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Introduction

Pulmonary hypertension represents a rare group of conditions including pulmonary arterial hypertension (PAH). This debilitating disease may lead to significant morbidity and continues to be related to high mortality rates despite the availability of numerous pharmacologic options. Challenges remain in the diagnosis and treatment of this disease, often leading to delays in care and subsequent worsening outcomes. Additionally, while disease progression can be slowed with increased patient adherence, therapeutic regimens for PAH are complex and associated with adverse drug reactions. This activity will highlight the most up-to-date evidence on PAH management and will also discuss the role of the pharmacist in the patient’s PAH journey.

Background

Pulmonary hypertension is a broad disease classification diagnosed when mean pulmonary artery pressure (mPAP) is greater than or equal to 25 mmHg.¹ This disease encompasses a variety of conditions and is categorized into five groups by the World Health Organization (WHO, Table 1). Group 1 pulmonary hypertension includes PAH and represents the rarest form of pulmonary hypertension, yet the most commonly studied group.¹ Subtypes of PAH include idiopathic PAH, heritable or familial PAH, drug- or toxin-associated PAH, and PAH associated with other diseases.

Presentation and Burden

The typical presentation of PAH involves women (nearly twice as commonly as men) in their fifth decade of life presenting with vague symptoms, such as dyspnea, declines in exercise capacity, or fatigue.^3,4 As the disease progresses, syncope and lower extremity edema may present, as well.¹ Left untreated, hallmarks of PAH, including increased pulmonary vascular resistance and right ventricular dysfunction, will eventually lead to right heart failure and death.⁵ One-year mortality rates are estimated between 2.8% and 21.2% in low- to high-risk groups, respectively.⁶ Five-year mortality rates for PAH are estimated at approximately 40%.^7,8 While this is still frustratingly high, it is lower than other pulmonary hypertension classifications because of advances in the treatment of PAH.⁷

Though PAH itself is associated with poor outcomes, it is also associated with numerous comorbidities, including, but not limited to, systemic hypertension, peripheral vascular disease, obesity, and chronic obstructive pulmonary disease (COPD).⁹ Pulmonary arterial hypertension is also associated with nutritional abnormalities. Deficiencies in vitamin D and iron are more commonly seen in PAH patients and may impact clinical outcomes.¹⁰ As such, supplementation with iron and vitamin D may improve the wellbeing of patients with PAH.

Given the significant morbidity associated with this disease, it should be no surprise that PAH is also associated with substantial financial costs. Estimates suggest that care for patients with PAH is approximately 4 to 5 times higher than those without this condition, equating to approximately $100,000 of spending per patient per year.¹¹ The primary driver of health care spending in this population is inpatient care, for which the average cost of a PAH-related hospitalization is more than $24,000.^11,12 In addition, pharmaceutical costs contribute heavily to spending on this disease, though estimates vary based on treatment strategy. For instance, greater spending is expected in those who receive initial combination therapy as compared to those treated with monotherapy upfront.⁸

Diagnosis

Diagnosis of PAH is complex and may take years from symptom onset to disease identification.^13,14 In fact, several studies have found the time from symptom onset to PAH diagnosis to be over 3 years.^13,15 This can occur due to a number of possible alternative diagnoses associated with the vague symptoms described previously. Often, PAH is misdiagnosed initially as asthma or COPD, leading to delays in treatment initiation. As early treatment is associated with improved outcomes, delays due to initial misdiagnosis may lead to worse clinical outcomes for patients.¹⁵ Further, given the complexity of diagnosis, patients will often require referral to a pulmonary specialist or pulmonary hypertension clinic for proper evaluation. Considering the rarity of this disorder, it is not reasonable to expect primary care providers to refer each patient who presents with shortness of breath to a specialist for evaluation up front. This underscores the challenges of balancing timely diagnosis with a conscientious use of scarce health care resources.

Further classification

In addition to the WHO classification of pulmonary hypertension subtypes described above, the WHO Functional Classification system is widely used to define disease severity based on the extent of physical activity limitation caused by the disease (Table 2). This severity index ranges from Functional Class I, in which patients have been diagnosed with pulmonary hypertension but are experiencing no limitations in physical activity, to Functional Class IV, where individuals cannot perform any physical activity without symptoms like dyspnea and fatigue.¹⁶

PH – pulmonary hypertension

Several risk-stratification tools also exist, which allow clinicians to estimate each individual patient’s likelihood of survival at different time periods.¹⁷ These risk estimators take into account a number of variables, including patient age, timeliness of diagnosis, the presence of comorbities, functional class, and other clinical parameters and designate patients as low-, moderate-, or high-risk.^17,18

Putting it all together, patients are categorized by low- to high-risk, by WHO group, and by WHO functional class. A patient’s classification can then be used to determine individualized treatment goals and therapeutic decisions.

