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INTRODUCTION

Pulmonary hypertension is a chronic disorder caused by changes in the pulmonary vasculature that results in an increase in blood pressure in the lungs.¹ Several complex mechanisms are proposed to play roles in the pathophysiology of this condition, including the up-regulation of endothelin production and the down-regulation of nitric oxide and prostacyclin. These physiologic changes favor vasoconstriction and smooth muscle cell proliferation, which raises blood pressure.²

The term "pulmonary hypertension" represents several conditions and is classified into 5 primary groups on the basis of underlying etiology (Table 1). This classification system was defined by the World Health Organization (WHO) and was most recently updated in 2013 at the Fifth World Symposium on Pulmonary Hypertension (WSPH).³

Table 1. Clinical Classification of Pulmonary Hypertension3
Group	Description
1	Pulmonary arterial hypertension
1.1	Idiopathic
1.2	Heritable
1.2.1	BMPR2 mutation
1.2.2	ALK-1, ENG, SMAD9, CAV1, or KCNK3 mutation
1.2.3	Unknown disease-associated gene mutations
1.3	Drug- and toxin-induced
1.4	Associated with
1.4.1	Connective tissue disease
1.4.2	HIV infection
1.4.3	Portal hypertension
1.4.4	Congenital heart diseases
1.4.5	Schistosomiasis
1.4.6	Chronic hemolytic anemia
1'	Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
1''	Persistent pulmonary hypertension of the newborn
2	Pulmonary hypertension owing to left heart disease
2.1	Left ventricular systolic dysfunction
2.2	Left ventricular diastolic dysfunction
2.3	Valvular disease
2.4	Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies
3	Pulmonary hypertension owing to lung diseases and/or hypoxia
3.1	Chronic obstructive pulmonary disease
3.2	Interstitial lung disease
3.3	Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4	Sleep-disordered breathing
3.5	Alveolar hypoventilation disorders
3.6	Chronic exposure to high altitude
3.7	Developmental lung diseases
4	Chronic thromboembolic pulmonary hypertension
5	Pulmonary hypertension with unclear multifactorial mechanisms
5.1	Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy
5.2	Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis
5.3	Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4	Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension
Abbreviations: ALK-1 = activin receptor-like kinase 1; BMPR2 = bone morphogenic protein receptor type II; CAV1 = caveolin-1; ENG = endoglin; HIV = human immunodeficiency virus; KCNK3 = potassium channel super family K member-3; SMAD9 = mothers against decapentaplegic 9.

Group 1 comprises various etiologies of pulmonary arterial hypertension (PAH), which is a specific subtype of pulmonary hypertension. PAH is associated with an increased mean pulmonary arterial pressure as a result of increased vascular resistance.¹ PAH itself is rare, with a prevalence of approximately 12 cases per 1 million individuals.⁴ PAH can be classified as idiopathic PAH, heritable PAH, drug-induced or toxin-induced PAH, and associated PAH.⁴

Idiopathic PAH is considered a disease of exclusion when family history and other identified underlying causes are ruled out.¹ Patients with a family history of PAH may be genetically predisposed to developing the condition: a mutation in known genes is seen in 75% of patients with heritable PAH.⁵ Finally, associated PAH includes disease that is related to other conditions, such as connective tissue disorders, HIV, and portal hypertension in patients with liver disease.³

Disease severity is grouped according to functional class (Table 2).⁶ This system was originally created by the New York Heart Association, then adopted and updated by the WHO.⁶ Patients are classified into 1 of 4 functional classes on the basis of their symptoms, primarily how limited they are in their physical activities. Those with WHO functional class I disease experience no physical limitations, while patients with WHO functional class IV disease are unable to participate in any physical activity without experiencing symptoms. Functional classification is a strong predictor of mortality and drives therapeutic decision-making.⁴

Table 2. World Health Organization Functional Classification for Pulmonary Hypertension (PH)6
Class	Description
I	Patients with PH but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue or dyspnea, chest pain, or heart syncope.
II	Patients with PH resulting in slight limitations of physical activity. They are comfortable at rest. Ordinary physical activity results in undue fatigue or dyspnea, chest pain, or heart syncope.
III	Patients with PH resulting in marked limitations of physical activity. They are comfortable at rest. Less than ordinary physical activity results in undue fatigue or dyspnea, chest pain, or heart syncope.
IV	Patients with PH resulting in an inability to carry out any physical activity without symptoms.  These patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present even at rest. Discomfort is increased by physical activity.

Historically, many clinical trials measured disease control using the 6-minute walk distance (6MWD). This easily administered, objective assessment allows providers to quickly evaluate disease progression and the effects of interventions.⁴ Unfortunately, the true clinical meaningfulness of the 6MWD is still debated, as a small change from baseline is not a clear indicator of important patient-oriented outcomes.^2,7 Recently, a shift from the 6MWD to more clinically significant endpoints, such as clinical worsening, hospitalization, and all-cause mortality, have been used in clinical trials.⁴

Burden of PAH

Left untreated, pulmonary hypertension can lead to right ventricular failure and death. Mortality has historically been high but has declined over the past several decades due to advances in treatment.^2,4 However, while mortality is trending downward, registry data suggests 1-to-3-year mortality rates may still be as high as 30%.²

PAH is also associated with an increased risk of various comorbidities, including hypertension, diabetes mellitus, and congestive heart failure.⁴ Whether there is correlation or causation between PAH and these underlying conditions is less clear. Further, the association between PAH and the development of other diseases is convoluted by the potential underlying causes of PAH, which carry their own risks of comorbidities. For example, PAH may result from the development of portal hypertension in patients with cirrhosis, which itself may lead to the development of myriad complications, such as hepatorenal syndrome, ascites, and hepatic encephalopathy.

