PAH for Clinicians
Basic Pulmonary Hypertension
Diagnosis and Evaluation of PAH
Pulmonary hypertension (PH) is a progressive disease with high rates of morbidity and mortality. It is defined as a hemodynamic state with a mean pulmonary artery pressure of 25 mm Hg or higher at rest. Pulmonary arterial hypertension (PAH) is defined as a mean artery pressure greater than 25 mm Hg at rest with a wedge pressure that is 15 mm Hg or lower. Clinical presentation is nonspecific and includes unexplained shortness of breath, dizziness, fainting, fatigue, or weakness. The first step is to rule out other diseases first. If other disease can’t completely explain the symptoms, then PH comes into play. Physical examination findings include regular tachycardia, tricuspid regurgitation, central venous distention, ascites, and foot and ankle edema. The World Health Organization classification has five PH groups:
- Group 1 is pulmonary arterial hypertension.
- Group 2 is PH caused by left heart disease, and it is the most common cause of PH.
- Group 3 is PH associated with lung disease and hypoxia.
- Group 4 is PH caused by chronic thromboembolic pulmonary hypertension (CTEPH), a potentially curable disease using surgery.
- Group 5 is a miscellaneous collection of conditions that are associated with PH but do not fit into any other WHO group.
One can argue there is a sixth group composed of patients who do not neatly fit into any of the five official classification groups. These patients may have heart or lung disease, but they also have severe PH that cannot be fully explained based on the severity of the underlying disease. Patient workup for PH starts by looking for significant left heart disease (WHO group 2), lung disease (WHO group 3), or CTEPH (WHO group 4). This can often be accomplished by the history and physical examination, echocardiography, pulmonary function tests, blood work (including HIV and connective tissue serologies), a ventilation-perfusion scan, overnight oximetry or a full sleep study, and a 6-minute walk test. Right heart catheterization is always needed to confirm the diagnosis before considering pulmonary vasodilator therapy.
- Pulmonary hypertension is a progressive disease with high rates of morbidity and mortality.
- Pulmonary hypertension is a hemodynamic state defined as a mean pulmonary artery pressure of 25 mm Hg or higher at rest.
- Pulmonary arterial hypertension is defined as mean PA pressure more than 25 mm Hg at rest with a wedge pressure that is 15 mm Hg or lower.
- Clinical presentation is nonspecific.
- The World Health Organization classification of PH includes five groups, but not all patients fit neatly into them.
- Workup for PH starts by eliminating significant left heart disease (WHO group 2), lung disease (WHO group 3), and CTEPH (WHO group 4).
- Right heart catheterization is always needed to confirm the diagnosis before considering pulmonary vasodilator therapy.
- Benza RL, Miller DP, Barst RJ, et al, An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142(2):448-56.
- Fares WH, Heresi GA. Chronic thromboembolic pulmonary hypertension: a worldwide view of how far we have come. Lung. 2016;194(3):483-5.
- Fedullo P, Kerr KM, Kim NH, Auger WR. Chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2011;183(12):1605-13.
- Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46(4):903-75.
- Lai YC, Potoka KC, Champion HC, et al. Pulmonary arterial hypertension: the clinical syndrome. Circ Res. 2014;115(1):115-30.
- Tunariu N, Gibbs SJ, Win Z, et al. Ventilation-perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension. J Nucl Med. 2007;48(5):680-4.
Contemporary Management of PAH
Selecting a treatment for PAH starts by determining the patient’s risk for disease progression. Low-risk patients are those who do not have right heart failure, rapidly progressive symptoms, or exertional syncope and are NYHA functional class 1 or 2, have a 6-minute walk distance of 440 meters (380 meters may be more reasonable), a normal brain-type natriuretic peptide (BNP) or NT-proB-type natriuretic peptide (NTBNP), only mildly reduced right ventricular function with no evidence of pericardial effusion on echocardiogram, and a preserved cardiac index (ideally at 2.5 liters/min/m2 or greater). High-risk patients are those with right heart failure, rapidly progressive symptoms, exertional syncope, NYHA functional class 4, have a 6-minute walk distance that is 165 meters or less, an elevated BNP, elevated right atrial size, elevated right atrial pressures, a pericardial effusion (which is a very poor prognostic indicator), and a low cardiac index. Patients who are between the high- and low-risk groups are considered to have intermediate risk.
One way to think of this is that it is not how high the mean pulmonary arterial pressure is, but how the heart is compensating, as reflected in the cardiac index and right atrial pressure.
Treatment goals can be different from the physician or the patient perspective. Most patients just want to feel better and live longer. From a medical perspective, that may mean improving functional class, quality of life, and survival. We measure these by looking at WHO functional class (aim for NYHA 1 or 2), 6-minute walk distance (aim for 380 to 440 meters), normal RV function, normal BNP, and favorable hemodynamics.
Although treatment guidelines are evolving (the most recent was from the European Respiratory Society in 2016), some standards remain constant: the need for PH to be confirmed by an expert, the need for a right heart catheterization, and the need to do an acute vasoreactivity test, when appropriate, to identify patients who will benefit from treatment with calcium channel blockers.
The FDA-approved PAH treatments include the phosphodiesterase type 5 inhibitors (sildenafil and tadalafil) and the soluble guanylate cyclase stimulator (riociguat), endothelin-receptor antagonists (bosentan, ambrisentan, and macitentan), and prostacyclin pathway medications (epoprostenol, treprostinil, iloprost, and selexipag).
Although the most recent treatment algorithm recommends initial monotherapy for low-risk patients, many practitioners start with oral combination therapy. For high-risk patients, the initial combination therapy usually includes a prostacyclin analogue. Parenteral prostacyclins are still the gold standard in high-risk patients because they have been proven to improve survival. Intermediate-risk patients are a harder group to treat. The primary determinant of treatment can be driven by right ventricular function and functional assessment. Many PH specialists are concerned that the availability and popularity of oral therapies will reduce referral of this particularly vulnerable population to PH specialty centers for assessment and treatment.
- Selecting a treatment for PAH starts by determining the patient’s risk of mortality and disease progression.
- Goals of treatment need to reflect the patient’s goals, which may just be to feel better and live longer.
- Diagnosis of PH needs to be confirmed by an expert who determines the performance of right heart catheterization and acute vasoreactivity testing before initiating therapy.
- The FDA-approved PAH treatments include sildenafil and tadalafil, the soluble guanylate cyclase stimulator (riociguat), endothelin-receptor antagonists (bosentan, ambrisentan, and macitentan), and prostacyclin pathway medications (epoprostenol, treprostinil, iloprost, and selexipag).
- Many specialists start low-risk patients on oral combination therapy rather than monotherapy.
- In high-risk patients, parenteral prostacyclins are still the therapeutic standard because they improve survival.
- Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119.
- McLaughlin VV, Gaine SP, Howard LS, et al. Treatment goals of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D73-81.
- McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53(17):1573-619.
- Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327(2):76-81.
- Barst RJ, Rubin LJ, Long WA, et al; Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5):296-301.
- Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111(23):3105-11.
Additional Disease State Resources & CME
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