETBarst
NoNo
6 MWDCW
--
12 wks52 wks
130116
Channick RN, et al. Lancet 2001; Badesch D, et al. Curr Ther Res 2002; Rubin LJ, et al. N Engl J Med 2002; Galiè N, et al. Circulation 2006; Galiè N, et al. Lancet 2008; Galiè N, et al. Circulation 2008; Oudiz R, et al. Chest 2006; Oudiz RJ, et al. J Am Coll Cardiol 2009; Galiè N, et al.
N Engl J Med 2005; Simonneau G, et al. Ann Intern Med 2008; Galiè N, et al. Circulation 2009.
RCTs in PAH approved: Oral+Non-oral drugs
Drugs Study Background Primary endpoint
2nd
endpointDuration No. of
subjects
Epoprostenol RubinBarstBadesch
NoNoNo
6 MWD6 MWD6 MWD
-Survival-
12 wks12 wks12 wks
2381111
Treprostinil SC SimonneauInh TRIUMPH
PO Freedoom MPO Freedoom C1
PO Freedoom C1
NoBosentan/SildenafilNoBosentanand/orSildenafilBosentanand/orSildenafil
6 MWD6 MWD
6 MWD6 MWD (-)
6 MWD (-)
--
--
-
12 wks12 wks
16 wks16 wks
16 wks
470235
185354
310
Iloprost AIRSTEPCOMBI
NoBosentanBosentan
6 MWD&FC6 MWD 6 MWD (-)
12 wks12 wks12 wks
2036740
Rubin LJ, et al. Ann Intern Med 1990; Barst RJ, et al. N Engl J Med 1996; Badesch DB, et al. Ann Intern Med 2000;Simonneau G, et al. Am J Respir Crit Care Med 2002; McLaughlin VV, et al. J Am Coll Cardiol 2010; Olschewski H, et al. N Engl J Med 2002;
McLaughlin VV, et al. Am J Respir Crit Care Med 2006.
Oral drugs Recent RCTs in PAH approved: Oral drugs
Drugs Study Background Primary endpoint
2nd
endpointDuration No. of
subjects
Macitentan SERAPHIN NoPDEVI or Inhiloprost
TTCW Safety 100 wks 742
Riociguat PATENT NoBosentan or Prostanoid
6 MWD TTCW 12 wks 462
Pulido T, et al. N Engl J Med 2013;369:809-18; Ghofani HA, et al. N Engl J Med 2013;369:330-40; Ghofani HA, et al. Am J Respir Crit Care Med. 2010 Nov 1;182(9):1171-7;
Hoeper MM , et al. Circulation 2013 Mar 12;127(10):1128-38. 60; 6 April 2014
Approval of PAH therapies
Bosentan(Tracleer) 2001 – US2002 – Europe
Epoprostenoli.v.(Flolan)1995 – US
2001 – Europe
Treprostinil i.v. or s.c. (Remodulin)2002 – US2005 – Europe
Iloprost inhaled (Ventavis)2004 – US2003 – Europe
Iloprost i.v.(Ilomedin) only approved in New Zealand
2010 201520051995 2000
Sildenafil(Revatio) 2005
Beraprost(Careload†) 2007
Ambrisentan (Letairis –US; Volibris – EU/Canada)2007 – US 2008 – Europe
Epoprostenol i.v.(Veletri – US and Europe; Caripul – Canada and Italy; Epoprostenol ACT – Japan)2012 – US, Switzerland* & Canada2013 – Japan
2009Treprostinilinhaled† (Tyvaso)
Tadalafil (Adcirca)
2013Macitentan†
(Opsumit)
Treprostiniloral† (Orenitram)US
Riociguat†
(Adempas)
*Approval in other European countries is ongoing†Approval of these therapies varies by country, and thus might not be approved in the indications mentioned in your country. Please refer to your local full SmPC before prescribing
61; 6 April 2014
Initial Use of Ambrisentan plus Tadalafilin Pulmonary Arterial Hypertension
Galiè N, et al. N Engl J Med 2015;373:834-44.
