Ashok Kirumaki MDDirector Pulmonary Hypertension Program

Assistant Professor Pulmonary, Critical Care and Sleep Department of Internal Medicine

Saint Louis University

Targeting Pulmonary Hypertension in Thromboembolic disease, Left heart

disease and Pulmonary disorders

No Financial Disclosures

Learning Objectives

• Classification and Brief overview of PAH• Pulmonary hypertension in Left heart disease• Pulmonary hypertension in venous

thromboembolism• Pulmonary hypertension in common lung

disease – COPD

Definition of Pulmonary Hypertension

PH Mean PAP ≥ 25 mm Hg

PAH Mean PAP ≥ 25 mm Hg plus PCWP/LVEDP ≤ 15 mm Hg

(Absent) AHA -PVR > 3 Wood Units

Badesch D et al. J Am Coll Cardiol. 2009; 54 S55- S66

ARTERIAL

VENOUS

(Dana Point) CLINICAL CLASSIFICATION 2009

THROMBI

HYPOXIA

Simonneau G et al. J Am Coll Cardiol. 2009 ; 54 ; S 43- S54

Pre capillary capillary Post

capillary

Pulmonary venous

Chronic lung

disease

CTEPH

Pulmonary Arterial

hypertension

TO SYSTEMIC CIRCULATION

LOCATION OF OBSTRUCTION

GOOD FLOW

NORMAL

REVERSIBLE VASOCONSTRICTION

ADVANCED VASULAR PLEXIFORM LESIONS

IRREVERSIBLE DISEASE

Smooth muscle

hypertrophy

Intimal proliferation

PATHOGENESIS OF PULMONARY ARTERIAL HYPERTENSION

DIAGNOSTIC APPROACH TO PULMONARY HYPERTENSION

PAH treatment Goals

Fewer / Less severe symptoms

Improved exercise capacity

Improved hemodynamics

Prevention of clinical worsening

Improved quality of life

Improved survival

ACCP Consensus :Definition of a responder

PAP mean decreased by 10 mm Hg&

Fall in PA Mean pressure < 40 mm Hg&

No change or increase in cardiac output

Survival in IPAH – (50% of acute responders or ≤ 6% of IPAH patients )

Sitbon O et al. Circulation 2005;111:3105-3111

Copyright © American Heart Association

p = 0.0007

Calcium Channel Blockers ONLY if “ Vasodilator Responsive”

Pulmonary Vasodilation Systemic vasodilation Neg Inotropy

↑cardiac output↓cardiac output

Highly Varibale –Needing larger doses

Influenced by the drug and the disease

Risks of getting it wrong : tachycardia,dyspnea ,syncope and death

CCBs should NOT be used empirically

Key Point

Endothelin 1Nitric Oxide

SildenafilTadalafil

Bosentan Ambrisentan

FDA approved Medications for PAH with their mechanisms of action

PROSTACYCLIN ANALOGUES

EpoprostenolTreprostinil

Treprostinil IloprostTreprostinil

What is the Optimal Treatment Strategy?

Etiology of pulmonary hypertension on Echocardiogram

KEY POINT --- PAH 2.3% majority in the patients are left heart disease and pulmonary disease

PH due to left heart disease WHO group II

• Due to systolic dysfunction--- heart failure with reduced ejection fraction HFREF

• Due to diastolic dysfunction- Heart failure with Preserved Ejection fraction

HFPEF

• Due to valvular heart disease – Aortic or Mitral valve disease

Pathogenesis of PH in Left heart disease

• Passive process-- backward transmission of elevated Left atrial pressure (LAP)

• Reactive (Out of Proportion)--Chronically elevated LAP with lead to pulmonary vascular remodeling causing functional and or structural abnormalities of distal pulmonary arteries

• Fixed- medial hypertrophy and intimal fibrosis

PH is present in 2/3rd of patients with heart failure with reduced ejection fraction

High PAP /low

RVEF

(J Am Coll Cardiol 2001;37:183–8)

Low pap/nl RV

Low pap/low

RVEF

High PAP/nl RVEF

Pre-transplant pulmonary hypertension, even when reversible to a PVR of <2.5 WU, is associated with a higher mortality

