Pulmonary Hypertension, Current Guidelines and Future Directions of Therapy.

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Health & Medicine

Published on January 18, 2009

Author: basselericsoussi

Source: slideshare.net

Bassel Ericsoussi, MD Pulmonary and Critical Care Fellow University of Illinois at Chicago

 

Classification The World Health Organization (WHO) classified pulmonary hypertension into five groups on the basis of mechanisms: Group I. Pulmonary arterial hypertension Group II. Pulmonary venous hypertension Group III. Pulmonary hypertension associated with hypoxemia Group IV. Pulmonary hypertension due to chronic thrombotic disease, embolic disease, or both Group V. Miscellaneous

The World Health Organization (WHO) classified pulmonary hypertension into five groups on the basis of mechanisms:

Group I. Pulmonary arterial hypertension

Group II. Pulmonary venous hypertension

Group III. Pulmonary hypertension associated with hypoxemia

Group IV. Pulmonary hypertension due to chronic thrombotic disease, embolic disease, or both

Group V. Miscellaneous

N ENGL J MED 351;16 WWW.NEJM.ORG OCTOBER 14, 2004

Definition Disease of the small pulmonary arteries Increased MPAP > 25 mm Hg at rest or > 30 mm Hg with exercise, with a PCWP and LVEDP of less than 15 mm Hg

Disease of the small pulmonary arteries

Increased MPAP > 25 mm Hg at rest or > 30 mm Hg with exercise, with a PCWP and LVEDP of less than 15 mm Hg

The Pathophysiology of PAH Vasoconstriction Remodeling: Smooth-muscle cell and endothelial-cell proliferation, vascular wall inflammation Chronic vascular thrombosis : Thrombotic arteriopathy , thrombosis in situ.

Vasoconstriction

Remodeling: Smooth-muscle cell and endothelial-cell proliferation, vascular wall inflammation

Chronic vascular thrombosis : Thrombotic arteriopathy , thrombosis in situ.

Also there is an abnormal angiogenic response to hypoxia, increased vascular endothelial growth factor (VEGF), formation of plexiform lesions N ENGL J MED 351;16 WWW.NEJM.ORG OCTOBER 14, 2004

Also there is an abnormal angiogenic response to hypoxia, increased vascular endothelial growth factor (VEGF), formation of plexiform lesions

Natural History and Survival In the 1980s, the median survival of patients was 2.8 years after diagnosis Death can result from a delay in the diagnosis and treatment of this disease The development of new drugs increased the survival rate to: 68-77% at 1 year 40-56% at 3 years 22-38%at at 5 years

In the 1980s, the median survival of patients was 2.8 years after diagnosis

Death can result from a delay in the diagnosis and treatment of this disease

The development of new drugs increased the survival rate to:

68-77% at 1 year

40-56% at 3 years

22-38%at at 5 years

Poor Prognostic Factors Elevated pulmonary vascular resistance History of right heart failure (NYHA) functional class III or IV Elevated right atrial pressure Decreased cardiac output Low mixed venous oxygen saturation. Six minutes walk test (the distance walked in six minutes) has a strong association with mortality

Elevated pulmonary vascular resistance

History of right heart failure (NYHA) functional class III or IV

Elevated right atrial pressure

Decreased cardiac output

Low mixed venous oxygen saturation.

Six minutes walk test (the distance walked in six minutes) has a strong association with mortality

 

 

Hypoxia and PAH Hypoxia: Vasoconstriction in the pulmonary vasculature Vasodilation in systemic vessels Chronic hypoxemia is due to: Impaired cardiac output Right-to-left shunting through a PFO or a congenital heart defect. Acute: reversible changes in vascular tone Chronic: induces structural remodeling

Hypoxia:

Vasoconstriction in the pulmonary vasculature

Vasodilation in systemic vessels

Chronic hypoxemia is due to:

Impaired cardiac output

Right-to-left shunting through a PFO or a congenital heart defect.