Supervised exercise training (IIa-B)Psycho-social support (I-C)Avoid strenuous physical activity (III-C)Avoid pregnancy (I-C)Influenza and pneumococcal immunisation (I-C)
General measures and supportive therapy
Oral anticoagulants:• IPAH, heritable PAH and PAH due to anorexigens (IIb-C)
•APAH (IIb-C)Diuretics (I-C)Oxygen (I-C)Digoxin (IIb-C)Expert referral (I-C)
Acute vasoreactivity test(I-C for IPAH, HPAH, DPAH)
(IIb-C for APAH)
Initial therapy with PAH-approved drugs
Non-vasoreactiveFC I-III
CCB (I-C)Sustained response
(FC I-II)
Continue CCB No
Vasoreactive
Yes
5th World Symposium and 2015 ESC Guideline on PH: Evidence-based treatment algorithm
General measures and supportive therapy
Galiè N, et al. J Am Coll Cardiol 2013; 62:D60-72.ESC guideline 2015. EHJ 2015.
APAH: associated PAH; CCB: calcium channel blockers; FC: functional class; IPAH: idiopathic PAH
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Mean PAP reached during acute vasodilator testing
0
10
20
30
40
50
60
70
80
90
Baseline Acutetesting
Baseline Acutetesting
mPA
P(m
mH
g)
Long-term CCB responders
Long-term CCB failure
33 / 38 long-term CCB responders had a mPAP < 40 mmHg with
normal or elevated CO during acute testing
O. Sitbon et al. Circulation 2005
Acute Responders: By diagnosis
13.5%
11.8%
10.1%
12.2%
1.6%
1.3%
0 5 10 15 20 25
Idiopathic PAH
Anorexigens-PAH
CTD-PAH
PVOD / PCH
HIV-PAH
Po-PH
Familial PAH and CHD-PAH: 0 %
(%)
O. Sitbon et al. Circulation 2005
6.8% long term responders
<1% long term responders
5th World Symposium and 2015 ESC Guideline on PH: Evidence-based treatment algorithm
Initial therapy with PAH approved drugsRecommendation(Evidence*)
FC II FC III FC IV
I (A or B) Ambrisentan BosentanMacitentanRiociguat†
Sildenafil
TadalafilSelexipagInitial combination therapy (Amb+Tad)
Ambrisentan, Bosentan,Epoprostenol i.v. ,Iloprost inhaled, Macitentan
Riociguat†, Sildenafil,Tadalafil,Treprostinil s.c., inhaled†
Selexipag, Initial combination therapy (amb+Tad)
Epoprostenol i.v.
IIa (C) Initial combination therapy (ERA+PDE5i)
Iloprost i.v.†
Treprostinil i.v.Initial combination therapy (ERA+PDE5i)
Initial combination therapy (+EpoIV)
IIb (B) Vadenafil Vadenafil, Treprostinil oralBeraprost†
IIb (C) Ambrisentan, Bosentan,Iloprost inhaled and i.v.†
Macitentan, Riociguat†, Sildenafil, Tadalafil, VadenafilTreprostinil s.c., i.v., inhInitial combination therapy (oral)
Inadequate clinical response
Sequential combination therapy (I-B to IIb-C)
ERAs
ProstanoidsPDE-5i
or sGCS
+
+
Initial therapy with PAH approved drugs
+
Referral forLUNG TRANSPLANTATION
(I-C; FCIII-IV)
Consider eligibility forlung transplantation
BAS (IIb-C; FCIII-IV)
Inadequate clinical response on
maximal therapy
BAS: balloon atrial septostomy; ERA: endothelin receptor antagonist; PDE-5i: phosphodiesterase-5 inhibitor; sGCS: soluble guanylate cyclase stimulator
5th World Symposium and 2015 ESC Guideline on PH: Evidence-based treatment algorithm
Combination therapy and interventional procedures
Galiè N, et al. J Am Coll Cardiol 2013; 62:D60-72.ESC guideline 2015. EHJ 2015
67; 6 April 2014
5th World Symposium and 2015 ESC Guideline on PH:
Goals of Therapy
• I or II, no syncopeFunctional Class
• Normalization of RV function (RAP < 8, CI > 2.5, SVO2>65%)Hemodynamics
• RA area<18 cm2, no pericardial effusionECHO/MRI
• BNP<50, NT-pro BNP<300 ng/l BNP level
• >440 m, may not be aggressive enough (young)6-minute walk
• Peak VO2 > 15 and VE/VCO2slope< 36CPET
McLaughlin VV, et al. J Am Coll Cardiol 2013; 62:D73-81.ESC guideline 2015. EHJ 2015
68; 6 April 2014
Heart Rate Recovery Predicts Clinical Worsening in Patients with PAH?
