Pulmonary hypertension treatment depends heavily on which of five clinical groups the disease falls into, but for the most common form requiring targeted therapy, pulmonary arterial hypertension (PAH), treatment now involves drugs that act on three biological pathways, often used in combination. A generation ago, few options existed beyond oxygen and diuretics. Today, dozens of approved drugs and several interventional procedures can lower pulmonary artery pressures, improve exercise capacity, and extend survival. One of the biggest shifts in recent years has been the approval of sotatercept, the first drug in a new class that targets the disease’s underlying vascular remodeling rather than just dilating blood vessels.
Why the Type of Pulmonary Hypertension Matters
Pulmonary hypertension is not a single disease. It is classified into five groups based on the underlying cause, and the treatments differ dramatically across them. Group 1, called pulmonary arterial hypertension (PAH), involves progressive thickening and narrowing of the small pulmonary arteries. The walls of these vessels undergo structural changes across all their layers, driven by abnormal cell growth, inflammation, and fibrosis.1PubMed Central. Pulmonary vascular remodeling in pulmonary hypertension This is the form for which most targeted drug therapies were developed.
Group 2 is pulmonary hypertension caused by left heart disease, and it is by far the most common type overall. Here, the elevated lung pressures are a downstream consequence of problems like heart failure or valve disease. The priority is treating the heart condition itself, not adding PAH-specific drugs. In fact, medications like endothelin receptor antagonists and phosphodiesterase-5 inhibitors have been studied in this group with conflicting results and are generally not recommended.2PubMed Central. Therapeutic Challenges and Emerging Treatment Targets for Pulmonary Hypertension in Left Heart Disease Getting the diagnosis right is critical to avoid inappropriate treatment.3PubMed. Group 2 pulmonary hypertension: from diagnosis to treatment
Group 3 involves pulmonary hypertension related to chronic lung diseases like COPD or interstitial fibrosis. For these patients, supplemental oxygen therapy plays a central role. One study found that long-term oxygen therapy improved walking distance by about 39 meters in patients with precapillary pulmonary hypertension, while those in the control group actually declined.4Scientific Reports. Long-term oxygen therapy in precapillary pulmonary hypertension – SOPHA study Groups 4 and 5 involve blood clots in the lung arteries and miscellaneous causes, respectively, each with their own treatment approaches discussed below.
The Three Drug Pathways for PAH
Most approved PAH medications work by correcting imbalances in one of three signaling systems within the pulmonary blood vessels. The drugs do not cure the disease, but they can slow its progression, reduce symptoms, and improve how well you function day to day.
Prostacyclin Pathway
Prostacyclin is a naturally occurring molecule that relaxes blood vessels and prevents clotting. In PAH, the body produces too little of it. Synthetic versions and drugs that mimic its action are among the most effective treatments available, particularly for severe disease.5PubMed Central. Prostacyclin therapy for pulmonary arterial hypertension These include epoprostenol (given intravenously through a continuous pump), treprostinil (available by infusion, inhalation, or oral tablet), iloprost (inhaled), and selexipag (an oral pill that acts on the same receptor). A Cochrane review found that prostacyclins lowered mean pulmonary artery pressure by about 3.6 mmHg, improved cardiac output, reduced right atrial pressure, and improved both breathlessness and quality of life compared to controls.6Cochrane Database of Systematic Reviews. Prostacyclin and its analogues for pulmonary arterial hypertension in adults and children
Endothelin Pathway
Endothelin-1 is a powerful vessel-constricting molecule, and patients with PAH have elevated levels of it. Three endothelin receptor antagonists (ERAs) are approved: bosentan, ambrisentan, and macitentan. All of them block the type A receptor on smooth muscle cells that drives constriction and abnormal cell growth. Bosentan and macitentan also block the type B receptor, which in PAH becomes part of the problem because it gets upregulated on muscle cells while being lost from the endothelial lining where it would normally promote relaxation.7PubMed Central. Selection of Endothelin Receptor Antagonists in the Treatment of Pulmonary Arterial Hypertension: A Comprehensive Narrative Review ERAs are typically taken as daily pills and are commonly used as a backbone of combination therapy. They require periodic liver monitoring, particularly bosentan, and all three are teratogenic, meaning they can cause birth defects and must not be used during pregnancy.
