Approach Considerations
Supportive therapy includes oxygen therapy, diuretics, digoxin, exercise, and anticoagulation. Decisions regarding starting each of these therapies should be made on a patient-by-patient basis in the appropriate clinical scenario. These therapies are not specific to PAH and are frequently used in all WHO groups of pulmonary hypertension.
In contrast, advanced vasodilatory therapies are largely confined to cases of PAH. Guidelines recommend against using these advanced therapies in cases of pulmonary hypertension from left-sided heart disease or pulmonary disease, and initiation of these should be in specialized centers and by providers well experienced in treating PAH. [25] Since the WHO group 1 classification, multiple advanced vasoactive therapies have become available to treat the prostacyclin, endothelin, and nitric oxide/cyclic guanosine monophosphate (cGMP) pathways. Research is ongoing with new medications continually in the pipeline, with the hope that these new therapies may halt or reverse disease progression. [26]
The CHEST guideline, based on reviews of English-language literature published between 1990 and 2013 using the MedLine and the Cochrane databases, concluded that current pharmacotherapy for PAH should be based on high-level recommendations, but further study is needed to address gaps in such evidence-based information. [27]
Oxygen Supplementation
Oxygen has proved beneficial for reducing patient mortality in selected patients with pulmonary hypertension. Two large trials demonstrated a definite mortality benefit for patients with WHO group 3 pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD). Although long-term study results are not available for other WHO groups, it appears that oxygen administration likely benefits these other groups as well. Accordingly, long-term oxygen therapy should be prescribed for patients whose arterial oxygen tension (PaO2) is lower than 55 mm Hg at rest from any cause, those who have desaturation during exercise, and those who perform better on oxygen therapy.
Medicare indications for continuous long-term oxygen therapy include the following:
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PaO 2 of 55 mm Hg or less, or oxygen saturation (SaO 2) of 88% or less
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PaO 2 of 56-59 mm Hg or SaO 2 of 89%, in the presence of evidence of cor pulmonale, right-sided heart failure, or erythrocytosis (hematocrit >55%).
Preventive Care
To decrease the risk of developing pneumonia (which has been found to be the cause of death in 7% of patients with pulmonary arterial hypertension [PAH]), patients should receive vaccinations against influenza and pneumococcal pneumonia. [21]
Given the high mortality rate associated with pregnancy in patients with PAH, females of childbearing age should be offered birth control and counseled extensively about pregnancy.
Pharmacologic Therapy
Diuretics
Although no randomized controlled trials have evaluated diuretics for pulmonary arterial hypertension (PAH), practitioners frequently use these based on their clear value for fluid removal in patients with evidence of right-sided heart volume overload. Loop diuretics such as furosemide and bumetanide are first line, with aldosterone antagonists sometimes considered as adjunctive agents.
Diuretics are indicated in patients with PAH who have signs of right-sided heart volume overload, as evidenced by lower extremity edema, ascites, hepatic congestion, or elevated jugular venous pressure. As patients with right-sided heart failure are preload dependent, however, caution must be used. Hypovolemia should be avoided, as this can lead to a drop in cardiac output and hemodynamic compromise.
Digoxin
Digoxin is primarily used in PAH patients who have atrial tachyarrhythmias. Although its inotropic properties have been shown to be useful in acutely improving cardiac output in certain PAH patients, its long-term effects are unknown. [21] For this reason, its main indication remains slowing the ventricular rate in patients prone to arrhythmias.
Anticoagulants
Anticoagulation (specifically, with warfarin) may be helpful because evidence suggests that patients with idiopathic PAH (IPAH) develop thrombotic arteriopathy (with abnormalities of blood coagulation factors, antithrombotic factors, and the fibrinolytic system). [28] This contributes to a prothrombotic state. In a review of seven observational studies evaluating anticoagulation in IPAH, five demonstrated a mortality benefit. [29] Evidence also suggests a benefit for anticoagulation in patients with hereditary PAH, anorexigen-induced PAH, and pulmonary venoocclusive disease (PVOD). However, evidence in other forms of PAH is lacking, and decisions regarding anticoagulation in these cases should be made on a patient-by-patient basis after weighing the risks and benefits of anticoagulant therapy. Given limited experience with the novel oral anticoagulants such as dabigatran, rivaroxaban, and apixaban in PAH, warfarin remains the anticoagulant of choice. [21]
Specific drug therapy
Advanced therapies should be considered after right-sided heart catheterization for PAH patients in functional class II, III, or IV. Patients with IPAH, heritable PAH, or anorexigen-induced PAH should undergo a vasoreactivity test as these patients may be candidates for calcium channel blockers (per below). Of note, even in this subset of patients, only a small minority of patients are vasoreactive and thus candidates for calcium channel blocker therapy.
Therefore, for the majority of PAH patients, treatment requires initiation of one or more of the advanced vasodilatory therapies. At present, three main classes of therapy exist, with each targeting a separate pathophysiologic arm, as follows:
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Endothelin receptor antagonists (ambrisentan, bosentan, and macitentan): Activation of the endothelin system causes increased levels of the vasoconstrictor endothelin-1 in PAH patients. These agents act to antagonize this pathway.
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Phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil) and guanylate cyclase stimulators (riociguat): Cyclic guanosine monophosphate (cGMP) results in vasodilation through the nitric oxide/cGMP pathway, and PDE-5 is responsible for degrading cGMP. PDE-5 inhibitors thus prevent this degradation.
