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,

Overview

Treatment of pulmonary hypertension has passed through 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.

Before prescribing any medication, the physician must assess the severity, consider supportive treatment and lifestyle changes, then consider the combination of different drugs and the possibility of further interventions.

Treatment Goals

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

ESC/ERS Recommendations for General measures

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

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ESC/ERC Recommendations for supportive therapy:

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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: C) 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)

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ESC/ERS Recommendations for specific medical therapy

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

Specific Drug Therapies:

1- Calcium channel blockers: One of the traditional vasodilators used since mid 1980s. Their mode of action is decreasing smooth muscle hypertrophy, heyperplasia 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.

2- 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).

3-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.

4- 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.

ESC/ERS Recommendations for PAH associated with congenital cardiac shunts

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Class I 1. Bosentan(Endothelin receptor antagonist) is indicated in WHO-FC III patients with Eisenmenger syndrome (Level of Evidence: B) 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) Class III 1. The use of CCB is not recommended in patients with Eisenmenger's syndrome. (Level of Evidence: C)

”