Updates in Pulmonary Hypertension

Rajany V. Dy, MD, FCCP, the director of pulmonary vascular diseases at Los Angeles General Medical Center in Los Angeles, delivered a practical and informative session on pulmonary hypertension, emphasizing clinical updates relevant to hospital-based practitioners. Her talk focused on classification, diagnostic strategies, management approaches, and recent advances in the field.

There was a review of the pathophysiology of pulmonary arterial hypertension (PAH). In early disease, the pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) begin to rise. As PAP and PVR continue to increase, cardiac output declines, and patients develop symptoms that limit physical activity. In more severe disease, plexiform lesions—complex networks of vascular channels—begin to form within the pulmonary vessel lumens. These lesions further alter hemodynamics, particularly during exertion.

Risk stratification includes exercise capacity, cardiac biomarkers, imaging, invasive hemodynamic measurements (via right heart catheterization), and symptoms, which correspond to the WHO functional class. Several validated risk assessment tools are available and can generally be used interchangeably. Identifying a high-risk profile has important implications for treatment planning. The REVEAL 2.0 tool predicts one- and five-year mortality, as well as one-year risk of all-cause hospitalization or initiation of parenteral prostacyclins. A simplified version, REVEAL Lite, includes only noninvasive, modifiable variables. While slightly less accurate than the full version, it still provides strong clinical discrimination.

Treatment is guided by the pulmonary hypertension classification group, with Group 1 PAH having the most targeted therapies. There are four major therapeutic pathways:

The endothelin pathway, targeted by endothelin receptor antagonists such as ambrisentan, bosentan, and macitentan. Side effects include peripheral edema, nasal congestion, and anemia. These drugs are contraindicated in pregnancy and require monitoring of hemoglobin and liver function.

The nitric oxide pathway is targeted by PDE-5 inhibitors like sildenafil and tadalafil, which may cause headache, flushing, dyspepsia, and epistaxis. Rare complications include vision or hearing loss. These agents should not be used with nitrates or riociguat. This pathway also includes guanylyl cyclase stimulators such as riociguat, which has similar side effects, plus hypotension that may require dose adjustment. Riociguat is also contraindicated in pregnancy.

The prostacyclin pathway includes oral, inhaled, or parenteral prostanoids. Adverse effects include flushing, headache (often presenting as migraine in women), nausea, vomiting, and diarrhea. Sudden discontinuation of parenteral prostanoids can be life-threatening due to rebound pulmonary hypertension.

The newest pathway is the activin/BMP signaling pathway, targeted by sotatercept, a subcutaneous injection approved by the U.S. Food and Drug Administration in 2024 and administered every three weeks. Common side effects include headache, epistaxis, bleeding, and telangiectasias. While human data on pregnancy risk are limited, animal studies suggest potential effects on fertility. The PULSAR (Phase 2) and STELLAR (Phase 3) trials showed sotatercept to be safe and effective.^1,2 The ZENITH trial was recently stopped early due to substantial benefit in the treatment arm.³ The interim result analysis showed a 76% reduction in the outcomes of death, transplantation, or PAH related hospitalization compared to placebo.

There is a treatment algorithm for Group 1 PAH that begins with initial risk assessment. In patients who are not at high risk, dual combination therapy (typically an endothelin receptor antagonist plus a PDE-5 inhibitor) is appropriate. High-risk patients should be considered for triple therapy, including a parenteral prostanoid. Follow-up risk assessments should occur within three to four months and be repeated frequently to guide treatment escalation.

In patients presenting with acutely decompensated PAH, the first step is to identify a precipitating factor. Common triggers include supraventricular arrhythmias, infection, hypoxia, surgery, pulmonary embolism, anemia, or medication nonadherence. A clinical pearl that was shared is that in PAH patients with supraventricular arrhythmias, the use of beta blockers and calcium channel blockers should be avoided due to the negative inotropic effects, potentially impairing right ventricular systolic function. Often, digoxin and cardioversion should be considered. Volume optimization is the cornerstone of treatment, generally with intravenous loop diuretics. Renal replacement therapy may be considered in selected patients with diuretic-refractory volume overload, provided they are not severely hemodynamically unstable.

If diuretics alone are insufficient, inotropic or vasopressor support should be initiated. Dobutamine, a beta-1 agonist, is the inotrope of choice. Milrinone, an inodilator, can also be used but often requires a vasopressor to offset the associated drop in systemic vascular resistance.

Maintaining adequate aortic pressure is critical for preserving the right coronary perfusion and supporting the right ventricle. Although no dedicated studies define exact targets, a mean arterial pressure of 70 to 75 mmHg is a reasonable goal. Norepinephrine and vasopressin are the preferred vasopressors. Importantly, PAH-specific therapies are not emergency medications and should be avoided in hemodynamically unstable patients due to their potential to worsen hypotension.

Once the patient’s hemodynamics stabilize and organ congestion is resolved, optimizing pulmonary hypertension therapy before discharge is essential. In severe cases, anticipate the clinical trajectory early and engage in goals-of-care discussions, ideally in collaboration with a pulmonary hypertension specialist. In selected patients, advanced therapies such as extracorporeal membrane oxygenation or lung transplantation may be considered. When these are not options, focus should shift to end-of-life care and symptom management for patients with end-stage right heart failure.

This talk highlighted the use of validated risk tools and the emergence of a new pathway for the treatment of PAH with sotatercept that looks promising. There were also practical strategies for managing acute decompensation and the importance of trajectory planning in advanced disease.  

Dr. Miller is an associate professor of medicine and vice-section chief of hospital medicine at the University of New Mexico in Albuquerque, N.M. 

References

1. Humbert M, et al. Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med. 2021;384(13):1204-1215. doi:10.1056/NEJMoa2024277.
2. Hoeper MM, et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023;388(16):1478-1490. doi:10.1056/NEJMoa2213558.
3. Humbert M, et al. Sotatercept in patients with pulmonary arterial hypertension at high risk for death. N Engl J Med. 2025. doi:10.1056/NEJMoa2415160.