Chronic thromboembolic pulmonary hypertension

1. An overview of
Chronic Thromboembolic
Pulmonary Hypertension
(CTEPH)
Sarfraz Saleemi MRCP FCCP
Section of pulmonary medicine
Department of medicine
King Faisal Specialist Hospital & Research Center
Riyadh, Saudi Arabia

2. WHO Classification- Dana Point 2008
Group 1: Pulmonary Arterial Hypertension
Group 2: Pulmonary Hypertension Owing to
Left Heart Disease
Group 3: Pulmonary Hypertension Owing to
Lung Diseases and/or Hypoxia
Group 4: Chronic Thromboembolic Pulmonary
Hypertension (CTEPH)
Group 5: Pulmonary Hypertension With
Unclear or Multifactorial Etiologies

3. The Association for Research in CTEPH is based in Basel,
Switzerland and can be contacted as follows:
Association for Research in CTEPH
c/o artax Fide Consult AG
Gartenstrasse 95
CH-4002 Basel, Switzerland
e-Mail: info@cteph-association.org
Phone:+ 41 (0)61 225 66 66Fax:+ 41 (0)61 225 66 67

4. First international registry on chronic
thromboembolic pulmonary hypertension
(CTEPH)
Prof. Dr Gerald Simonneau, gerald.simonneau@abc.aphp.fr, MD1, Prof. Dr Marion Delcroix,
marion.delcroix@uz.kuleuven.ac.be, MD2, Prof. Dr Eckhard Mayer, emayer@kkmainz.de, MD3,
Prof. Dr Irene Lang, irene.lang@meduniwien.ac.at, MD3 and Dr. Joanna Pepke-Zaba,
Joanna.PepkeZaba@papworth.nhs.uk, MD5. 1Service Pneumologie, Hopital
Antoine Beclere, Paris, France; 2Pneumology, University Hospital Gasthuisberg, Leuven Belgium;
3Thoracic Surgery, Catholic Hospital Mainz SHK, Mainz, Germany; 4Cardiology, Medical
University of Vienna, Vienna, Austria and Pulmonary Vascular Disease Unit, Papworth Hospital,
Cambridge, United Kingdom.
42 registered sites in 20 European countries and Canada

5. Unique form of pulmonary
hypertension amenable to curative
intervention.
Ann Thorac Surg 2007;83:1075– 81

6. Epidemiology of CTEPH:
old studies
Estimated incidence:
0.1-0.5% of patients with PE



Moser KM, et al Circulation. 1990;81:1735-43
Jamieson SW, Kapelanski DP. Curr Probl Surg. 2000; 37:165-252
Fedullo RF, et al. New Engl J Med. 2001;345:1465-72

7. Incidence of chronic thromboembolic pulmonary
hypertension after pulmonary embolism
Pengo V, et al. N Engl J Med. 2004; 350:2257-64

7/223 patients (5 patients in NYHA class II, 2 patients in NYHA class III)
None of the remaining patients developed CTEPH after 2 years
Cumulative incidence
Of CTEPH
3 months
0%
6 months
1.0%
1 year
3.1%
2 years
3.8%
Cumulative incidence of CTEPH (%)

*90% CI = 1.1 – 6.5
Pengo V, et al. N Engl J Med. 2004; 350:2257-64

8. Proposed annual incidence of CTEPH in USA
DIAGNOSED PE
600,000
CTEPH
25,000

9. Survival without treatment- CTEPH
mPAP 31-40 mmHg - 5-years survival 45%
mPAP 41-50 mmHg - 5-years survival 33%
mPAP >50 mmHg - 5-years survival 14%
26 patients
Follow up 15 yrs

10. Survival


49 CTEPH patients treated only with anticoagulants
3-year mortality of 90% when the mean pulmonary
artery pressure was ≥ 30 mm Hg.
Lewczuk J et al. Chest. 2001;119:818–823

11. Pathophysiology of CTEPH
VTE/DVT
PE
Obstructed pulmonary vessels
Honeymoon period
Thrombus organization
in occluded vessels
Shear forces in
non-occluded vessels
Small vessel arteriopathy in
non-occluded circulation
PVR
Progressive
pulmonary hypertension
Curr opin cardiol 2008, Nov;23(6)
Right heart failure

12. Pathophysiology
Why thrombus does not resolve in CTEPH is not known



Misguided thrombus resolution triggered by infection
(staphylococcus) , inflammation, autoimmunity and
malignancy
Abnormal fibrin resistant to fibrinolysis
Fibrinogen Aa Thr 312 Ala allele and genotype
J Suntharalingam et al
Bonderman D
et al.
rterioscler Thromb Vasc Biol 2008; 28: 678–684.

