Treating PAH
Pulmonary arterial hypertension (PAH) is a rare, complex disease defined by hemodynamic values not influenced by other heart or lung diseases.1,2 The underlying cause of these abnormal hemodynamics are pathologic changes within the lungs.1 PAH is treated using therapies that target one specific dysfunctional aspect in the lung vasculature, known as a treatment pathway.1 Today's approach to PAH care includes using more than one medication to treat multiple pathways to achieve clinical goals.1 In addition, identifying each patient’s personal goals are critical components of patient management to improve outcomes.1,3,4
PAH treatment goals
The primary treatment goals identified in PAH treatment guidelines and expert consensus recommendations are achieving and maintaining low-risk status to help improve your patient’s prognosis.1,4 Considering how PAH affects the heart and that right heart dysfunction is a leading indicator for disease progression, another key goal is treating to near-normalization of the right heart.4
Aim for low risk
- Treat to low risk1,4
- Frequent risk assessments help determine your patient’s progress to low risk1
- If patients are not at low risk, experts recommend adjusting their treatment plans to help them get there1
Strive for near-normalization of right heart
- Near-normalization of the right heart is another important treatment goal4
- Frequent monitoring of the right heart’s structure and function helps identify changes before lagging symptoms are observed, ie, changes in FC or 6MWD1,3-6
- If there is insufficient improvement or a decline in right heart parameters, patients have not reached low risk, and treatment adjustment is indicated1
Patients who have achieved low-risk status in their first year after diagnosis have a better prognosis than those who have not7
“The right heart, as I say, is the key to the whole game. And if we get near‑normalization of the right heart, then we are in a really good spot to give the patients the best possible outcomes that they can have.”
— John Ryan, MD, BCH, BAO, Associate Professor, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT
Learn about the latest treatment pathway
Activin SignalingExplore the latest in prostacyclin administration forms
Prostacyclin FormsAchieve treatment goals through frequent monitoring
Frequent monitoring and timely treatment adjustments are required to achieve a patient’s treatment goals. The baseline multiparameter risk assessment determines their initial treatment plan, while frequent follow-up assessments help determine whether your patient requires a treatment plan adjustment, including adding a different class of therapy, adjusting dose(s), and changing forms of therapy.1
Consider referring your patient to or consulting with a PH Expert Center to support your patient management and facilitate prompt treatment modifications if your patient is not at low risk.1
Patients start treatment based on their baseline risk status.
At or within 3 months, patients should be risk-assessed, with providers aiming for low-risk status within the first year after diagnosis.
Note that optimization of PAH therapy should be considered on an individual basis when clinically appropriate, while acknowledging that low-risk status is not always achievable.
- If a patient is at low risk, treatment should be maintained while assessing risk as often as every 3-6 months
- If a patient is not at low risk, the treatment plan should be adjusted by:
- Adding therapy
- Switching therapy
- Increasing dose of therapy
- Considering referral for lung transplantation
- Assessing risk as often as every 3-6 months
“Every single encounter with a patient is an opportunity for risk assessment and adjustment of therapy.”
— Vallerie McLaughlin, MD, Director, Pulmonary Hypertension Program and endowed Professor of Medicine, University of Michigan, Ann Arbor, MI
PAH pathophysiology is complex and multifaceted
PAH pathogenesis is characterized by a chronic over- or underproduction of several naturally occurring substances present in the lungs. Each substance is involved in different pathways. Imbalances in these pathways contribute to the PAH disease state, leading to increased pulmonary arterial pressure and right heart strain and, eventually, disease progression.9,10 Treatment of PAH involves using multiple therapies to target multiple pathways. Today, therapies are approved to address the imbalances in 4 different pathways.1,9,11
PAH treatment pathways
Prostacyclin
Prostacyclin is a naturally produced and potent vasodilator that inhibits platelet activation and adhesion, and inhibits cell growth of vascular endothelial and smooth muscle cells.1,12 In PAH, the prostacyclin metabolic pathway is downregulated; patients with PAH have decreased levels of prostacyclin synthase in the pulmonary arteries compared with those with no PAH.1,13 Lower levels of prostacyclin are linked to vasoconstriction, increased cell growth, and increased risk of blood clotting.1,13,14
- Prostacyclin-class therapies were the first type of medication approved to treat PAH, with the first agent approved in 1995.15 Now, 3 routes of delivery are available: inhaled, oral, and infused. Inhaled options come in DPI and nebulized forms, oral options in pill form, and infused options in IV and SC forms.1,16-19 These therapies mimic the effects of endogenous prostacyclin and help replace some of what is downregulated1,9
Nitric oxide
