Pulmonary hypertension medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-in-Chief: Ralph Matar, Rim Halaby

Overview

Treatment of pulmonary hypertension has undergone a dramatic evolution in the past few years, in part owing to advances in the understanding of the basic pathophysiological contributors to the disease. However, despite all the modern therapeutic agents, pulmonary hypertension remains a chronic disease with no cure.

Prior to the initiation of any therapy, the physician must perform a precise diagnostic evaluation on patients with pulmonary hypertension to reveal the true pathogenesis of their disease. Hence, right heart catheterization, pulmonary functions tests, imaging studies(V/P scan), and arterial oxygen saturation should be obtained for every patient with PAH, in order to plan the therapy accordingly.

Medical Therapy

Treatment Goals

• Improving the patient's symptoms and quality of life.
• Enhancing functional capacity.
• Lowering Pulmonary arterial pressure and normalizing cardiac output.
• Prevent or at least slow the progression of the disease.
• Decrease the hospitalization rate.
• Improve Survival.

Algorithm for the Treatment of Pulmonary Hypertension

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• Right heart catheterization is essential to confirm diagnosis; and it should always be done prior to the initiation of therapy
• Vasodilator testing is used to help choose the therapeutic plan
• Definition of vasodilator response

- Decrease in mean PAP by  10 mm Hg

- Decrease of mean PAP to 40 mmHg or less

- Cardiac output does not get worse

• Vasodilators that are used are:

Prostanoids, inhaled NO, adenosine

• Only patients with positive vasodilator response are started on ‘’’calcium channel blockers’’’. Adjunctive ‘’’supportive therapy’’’ (Oral anticoagulant, diuretics, supplemental oxygen and digoxin) can be used.
• Patients with negative vasodilator response need ‘’’specific medical therapy’’’.

Specific Drug Therapies

Calcium channel blockers

Calcium channel blockers of the traditional vasodilators used since mid 1980s. Their mode of action is decreasing smooth muscle hypertrophy, hyperplasia and vasoconstriction. The most commonly used CCB are:

• Nifedipine.
• Diltiazem.
• Amlodipine.

Nifedipine and Amlodipine are preferred in cases of relative bradycardia, whereas Diltiazem is preferred in cases of relative tachycardia.

Prostanoids

Prostacyclins are potent vasodilators and potent inhibitors of platelet aggregation in vascular beds. Patients with PAH have been shown to have low levels prostacyclin levels, so stable analogues of prostacyclin have been made for that purpose. These include

• Epoprostenol.
• Beraprost.
• Iloprost.
• Treprostinil(analogue of Epoprostenol).

Endothelin receptor antagonist

There has been a clear role for endothelin system in the pathogenesis of PAH. Endothelin-1 exerts vasoconstrictor and mitogenic effects by binding to two different receptor isoforms: ET-A and ET-B.

• Bosentan: antagonises both ET-A and ET-B receptors and was shown to improve haemodynamics, exercise capacity, functional class and delay progression of disease.
• Sitaxentan: a selectively orally active ET-A receptor antagonist was also shown to improve exercise capacity and haemodynamics.
• Ambrisentan: Selective ET-A receptor antagonist.Proven to be efficacious on improving symptoms, exercise capacity, haemodynamics, and time to clinical worsening.

Phosphodiesterase type-5 inhibitors

Inhibiting cGMP-degrading enzymes leads to increased levels of cGMP and subsequently improved vasodilation. All phosphodiesterase inhibitors originally approved for the treatment of erectile dysfunction cause significant pulmonary vasodilation:

• Sildenafil: Maximum effect is observed after 60min from administration of the drug. Its orally active,potent and a selective type-5 phosphodiesterase inhibitor. Favorable effects on symptoms, haemodynamics and exercise capacity were shown in several studies.
• Taladafil: Maximum effects observed after 75-90min. Single daily dose is available. Studies showed favorable results on symptoms, haemodynamics,exercise capacity, and times to clinical worsening when the largest dose was used.