PAH is a very costly disorder, with some data suggesting medical spending is 4 to 5 times higher for patients with PAH than for matched patients without PAH.⁴ Costly specialty medications and the requirement for extensive medical oversight contribute to the high cost of care for this hard-to-manage condition.

PHARMACOLOGIC THERAPY FOR PAH

Four classes of targeted therapies are available for the treatment of PAH: prostanoids and a selective prostacyclin receptor agonist, endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE5) inhibitors, and selective guanylate cyclase stimulators (Table 3).⁸ These classes work on the underlying pathophysiologic causes of PAH previously discussed, including the endothelin, nitric oxide, and prostacyclin pathways. Medications for PAH have been studied most extensively in idiopathic and heritable PAH.¹

Table 3. Availability and Dosing Information for FDA-approved Medications for Pulmonary Arterial Hypertension8
Brand name	Active ingredient	Formulation	Available strengths	Initial dose	Usual dose
Prostacyclin receptor agonist
Uptravi	Selexipag	Oral tablet	200, 400, 600, 800, 1000, 1200, 1400, and 1600 mcg	200 mcg twice daily	Titrate up to 1600 mcg twice daily according to patient tolerability
Prostanoids
Orenitram	Treprostinil	Oral tablet	0.125, 0.25, 1, 2.5, and 5 mg	0.125 mg every 8 hours or 0.25 mg every 12 hours	Titrate according to patient tolerability
Remodulin	Treprostinil	IV/SC solution	1, 2.5, 5, and 10 mg/mL	1.25 ng/kg/min	Titrate up to 40 ng/kg/min according to patient tolerability
Tyvaso	Treprostinil	Solution for inhalation	0.6 mg/mL	3 inhalations 4 times daily	9 inhalations 4 times daily
Flolan	Epoprostenol	IV solution	0.5 and 1.5 mg	2 ng/kg/min	Titrate according to patient tolerability
Veletri	Epoprostenol	IV solution	0.5 and 1.5 mg	2 ng/kg/min	Titrate according to patient tolerability
Ventavis	Iloprost	Solution for inhalation	10 and 20 mcg/mL	2.5 mcg (1 inhalation of the 10 mcg/mL concentration) once daily	2.5 to 5 mcg (1 inhalation of the 10 or 20 mcg/mL concentration, respectively) 6 to 9 times daily
Soluble guanylate cyclase stimulator
Adempas	Riociguat	Oral tablet	0.5, 1, 1.5, 2, and 2.5 mg	1 mg 3 times daily	Titrate up to 2.5 mg 3 times daily according to patient tolerability
Endothelin receptor antagonists
Opsumit	Macitentan	Oral tablet	10 mg	10 mg once daily	10 mg once daily
Letairis	Ambrisentan	Oral tablet	5 and 10 mg	5 mg once daily	10 mg once daily
Tracleer	Bosentan	Oral tablet	62.5 and 125 mg	62.5 mg twice daily	Weight > 40 kg: 125 mg twice daily Weight < 39 kg: 62.5 mg twice daily
Phosphodiesterase type 5 inhibitors
Adcirca	Tadalafil	Oral tablet	20 mg	40 mg once daily	40 mg once daily
Revatio	Sildenafil	Oral tablet	20 mg	5 mg or 20 mg 3 times daily	Up to 20 mg 3 times daily
Revatio	Sildenafil	Oral solution	10 mg/mL	5 mg or 20 mg 3 times daily	Up to 20 mg 3 times daily
Revatio	Sildenafil	IV solution	10 mg/12.5 mL	2.5 or 10 mg 3 times daily	Up to 10 mg 3 times daily
Abbreviations: FDA = United States Food and Drug Administration; IV = intravenous; SC = subcutaneous.

Prostanoids and selective I-prostanoid receptor agonist

Prostacyclin is formed from the breakdown of arachidonic acid through the cyclooxygenase pathway, but it is also produced in the endothelial cells. Prostacyclin then binds to the I-prostanoid (IP) receptor, which activates adenylyl cyclase to increase cyclic adenosine monophosphate (cAMP). An increase in cAMP levels ultimately leads to vasodilation in the smooth muscle through activation of protein kinase A.^2,9 Prostacyclin analogs, including epoprostenol, iloprost, and treprostinil have therapeutic value by mimicking the effects of prostacyclin, while a closely related medication, selexipag, works as a selective IP receptor agonist.^9,10

In 1995, epoprostenol (Flolan, Veletri) became the first prostacyclin analog introduced to the market.⁸ Unfortunately, due to stability issues, epoprostenol requires continuous intravenous (IV) infusion through a central catheter.^8-10 Not only is this inconvenient, but IV ports are also associated with potentially serious complications, such as infections and thromboembolism.¹¹ Newer prostacyclin analogs are available, including inhaled iloprost (Ventavis) and treprostinil, which is available as a continuous subcutaneous (SC) or IV infusion (Remodulin), inhalation solution (Tyvaso), and an oral tablet (Orenitram).⁸ Selexipag (Uptravi) was the most recent medication to gain approval by the United States (U.S.) Food and Drug Administration (FDA) for the treatment of PAH.⁸

