Chronic Thromboembolic Pulmonary artery Hypertension

Chronic Thromboembolic Pulmonary Artery Hypertension(CTEPH)

By-Dr Awadhesh Kr Sharma

The Truth about Chronic Thrombo-embolic Pulmonary Arterial Hypertension (CTEPH)

CTEPH is a deadly diseaseInsidious in onsetOnce symptomatic, progresses rapidly

without treatmentMedical therapies exist, but most

tested in patients with advanced disease

(NEJM Jan 27,2011 Page351-360)

CTEPHChronic thromboembolic pulmonary hypertension

(CTEPH) is an important cause of pulmonary hypertension that is commonly considered to be the consequence of acute pulmonary embolic disease.

Following an acute event, unresolved residual thrombus becomes organised and fibrosed, leading to ongoing obstruction to pulmonary blood flow.

Untreated, this leads to progressive pulmonary hypertension, right ventricular dysfunction and death

(Suntharalingam J. et al. Thorax 2007)

“Not a disease, but a syndrome in which the pressure in the pulmonary circulation is raised.”

Peacock, Pulmo Circ 2nd ed

DefinitionChronic thromboembolic pulmonary

hypertension is defined as-mean pulmonary-artery pressure greater than

25 mm Hg that persists 6 months after pulmonary embolism is diagnosed

(J Am Coll Cardiol 2009;54:Suppl:S43-S54.)

Occurs in 2 to 4% of patients after acute pulmonary embolism.

(Chest 2006;130:172-5)

Natural History of CTEPHHoneymoon period after acute PEUsually present in their 40sLater presents with dyspnea,

hypoxemia & RV dysfunctionDeath usually due to RV failure

Riedel M, Stanek V, Widimsky J, et al. Longterm follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982;81:151–8.

mPAP>50 mean survival 6.8 yrsFibrinolysis in acute PE shown to

reduce the frequency of CTEPH.Most of CTEPH pts. even on

anticoagulants will progress to Rt heart failure and death untreated

(Kline J et al,Chest

2009;136:1202-10)

Incidence0.5% to 3.8% of pts after an acute PE & in upto 10% of those with

a history of recurrent PE will develop CTEPH. A prospective follow-up study of 78 survivors of acute pulmonary

embolism, Four patients (5.1%) developed definite CTEPH, and 3 of these subsequently underwent successful PEA.

(Ribeiro A, Lindmarker P, Johnsson H, Juhlin-Dannfelt A, Jorfeldt L. Pulmonary embolism: one-year follow-up with echocardiography Doppler and five-year survival analysis. Circulation. 1999;99:1325–1330.)

The only identifiable risk factors for persistent pulmonary hypertension were an age 70 years and a systolic pulmonary artery pressure 50 mm Hg at the initial presentation.

In another prospective follow-up study of 223 patients who presented with acute pulmonary embolism, the incidence of symptomatic CTEPH was 3.1% at 1 year and 3.8% at 2 years (Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F,Albanese P, Biasiolo A, Pegoraro C, Iliceto S, Prandoni P. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350:2257–2264. )

Risk factors for CTEPH

VTE Risk factorsHypercoagulability

MalignancyNonmalignant thrombophilia

PregnancyPostpartum status (<4wk)Estrogen/ OCP’s Genetic mutations (Factor V Leiden, Protein C & S

deficiency, Factor VIII, Prothrombin mutations, anti-thrombin III deficiency)

Venous StatisBedrest > 24 hr Recent cast or external fixatorLong-distance travel or prolong automobile travel

Venous InjuryRecent surgery requiring endotracheal intubationRecent trauma (especially the lower extremities and pelvis)

VTE Risk factorsSpecific to women:Obesity BMI ≥ 29Pregnancy HypertensionHeavy smoking (> 25cigs/day)Hormone replacement therapyOCP’s 10-30/100,000 users vs. 4-8/100,000

non-users.

While the hypercoagulable state has been clearly associated with the development of CTEPH, not all of the aforementioned factors have been clearly linked with CTEPH.

Plasma VIII elevated in 41% of pts of CTEPH.Lupus anticoagulant 10% of CTEPHAnticardiolipin antibody in 20% CTEPHProtein C,S & antithrombin deficiencies <1%

of pts with CTEPH.

Factors specific to pulmonary embolismRecurrent or unprovoked pulmonary

embolismLarge perfusion defects when pulmonary

embolism detectedYoung or old age when pulmonary embolism

detectedPulmonary-artery systolic pressure >50 mm

Hg at initial manifestation of pulmonary embolism

Chronic medical conditionsInfected surgical cardiac shunts or

pacemaker or defibrillator leadsPost-splenectomyChronic inflammatory disordersCancer

Thrombotic factorsLupus anticoagulant or antiphospholipid

antibodiesIncreased levels of factor VIIIDysfibrinogenemia

Genetic factorsABO blood groups other than OHLA polymorphismsAbnormal endogenous fibrinolysis

CTEPH: ASSOCIATIONS Non O blood type

CTEPH vs PAH ( 88% vs. 56%)

Lp (a)

CTEPH vs. PAH vs. Control ( 26.6 mg/dl, 9.6 mg/dl, 7.2 mg/dl)

†† Bonderman D, et al. High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension. Thromb Haemost 2003;90:372–376.