• 75 patients
• HRR 1 defined as the difference in HR at the end of 6MW
and at 1 minute after completion
– HRR≤16 more likely to show clinical worsening
– Report HRR<16 and mPAP as the best predictors via multivariate
analysis
– Compared with 6MWD, HRR1 < 16 a better predictor of CW and
TCW
– The addition of HRR1 to 6 MWD increases the capacity of 6MWD
to predict clinical worsening and TCW in patients with PAHMinai OA et al. AJRCCM 2012;185:400
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69; 6 April 2014
Atrial septostomy as a bridge to transplant
• Creation of inter-atrial right-to-left shunt can:– Decompress right heart chambers
– Increase left ventricle pre-load
– Increase cardiac output
• A pre-procedural risk assessment reduces mortality
• Atrial septostomy should be avoided in end-stage patients with:– Baseline mean right atrial pressure > 20 mmHg
– O2 saturation at rest of < 85% on room air
Galiè N, et al. J Am Coll Cardiol 2013; 62:D60-72. 70; 6 April 2014
Survival rates for lung transplant recipients have improved significantly
ISHLT registry data showing adult lung transplant recipients Kaplan-Meier survival by era (transplants January 1988-June 2011)
0
20
40
60
80
100
Surv
ival
(%)
Years0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
1988-1995 (n = 5953; number at risk = 518)
1996-2003 (n = 12654; number at risk = 169)
2004-6/2011 (n = 21256; number at risk = 924)
All pairwise comparisons were significant at p < 0.001
ISHLT: International Society for Heart and Lung Transplantation
Yusen RD, et al. J Heart Lung Transplant 2013; 32: 965-78.
Long-term outcomes are improved in the modern treatment era
1. Humbert M, et al. Eur Respir J 2010; 36:549–555.2. Benza RL, et al. Chest 2012;142(2):448-56.
100
80
60
40
00 1 2 3 4 5 6 7
Surv
ival
(%
)
Time from diagnosis (years)
No. at risk: 279 377 390 388 328 240 153 88
90.5 ± 2.2
74.5 ± 2.5
64.5 ± 2.558.9 ± 2.7
68.2
46.9
35.6 32.0
**
*
20 *REVEAL unweighted NIH cohort 2
Predicted survival by NIH equation 2
French Registry1
Ghofrani HA, et al. AJRCCM 2010;182:1171-7
Recent RCTs in PAH drug
Drugs Study Background Primary endpoint
2nd
endpointDuration No. of
subjects
Imatinib PHASE 2
IMPRES
Bosentanand/or Sildenafil and/or ProstanoidBosentanand/or Sildenafil and/or Prostanoid
6 MWD (-)
6 MWD
-
TTCW (-)
24 wks
24 wks
59
202
Pulido T, et al. N Engl J Med 2013;369:809-18; Ghofani HA, et al. N Engl J Med 2013;369:330-40; Ghofani HA, et al. Am J Respir Crit Care Med. 2010 Nov 1;182(9):1171-7;
Hoeper MM , et al. Circulation 2013 Mar 12;127(10):1128-38.