Dosing information for all medications is available in Table 3.⁸ A few points are noteworthy about the dosing of the prostacyclin analogs. First, continuous infusion by the SC route for injectable treprostinil is preferred over the IV route due to the risk of catheter-related blood infections associated with IV administration but not with SC infusion.⁸ Oral treprostinil and epoprostenol should be titrated to the maximum dose that is tolerated by the patient.⁸ Inhaled iloprost should be dosed 6 to 9 times daily but no more frequently than every 2 hours.⁸ While only the dose of inhaled treprostinil should be reduced in renal insufficiency, the doses of all of these agents, except IV epoprostenol, should be reduced in hepatic impairment.⁸ Orenitram is contraindicated in patients with severe hepatic impairment.⁸ Finally, selexipag should be taken with food to increase tolerability.⁸

Each of the prostacyclin analogs has been studied for different classes of functional impairment. Treprostinil—both SC and IV administration—was investigated in WHO functional classes II through IV; oral treprostinil and selexipag were investigated primarily in classes II and III; inhaled treprostinil was primarily investigated in class III; and iloprost and epoprostenol were investigated mostly in classes III and IV.⁸ Data from a single prostanoid cannot necessarily be safely extrapolated to alternative prostacyclin analogs. Therefore, subtle differences in which WHO functional classes were studied are important to note to make the most evidence-based and patient-centered recommendations.

The prostanoids and selexipag are a complex class of medications; they have been extensively studied in the past, though limited recent data are available. Therefore, only a brief description of the efficacy of these agents is included here. Treprostinil administered by SC, IV, and inhaled routes have generally been shown to improve 6MWD and quality of life, but they have not consistently improved functional class and have no mortality data to support their use.¹² Epoprostenol has shown positive effects on 6MWD and quality of life compared to placebo, as well as mortality benefit.^13,14 Inhaled iloprost was shown to improve the composite endpoint of increased 6MWD, improved functional class, and absence of clinical deterioration in the Aerosolized Iloprost Randomized (AIR) trial.¹⁵

The 2 newest medications from this class, selexipag and oral treprostinil, warrant deeper discussion. Oral treprostinil was studied in a series of 3 trials – Oral Treprostinil as Monotherapy for the Treatment of PAH (FREEDOM-M),¹⁶ Oral Treprostinil in Combination With an ERA and/or a PDE5 Inhibitor for the Treatment of PAH (FREEDOM-C),¹⁷ and Oral Treprostinil for the Treatment of PAH in Patients Receiving Background ERA and PDE5 Inhibitor Therapy (FREEDOM-C2).¹⁸ FREEDOM-M examined the use of oral treprostinil as monotherapy for patients with PAH not receiving other background therapies.¹⁶ This randomized, double-blind, placebo-controlled study found a significant improvement in exercise capacity with oral treprostinil as measured by 6MWD. However, oral treprostinil did not significantly improve functional class or symptoms of PAH. FREEDOM-C and FREEDOM-C2 are discussed in the "Combination therapy for PAH" section.

Selexipag was studied in the landmark Selexipag for the Treatment of PAH (GRIPHON) trial, which was an event-driven, double-blind, randomized, placebo-controlled clinical trial.¹⁹ In this trial, the effects of selexipag were investigated for the primary endpoint of death from any cause or complication from PAH, including disease progression or worsening PAH that resulted in hospitalization, initiation of parenteral prostanoid or long-term oxygen therapy, or the need for lung transplantation or balloon septostomy as judged by the physician. Selexipag was shown to significantly reduce the primary endpoint, though the outcome was primarily driven by PAH complications and, thus, no difference between placebo and selexipag with regard to all-cause mortality alone was observed. Selexipag also improved 6MWD compared to placebo, but it did not improve functional class.

Several notable pearls exist regarding the safety of the prostacyclin analogs. First, abrupt discontinuation of the prostanoids should be avoided due to the risk of withdrawal and rebound PAH symptoms.⁸ The orally administered medications, treprostinil and selexipag, should be retitrated from the lowest starting dose if patients miss more than 3 days of doses.⁸ Next, since both inhaled medications, iloprost and treprostinil, may increase the risk of bronchospasm, they have not been studied in patients with severe asthma or chronic obstructive pulmonary disease.⁸ Finally, an increased risk of mortality was seen in patients taking epoprostenol who also had congestive heart failure due to severe left ventricular systolic dysfunction, and, therefore, epoprostenol use in this population is contraindicated.⁸

Adverse reactions to the prostacyclin analogs vary, but side effects are primarily related to the mechanism of action of these agents and include hypotension, syncope, flushing, and headache, as well as increased risk of bleeding due to decreased platelet aggregation.⁸ Side effects are also driven by the delivery system of these agents with reactions such as cough and throat irritation with inhaled agents and infusion site reactions such as pain, infection, and systemic infection with medications that are continuously infused.⁸ Some other reactions include pulmonary edema specifically in patients with pulmonary veno-occlusive disease, jaw pain, and musculoskeletal pain with selexipag and epoprostenol.⁸

Few drug interactions exist with these agents. Strong inhibitors of the cytochrome P450 (CYP)2C9 enzyme, such as gemfibrozil, can increase exposure to certain prostanoids. Concomitant use of strong inhibitors of this enzyme should be avoided with infused treprostinil, while inhaled and oral treprostinil and selexipag should be used at lower doses or should have their doses titrated more slowly.⁸ Additionally, concomitant use of anticoagulants can increase the risk of bleeding with agents that inhibit platelet aggregation, including inhaled and oral treprostinil.⁸

Endothelin receptor antagonists

The endothelin pathway is mediated by endothelin-1 binding to ET-A and ET-B receptors. Activation of ET-A and ET-B receptors in the vascular smooth muscle causes vasoconstriction, fibrosis, and cellular proliferation.² Antagonists of these receptors promote vasodilation and antiproliferation. Two agents in this class, bosentan and macitentan, are unselective ET-A/ET-B receptor antagonists; a third ERA, ambrisentan, is selective for ET-A receptors, though the true benefit of this selectivity is unknown.^2,8

