Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Epidemiology

The incidence of CTEPH is uncertain, but it occurs in up to 4% of patients after an acute pulmonary embolism
[Tapson VF, Humbert M. Incidence and prevalence of chronic thromboembolic pulmonary hypertension: from acute to chronic pulmonary embolism. Proc Am Thorac Soc 2006;3:564–7]
[Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257–64]
Currently there is no consensus among experts about the definitions of proximal and distal CTEPH (92).
Only 4% of acute PE cases will develop CTEPH
40-50% of CTEPH cases have an antecedent hx of acute PE

Risk/Etiologic Factors

Anti-Phospholipid Antibody Syndrome (see Anti-Phospholipid Antibody Syndrome, [[Anti-Phospholipid Antibody Syndrome]]): anti-phospholipid antibodies have been identified in 10-20% of CTEPH patients
Elevated Factor VIII Level: noted in 41% of CTEPH patients

Physiology

Pulmonary HTN due to obstruction of major pulmonary art-eries (main/ lobar/ segmen-tal) by clot that does not normally resolve with probable pulmonary vasoconstriction
In about 50% of cases, initial PE was not clinically evident
RV begins to fail at PA pressures >40-45 mm Hg (however, the gradual rise in PA pressures seen in CTEPH may allow RV compensation to very high pressures)

Diagnosis

Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]])

Hypocapnia with Respiratory Alkalosis (see Respiratory Alkalosis, [[Respiratory Alkalosis]]): due to hyperventilation
Elevated A-a Gradient Hypoxemia (see Hypoxemia, [[Hypoxemia]]): due to V/Q mismatch, intrapulmonary shunt, and decreased cardiac with low SvO2

Electrocardiogram (EKG) (see Electrocardiogram, [[Electrocardiogram]])

Right Ventricular Hypertrophy (RVH)
Right Axis Deviation (RAD)
Right Ventricular Strain Pattern
P-Pulmonale

Chest X-Ray (see xxxx, [[xxxx]])

Features
- Enlarged or Irregular Pulmonary Arteries (May Be Asymmetric): enlargement for right PA is defined as >16 mm
- Enlarged Superior Vena Cava
- Enlarged Azygos Vein
- Enlarged Right Ventricle with Loss of Retrosternal Air Space

Echocardiogram (see Echocardiogram, [[Echocardiogram]])

Right Atrial Enlargement
RV Enlargement, Usually with Decreased RV Ejection Fraction: RV ejection fraction fails ot increase normally with exercise
Tricuspid Regurgitation (TR) (see Tricuspid Regurgitation, [[Tricuspid Regurgitation]])
- Calculation of Pulonary Artery Pressure from TR Jet: peak velocity squared x 4 + RA pressure
Pulmonic Regurgitation (PR) (see Pulmonic Regurgitation, [[Pulmonic Regurgitation]])
Bubble Study: negative (rules out intracardiac shunt
Normal Left Ventricular Ejection Fraction (LV-EF): rules out left-sided heart disease

Swan-Ganz Catheter (see Swan-Ganz Catheter, [[Swan-Ganz Catheter]])

RA: normal (at rest)
RV-Sys: elevated (with normal RV-EDP)
PA-Sys, PA-Dia, PA-Mean: elevated (may be severe)
PA-SaO2: lack of “step-up” excludes intracardiac shunt
PCWP: normal (reflects normal LA and LV-EDP)
CO: normal-decreased at rest (does not rise appropriately with exercise)
PVR: elevated

Cardiac Catheterization (see Cardiac Catheterization, [[Cardiac Catheterization]])

May Be Necessary to Exclude Intracardiac Shunt

Lower Extremity Venous Doppler Ultrasound (see Lower Extremity Venous Doppler Ultrasound, [[Lower Extremity Venous Doppler Ultrasound]])

Useful to Rule Out Lower Extremity Deep Venous Thrombosis (DVT) (se Deep Venous Thrombosis, [[Deep Venous Thrombosis]])

CT Pulmonary Angiogram (CTPA) (see Computed Tomography Pulmonary Angiogram, [[Computed Tomography Pulmonary Angiogram]])

