MEDICAL THERAPY
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Transcript of MEDICAL THERAPY
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MEDICAL THERAPY
Prof. Dr. Orhan Arseven
Istanbul University Istanbul Medical Faculty
Department of Pulmonary Disease
Diagnostic and treatment approaches to PAH due to recurrent pulmonary thromboembolism
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Symptomatic CTEPH may affect 3.6% of patients within 2 yr after a first episode of symptomatic PE Pengo V,Lensing AW,et al.N.Engl.J Med 2004;350:2257-64
% 0.1-0.5 ! Tapson VF,et al.Proc Am Thorac Soc 2006;3(7):564-7. Auger VR,et al. Clin Chest Med. 2007 Mar;28(1):255-69
Progressif pulmonary vascular remodelling
Generalized hypertensive pulmonary arteriopathy
Dartevelle P, Fadel E, et al. N. Engl J Med;2001;345:1465-72
Chronic thromboembolic pulmonaryHypertension(CTEPH)
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Time / Severity
PAP
PVR
Cardiacoutput
Pre-clinic Symptom stable
Thereshold of Symptom
RV disfunction
Progressive deterioration
Progression of pulmonary hypertension
Exercise
Rest
Lev
el
>3 Mo - < 2 years
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CTEPH…….Prognosis
5 Years survey :
PAB > 40mmHg……………. %30 PAB > 50mmHg……………. % 10
• Related with right ventricular disfunction
Riedel M, et al.Chest 1982;81:151-158Lewzcuk J,Pizko P,et al.Chest 2001;119:818-21
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Pulmonary endarterectomy (PEA)
• Effective and often curative in patients with severe CTEPH
But : ~ 50 % Inoperabl
• Poor candidacy for PEA surgery (PH due to concomitant small-vessel arteriopathy )
CTEPH therapy
Skoro-sajer N, et al. J Thromb Haem 2007;5:483-489.
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Medical therapy : When is appropriate ?
1. Where PEA is not suitable due to distal thromboembolic disease
2. “ Therapeutic bridge “ to PEA In high risk patient due to extremely poor hemodinamics
3. Persistant or residual PH after PEA
4. When surgery is contrindicated due to significant comorbidity
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2004 ACCP practice guideline on CTEPH
• Inoperabl CTEPH…… “ May be considered “
• Benefit small and weak
• Recommendation ……… C
Medical therapy :
Doyle RL,McCrory D, et al:Surgical treatments/interventions for pulmonary arteryHypertension. ACCP evidence-based clinical practice quidelines.Chest 2004;126;63S-71S.
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Medical therapy
• Anticoagulants• Diuretics• Dijitalis• Calcium canal blockers
• Life-long anticoagulation
Hoeper MM,Mayer E, simonneau G, Rubin L. Circulation 2006;113:2011-2020.
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Targets of therapy
Control of
disease
Symptomatic benefit
Improvement
in QOLIncrease in
lifetime
Slide courtesy of Marius Hoeper
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Medical therapy
IPAH / CTEPH !
• Prostacyclin analog ( epoprostenol, iloprost )
• Endotelin receptor antagonist ( bosentan )
• Phosphodiesterase-5 inhibitör ( Sildenafil )
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Updated ACCP Guidelines Chest 2007;131:1917-28
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Pre-PEA “ Bridging “ therapy
Therapeutic bridge between : CTEPH diagnosis and PEA
High risk patients :
• Class IV ( NYHA )
• mPAP > 50 mmHg• Cardiac index < 2.0 L.min /m2• PVR > 1.000 dyn.s.cm-5
What is the optimal medical therapy period ?
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Post-PEA therapy
Persistan PH after surgery 10-15 %
Auger WR, Kerr KM, et al. Cardiol Clin 2004;22:453-466
• Probably distal thromboembolic pathology !
• Postoperative PVR > 500 dynes.sec.cm-5
• There is no guide available!
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Medical therapy : Evidence to date
Data from clinical trials :
• Limited• Based on preliminary trial findings
Randomized , controlled trials !
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Prostacyclin analogs
• Oral Beraprost sodium
- Minimal survival benefit - Placebo controlled trial lacking - Is not approved for CTEPH
Nagaya N, et al. Hearth 2002;87:340-5 Ono F, et al. Chest 2003;123:1583-8 Ono F, et al. Circ J 2003;67:375-8
• I.V. Epoprostenol
• Aerosolized Iloprost …Randomized controlled
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I.V. Epoprostenol… Bridging treatment
6 wk before PEA n= 12 Severe CTEPH
• Significant improvements in PVR , cardiac output• But not mPAP• BNP marked decreased after treatment :
- İmproved right-heart function - excellent post-PEA outcome
İt is not clear whether this was as a result of preoperative epoprostenol treatment , a succesful surgical procedure or both ?