In 2001, bosentan (Tracleer) was the first ERA approved for PAH by the FDA; it was followed by ambrisentan (Letairis) in 2007 and, most recently, macitentan (Opsumit) in 2013.⁸ While bosentan has been studied in patients with WHO functional class II, III, and IV disease, ambrisentan and macitentan have primarily been studied in WHO functional class II and III disease.⁸ However, patients with WHO functional class IV disease were not excluded from clinical trials for ambrisentan and macitentan and the use of these medications is not precluded in these patients.²⁰ All of the ERAs are available as oral tablets to be dosed once daily (macitentan) or twice daily (ambrisentan, bosentan).⁸

The ERAs have all been shown to be effective in increasing exercise capacity as measured by 6MWD when used as monotherapy.²¹ Ambrisentan and bosentan have also shown reduced clinical worsening compared to placebo.^22-24 Not enough data are available to determine a treatment effect on mortality for bosentan and ambrisentan.²⁵ Macitentan reduced the composite endpoint of all-cause mortality or morbidity, defined as disease worsening or the need for IV or SC prostanoids, lung transplantation, or atrial septostomy.²⁶ This was primarily driven by reduced morbidity, as all-cause mortality was not significantly reduced when analyzed as its own endpoint.²⁶ There appears to be no difference in clinical effectiveness among the ERAs at this time.²¹

All of these agents have similar black box warnings and Risk Evaluation and Mitigation Strategies (REMS) programs due to the risk of embryo-fetal toxicity observed in animal studies with bosentan.²⁷ These programs require negative pregnancy tests before treatment begins, monthly tests during therapy, and tests for 1 month after treatment is discontinued for all female patients of reproductive potential. These programs also have registration, counseling, and distribution requirements, which impact health care providers and pharmacies.

Bosentan also carries a black box warning and an additional REMS program regarding the risk of hepatotoxicity.^8,27 Bosentan has been associated with elevations in liver transaminases to levels greater than 3 times the upper limit of normal and cannot be ruled out as a cause of unexplained cirrhosis in rare instances.^8,22 Therefore, prescribers must assess each patient's liver function tests (LFTs) at baseline and monthly thereafter to ensure the patient is not at risk for hepatotoxicity.^8,27 Further, using bosentan with glyburide is contraindicated, as increased LFTs have been seen with concomitant use of these medications.⁸ In contrast, ambrisentan has been shown to decrease the risk of hepatotoxicity compared to placebo.²⁸

Other serious adverse events associated with the ERAs include pulmonary edema (bosentan and ambrisentan) and anemia (bosentan and macitentan).²⁸ The labels for all of the ERAs warn of decreased sperm counts.⁸ Common adverse reactions seen with the ERAs are limited to events such as headache, sinusitis, respiratory tract infections, and flushing.⁸ Ambrisentan appears to be the most well tolerated of the ERAs.²¹ Bosentan is a substrate and an inducer of the CYP2C9 and CYP3A enzymes, and macitentan is a substrate of CYP3A4.⁸ These potential drug interactions should be considered when choosing an agent. Ambrisentan does not have any unique major drug interactions.⁸

PDE5 inhibitors

Nitric oxide is a known vasodilator. It exerts its vasodilatory effects in the pulmonary smooth muscle through the activation of soluble guanylate cyclase (sGC), which, in turn, promotes the conversion of guanosine 5′-triphosphate (GTP) to the cyclic form of guanosine 3',5'-monophosphate (GMP).^2,29 Cyclic GMP (cGMP) is responsible for these vasodilatory and antiproliferative effects.² However, PDE5- mediated hydrolysis of cGMP to GMP reduces these effects in an effort to balance vasodilation and vasoconstriction.² PDE5 inhibitors prevent the breakdown of cGMP to GMP, which induces and maintains vasodilation.³⁰

Two PDE5 inhibitors, sildenafil (Revatio) and tadalafil (Adcirca), are FDA approved for use in WHO functional class II and III PAH. When examined as a group, these agents have shown improvement in clinical markers of disease control including functional class and exercise capacity, as well as reduced all- cause mortality.³¹ The individual PDE5 inhibitors, however, have demonstrated varied outcomes. Sildenafil has been shown to reduce clinical worsening and improve 6MWD, functional class, and subjectively reported quality of life compared to placebo.³² Conversely, in a meta-analysis, sildenafil was found to have no improvement in mortality compared to placebo.³⁰ In the phase 3 trial Tadalafil Therapy for PAH (PHIRST-1), tadalafil was shown to increase 6MWD, time to clinical worsening, and quality of life, but it significantly reduced the incidence of clinical worsening compared to placebo.³³ In a follow-up study, Tadalafil for the Treatment of PAH: a double-blind 52-week uncontrolled extension study (PHIRST-2), 6MWD was maintained to 52 weeks.³⁴ The effects of tadalafil monotherapy on mortality have not been reported to date. Vardenafil has also been studied in PAH and has shown promise, but it has not been approved for use by the FDA.³⁵

Sildenafil and tadalafil are generally well tolerated, with the majority of adverse events being related to their vasodilatory properties. The most common adverse events include headache, flushing, dyspepsia, and visual disturbances.^30,32-34 For patients who are intolerant to sildenafil, switching from sildenafil to tadalafil is an option that is typically met without undue adverse events.³⁶ More data exist for transitioning patients from sildenafil to tadalafil than for transitioning from tadalafil to sildenafil. This is likely due to sildenafil often being a preferred first-line option, since it has more clinical experience and a lower cost than tadalafil.