Management Of Special Scenarios

Pregnancy

• Patients with pulmonary hypertension should avoid pregnancy

General anesthesia

• Epidural rather than general anesthesia should be administered for surgical procedures given the potential for hypotension

Oxygen

• In-flight oxygen should be considered for those patients who have a resting oxygen pressure less than 60 mm Hg.

Anticoagulation

• Anticoagulation should be considered in patients with pulmonary hypertension in the absence of hemoptysis
• If the pulmonary hypertension is due to chronic thromboembolic pulmonary hypertension, and thrombectomy may be indicated.

Phlebotomy

• Phlebotomy should be used if the hemoglobin is greater than 20 and/or the hematocrit is greater than 65% or if symptoms of hyper viscosity develop.

ESC/ERS (2009) Recommendations for Specific Medical Therapy

First-Line Therapies

• First-line therapies or type I pulmonary hypertension or world of organization class to pulmonary hypertension include the endothelin receptor antagonists bosentan or ambrisentan and Viagra

Calcium Channel Blockade

• Nifedipine can be used in these patients, but should not be given to patients who are not reactive to inhaled nitric oxide as it will not work in that scenario. Calcium channel blocker should not be used in patients with Eisenmenger syndrome.

Advanced Pulmonary Hypertension

• The prostaglandins can be useful in these patients and include epoprosterol and iloprost.

Table 1:Recommendation for specific drug therapy according to WHO-FC

Medication	WHO-FC II	WHO-FC III	WHO-FC IV
Calcium channel blockers	I-C	I-C	--
Ambrisentan	I-A	I-A	IIa-C
Bosentan	I-A	I-A	IIa-C
Sitaxentan	IIa-C	I-A	IIa-C
Sildenafil	I-A	I-A	IIa-C
Tadalafil	I-B	I-B	IIa-C
Beraprost	--	IIb-B	--
Epoprostenol(IV)	--	I-A	I-A
Iloprost(inhaled)	--	I-A	IIa-C
Iloprost(IV)	--	IIa-C	IIa-C
Treprostinil(subcutaneous)	--	I-B	IIa-C
Treprostinil(IV)	--	IIa-C	IIa-C
Treprostinil(Inhaled)	--	I-B	IIa-C
Initial drugs combination therapy	--	--	IIa-C
Sequential drugs combination therapy	IIa-C	IIa-B	IIa-B

Table Key:

• WHO-FC: World health organization functional classification.
• I/II/III represent the classes of recommendation
• A/B/C represent the level of confidence

ESC/ERS (2009) Recommendations for the Treatment of Pulmonary Hypertension (DO NOT EDIT)

ESC/ERS (2009) Recommendations for General Measures (DO NOT EDIT)

Class I

"1. It is recommended to avoid pregnancy in patients with PAH. (Level of Evidence: C) "

"2. Immunization of PAH patients against influenza and pneumococcal infections is recommended. (Level of Evidence: C) "

Class III

"1. Excessive physical activity that leads to distressing symptoms is not recommended in patients with PAH. (Level of Evidence: C) "

Class IIa

"1. Physically deconditioned PAH patients should be considered for supervised exercise rehabilitation. (Level of Evidence: B) "

"2. Psychosocial support should be considered in patients with PAH. (Level of Evidence: C) "

"3. In-flight oxygen administration should be considered for patients in WHO-FC III and IV and those with arterial oxygen pressure consistently less than 60mmHg coronary disease. (Level of Evidence: C) "

"4. Epidural anesthesia instead of general anesthesia should be utilised if possible for elective surgery. (Level of Evidence: C) "

ESC/ERS (2009) Recommendations for Supportive Therapy (DO NOT EDIT)

Class I

"1. Diuretic treatment is indicated in PAH patients with signs of RV failure and fluid retention. (Level of Evidence: C) "

"2. Continous long-term oxygen therapy is indicated in PAH patients when arterial oxygen pressure is consistently less than 60mmHg. (Level of Evidence: C) "

Class IIa

"1. Oral anticoagulant treatment should be considered in patients with IPAH, heritable PAH, and PAH due to use of anorexigens. (Level of Evidence: B) "