J Heart Lung Transplant 2005;24:170 –7

This group of patients will need heart and lung transplantation

Fixed Pulmonary hypertension in a contraindication to heart transplantation alone

FIRST TRIAL -EPOPROSTENOL

A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST)

471 PATIENTS WITH ADVANCED HFREF

CONTINUOUS EPOPROSTENOL

INFUSION + STANDARD OF CARE

STANDARD OF CARE

American Heart Journal - Volume 134, Issue 1 (July 1997)

Increased mortality rates and no evidence of improved quality of life

American Heart Journal - Volume 134, Issue 1 (July 1997)

CHRONIC USE OF EPOPROSTENOL IN PATINETS WITH HEART FAILURE IS CONTRAINDICATED

American Heart Journal - Volume 134, Issue 1 (July 1997)

Endothelin Receptor Antagonists

• Endothelin plasma levels are elevated in heart failure and correlate with severity

• In animal models of HF – ERAs prevented LV remodeling and improved exercise capacity

• Short-term hemodynamic effects were encouraging with ERA bosentan and tezosentan which led to RCT

Research on Endothelein Antagonists in Chronic Heart Failure (REACH -1)

NYHA class III /IV 370 patinet

Heart failure

PLACEBOBOSENTAN 500MG BID

26 WEEKS

STOPPED PREMATURELY – SAFETY ELEVATED LIVER FUNCTION TEST

European Journal of Heart Failure 1999;1:197-200

Randomized

Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure (ENABLE)

NYHA class III /IV 1613 Patients

Heart failure EF< 35%

PLACEBOBOSENTAN 125 MG BID

1.No improvements in Outcomes 2.Increased risk of early heart failure

exacerbation due to fluid retention with Bosentan

Circulation. 2007;116:1555-1562

Randomized to 12 weeks of treatment withSildenafil (50 mg orally 3 times daily) or placebo

Improvement in 6-minute walk distance (29 m versus placebo; P 0.047) and

Minnesota Living With Heart Failure score (14 versus placebo; P 0.01)

Sildenafil group experiencedfewer hospitalizations for HF

Sildenafil Improves Exercise Capacity and Quality of Life in Patients with Systolic heart failure with pulmonary Hypertension

PDE 5 inhibitor in heart failure

• NO RCT has looked into long term use of this class of drugs in pulmonary Hypertension due to HFpEF

Management of Pulmonary Hypertension due to left heart disease

• Optimizing traditional therapies for Heart failure

• Out of proportion Pulmonary hypertension – look for other causes –V/Q scan, PFT and PSG

• RHC can be done to clarify hemodynamic details

• NO CLEAR INDICATIONS FOR ADDITIONAL PAH specific therapies

NO evidence that Drugs approved for PAH are effective or safe in this setting

Medications that lower PVR increase flow and this increase in venous return to the left ventricle may increase left ventricular filling pressure resulting in deterioration rather than improvement

HF with Preserved EF -- HEFPF

Occurs with the Left ventricle is unable to accommodate an adequate volume of blood during diastole and maintain an appropriate stroke volume

Commonly due to Left ventricular diastolic dysfunction

Risk factors

• Post menopausal Women• Hypertension• Ischemic Heart Disease• Diabetes Mellitus• Obesity• Atrial fibrillation• Age --- 50% in HF patient greater than 70 years

RHC – in HFPEF

PCWP – may be borderline high at rest

Saline challenge or exercise challenge in this setting may induce an increase of PCWP

No consensus on protocols for either saline or exercise testing

Page 32 Pulmonary hypertension with preserved ejection fraction work up

Even after normalization of the left atrial pressure

Whether modification of the metabolic syndrome features dietary modification, weight reduction and aggressive blood pressure control results in improvements in patients symptoms and PAP with HFPEF with elevated pap is still unknown?RELAX trial – ongoing – Sildenafil in HFPEF

Summary - WHO class II

• Optimizing traditional therapies for Heart failure

• NO PAH medication is FDA approved and may be harmful

• Remember a normal PCWP at rest does not rule out Diastolic heart failure as the cause of Pulmonary hypertension

Definition of CTEPH WHO class IV

• At least 3 months of effective anticoagulation• Mean pulmonary artery pressure ≥ 25 mmhg

and PCWP ≤ 15 mmhg• One of more mismatched segmental or large

perfusion defects detected by V/Q scanning, pulmonary angiography or multidetector CT angiography

Natural history of Acute PE

• Total or near total resolution and restoration of normal pulmonary hemodynamics within 30 days in more than 90 percent of patients.