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Prostacyclin analogues (beraprost, epoprostenol, iloprost, treprostinil) and prostacyclin receptor agonists (selexipag): Prostacyclin is a potent vasodilator, and dysregulation of prostacyclin synthesis metabolism has been identified in PAH patients.
For patients with WHO functional class II or III disease, experts often begin with a combination of two oral agents targeting separate pathways. The combination of ambrisentan and tadalafil is the most frequently used combination and was approved as first-line treatment by the US Food and Drug Administration (FDA) in October 2015 based on the AMBITION trial. [30] The trial involved 605 patients with WHO functional class II or III PAH. Patients were randomly assigned to receive once-daily ambrisentan plus tadalafil or to either drug alone. Doses were titrated from 5-10 mg/day for ambrisentan and from 20-40 mg/day for tadalafil. Treatment with the combination was associated with an approximately 50% reduction in risk for clinical failure compared with either drug alone (P = .0002), with improved exercise ability as well as decreased disease progression and hospitalization. [30]
Other trials have looked at other combinations as well. In a controlled study of 25 patients with IPAH and scleroderma-associated PAH in whom monotherapy with bosentan had failed and sildenafil was added, a significant improvement in WHO functional status and exercise capacity was observed in patients with IPAH but not in the patients with scleroderma-associated PAH. [31] In another controlled trial, sildenafil 80 mg was added to an intravenous epoprostenol regimen, and the combination proved to be more effective than placebo for improving exercise capacity and pulmonary arterial pressure. [32] It also demonstrated a significant reduction in the number of patients showing clinical worsening and an improvement of survival among the patients with the most severe disease.
Patients with WHO functional class IV disease are typically started on parenteral prostanoid therapy.
For patients who progress or are poorly responsive to initial therapy, practitioners typically add agents from a different class. Agents within the same class (including PDE-5 inhibitors and guanylate cyclase stimulators) should not be used together.
For more details on the specifics of agents within these classes, see the Medication.
Balloon Atrial Septostomy
Balloon atrial septostomy involves creation of an atrial right-to-left shunt by graded balloon dilation of the atrial septum. The technique has been performed via a femoral catheter, with a Brockenbrough septal needle and Mansfield balloons to dilate the septostomy.
This has been used with success in carefully selected patients who are symptomatic despite maximal medical therapy. The benefit (improved exercise function) occurs at the cost of a fall in arterial SaO2. Important to note is that this should only be regarded as a palliative or bridging procedure (prior to transplantation) and is not part of the recommended pulmonary arterial hypertension (PAH) treatment guidelines at this time.
Lung Transplantation
Although lung transplantation is reserved for patients with severe pulmonary arterial hypertension (PAH), a number of patients have undergone successful transplantation at several centers. These patients had PAH due to collagen-vascular disease, drug-induced PAH, or pulmonary veno-occlusive disease (PVOD). The stability of the underlying causative disorder and the ability of the patient to tolerate an extensive operation are prerequisites. Heart-lung transplantation has been performed in patients with PAH due to congenital cardiac disease or severe left ventricular dysfunction. [33]
Although lung transplantation has historically been the treatment of choice for severe PAH, at present it is typically needed only for patients who are still in New York Heart Association (NYHA) functional class IV after 3 months of therapy with epoprostenol. The long-term outcomes of lung transplantation remain disappointing, with 50% survival at 5 years.
Prevention
The majority of cases of pulmonary arterial hypertension (PAH) are not preventable. Patients should avoid using anorexigen drugs as well as illicit stimulant drugs such as amphetamine-derivatives and cocaine. To minimize potential contributions from WHO group 3 disease, patients should not smoke. Those with obstructive sleep apnea or other lung disease should be optimally treated for these diseases to avoid further insults from hypoxemia/chronic pulmonary disease.
Long-Term Monitoring
Once a diagnosis of pulmonary arterial hypertension (PAH) has been made, patients should be evaluated at regular intervals by a PAH specialist. Medical assessment including 6-minute walk distance (6MWD) testing should be performed at least twice a year to assess for a decline in functional status. [4] Transthoracic echocardiography is often performed on at least an annual basis as well, with right-sided heart catheterization undertaken for patients who have a change in clinical status.
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Gross pathology on patient who died of severe pulmonary arterial hypertension secondary to persistent patent ductus arteriosus.
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Close-up view of gross pathology on patient who died of severe arterial pulmonary hypertension secondary to persistent patent ductus arteriosus.
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Chest radiograph of patient with nonidiopathic pulmonary hypertension shows enlarged pulmonary arteries. This patient had atrial septal defect.
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54-year-old woman with history of scleroderma (CREST variety—ie, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) developed dyspnea that worsened upon exertion. The patient was found to have severe pulmonary arterial hypertension.
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54-year-old woman with history of scleroderma (CREST variety—ie, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) developed dyspnea that worsened on exertion. Spiral CT showed enlarged pulmonary arteries but no evidence of thromboembolism.
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Ventilation-perfusion scan of bilateral mismatched segmental and subsegmental defects, suggesting chronic thromboembolic hypertension.
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A 34-year-old woman with history of scleroderma (CREST variety—ie, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) developed dyspnea that worsened upon exertion. The patient was found to have severe pulmonary arterial hypertension.
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A 34-year-old woman with history of scleroderma (CREST variety—ie, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) developed dyspnea that worsened upon exertion. The patient was found to have severe pulmonary arterial hypertension.
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A 34-year-old woman with history of scleroderma (CREST variety—ie, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) developed dyspnea that worsened on exertion. A CT pulmonary angiogram showed a massively enlarged pulmonary artery.