‡ ‡ Ignatescu M, et al. Plasma Lp(a) levels are increased in patients with chronicthromboembolic pulmonary hypertension. Thromb Haemost 1998;80:231–232.

SPLENECTOMY AS A RISK FACTOR FOR CTEPHPrevalence of Splenectomy in CTEPH is

significantly higher than in IPAP and control.Mean interval from S/p Splenecotmy CTEPH onset:

16 +_ 9 yrsRetrospective Chart Review of 257 pt referred for

CTEPH over 10 yrs vs. IPAH vs. other pulm diseases. in CTEPH – 8.6% ( CI 95%, [5.2-12.0%]) had splenectomy vs. 2.5% ( CI 95%, [ 0.7-4.4%]) IPAP and 0.56% ( CI 95%,[0-1.6%]) in other pulm diseases †

Again most Splenectomy – distal CTEPH, not PEA candidates.

Jais X, et al Splenectomy and chronic thromboembolic pulmonary hypertension. Thorax 2005;60:1031–1034

PathophysiologySmall vessel arteriopathy- - medial hypertrophy - intimal proliferation - microvascular thrombosis - plexiform lesion formation Persistent macrovascular obstruction Vasoconstriction Neurohumoral factors -endothelin 1- potent

vasoconstrictiors/triggers of microvascular changes. (Reesink HJ et al,Circ J

2005;70:1058-63)

Progression of CTEPH

Acute or recurrent PTE in pulmonary arteries

Organisation these thrombi

Occurence in situ thrombus due to slow blood flow in obstructed

pulmonary arteries

Occurence of arteritis in non obstructed small distal pulmonary

arteries(remodelling)

Increased PVR, pulmonary hypertension

CTEPH

Histopathological paradoxTissues/vessels distal to occluded segment-

normalDistal vessel distal to patent pulmonary

arterial segments- small vessel abnormalities

Arrows – not perfused due obstruction by clots. ( normal vessels downstream)RUL get all the flow of R lung – remodeling on Bx

Moser,Braunwald et al,Chest 1973;64:29-35

Chronic thromboembolic pulmonary hypertension (CTEPH)

Clinical presentation -

The diagnosis of CTEPH is usually not made until the degree of pulmonary hypertension is advanced

A patient may carry on relatively normal activities following a pulmonary embolic event, whether clinically apparent or occult, even when extensive pulmonary vascular occlusion has occurred (asymptomatic –honeymoon – period)

Fedullo PF et al.N Engl J Med 2001

Chronic thromboembolic pulmonary hypertension (CTEPH)

Clinical presentation - Patients who have CTEPH typically complain of

exertional dyspnea and a gradual decrease in exercise tolerance over months to years

Diagnostic delay : Nonspesific nature of symptoms Absence of a history of prior acute symptomatic venous

thromboembolism (DVT / PE)

The average delay from the onset of cardiopulmonary symptoms to establisment of the correct diagnosis can range from 2 to 3 years

Fedullo PF et al.Semin Resp Crit Care Med 2003Auger WR et al. Clin Chest Med 2007

Chronic thromboembolic pulmonary hypertension (CTEPH)

Clinical presentation - Progressive dyspnea and exercise intolerance due to

CTEPH are often erroneously attributed to ; coronary artery disease cardiomyopathy congestive heart failure interstitial lung disease COPD (mild) asthma physical deconditioning psychogenic dyspnea

Prior to consideration of a pulmonary vascular problem as a basis for their complaints, many patients with CTEPH have undergone ;

left-sided cardiac catheterizations (one or more ) coronary angiograms lung biopsy. enrolling in an exercise program seeking psychiatric help.

Fedullo PF et al.N Engl J Med 2001Auger WR et al. Clin Chest Med 2007

Chronic thromboembolic pulmonary hypertension (CTEPH)

Clinical presentationSymptoms

Progressive dyspnea Nonproductive cough (especially with exertion) Hemoptysis Palpitations A change voice quality or hoarseness Exertional chest pain Near-syncope or syncope Lower extremity edema

Fedullo PF et al.Semin Resp Crit Care Med 2003Auger WR et al. Clin Chest Med 2007

Chronic thromboembolic pulmonary hypertension (CTEPH)

Clinical presentationPhysical examination - May be subtle early in the course of the illness.In time obvious findings develop, which may include :

Right ventricular lift Jugular venous distension Prominent A and V wave venous pulsations Fixed splitting of S2 with an accentuated pulmonic

component A right ventricular S4 gallop A tricuspid regurgitation murmur Hepatomegaly Ascites Peripheral edema, which may be a result of either chronic

lower extremity venous outflow obstruction or right ventricular failure.