Current and Emerging Rx for PAH
O’Callaghan D, et al. Nat Rev Cardiol 2011;8:526–38.
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Anti-TNF alpha Prevents Pulmonary Vascular Remodeling in CIH-PH Rat Model
Jaimchariyatam N, et al, 2014 76; 6 April 2014
Potential Targets for PAH treatment
PDGF ET-1 NO PCI2
ACE2/Ang(1-7)/Mas Beta adrenergic SphK1/S1PLeptin TNF-alpha/NF-kB
Medications N Comments
Endothelin receptor antagonists
Hoeper, et al (bosentan) 18 1-and3-year survivals 94% and 89%, respectively
Cartin-Cebaetal (ambrisentan) 13 At 1 y, MPAP and PVR improved in 8/8; PVR normalized in 5
Savale, et al. (bosentan) 34 At 5 mo 31% reduction in PVR, 39% increase in CI
Phosphodiesterase inhibitors
Reichenberger, et al (sildena l) 12 Improvement at 3 mo; not sustained at 1y
Goughand White (sildena l) 11 PVR decreased in all at rst RHC follow-up
Hemmesand Robbins (sildena l) 10 At 1-year MPAP and PVR decreased in 3/5 patients
Prostacyclins
Kuo, et al (IV epoprostenol) 4 MPAP and PVR improved
Krowka, et al (IV epoprostenol) 15 MPAP and PVR improved
Ashfaq, et al (IV epoprostenol) 16 Successful LT in 11 patients; 5-year survival 67%
Fix, et al (IV epoprostenol) 19 PVR improved in 14/14; MPAP improved in 11/14
Sussman, et al (IV epoprostenol) 8 MPAP and PVR improved in 6/7
Sakai, et al (IV treprostinil) 3 Successful LT in two patients (moderate POPH)
Hoeper, et al (inhaled iloprost) 13 1-and 3-year survivals 77% and 46%, respectively
Melgosa, et al (inhaled iloprost) 21 Acute, but no long-term hemodynamic improvement
Case 1
• 6MWT– 6MWD 520 m, O2 sat 92%->88%
– Borg 4->6 – BP 133/72 -> 115/82
• ได้รับการรักษาด้วย Sildenafil 20 mg tid, Beraprost 60 mcg/d
• สง่ปรึกษา GI เพื�อประเมิน
–ภาวะ biliary cirrhosis ?
– Liver transplantation
3 months later
• 6MWT
– 6MWD 620 m, O2 sat 98%->96%
– Borg 2->4
– BP 123/72 -> 149/82
• Note form GI: “Can liver transplantation be done safely in this patient?”
POPH and Liver Transplantation
Stage mPAP(mmHg)
Operative mortality
Mild 25-34 0
Moderate 35-44 50
Severe ≥45 100
Rodriguez-Roisin, et al.Eur Respir J 2004;24:861–80.Krowka MJ, et al. Liver Transpl 2000;6:443–50.
Delcroix M. Eur Respir Mon 2006;34:129–38.
04/03/60
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POPHPOPH
mPAP <35mPAP <35 mPAP 35-50mPAP 35-50 mPAP > 50mPAP > 50
Proceed to liver Tx
PVR≤250PVR≤250 PVR>250PVR>250
Proceed to liver Tx
Response to PAH Rx
No response To PAH Rx
Noliver Tx
Porres-Aguilar M, et al. Eur Respir Rev 2012;21:223-33
2nd Echocardiography
• Normal LV size (1st: D-shape), LVEF 85%, LA 28 mm, Mitral e/e’ 12
• Dilated RV (44 mm), PA (30 mm), TAPSE 24 mm (1st: 15)
• TRV 3.9, est RA 10, RVSP 70.84 (1st: 89)
• No intracardiac shunt
Case 1
• She was scheduled for RHC
• She refused to undergo OLT and thus, RHC was cancelled.