Both sildenafil and tadalafil are available as oral tablets, and sildenafil is also available as a solution for oral administration or as a solution for IV infusion.⁸ For PAH, tadalafil has the advantage of once-daily dosing compared to sildenafil's 3-times-daily dosing schedule.⁸ Both agents are indicated for as-needed use in erectile dysfunction, and tadalafil can also be used daily for erectile dysfunction and/or benign prostatic hyperplasia.⁸ Tadalafil requires dose reduction in patients with renal and/or hepatic impairment, but sildenafil does not.⁸ Finally, both agents are major substrates of CYP3A4 and should be used cautiously with inducers or inhibitors of this enzyme.⁸

sGC stimulator

As previously reviewed, in the nitric oxide pathway, sGC promotes the conversion of GTP to cGMP. By stimulating sGC, riociguat (Adempas) increases vasodilation and antiproliferation through increased cGMP production.^2,29

Riociguat is FDA approved for PAH, as well as another form of pulmonary hypertension with no pharmacologic alternatives, chronic thromboembolic pulmonary hypertension.⁸ For the treatment of PAH, riociguat was shown to improve exercise capacity and reduce clinical worsening without an effect on mortality or functional class status.^31,37

Riociguat is available as a tablet for oral administration and is to be dosed 3 times daily. No dosage adjustments are necessary in either renal or hepatic impairment.⁸ The most common adverse reactions with riociguat include headache, dyspepsia, and dizziness.⁸ Major adverse events associated with this medication are hypotension and bleeding, including severe hemoptysis.⁸ Concomitant use of strong inhibitors of CYP enzymes, P-glycoprotein, and the BCRP (breast cancer resistance protein) transporter may increase levels of riociguat and lead to hypotension, while strong inducers of CYP3A enzymes may lower riociguat exposure.⁸ Dosage adjustments are recommended when riociguat is used with any of these agents.

The combination of PDE5 inhibitors and riociguat is contraindicated.⁸ The use of this combination was shown in the Blinded, Randomized and Extension Study of Riociguat Plus Sildenafil in PAH (PATENT- PLUS) trial not to improve clinical parameters but to increase the likelihood of developing significant hypotension.³⁸ Riociguat should not be administered within 24 hours of sildenafil and not within 24 hours before or 48 hours after tadalafil.⁸ Riociguat is also contraindicated with nitrates due to the risk of hypotension.⁸

Finally, riociguat has consistently been associated with fetal harm in animal studies.⁸ As a result, this agent is labeled with a black box warning and has a REMS program associated with its use. The program requires monthly pregnancy testing for patients during therapy and for 1 month after stopping treatment. Registration, counseling, and dispensing requirements also exist for providers and pharmacies.^8,27

Comparative data

In determining appropriate first-line therapy, clinicians should take into account patient-specific factors and choose the safest and most efficacious therapy. The data presented thus far have focused primarily on the use of pharmacologic agents as monotherapy. Though a large amount of data is available to help guide appropriate therapy, head-to-head studies for PAH medications are lacking.

Several recent meta-analyses aimed to clarify these muddy waters. One meta-analysis showed monotherapy with either bosentan or sildenafil was at least equally efficacious but perhaps more effective than monotherapy with ambrisentan or tadalafil in the improvement of functional class.³⁹ No difference was seen among these agents with regard to 6MWD.^25,39 Epoprostenol appears to extend 6MWD beyond what has been seen with iloprost or treprostinil.⁴⁰ In terms of tolerability, the prostacyclin analogs and selexipag appear to be the least well tolerated of the therapies available for PAH, while iloprost appears to be the best tolerated of the group.^40,41

The cost-effectiveness of the agents also varies. One analysis from Canada found sildenafil to be the most cost-effective therapy for WHO functional class II and III PAH.⁴² Though this analysis may not speak directly to the value of medications in the U.S., several factors support the likelihood that these findings hold true in the U.S. First, sildenafil is currently the only generically available oral medication for the treatment of PAH.⁸ Epoprostenol is also generically available, but it is still quite costly. While no remaining patents or exclusivities exist for Tracleer (bosentan), to date, no generic formulations have entered the market.⁸ The significantly lower cost of generic sildenafil compared to the alternatives combined with similar efficacy maintains that these cost-related findings are applicable to the U.S.

Combination therapy for PAH

The use of combination therapy for PAH has been shown to improve 6MWD and functional class and to reduce the composite endpoint of clinical worsening, including, but not limited to, death and hospitalization, without an effect on mortality alone.⁴³ However, individual trials have not consistently shown these outcomes due to unexpected differences among agents within the same class. In addition, different treatment approaches, such as utilizing up-front combination therapy or adding medications to background therapy in a particular order, appear to play a significant role in the success of any given regimen.

