There are three U.S. Food and Drug Administration (FDA) approved medications in this class including bosentan (Tracleer), ambrisentan (Letairis), and macitentan (Opsumit). All ERAs are considered to be teratogenic based on animal studies. Importantly, women of child-bearing potential (WCBP) taking an ERA must be taught about pregnancy avoidance and acceptable forms of birth control. A negative pregnancy test is required prior to starting therapy, monthly while on therapy and 1 month after discontinuation of therapy. Patients should use two reliable forms of birth control while on therapy and up to 1 month after discontinuing therapy. Should pregnancy be suspected while on therapy, patients must contact their PH provider immediately.

Bosentan (Tracleer) was approved by the FDA in 2001 and was the first available oral therapy for the treatment of PAH. Because of the risks of hepatotoxicity and teratogenicity, bosentan is available only through the restricted Tracleer Access Program (T.A.P.), which is a component of the Tracleer Risk Evaluation and Mitigation Strategy (REMS). Tracleer REMS requires the prescribers, patients, and pharmacies must enroll in the program. Patients must be counseled that co-administration of cyclosporine A and glyburide are contraindicated with bosentan. Other drug-drug interactions can occur with ritonavir, ketaconozole, sildenafil, rifampin, tacromilus, simvastatin and other statins, requiring close surveillance of patients’ medication regimens. Providing a list of potential drug-drug interactions to patients may be useful. The recommended starting dose of bosentan is 62.5 mg twice daily with a maximum approved dosage of 125 mg twice daily. It carries a black box warning for liver injury, therefore any patient on this medication will require education about monthly liver function testing (liver aminotransferases [ALT and AST] [3]. Dependent upon results of liver function tests, dose reduction or discontinuation may be necessary. A decrease in hemoglobin concentration has been associated with the use of bosentan; therefore, monitoring hemoglobin is recommended prior to starting, after 1 and 3 months, and quarterly thereafter [4].

The second ERA to gain approval through the FDA for PAH was ambrisentan (Letairis) in 2007. Because of the risk of embryo-fetal toxicity, females can only receive ambrisentan through a restricted program called the Letairis REMS program. Because co-administration of ambrisentan with cyclosporine has been shown to increase ambrisentan exposure in healthy volunteers; the ambrisentan dosage should be limited to 5 mg once daily when administered together. Ambrisentan is supplied as a 5 mg or 10 mg tablet. The recommended starting dose is 5 mg daily, and if tolerated, up-titration to 10 mg daily can be considered. WCBP require a negative pregnancy test prior to therapy initiation, monthly pregnancy tests while on therapy and 1 month after discontinuation of therapy. Providers must obtain and review pregnancy tests monthly. Though elevations of liver function tests have been reported with ambrisentan, there was no statistical difference between groups in clinical trials. Thus, hepatic function monitoring is not required. Decreases to hemoglobin concentration and hematocrit can be associated with the use of ambrisentan, and, therefore, hemoglobin should be assessed prior to initiation of ambrisentan, at 1 month, and periodically thereafter [5].

Macitentan (Opsumit) is the most recent ERA to gain FDA approval in 2013. For all females, macitentan is available only through a restricted program called the Opsumit REMS Program because of the risk of embryo-fetal toxicity. The recommended dosage is 10 mg daily. For WCBP, providers must obtain and review pregnancy tests prior to starting therapy, monthly while on therapy and 1 month after discontinuation of therapy. It is recommended that liver function testing occur prior to starting macitentan and be repeated periodically at the discretion of the treating physician. Decreases in hemoglobin concentrations have occurred in patients taking macitentan. Hemoglobin should be assessed at baseline and repeated during treatment as clinically indicated [6]. Concomitant use of macitentan with strong CYP3A4 inducers, such as rifampin, should be avoided as they significantly reduce macitentan levels. Conversely, co-administration of strong CYP3A4 inhibitors like ketoconazole significantly increase macitentan exposure and should be avoided.