Acute: reversible changes in vascular tone

Chronic: induces structural remodeling

Appetite Suppressant and PAH Dexfenfluramine Chronic use > 3 mon: PAH Increases the release of serotonin from platelets and inhibits its reuptake Serotonin: Vasoconstrictor Smooth-muscle cell hypertrophy and hyperplasia

Dexfenfluramine

Chronic use > 3 mon: PAH

Increases the release of serotonin from platelets and inhibits its reuptake

Serotonin:

Vasoconstrictor

Smooth-muscle cell hypertrophy and hyperplasia

CNS Stimulants and PAH Methamphetamine , cocaine: Medial hypertrophy of the pulmonary arteries

Methamphetamine , cocaine:

Medial hypertrophy of the pulmonary arteries

CTD and PAH Especially CREST syndrome: 80 % histopathological changes consistent with PAH 10-15 % clinically significant PAH. SLE mixed CTD RA

Especially CREST syndrome:

80 % histopathological changes consistent with PAH

10-15 % clinically significant PAH.

SLE

mixed CTD

RA

HIV and PAH 0.5 % of HIV patients have PAH (x 6-12 normal) Related to the duration of HIV infection. Independent of the CD4 cell count The mechanism is unclear

0.5 % of HIV patients have PAH (x 6-12 normal)

Related to the duration of HIV infection.

Independent of the CD4 cell count

The mechanism is unclear

HHV-8 and PAH HHV-8 causes Kaposi’s sarcoma Endothelial changes in Kaposi’s sarcoma similar to the plexiform lesions in PAH 10/16 pts with PAH: HHV-8 infection in lung tissue specimens

HHV-8 causes Kaposi’s sarcoma

Endothelial changes in Kaposi’s sarcoma similar to the plexiform lesions in PAH

10/16 pts with PAH: HHV-8 infection in lung tissue specimens

Portal HTN and PAH Cirrhosis: 0.73 % histologic changes c/w PAH (x 6 normal) 2-5 % hemodynamic studies showed PAH The risk increases with the duration of portal hypertension The diagnosis of PAH is usually made within 4-7 years after the diagnosis of portal HTN Cirrhosis without portal HTN appears to be insufficient for the development of PAH The mechanism is unclear

Cirrhosis:

0.73 % histologic changes c/w PAH (x 6 normal)

2-5 % hemodynamic studies showed PAH

The risk increases with the duration of portal hypertension

The diagnosis of PAH is usually made within 4-7 years after the diagnosis of portal HTN

Cirrhosis without portal HTN appears to be insufficient for the development of PAH

The mechanism is unclear

Myelodysplastic and PAH Chronic myelodysplastic syndromes, thrombocytosis Caused by: Splenectomy Portal HTN Pulmonary vascular obstructive disease as a result of chemotherapy Infiltration of hematopoietic cells into the pulmonary parenchyma Platelet-derived serotonin, platelet-derived growth factor Vasoconstriction smooth-muscle cell proliferation Correlation between with the platelet count and the level of PAH

Chronic myelodysplastic syndromes, thrombocytosis

Caused by:

Splenectomy

Portal HTN

Pulmonary vascular obstructive disease as a result of chemotherapy

Infiltration of hematopoietic cells into the pulmonary parenchyma

Platelet-derived serotonin, platelet-derived growth factor

Vasoconstriction

smooth-muscle cell proliferation

Correlation between with the platelet count and the level of PAH

Hemoglobinopathies and PAH b -thalassemia: 75 % echocardiograph showed PAH (overestimated) Sickle cell disease: 8-30 % echocardiograph showed PAH The higher the MPAP the higher the mortality PAH increases the risk of death in patients with sickle cell disease Mechanism: Hemolysis, oxyhemoglobin (cell-free hemoglobin) inactivates nitric oxide Vasoconstriction Proliferation Thrombosis

b -thalassemia: 75 % echocardiograph showed PAH (overestimated)