Many trials support an add-on approach to therapy; that is, if clinical targets are not met with a single medication, the addition of a second or third agent from a different class should be considered. For instance, in GRIPHON, selexipag showed consistent results in the primary composite endpoint of all-cause mortality and complications from PAH regardless of background therapy with an ERA, a PDE5 inhibitor, or both.¹⁹ Patients not responding to background PDE5 inhibitor therapy can benefit from the addition of ambrisentan, as was shown in the Study of Add-on Ambrisentan Therapy to Background PDE5 Inhibitor Therapy in PAH (ATHENA-1).⁴⁴ Alternatively, those not responding to PDE5 inhibitor and/or oral prostanoid therapy were shown to benefit from the addition of ambrisentan in the Ambrisentan Therapy in a Diverse Population of Patients with Pulmonary Hypertension (ARIES-3)⁴⁵ trial or macitentan in the Study with an ERA in PAH to Improve Clinical Outcome (SERAPHIN).⁴⁶ Finally, a Cochrane review concluded that riociguat can be effective when added to background therapy consisting of either prostanoid or ERA therapy, but it should not be used in combination with PDE5 inhibitors.³⁷

Though there are plenty of data to support an add-on approach, FREEDOM-C, FREEDOM-C2, and Bosentan Added to Sildenafil Therapy in Patients With PAH (COMPASS-2) were important studies that countered this way of thinking. In FREEDOM-C and FREEDOM-C2, the addition of oral treprostinil to background therapy was investigated.^17,18 Oral treprostinil was shown to have benefit as monotherapy, but FREEDOM-C found no improvement in 6MWD and more treatment discontinuations with the addition of oral treprostinil to an ERA, a PDE5 inhibitor, or both compared to the addition of placebo.¹⁷ Adding oral treprostinil to background therapy with an ERA and PDE5 inhibitor was not shown to improve 6MWD or functional class compared to the addition of placebo in FREEDOM-C2.¹⁸

COMPASS-2 was a prospective, double-blind, event-driven trial that examined the effect of adding bosentan to stable sildenafil therapy predominantly in WHO functional class III PAH.⁴⁷ The composite primary end-point was the time to the first morbidity or mortality event, which was defined as all-cause death, hospitalization for worsening disease or for IV prostanoid initiation, atrial septostomy, lung transplant, or worsening PAH. Though the addition of bosentan to sildenafil improved the secondary endpoint of 6MWD, combination therapy did not show a significant improvement in the primary endpoint compared to placebo. Notably, however, there were some limitations to the study, including a high discontinuation rate, a lower-than-anticipated event rate, and the inclusion of older, sicker patients compared to many other trials. As such, these results should be interpreted cautiously. Still, these studies highlight the fact that efficacy of sequential therapies cannot be assumed and that alternative approaches such as up-front combination therapy may play an important role in the management of PAH.

Initial or up-front combination therapy involves the first-line use of more than 1 pharmacologic agent in treatment-naïve patients. Unfortunately, studies examining initial combination therapy got off to a rough start with the Combination of Bosentan with Epoprostenol in PAH (BREATHE-2) trial.⁴⁸ In this study, patients who were scheduled to start IV prostanoid therapy with epoprostenol were randomized to also begin placebo or the ERA, bosentan. No statistically significant difference was found in this trial with regard to hemodynamic stability or 6MWD between the 2 groups.

However, a recent breakthrough trial, Ambrisentan and Tadalafil in Patients with PAH (AMBITION), compared initial combination therapy with the ERA ambrisentan plus the PDE5 inhibitor tadalafil against either agent alone in treatment-naïve patients with WHO functional class II or III PAH.⁴⁹ In this event-driven, randomized, double-blind trial, upfront combination therapy led to fewer clinical failures, a composite endpoint made up of death, hospitalization for worsening disease, disease progression, or unsatisfactory long-term clinical response. This endpoint was primarily driven by hospitalization for worsening disease. There was no difference in change in all-cause hospitalization or functional class shown in the study. Still, the results of this trial support up-front combination therapy, an approach not heavily studied prior to this point.

Recently, a small (n = 97), retrospective study using real-world data also showed promise with initial combination therapy in patients with WHO functional class III or IV disease.⁵⁰ This analysis found that initial combination therapy with bosentan and sildenafil, bosentan and tadalafil, or ambrisentan and tadalafil led to significant improvements in functional class and exercise capacity in patients with WHO functional class III or IV disease. Another small (n = 19) retrospective analysis examined the effect of up- front triple therapy for patients with WHO functional class III or IV disease.⁵¹ Results showed very favorable responses: all but 1 patient experienced an increase in 6MWD; all but 2 improved to WHO functional class I or II disease; and all patients were alive at year 3. (The predicted survival rate was 49%.) Though these 2 studies were limited by their sample sizes and did not have comparator groups, the results support initial combination therapy. Up-front triple therapy appears to be a promising therapeutic approach but requires future study.

GUIDELINE RECOMMENDATIONS

Medication therapy for PAH has evolved considerably within the past 2 decades. But, while numerous therapeutic options exist, there is still uncertainty surrounding the ideal approach to treatment. Several recent guidelines exist to aid in the decision-making process.^20,52,53 While the results of recent landmark trials and the introduction of selexipag have been incorporated into certain guidelines, others have yet to be updated with these results. Therefore, as with all disease states, caution must be exercised when interpreting outdated guidelines in a rapidly evolving pharmacologic landscape.

The 3 most recent guidance documents include the 2013 Updated PAH Treatment Algorithm from the Fifth WSPH,²⁰ the 2014 CHEST guidelines,⁵² and, most recently, the 2015 European Society of Cardiology (ESC) and the European Respiratory Society (ERS) guidelines.⁵³ The 2013 treatment algorithm from the Fifth WSPH and the 2015 ESC/ERS guidelines group their findings according to classes of recommendations and evidence levels, as shown in Table 4 and Table 5, respectively.^20,53

Table 4. Classes of Recommendations Used in Guidelines20,53
Class	Definition	Suggested wording
Class I	Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, and effective	Is recommended, is indicated
Class II	Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure
Class IIa	Weight of evidence/opinion is in favor of usefulness/efficacy	Should be considered
Class IIb	Usefulness/efficacy is less well-established by evidence/opinion	May be considered
Class III	Evidence or general agreement that the given treatment or procedure is not useful/effective and in some cases may be harmful	Is not recommended