Clinical Outcomes

Various measures of disease control are used in clinical trials for PAH to determine the effectiveness of therapy. One of the most common measures, 6-minute walk distance (6MWD) measures the improvement in how far patients can walk in a specified time period after treatment initiation. A longer 6MWD (over 400 meters) is associated with improved prognosis.¹⁹ Change in WHO functional class is another commonly reported measure. Though subjective, this measure is an important indicator of patient perception of disease severity.

Broad terms, including clinical worsening or disease progression, typically encompass other meaningful measures of disease control, such as hospitalization-related outcomes, the need for parenteral prostanoid therapy, lung transplant, or other medical intervention. In recent years, more emphasis has been placed on mortality in clinical trials, typically as a composite endpoint with other events.

Several hemodynamic measures are used commonly in clinical trials as well, including mPAP, pulmonary vascular resistance (PVR), N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac function as measured by the cardiac index.²⁰

Medications

Five medication classes, including phosphodiesterase 5 (PDE-5) inhibitors, endothelin receptor antagonists (ERAs), a soluble guanylate cyclase (sGC) stimulator, prostanoids, and a prostacyclin receptor agonist, are used in the treatment of PAH. The medications in each class and additional dosing related information can be found in Table 3.

Phosphodiesterase 5 inhibitors

The most commonly prescribed initial therapy for PAH includes PDE-5 inhibitors, with the majority of prescriptions written for sildenafil.^8,35 The two PDE-5 inhibitors approved by the United States Food and Drug Administration (FDA) include sildenafil (Revatio®) and tadalafil (Adcirca®, Alyq^TM). By inhibiting PDE-5, these agents increase cyclic guanosine monophosphate (cGMP), leading to vascular smooth muscle relaxation and pulmonary vasodilation.^21,23

Pharmacists should be aware that though sildenafil and tadalafil are also indicated for the treatment of erectile dysfunction (ED) and tadalafil for benign prostatic hyperplasia (BPH), the doses used in PAH differ:

• Sildenafil tablets are dosed as 5 mg or 20 mg three times daily for PAH, while 25 mg, 50 mg, or 100 mg should be taken one hour before anticipated sexual activity for ED.
• Tadalafil should be dosed at 20 mg twice daily for PAH. For ED, 10 mg to 20 mg 30 minutes before anticipated sexual activity or 2.5 mg to 5 mg once daily can be used, while the recommended dose for BPH is 5 mg once daily.

The PDE-5 inhibitors are one of the most extensively studied PAH medication classes. A recent Cochrane review found that PDE-5 inhibitor use is expected to not only improve functional class and 6MWD, but also decrease the likelihood of death.³⁶ Mortality rates in PDE-5 inhibitor-treated patients were an average of 22% lower than placebo over a 14-week period, with only 32 patients needing to be treated to prevent one additional death.³⁶

Generally speaking, PDE-5 inhibitors are well-tolerated, but use may be accompanied by untoward adverse events. These may include epistaxis, headache, gastrointestinal upset, flushing, and myalgia.^21,23,36 Use of PDE-5 inhibitors in combination with nitrates (e.g., isosorbide mononitrate, nitroglycerin) or riociguat, a sGC stimulator discussed in more detail later, are contraindicated due to the risk of hypotension.^21,23

Endothelin Receptor Agonists

In 2001, bosentan (Tracleer®) was the first ERA approved in the United States.²⁶ This was followed by ambrisentan (Letairis®) in 2007 and macitentan (Opsumit®) in 2013.^24,25 These agents work by preventing the binding of the neurohormone endothelin-1 (ET-1) to endothelin receptors ET_A and ET_B, thereby reducing vascular hypertrophy and organ damage.^24-26

Bosentan has consistently been shown to improve various measures of PAH control including improvements in 6MWD, prevention of worsening in functional class, and reduced clinical worsening, along with improvement in various hemodynamic measures like reduced mPAP and reduced PVR.³⁷ A recent meta-analysis for ambrisentan found similar results, including improved exercise tolerance, cardiac function, and hemodynamic measures.³⁸

