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

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)

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

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

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.

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

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.

Medical therapy

• Anticoagulants• Diuretics• Dijitalis• Calcium canal blockers

• Life-long anticoagulation

Hoeper MM,Mayer E, simonneau G, Rubin L. Circulation 2006;113:2011-2020.

Targets of therapy

Control of

disease

Symptomatic benefit

Improvement

in QOLIncrease in

lifetime

Slide courtesy of Marius Hoeper

Medical therapy

IPAH / CTEPH !

• Prostacyclin analog ( epoprostenol, iloprost )

• Endotelin receptor antagonist ( bosentan )

• Phosphodiesterase-5 inhibitör ( Sildenafil )

Updated ACCP Guidelines Chest 2007;131:1917-28

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 ?

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!

Medical therapy : Evidence to date

Data from clinical trials :

• Limited• Based on preliminary trial findings

Randomized , controlled trials !

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

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

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

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.

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

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.

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

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

CHANGE OF HAEMODYNAMYIC VARIABLES

Kaplan-Meier survival estimates

25 inoperabl CTEPH

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.

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.

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

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

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)

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

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

Combination therapy

• 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 ?

• 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 ?

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.

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 !!

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.

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

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

Limitations on current data

Majority of data :

* Small , uncontrolled * Retrospective evaluations

* Unpublished clinical experience

* Primarly assessing PAH ( CPETH ? )

* Heterogeneous populations* Variable periods of time

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