Table 5. Levels of Evidence Used in Guidelines20,53
Level	Definition
A	Data derived from multiple randomized clinical trials or meta-analyses
B	Data derived from a single randomized clinical trial or large non-randomized studies
C	Consensus of opinion of the experts and/or small studies, retrospective studies, or registries

WSPH treatment algorithm

The 2013 Updated PAH Treatment Algorithm from the Fifth WSPH places emphasis on supportive care but also suggests which therapies have the most data to support their use in each functional class. The algorithm for monotherapy is shown in Table 6.²⁰

Table 6. 2013 Updated Pulmonary Arterial Hypertension Treatment Algorithm from the Fifth World Symposium on Pulmonary Hypertension20
Recommendation	Evidence	WHO-FC II	WHO-FC III	WHO-FC IV
I	A or B	Ambrisentan Bosentan Macitentan Riociguat Sildenafil Tadalafil	Ambrisentan Bosentan Epoprostenol IV Iloprost inhaled Macitentan Riociguat Sildenafil Tadalafil Treprostinil SC, inhaled	Epoprostenol IV
IIa	C		Treprostinil IV	Ambrisentan Bosentan Iloprost inhaled Macitentan Riociguat Sildenafil Tadalafil Treprostinil SC, IV, or inhaled
IIb	B	The only agent recommended with this level of evidence is not approved by the FDA for use in the United States.
	C		Initial combination therapy	Initial combination therapy
Abbreviations: FDA = Food and Drug Administration; IV = intravenous; SC = subcutaneous; WHO-FC = World Health Organization Functional Class.

For WHO functional class II PAH, this guidance document suggests any ERA, any PDE5 inhibitor, or riociguat. For WHO functional class III PAH, the same 3 classes are recommended, as is any prostanoid. It is highlighted that less evidence exists for IV treprostinil and only expert consensus supports initial combination therapy. Finally, in WHO functional class IV PAH, IV epoprostenol is recommended, while all other therapies used alone should be considered. Initial combination therapy is the least well- established, but it may be considered. Notably, the results of AMBITION were not published at the time this algorithm was established. After initial failure, sequential add-on therapy with any of the other classes is recommended.²⁰

CHEST guidelines

The 2014 CHEST guidelines take their recommendations a step further than the algorithm from the Fifth WSPH. Their pharmacologic recommendations begin similarly by suggesting that patients with WHO functional class II PAH be treated with an ERA, a PDE5 inhibitor, or riociguat. However, they delve deeper and suggest particular agents for individual outcomes. To improve 6MWD, they recommend ambrisentan or sildenafil as first-line therapy. Expert consensus also suggests that tadalafil or riociguat can be used. Also on the basis of consensus, the guideline suggests that bosentan, macitentan, or riociguat can improve time to clinical worsening. They suggest that parenteral or inhaled prostanoids should not be used as first-line or even second-line therapy for WHO functional class II patients.⁵²

For WHO functional class III patients, an ERA, a PDE5 inhibitor, or riociguat is appropriate first-line therapy. Specifically, the guidelines highlight that bosentan, macitentan, and sildenafil are recommended to improve 6MWD, while tadalafil and riociguat are suggested alternatives; sildenafil may lower functional class and bosentan can decrease hospitalizations in the short term. Tadalafil, riociguat, and macitentan are suggested alternatives to improve functional class and to delay the time to clinical worsening. Infused or inhaled prostanoids may be used as third-line agents in these patients, but they can be considered sooner in patients with a poor prognosis or rapidly progressing disease.⁵²

For WHO functional class IV PAH, IV epoprostenol or IV or SC treprostinil are suggested to improve 6MWD, while IV epoprostenol can also be useful for improving WHO functional class. The suggested approach for those unable to utilize infused therapy includes inhaled iloprost or treprostinil in combination with bosentan.⁵²

The 2014 CHEST guidelines also provide some specific suggestions for managing inadequate responses to initial therapy in WHO functional class III or IV disease. The only recommendation provided for up- front combination therapy is to avoid routine use of bosentan in combination with IV epoprostenol, which is based on the BREATHE-2 trial. Many of the suggestions for sequential therapy are similar to those presented in the 2015 ESC/ERS guidelines, which is discussed next. One exception is that the CHEST guidelines suggest riociguat or macitentan can be added for patients not controlled on inhaled prostanoid therapy alone; this recommendation is absent from the ESC/ERS guidelines.

ESC/ERS guidelines

In 2015, the ESC/ERS released the most up to date guidelines available at this time. Many of the recommendations are similar to those noted in the previous guidelines. However, notable differences exist.

For monotherapy (Table 7), the ESC/ERS guidelines differ from the 2013 WSPH algorithm in that selexipag was added as a class IB recommendation for WHO functional class II or III disease and oral treprostinil was added as a class IIbB recommendation for WHO functional class III disease only. For WHO functional class IV disease, all guidelines agree that IV epoprostenol should be first-line therapy, but the ESC/ERS guidelines have downgraded all other therapies from class IIaC to IIbC, which means the authors have determined therapy to be less well-established by evidence.⁵³