Nitric Oxide Pathway
Nitric oxide is the body’s own vessel-relaxing signal, and in PAH, its production and effectiveness are impaired. Two classes of drugs boost this pathway. Phosphodiesterase-5 inhibitors (PDE5 inhibitors) like sildenafil and tadalafil work by preventing the breakdown of a molecule that nitric oxide uses to relax smooth muscle. Riociguat takes a different approach: it directly stimulates the enzyme that produces that same relaxation signal, and it works even when nitric oxide levels are very low.8PubMed. Successful Transition From Phosphodiesterase-5 Inhibitors to Riociguat Without a Washout Period in Patients With Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension You cannot take a PDE5 inhibitor and riociguat at the same time due to dangerously low blood pressure, but switching from one to the other is sometimes done when response plateaus.
Combination Therapy Is Now the Standard
For most newly diagnosed PAH patients, treatment guidelines now recommend starting with two drugs from different pathways rather than a single agent. The logic is straightforward: the disease involves dysfunction across multiple signaling systems, so hitting more than one at a time produces better results than escalating one drug at a time. An ERA paired with a PDE5 inhibitor or riociguat is a common starting regimen for patients at intermediate risk.
Early data on some newer pairings look encouraging. A study of 25 patients with newly diagnosed PAH at intermediate risk who started upfront macitentan and riociguat found that BNP levels (a marker of heart strain) dropped by about 61% at six months, walking distance improved by 51 meters, and nearly two-thirds of patients moved to a low-risk profile.9European Heart Journal. Safety and efficacy of macitentan and riociguat upfront combination therapy in patients with idiopathic pulmonary arterial hypertension at intermediate risk Early work combining sildenafil with inhaled iloprost showed that the vasodilating effect of the two together was nearly double what either drug achieved alone, suggesting their mechanisms truly complement each other.10PubMed Central. Combination Therapy in Pulmonary Arterial Hypertension—Targeting the Nitric Oxide and Prostacyclin Pathways
Sotatercept and the Shift Toward Reversing Vascular Remodeling
All three traditional drug pathways primarily work by relaxing blood vessels. They help blood flow more easily through narrowed arteries, but they do not undo the thickening of those artery walls. Sotatercept, approved in 2024, represents a fundamentally different strategy. It is a fusion protein that intercepts certain growth signals from the TGF-β superfamily, restoring a balance between signals that tell pulmonary artery cells to multiply and signals that tell them to stop.11PubMed Central. Sotatercept: A novel therapeutic approach for pulmonary arterial hypertension through transforming growth factor-β signaling modulation In preclinical studies, this rebalancing actually reversed some of the structural damage in the pulmonary vessels.
Sotatercept is given as a subcutaneous injection every three weeks and is approved as an add-on to existing background therapy.12PubMed Central. A new day has come: Sotatercept for the treatment of pulmonary arterial hypertension Its arrival is widely seen as one of the most significant advances in PAH treatment in years, because it opens a fourth treatment pathway and targets the disease’s biology in a way no prior drug did. Its long-term effects on survival are still being studied, but clinical trials showed clear improvements in exercise capacity and pulmonary vascular resistance.
When Blood Clots Are the Cause
Group 4 pulmonary hypertension, called chronic thromboembolic pulmonary hypertension (CTEPH), develops when blood clots in the lungs fail to dissolve and instead organize into scar tissue that permanently obstructs blood flow. Unlike PAH, CTEPH can often be treated mechanically.
The traditional gold-standard intervention is pulmonary endarterectomy (PEA), a major open-heart surgery in which surgeons physically remove the organized clot material from the pulmonary arteries. A worldwide registry showed 3-year survival of 94% for patients who underwent PEA, compared to 71% for those who received only medical therapy.13PubMed Central. Worldwide CTEPH Registry: Long-Term Outcomes With Pulmonary Endarterectomy, Balloon Pulmonary Angioplasty, and Medical Therapy PEA tends to produce the largest and most durable drops in pulmonary pressures, but it is a high-risk procedure that requires deep hypothermia and circulatory arrest, and not all clot locations are surgically reachable.