Nitric oxide is another pathway that, like the prostacyclin pathway, promotes vasodilation and antiproliferation and reduces platelet activation and adhesion. Nitric oxide is underexpressed in PAH, contributing to increased vasoconstriction, cellular proliferation, and risk of blood clotting.1,14
- Therapies treating the nitric oxide pathway have been approved since 2005, with 3 approved therapies, all in oral form.1,9,20 Treating this pathway helps dilate vessels and reduce cellular proliferation1
Endothelin
Endothelin promotes proliferation and vasoconstriction of smooth muscle cells, in addition to modulating inflammation. In PAH, overexpression of endothelin is linked to overabundant arteriolar vasoconstriction, smooth muscle proliferation, and inflammation.1,14
- Therapies treating the endothelin pathway have been approved since 2001, with 3 approved therapies, all in oral form.1,9,21 Targeting this pathway helps slow constriction of the pulmonary arteries and reduce cellular proliferation1
Activin signaling
A fourth pathway―activin signaling―is also part of PAH pathophysiology.9 Unlike the previous 3 pathways, this latest approach to PAH treatment is not part of a vasodilation pathway but, instead, focuses on modulating cellular proliferation.1,9,11 In PAH, abnormalities in this pathway result in increased cell growth of the endothelium and smooth muscle cells, leading to detrimental remodeling of the pulmonary arteries.1,9,22
- The first therapy to treat the activin signaling pathway was approved in 2024.23 This therapy is an injectable form.23 Treating with an activin signaling inhibitor helps rebalance vascular homeostasis by inhibiting cell growth and promoting apoptosis22
Current therapies treat specific pathways
Each class of therapy available today addresses pathologic imbalances and supports the lungs in different ways, depending on the pathway involved.9 Using a combination of therapies from different classes helps improve exercise capacity, right heart hemodynamics, and other key measures that can impact patient outcomes.1,3,11 Determining the therapies to use is partly based on individual patient risk scores.1,3
PAH therapy class
Available forms1,22
Prostacyclin-class therapies target the prostacyclin pathway1,9
- Induce vasodilation
- Inhibit platelet aggregation
- Inhibit smooth muscle cell proliferation
PDE-5i therapies and sGCS target the nitric oxide pathway1,9
- Induce vasodilation
- Inhibit proliferation
ERA therapies target the endothelin pathway1,9
- Prevent vasoconstriction
- Prevent proliferative effects
Activin signaling therapy targets the activin signaling pathway22
- Modulates vascular proliferation
Why treat multiple pathways?
PAH is a progressive disease with a complex pathology, including increased smooth muscle cell and endothelial cell proliferation, inflammation, and dysregulated angiogenesis.9 Constructing treatment regimens with a combination of therapies from different pathways is critical to patient outcomes.1,11 Importantly, evidence shows that treatment of each pathway should be maintained, even as patients reach low risk.1
Current treatment guidelines stress the necessity of helping patients achieve low-risk status. To accomplish this goal, consider these recommendations1:
- Treating multiple pathogenic pathways
- Conducting frequent follow-up, including risk assessments
- Striving toward and maintaining the treatment goals (low risk and near-normalization of right heart)4
- Escalating therapy when not at low risk by increasing doses or switching therapies within a class or adding therapy classes
- Referring patients to PH Expert Centers
PH Expert Centers help manage treatment
Today, your patients have choices, and not all therapies are right for every patient. Consultation with a PH Expert Center should be considered to help your patients reach the goal of low-risk status in the first year.1
Treatment guidelines recommend all patients with PH receive a consult at a PH Expert Center, including1:
- At diagnosis
- When establishing a treatment plan
- During periodic follow-up
Co-management for ongoing care may be an option for your patients, depending on the recommended treatment plan and patient preference1
Why experience matters
The 2022 ESC/ERS Treatment Guidelines recommend collaborating with PH Expert Centers for timely, individualized patient support at all risk levels.1
Patient circumstances and profiles will evolve over time. To navigate patient variables such as lifestyle, risk status, and medication adherence, HCPs need to be adept in managing PAH care using highly individualized treatment plans.1
Timely adjustments to treatment regimens help patients reach their goals of low risk and near-normalization of right heart. HCPs need to escalate therapy quickly when patients are not yet at their goals. Multiple treatment forms help individualize care for each patient.1,4
Continual monitoring at least every 3 to 6 months per the current PAH treatment guidelines is critical, as patient needs change over time. HCPs must understand how to monitor patients, when a dose change is required, and how to help patients incorporate additional therapy and lifestyle modifications.1
“There are huge benefits to having a patient evaluated at a PH Center. Certainly, this takes into account how complex PAH is, not just the diagnosis, but we have more treatment options now than ever. And it's important to make sure we find the right fit for the right person. In other words, not every medication or every combination approach is right for each individual.”
— Scott Visovatti, MD, Associate Professor of Medicine and Director, Pulmonary Hypertension Program, Ohio State University, Columbus, OH