• 1 y later: significant improvement (FCI, 6MWD 650 m)
–Discontinued beraprost
Case 2
• ผู้ป่วยชายไทยอายุ 59 ปี รบัราชการ
• มานอนโรงพยาบาลด้วยอาการเหนื�อยง่ายมากขึ�น 6 เดือนก่อนมาโรงพยาบาล เป็นมากขณะออกกาํลงั (FCIII) ครั �งนี� เหนื�อยมากขึ�นแม้ขณะพกัในช่วงสองสามสปัดาห์
• ประวติัอดีตเป็นถงุลมโป่งพอง มา 3 ปี เคยนอนโรงพยาบาลด้วย COPD acute exacerbation เมื�อ 3 ปีก่อนหลงัจากนั�นไม่ได้มานอนโรงพยาบาลอีก
• สูบบหุรี� 30 packs-year หยุดสูบมาสามปี
Case 2
• BT 36.7, HR 120 /min, RR 26/min, BP 120/85 mmHg
• O2 saturation 88% on room air
• Auscultation revealed a grade III systolic murmur along LLPSB with an accentuated P2
• Prolonged expiration without any wheezes or rhonchi was noted
• Mild liver enlargement and mild pitting edema noted
04/03/60
15
Estimated RAP = 10 mmHg
• Echocardiogram:
– LA and LV are normal, LAVI 20, e/e’ 9
– LVEF 55%
– RA and RV are markedly dilated (RV 4.4 cm at mid part, RA 21.4 cm2, L=51 mm)
– Severely impaired RV systolic function (TAPSE =1.0 cm, lateral TDI = 7 cm/sec)
– Normal MV with mild MR
– TRV 4.7 m/s, estimated RAP 10 mmHg, RVSP 98.4
Investigation to confirm diagnosis
• No step-up oxygen saturation
• Mean PAP = 74 mmHg
• PAWP = 10 mmHg
• Mean RAP = 16 mmHg
• CO = 3.92 L/min (thermodilution), CI = 1.97
• Not respond to vasodilator agent (inhaled Iloprost)
Right cardiac catheterization
• FVC 2.56 L (64.9% of predicted value)
• FEV1 1.56 L (68.98% of predicted value)
• FEV1/FVC ratio 61%
• Residual volume 2.81 L (171.3% of predicted value)
• Carbonmonoxide diffusion capacity (DLCO) 31.0% of predicted value
Pulmonary Function Test
92; 6 April 2014
PH in chronic lung disease
04/03/60
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93; 6 April 2014
PH in chronic lung disease: Differential diagnosis between groups 1 and 3
Seeger W, et al. J Am Coll Cardiol 2013; 62:D109-16.ESC guideline 2015. EHJ 2015
Criteria favouring group 1 (PAH) Parameter Criteria favouring group 3 (PH due to lung disease)
Normal or mildly impairment:• FEV1 > 60% predicted (COPD)• FVC > 70% predicted (IPF)
Ventilatory function
Moderate to very severe impairment:• FEV1 < 60% predicted (COPD)• FVC < 70% predicted (IPF)
Absence of or only modest airway or parenchymal abnormalities
High-resolution CT
scan
Characteristic airway and/or parenchymal abnormalities
Features of exhausted circulatory reserve:• Preserved breathing reserve• Reduced oxygen pulse• Low CO/VO2 slope• Mixed venous oxygen saturation at lower
limit• No change or decrease in PaCO2 during
exercise
Features of exhausted ventilator reserve:• Reduced breathing reserve• Normal oxygen pulse• Normal CO/VO2 slope • Mixed venous oxygen saturation above
lower limit• Increase in PaCO2 during exercise
CO: cardiac output; COPD: chronic obstructive pulmonary disease; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity;IPF: idiopathic pulmonary fibrosis; PaCO2: partial pressure ofcarbon dioxide in arterial blood; VO2: oxygen consumption 94; 6 April 2014
Management of PH in chronic lung disease setting
Underlying lungdisease
mPAP < 25 mmHg at rest
mPAP ≥ 25 mmHg and < 35 mmHg at rest
mPAP ≥ 35 mmHg at rest
COPD with FEV1 ≥ 60% of predicted