Balloon pulmonary angioplasty (BPA) is a less invasive alternative that has grown rapidly in the past decade. Small balloons are threaded into blocked pulmonary arteries and inflated to restore flow, usually over several sessions. A meta-analysis found that BPA had higher perioperative survival rates than PEA and fewer types of complications, though PEA produced more sustained improvements in hemodynamic measurements over the long term.14PubMed. Balloon pulmonary angioplasty vs. pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension: a systematic review and meta-analysis Some centers now combine both approaches: surgery first to clear central disease, followed by BPA to reach residual distal obstructions. One study found zero mortality in this combination group and a roughly 74% reduction in pulmonary vascular resistance.15PubMed. The role of balloon pulmonary angioplasty and pulmonary endarterectomy: Is chronic thromboembolic pulmonary hypertension still a life-threatening disease? Riociguat is the only PAH-specific drug also approved for inoperable CTEPH or persistent disease after surgery.
Risk Stratification Guides Every Treatment Decision
PAH treatment is not a “set it and forget it” situation. Clinicians use risk stratification tools that combine symptoms, exercise testing, heart imaging, blood markers, and hemodynamic measurements to classify patients as low, intermediate, or high risk of deterioration. This risk profile determines the starting regimen and, crucially, whether the current treatment is working well enough. The goal for most patients is to reach and maintain a low-risk profile.16PubMed Central. Risk Stratification in Pulmonary Arterial Hypertension, Update and Perspectives
A systematic review found that follow-up risk assessments predicted outcomes more accurately than the initial assessment at diagnosis, and changes in risk status between visits tracked closely with changes in survival.17PubMed Central. Prognostic Value of Serial Risk Stratification in Adult and Pediatric Pulmonary Arterial Hypertension: A Systematic Review In practical terms, if you are sitting at an intermediate-high or high-risk level despite treatment, that is a signal to escalate: add another drug class, switch routes of delivery, or begin evaluating for transplant. Staying in that risk category is now considered an inadequate outcome. The European guidelines describe risk stratification as the cornerstone of the treatment algorithm, especially in the first year after diagnosis, which is the most critical period.18European Respiratory Journal. Risk stratification and treatment goals in pulmonary arterial hypertension
Protecting the Right Ventricle
In PAH, the real threat to life is not the lungs themselves but the right side of the heart. The right ventricle has to pump against progressively higher resistance, and over time it enlarges, stiffens, and eventually fails. Managing right ventricular function involves reducing the afterload (which is what all the PAH-specific drugs are doing), optimizing fluid balance with diuretics, and in acute decompensation, using inotropic drugs to boost the heart’s squeezing power.19PubMed Central. Treatment of right ventricular dysfunction and heart failure in pulmonary arterial hypertension
When PAH-specific treatment works well, the right ventricle can actually recover to some degree. Researchers have begun characterizing what this functional recovery looks like on imaging to better understand which patients are likely to improve and which may need more aggressive intervention.20PubMed Central. Classification and Predictors of Right Ventricular Functional Recovery in Pulmonary Arterial Hypertension When treatment is not enough, atrial septostomy (creating a small hole between the heart’s upper chambers to relieve right-sided pressure) can serve as a bridge while waiting for lung transplantation, which remains the ultimate option for end-stage disease.21PubMed Central. Atrial septostomy for pulmonary arterial hypertension
Exercise Rehabilitation as Adjunct Therapy
For a long time, patients with pulmonary hypertension were told to avoid exercise out of concern that it could strain the right heart. That thinking has shifted substantially. A meta-analysis of seven randomized controlled trials found that structured exercise training improved six-minute walking distance by about 52 meters and peak oxygen uptake by about 3 ml/kg/min compared to controls.22PubMed Central. The benefit of exercise-based rehabilitation programs in patients with pulmonary hypertension: a systematic review and meta-analysis of randomized controlled trials Exercise rehabilitation also appears to improve respiratory and skeletal muscle performance, heart and lung function, and quality of life when used alongside disease-specific drug therapy.23PubMed. Exercise Rehabilitation Training in Patients With Pulmonary Hypertension: A Review
The key is supervised, carefully dosed exercise. This is not a matter of joining a gym and pushing through breathlessness. Pulmonary rehabilitation programs for PH patients typically involve low-to-moderate-intensity aerobic training, resistance exercises, and breathing techniques, all guided by professionals who can monitor hemodynamics and symptoms.24PubMed Central. Pulmonary rehabilitation and exercise in pulmonary arterial hypertension: An underutilized intervention Despite the evidence, exercise-based rehabilitation remains underused in PH care.