The most common side effects of the ERA class are edema and nasal congestion. Edema can often be managed with diuresis though the medication may ultimately need to be discontinued if it persists. Clinicians should pay close attention to educating patients about the potential to develop edema or experience worsening edema with the initiation of ERA therapy. Increased dyspnea and general sense of malaise may occur. These symptoms should trigger patients to contact their PH specialist office immediately. Tracking daily weights during ERA initiation is helpful to monitor for potential edema. Nasal congestion is also commonly associated with ERA treatment. Saline rinses can help to reduce tissue swelling in the nasal passages [7]. Nasal decongestants can potentially worsen the condition and must be avoided in this patient population. Steroid-based nasal sprays can help reduce swelling in some patients. For severe nasal congestion, consider referral to an otolaryngologist for other potential interventions. While some patients experience a degree of relief with these measures, intervention is typically temporary or ineffective. Dependent on the severity of the nasal congestion, therapy may need to be discontinued.

The PDE-5i drug class includes two different oral compounds, sildenafil (Revatio) and tadalafil (Adcirca). These medications are the least expensive PAH specific treatments. Sudden decrease or loss of hearing and vision has been reported in people taking PDE-5i. Patients are advised to seek a baseline eye examination prior to initiating therapy and periodically while on treatment. The most common side effects reported with the PDE5 inhibitors include headache, dyspepsia, epistaxis, diarrhea, and flushing. Epistaxis can be severe enough to require intervention such as nasal packing. Myalgia, which can be quite severe, is also reported, more often by patients on tadalafil versus sildenafil. Over the counter medications for headache, GI upset and myalgia may prove helpful. After initial exposure of this medication class, side effects generally subside within 1–2 weeks and can be managed successfully through this period. Importantly, patients are educated not to take PDE5 inhibitors in conjunction with nitrates of any form, or α-receptor antagonists due to the risk of systemic hypotension.

Sildenafil for pulmonary hypertension is supplied in a 20 mg tablet. The recommended dosage is 20 mg three times a day. There is clinical experience and data demonstrating dose related improvement with higher doses of sildenafil [8]. Because of the need for three times daily dosing, ongoing patient counseling should occur to assure continued medication compliance, particularly with the middle day dose.

Concomitant use of sildenafil with ritonavir and other potent CYP3A inhibitors is not recommended due to an increased potential for sildenafil-associated adverse events. Bosentan significantly decreases the plasma concentration of sildenafil when co-administered to patients with pulmonary hypertension [9]. Considerations for dose adjustment of sildenafil should be made if using these two medications in combination. When appropriate, clinicians should be certain patients understand not to use PDE5 inhibitors prescribed for erectile dysfunction in conjunction with those prescribed for PAH.

Tadalafil is supplied in a 20 mg tablet with recommended dosage of 40 mg once daily, which is helpful for improving medication compliance. To potentially improve tolerance throughout the day with tadalafil, consider dosing before bedtime for patients with significant headache. Dose adjustments may be required with co-administration of ritonavir. Clinicians should avoid use of CYP3A inhibitors and inducers, including ketoconazole, itraconazole, and rifampin.

Riociguat, a soluble guanylate cyclase (sGC) stimulator, was the first therapy approved to treat inoperable or persistent chronic thromboembolic pulmonary hypertension (CTEPH) (WHO Group 4). It is also approved to treat PAH WHO Group 1 patients. Due to teratogenicity effects, riociguat is only available through a restricted REMS program for female patients. WCBP must be taught about pregnancy avoidance and acceptable forms of birth control. A negative pregnancy test is required prior to starting therapy, monthly while on therapy and 1 month after discontinuation of therapy.

The recommended starting dose of riociguat is 1 mg three times daily, however for patients that may not tolerate the hypotensive effect of the drug, consider starting at 0.5 mg three times daily. Up titration of drug occurs by 0.5 mg dosages at intervals no sooner than 2 weeks as tolerated to a maximum dosage of 2.5 mg three times a day. Riociguat should not be taken in conjunction with nitrates in any form or PDE inhibitors due to risk of hypotension [10].

Precaution should be taken with concomitant use of ritonavir and ketoconazole, which can be associated with increased circulating levels of bioactive riociguat, resulting in systemic hypotension.

The most common reported side effects of riociguat are headache, GI upset, dizziness, nausea, hypotension, vomiting, and anemia. Though not mandated, some practices monitor for anemia at baseline and repeat during treatment as clinically indicated. Other less common side effects include hemoptysis, epistaxis, peripheral edema, and palpitations [10]. Patients should be counseled to report any sign of bleeding immediately. As hypotension is a more common side effect of riociguat, home monitoring and periodic assessment by a SP nurse of vital signs and is advisable between clinic visits. There is no additional cost to the patient for this service.