IPF with FVC ≥ 70% of predicted
CT: absence of or only very modest airway or parenchymal abnormalities
No PH
No PAH treatment recommended
PH classification uncertain
No data currently support treatment with PAH-approved drugs
PH classification uncertain: discrimination between PAH (group 1) with concomitant lung disease or PH caused by lung disease (group 3)
Refer to a centre with expertise in both PH and chronic lung disease
COPD with FEV1 < 60% of predicted
IPF with FVC < 70% of predicted
Combined pulmonary fibrosis and emphysema on CT
No PH
No PAH treatment recommended
PH-COPD, PH-IPF, PH-CPFE
No data currently support treatment with PAH-approved drugs
Severe PH-COPD, severe PH-IPF, severe PH-CPFE
Refer to a centre with expertise in both PH and chronic lung disease for individualised patient care because of poor prognosis; RCTs required
Seeger W, et al. J Am Coll Cardiol 2013; 62:D109-16.ESC guideline 2015. EHJ 2015
• The elevated PAPs do not correlate with the severity of COPD
• Mean PAP > 40 mmHg (severe PH with mPAP > 40 mmHg occurs in only 0.8% to 3.7% of COPD patients)
• More severe hypoxemia, and hypocapnia
• Very low DLCO (not explained by severity of COPD)
Disproportionate PH in COPD
Minai OA, et al. Chest 2010;137:39S-51SChaouat A, et al. Am J Respir Crit Care Med 2005;172:189-194,2005
Stevens D, et al. Ann Transplant 2000;5:8-12
• Disproportionate pulmonary hypertension in COPD, likely due to pulmonary arterial hypertension
–COPD plus
–IPAH
Final Diagnosis
Hypoxic VasoconstrictionHypoxic pulmonary vasoconstriction
PAO2 decrease
Improve V/Q matching
Increase BF to ventilated alveoli
Sildenafil
Hypoxic VasoconstrictionHypoxic pulmonary vasoconstriction
PAO2 decrease
Decrease BF to ventilated alveoli
Sildenafil
Increase BF to Non-ventilated alveoli
04/03/60
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Inhaled Iloprost
100;6 April 2014
PAH and congenital heart disease
• A 22 y/o male suspected PH, FC III
• Echocardiogram:
– ASD secundum (1.5 x 1.5 cm) with bi-directional
shunt
– TR, RVSP 55 mmHg
• RHC and LHC
– mPAP 58 mmHg, PCWP 5 mmHg, PVR 11 WUs
– CI 3.2, SVR 13 WUs
– No vasodilator response
Case 35th World Symposium & 2015 ESC Guideline on PH :
Updated clinical classification of PAH-CHD
Clinical classification of PAH-CHD
Eisenmenger syndromeIncludes large intra- and extra-cardiac defects which begin as systemic-to-pulmonary shunts and progress with time to severe elevation of PVR and reversal (pulmonary-to-systemic) or bidirectional shunting; cyanosis, secondary erythrocytosis and multiple organ involvement are usually present
Left-to-right shunts• Correctable*• NoncorrectableIncludes moderate to large defects; PVR is mildly to moderately increased; systemic-to-pulmonary shunting is still prevalent, whereas cyanosis is not a feature
PAH with coincidental CHDMarked elevation in PVR in the presence of small cardiac defects, which themselves do not account for development of elevated PVR; clinical picture very similar to IPAH. Defect closure is contra-indicated
Post-operative PAHCHD is repaired but PAH either persists immediately after surgery or recurs/develops months or years after surgery in the absence of significant post-operative haemodynamic lesions. The clinical phenotype is often aggressive
Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34-41.ESC guideline 2015. EHJ 2015
*Correctable with surgery or intravascular non-surgical procedureCHD: congenital heart disease; IPAH: idiopathic PAH; PVR: pulmonary vascular resistance
QP:QS > 1.5:1, PVR < 8
PVR < 6-8 WU, resting O2 desaturation
Acute vasoreactivity test in CHD-PH
• Severe PAH with high PVR
• Predictor of candidacy for successful systemic-to-pulmonary shunt closure
Positive response Agent Recommendation
PVR reduce to < 6-8 WU any 1, ++
PVR:SVR reduce to < 0.42 O2 1, ++
PVR:SVR reduce to < 0.3 iNO or Iloprost
1, ++
PVR:SVR reduce to < 0.27 iNO+O2 1, ++
Thai PH Guideline 2013104;6 April 2014
Treatment of PAH-CHD
ESC guideline 2015. EHJ 2015
04/03/60
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105;6 April 2014
RV adaptation in IPAH versus PAH-CHD
• Compared with IPAH, Eisenmenger’s syndrome patients have higher CI and lower mRAP (despite having a higher mPAP)1
1. Chin KM, et al. Coron Artery Dis 2005; 16:13-8.2. Bristow MR, et al. Chest 1998; 114:S101-6.
Elevated mPAP
PAH-CHDRV adaptation = Better prognosis
Compensation2:• Increased RV wall thickness• Mild RV dilation
IPAHRV inability to adapt = Worse prognosis
Decompensation2:• RV dilation• RV failure
CHD: congenital heart disease; CI: cardiac index; IPAH: idiopathic PAH; mPAP: mean pulmonary arterial pressure; mRAP: mean right atrial pressure; RV: right ventricle/ventricular
106;6 April 2014 Manes A, et al. Eur Heart J 2013; Epub ahead of print.
Survival rates of clinical subgroups of PAH-CHD
Survival rates in a predominantly adult population (n = 192) over a 20-year period
CD: cardiac defect correction; CHD: congenital heart disease; ES: Eisenmenger syndrome; SD: small defects; SP: systemic-to-pulmonary shunts
0.00
Follow-up (years)
Surv
ival
5 10 15 20
0.2
0.4
1.0
0.8
0.6
ES
PAH-SP
PAH-SD
PAH-CD
Log-rankp < 0.0001
ES 90 71 59 52 48PAH-SP 48 22 18 11 10PH-SD 10 4 4 2 0PAH-CD 44 22 12 4 3
Patients at risk:
ES
PAH-SP
PAH-SD
PAH-CD
107;6 April 2014
Treatment of PAH-CHD
ESC guideline 2015. EHJ 2015 108;6 April 2014
New insights into CTEPH management
109;6 April 2014Piazza G, et al. N Engl J Med 2011;364:351-60.
110;6 April 2014
Pulmonary Endarterectomy
04/03/60
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111;6 April 2014
CTEPH registry: Survival is significantly improved following PEA
Operated Non-operated
PVR (dsc-5) 728 (97 - 2880) 676 (165 - 2800)
Simonneau G, et al. Am J Respir Crit Care Med 2013; 187:A5365.
88%79%
70%
93% 91% 89% Operated n = 404
Non-operated n = 275
1.00
0.80
0.60
0.40
0.20
0.00
Cu
mu
lati
ve s
urv
ival
0 6 12 18 24 30 36 42 48 54 60 66
Months from diagnosis
p ≤ 0.0001
Patients at risk at the end of the time period:404 382 374 366 361 355 336 244 158 62 3 0275 246 228 214 200 188 164 120 58 20 2 0
CTEPH: chronic thromboembolic pulmonary hypertension; PEA: pulmonary endarterectomy; PVR: pulmonary vascular resistance
112;6 April 2014
CTEPH: The potential role of medical therapy
When is medical therapy for CTEPH appropriate?