Macitentan was studied in the SERAPHIN trial, which found that the 10 mg strength reduced the risk of the primary composite endpoint of worsening of PAH, death from any cause, initiation of intravenous (IV) or subcutaneous (SC) prostanoid therapy, or lung transplantation by approximately 45%.³⁹ However, this was primarily driven by a reduced worsening of the disease, while no meaningful differences in mortality were found. Functional class improvements were also seen in a larger proportion of macitentan-treated patients compared to placebo.³⁹

Data are mixed when considering intraclass comparability. Broadly speaking, ERA monotherapy can be expected to improve 6MWD and functional class.^40,41 Unfortunately, all three agents are not expected to have any impact on mortality.⁴⁰

Endothelin receptor antagonists are associated with safety concerns that may limit their tolerability. All ERAs share a black box warning for embryo-fetal toxicity. For this reason, a Risk Evaluation and Mitigation Strategy (REMS) program exists on each product for providers, pharmacies, and patients, requiring appropriate contraception for patients, and appropriate baseline and monthly monitoring. Pregnancy must be avoided while using these products and for one month after discontinuation.^24-26,42 Notably, the manufacturer’s labeling highlights that hormonal contraceptives may be less effective when used with bosentan, a warning not shared with the other ERAs, so alternative contraceptive methods should be used.²⁶

Additionally, because elevations in liver function tests were seen in up to 14% of bosentan-treated patients, bosentan also has a black box warning and REMS requirements regarding the risk of hepatotoxicity.²⁶ The risk was increased further when used in combination with glyburide, resulting in a labeled contraindication for coadministration of these medications. Macitentan may also increase the risk of hepatotoxicity, though to a much smaller extent than bosentan, while ambrisentan has not been shown to have this adverse event.^24,25

Further warnings for these medications include peripheral edema, pulmonary veno-occlusive disease, hematological abnormalities like decreased hemoglobin and hematocrit, and suppressed sperm counts. Outside of these, each agent is associated with various adverse events, most notably respiratory tract infection with bosentan, nasal congestion with ambrisentan, and nasopharyngitis, bronchitis, and headache with macitentan.^24-26

With regard to drug interactions, bosentan is a substrate of both cytochrome p450 (CYP) 3A4 and CYP2C9, so inhibitors and inducers of these enzymes may affect drug concentrations.²⁶ Macitentan is also a CYP3A4 substrate.²⁴ Interestingly, no drug interactions outside of concomitant cyclosporine use are highlighted for ambrisentan, suggesting this may be a safer choice for patients on complex medication regimens.²⁵

Soluble Guanylate Cyclase Stimulator

One sGC stimulator, riociguat (Adempas®), is approved for use in the United States for the treatment of PAH. This agent works by sensitizing the nitric oxide (NO) receptor, sGC, to endogenous NO, while also directly stimulating the receptor independent of NO.²⁷ Similar to PDE-5 inhibition, this raises cGMP leading to the desirable effects discussed earlier. In addition to PAH, riociguat is indicated for chronic thromboembolic pulmonary hypertension (WHO Group 4 disease), the only FDA-approved medication for this form of pulmonary hypertension.

Riociguat was approved for PAH on the basis of the PATENT-1 study. This trial found riociguat, titrated to an individually tolerated dose of up to 2.5 mg three times daily, was associated with a significantly improved 6MWD compared to placebo, functional class, and time to clinical worsening, amongst other outcomes.⁴³ Additional data also support the benefit of riociguat in PAH, including a nearly 25% improvement in a patient-reported health-related quality of life scale.^44-46 Though more data is needed, it has also been suggested that patients who do not experience the desired treatment outcomes with PDE-5 inhibitors, may benefit from a switch to riociguat.⁴⁶

Riociguat has a black box warning for embryo-fetal toxicity due the risk that it may cause fetal harm if used in pregnant patients.²⁷ As such, pregnancy must be ruled out prior to initiating therapy in females of reproductive potential, during therapy, and for one month after discontinuation. Fittingly, prescribers, patients, and pharmacies must be certified with the Adempas REMS program.^27,42

Riociguat is also associated with an increased risk of serious bleeding and may worsen pulmonary veno-occlusive disease. More commonly, adverse events include headache, dyspepsia, gastritis, dizziness, nausea/vomiting, diarrhea, hypotension, and anemia.²⁷

