Classification and pathophysiology of pulmonary hypertension - Sysol - 2018 - Continuing Cardiology Education
Sotatercept Demonstrates Major Risk Reduction In Advanced PAH: ZENITH Trial
Sotatercept significantly reduced the risk of all-cause mortality, lung transplantation, or ≥24-hour hospitalization for worsening pulmonary arterial hypertension by 76% in high-risk patients on maximally tolerated background therapy, a new study has reported.
In a pivotal advance for patients with pulmonary arterial hypertension (PAH) at high risk of death, the ZENITH phase 3 trial has demonstrated that add-on sotatercept therapy significantly reduces major clinical events including death,lung transplantation, and PAH-related hospitalization. Published in the New England Journal of Medicine (May 2025 issue), the trial provides compelling evidence for the use of sotatercept as a disease-modifying agent in a population with WHO functional class III or IV PAH and a REVEAL Lite 2 risk score ≥9.
In this double-blind, placebo-controlled trial, 172 patients already receiving the maximum tolerated dose of background double or triple therapy were randomized 1:1 to receive sotatercept (initiated at 0.3 mg/kg and titrated to 0.7 mg/kg every 3 weeks) or placebo. The primary endpoint was a time-to-first-event composite of all-cause mortality, lung transplantation, or hospitalization ≥24 hours for worsening PAH.
Results were striking: 17.4% of patients in the sotatercept arm experienced a primary event compared to 54.7% in the placebo group. This corresponds to a 76% relative risk reduction (hazard ratio 0.24; 95% CI, 0.13–0.43; P<0.001). Component outcomes showed consistent trends—hospitalizations were reduced from 50.0% to 9.3%, deaths from 15.1% to 8.1%, and lung transplantations from 7.0% to 1.2% in placebo vs sotatercept arms, respectively.
Secondary endpoints favored sotatercept across multiple clinically relevant measures. Transplantation-free survival showed a hazard ratio of 0.34 (95% CI, 0.15–0.78). Sotatercept significantly improved the REVEAL Lite 2 risk score by a median of –3.0 points at week 24 compared to no change in the placebo group. NT-proBNP levels were reduced by a median of 1233 pg/mL (vs an increase of 255 pg/mL in the placebo group), and pulmonary vascular resistance decreased by 157 dyn·s·cm⁻⁵ (vs an increase of 47 dyn·s·cm⁻⁵ with placebo).
Functionally, 55.8% of patients on sotatercept improved in WHO class versus 27.9% on placebo. The 6-minute walk distance improved by a median of 45.4 meters with sotatercept and declined by 5.4 meters in the placebo group (difference: +63 meters; 95% CI, 23.2–102.7).
The trial was halted early following a prespecified interim analysis due to overwhelming efficacy, a rare occurrence in advanced PAH trials, particularly given that enrolled patients were already on optimized therapy.
Safety data were largely consistent with prior studies. Epistaxis (44.2%), telangiectasia (25.6%), and gingival bleeding (10.5%) were more frequent with sotatercept, likely reflecting vascular remodeling mechanisms. Serious adverse events occurred in 53.5% of sotatercept patients versus 64.0% in the placebo group, and discontinuation due to adverse events was observed only in the placebo arm.
These findings position sotatercept as a transformative addition to the therapeutic arsenal in advanced PAH. By targeting activin signaling pathways rather than relying solely on vasodilatory mechanisms, sotatercept directly addresses pulmonary vascular remodeling, offering durable improvements in risk profile, hemodynamics, and hard clinical outcomes.
Reference: Humbert M, McLaughlin VV, Badesch DB, et al.; ZENITH Trial Investigators. Sotatercept in patients with pulmonary arterial hypertension at high risk for death. N Engl J Med. 2025 Mar 31. PMID: 40167274. Doi:10.1056/NEJMoa2415160
Pulmonary Arterial Hypertension
Pulmonary hypertension is a life-threatening condition that gets worse over time, but treatments can help your symptoms so you can live better with the disease. It may take some planning, but plenty of people who have it find ways to do all the things they love, just as they did before they were diagnosed.
Having pulmonary arterial hypertension (PAH) means that you have high blood pressure in the arteries that go from your heart to your lungs. It's different from having regular high blood pressure.
With PAH, the tiny arteries in your lungs become narrow or blocked. It's harder for blood to flow through them, and that raises the blood pressure in your lungs. Your heart has to work harder to pump blood through those arteries, and after a while the heart muscle gets weak. Eventually, it can lead to heart failure.
Sometimes doctors can't find a reason for high blood pressure in the lungs. In that case, the condition is called idiopathic pulmonary hypertension. Genes may play a role in why some people get it.
In other cases, there is another condition that's causing the problem. Any of these illnesses can lead to high blood pressure in your lungs:
You may not notice any symptoms for a while. The main one is shortness of breath when you're active. It usually starts slowly and gets worse as time goes on. You may notice that you can't do some of the things you used to without getting winded.
Other symptoms include:
If you have shortness of breath and see your doctor, they will ask you about your medical history. They may also ask you:
Your doctor may order tests, including:
Echocardiogram: This ultrasound picture of the beating heart can check blood pressure in the pulmonary arteries.