The prostacyclin medications are more complex and historically have only been available in non-oral forms that include inhaled, subcutaneous and intravenous. Recently an oral formulation of treprostinil as monotherapy, marketed as Orenitram, was approved by the FDA.

PH program staff submits a referral and clinical documentation for all prostacyclin medications to an SP, who starts an insurance verification process. The PH coordinator initiates education, which is supplemented by SP cardiopulmonary nurse specialists. Patients placed on prostacyclin therapy require in-depth and extensive continuing education and close monitoring. Clinicians prescribing these medications must have adequate expert staff to support these therapies.

In addition to education around specific PAH medical therapies, some patients will require anticoagulation, especially those patients with chronic thromboembolic pulmonary hypertension (CTEPH). In most cases, warfarin will be the anticoagulant of choice. However, newer factor Xa inhibitors are used more increasingly, although data remains lacking in regards to the efficacy of this drug class in the PAH population. The PHC staff are well positioned to educate patients of importance of regular INR monitoring, and the potential for drug-drug and drug-food interactions.

Most patients will be placed on a low sodium diet and often a fluid restriction if they have evidence of right ventricular failure and fluid retention. The PHC generally is responsible for this education, possibly in conjunction with a dietician, and includes instruction on measuring daily sodium intake and preparing low sodium meals. Patients are taught the importance of daily weights and immediately notifying the PH center of weight gain of >2 lbs. in 1 day or >5 lbs. in 1 week. Ongoing contact with patients regarding early awareness and management of fluid retention is critical in maintaining appropriate volume status.

Some PAH patients will require oxygen therapy. The PHC works with the patient and oxygen supplier to obtain the most appropriate oxygen device for the patient, both at rest and with exertion. Extensive education will be required including the importance of preventing hypoxia and traveling with oxygen [22]. Pulmonary or cardiac rehabilitation may be ordered by the PH provider, but patients who cannot participate in medically monitored exercise programs need to be counseled about the benefit of exercise and their restrictions. The PHC often provides general guidelines for exercise including the need to stop or slow down if they experience chest pain, excessive dyspnea, or light-headedness [23].

The PH coordinator is also responsible for teaching patients about early recognition of changes in their status and when to seek emergency medical care. Some patients with significant activity intolerance and advanced disease may need to obtain temporary or permanent disability. If this is deemed appropriate by the treating physician and established guidelines, the PHC, preferably in conjunction with a social worker, will teach the patient how to begin the process and assist with completing disability forms.

As a clinician, frustration can occur when the therapy that may be the most beneficial to a patient is not practical or available due to social or physical limitations. This typically comes into play when a prostanoid infusion is being considered, but can also be relevant with oral or inhaled treatments. Issues that may impede starting a therapy can include lack of support, age, drug dependency, history of non-compliance, or lack of dexterity from an underlying condition like systemic sclerosis. SP nurses can provide valuable insight into a patient’s ability to handle a specific therapy through a home assessment and pre teaching on a therapy.

Caring for this patient population requires a tremendous amount of monitoring and follow up. Adopting a team approach inclusive of physicians, nurses, pharmacists, respiratory therapists, and other specialized providers such as social workers and SP professionals is necessary to make certain the patient’s needs are being fully met. Establishing early in the care process a clear access route by which patients may contact their health care provider, PHC, and SP is critical to minimize the probability of avoidable problems. Finally, it is imperative that patients have a true understanding of their disease, are aware of all available options, and understand the implications associated with the various therapies.

The use of supplemental oxygen to maintain a PaO₂ > 60 mmHg remains part of the supportive care recommendations for treatment of PAH [29]. Resting, exertional and nocturnal hypoxemia should be assessed and documented as part of a comprehensive evaluation. Patients need to understand hypoxemia may be present even in the absence of dyspnea. Significant time should be devoted to selecting the appropriate oxygen delivery system, either stationary and/or portable to meet the patient’s current medical needs and capacity, and maintain clinical status. There are numerous portable oxygen concentrators (POCs) now available that vary in flowrate range, ability to deliver continuous vs. intermittent flow, size and weight. Generally, POC units capable of providing higher flowrates are heavier in weight. These devices may be insufficient to meet patient demand and other portable systems will need to be considered. Careful testing should be performed on the chosen system to ensure patients’ needs are met prior to purchase or rental.