Fedullo PF et al.N Engl J Med 2001Auger WR et al. Clin Chest Med 2007

Chronic thromboembolic pulmonary hypertension (CTEPH)

Clinical presentationPhysical examination - The presence of flow murmurs over the lung fields(30 percent of patients).

turbulent flow through partially obstructed or recanalized pulmonary arteries

high pitched and blowing in quality

heard over the lung fields rather than the precordium, accentuated during inspiration

frequently heard only during periods of breath-holding

they have not been described in primary pulmonary hypertension, which represents the most common competing diagnostic possibility

Fedullo PF et al.N Engl J Med 2001Auger WR et al. Clin Chest Med 2007

Chronic thromboembolic pulmonary hypertension

(CTEPH)

DiagnosisPulmonary function tests

Useful for excluding coexisting parenchymal lung disease or airflow obstruction

Often within normal limits

The majority of patients with CTEPH have a reduction in the single breath diffusing capacity for carbon monoxide (DLCO); a normal value, however, does not exclude the diagnosis

Approximately 20 percent of patients demonstrate a mild to moderate restrictive defect

A mild obstructive defect may be present as a result of mucosal hyperemia, which is related to development of a large bronchial arterial collateral circulation

Steenhuis KS. Et al. Eur Respir J 2000Auger WR et al. Clin Chest Med 2007

Chronic thromboembolic pulmonary hypertension (CTEPH)

DiagnosisBlood gas analysis

Resting arterial PO2 may be within normal limits

Hypoxemia at rest implies very severe right ventricular disfunction or the presence of a right -to- left shunt, as through a patent foramen ovale

Majority of patients have a decline in the arterial PO2 with exercise

The alveolar-arterial oxygen gradient is typically widened

Dead space ventilation (VD/VT) is often increased at rest and worsens with exercise

Minute ventilation is typically elevated as a result of the increased dead space ventilation.

Fedullo PF et al. N Engl J Med 2001Auger WR et al. Clin Chest Med 2007

Chronic thromboembolic pulmonary hypertension (CTEPH)

DiagnosisChest radiography

Often normal Enlargement of both main

pulmonary arteries or asymmetry in the size of the central pulmonary arteries

Areas of hypoperfusion or hyperperfusion

Evidence of old pleural disease, unilaterally or bilaterally

Right atrial or right ventricular enlargement, based on the outline of the right cardiac border ( especially on the lateral film by encroachment on the normally empty retrosternal space)

Cardiomegaly

Eur Radiol 2007;17:11-21

Chronic thromboembolic pulmonary hypertension (CTEPH)

DiagnosisElectrocardiography (ECG)

Right axis deviation Right ventricular hypertrophy Right atrial enlargement Right bundle – branch block ST segment displacement T- wave inversions in anterior precordial and inferior limb

leads

Auger WR et al. Clin Chest Med 2007

Chronic thromboembolic pulmonary hypertension (CTEPH)

DiagnosisEchocardiography

Enlargement and reduced systolic function of the right ventricle are usually apparent,

Leftward septal displacement can impair left ventricular filling and performance

ECHO is useful for the excluding;

Left ventricular dysfunction

Valvular disease Cardiac malformations

Sensitive but not specificMenzel T et al. Chest 2000Auger WR et al. Clin Chest Med 2007

Chronic thromboembolic pulmonary hypertension (CTEPH)

DiagnosisRadioisotopic V / Q scanning –

In chronic thromboembolic disease, at least one (and more commonly, several) segmental or larger mismatched ventilation-perfusion defects are present but not spesific for this condition

In idiopathic pulmonary arterial hypertension (IPAH) , perfusion scans are either normal or exhibit a "mottled" appearance characterized by subsegmental defects

V- scannig of the lungs is almost always normal

J Nuclear Med 2007;48:680-4

Chronic thromboembolic pulmonary hypertension (CTEPH)

DiagnosisRadioisotopic V / Q scanning –

Conditions indistinguishable from CTEPH in V/Q appearance :

Extrinsic vascular compression from mediastinal adenopathy or fibrosis Primary pulmonary vascular tumors ( ie. Angiosarcoma ) Pulmonary veno-occlusive disease Large-vessel pulmonary arteritis

Additional imaging studies are needed to define the vascular abnormality and establish the diagnosis

Cannot localize the extent of the disease Cannot determine surgical accessibility

Hasegawa I et al. AJR 2004Fedullo PF et al. N Engl J Med 2001

Chronic thromboembolic pulmonary hypertension (CTEPH)

