Prior to the initiation of therapy for pulmonary hypertension, a right heart catheterization should be performed to exclude (as a cause of the pulmonary hypertension. If type II pulmonary hypertension is confirmed than a vasodilator challenges performed to assess the reactivity of the pulmonary vasculature. If the pulmonary vasculature is reactive, then calcium channel blockers may be an appropriate therapy. If the pulmonary vasculature is not reactive than endothelin antagonist and processed annoyance are the optimal management. Patients with eisenmenger syndrome should not be administered calcium channel blockers. Pulmonary functions tests, imaging studies(V/P scan), and arterial oxygen saturation should also be obtained for every patient with PAH, in order to plan the therapy accordingly.
Medical Therapy
Treatment Goals
Improve the patient's symptoms and quality of life
Prevent or at least slow the progression of the disease
Decrease the hospitalization rate
Improve survival
Treatment Algorithm
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 and Amlodipine are preferred in cases of relative bradycardia, whereas Diltiazem is preferred in cases of relative tachycardia.
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: antagonizes both ET-A and ET-B receptors and was shown to improve haemodynamics, exercise capacity, functional class and delay progression of disease.
Macitentan: antagonizes both ET-A and ET-B receptors.
Ambrisentan: Selective ET-A receptor antagonist.Proven to be efficacious on improving symptoms, exercise capacity, haemodynamics, and time to clinical worsening.
Sitaxentan: a selectively orally active ET-A receptor antagonist was also shown to improve exercise capacity and haemodynamics.
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.
Tadalafil: 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.
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.
Oxygen therapy: continuous oxygen therapy is needed for patients with oxygen saturation less than 60 mmHg
Oral anticoagulation: to decrease the risk of venous thromboembolism in patients with idiopathic PAH, heritable PAH, anorexigenic related PH, and possibly in associated PAH
Specific Drug Therapies in Treatment-Naïve PAH Patients
WHO Functional Class I
Patients with WHO functional class I PAH or those at elevated risk of developing PAH, as in the case of systemic sclerosis, should be monitored for the occurrence of PAH-related symptoms.
Patients among whom calcium channel blocker trial failed to improve the clinical status or those who are not candidates for calcium channel blockers should receive monotherapy with one of the following:[1]
Patients among whom calcium channel blocker trial failed to improve the clinical status or those who are not candidates for calcium channel blockers should receive monotherapy with one of the following:[1]
Patients with WHO class III PAH whose disease is rapidly progressing and associated with poor prognostic markers, should be administered parenteral prostanoid as initial therapy instead of oral therapy.[1]
Patients with WHO class III PAH whose symptoms are not improved on the initial therapy with either endothelin receptor antagonist or phosphodiesterase 5 inhibitors should receive any of the following as an add-on to their initial therapy:[1]
Inhaled treprostinil (3 inhalations (18 μg) every 6 hours, can titrate up to 9 inhalations (54 μg) every 6 hours)
Patients with WHO class III PAH and rapid progression of the disease despite initial therapy with one or more oral medication should be administered parenteral or inhaled prostanoids.[1]
WHO Functional Class IV
The initial treatment for patients with WHO class IV PAH is a monotherapy with a parenteral prostanoid:[1]
If the patient refuses or is unable to receive parenteral therapy, the alternative treatment is a combination of inhaled prostanoid (iloprost or treprostinil) and endothelin receptor antagonist (bosentan).[1]
Specific Drug Therapies in Patients on Established PAH Treatment
Patients with WHO functional class III or IV whose clinical status is unacceptable despite monotherapy should receive an add-on to their treatment:
If already on endothelin receptor antagonist, add:
Patients with WHO functional class III or IV whose clinical status is unacceptable despite dual therapy with two classes of PAH specific medications should receive a third class add-on to their treatment.
Algorithm for the Treatment of Pulmonary Hypertension
Shown below is an algorithm for determining the optimal therapy for a patient with pulmonary hypertension. A right heart catheterization is essential to confirm diagnosis; and a right heart catheterization should always be done prior to the initiation of therapy. If the pulmonary hypertension is thought to be due to left heart failure(Type 1 pulmonary hypertension), then adjunctive supportive therapy such as oral anticoagulation, diuretics, supplemental oxygen and digoxin are begun. If left heart failure (Type 1 pulmonary hypertension) is excluded as a cause of the pulmonary hypertension, and the patient is felt to have Type 2 pulmonary hypertension, then vasodilator testing is performed to assist in the selection of the optimal therapy. A vasodilator (prostanoids, inhaled NO, adenosine) is administered, and it is determined if the patient has a positive "vasodilator response".
Several definitions for positive vasodilator response have been proposed, the most recent of which is the following:
A positive vasodilator response is defined as a decrease in the mean PAP of more than 10 mmHg to a level below 40 mmHg in the absence of any decrease in the cardiac output[2].
As shown in the algorithm below, those patients who have a positive vasodilator response are started on ‘’’calcium channel blockers’’’. Patients who do not have a positive vasodilator response require ‘’’specific medical therapy’’’ as described below. First-line treatment would be an endothelin antagonist, and patients with more severe symptoms are treated with prostanoids.
500
ESC/ERS (2009) Recommendations for Specific Medical Therapy [3]
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 Sildenafil (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
Management Of Special Scenarios
Pregnancy
Patients with PAH should avoid pregnancy. Patients on PAH specific should receive dual contraceptive. Estrogen-containing contraceptives should be avoided because they increase the risk of venous thromboembolism.
Patients with PAH should avoid high altitude. In case of exposure to high altitude or travel, patients should receive supplemental oxygen therapy (oxygen saturation >91%)
"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) "
"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) "
"1. Oral anticoagulant treatment should be considered in patients with IPAH, heritable PAH, and PAH due to use of anorexigens. (Level of Evidence: B) "
"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) "
"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) "
"1. Echocardiographic screening for the detection of PH is recommended in symptomatic patients with scleroderma spectrum of diseases. (Level of Evidence: C) "
PAH Associated with Portal Hypertension (DO NOT EDIT) [3]
"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) "
PAH Associated with Human Immunodeficiency Virus Infection (DO NOT EDIT) [3]
"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) "
PAH Associated with Pulmonary Veno-Occlusive Disease(PVOD) (DO NOT EDIT) [3]
"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) "
"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) "
PH Associated with Left Heart Disease (DO NOT EDIT) [3]
"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) "
"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) "
"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) "
"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) "
"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) "
"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) "
PH Associated with Chronic Thromboembolic Pulmonary Hypertension(CTEPH) (DO NOT EDIT) [3]
"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) "
"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) "
"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) "
PAH Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death (DO NOT EDIT) [4]
"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) "
↑ Rich S. The effects of vasodilators in pulmonary hypertension, pulmonary vascular or peripheral vascular?. Circulation: Heart Failure. 2009; 2: 145-150