Sickle cell disease: 8-30 % echocardiograph showed PAH

The higher the MPAP the higher the mortality

PAH increases the risk of death in patients with sickle cell disease

Mechanism: Hemolysis, oxyhemoglobin (cell-free hemoglobin) inactivates nitric oxide

Vasoconstriction

Proliferation

Thrombosis

Hereditary Hemorrhagic Telangiectasia and PAH Osler–Rendu–Weber syndrome: 15 % PAH Genes mutations : Transforming growth factor b (TGF- b ) Activin-receptor–like kinase 1 (ALK1)

Osler–Rendu–Weber syndrome: 15 % PAH

Genes mutations :

Transforming growth factor b (TGF- b )

Activin-receptor–like kinase 1 (ALK1)

Genetic Abnormalities and PAH Familial PAH 6% Autosomal dominant In a successive generation, PAH occurs at a younger age and with greater severity than in the preceding generation.

Familial PAH 6%

Autosomal dominant

In a successive generation, PAH occurs at a younger age and with greater severity than in the preceding generation.

 

 

 

Therapeutic Approaches to Pulmonary Hypertension No cure for PAH Goal of treatment: Symptomatic relief Survival prolongation Quality of life improvement

No cure for PAH

Goal of treatment:

Symptomatic relief

Survival prolongation

Quality of life improvement

 

Basic (Conventional) Therapy Activities as tolerated Advanced PAH: limited activity is advised (life-threatening syncope) Oxygen: maintain O2 Sat > 90% Diuretic: right heart failure Digoxin: concomitant intermittent or chronic atrial fibrillation. Pregnancy and labor are contraindicated (OCP if no h/o thromboembolic disease or thrombophilia)

Activities as tolerated

Advanced PAH: limited activity is advised (life-threatening syncope)

Oxygen: maintain O2 Sat > 90%

Diuretic: right heart failure

Digoxin: concomitant intermittent or chronic atrial fibrillation.

Pregnancy and labor are contraindicated (OCP if no h/o thromboembolic disease or thrombophilia)

Anticoagulion in PAH PAH: Thrombotic arteriopathy, thrombosis in situ Recommended in: IPAH Pulm HTN due to chronic thrombotic/embolic disease (group IV) Pulm HTN a/w a-fib RFs for VTE: Heart failure Sedentary lifestyle Thrombophilic predisposition Controversial in PAH associated with an underlying condition Scleroderma –CREST syndrome: increased risk of GI bleeding from luminal telangectasia during anticoagulation Improve prognosis an survival (especially if no response to vasodilators) Warfarin with a target INR between 1.5-2.5 is recommended

PAH: Thrombotic arteriopathy, thrombosis in situ

Recommended in:

IPAH

Pulm HTN due to chronic thrombotic/embolic disease (group IV)

Pulm HTN a/w a-fib

RFs for VTE:

Heart failure

Sedentary lifestyle

Thrombophilic predisposition

Controversial in PAH associated with an underlying condition

Scleroderma –CREST syndrome: increased risk of GI bleeding from luminal telangectasia during anticoagulation

Improve prognosis an survival (especially if no response to vasodilators)

Warfarin with a target INR between 1.5-2.5 is recommended

Simvastatin in PAH Statins: Antiproliferative and anti-inflammatory effects Induce endothelial NO Simvastatin 20-80 mg/day: Improves in 6MW performance Improves in CO Decreases in RVSP Improves survival (Class IV patients )

Statins:

Antiproliferative and anti-inflammatory effects

Induce endothelial NO

Simvastatin 20-80 mg/day:

Improves in 6MW performance

Improves in CO

Decreases in RVSP

Improves survival (Class IV patients )

Aspirin and Plavix in PAH IPAH: Thrombosis in situ Increased Tx A2 (Platelets aggregation) A randomized, double-blinded, placebo-controlled study: ASA and Plavix inhibit platelet aggregation ASA reduces Tx A2 metabolite production without affecting PGI2 metabolite synthesis More studies should be done