Class IIb

"1. Oral anticoagulant treatment should be considered in patients with APAH. (Level of Evidence: C) "

"2. Digoxin may be considered in patients with PAH who develop atrial tachyarrhythmias to slow ventricular rate. (Level of Evidence: C) "

ESC/ERS (2009) Recommendations for PAH Associated with Congenital Cardiac Shunts (DO NOT EDIT)

Class I

"1. Bosentan (Endothelin receptor antagonist) is indicated in WHO-FC III patients with Eisenmenger syndrome. (Level of Evidence: B) "

Class III

"1. The use of CCB is not recommended in patients with Eisenmenger's syndrome. (Level of Evidence: C) "

Class IIa

"1. Other endothelin receptor antagonist, phosphodiesterase inhibitors, and prostanoids should be considered in patients with Eisenmenger's syndrome. (Level of Evidence: C) "

"2. In the absence of significant haemoptysis, oral coagulant treatment should be considered in patients with PA thrombosis or signs of heart failure. (Level of Evidence: C) "

"3. The use of supplemental oxygen therapy should be considered in cases in which it produces a consistent increase in arterial oxygen saturation and reduces symptoms. (Level of Evidence: C) "

"4. If symptoms of hyperviscosity are present, phlebotomy with isovolumic replacement should be considered usually when the haematocrit is > 65%. (Level of Evidence: C) "

Class IIb

"1. Combination therapy may be considered in patients with Eisenmenger's syndrome. (Level of Evidence: C) "

ESC/ERS (2009) Recommendations for PAH Associated with Connective Tissue Diseases (CTD) (DO NOT EDIT)

Class I

"1. In patients with PAH associated with CTD the same treatment algorithm as in patients with IPAH is recommended. (Level of Evidence: A) "

"2. Echocardiographic screening for the detection of PH is recommended in symptomatic patients with scleroderma spectrum of diseases. (Level of Evidence: B) "

"3. Echocardiographic screening for the detection of PH is recommended in symptomatic patients with all other CTDs. (Level of Evidence: C) "

"4. Right heart catheterization is indicated in all cases of suspected PAH associated with CTDs, in particular if specific drug therapy is considered. (Level of Evidence: C) "

Class IIa

"1. Oral anticoagulation should be considered on an individual basis. (Level of Evidence: C) "

Class IIb

"1. Echocardiographic screening for the detection of PH is recommended in symptomatic patients with scleroderma spectrum of diseases. (Level of Evidence: C) "

ESC/ERS (2009) recommendations for PAH Associated with portal hypertension (DO NOT EDIT)

Class I

"1. Echocardiographic screening for the detection of PH is recommended in symptomatic patients with liver diseases and/or in candidates for liver transplantation. (Level of Evidence: B) "

Class III

"1. Anticoagulation is not recommended in patients with increased risk of bleeding. (Level of Evidence: C) "

"2. Significant PAH is a contraindication to liver transplantation if mean PAP is .35 mmHg and/or pulmonary vascular resistance is > 250 dynes.s.cm^-5 (Level of Evidence: C) "

Class IIa

"1. In patients with pulmonary arterial hypertension associated with portal hypertension the same treatment algorithm as in patients with idiopathic pulmonary hypertension should be considered, taking into consideration co-morbidities. (Level of Evidence: C) "

ESC/ERS (2009) Recommendations for PAH Associated with Human Immunodeficiency Virus infection (DO NOT EDIT)

Class I

"1. Echocardiography is indicated in patients with unexplained dyspnea to detect HIV-related cardiovascular complications. (Level of Evidence: C) "

Class III

"1. Anticoagulation is not recommended in patients with increased risk of bleeding. (Level of Evidence: C) "

Class IIa

"1. In patients with pulmonary arterial hypertension associated with HIV-infection the same treatment algorithm as in patients with idiopathic pulmonary hypertension should be considered, taking into consideration co-morbidities and drug-drug interactions. (Level of Evidence: C) "

ESC/ERS (2009) Recommendations for PAH Associated with Pulmonary Veno-Occlusive Disease(PVOD) (DO NOT EDIT)