13. Risk factors for CTEPH
687 patients assessed at the time of diagnosis between 1996 and 2007
VA-shunts and infected pacemakers
Splenectomy
Previous venous thromboembolism (VTE)
Recurrent VTE
Blood groups non-0
Lupus anticoagulant/anti-phosph antibodies
History of malignancy
Thyroid replacement therapy
p<0.001
p=0.017
p<0.001
p<0.001
p=0.019
p=0.004
p=0.005
p<0.001
ERJ Express Published on September 17, 2008

14. Other Potential predictors of CTPH







Age
Persistent residual embolism
Idiopathic PE
Severity of perfusion defect
Right ventricular dysfunction
Myeloproliferative syndromes
Chronic Inflammatory disease (IBD, Osteomyelits)
Thromb Haemost. 2005;93:512-516.
Pengo V, et al, N Engl J Med 2004;350:2257-64

15. CTEPH and history of VTE

142 consecutive patients with CTEP 63% did not
have a history of symptomatic VTE at presentation.
N Engl J Med 2004;350:2236–2238

500 consecutive PEA cases at UCSD Only 45% of
CTEPH patients had a history of VTE
Ann Thorac Surg. 2003;76:1457-1464

Perfusion lung scans in 622 outpatients with
proximal DVT confirmed by venography and no
clinical indication of PE.
40–50% had silent PE.

16. CTEPH and Thrombophilia
No clear link between CTEPH and
antithrombin, protein S, protein C, factor II or
factor V Leiden
.
Antiphospholipid antibodies have been reported
in approximately 20% of CTEPH cohort.
Proc Am Thorac Soc 2006
Prothrombotic factor VIII was also found to be
elevated in 41% of a CTEPH cohort.
Eur Respir J. 2000;15:395-399
Thromb Haemost. 2003;90:372.

17. Diagnosis of CTEPH



Symptoms
A transthoracic echocardiogram
Ventilation-perfusion (V˙/Q˙) lung scan -Screening
test of choice to differentiate CTEPH from PAH
ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S

19. Ventilation–Perfusion Scintigraphy Is More Sensitive than
Multidetector CTPA in Detecting Chronic Thromboembolic
Pulmonary Disease as a Treatable Cause of Pulmonary Hypertension
Nina Tunariu1, Simon J.R. et al
J Nucl Med 2007; 48:680–684
CTPEA
Non--CTEPA
Intermediate-High
High

20. 
A normal V˙/Q˙ scan virtually rules out CTEPH

A normal contrast-enhanced CT scan or MRI
scan does not rule out a diagnosis of CTEPH

Right heart catheterization

Pulmonary angiogram
N Engl J Med 2001;345:1465–1472.
Chest 1983;84:679–683.
Eur Radiol 2003;13:2365–2371

21. Contrast enhanced MRA (CEMRA)
Pulmonary angiography
MRA

22. Management of CTEPH
Diagnosis of CTEPH with functional impairment
and/or right heart failure
Anticoagulation
Advanced pulmonary vascular disease
PVR disproportionately elevated
Estimated reduction in PVR <50%
Surgically accessible obliteration
of pulmonary vessels
Estimated reduction in PVR>50%
Severe comorbidities
Precluding surgery
No
PEA
Severe comorbidities
Precluding surgery
Yes
Yes
Medical
Therapy
Persistent symptomatic PHT
No
Lung transplant
Persistent symptomatic PHT
Circulation 2006;113;2011-2020

23. Pulmonary Endartrectomy (PEA)
Calif Med. 1957 February; 86(2): 108–114.
THE SURGICAL TREATMENT OF
ARTERIOSCLEROTIC OCCLUSIVE DISEASE—
Thromboendarterectomy in Selected Cases
Charles A. Kruse and Frederick G. Kirby