IPAH:

Thrombosis in situ

Increased Tx A2 (Platelets aggregation)

A randomized, double-blinded, placebo-controlled study:

ASA and Plavix inhibit platelet aggregation

ASA reduces Tx A2 metabolite production without affecting PGI2 metabolite synthesis

More studies should be done

ASA and Simvastatin in PAH Still under investigation Study completion date: March 2010 Randomized, double blinded study: Group I: Aspirin 81 mg + Simvastatin 40 mg (6 mon) Group II: Aspirin 81 mg + Placebo (6 mon) Group III: Placebo + Simvastatin 40 mg (6 mon) Group IV: Placebo + Placebo (6 mon)

Still under investigation

Study completion date: March 2010

Randomized, double blinded study:

Group I: Aspirin 81 mg + Simvastatin 40 mg (6 mon)

Group II: Aspirin 81 mg + Placebo (6 mon)

Group III: Placebo + Simvastatin 40 mg (6 mon)

Group IV: Placebo + Placebo (6 mon)

CCB in PAH Identify pts that may benefit from CCB Acute vasodilator challenge during right heart catheterization (short-acting agents): IV prostacyclin IV adenosine NO inhaler Don’t use CCB during the acute vasodilator challenge: severe, life-threatening hemodynamic compromise Response to vasodilation: Decrease in the MPAP and of PVR by at least 20% OR, decrease in the MPAP more than 10 mm Hg, to a value lower than 40 mm Hg, with a normal or high CO Response to CCB (10% of all pts): NYHA functional class I or II Normal MPAP, PVR after at least one year of follow-up CCB prolongs survival among these pts

Identify pts that may benefit from CCB

Acute vasodilator challenge during right heart catheterization (short-acting agents):

IV prostacyclin

IV adenosine

NO inhaler

Don’t use CCB during the acute vasodilator challenge: severe, life-threatening hemodynamic compromise

Response to vasodilation:

Decrease in the MPAP and of PVR by at least 20%

OR, decrease in the MPAP more than 10 mm Hg, to a value lower than 40 mm Hg, with a normal or high CO

Response to CCB (10% of all pts):

NYHA functional class I or II

Normal MPAP, PVR after at least one year of follow-up

CCB prolongs survival among these pts

Prostacyclin Therapy in PAH Intravenous Prostacyclin ( IV Epoprostenol) Subcutaneous Prostacyclin (SQ Treprostinil) Oral Beraprost Approved therapy for pulmonary arterial hypertension in Japan Inhaled Iloprost Not an approved therapy in the USA

Intravenous Prostacyclin ( IV Epoprostenol)

Subcutaneous Prostacyclin (SQ Treprostinil)

Oral Beraprost

Approved therapy for pulmonary arterial hypertension in Japan

Inhaled Iloprost

Not an approved therapy in the USA

IV Prostacyclin ( IV Epoprostenol) Stimulates the production of cAMP Vasodilation Inhibits proliferation Inhibits platelet aggregation After 3 mon therapy Clinical functional improvement Improve mortality (but not in pts with scleroderma), long-term survival Decreases MPAP, PVR May prevent the need for lung transplantation, but if no functional improvement after 3 months consider lung transplant

Stimulates the production of cAMP

Vasodilation

Inhibits proliferation

Inhibits platelet aggregation

After 3 mon therapy

Clinical functional improvement

Improve mortality (but not in pts with scleroderma), long-term survival

Decreases MPAP, PVR

May prevent the need for lung transplantation, but if no functional improvement after 3 months consider lung transplant

Intravenous Prostacyclin (cont.) Short half-life (3 min), continuous intravenous infusion Expensive Side effects : jaw pain, headache, diarrhea, flushing, leg pain, and nausea Catheter related complications: catheter-related sepsis Pump failure or dislocation of the central venous catheter

