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• Treating pulmonary arterial hypertension (PAH) with two or more therapies, known as combination therapy, is an effective way to manage this condition.
• Medications used in PAH combination therapy help widen blood vessels and lower blood pressure in several ways.
• Studies show that dual therapy improves PAH symptoms and exercise capacity, helping to improve overall quality of life.

PAH is a complex condition that needs treatment to keep you healthy. This usually means taking medications that help lower the pressure in the blood vessels of your lungs.

Doctors and researchers have found that 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 a longer, healthier life.

What Is Combination Therapy?

Monotherapy — taking a single medication for a disease or health condition — used to be the standard for treating pulmonary arterial hypertension. 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 involves prescribing multiple medications to help widen blood vessels, which lowers blood pressure. These medications are generally called vasodilators, and they help reduce PAH symptoms and prevent complications such as right heart failure.

Combination therapy for pulmonary arterial hypertension involves prescribing multiple medications.

These therapies may be combined in several ways. When determining your treatment plan, your doctor will consider factors such as the severity of your PAH, 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 stimulators (sGC) stimulate the enzyme sGC, which helps relax and widen blood vessels.
• Activin signaling inhibitors block proteins called activins, which help control smooth muscle cell growth and can reduce thickening of the blood vessels in the lungs.

Dual Therapy Medication Combinations

Before beginning 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 pulmonary arterial hypertension is severe, your doctor may add prostacyclin medications into dual or triple combination therapy for added effects.

Several clinical trials have studied sequential dual therapy. In these studies, participants started on the first medication and added another or a placebo (inactive drug) for comparison. The results showed that combination therapy significantly reduced the worsening of PAH. Examples of sequential combinations studied for dual therapy include:

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

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.

Activin signaling inhibitors are a newer type of PAH medication and may be prescribed along with other PAH medications. Since activin signaling inhibitors haven’t been around as long, there’s less research on how well they work as part of combination therapy.

Some clinical trials have 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. So far, only two studies have focused on using combination therapy from the beginning. Most looked at adding one drug to an existing treatment. One study, called the Triton study, looked at starting with three drugs instead of two, but it didn’t show any added benefit.

Because dual therapy for PAH is still being studied, doctors and researchers haven’t found the ideal combination. Your doctor will work with you to find which approach works best for you.

Who Is a Candidate for Combination Therapy?

The medications your doctor recommends will depend on how serious your pulmonary arterial hypertension is. If you’re taking one medication and your PAH symptoms haven’t improved, your doctor may add a second medication that works in a different way. 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.

Your PAH treatment regimen will depend on factors like your functional class, results of your six-minute walk distance test, and levels of certain markers in your blood.

These factors help determine your risk group and estimate your one-year mortality risk (risk of dying in one 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 received 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 for you after a careful exam and a detailed conversation about your health and needs.

Symptom Improvement With Combination Therapy

PAH symptoms are caused by increased blood pressure in the lungs’ arteries. This can lead to:

• 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.

Studies show that dual therapy helps improve PAH symptoms by lowering mean pulmonary arterial pressure, or the blood pressure in the lungs’ arteries.

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.

Talk With Others Who Understand

On myPHteam, the social network for people with pulmonary hypertension and their loved ones, more than 56,000 members come together to ask questions, give advice, and share their stories with others who understand life with pulmonary hypertension.

Are you taking combination therapy for the treatment of pulmonary arterial hypertension? Has this approach made a big difference in your symptoms? Share your experience in the comments below, or start a conversation by posting on your Activities page.

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