Patients with predominantly distal disease that is not
surgically accessible1
PEA contraindicated due to prognostically significant
comorbidity1
Patients with persistent or residual
PH post-PEA1,2
Patients who are ‘high-risk’ due to extremely poor
haemodynamics prior to PEA1
1. Hoeper MM, et al. J Am Coll Cardiol 2009; 54:S85-96.2. Kim NH, et al. J Am Coll Cardiol 2013; 62:D92-9.
? ?
CTEPH: chronic thromboembolic pulmonary hypertension; PEA: pulmonary endarterectomy
113;6 April 2014
Short term RCTs of medical therapy in CTEPH have shown varying degrees of efficacy
Kim NH, et al. J Am Coll Cardiol 2013; 62:D92-9.
Drug First author, year Studydesign
Duration n NYHAFC
6MWD* Effect PVR# Effect
Epoprostenol (i.v.) Cabrol, 2007 - 3 months 23 III-IV 280 ± 112 66 (T) 29 ± 7† -21%
Treprostinil (s.c.) Skoro-Sajer, 2007 - 6 months 25 III-IV 260 ± 111 59 924 ± 347 -13%
Iloprost (inh) Olschewski, 2002 RCT 3 months 57 III-IV NA NS NA NS
Sildenafil (PO) Ghofrani, 2003 - 6 months 12 NA 312 ± 30 54 1935 ± 228 -30%
Sildenafil (PO) Reichenberger, 2007 - 3 months 104 II-IV 310 ± 11 51 863 ± 38 -12%
Sildenafil (PO) Suntharalingam, 2008 RCT 3 months 19 II-III 339 ± 58 18 (NS) 734 ± 363 -27%
Bosentan (PO) Hoeper, 2005 - 3 months 19 II-IV 340 ± 102 73 914 ± 329 -33%
Bosentan (PO) Hughes, 2005 - 3 months 20 II-IV 262 ± 106 45 (T) 1165 ± 392 -21%
Bosentan (PO) Bonderman, 2005 - 6 months 16 II-IV 299 ± 131 92 712 ± 213 NA
Bosentan (PO) Seyfarth, 2007 - 6 months 12 III 319 ± 85 72 1008 ± 428 NA
Bosentan (PO) Jais, 2008 RCT 4 months 157 II-IV 342 ± 84 2 (NS) 783 (703-861) -24%
Riociguat (PO) Ghofrani, 2010 - 3 months 41 II-III 390 (330-441) 55 691 (533-844) -29%
Riociguat (PO) Ghofrani, 2013 RCT 4 months 261 II-IV 347 ± 80 46 787 ± 422 -31%
*Mean ± SD or median (interquartile range) in meters#PVR dyn·s/cm5 in †Woods unit, dyn·s/cm5/m2
6MWD: 6-minute walk distance; CTEPH: chronic thromboembolic pulmonary hypertension; NYHA FC: New York Heart Association functional class; RCT: randomised controlled trial; PO: per os; PVR: pulmonary vascular resistance
114;6 April 2014
Pulmonary endarterectomy
5th World Symposium & 2015 ESC Guideline on PH:CTEPH treatment algorithm
Kim NH, et al. J Am Coll Cardiol 2013; 62:D92-9.ESC guideline 2015. EHJ 2015
CTEPH diagnosisContinue lifelong anticoagulation
Operability assessment by CTEPH team
Operable Non-operableNon-operable
Targeted medical therapy
Persistent symptomatic PH
Referral for lung
transplantation
Percutaneoustransluminal pulmonary
angioplasty?
Operable
CTEPH: chronic thromboembolic pulmonary hypertension
Persistent symptomatic PH