24. Pulmonary Endartrectomy (PEA)
Pioneered at the University of California, San Diego (UCSD).
1,500 cases of PEA
Excellent long-term outcome
Surgical mortality rate of 4.4% in the last 500 cases
Ann Thorac Surg 2003; 76:1457–1462
J Thorac Cardiovasc Surg 2006;131:307-313

25. PEA mortality and PVR

26. Surgery for Chronic Thromboembolic Pulmonary
Hypertension—Inclusive
Experience From a National Referral Center
Munir Boodhwani, Marc Ruel, Carole J. Dennie and Thierry Mesana
Fraser D. Rubens, Michael Bourke, Mark Hynes, Donna Nicholson, Marian Kotrec,
Ann Thorac Surg 2007;83:1075-1081



106 PATIENTS
30 DAY PERIOPERATIVE MORTALITY 9.4%
Most common cause of mortality-persistent
pulmonary hypertension

27. Advanced secondary
arteriopathy ?
Proximal, accessible
lesions
Patient consent
mPAP ≥ 40 mm Hg
PEA
Absence of severe
comorbidity
PVR > 300 dyn.s.cm -5
NYHA functional
class III/IV
Surgical expertise
ACCP guidelines

28. 
Concomitant coronary artery disease or cardiac
valvular defect is not a contraindication and can be
corrected at the time of PEA.
Ann Thorac Surg. 2001;72:13-19

Severe right heart failure does not exclude a patient
from being a PEA candidate; indeed, such patients
often have the most dramatic improvements
following surgery
J Thorac Cardiovasc Surg. 2006;131:307-313.

29. Reverse right ventricular remodeling after
pulmonary endarterectomy
RV before PEA
RV after PEA
J Thorac Cardiovasc Surg 2007;133:58-64

30. The two major postoperative complications
Persistent PH
 Reperfusion pulmonary edema (RPE).


31. Predictors of Surgical Success
Prior history of pulmonary embolism and/or deep vein thrombosis
“honeymoon period” (period of months to years between acute embolic
event and clinical symptoms of chronic thromboembolic pulmonary
hypertension)
Angiographic lesions located proximally in pulmonary arteries or lobar
branches
Correlation between pulmonary vascular resistance and anatomic
obstruction

32. Medical therapy



CTEPH is inoperable in as many as 50% of cases
Around 10-15% patients do not respond to PEA
Patients left untreated have a poor prognosis.

33. Mid-1990s, Late Ken Moser,
world authority on the subject
“Why would we use vasodilator therapy for
CTEPH?—it’s a mechanical problem.”

34. Targets for Current or Emerging Therapies
Prostacyclin Pathway
Endothelin Pathway
Nitric Oxide Pathway
Arachidonic Acid
Big Endothelin
Arginine
Prostacyclin
Synthase
Endothelinconverting
Enzyme
Nitric Oxide
Synthase
Prostacyclin
Endothelin-1
Nitric Oxide
cAMP
cGMP
Prostacyclin
Prostacyclin
Derivatives
Derivatives
Endothelin
Receptor
Antagonists
Endothelin
Receptor A
Vasodilatation
and
Antiproliferation
Endothelin
Receptor B
Vasoconstriction
and
Proliferation
Exogenous
Nitric Oxide
Phosphodiesterase Type-5
Phosphodiesterase
Type-5 Inhibitors
Vasodilatation
and
Antiproliferation
Humbert M et al. N Engl J Med. 2004;351:1425-1436.

35. Indication for medical therapy



Where there is inoperable distal disease or
comorbidities that make PEA a high-risk
option;
As a therapeutic bridge to PEA or lung
transplant for high-risk patients; or
Patients with persistent or residual PH after
PEA

36. Prostanoids
Therapeutic
agent
No. of
pts. with
CTEPH
Hemody- Clinical
namics
Dyspnea/
6 min walk
Epoprostenol
9
Epoprostenol
11
+
Trepostinil
23
NA
Iloprost
10
Beraprost
8
Beraprost
43
+
_
_
+
References
NA
Eur Respir J 2004; 23: 595–600
+
+
Ital Heart J 2004;5:618–623
NA
Ann Thorac Surg
2003;76:711–718.
+
+
Cardiology 2006;106:168-173
Chest 2006;129;1636-1643
Chest 2003;123:1583–1588