Nagaya N,et al. Chest 2003;123:338-343
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Use during the preoperative period :
• Unclear whether the potential benefits
outweight the risk of disease progression
during the delay to surgical interventions
I.V. Epoprostenol… Bridging treatment
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Aerosolized Iloprost
CTEPH, PAH
Failed to show significant benefical effect in the CTPEH :
n= 203 ( 101: inhaled iloprost……. 33 CTEPH)
12 weeks… 6MWD increased 58.8m in IPAH
12 m in CTEPH Olschewski H, et al. N Engl J Med2002;347:322-9.
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Aerosolized Iloprost …. AIR study
• Immediately before PEA ….. No significant effect on mPAP, PVR, CI
• Postoperative iloprost inhalation….. Benefical effect on PVR , mPAP
( Benefit of surgery ! )
- Reduce reperfusion injury, - improve early outcome after PEA
Kramm T,et al.Ann Trorac Surg 2003;76:711-718
Randomised controlled
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Treprostinil sodium
• IV. Epoprostenol….. Short half-life ( 1 to 2 minute )
• Continuous infusion…. Permanently inplanted IV catheter
• Catheter releated thrombosis, infections, sepsis,malfunctions
• Treprostinil sodium … Subcutaneous
• Comparable acute hemodynamic effects Vachieri JL, et al. Expert Rev Cardiovasc Ther 2004;2: 183-191
• Stable at room temparature and neutral pH
• Longer half life ( 3 to 6 h ) mean 4.6 h
Simonneau G, et al. Am J Respir Crit Care Med 2002; 15: 800-4.
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Treprostinil sodium
n= 99 PAH ( 23 = CTEPH ) NYHA class : II-IVFollowed up 26.2 + 17.2 months
NYHA class :
3.20+0.04 to 2.1+0.1 p=0.0001
6MWD:
305+11 to 445+12 p=0.0001
Survival 88.6 % at 1 year, 70.6 % at 3 year
Lang I, et al. Chest 2006;129:1636-43
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Treprostinil sodium - CTEPH
n= 25 inoperabl CTEPH
• WHO func. Class : III or IV• 6MWD < 380 m• At least one hospitalization for right heart decomp. within the prior 6 months
• Min. 12 Months (12-33 Mo.) treatment
• Control: Historical group of 31 patients at their centers with inoperabl CTEPH
Skoro-sajer N, et al. J Thromb Haem 2007;5:483-489
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CHANGE OF HAEMODYNAMYIC VARIABLES
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Kaplan-Meier survival estimates
25 inoperabl CTEPH
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Endothelin receptor antagonists
• Plasma concentrations of endothelin are increased in patients with CTEPH
• Pulmonary endothelin type B receptors are increased on vascular smooth muscles cells
• Endothelin mediated pulmonary vascular remodelling has been demostrated in a canine model of CTEPH
Bauer M, et al.Circulation 2002;105:1034-6Reesink HJ, et al.Eur Respir J 2004;24: 110s.
Kim H, et al.Eur Respir J 2000;15:640-48.
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KTEPH - Bosentan Ref Indication N Duration
of therapy Results
Bonderman et al.Chest 2005; 128: 25992603
CTEPH Notoperated
16 6 mo.
Hoeper MM et al.Chest 2005; 128: 23632367
CTEPH Notoperated
19 3 mo. PVR significantly 6-MWD “proBNP “
Hughes et al.Thorax 2005; 60: 707
CTEPH notOperated,Post-PEApersistant PH
15
5
≥3 mo. TPR, CI, PVR and 6-DYM
Significantly improved
Hughes et al.Eur Respir J 2006; 28: 138143
CTEPH notOperated,Post-PEAPersistant PH
47 1 year TPR, FK,CI ve 6-MWD
With long time … improvement
Seyfarth et al.Respiration 2006 May 11; [Epub ahead of print]
CTEPH notoperated
12 2 years In 6. Mo.(Tei Index and 6-MWD )Sign. İmprov. And this improvment not decreased for 24 Mo. NYHA class improved or not changed
NYHA Class improved : 70 %6MWD significantly improved ( p=0.01 )
proBNP signif.
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Endothelin receptor antagonists
Inoperabl CTEPH n= 16 6 mo. Bosentan therapy
• NYHA Class improved : 70 %
• 6MWD significantly improved (p=0.01 )
Bonderman D, et al. Chest 2005;128:2599-2603
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Prospective, multicenter, open-label trialn=193 mo. bosentan therapy …. Mixt CTEPH
PVR 914+329 to 611+ 220 dyn.s.cm-5 p<0.001
6 MWD 340+ 102 to 413+ 130 m p= 0.009
Significant improv. : ProBNP levels , mPAP, CO, CI, SVR
Hooper MM, et al. Chest 2005; 128:2363-67
Endothelin receptor antagonists
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Bosentan………BENEFIT study
n= 157Double-blind, placebo-controlled, multicenter study
Inoperable CTEPH , post-PEA Significant improvements :
• PVR ( p < 0.001 ), cardiac index (p=0.0007).