CT scan: This can show enlarged pulmonary arteries. A CT scan can also spot other problems in the lungs that could cause shortness of breath.
Ventilation-perfusion scan (V/Q scan): This test can help find blood clots that can cause high blood pressure in the lungs.
Electrocardiogram (EKG or ECG): An EKG traces the heart's activity and can show whether the right side of the heart is under strain. That's a warning sign of pulmonary hypertension.
Chest X-ray: An X-ray can show if your arteries or heart are enlarged. Chest X-rays can help find other lung or heart conditions that may be causing the problems.
Exercise testing: Your doctor may want you to run on a treadmill or ride a stationary bike while you are hooked up to a monitor, so they can see any changes in your oxygen levels, heart function, lung pressure, or other things.
Your doctor may also do blood tests to check for HIV and conditions like rheumatoid arthritis or lupus.
If these tests show that you might have pulmonary hypertension, your doctor will need to do a right heart catheterization to be sure. Here's what happens during that test:
Right heart catheterization is safe. The doctor will give you a sedative and use local anesthesia. You can usually go home the same day, although you will need someone to drive you home.
You may want to write down a list of questions before your appointment, so you can make sure you ask your doctor everything you want to. It can also help to have a friend or family member with you to help you get the answers you want.
Some possible questions are:
Pulmonary hypertension varies from person to person, so your treatment plan will be specific to your needs. Ask your doctor what your options are and what to expect.
First, your doctor will treat the cause of your condition. For example, if emphysema is causing the problem, you'll need to treat that to improve your pulmonary hypertension.
Most people also get treatment to improve their breathing, which makes it easier to be active and do daily tasks. Oxygen therapy, when you breathe pure oxygen through prongs that fit in your nose, will help if you're short of breath and have low oxygen levels in your blood. It helps you live longer when you have pulmonary hypertension. If you are at risk for blood clots your doctor will recommend blood thinners. Other medicines improve how well your heart works and keep fluid from building up in your body.
If you have severe pulmonary hypertension, your doctor may prescribe medications called calcium channel blockers. These medicines lower blood pressure in the lungs and the rest of the body.
If calcium channel blockers aren't enough, your doctor may refer you to a specialized treatment center. You may need more targeted therapies that can open up your narrowed blood vessels. They may be pills, medicines you breathe in, or drugs that are given through an IV. Options include:
In more severe cases, or if medicines don't help, your doctor may recommend a lung transplant or a procedure called atrial septostomy. A surgeon creates an opening between the right and left sides of the heart. This surgery can have serious side effects.
One of the best things you can do for yourself is to stay active, even if you have shortness of breath. Regular exercise, like taking a walk, will help you breathe better and live better. Talk to your doctor first to find out what kind of exercise is best for you, and how much you should do. Some people may need to use oxygen when they exercise.
Get plenty of rest, too. Pulmonary hypertension makes you tired, so get a good night's sleep and take naps when you need to.
Just like anyone else, it's good for you to eat a healthy diet with lots of fruits, vegetables, and whole grains. That's important for your overall health.
A lot depends on what's causing your pulmonary hypertension. Treating an underlying condition will help you feel better. There's no cure for pulmonary hypertension, but the earlier it's diagnosed, the easier it is to live with.
If you have idiopathic pulmonary hypertension -- the kind where doctors can't find a cause -- your symptoms may get worse over time. But treatment can slow down the progress of the disease and help you live longer.
Remember that each person is different, and there are good treatments available. Work with your doctor to find what's right for you.
The Pulmonary Hypertension Association offers in-depth information on everything from medications to tips on making daily tasks easier. It also has an active online support community.
Differential Diagnosis Of Pulmonary Arterial Hypertension
Panelists discuss how pulmonary arterial hypertension diagnosis requires comprehensive evaluation including right heart catheterization to confirm hemodynamic criteria, with normal mean PA pressure being ≤20 mmHg and the need to rule out other causes of pulmonary hypertension.
Diagnostic Criteria and Disease Classification
Pulmonary arterial hypertension diagnosis requires comprehensive evaluation to distinguish it from other forms of pulmonary hypertension, as PAH represents a rare subset of the broader pulmonary hypertension spectrum. The definitive diagnostic tool remains right heart catheterization, which provides accurate hemodynamic assessment essential for proper classification. Current diagnostic criteria have evolved to define normal mean pulmonary artery pressure as ≤20 mmHg, with pulmonary hypertension diagnosed when pressures exceed this threshold.
Pre-capillary pulmonary hypertension, which includes PAH, is characterized by elevated pulmonary artery pressures with normal left-sided filling pressures (≤15 mmHg) and elevated pulmonary vascular resistance (≥2 Wood units). These three hemodynamic components must be present to establish a diagnosis of pre-capillary pulmonary hypertension. However, clinical presentation often involves mixed disease patterns, requiring careful evaluation to rule out lung disease, chronic thromboembolic disease, and other secondary causes.
The diagnostic process is complicated by significant overlap between different forms of pulmonary hypertension and the reality that patients often present with multiple comorbidities. Comprehensive evaluation must exclude heart disease, lung disease, and chronic blood clots while considering the possibility of mixed-type pulmonary hypertension with both pre-capillary and post-capillary components. This complexity underscores the importance of specialist evaluation and systematic diagnostic approaches.
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