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On December 20, 2013, the U.S. Food and Drug Administration (FDA) approved an extended-release oral formulation of treprostinil, a prostacyclin analog used in the treatment of pulmonary hypertension in patients not responsive to calcium-channel blockers. The monograph below described subcutaneous administration; treprostinil was also previously available in intravenous and inhaled formulations.
On October 18, 2013, the FDA approved macitentan, an endothelin receptor blocker, for the treatment of pulmonary hypertension. Similar to bosentan and ambrisentan, both described below, and other members of its drug class, macitentan carries a black box warning that the drug should not be used during pregnancy, and female patients must enroll in a Risk Evaluation and Mitigation Strategy (REMS) program to ensure compliance with pregnancy testing and contraception requirements prior to initiating treatment.
Summary
Description
- Pulmonary hypertension (PH) is defined as persistent elevation of the pulmonary arterial pressure. PH may be a primary process of the pulmonary arterial bed (pulmonary arterial hypertension (PAH)) or secondary to thrombotic, pulmonary, or cardiac disorders
- PAH is defined hemodynamically as a mean pulmonary artery pressure (mPAP) 25mmHg or more and pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) of 15 mmHg or less
- Unrelieved PH, regardless of underlying cause, leads to right ventricular failure and early mortality
- Extensive pulmonary vascular changes are often present before PH results, and many patients do not develop noticeable symptoms until late in the disease course
- Prognosis depends on functional class and hemodynamic variables; PH is frequently life-threatening and requires aggressive management
Synonyms
Immediate action
PH is a diagnosis of exclusion, usually presenting with nonspecific symptoms such as dyspnea or atypical chest pain in a patient at risk for the disease.
Immediate actions include:
- Administration of supplemental oxygen if respiratory distress, cyanosis, or hypoxemia is observed
- Investigations to rule out acute, life threatening causes of dyspnea or chest pain, such as myocardial infarction or pulmonary embolism
- In patients with risk factors for PH, pulmonary artery catheterization or determination and estimate of pulmonary artery pressure by echocardiography should be considered early
- Early consult with a pulmonary specialist is indicated in patients with signs and symptoms of decompensation and pulmonary hypertension
Urgent action
Administration of supplemental oxygen may acutely reverse some of the pulmonary artery pressure elevation and provide symptomatic relief in patients who are severely dyspneic.
Key points
- PAH is a diagnosis of exclusion
- Extensive pulmonary vascular changes are often present before PH results, and many patients do not develop noticeable symptoms until late in the disease course
- PH is frequently life-threatening and requires aggressive management
- Prognosis for all patients with PH was previously very poor but newer therapies have improved quality of life and overall survival
- Despite developments, therapy for PAH is essentially palliative, and lung or heart lung transplantation is indicated in patients who fail other treatment
Background
Cardinal features
- In idiopathic pulmonary arterial hypertension (IPAH) symptoms are nonspecific and include dyspnea, unexplained fatigue, and syncope
- Prognosis depends on functional class, among other factors; pulmonary hypertension (PH) is frequently life-threatening and requires aggressive management
- Right heart catheterization is central to the evaluation of PH
- Medical therapies have improved survival and quality of life of many patients with PH
Causes
Common causes
IPAH:
- Cases are usually sporadic
- An estimated 12% to 20% of cases are familial, associated with autosomal dominance inheritance with incomplete penetrance
PH may be secondary to other diseases including:
- Schistosomiasis (the most common cause of pulmonary hypertension world wide)
- Collagen vascular disease (eg, scleroderma, systemic lupus erythematosus (SLE))
- HIV infection
- Drugs, particularly anorexigens, amphetamines, and methamphetamines
- Thyroid disorders
- Chronic obstructive pulmonary disease (COPD)
- Interstitial lung disease
- Obstructive sleep disorder
- Left-sided atrial, ventricular or valvular heart disease
- Congenital systemic to pulmonary shunts, such as patent ductus arteriosus
- Chronic thrombotic and/or embolic disease (conditions such as deep vein thrombosis, thrombophlebitis and pulmonary embolism)
- Portal hypertension
- Hemoglobinopathies
Rare causes
- Pulmonary veno-occlusive disease (PVOD)
- Hereditary hemorrhagic telangiectasia
- Glycogen storage disease
- Gaucher disease
- Myeloproliferative disorders
- Splenectomy
- Pulmonary capillary hemangiomatosis
- Alveolar hypoventilation disorders
- Chronic exposure to high altitudes
- Developmental abnormalities
- Sarcoidosis
- Histiocytosis X
- Lymphangiomatosis
- Compression of pulmonary vessels (eg, by adenopathy, tumor, fibrosing mediastinitis)
- Exposure to toxins (eg, aniline and acetanilide dyes)
Serious causes
- Idiopathic PAH (IPAH)
- COPD
- Severe obstructive lung disease
- Interstitial lung disease
- Congenital heart disease with systemic-to-pulmonary shunting
- Portal hypertension
- Left-sided atrial, ventricular or valvular disease
- Chronic thrombotic and/or embolic disease
- Pulmonary veno-occlusive disease
- Myeloproliferative disorders
Contributory or predisposing factors
PAH occurs in only a fraction of patients who have the disorders listed above. This suggests an underlying genetic basis for the condition. Abnormality of bone morphogenetic protein receptor type II has been identified in a large fraction of familial cases and smaller proportions of sporadic cases.
Epidemiology
Incidence and prevalence
IPAH is rare and occurs less frequently than PH associated with other diseases.
Incidence
Estimated annual incidence of IPAH is 0.1-0.5/100,000.
Demographics
Age
IPAH is most common in people between the ages of 20 and 40 years.
Gender
- During childhood, IPAH affects the genders equally
- After puberty, it is more common in women than in men, at a ratio of 1.7: 1
Race
There is no racial predilection in IPAH.
Genetics
- Mutations in the gene encoding bone morphogenetic protein receptor type II (BMPR2), localized to chromosome 2q31, may underlie approximately 50% of cases of familial PH
- Mutations in BMPR2 have been identified in up to 25% of sporadic cases of IPAH, and the gene has been designated the PPH-1 gene
- Familial PH is inherited in autosomal dominant fashion with reduced penetrance and genetic anticipation
- Genetic studies have demonstrated that the chance of a carrier of the BMPR2 mutation developing clinical pulmonary hypertension is as low as 20%. Therefore, other genetic and environmental factors must combine to contribute to susceptibility
- Siblings or offspring of individuals with familial PH or of those carrying the BMPR2 mutation have an estimated 10% lifetime risk of developing the disease
- Further information on BMPR2 in PH may be found at Online Mendelian Inheritance in Man—Pulmonary hypertension, primary (OMIM) and GeneReviews—Primary pulmonary hypertension
Codes
ICD-9 code
- 416.0 Primary pulmonary hypertension (essential) (idiopathic) (primary)
- 416.8 Pulmonary hypertension, secondary
- 747.83 Primary pulmonary hypertension of newborn