Similar to the PDE-5 inhibitors, concomitant use of riociguat and nitrates or PDE-5 inhibitors is contraindicated due to the risk of hypotension. Beyond this, lower doses of riociguat should be considered in patients receiving strong CYP and P-glycoprotein/breast cancer resistance protein inhibitors, including azole antifungals and protease inhibitors, like ritonavir.²⁷ Finally, higher doses of riociguat should be considered in smokers, even above the FDA-approved dose of 2.5 mg three times daily, due to reduced riociguat plasma concentrations by up to 60% in these patients. Conversely, lower doses should be considered in patients considering quitting smoking.²⁷

The recent approval of another sGC stimulator, vericiguat (Verquvo®) may lead to confusion given the sound-alike nature of the nonproprietary names of these agents. Vericiguat is only FDA-approved for heart failure with reduced ejection fraction (HFrEF) and should not be used for PAH. Similarly, riociguat is not FDA-approved for HFrEF and should not be used for this condition.

Prostanoids

Prostanoids, also referred to as prostaglandin analogs, encompass a class of three unique compounds – epoprostenol, iloprost, and treprostinil. These agents exert their therapeutic effects by mimicking the effects of prostacyclin, which leads to direct vasodilation of the pulmonary and systemic arterial vasculature.

The first prostaglandin analog, epoprostenol (Flolan®, Veletri®), was approved in 1995.^31,32 This agent has primarily been studied in patients with WHO Functional Class III-IV PAH. It was found to not only improve 6MWD and quality of life compared to placebo, but also reduced the risk of mortality.^47,48 Use of epoprostenol is limited, however, by its short half-life requiring administration as a continuous IV infusion through an indwelling central venous catheter. This route of administration may increase the patient’s risk of developing device-related infections, including sepsis.^31,32

A second prostanoid, Iloprost (Ventavis®), is administered as an oral inhalation and was approved in the United States in 2004.³³ Iloprost was also primarily studied in WHO Functional Class III-IV PAH patients, limiting its use to more severe disease. Compared to placebo, iloprost has been shown to increase survival, as well as functional class, dyspnea, and quality of life.⁴⁹ Despite a more favorable dosage form compared to epoprostenol, iloprost use is limited by frequent dosing of up to 9 inhalations per day with at least 2 hours between each dose.³³

The final agent in this class, treprostinil, was initially approved by the FDA in 2002 as a continuous IV or SC infusion (Remodulin®).²⁹ A treprostinil inhalation solution, Tyvaso®, was approved next in 2009, and was followed by an extended release oral tablet (Orenitram®) in 2013.^28,30 Data support the use of treprostinil administered via the IV, SC, or inhaled routes in patients with PAH, showing improvement in 6MWD and quality of life.⁵⁰ Unfortunately, however, consistent improvement in Functional Class has not been shown and there are no data to suggest these agents improve survival.⁵⁰ Oral treprostinil was also found to have mixed results in clinical studies. When used as monotherapy, this medication improved 6MWD as monotherapy, but did not improve functional class or PAH symptoms.⁵¹

Several considerations with regard to safety should be kept in mind for patients treated with prostanoids. Caution should be used when dosing epoprostenol and treprostinil injection as these agents are supplied in milligrams, but are to be dosed in nanograms. Because of an increased risk of mortality in patients with left ventricular systolic dysfunction treated with epoprostenol, this medication is contraindicated in this population.^31,32 In addition, treprostinil tablets should be avoided in patients with moderate hepatic impairment and are fully contraindicated in patients with severe hepatic impairment.²⁸ Lower doses of iloprost or treprostinil injection or inhalation should be utilized for patients with hepatic impairment, though these agents are not contraindicated in this population.^29,30,33 Patients with bronchospastic disease, such as asthma or COPD, should use inhaled medication cautiously, if at all.^30,33

Adverse events associated with prostanoids vary, but patients may experience hypotension, syncope, flushing, and headache secondary to these agents’ vasodilatory properties. Additionally, bleeding may occur as these agents also inhibit platelet aggregation. All of the non-inhaled prostaglandin analogues may cause rebound symptoms with abrupt discontinuation, and oral treprostinil, specifically, should be retitrated if more than 3 days have passed since the last dose.^29,30,32,33

Prostaglandin Receptor Agonist

The most recently approved medication for PAH is selexipag (Uptravi®). Selexipag is chemically distinct from prostacyclin, so unlike the prostacyclin analogs, it does not mimic the effects of the hormone. Instead it selectively binds and activates prostacyclin receptors, specifically the IP receptor, thereby inducing relaxation of vascular smooth muscle.⁵²