Sensitivity for Diagnosis of CTEPH: 90-100%
- Central Pulmonary Emboli are Detected with Similar Accuracy to Conventional Pulmonary Artery Angiogram, But Has Poorer Sensitivity in Detecting Chronic Segmental Thromboemboli [MEDLINE]
Specificity for Diagnosis of CTEPH: 94-100%
Features
- Bronchial Artery Collateral Flow
- Chronic Thromboemboli in Dilated Central Pulmonary Arteries
- Mosaic Attenuation of Pulmonary Parenchyma
- Right Ventricular Enlargement
Limitations
- Poor Sensitivity in Detecting Chronic Segmental Thromboemboli [MEDLINE]
- Inability to Differentiate Intraluminal Thrombus from a Well-Endothelialized Chronic Thrombus

Gadolinium-Enhanced Magnetic Resonance Pulmonary Angiogram (MRA) (see Magnetic Resonance Pulmonary Angiogram, [[Magnetic Resonance Pulmonary Angiogram]])

Advantages
- No Exposure to Iodinated Radiographic Contrast
- No Radiation Exposure
Diagnostic Accuracy in Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
- ASPIRE Registry-3D Contrast-Enhanced Lung Perfusion MRI (2013) [MEDLINE]: compared to V/Q scan and CT pulmonary artery angiogram, MRI had similar sensitivity (97% vs 94% and 96%) and specificity (92% vs 98% and 90%) for the diagnosis of CTEPH

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])

Restrictive Pattern: observed in 22-29% of cases
- Mechanism: likely due to parenchymal scarring from recurrent infarcts (but is not believed to be due to pleural abnormalities, enlarged proximal pulmonary arteries, displacement of lung volume by pulmonary arteries, or increased thoracic blood volume)
Normal-Mildly Decreased DLCO
- Mechanism: due to loss of capillary blood volume
- May be only PFT abnormality

Exercise Test (see Exercise Test, [[Exercise Test]])

Exertional Dyspnea
Exercise-Associated Desaturation
Normal-Mildly Elevated VD/VT Ratio
- Rest: normal-elevated (especially with large vessel obstruction)
- Exercise: elevated

Ventilation/Perfusion (V/Q) Scan (see Ventilation-Perfusion Scan, [[Ventilation-Perfusion Scan]])

Clinical Utility: V/Q scan has traditionally been considered the screening method of choice for chronic thromboembolic pulmonary hypertension because of its higher sensitivity than CT pulmonary angiogram (especially in inexperienced centers)
Features
- One or More Segmental/Lobar Unmatched Defects: usually
  - In contrast, normal or “mottled” appearance (small peripheral unmatched or non-segmental perfusion defects) on V/Q scan instead suggests small vessel pulmonary hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]]) or pulmonary veno-occlusive disease (PVOD) (see Pulmonary Veno-Occlusive Disease, [[Pulmonary Veno-Occlusive Disease]])

Pulmonary Artery Angiogram (see Pulmonary Artery Angiogram, [[Pulmonary Artery Angiogram]])

Features
- Pulmonary Emboli
- Recanalized Vessels
- Stenoses
- Webs

Pulmonary Artery Angioscopy (see Pulmonary Artery Angioscopy, [[Pulmonary Artery Angioscopy]])

May Be Useful to Demonstrate Thrombi (Old or Fresh) vs Stenosis/Compression

Open Lung biopsy

May Be Necessary to Exclude Pulmonary Vasculitis in Some Cases

Clinical Manifestations

General Comments

History of Prior Acute Venous Thromboembolic Event: can be elicited in approximately 60% of surgically-accessible CTEPH
- Event Typically Precedes Onset of Dyspnea by Months-Years

Cardiovascular Manifestations

Accentuated P2 Component of Second Heart Sound
Aortic-Pulmonic Splitting of Second Heart Sound
Chest Pain (see Chest Pain, [[Chest Pain]]): due to dilation of PA root
Jugular Venous Distention: with prominent A and V wave venous pulsations
Pulmonic Regurgitation Murmur (see Pulmonic Regurgitation, [[Pulmonic Regurgitation]])
Right Ventricular Heave
Right Ventricular S3
Symptoms of Right Ventricular Heart Failure
- Ascites (see Ascites, [[Ascites]])
- Hepatomegaly (see Hepatomegaly, [[Hepatomegaly]])
- Peripheral Edema (see Peripheral Edema, [[Peripheral Edema]]): peripheral edema may occur due to chronic lower extremity venous outflow obstruction (from prior DVT) or from right ventricular heart failure associated with pulmonary hypertension
Syncope (see Syncope, [[Syncope]])
Tricuspid Regurgitation (TR) Murmur (see Tricuspid Regurgitation, [[Tricuspid Regurgitation]])