Table 7. 2015 European Society of Cardiology and the European Respiratory Society Guidelines Recommendations for Monotherapy53
Treatment				Class of recommendation/level of evidence
Class	Generic name		Brand name	WHO-FC II		WHO-FC III		WHO-FC IV
ERAs	Ambrisentan		Letairis	I	A	I	A	IIb	C
	Bosentan		Tracleer	I	A	I	A	IIb	C
	Macitentan		Opsumit	I	B	I	B	IIb	C
PDE5 inhibitors	Sildenafil		Revatio	I	A	I	A	IIb	C
	Tadalafil		Adcirca	I	B	I	B	IIb	C
sGC stimulator	Riociguat		Adempas	I	B	I	B	IIb	C
Prostanoids	Epoprostenol	IV	Flolan, Veletri	-	-	I	A	I	A
	Iloprost	Inhaled	Ventavis	-	-	I	B	IIb	C
	Treprostinil	SC	Remodulin	-	-	I	B	IIb	C
		Inhaled	Tyvaso	-	-	I	B	IIb	C
		IV	Remodulin	-	-	IIa	C	IIb	C
		Oral	Orenitram	-	-	IIb	B	-	-
IP receptor agonist	Selexipag		Uptravi	I	B	I	B	-	-
Abbreviations: ERA = endothelin receptor antagonist; IP receptor = I-prostanoid receptor; IV = intravenous; PDE5 = phosphodiesterase type 5; SC = subcutaneous; sGC = soluble guanylate cyclase; WHO-FC = World Health Organization Functional Class.

The ESC/ERS guidelines have included a section for both up-front combination therapy and sequential therapies (Table 8 and Table 9, respectively). On the basis of the results from the AMBITION trial, ambrisentan and tadalafil have the highest level of evidence for initial combination therapy, while other dual and triple up-front combinations are considered to be much less evidence based.⁵³

Table 8. 2015 European Society of Cardiology and the European Respiratory Society Guidelines Recommendations for Initial Combination Therapy53
Treatment	Class of recommendation/level of evidence
	WHO-FC II		WHO-FC III		WHO-FC IV
Ambrisentan + tadalafil	I	B	I	B	IIb	C
Other ERA + PDE5 inhibitor	IIa	C	IIa	C	IIb	C
Bosentan + sildenafil + IV epoprostenol	-	-	IIa	C	IIa	C
Bosentan + IV epoprostenol	-	-	IIa	C	IIa	C
Other ERA or PDE5 inhibitor + SC treprostinil	-	-	IIb	C	IIb	C
Other ERA or PDE5 inhibitor + other IV prostacyclin analogs	-	-	IIb	C	IIb	C
Abbreviations: ERA = endothelin receptor antagonist; IV = intravenous; PDE5 = phosphodiesterase type 5; SC = subcutaneous; WHO-FC = World Health Organization Functional Class.

Table 9. 2015 European Society of Cardiology and the European Respiratory Society Guidelines Recommendations for Sequential Therapy53
Treatment	Class of recommendation/level of evidence
	WHO-FC II		WHO-FC III		WHO-FC IV
Macitentan added to sildenafil	I	B	I	B	IIa	C
Riociguat added to bosentan	I	B	I	B	IIa	C
Selexipag added to ERA and/or PDE5 inhibitor	I	B	I	B	IIa	C
Sildenafil added to epoprostenol	-	-	I	B	IIa	B
Treprostinil inhaled added to sildenafil or bosentan	IIa	B	IIa	B	IIa	C
Iloprost inhaled added to bosentan	IIb	B	IIb	B	IIb	C
Tadalafil added to bosentan	IIa	C	IIa	C	IIa	C
Ambrisentan added to sildenafil	IIb	C	IIb	C	IIb	C
Bosentan added to epoprostenol	-	-	IIb	C	IIb	C
Bosentan added to sildenafil	IIb	C	IIb	C	IIb	C
Sildenafil added to bosentan	IIb	C	IIb	C	IIb	C
Other double combinations	IIb	C	IIb	C	IIb	C
Other triple combinations	IIb	C	IIb	C	IIb	C
Riociguat added to sildenafil or other PDE5 inhibitor	III	B	III	B	III	B
Abbreviations: ERA = endothelin receptor antagonist; PDE5 = phosphodiesterase type 5; SC = subcutaneous; WHO-FC = World Health Organization Functional Class.

Rather than suggesting that any agent from another class can be added on after a less-than-anticipated response is seen with initial monotherapy as the 2013 WSPH treatment algorithm did, the ESC/ERS guidelines present sequential combination therapy as it has been studied. For instance, bosentan added to sildenafil and sildenafil added to bosentan are considered separately. The best data for add-on therapy belongs to macitentan added to sildenafil, riociguat added to bosentan, and selexipag added to background therapy with an ERA or a PDE5 inhibitor for patients with WHO functional class II or III PAH. Sildenafil added to epoprostenol is also recommended, but specifically in functional class III disease. The guidelines do not suggest specific sequential triple therapy recommendations for any WHO functional class, nor are there any class I recommendations for WHO functional class IV disease, indicating that supportive data in these areas is lacking. Finally, as was recommended in previous guidelines and in manufacturer labeling, the addition of riociguat to any PDE5 inhibitor is considered to be harmful and should be avoided.⁵³

CONCLUSION

Currently, ERAs or PDE5 inhibitors are the agents of choice for WHO functional class II or III PAH, while IV epoprostenol, inhaled iloprost, and SC or inhaled treprostinil are appropriate for WHO functional class III disease. The use of IV epoprostenol is recommended as first-line treatment for WHO functional class IV disease. Initial combination therapy is an area of growing interest, with up-front triple therapy being an interesting area of study for the future. Sequential combination therapy continues to be a mainstay of therapy, though ideal regimens prove elusive as evolving clinical data continue to be published.

It is important that clinicians stay up to date with new data and do not rely fully on guidelines to help with clinical decision-making in this fast-moving field of study. Armed with an updated knowledge base of recent drug approvals and key studies and guidelines, pharmacists can maintain their understanding of PAH treatment on an ongoing basis, which is imperative for this complex condition.

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