Short half-life (3 min), continuous intravenous infusion

Expensive

Side effects : jaw pain, headache, diarrhea, flushing, leg pain, and nausea

Catheter related complications:

catheter-related sepsis

Pump failure or dislocation of the central venous catheter

Subcutaneous Prostacyclin (SQ Treprostinil) Continuous subcutaneous infusion After 3 mon therapy Symptomatic improvement Exercise capacity (6 min walk test) improvement Hemodynamics (MPAP, PVR) improvement Side effect: Local pain at the infusion site (85%) No catheter related complications: Preferred over IV prostacyclin

Continuous subcutaneous infusion

After 3 mon therapy

Symptomatic improvement

Exercise capacity (6 min walk test) improvement

Hemodynamics (MPAP, PVR) improvement

Side effect: Local pain at the infusion site (85%)

No catheter related complications: Preferred over IV prostacyclin

Endothelin-receptor Blockers in PAH Endothelin-1 receptors: A receptors: Vasoconstriction Vascular smooth-muscle cells proliferation B receptors: Endothelin clearance NO and prostacyclin production (vasodilation) Fibrosis Pro-inflammatory mediator (enhance the expression of adhesion molecules)

Endothelin-1 receptors:

A receptors:

Vasoconstriction

Vascular smooth-muscle cells proliferation

B receptors:

Endothelin clearance

NO and prostacyclin production (vasodilation)

Fibrosis

Pro-inflammatory mediator (enhance the expression of adhesion molecules)

Bosentan Non-selective endothelin (A and B) blocker Block receptors A: Vasodilation, inhibit proliferation Block receptors B: inhibit clearance, vasodilation (NO, Prostacyclin) Studies showed: Exercise capacity improvement Hemodynamics (MPAP, PVR, CO, CI) improvement Improvement in the time to clinical worsening Side effect: Acute hepatitis: dose-dependent (Monthly monitoring of liver function tests is mandatory) Teratogenic: contraindicated during pregnancy

Non-selective endothelin (A and B) blocker

Block receptors A: Vasodilation, inhibit proliferation

Block receptors B: inhibit clearance, vasodilation (NO, Prostacyclin)

Studies showed:

Exercise capacity improvement

Hemodynamics (MPAP, PVR, CO, CI) improvement

Improvement in the time to clinical worsening

Side effect:

Acute hepatitis: dose-dependent (Monthly monitoring of liver function tests is mandatory)

Teratogenic: contraindicated during pregnancy

Sitaxsentan and Ambrisentan Selective endothelin A blocker Block receptors A: Vasodilation, inhibit proliferation No effect on receptors B: clearance, vasodilation (NO, Prostacyclin) Side effect: Acute hepatitis, continuous monitoring of liver function

Selective endothelin A blocker

Block receptors A: Vasodilation, inhibit proliferation

No effect on receptors B: clearance, vasodilation (NO, Prostacyclin)

Side effect:

Acute hepatitis, continuous monitoring of liver function

Nitric Oxide in PAH Endothelium derived Increases intracellular (cGMP): Vasodilatation Antiproliferation Antithrombosis Pts with PAH have decreased NO Short-term inhalation (part of the acute vasodilation challenge) Long-term Tx is not preferred: an interruption in its administration can cause hemodynamic deterioration L-arginine: product of nitric oxide synthase reduces pulmonary-artery pressure increases exercise tolerance

Endothelium derived

Increases intracellular (cGMP):

Vasodilatation

Antiproliferation

Antithrombosis

Pts with PAH have decreased NO

Short-term inhalation (part of the acute vasodilation challenge)

Long-term Tx is not preferred: an interruption in its administration can cause hemodynamic deterioration

L-arginine: product of nitric oxide synthase

reduces pulmonary-artery pressure

increases exercise tolerance

Sildenafil in PAH PDE-5 inhibitors Inhibits the breakdown of cGMP: Vasodilatation Antiproliferation Antithrombosis IV sildenafil: short term Tx, acute pulmonary vasodilator Oral sildenafil: long-term Tx: Exercise capacity improvement Hemodynamics improvement