Pulmonary Manifestations

“Branch Stenosis Murmur”: systolic or continuous murmur over lung field at site of embolic narrowing
- Quality: high-pitched and blowing, accentuated during inspiration, and are often heard only during periods of breath-holding
- These murmurs have not been described in other type of pulmonary hypertension
Cyanosis (see Cyanosis, [[Cyanosis]]) due to hypoxemia
Dry Cough (see Cough, [[Cough]])
Dyspnea (see Dyspnea, [[Dyspnea]]): always present
Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
Tachypnea (see Tachypnea, [[Tachypnea]])

Treatment

General Measures

Tobacco Smoking Cessation (see Tobacco, [[Tobacco]]): crucial
Supplemental Oxygen (see Oxygen, [[Oxygen]]): as required
Pulmonary Rehabilitation (see Pulmonary Rehabilitation, [[Pulmonary Rehabilitation]]): as required
Vaccinations
- Influenza Vaccination (see Influenza Virus, [[Influenza Virus]])
- Pneumocccal Vacccination (see Streptococcus Pneumoniae, [[Streptococcus Pneumoniae]])

Operable Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Anticoagulation

Indicated

Pulmonary Thrombendartereectomy (PTE)

Indications: resting PVR >300, clot in main/lobar/segmental arteries, and no significant coexisting disease
Technique
- Pulmonary Thrombendarterectomy via Median Sternotomy with Cardiopulmonary Bypass (see xxxx, [[xxxx]])
Surgical Mortality Rate: 9% (all deaths in NYHA class 4 cases)
Clinical Efficacy: progressive improvement occurs for 6-9 mo post-PTE
Complications
- Inability to Come Off CPB: may occur in cases where PVR does not fall after clot removal or where there is concomitant small vessel pulmonary vascular disease
- Reperfusion Pulmonary Edema
- Persistent Pulmonary Hypertension Post-PTE: see below

Prostacyclin Analogues

Epoprostenol (PGI2, Prostacyclin, Flolan, Veletri) (see Epoprostenol, [[Epoprostenol]]): probably no clinical benefit [MEDLINE]

Riociguat (Adempas) (see Riociguat, [[Riociguat]])

Use of Riociguat as a Bridge to PTE Surgery Has Not Been Studied

Persistent Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Post-PTE

Anticoagulation

Indicated

Prostacyclin Analogues

Indications: preferred agents for severe (functional class IV) persistent pulmonary hypertension in CTEPH post-PTE surgery
Epoprostenol (PGI2, Prostacyclin, Flolan, Veletri) (see Epoprostenol, [[Epoprostenol]])
Inhaled Iloprost (Ilomedin, Ventavis) (see Iloprost, [[Iloprost]])
Treprostinil (Remodulin, Tyvaso) (see Treprostinil, [[Treprostinil]])

Endothelin Receptor Antagonists (see Endothelin Receptor Antagonists, [[Endothelin Receptor Antagonists]])

Agents
- Bosentan (Tracleer) (see Bosentan, [[Bosentan]])
  - BENEFiT Trial of Bosentan in CTEPH (2008) [MEDLINE]: in subset of patients with persistent pulmonary hypertension after PTE surgery, bosentan improved hemodynamics (PVR), but had no effect on exercise capacity

Riociguat (Adempas) (see Riociguat, [[Riociguat]])

Indications: preferred agent for persistent pulmonary hypertension in CTEPH post-PTE surgery (particularly in those with functional class II-III disease)
CHEST-1 Study of Riociguat in Patients with Inoperable CTEPH/Persistent or Recurrent CTEPH After Pulmonary Thrombendarterectomy (PTE) Surgery (2013) [MEDLINE]
- Riociguat Improved Exercise Capacity (6-Minute Walk Test)
- Riociguat Improved Pulmonary Vascular Resistance (PVR)
- Riociguat Decreased NT Pro-BNP Levels
- Riociguat Improved WHO Functional Class

Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Anticoagulation

Indicated

Prostacyclin Analogues

Epoprostenol (PGI2, Prostacyclin, Flolan, Veletri) (see Epoprostenol, [[Epoprostenol]])
Inhaled Iloprost (Ilomedin, Ventavis) (see Iloprost, [[Iloprost]])
Treprostinil (Remodulin, Tyvaso) (see Treprostinil, [[Treprostinil]])

Endothelin Receptor Antagonists (see Endothelin Receptor Antagonists, [[Endothelin Receptor Antagonists]])

Agents
- Ambrisentan (Letairis) (see Ambrisentan, [[Ambrisentan]])
- Bosentan (Tracleer) (see Bosentan, [[Bosentan]])
  - BENEFiT Trial of Bosentan in CTEPH (2008) [MEDLINE]: bosentan improved hemodynamics, but had no effect on exercise capacity
  - Systematic Review/Meta-Analysis of Bosentan in CTEPH (2010) [MEDLINE]: bosentan improved hemodynamics and probably exercise capacity
- Macitentan (Opsumit) (see Macitentan, [[Macitentan]])

Phosphodiesterase Type 5 Inhibitors (see Phosphodiesterase Type 5 Inhibitors, [[Phosphodiesterase Type 5 Inhibitors]])

Sildenafil (Viagra, Revatio) (see Sildenafil, [[Sildenafil]])
- Trial of Sildenafil in CTEPH (2008) [MEDLINE]: sildenafil improved 6-minute walk distance, activity and symptom components of quality of life, cardiac index, PVR, and NT-proBNP
Tadalafil (Adcirca, Cialis) (see Tadalafil, [[Tadalafil]])

Riociguat (Adempas) (see Riociguat, [[Riociguat]])

Indications: preferred agent for inoperable CTEPH with functional class II-III
Pharmacology: riociguat increases the sensitivity of the guanylate cyclase receptor to nitric oxide, a pulmonary vasodilator
CHEST-1 Study of Riociguat in Patients with Inoperable CTEPH/Persistent or Recurrent CTEPH After Pulmonary Thrombendarterectomy (PTE) Surgery (2013) [MEDLINE]
- Riociguat Improved Exercise Capacity (6-Minute Walk Test)
- Riociguat Improved Pulmonary Vascular Resistance (PVR)
- Riociguat Decreased NT Pro-BNP Levels
- Riociguat Improved WHO Functional Class

Balloon Pulmonary Angioplasty

Indications
- Non-Surgical CTEPH
Clinical Efficacy: improves pulmonary blood flow distribution, RV afterload, and 6-minute walk distances

References

Chronic thromboembolism: diagnosis with helical CT and MR imaging with angiographic and surgical correlation. Radiology. 1997;204(3):695 [MEDLINE]
Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003;76:1457– 62.
Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257–64
Chronic thromboembolic pulmonary hypertension. Eur Respir J 2004;23:637-48
Assessment of operability in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc 2006;3:584–8.
Incidence and prevalence of chronic thromboembolic pulmonary hypertension: from acute to chronic pulmonary embolism. Proc Am Thorac Soc 2006;3:564–7
Current and future management of chronic thromboembolic pulmonary hypertension: from diagnosis to treatment responses. Proc Am Thorac Soc 2006;3:601–7
Chronic thromboembolic pulmonary hypertension – assessment by magnetic resonance imaging. Eur Radiol. 2007;17(1):11 [MEDLINE]
3D contrast-enhanced lung perfusion MRI is an effective screening tool for chronic thromboembolic pulmonary hypertension: results from the ASPIRE Registry. Thorax. 2013 Jul;68(7):677-8. Epub 2013 Jan 24 [MEDLINE]

Treatment

Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Chest. 2003;123(2):338 [MEDLINE]
Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension. Chest 2008;134:229-36 [MEDLINE]
Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension; BENEFiT (bosentan effects in inoperable forms of chronic thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol 2008:16:2127–34 [MEDLINE]
Riociguat for chronic thomboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J 2010;36:792-799 [MEDLINE]
Bosentan for chronic thromboembolic pulmonary hypertension: findings from a systematic review and meta-analysis. Thromb Res. 2010;126(1):e51 [MEDLINE]
Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013 Jul 25;369(4):330-40. doi: 10.1056/NEJMoa1209655 [MEDLINE]
Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013 Jul 25;369(4):319-29. doi: 10.1056/NEJMoa1209657 [MEDLINE]