Selexipag was studied in the event-driven Phase 3, randomized, double-blind, placebo controlled GRIPHON trial, which investigated the therapeutic effects of selexipag alone or in combination with alternative PAH therapies.⁵³ Selexipag was found to significantly decrease the time to first composite event including death or the development of a complication related to PAH, such as disease progression, PAH-related hospitalization, initiation of parenteral prostanoid or oxygen therapy, or the need for lung transplantation or other medical intervention. However, this finding was primarily driven by PAH complications, and unfortunately, no improvement in survival was observed. Despite a lack of improvement in functional class between treatment groups, a significant change in 6MWD was shown.⁵³

Selexipag is contraindicated when used concomitantly with strong CYP2C8 inhibitors, including gemfibrozil. Use should also be avoided in patients with severe hepatic impairment, while those with moderate hepatic impairment should receive less frequent dosing – once daily dosing versus twice daily for patients with mild or no hepatic impairment.³⁴

Selexipag should be titrated in increments of 200 mcg twice daily in weekly intervals up to a target dose of 1600 mcg twice daily. However, patients who are unable to tolerate a certain dose should return to the last dose that they are able to tolerate. Unlike oral treprostinil which must be taken with food due to improved absorption, selexipag should be taken with food to improve tolerability.³⁴

Patients should be counseled on common adverse events, including headache (seen in up to 65% of selexipag-treated patients), diarrhea, jaw pain, nausea, and myalgia. In addition, patients who miss 3 days of therapy or more should be educated to contact their prescriber as retitration of therapy may be required.³⁴ However, patients should be encouraged that while temporary treatment interruptions due to adverse reactions are common, reinstitution of treatment is often tolerable.⁵⁴ Data also suggests that patients switching from alternative prostanoids may benefit from the convenience of selexipag without jeopardizing clinical outcomes.⁵⁵

Combination Therapy

A common approach to PAH treatment involves initiating patients on a single agent and adding further therapy if the initial regimen does not adequately control the patient’s symptoms. The data for this approach are mixed. A brief summary of available data is below.

• Overall, it is anticipated that PDE-5 inhibitors in combination with ERAs may offer significant benefit to patients.^56,57 Despite this, some data muddy the waters, suggesting inconsistent results depending on the combination of specific agents.^39,58
  

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• Not only should the combination of PDE-5 inhibitors and riociguat be avoided due to the risk of hypotension, but this therapeutic approach was also found to offer no additional clinical benefit in the PATENT-PLUS trial.⁵⁹ Still, riociguat may be effective when added to background therapy consisting of either prostanoid or ERA therapy.⁶⁰
  
  
• A post-hoc analysis of the GRIPHON trial found that the addition of selexipag to existing dual PDE-5/ERA therapy was consistent with the benefits seen in the full trial population.⁶¹
  
  
• One of the newer agents for PAH, oral treprostinil, offers a cautionary tale in assuming monotherapy benefit equates to add-on benefit. Oral treprostinil was studied as add-on therapy in the FREEDOM-C and FREEDOM-C2 studies.^62,63 Despite the positive clinical effects of monotherapy, these studies failed to show improvement in exercise capacity when oral treprostinil was added to background therapy with a PDE-5 inhibitor, an ERA, or a combination of both.^62,63

Another treatment approach involves initial combination therapy with two or even three agents. This approach is less commonly used with only about 5% of patients started on initial combination therapy according to a recent estimate.³⁵

The primary approach of upfront combination therapy involves the use of ambrisentan and tadalafil. This is based on the AMBITION trial, which randomized 500 treatment-naïve PAH patients to receive one of three regimens: ambrisentan 10 mg plus tadalafil 40 mg, ambrisentan 10 mg plus placebo, or tadalafil 40 mg plus placebo. Patients in the combination therapy arm experienced a significantly lower risk of a clinical failure, defined in the study as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response.⁶⁴ What’s more is that these results were found to be consistent regardless of baseline patient risk score.⁶⁵

It is unknown, however, if these results can be extrapolated to other PDE-5 inhibitor/ERA combinations, though early data suggest benefit regardless of which agents are combined.⁶⁶ One small (n=97) retrospective analysis identified disease improvements in various measures of control, including functional class, exercise capacity, and dyspnea at 4 months of therapy of either bosentan or ambrisentan plus either sildenafil or tadalafil. In addition, survival rates were higher than anticipated values.⁶⁶