DiagnosisComputed tomogaphy (CT)CT findings in CTEPH :

Right atrial and ventricular enlargement

Chronic thromboembolic material within dilated central pulmonary arteries

Central pulmonary artery enlargement

Variations in the size of lobar and segmental- level vessels

Mosaic perfusion of the lung parenchyma

Peripheral, scar- like densities in hypo-attenued lung regions

Presence of mediastinal collateral vessels arising from the systemic arterial circulation

(Eur J Radiol 2009;71:49-54)

DiagnosisComputed tomogaphy (CT) -

CT imaging is also valuable in :Assesment of the lung parenchyma in patients who

have coexisting emphysematous or restrictive lung disease

Detection mediastinal pathology that might account for occlusion of the central pulmonary arteries

CTACT angiography efficacy graeter in the main

& lobar pulmonary arteriesCTA efficacy decreases in the segmental &

subsegmental vessels.

(Eur Radiol 2009;71:49-54)

M R AngiographyLimited sensitivityNo extra advantage over CTA

(Ann Med Intern2010;1 52:434-43)

Chronic thromboembolic pulmonary hypertension (CTEPH)

DiagnosisPulmonary angiography

Pouch defects Pulmonary artery webs or

bands Intimal irregularities Abrupt narrowing of the

major pulmonary arteries Obstruction of lobar or

segmental vessels at their point of origin, with complete absence of blood flow to pulmonary segments normally perfused by those vessels

Fedullo PF et al. N Engl J Med 2001

Chronic thromboembolic pulmonary hypertension (CTEPH)

Diagnosis

Cardiac catheterization Defines the severity of the pulmonary hypertension and

degree of cardiac dysfunction

Biplane imaging provides optimal anatomical detail

When dilated and overlapping vessels are present, the lateral view provides more detailed images of lobar and segmental anatomy than those obtained with an anterior–posterior view alone

Fedullo PF et al. N Engl J Med 2001Auger WR et al. Clin Chest Med 2007

Chronic thromboembolic pulmonary hypertension (CTEPH)

DiagnosisPulmonary angioscopy

A diagnostic fiberoptic device, was developed specifically for preoperative

evaluation.The angioscopic features of organized, chronic emboli :

Roughening or pitting of the intimal surface, Bands and webs traversing the vascular lumen, Pitted masses of chronic embolic material within the lumen, Partial recanalization. Intimal plaques are a nonspecific finding in pulmonary hypertension of any cause. Angioscopy is performed in approximately 30 percent of patients

undergoing evaluation for thromboendarterectomy

Fedullo PF et al. N Engl J Med 2001

(NEJM Jan 27,2011 Page351-360)

Proposed algorithm for the diagnostic approach to patients with CTEPH. Ventilation-perfusion scanning is the recommended screening procedure because a normal perfusion scan virtually rules

out CTEPH. When perfusion scans show indeterminate results...

Hoeper M M et al. Circulation 2006;113:2011-2020

Copyright © American Heart Association

Treatment of CTEPH

Proposed Treatment approach

Hoeper M et al, Chronic Thromboembolic Pulmonary Hypertension, Circulation 2006; 113; 2011 - 2020

Pulmonary thromboendarterectomy The most effective therapy –- Pulmonary thromboendarterectomy. (J Am Coll Cardiol 2009;54:Suppl:S67-

S77.) Improvement in hemodynamics after pulmonary thrombo-

endarterectomy causes - Reverse right ventricular remodeling The beneficial effect usually persists, unless small-vessel

arteriopathy or recurrent pulmonary embolism develops. (Long-term outcome after pulmonary

endarterectomy. Am J Respir Crit Care Med 2008;178:419-24.)

Pulmonary thromboendarterectomy is considered in symptomatic patients who have hemodynamic or ventilatory impairment at rest or with exercise.

The mean pulmonary vascular resistance in patients undergoing surgery is 800 to 1000 dyn·sec·cm.

Thromboendarterectomy is also considered in patients who have normal or nearly normal pulmonary hemodynamics at rest but in whom marked pulmonary hypertension develops during exercise.

Pulmonary endarterectomy is performed during circulatory arrest, removing obstructive material from each pulmonary artery, and its lobar and segmental branches, (20–30 branches in total), and is the only way to reduce pulmonary vascular resistance by at least 50%.

The operation is performed entirely through a median sternotomy and through the pericardium without having to open the pleura or to dissect the pulmonary artery outside the pericardium.

Circulation. 2006;113:2011-2020

It is interesting to note that the mortality rate from this operation is closely related to the haemodynamic severity. For pulmonary resistance 900 dynes/s/cm-5, the mortality rate was 4%, and increased to 10% in patients with resistance between 900–1,200 dynes/s/cm-5, and to 20% for higher resistance.