37. Inhaled Iloprost
AIR study randomized
controlled clinical trial
203 patients
57 patients with CTEPH.
Overall positive study
No significant beneficial
effects of inhaled Iloprost in
the subgroup of CTEPH
patients
Volume 347:322-329

38. Sildenafil
No. of
Hemodynamics Clinical
pts. with
Dyspnea/
CTEPH
6 min walk
References
12
+
Am J Respir Crit Care Med 2003;167:1139–1141
+
Eur Respir J 2007; 30:922-927
104
+
+

39. Long-term Use of Sildenafil in Inoperable Chronic
Thromboembolic Pulmonary Hypertension
(CHEST 2008; 134:229–236)
Double-blind, placebo-controlled pilot study
19 subjects with inoperable CTEPH
Randomly assigned to sildenafil (10) or placebo(9) for 12 weeks.
All subjects were transferred to open-label sildenafil at the end of
the study and offered repeat assessment at 12 months.

40. Primary end point- change - 6-min walking distance
(6MWD).
p=NS
Sidenafil
Placebo
Baseline
6 weeks
12 weeks

41. Secondary endpoints
statistically significant improvements in
Pulmonary vascular resistance,
Change in WHO functional class,
Quality of life Score (CAMPHOR)

42. Outcome Measures at Baseline and at 12 Months (n 17)*

43. Endothelin Receptor Antagonists
No. of pts. with
CTEPH
Hemodynamics
Clinical
Dyspnea/
6 min walk
16
+
+
+
+
+
+
19
47
16
8
43
+
_
+
+
+
+
References
Chest 2005;128;2363-2367
Hoeper MM et al.
Eur Respir J 2006; 28: 138–143
SWISS MED WKLY 20 07;137:573–580
Cardiology 2006;106:168-173
Chest 2003;123:1583–1588

44. BENEFiT
Trial design: Patients with inoperable CTEPH or persistent pulmonary hypertension after
pulmonary endarterectomy were randomized to bosentan (n = 77) or placebo (n = 80). Follow-up
was 16 weeks.
PVR: -146 dyn⋅sec⋅cm-5
with bosentan vs. +30 dyn⋅sec⋅cm-5 with placebo (P<0001)
WHO functional Class and NT-BNP
Change (300 dyn⋅sec⋅cm-5)
6-minute walk
improved significantly
distance: +2.9 m vs. +0.8 m respectively, (p = 0.54)
Conclusion:
30
(p < 0.0001)
The improvement in pulmonary
vascular resistance did not
translate into a beneficial effect
on 6-minute walk distance.
-146
Bosentan
Placebo
Jais X, et al. J Am Coll Cardiol 2008;52:212734

45. Survival in CTEPH
Without treatment
With medical treatment
Longterm survival of inoperable chronic thromboembolic pulmonary hypertension (CTEPH)
N. Saouti, F. de Man, A. Boonstra, A. Vonk-Noordegraaf (Amsterdam, Netherlands)

46. Survival after treatment-Swiss registry
No significant difference in survival of the main 3 WHO groups
Total patients 222
SWISS MED WKLY 20 08;138(25–26):371–378

47. Investigational/New Therapies







Ambrisentan
Sitaxsentan
Tadalafil
Inhaled treprostinil
Oral treprostinil
Inhaled vasoactive intestinal peptide (VIP)
Imatinib (PDGF-inhibitor)

48. Investigational/New Therapies
• Tyrosine kinase/growth factor receptor inhibitors
– Imatinib Imatinib, sorafenib sorafenib
• Guanylate cyclase (sGC) stimulators
- Riociguat
• Vasoactive intestinal peptide (VIP)
• Serotonin transporter agonists
• Adrenomedullin
• Rho-kinase inhibitors
• Cicletanine
• Endothelial progenitor cells
• Gene therapy
– Vectors expressing

49. SUMMARY





PEA should be considered as the first line treatment
option in patients with CTEPH
Pulmonary hypertension is likely to persist in 10-15%
after PEA
Medical intervention in inoperable patients and those
post-PEA persistent PH should be given
Anticoagulation therapy should be continued for life
Lung transplantation may be undertaken where
PEA has failed and in non-responders to medical
therapy

50. Thanks