There is no single best medication for pulmonary hypertension. The right treatment depends on which type you have, how severe it is, and how your body responds. Most people with pulmonary arterial hypertension (the most common treatable form) now start on a combination of two drugs from different classes rather than a single pill. A newer drug approved in 2024, sotatercept, has changed the treatment landscape by targeting the disease in a fundamentally different way than anything before it.
Understanding why your doctor recommends one medication over another starts with knowing which type of pulmonary hypertension you have and how advanced it is.
Not All Pulmonary Hypertension Is Treated the Same
Pulmonary hypertension is classified into five groups based on what’s causing the elevated pressure in your lung arteries. The targeted medications most people think of when searching for PH treatments are only proven effective for Group 1 (pulmonary arterial hypertension, or PAH) and Group 4 (caused by chronic blood clots in the lungs). For the other three groups, which include PH caused by left heart disease, lung disease, or unclear mechanisms, these same drugs have not shown benefit and can sometimes cause harm. Treatment for those groups focuses on managing the underlying condition.
If you have Group 1 PAH, there are four main drug classes available, and current guidelines often recommend starting with drugs from two classes simultaneously.
How Doctors Decide Your Starting Treatment
Before choosing medications, your care team assigns you a risk level: low, intermediate, or high. This assessment uses a combination of factors including your functional class (how limited your physical activity is), how far you can walk in six minutes, blood markers like BNP levels, and imaging of your heart’s right side. A six-minute walk distance above 440 meters generally suggests lower risk, while signs like fluid around the heart, a very high right atrial pressure, or a BNP above 340 pg/mL point toward higher risk.
The 2022 European guidelines, which are the current gold standard, recommend the following approach for most PAH patients without significant other heart or lung conditions:
- Low or intermediate risk: Start with two oral drugs together, specifically an endothelin receptor antagonist plus a PDE5 inhibitor. The recommended pairings are ambrisentan with tadalafil, or macitentan with tadalafil.
- High risk: Start with three drugs, adding an intravenous or subcutaneous prostacyclin to the two-drug oral combination.
- PAH with other heart or lung conditions: Start with a single oral drug, either an endothelin receptor antagonist or a PDE5 inhibitor alone, then reassess.
PDE5 Inhibitors: The Most Widely Used Class
Sildenafil and tadalafil work by relaxing the blood vessels in your lungs, reducing the pressure your heart has to pump against. They are often the backbone of PAH treatment. In pooled clinical trials, patients taking these drugs walked an average of 48 meters farther in six minutes compared to placebo and were 22% less likely to die over a 14-week period.
Sildenafil is taken three times daily (typically 20 mg per dose for PAH), while tadalafil is a once-daily pill (up to 40 mg). In subgroup comparisons, sildenafil showed a slightly larger improvement in walking distance (about 57 meters vs. 38 meters for tadalafil), though they were never tested head-to-head in the same trial. Tadalafil’s once-daily dosing is more convenient, but it tends to cause more headaches, stomach upset, and muscle or joint pain than sildenafil.
Endothelin Receptor Antagonists
These drugs block a protein called endothelin-1 that causes blood vessels in the lungs to narrow and thicken. Three are available: bosentan, ambrisentan, and macitentan. They differ in how precisely they target the problem and what monitoring they require.
Bosentan was the first to market and blocks both types of endothelin receptors. Its major drawback is liver toxicity: roughly 10% to 17% of patients develop elevated liver enzymes, requiring monthly blood tests. Ambrisentan is far more selective for the receptor subtype that drives vessel narrowing, which theoretically preserves some of the body’s natural vessel-relaxing functions. Its most common side effects are peripheral swelling (about 11% of patients) and flushing. Macitentan, the newest of the three, binds to its target with slower release and better tissue penetration, giving it enhanced activity in the lungs. It was specifically approved for long-term management and is the most commonly used endothelin blocker in current practice.
All three carry serious risks during pregnancy and are absolutely off-limits for women who are or could become pregnant. Women of childbearing age must use two forms of contraception and undergo monthly pregnancy testing while on these drugs.
Prostacyclin Pathway Agents
Prostacyclins are the most potent vasodilators used in PAH and are typically reserved for more severe disease or added when other drugs aren’t enough. They mimic a natural substance your body makes to keep blood vessels open and prevent clotting. The trade-off is that they are more complex to use.
Epoprostenol is the oldest and most powerful option, delivered through a permanent intravenous catheter connected to a portable pump. It requires refrigeration, constant attention, and carries risks of catheter infection and pump malfunction. Despite these challenges, it remains the go-to for patients with the most severe disease because of its strong survival benefit.
Treprostinil offers more flexibility. It can be given intravenously, subcutaneously (via a small pump under the skin), or by inhalation. It’s stable at room temperature and has a longer half-life, making it easier to manage day to day. Inhaled treprostinil is a popular option for patients who need prostacyclin-level therapy but want to avoid a catheter. Iloprost is another inhaled option, though it needs to be taken more frequently throughout the day.
Selexipag is an oral pill that works on the same pathway. It’s less potent than the infused prostacyclins but far more convenient, and it’s used as an add-on to other therapies.
Riociguat: The Dual-Indication Drug
Riociguat works by stimulating an enzyme that helps blood vessels relax. It is the only drug approved for both Group 1 PAH and Group 4 chronic thromboembolic pulmonary hypertension (CTEPH). For Group 4 patients who can’t have surgery to remove blood clots from their lungs, or who still have elevated pressures after surgery, riociguat is a first-line option.
In PAH, riociguat can be used as an alternative to a PDE5 inhibitor, but the two cannot be combined. If you’re already on sildenafil or tadalafil, riociguat is not an option unless you switch off the PDE5 inhibitor first.
Sotatercept: A New Approach Approved in 2024
Sotatercept (brand name Winrevair) represents a genuinely new treatment strategy. Rather than simply relaxing blood vessels, it targets the abnormal cell growth that thickens and stiffens pulmonary artery walls in PAH. It works by intercepting signals that drive excessive proliferation of the cells lining the blood vessels, helping to rebalance vessel wall remodeling.
The STELLAR trial tested sotatercept in 323 patients with PAH who were already on background therapy. Results were striking: patients gained a median of 41 additional meters on the six-minute walk test compared to placebo, 29% improved by at least one functional class (vs. 14% on placebo), and there was an 84% reduction in the combined risk of death or disease worsening. It’s given as a subcutaneous injection every three weeks.
Sotatercept is currently used as an add-on to existing PAH medications rather than a standalone treatment. Because it works through a completely different mechanism than any other approved drug, it can be layered on top of the standard combination therapies.
What to Expect With Ongoing Treatment
PAH treatment is not a one-time decision. Your care team will reassess your risk level at regular intervals, typically every three to six months, using the same markers that guided the initial choice: walking distance, functional class, blood markers, and heart imaging. If you’re not reaching low-risk status on your current regimen, additional drugs from other classes will be added. The goal is always to get you to low risk and keep you there.
Side effects vary by class but commonly include headaches, flushing, nausea, and fluid retention in the legs. Diuretics (water pills) are frequently prescribed alongside PAH-specific drugs to manage fluid buildup, and reducing salt intake helps. If you’re on bosentan, expect monthly liver function tests. If you’re on intravenous epoprostenol or treprostinil, periodic blood count monitoring is standard. Jaw pain during eating is a well-known side effect of prostacyclin therapy that can be uncomfortable but is not dangerous.
The medications available today can significantly improve quality of life and survival, but they work best when started early and adjusted proactively based on how you’re responding.