Treating Children with PAH
Pediatric PAH overlaps with the adult disease in its drug targets but diverges in important ways. The causes are often different; congenital heart disease accounts for a large share of cases in children. Only two PAH-specific drugs, bosentan and sildenafil, are formally approved for pediatric use, and there is no strong evidence that starting children on combination therapy improves survival compared to single-drug treatment.25PubMed Central. Treatment of pulmonary arterial hypertension in children Treatment guidelines for children are largely based on expert opinion and adult data rather than pediatric clinical trials, leaving clinicians with less certainty about optimal strategies.26European Respiratory Journal. Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management Prognosis has improved in recent years thanks to more aggressive treatment approaches, but the lack of pediatric-specific evidence remains a significant gap.
Pregnancy and PAH
Pregnancy in a woman with PAH carries extremely high risk. The hemodynamic demands of pregnancy, including increased blood volume, faster heart rate, and large fluid shifts during delivery, place enormous stress on a right ventricle already struggling against high pulmonary pressures. Maternal and perinatal mortality rates are significantly elevated, and current guidelines strongly recommend reliable contraception for women of childbearing age with PAH.27PubMed Central. Management of pregnant patients with pulmonary arterial hypertension If pregnancy does occur, management focuses on minimizing hemodynamic swings, and care typically requires a multidisciplinary team at a specialized center. Adding complexity, several PAH medications, including all ERAs, are known to cause birth defects and must be stopped.
Emerging Drugs in the Pipeline
Beyond sotatercept, researchers are pursuing other novel approaches. Seralutinib is an inhaled tyrosine kinase inhibitor that targets receptors involved in abnormal cell growth in the pulmonary arteries. In lab studies, it was substantially more potent than imatinib (an older cancer drug previously tested in PAH) at blocking proliferation of pulmonary artery smooth muscle cells and lung fibroblasts.28PubMed Central. Inhaled seralutinib exhibits potent efficacy in models of pulmonary arterial hypertension In a phase 2 trial, inhaled seralutinib lowered pulmonary vascular resistance significantly more than placebo over 24 weeks in patients already on background PAH therapy, with cough being the most common side effect.29The Lancet Respiratory Medicine. Seralutinib in patients with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled, phase 2 trial The inhaled delivery route is appealing because it concentrates the drug in the lungs and could limit systemic side effects, which were a major problem with earlier oral tyrosine kinase inhibitors tested in PAH.
The Problem of Late Diagnosis and Unequal Access
One of the biggest obstacles to good outcomes in pulmonary hypertension has nothing to do with which drug you take. It is how long it takes to get diagnosed in the first place. The early symptoms, primarily breathlessness and fatigue, are vague and easily attributed to being out of shape, asthma, or anxiety. Diagnostic delays average roughly two and a half years, and patients who arrive at a PH center with advanced disease have limited room for improvement.30PubMed Central. Artificial intelligence in pulmonary hypertension: a systematic review
Even after diagnosis, access to care is uneven. A study of patients with idiopathic PAH found that those in the lowest socioeconomic bracket had roughly three times the death rate of those in the highest, a gap that persisted even after adjusting for disease severity and type of treatment received.31PubMed Central. Lower socioeconomic status is associated with worse outcomes in pulmonary arterial hypertension Racial disparities compound the problem. Black patients with PAH in the United States tend to be younger at diagnosis yet have lower income, less education, and higher comorbidity burdens, with social determinants of health partially explaining the gap in outcomes.32PubMed. Racial disparities in treatment patterns, healthcare resource use, and outcomes in patients with pulmonary arterial hypertension in the United States Among veterans, the median time from diagnosis to starting treatment was 16 weeks, and those with lower household income experienced even longer delays.33PubMed Central. Socioeconomically disadvantaged veterans experience treatment delays for pulmonary arterial hypertension In a disease where early, aggressive treatment matters this much, a 16-week wait or longer is not a minor inconvenience; it is a potentially life-shortening delay.