Class I

"1. Referral of patients with PVOD to a transplant center for evaluation is indicated as soon as the diagnosis is established. (Level of Evidence: C) "

Class IIa

"1. Patients with PVOD should be managed only in centers with extensive experience in pulmonary arterial hypertension due to the risk of lung edema after the initiation of PAH-specific drug therapy. (Level of Evidence: C) "

ESC/ERS (2009) Recommendations for PH Associated with Left Heart Disease (DO NOT EDIT)

Class I

"1. The optimal treatment of the underlying left heart disease is recommended in patients with pulmonary hypertension due to left heart disease. (Level of Evidence: C) "

Class III

"1. The use of PAH specific drug therapy is not recommended in patients with pulmonary hypertension due to left heart disease. (Level of Evidence: C) "

Class IIa

"1. Patient with "out of proportion" pulmonary hypertension due to left heart disease should be enrolled in randomised controlled trials targeting pulmonary hypertension specific drugs. (Level of Evidence: C) "

Class IIb

"1. Increased left-sided filling pressures may be estimated by Doppler echocardiography. (Level of Evidence: C) "

"2. Invasive measurements of pulmonary wedge pressure of left ventricular end-diastolic pressure may be required to confirm the diagnosis of pulmonary hypertension due to left heart disease. (Level of Evidence: C) "

"3. Right heart catheterization may be considered in patients with echocardiographic signs suggesting severe pulmonary hypertension in patients with left heart disease. (Level of Evidence: C) "

ESC/ERS(2009) Recommendations for PH Associated with Lung Disease (DO NOT EDIT)

Class I

"1. Echocardiography is recommended as a screening tool for the assessment of PH due to lung diseases. (Level of Evidence: C) "

"2. Right heart catheterization is recommended for a definite diagnosis of pulmonary hypertension due to lung diseases. (Level of Evidence: C) "

"3. The optimal treatment of the underlying lung disease including long-term oxygen therapy in patients with chronic hypoxemia is recommended in patients with pulmonary hypertension due to lung diseases. (Level of Evidence: C) "

Class III

"1. The use of PAH specific drug therapy is not recommended in patients with pulmonary hypertension due to lung diseases. (Level of Evidence: C) "

Class IIa

"1. Patients with "out of proportion" pulmonary hypertension due to lung diseases should be enrolled in randomised controlled trials targeting PAH-specific drugs. (Level of Evidence: C) "

ESC/ERS(2009) Recommendations for PH Associated with Chronic Thromboembolic Pulmonary Hypertension(CTEPH) (DO NOT EDIT)

Class I

"1. The diagnosis of CTEPH is based on the presence of pre-capillary pulmonary hypertension(mean PAH>25mmHg,PWP<15mmHg,Pulmonary vascular resistance>2 Wood units) in patients with multiple chronic/organized occlusive thrombi/emboli in the elastic pulmonary arteries (main, lobar, segmental, subsegmental). (Level of Evidence: C) "

"2. In patients with CTEPH, lifelong anticoagulation is indicated. (Level of Evidence: C) "

"3. Surgical pulmonary endarterectomy is the recommended treatment for patients with CTEPH. (Level of Evidence: C) "

Class IIa

"1. Once perfusion scanning and/or CT angiography show signs compatible with CTEPH, the patient should be referred to a center with expertise in surgical pulmonary endarterectomy. (Level of Evidence: C) "

"2. The selection of patients for surgery should be based on the extent and location of the organized thrombi, on the degree of pulmonary hypertension, and on the presence of co-morbidities. (Level of Evidence: C) "

Class IIb

"1. PAH-specific drug therapy may be indicated in selected CTEPH patients such as patients not candidates for surgery or patients with residual pulmonary hypertension after pulmonary endarterectomy. (Level of Evidence: C) "

ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death - Pulmonary Arterial Hypertension (DO NOT EDIT)

Class III (Harm)

"1. Prophylactic antiarrhythmic therapy generally is not indicated for primary prevention of SCD in patients with pulmonary arterial hypertension or other pulmonary conditions. (Level of Evidence: C) "