For the last 40 patients of the series,the authors excluded operating on patients with the very distal form of thomboembolism associated with severe haemodynamic alterations, and the mortality rate dropped to 5%.

Circulation. 2006;113:2011-2020

Aspirating>dissector

Patent lumen

Obstructed lumen

Thromboembolicmaterial being removedwith forceps Circulation. 2006;113:2011-2020

The only absolute contraindication to thromboendarterectomy is the presence of severe underlying lung disease, either obstructive or restrictive

Advanced age, severe right ventricular failure, and the presence of collateral disease influence the risk assessment but are not absolute contraindications.

Placement of a filter in the inferior vena cava is recommended before surgery in all pts except those with a clearly defined source of emboli other than the deep veins in the legs.

Preoperative predictors of favorable outcomes include

1- A pulmonary vascular resistance of less than 1200 dyn • sec • cm−5

2- The absence of major coexisting conditions.Patients in whom the postoperative pulmonary vascular

resistance decreases by at least 50%, to a value of less than 500 dyn • sec • cm−5, have a more favorable.

(Circulation 2007;115:2153-8.)

Pulmonary EndarterectomyChance of cure in proximal obstruction driven

Pulmonary Hypertension only

Surgical classification Group1: fresh thrombus in main lobarGroup 2: intimal thickening prox. to segmental

arteriesGroup 3: within distal segmental arteriesGroup 4: distal vasculopathy w/o visible

thromboembolic ds.

Group 1 & 2 - most favorable outcome.(J Thorac Cardiovasc Surg 2007;133:58-64.)

Early diagnosis and PEA early can decrease small vessel contribution to PVR i.e and make a patient better PEA candidate

Medical bridge to PEA with vasodilators in pts. with high Pre –Op PVR who otherwise are good PEA candidate .

Proposed way to determine if PEA will lower PVR

Rt heart cath with Pulm. Artery Occlusion technique:

- based on assumption of decay PAOP waveform.

- PVR may be partitioned to large arterial ( upstream) and small arterial + venous ( downstream).

Sample pulmonary artery pressure occlusion waveforms from 2 patients with (A) primarily upstream resistance (note the relatively rapid drop in pressure to Ppao) and (B) significant downstream resistance (longer time is needed for the pressure to reach Ppao)

N Eng J Med,2011, V ol 345, No 20

The 30-day mortality ranges from less than 5% in the most experienced centers to 10% in general.

The two most common anticipated postoperative sequelae are –

1-The pulmonary-artery steal syndrome 2-Reperfusion pulmonary edema

(J Thorac Cardiovasc Surg 2007;133:58-64.)

EXPERIENCE AND RESULTS WITH PULMONARY THROMBOENDARTERECTOMY-A SINGLE INSTITUTION EXPERIENCE INTHE INDIAN SUBCONTINENTChattuparambil B, Shetty D P, Cherian G, Murali Mohan BV, Karthik GA, Punnen JNarayana Hrudayalaya Institute of Cardiac Sciences, No. 258/A, Bommasandra IndustrialArea, Anekal Taluk, Bangalore, India .PIN-560099

Between June 2004 and December 2010 209 patients referred to our institute with CTEPH underwent Pulmonary Thrombo Endarterectomy. The diagnosis was based on 64-slice CT Pulmonary Angiography. The data was analysed retrospectively.

RESULTS209 patients in the 15-69 year age group underwent PTE between June 2004 andDecember 2010. The male: female ratio was 1.5:1.2 ,5 patients had CTEPH, 4 had acutepulmonary embolism with unstable hemodynamics and failure of thrombolysis. Twopatients underwent redo PTE. 154 cases were isolated PTE while 55 were combinedprocedures. 47.8% (100/209) had proven deep venous thrombosis .The overall mortalityfor the procedure was 12.9% (27/209). The causes of mortality were persistent pulmonaryarterial hypertension in 66.6% (18/27), reperfusion edema in 22.2 % (6/27) andmechanical injury in 11.1%(3/27).The pulmonary arterial pressure regressed to <40 mmHg in 71.7% (150/209) .The mean duration of ICU stay was 6 days (3-50).The meanduration of ventilatory support was 3.3 days (1-19).15 patients required ExtracorporealMembrane Oxygenation (ECMO) support for varied reasons. Of these, there were twosurvivors. The mean duration of hospital stay was 13 days (9-60). Two patients died outof hospital, one of recurrent pulmonary embolism following discontinuation ofanticoagulation and one of persistent pulmonary arterial hypertension.180 patients arestill on regular follow up, and 30 of them have persistent pulmonary hypertension withNYHA class I-III symptoms. The rest are doing extremely well with good quality of life.

Balloon Pulmonary-Artery AngioplastyBalloon pulmonary-artery angioplasty is an alternative

therapy in selected patients who have inoperable disease due to distal surgically inaccessible disease or persistent or recurrent pulmonary hypertension after thromboendarterectomy.