• Borg dyspnoea index (p=0.0386)
• Significant decrease in NT-proBNP (p = 0.0028), ( indicator of disease severity )
Lang I, et al. ESC Sept. 2007; FP 4505
No effect on exercise capacity (p = 0.5449)
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PDE-5 INHIBITION
SUPER-1 trial : Oral sildenafil, PAH Large, multicentric, double blind, placebo controlled
Sildenafil improved in 6MWD,mPAP and WHO functional class. Galie N, et al.N.Engl J Med 2005;353:2148-57.
n=12 CTEPH patients… Open label study …. 6 mo follow-up ……Sildenafil 50 mg tid
• 6 MWD increased from 312m to 366 m.
• Comparable with BREATHE-1 ( Bosentan) ( Rubin LJ, et al. N Engl J Med 2002;346:896-903 )
Ghofrani HA, et al. Am J Respir Crit care Dis 2003;167:1139-1141
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PDE-5 INHIBITION
CI ………2.0 to 2.4 L min-1m-2
CVP ……..11 to 4.8 mmHgmPAP……..52.6 to 44.9mmHg
Ghofrani HA, et al. Am J Respir Crit care Dis 2003;167:1139-1141
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Combination therapy
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• Generaly older than those with PAH
• Comorbidity ( COPD , cardiac diseases )
• Drug – drug interactions
- Bosentan… Mild CYP3A4-inducing effect Reduction in warfarin exposure…Hypocoagulability
Murphey LM, et al. Ann Pharmacother 2003;37: 1028-1031
- Sildenafil , Citaxsentane ……. Hypocoagulability ( warfarin )
Widlitz AC, et al. Exp Rev Cardiovasc Ther 2005;3: 985-991
CPETH - Combination therapy / safety ?
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• Sildenafil has inhibitory effect on hepatic CYP3A4
• Bosentan + Sildenafil :
•Bosentan decreases the plasma concentration of sildenafil
• But bosentan doesn’t decrease it’s efficiency
Interaction during combination therapy !
Paul GA, et al. Br J Clin Pharmacol 2005;60:107-112
CPETH - Combination therapy / safety ?
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Bosentan and sildenafil
Beginning 3.Mo
6-MWD (m)
500
400
300
200
100
BeforeSildenafil
’
3.Mo 6-12 Mo
346 ± 66
403 ± 80 392 ± 61 406 ± 53
Bosentan started
Sildenafiladded
277 ± 80
n = 9
Hoeper MM, et al. Eur Respir J 2004; 24:1007-10.
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Combination therapy
BREATHE-2………..Bosentan + Epoprostenol IPAH• Benefical effect Humbert M, et al. Eur Respir J 2004; 24: 353-359.
Hoeper MM, et al. Eur Respir J 2005;26: 868-863.
Goal- oriented therapy in PAH
Bosentan and/or iloprost and/or sildenafil…….Historical control group
* Survival benefits
CTEPH !!
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GOAL-ORIENTED THERAPY
• 6 MWD > 380 m
• VO2max >10.4 ml / min / kg
• Peak sist.blood pressure during exercise > 120 mm/Hg
Hoeper MM, et al. Eur Respir J 2005;26: 868-863.
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Combination therapy
n=16 CTEPH ……….. Inhal. Iloprost + Bosentan
• After 6 mo. * 6MWD increased significantly
* NYHA Class improvemet…. 9/16 patients
Seyfarth HJ, et al. Chest 2005;128: 709-13
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Therapy - 1 6MWDm.
Therapy - 2 6MWDm.
Therapy– 3 6MWD m
İnh ilopr 44 III
7 Mo.
3 Mo.+ 200 II4 Mo. - 60
BosentanIV
22 Mo.
+ 210III
Bosentan +
sildenafil
+ 10032 Mo.
0..ex
İnh ilopr39 + III
Sildenafil1 Mo.
-20IV
Bosentan+
Sildenafil4 Mo.
+ 40IV
18 Mo.
Ex
Bosentan56 IIIAdv. Eff. -stop
İnhale ilopro
Adv. Eff. -stop
+ 150 III 9. Mo.
İnh. ilopr64 IV
3 Mo.+ 150 II
4. Mo.
25 IVSildenafil + 110 PEA
EX Ex Post- op
10 days
48 IIISildenafil + inh
ilopr.
PEA ? 26. Mo.
51 IIIBosentan 11 Mo
+ 60 II İnh.iloprost 9 Mo
+ 40 III 20.Mo
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Limitations on current data
Majority of data :
* Small , uncontrolled * Retrospective evaluations
* Unpublished clinical experience
* Primarly assessing PAH ( CPETH ? )
* Heterogeneous populations* Variable periods of time
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Future trials….
• Prospective, • Randomized, • Controlled …………..clinical trials !
- Selection of patients………those with similar stage !- > One year duration ( Not 3-4 mo.)
- Long term mortality results- 6 MWD , other types of exercise testing / more complex- Assessment of vascular histopathology
Rich S. The current treatment of pulmonary arterial hypertension. Chest 2006; 130: 1198-1202
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