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Pulmonary arterial hypertension (PAH) is a type of high blood pressure in the arteries in your lungs. Treatment aims to lower that pressure so your heart doesn’t have to work as hard. This often involves medications that relax those blood vessels.

Doctors and researchers have found that for many people, using more than one type of medication — called combination therapy — can be the most effective way to treat PAH. Each medicine targets a different part of the disease and may help you feel better and live longer.

What Is Combination Therapy?

Monotherapy — taking one medication for a disease or health condition — used to be the standard treatment for PAH. However, studies found that people who took only one medication for their PAH tended to have worse outcomes. As a result, doctors began prescribing more than one medication at a time.

Combination therapy for PAH uses more than one medication to relax blood vessels and lower pressure. These medications are generally called vasodilators, and they help reduce PAH symptoms and prevent complications such as right heart failure.

These therapies may be combined in several ways. When choosing your treatment plan, your doctor will consider how severe your PAH is, other health conditions you have (comorbidities), and your preferences and lifestyle.

How Does Combination Therapy Work?

The U.S. Food and Drug Administration (FDA) has approved different types of treatments for PAH, and each works in its own way. By using two or more of these approaches in combination therapy, you’re more likely to see an improvement in your symptoms and overall health.

Here’s an overview of the types of PAH medications that may be used in combination therapy:

• Endothelin receptor antagonists (ERAs) block the effects of endothelin, a protein that causes blood vessels in the lungs to tighten. ERAs help the blood vessels relax and stay open.
• Phosphodiesterase-5 inhibitors (PDE5) block an enzyme called PDE5. This helps increase the effects of nitric oxide, a substance that relaxes and widens the lungs’ blood vessels, making it easier for blood to flow.
• Prostacyclin medications act like natural substances in your body called prostaglandins. These drugs help widen blood vessels and slow scarring in the lungs’ arteries to prevent disease progression.
• Soluble guanylate cyclase (sGC) stimulators stimulate the enzyme sGC, which helps relax and widen blood vessels.
• Activin signaling inhibitors (like sotatercept) help rebalance signals that control how the lung’s blood vessels grow and tighten. This can lower pressure in the lungs.

Dual Therapy Medication Combinations

Before you begin a combination therapy, your doctor will discuss your treatment options and determine which are best for you. Common oral combination therapies include ERAs with PDE5 inhibitors or ERAs with sGC stimulators. If your PAH is severe, your doctor may add a prostacyclin medication as part of dual or triple combination therapy for added effects. Some people can now take a single daily pill that combines two medicines — an ERA and a PDE5 inhibitor. This may simplify treatment and help with sticking to a treatment plan.

Several clinical trials have studied sequential dual therapy (adding a second medicine later). Participants started on the first medication and added another or a placebo (inactive drug) for comparison. Combination therapy lowered the risk of PAH getting worse. Examples of sequential combinations studied for dual therapy include:

• ERA plus a prostacyclin medication
• PDE5 inhibitor plus a prostacyclin medication
• ERA plus an sGC stimulator
• ERA plus a PDE5 inhibitor

Don’t take a PDE5 inhibitor (like sildenafil or tadalafil) together with an sGC stimulator (like riociguat). This mix can cause your blood pressure to drop too much.

Researchers have also studied what happens when the order of medications is switched. For example, some participants started treatment with an ERA and later added a prostacyclin. Others started with a prostacyclin and then added an ERA. The results help doctors understand the best way to start and adjust treatment over time.

Researchers have studied what happens when the order of PAH medications is switched.

Activin signaling inhibitors are now an FDA-approved option for adults with PAH. They can be used along with other PAH medicines.

Some clinical trials looked at whether it’s better to start with two PAH treatments at the same time (called initial combination therapy) or to start with one treatment and add another later on. More recent studies support starting with combination therapy for many people, and one trial of starting three drugs at once didn’t show extra benefit.

Specific strategies for dual therapy in PAH are still being studied. Your doctor will help you find the approach that’s best for you.

Who Is a Candidate for Combination Therapy?

The medications your doctor recommends will depend on how serious your PAH is. If you’re taking one medication and your PAH symptoms haven’t improved, your doctor may add a second medication that works differently. This is called sequential combination therapy.

If you’ve just been diagnosed with PAH, you’ll likely be started on combination therapy. The European Society of Cardiology/European Respiratory Society (ESC/ERS) created guidelines to help doctors decide which medications to use and when to start them. These recommendations depend on different aspects of your PAH and overall health status, including:

• Your World Health Organization (WHO) functional class — This shows how severe your PAH symptoms are and how much they affect your daily activities.
• Results of your six-minute walk test (6MWT) — During this test, your oxygen levels are measured while you walk for six minutes. The distance you walk in that time, called your six-minute walk distance (6MWD), helps doctors see how well your body handles physical activity.
• Your levels of certain blood markers, such as brain natriuretic peptide — These markers give doctors clues about how hard the right side of your heart is working. They can help show if your heart is under stress, but they aren’t specific to pulmonary hypertension.

If you’ve just been diagnosed with PAH, you’ll likely be started on combination therapy.

These factors help doctors estimate your risk over the next year. It’s recommended that people who are at low or intermediate risk start dual combination therapy with two oral medications.

People who haven’t had PAH treatment before and are considered high risk may start combination therapy that includes a prostacyclin analog. This medicine is given through an injection or a continuous infusion, either into a vein or under the skin, to help open up the blood vessels.

Keep in mind that these are general guidelines. Your PAH specialist will decide what’s best after a careful exam and a conversation about your health and needs.

Symptom Improvement With Combination Therapy

PAH raises blood pressure in the arteries in your lungs. This can cause:

• Shortness of breath
• Lightheadedness or dizziness
• Fainting spells
• Palpitations (rapid or racing heartbeat)
• Chest pain
• Cough

Studies show that dual therapy helps improve PAH symptoms by lowering mean pulmonary arterial pressure (blood pressure in the lungs’ arteries). Many people also see improvements in their exercise capacity. Doctors can measure your clinical response to combination treatment through the 6MWD from the six-minute walk test.

PAH combination therapy can help lower blood pressure in the arteries in the lungs as well as improve exercise capacity.

Side Effects of Combination Therapy

Taking more than one PAH medication can raise your chances of adverse events (side effects). Because these drugs work by widening blood vessels to help lower blood pressure, you may notice more side effects than if you were taking only one drug. Common side effects include:

• Headaches
• Hypotension (low blood pressure)
• Edema (swelling in the arms and legs caused by extra fluid in your body)

Studies show that some side effects are just as common in monotherapy treatment as they are in combination therapy. If you’re concerned about any new side effects, your doctor can help you find ways to manage them.

Join the Conversation

On myPHteam, people share their experiences with pulmonary hypertension, get advice, and find support from others who understand.

Are you taking combination therapy for the treatment of pulmonary arterial hypertension? Has this approach made a big difference in your symptoms? Let others know in the comments below.