Successful balloon pulmonary angioplasty may reduce pulmonary-artery pressure in patients with chronic thromboembolic pulmonary hypertension

However, experience with this procedure is very limited, and it is rarely performed

Masaharu Kataoka, MDCIRCINTERVENTIONS.112.971390 Published online before print November 6, 2012

Balloon Pulmonary Angioplasty for Treatment of Chronic Thromboembolic Pulmonary HypertensionJeffrey A. Feinstein, MD, MPH; Samuel Z. Goldhaber, MD; James E. Lock, MD;Susan M. Ferndandes, PA-C;

Michael JLandzberg, MD

Background—Although pulmonary thromboendarterectomy is increasingly successful for the definitive treatment of chronic thromboembolic pulmonary hypertension (CTEPH), not all patients have surgically accessible disease. Others are poor surgical candidates because of comorbid illness. Therefore, for selected patients, we defined and implemented an alternative interventional strategy of balloon pulmonary angioplasty (BPA).

Methods and Results—Eighteen patients (mean age, 51.8 years; range, 14 to 75 years) with CTEPH underwent BPA; they averaged 2.6 procedures (range, 1 to 5) and 6 dilations (range, 1 to 12). Selection of pulmonary artery segments for

dilation required (1) complete occlusion, (2) filling defects, or (3) signs of intravascular webs. After an average of 36

months of follow-up (range, 0.5 to 66 months), the average New York Heart Association class improved from 3.3 to

1.8 (P,0.001), and 6-minute walking distances increased from 209 to 497 yards (P,0.0001). Pulmonary artery mean

pressures decreased from 43.0612.1 to 33.7610.2 mm Hg (P50.007). Eleven patients developed reperfusion

pulmonary edema; 3 required mechanical ventilation.

Conclusions—BPA reduces pulmonary artery hypertension in patients with CTEPH and is associated with long-term improvement in New York Heart Association class and 6-minute walking distances. BPA is a promising interventional technique that warrants randomized comparison with medical therapy in CTEPH patients who are not surgical candidates. (Circulation. 2001;103:10-13.)

Key Words: balloon n angioplasty n embolism n thrombus n pulmonary heart disease

Pulmonary transplantationThe lungs, in contrast to other transplantable organs, are

in contact with the external milieu through the tracheobronchial tree and are at risk of pneumonia during donor resuscitation.

Recipient selection criteria1. age <55 yrs; 2. absence of mechanical respiratory insufficiency due to

scoliosis;3. absence of phrenic paralysis4. absence of recent neoplastic disease or other potentially

life-threatening diseases.

Indications for transplant Patients with a life expectancy of <1 yr,consistent with a

functional status of NYHA stage III orIV.

Recent worsening of dyspnoea and haemodynamic

parameters, such as a right atrial pressure of >12 mmHg,

pulmonary arterial pressure >60 mmHg, a cardiac index

<2.2 L/min-1/m-2 or indexed pulmonary resistance >30 U

Lung transplant for CTEPH

Heart and lung, b/l lungs, single lungHeart lung best less bronchial ischemia,

heart already adapted to pulm. CirculationAn advantage of bilateral lung

transplantation is that the donor heart can be transplanted into another recipient awaiting heart transplantation alone

True to all: life long immune supression, rejections ( acute, chronic), susceptibility to viral, fungal infections)

Eur Respir J 2004; 23: 637–648.

In the series of 101 pulmonary transplants performed for pulmonary hypertension at the Marie-Lannelongue Hospital between 1986–2002, 18 were for CTEPH. There were 70 heart-lung, 28 bilateral and only three single lung transplants. The perioperative mortality was y20% and was not significantly different between the operation performed

Eur Respir J 2004; 23: 637–648.

Eur Respir J 2004; 23: 637–648.

Medical TherapyAnticoagulation is prescribed in most

patients with chronic thromboembolic pulmonary hypertension.

Among patients with unprovoked or idiopathic pulmonary embolism, an indefinite duration of anticoagulation has reduced the risk of recurrent venous thromboembolism & CTEPH.

(Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003;349:631-9.)

About 50% CTEPH rejected for PEAPt. w/ high PVR mainly d/t small vessels – poor surgical

candidates.

Traditional therapies: Anticoagulants, diuretics, digitalis, oxygenAgreement on Anticoagulation to in situ thrombosis

( goal INR 2-3) Diuretics for volume overload in R CHF.

Novel Therapies Prostacyclin analogues, Endothelin receptor blocker PDE 5 inhibitor

Situations for medical RX in CTEPH

1) can’t do PEA ( too much distal or small vessel dz) or not a candidate for other reasons.

2) can do PEA, but PVR too risky high or PEA is far away

bridge to PEA.