• Right heart pressures return to near normal values in most patients within 10 to 21 days.

• A minority of patients who have survived an acute PE develop CTEPH

Acute PE – clot removed from Trendlenberg embolectomy

CTEPH – white fibrotic clot

Incidence of Symptomatic CTEPH

1.0 % at 6 months3.1 % at 1 year 3.8 % at 2 years

No cases after 2 years -10 year follow up

N Engl J Med 2004;350:2257-64.

CTEPH is a dual vascular disorder

• Obstruction of the vascular bed by non resolving or recurrent thromboembolism or in situ pulmonary-artery thrombosis

• In the non occluded areas pulmonary vascular remodeling and the development of a hypertensive pulmonary arteriopathy are seen

• The extent of vascular obstruction is a major determinant of pulmonary hypertension

• In majority of patients, more than 40 percent of the pulmonary vascular bed is obstructed.

Natural History of CTEPH

• “Honey-moon” period of months to years, during which the patient has no clinical symptoms

• For this reason, the early natural history of the condition is not completely known

• 25-30 % deny previous symptoms or diagnosis of VTE

• Estimated from PE registries 0.1- 9.1%

Presentation

• Nonspecific symptoms including exercise intolerance and dyspnea, chest pain, fatigue and syncope

• Most patients with chronic thromboembolic pulmonary hypertension present late in the course of the disease with Progressive dyspnea, hypoxemia and Right ventricular failure

RISK factors for CTEPH

• Traditional plasmatic prothrombotic risk factors are not risk factors for CTEPH

• A negative CT PE protocol does not rule out CTEPH however a negative V/Q scan rules out this disorder

Risk factors -Observational case –control analysis

• History of splenectomy• VA shunts and pacemakers with history of device

infection• IBD• Thyroid hormone replacement• Circulating antiphospholipid antibody• Survived cancer• Non-O blood groups• Elevated plasma coagulation factor VIII• Carriers of Fibrinogen A alpha THr312a1a polymorphism

Circulation. 2007;115:2153-2158

CTEPH patients with history of splenectomy, infected VA shunt, inflammatory bowel disease or osteomyelitis have worse outcome compared to one without a clinical risk factor

Circulation. 2007;115:2153-2158

The presence of associated medical conditions predicts increased operative risk and worse long-term outcome in CTEPH.

Predictors of Outcome in Chronic Thromboembolic Pulmonary HypertensionDiana Bonderman, MD; Nika Skoro-Sajer, MD; Johannes Jakowitsch, PhD;Christopher Adlbrecht, MD; Daniela Dunkler, MSc; Sharokh Taghavi, MD; Walter Klepetko, MD;Meinhard Kneussl, MD; Irene M. Lang, MD

N Engl J Med, Vol. 345, No. 20 November 15, 2001

Pulmonary Thromboendarterectomy

Curative in patients with CTEPH

Pulmonary Endarterectomy is the treatment of choice

Operable mortality rates in specialized centers is < 5% but 36 % are non operable

Am J Respir Crit Care Med Vol 178. pp 419–424, 2008

1994 and 2006, 157 patients

Long-term survival after PEA is excellent

Long-term Outcome after Pulmonary Endarterectomy

75% of patients, the long-term functional outcome was good and almost a half of the patients recovered good exercise tolerance.