It’s also unknown if the concept of initial combination therapy is effective using alternative classes. One small study investigated the upfront use of iloprost and bosentan in combination and found promising results on 6MWD, quality of life, and various hemodynamic measurements. The study concluded that further research is needed with larger populations.⁶⁷ Similarly, initial triple therapy with IV epoprostenol, bosentan, and sildenafil has shown promise, though also only in a small, pilot study.⁶⁸

While there is some benefit to initial combination therapy, this approach should be limited to tadalafil and ambrisentan until further data become available to support alternative upfront combination therapy approaches. With the recent approval of generic tadalafil and ambrisentan, it is possible that the lower cost of initial combination therapy paired with the data from the AMBITION trial previously described will lead to increased use of this approach.^69,70

In all, it appears that using PAH medications in combination is more complex than meets the eye. Fittingly, the most recent treatment guidelines, discussed in more detail ahead, state, “…the addition of therapies to existing treatments or the use of multiple therapies remains a complicated issue.” It is suggested that certain regimens, including PDE-5/ERA or ERA/prostanoid combinations may be most beneficial, while PDE-5/riociguat and PDE-5/prostanoid combinations offer less benefit.⁷¹

Managing Pulmonary Arterial Hypertension

Given the number of available therapeutic options and the complexity in appropriate medication selection, PAH is a challenging condition to manage. Fortunately, recently updated guidelines provide some guidance to aid in selecting patient-specific therapies.

Prior to initiating therapy with PAH-specific agents, patients, as part of the diagnostic workup, should undergo vasoreactivity testing.⁷² This test involves the administration of a pulmonary vasodilator agent, including inhaled NO, IV epoprostenol, or IV adenosine, to determine if patients would benefit from therapy with a calcium channel blocker (CCB). A positive vasoreactivity tests confers a good prognosis and may prevent the patient from needing more aggressive PAH therapy.⁷³ Treatment for these patients should high dose CCBs, including nifedipine 120 mg to 240 mg, diltiazem 240 mg to 720 mg, or amlodipine 20 mg.⁷²

If patients have a negative vasoreactivity test, are unable to tolerate or have a contraindication to therapy CCB therapy, it is recommended to base treatment on the severity of their PAH symptoms. For treatment-naïve patients with WHO Functional Class I disease should be carefully monitored for disease progression. No therapy is recommended in these patients, though contributing causes of pulmonary hypertension, such as sleep apnea and systemic hypertension, should be treated to prevent worsening of PAH.⁷²

Treatment-naïve patients with WHO Functional Class II disease or rapidly progressing Functional Class III disease with a poor prognosis should receive initial combination therapy with ambrisentan and tadalafil.⁷² Though there is limited evidence for this recommendation, the AMBITION trial, previously described, suggests that upfront combination therapy in treatment-naïve patients may provide benefit over initial monotherapy.⁶⁴

If patients in these groups are not willing to use or are not able to tolerate upfront combination therapy, it is recommended that monotherapy with an ERA, PDE-5 inhibitor, or riociguat be used.⁷² The guideline notes that none of these agents are preferred on the basis of clinical value, considering there is a lack of direct comparative evidence to support one agent over another. Instead, provider, patient, and insurance preference should be considered along with the drug-specific factors discussed earlier.

Patients with rapidly progressive WHO Functional Class III disease or poor prognosis should be initiated on parenteral prostanoids (IV epoprostenol or SC or IV treprostinil) if they are willing and able to comply with the dosing requirements of these agents. If not, it is conditionally recommended to use inhaled or oral treprostinil, though the guideline notes no evidence is available to support this recommendation.⁷²

Similarly, patients with WHO Functional Class IV disease should be initiated on parenteral prostanoids, or, if they are unable or unwilling to use these agents, they should be considered for combination therapy with triple therapy consisting of inhaled iloprost, a PDE-5 inhibitor, and an ERA. Despite the lack of data available for oral medications in such advanced disease, this is a last line option and patients should be considered for other medical intervention, such as lung transplantation.⁷²

If patients with WHO Functional Class III or IV disease do not have an adequate response to initial therapy with a single agent, a second class of medications should be initiated based on Table 4 below.⁷² The guidelines do note, however, that there are significant gaps in the evidence with regard to add-on therapy approaches and more data are needed to identify an ideal patient-specific approach.