3) post PEA still w/ symptoms and PVR high

Prostacyclin agonist

Powerfull systemic & pulmonary vasodilator

Platelet aggregation inhibitorAntiproliferativeCytoprotectiveFibrinolytic

Epoprostenol- - short half life of 3 min - continuous iv infusion through tunnelized catheter - started at 1ng/kg/min & gradually increased toby 1

ng/kg/min every 12 hr upto 10 ng/kg/min - side effects are jaw

pain,headache,diarrheas,flushes,lower limb pain,nausea,vomitting (Robbins et al

1998,chest 114:1269-1275)

Treprostinil - S/C administration - 22.5 ng/kg/min(Results based on TRIUMPH study) ILLOPROST - By inhalation - six to nine inhalation a day for at least 30 min - Iloprost is given by 2.5- or 5.0-µg ampules via a dedicated

nebulizer  (Olschewski et al ,2002)Beraprost - oral - significant improvement on the 6 MWD in IPAH in double

blind study conducted by Galie et al .2002,NEJM 353:2148-2157.

EpoprostenolBressler P. et al evaluated bridging x 6

wks pre PEA ( n=6) w severe CTEPH ( PVR>1200).

Result: mean reduction in PVR of 28% ( median 33%). Post PEA improved CI, mPAP and TPR

P. Bresser et al Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension Eur Respir J 2004; 23: 595 - 600

Endothelin receptors antagonistPowerful vasoconstrictor(ET-A receptors)Promoter of smooth muscle cell proliferation(ET-B receptors)

Dual ET-1 receptors antagonist Bosentan-(2008 International PHA Conference and Scientific

Sessions)

- side effects systemic vasodilation and hepatic dysfunction

- The approved dosage of bosentan is 125 mg twice dailySelective ET-A receptor antagonists- Sitaxsentan – 100mg daily dose - 65 m increase in 6MWD (Barst et al.2002) - once daily at a 100 mg dose Ambrisentan- once daily at a 5-mg dose

Eur Respir J 2012; 20: 203 - 400

PDE 5 inhibitiorsSildenafil (The recommended dosage is 20 mg three times

daily, but dosages as high as 80 mg three times daily have been used safely )

Tadalafil (The effective dose was 40 mg once daily.)

Vardenafil Stabilizes c GMP and NO; potent

pulmonary vasodilator.

(Chronic thromboembolic and pulmonary arterial hypertension share acute vasoreactivity properties. Chest 2006;130:841-6.)

J Heart Lung Transplant. 2010 Jun;29(6):610-5

Nonoperable distal progressive CTEPH ( mPAP= 52, PVRI 1,935) On cath pt. had vasodilator reactivity to inhaled nitric oxide.

Results: after 6 month 6MWD and PVR improved.

Ghofrani et. al; Sildenafil for long –term treatment of non – operable chronic thromboembolic pulmonary hypertension. Am J Resp Crit Care Med 2003; 167: 1139 - 1141

Calcium channel blockers

- vasodilator

- Nifedipine 90-240 mg/day or dilitiazem 360-900 mg/day

- effective in pts having positive response to acute testing with vasodilators

- only 12.6% of pts could be treated by CCB

(Based on studies by Rich et al & Sitbon et al study on 557 pts in 1998 published in Eur Respir J 2:265-270)

Role of IVC filters in CTEPH sparse evidence in CTEPH

F/u study (n=18) IVC Filter to prevent recurrence PE long term as well as high risk periop period.*

IVC Filters + A/C reoperation in post PEA**

Experts disagree on utility of IVC, slightly more agreement on periop IVC Filter placement for PEA.

**Hajduk et al, implantation of LGM inferior vena Cava Filters in patients with Chronic Pulmonary Hypertension during a course of major vessel Thromboembolism: observation of 18 patient ( in polish). Pneumonol Alergol Pol 1996; 64:154 – 160

**Mo M et al, Reoperative pulmonary Thromboendarterectomy. Ann Thorac Surg 1999; 68 : 1770 - 1776

Potential future therapiesTyrosine kinase inhibitors - PDGF inhibitors - causes regression of pulmonary vascular remodellingRho Kinase inhibitors - causes vasodilation & prevents vascular remodeling - Fasudil ( Fagan et al 2010,Am J Physiol Lung Cell Mol Physiol 287:L 656-

664)Statins- - enhances bone morphogenetic receptor II ( BMPR-II) ( Hu et al 2006,Biochem Biophys Res Commun 339:59-64)Vasoactive Intestinal Peptide- - potent bronchodilator - systemic & pulmonary vasodilator - via inhalation (Said et al 2007,circulation 115:1260-1268)

SSRI - Protective effects on occurrence of

PAH in animal modelAdrenomedullin- - vasodilator peptide - smooth muscle cell proliferator

inhibitor - iv/inhalation ( Nagaya et al 2004,circulation

109:351-356)

Guanylate cyclase (sGC) stimulatorData from the Phase 3 CHEST-1 trial (Chronic

Thromboembolic Pulmonary Hypertension sGC-Stimulator Trial)

261 patients were randomized and treated with either riociguat or placebo 

Riociguat also showed statistically significant improvements in select secondary endpoints, including pulmonary vascular resistance (PVR) (P<0.0001), N-terminal prohormone brain natriuretic peptide (NT-proBNP) (P<0.0001) and WHO functional class (FC) (P=0.0026).