PDE-5 inhibitors

Inhibits the breakdown of cGMP:

Vasodilatation

Antiproliferation

Antithrombosis

IV sildenafil: short term Tx, acute pulmonary vasodilator

Oral sildenafil: long-term Tx:

Exercise capacity improvement

Hemodynamics improvement

 

VIP in PAH Vasoactive intestinal peptide Pulmonary vasodilation Inhibits proliferation of vascular smooth-muscle cells Inhibits platelet activation Inhalation Functional improvement Hemodynamics improvement

Vasoactive intestinal peptide

Pulmonary vasodilation

Inhibits proliferation of vascular smooth-muscle cells

Inhibits platelet activation

Inhalation

Functional improvement

Hemodynamics improvement

SSRIs in PAH IPAH Elevated levels of plasma serotonin Reduced content of serotonin in platelets Serotonin: Vasoconstrictor Promotes smooth-muscle cell hypertrophy and hyperplasia The level of serotonin itself is probably not a determinant of pulmonary hypertension SSRIs are not associated with an increased incidence of pulmonary hypertension Fluoxetine may provide protection against pulmonary hypertension!!!!

IPAH

Elevated levels of plasma serotonin

Reduced content of serotonin in platelets

Serotonin:

Vasoconstrictor

Promotes smooth-muscle cell hypertrophy and hyperplasia

The level of serotonin itself is probably not a determinant of pulmonary hypertension

SSRIs are not associated with an increased incidence of pulmonary hypertension

Fluoxetine may provide protection against pulmonary hypertension!!!!

Combination Therapy in PAH To maximize the clinical benefit: Prostacyclin + sildenafil Prostacyclin + bosentan (ETRB) Other study: Addition of long-term treatment with sildenafil had minimal effects on functional status and right-heart function

To maximize the clinical benefit:

Prostacyclin + sildenafil

Prostacyclin + bosentan (ETRB)

Other study:

Addition of long-term treatment with sildenafil had minimal effects on functional status and right-heart function

10 % Defined as NYHA functional class I or II who have normal hemodynamic values after at least one year of follow-up

References Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004 Oct 14;351(16):1655-65. Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 2007 Jun;131(6):1917-28. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004 Sep 30;351(14):1425-36. Review. Johnson SR, Granton JT, Mehta S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest. 2006 Aug;130(2):545-52. Review. Kao PN. Simvastatin treatment of pulmonary hypertension: an observational case series. Chest. 2005 Apr;127(4):1446-52. Robbins IM, Kawut SM, Yung D, Reilly MP, Lloyd W, Cunningham G, Loscalzo J, Kimmel SE, Christman BW, Barst RJ. A study of aspirin and clopidogrel in idiopathic pulmonary arterial hypertension. Eur Respir J. 2006 Mar;27(3):578-84. A Study of Aspirin and Simvastatin in Pulmonary Arterial Hypertension. ClinicalTrials.gov Identifier: NCT00384865

Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004 Oct 14;351(16):1655-65.

Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 2007 Jun;131(6):1917-28.

Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004 Sep 30;351(14):1425-36. Review.

Johnson SR, Granton JT, Mehta S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest. 2006 Aug;130(2):545-52. Review.

Kao PN. Simvastatin treatment of pulmonary hypertension: an observational case series. Chest. 2005 Apr;127(4):1446-52.

Robbins IM, Kawut SM, Yung D, Reilly MP, Lloyd W, Cunningham G, Loscalzo J, Kimmel SE, Christman BW, Barst RJ. A study of aspirin and clopidogrel in idiopathic pulmonary arterial hypertension. Eur Respir J. 2006 Mar;27(3):578-84.

A Study of Aspirin and Simvastatin in Pulmonary Arterial Hypertension. ClinicalTrials.gov Identifier: NCT00384865

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