Patient Journey and Pharmacist Role

The diagnosis of PAH is one of the most challenging aspects of this disease. A number of much more common differential diagnoses, presentation months or years after the onset of vague symptoms, and the need for invasive testing like right heart catheterization to confirm the diagnosis may delay this process. All the while, patients may be experiencing symptoms which can significantly impact quality of life.

In the early stages of PAH, patients may have decreased exercise tolerance, dyspnea, and fatigue. This may require them to alter their active lifestyles, step back from hobbies they enjoy and have taken part in for years, and even spend less time with family or friends. For this reason, as serious a diagnosis as PAH is, once properly diagnosed, patients may find relief in finally understanding the cause for their symptoms. This allows them to institute lifestyle changes around the disease and initiate treatment that may help slow the progress of the disease.

Pharmacists have a role in helping patients understand their vague symptoms by offering them information on potential differential diagnoses. For instance, in a routine follow-up with a patient after the initiation of inhaled medications for misdiagnosed COPD, if a patient is not experiencing anticipated relief, the pharmacist should have the patient ask their provider about other potential reasons for their shortness of breath and fatigue, like PAH. Notably, PAH is only one of many potential causes of dyspnea and an uncommon one at that;⁷⁴ however, encouraging patients to ask their provider about this may reduce the time to diagnosis and allow for earlier treatment initiation.

Adherence to PAH therapy is imperative to a successful outcome. Data suggest that as adherence to PAH therapy improves, hospitalization and rehospitalization rates decline.^35,75 Unfortunately, as previously discussed, medications for PAH come with a number of side effects that may be intolerable for patients. Careful monitoring, recurrent follow-up, and detailed counseling at the start of any new therapy is essential to ensure the best outcome for patients.

Even those who do not experience an adverse event from their drug therapy may struggle to remain adherent to PAH treatment regimens. Patients who were otherwise healthy prior to the onset of PAH may need to initiate therapy with a number of different agents (e.g., with tadalafil and ambrisentan upfront). Alternatively, patients started on parenteral prostanoid therapy, for example, must learn how to properly care for their infusion sites to avoid complications. Pharmacists play an important role in ensuring proper adherence to complex regimens and can help patients avoid drug related problems that may arise.

Pharmacists can use communication skills to help patients overcome drug-related challenges. Behavioral counseling techniques, like motivational interviewing, can effectively improve adherence or increase the likelihood of accepting change.⁷⁶ Motivational interviewing in particular involves pharmacists building trust with patients by putting them in control of the counseling session. This is done by actively listening and empathetically responding to concerns, asking for permission before providing information, and allowing patients to set their own goals and find their own reasons for change. One foundational principle of this process is that it allows for change to take place slowly over time, as opposed to expecting a single counseling session to lead to meaningful and lasting change. This may help patients cope with the stress of a new PAH diagnosis, identify their motivating factors to maintain adherence, and give them the strength to find their new normal.

Outside of this, pharmacists may play a role in improving patient access. Pharmacists in a managed care setting, for instance, may develop formulary and coverage recommendations and review prior authorization requests for these medications, while pharmacists in other settings can offer expertise in helping get these agents covered through insurance.

Pharmacists can also help ensure appropriate dosing, which can be particularly challenging for prostanoids that require continuous infusion. More specially trained pharmacists can help identify ideal treatment regimens based on current evidence and recommend changes if patients experience ongoing symptoms between scheduled specialist visits.

Finally, pharmacists can add to the patient’s support network by being a consistent, available resource for them. Pharmacists continue to be one of the most accessible health care providers with patients visiting community pharmacies almost twice as frequently as primary care providers.⁷⁷ Pharmacists should offer support between provider visits to remind patients to get their regular laboratory testing done, check in on their overall wellbeing, and, if necessary, point patients in the direction of available resources and support.

Conclusion

Pulmonary arterial hypertension is a devastating diagnosis to receive and is commonly associated with short life expectancy following diagnosis. One of the hardest parts, however, is getting to that final diagnosis. With vague symptoms and numerous differentials, it is a notoriously difficult diagnosis to make. While pharmacists are not trained as diagnosticians, they can and should help frustrated patients with consistent symptoms discuss possible alternative diagnoses with their providers. In addition, early treatment initiation and adherence to a regimen consisting of one or several medications can improve outcomes. Pharmacists can play various roles in helping patients with their therapy and should consistently look to support patients through their PAH journeys.

references

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