Recommendations for chronicthromboembolic pulmonary hypertensionStatement Class Level

The diagnosis of CTEPH is based on the presenceof pre-capillary PH (mean PAP 25 mmHg,PWP 15 mmHg, PVR .2 Wood units) inpatients with multiple chronic/organizedocclusive thrombi/emboli in the elasticpulmonary arteries (main, lobar, segmental,subsegmental)

I C

In patients with CTEPH lifelong anticoagulation isindicated

I C

Surgical pulmonary endarterectomy is therecommended treatment for patients withCTEPH

I C

European Heart Journal (2009) 30, 2493–2537

Statement Class Level

Once perfusion scanning and/or CT angiographyshow signs compatible with CTEPH, the patientshould be referred to a centre with expertise insurgical pulmonary endarterectomy

IIa C

The selection of patients for surgery should bebased on the extent and location of theorganized thrombi, on the degree of PH, and onthe presence of co-morbidities

IIa C

PAH-specific drug therapy may be indicated inselected CTEPH patients such as patients notcandidates for surgery or patients with residualPH after pulmonary endarterectomy

IIb C

European Heart Journal (2009) 30, 2493–2537

In patients with operable CTEPH, PTE is the treatment of choice for improved hemodynamics functional status, and survival. Level of evidence: low; benefit: substantial; grade of recommendation: B.

In patients with CTEPH deemed inoperable or with significant residual postoperative PH, balloon dilation, PAH medical therapy, or LT may be considered. Level of evidence: low; benefit: small/weak; grade of recommendation: C.

Pulmonary Arterial Hypertension: ACCP Guidelines 2007

Indian perspectiveFirst heart-lung transplant in India in 1999 in

Madras medical mission 2 more patients underwent transplant afterthatinitial experience is encouraging

Apixaban for Extended Treatment of VenousThromboembolismBackgroundApixaban, an oral factor Xa inhibitor that can be

administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism.

MethodsPatients with venous thromboembolism who had

completed 6-12 months of anticoagulation therapy were randomized to apixaban 2.5 mg twice daily (n = 840), apixaban 5 mg twice daily (n = 813), versus placebo twice daily (n = 829). Study drugs were administered for 12 months.

 N Engl J Med 2012;Dec 8

Interpretation:Among patients with venous

thromboembolism who had completed 6-12 months of anticoagulation therapy, extended therapy with apixaban (2.5 mg or 5 mg twice daily) reduced symptomatic recurrent venous thromboembolism or death. Clinical benefit was accomplished without an increase in major bleeding; however, clinically relevant nonmajor bleeding was increased with apixaban 5 mg compared with placebo

N Engl J Med 2012;Dec 8

ASPIRE

Recurrent venous thromboembolism at 37 months: 14% with aspirin vs. 18% with placebo (p = 0.09)

The following events are reported per year for aspirin vs. placebo:

Major vascular event: 5.2% vs. 8.0% (p = 0.01)

Major bleeding and clinically relevant nonmajor bleeding: 1.1% vs. 0.6% (p = 0.22)

Major vascular event, major bleeding, or all-cause mortality: 6.0% vs. 9.0% (p = 0.01)

Trial design: Patients who had a first episode of unprovoked venous thromboembolism and completed initial anticoagulation therapy were randomized to aspirin 100 mg daily (n = 411) vs. placebo daily (n = 411).

Results

Conclusions• Among patients with unprovoked first venous

thromboembolism who completed initial anticoagulation therapy, the use of aspirin failed to reduce the primary outcome of recurrent venous thromboembolism

Brighton TA, et al. N Engl J Med 2012;Nov 4:[Epub]

(p = 0.09)

Aspirin

% 14

18

Placebo

ConclusionsChronic thromboembolic pulmonary hypertension

(CTEPH) is an important complication of acute VTE

The average delay from the onset of symptoms to establisment of the correct diagnosis can range from 2 to 3 years

2D ECHO is an early & important laboratory method to determine the severity of the disease

V/Q sscannig gives considerable clues in the diagnosing of CTEPH

Right- heart catheterization should be considered in any patient with unexplained dyspnea and segmental or larger defects on V/Q perfusion scanning, especially if there is echocardiographic evidence of right atrial or right ventricular dysfunction