Managing Pulmonary Arterial Hypertension: Diagnosis, Classification, and Treatment Strategies

Pulmonary hypertension is a generic term encompassing a group of diseases that is diagnosed using a right heart catheterization, which is an invasive procedure with venous puncture, explained Zachary R Smith, PharmD, FCCP, BCPS, BCCCP, during Asembia's AXS24 Summit in Las Vegas. Smith, who is a clinical pharmacy specialist: pulmonary hypertension, critical care and PGY2 residency program director, critical care, at Henry Ford Hospital in Detroit, Michigan, explained further that right heart catheterization involves threading a catheter up through the right atrium and right ventricle to the pulmonary arteries to measure the pressures in their heart and lungs.

“In large epidemiologic studies of patients, a normal mean pulmonary arterial pressure [mPAP] is 14 mm Hg. For patients with pulmonary hypertension, it's defined as an mPAP greater than 20 [mm Hg],” Smith said. “This was recently decreased at the 6th World Symposium on Pulmonary Hypertension in 2019 from the historical value of 25 [mm Hg], so anyone with an mPAP of 20 [mm Hg] has pulmonary hypertension.”

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However, Smith explained that the clinical classification for pulmonary hypertension requires further specification to one of 5 groups, including pulmonary arterial hypertension (PAH), pulmonary hypertension associated with left heart disease, pulmonary hypertension associated with lung disease, pulmonary hypertension associated with pulmonary artery obstructions, and pulmonary hypertension with unclear and/or multifactorial mechanisms.

“If you say someone has pulmonary hypertension, [this] is not specific, and [it] really could be any of these 5 groups,” Smith said during the session. “The group we'll be talking about today is group 1, which is [PAH].”

According to Smith, the PAH group includes patients who have idiopathic disease, heritable disease, and drug-induced disease. Depending on the study, investigators estimate between 1 to 50 patients per million are affected by PAH, Smith explained.

“When looking at the pathophysiology of the disorder, there is an imbalance of vasoconstrictors and vasodilators, and [what’s] kind of the classic [is] an upregulation, or increased levels, of endothelin [EDN], which is a potent vasoconstrictor and also causes proliferation of the pulmonary arteries,” Smith said. “Then there's a decrease in levels of nitric oxide [NO] and prostacyclin [PCN], which are your vasodilators.”

According to Smith, traditional PAH drug classes include those that target the EDN pathway, the PCN pathway, and NO pathway. EDN receptor agonists that target the EDN pathway include bosentan (Tracleer; Actelion Pharmaceuticals US, Inc), ambrisentan (Letairis; Gilead), and macitentan (Opsumit; Actelion Pharmaceuticals Ltd). Drugs that target the PCN pathway include selective PCN IP agonists, such as selexipag (Uptravi; Actelion Pharmaceuticals Ltd), and synthetic PCN and PCN analogs, such as epoprostenol, teprostinil (Tyvaso; United Therapeutics), and iloprost (Ventavis; Janssen). Drugs that target the NO pathway include phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil and tadalafil, and soluble guanylate cyclase stimulators, such as riociguat (Adempas; Bayer).

“What [PAH] really is is a failure of the right ventricle,” Smith said. “The hemodynamic definition for [PAH] is a patient that has an mPAP above 20 mm Hg, [and] the pulmonary arterial wedge pressure is less than or equal to 15 [mm Hg], so that is essentially ruling out left heart disease.” Smith noted further that he characterizes the disease to patients as being hypertension in the lungs that ultimately results in the right ventricle failing.

For patients who meet the necessary criteria, Smith explained that vasoreactivity testing is performed. For this testing, 1 of 3 drugs is administered during right heart catheterization and the mPAP is watched to see if it drops in pressure.

“What we’re looking for is the mPAP to drop by at least 10 mm Hg to a level that's less than 40 [mm Hg]. That would be a vasoreactive positive patient. If that was the case, you would start a calcium channel blocker for your patient and reassess in 3 to 6 months,” Smith said. “Only about 10% of patients have a response to the calcium channel blocker vasoreactivity test, so it’s a minority of patients. If the patient is non-vasoreactive, which is most patients, you will then perform a risk stratification at diagnosis.”

According to Smith, one of the unique things about PAH management is that it uses a prognosis-based algorithm. Currently, the European prognosis-based algorithm is used across the United States and categorizes patients into 1 of 3 groups: low risk, intermediate risk, and high risk. Smith explained that these categories are based on the predicted mortality rate at one year. For those in the low risk group, they have a predicted mortality rate of less than 5%, while the intermediate group has a risk of 5% to 20%. The high risk group has a predicted mortality rate greater than 20%.

There are also certain variables that are assessed at the time of diagnosis, such as the 6-minute walk distance, brain natriuretic peptide (BNP) levels, and World Health Organization (WHO) functional class. “So, a patient and their physician would categorize the patient based on all of these variables into 1 of these 3 categories [of risk], and that's going to drive your initial treatment decision.”

According to Smith, patients who are lower or intermediate risk will be started on oral combination therapies, such as macitentan and tadalafil (Opsynvi; Johnson & Johnson), which is an EDN receptor agonist and PDE5 inhibitor that was approved in March 2024. For patients who are categorized as high risk, they would be started on the oral combination therapy and a PCN therapy. Once the regimen is initiated, the patient would then be reassessed in 3 to 6 months.

“In 3 to 6 months, there's a simplified algorithm that's used to risk stratify a patient. When [those who developed the algorithm] looked at the intermediate category, they saw that it was pretty heterogeneous in terms of outcomes, so they really were trying to sparse out different groups and also make actionable categories for clinicians,” Smith said. “In the reassessment, they have 4 strategies that are used. There's low risk, intermediate low risk, intermediate high risk, and then high risk.”

Additionally, the algorithm at the 3 to 6 month follow up includes only 3 variables to be assessed, including 6-minute walk distance, BNP, and WHO functional class.

“The goal of pharmacotherapy is to get all patients to low risk, so if you're reassessing a patient and they're not low risk, you're either going to be changing a drug, increasing the dose, or adding an additional agent,” Smith said. “If [the patient is] intermediate high or high risk, you would add a therapy or refer the patient to lung transplant, which would be the curative procedure for this disorder.”

REFERENCE

Smith ZR. The Evolving Treatment Paradigm for the Management of PAH: Strategies to Optimize Care. AXS24 Summit; Las Vegas, NV; April 28-May 2.