Am J Respir Crit Care Med Vol 178. pp 419–424, 2008

Long-term Outcome after Pulmonary Endarterectomy

Candidates for Endarterectomy

• Confirmed CTEPH in NYHA class II, Class III and class IV

• A preoperative PVR > 300 dynes.s.cm-5• Proximal disease – Thrombi in the main lobar or

segmental pulmonary arteries • Absence of severe comorbidities

• 40% of all newly diagnosed patients are currently on PAH vasodilator treatment in clinical trials in Europe

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;52(25):2127-2134

16 week studySymptomatic Inoperable

CTEPH with 6MWD<450m

BENEFiT STUDY

Bosentan for Treatment of Inoperable Chronic Thromboembolic Pulmonary Hypertension

TREATMENT effect1.Statistically significant decrease in

PVR and hemodynamic improvement

NO CHANGE IN 6MWD

J Am Coll Cardiol. 2008;52(25):2127-2134

BNP

Ongoing multicenter trials in CTEPH

• CTREPH--- subcutaneous Treprostinil

• CHEST– Riociguat

• Ongoing Vasodilator trials in patients with nonoperable CTEPH will clarify whether medical therapy for CTEPH is effective

Pulmonary hypertension associated with lung disease or Hypoxemia WHO Group III

• COPD• ILD• Alveolar hypoventilation disorder• Sleep apnea

Pathogenesis of Pulmonary hypertension in COPD

Pulmonary Hypertension and COPD

• PH when present in patients with severe COPD is mild to moderate - extremely prevalent

Mild (PAP 26–35 mmHg)Moderate (36–45 mmHg)Severe (45 mmHg)

• In patients listed for LVRS or lung transplantation the prevalence of PH would lie between 70–90%.

Natural History of PH in COPD

• PH may first appear during exercise and during sleep

• PH occurs in COPD - cardiac output is usually normal and PVR increases mildly

• The main feature of PH in COPD is it mild to moderate degree 20-35 mmHg

Suspect PH In COPD if

• Distinctive PFT pattern with less severe airflow obstruction but more severe hypoxemia, hypocapnia and markedly reduced DLCO

• PH even if mild at baseline may worsen in sleep , during exercise and during acute exacerbation of the disease

The progression of pH in COPD is generally slow and PAP usually remains stable over 2-5 years

The level of PAP is a good indicator of prognosis

Thorax 1981 ;36:752-758Weitzenblum, Hirth, Ducolone, Mirhom, Rasaholinjanahary, Ehrhart

Ari Chaouat, et al Am J Respir Crit Care Med Vol 172. pp 189–194, 2005

Survival of patinets with pulmonary hypertension with no other cause and COPD in 3 groups PAP > 40 mmHg ,

Between 40 and 20 ,and < 20 mmHg

Sleep and COPD

• Some patients experience transient arterial hypoxemia during REM sleep

• Not related to apneas but alveolar hypoventilation or V/Q mismatch

• The more profound the dips of hypoxemia the more severe the peaks of PH

• Home oxygen protocol reduced mean PAP in 8 weeks of therapy

Treatment of PH in COPD is based on oxygen therapy

LTOT –Long term Oxygen therapy for greater than 18 hours per day significantly decreased resting and exercise PAP after 6

months of use

NOTT –Nocturnal Oxygen therapy trialMRC – Medical research council study

The oral administration of the endothelin receptor antagonist bosentan not only failed to improve exercise capacity but also deteriorated hypoxemia and functional status in severe chronic obstructive pulmonary disease patients

Eur Respir J 2008; 32: 619–628

Key points of PH in COPD

• A pap pressure of >40 mmhg is unusual in a stable state of COPD with PH

• PH even if mild at baseline may worsen in sleep , during exercise and during acute exacerbation of the disease

Summary

• PAH – pulmonary arterial hypertension is present in 2.3 % and is relatively uncommon and most patinet (90%) with PH are not appropriate for therapies with PAH specific medication .

• No PAH medication is approved in patients with left heart disease, COPD or CTEPH and in fact is likely to cause harm in these settings.

Summary• A normal PCWP on RHC at rest does not rule out

Diastolic dysfunction as the cause of PH

• CTEPH is a dual vascular disease with risk factors very different from acute PE

• A negative V/Q scan (and not CT PE protocol) is needed to rule out CTEPH

• Pulmonary endarterectomy is the treatment of choice in CTEPH and is curative

Summary

• In COPD patinets PH is usually seen in advanced disease and is usually mild with PAP less than 40 mmHg but worsens in REM sleep, periods of acute exacerbation and with exertion and has poor prognosis

• No Role for PAH specific therapies in patinets with PH due to left heart disease,COPD or CTEPH except in an approved clinical trial

Thank you

Thank You