• 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 combination therapy for PAH help widen blood vessels and lower blood pressure in several different ways.
• Studies show that dual therapy improves PAH symptoms and exercise capacity, helping improve overall quality of life.

PAH is a complex condition that requires treatment in order to keep you healthy. This typically involves medications that help control your blood pressure.

Doctors and researchers are now learning that the best way to treat PAH is to prescribe multiple medications to help control different factors in PAH. This practice is known as combination therapy, and it’s been proven to help people with PAH live longer, healthier lives.

What Is Combination Therapy?

Monotherapy involves taking a single medication for a certain disease or health condition. It used to be the standard for treating PAH. However, studies have found that people who took only one medication for their PAH tended to have worse outcomes. As a result, doctors began prescribing other medications in addition to monotherapy.

Combination therapy for PAH involves prescribing multiple medications to widen your blood vessels, which helps lower blood pressure. These medications are called vasodilators and reduce PAH symptoms and prevent other complications such as right heart failure.

Common PAH medications used in combination therapy include:

• Endothelin receptor antagonists (ERAs) — Bosentan (Tracleer), ambrisentan (Letairis), macitentan (Opsumit)
• Phosphodiesterase-5 (PDE-5) inhibitors — Sildenafil (Revatio), tadalafil (Adcirca)
• Prostacyclin and prostanoid medications — Treprostinil (Tyvaso, Orenitram, Remodulin), iloprost (Ventavis), epoprostenol (Flolan, Veletri), selexipag (Uptravi)
• Soluble guanylate cyclase (sGC) stimulators — Riociguat (Adempas)

There are several different ways these therapies may be combined. For example, Opsumit combination therapy in PAH may also include PDE-5 inhibitors or inhaled prostanoids.

Uptravi combination therapy in PAH reduces lung pressure and strain on the right side of the heart to slow disease progression. Doses of selexipag range from 200 to 1,600 micrograms, so your health care provider will help determine the right level based on your baseline health, the severity of your condition, and other meds you’re taking.

How Does Combination Therapy Work?

The U.S. Food and Drug Administration (FDA) has approved several different types of treatments for PAH that each target a different pathway in the disease. By targeting two or more of these pathways with combination therapy, you’re more likely to see an improvement in your symptoms and overall health.

Here’s an overview of PAH medications:

• Endothelin receptor antagonists block the protein endothelin, which helps widen the blood vessels in your lungs.
• Phosphodiesterase-5 inhibitors block the enzyme PDE-5 from working to increase nitric oxide levels, which helps widen the blood vessels in your lungs.
• Prostacyclin medications act like the prostaglandin compounds in your body, which help widen blood vessels and slow scarring in the lungs’ arteries to prevent disease progression.
• Soluble guanylate cyclase stimulators stimulate the enzyme sGC to help widen blood vessels.

Who Is a Candidate for Combination Therapy?

The medications that your doctor prescribes will vary depending on the severity of your PAH. If you’re currently taking a single PAH medication and your symptoms haven’t improved, your doctor may prescribe a second medication to help lower your blood pressure in a different way. This is called sequential combination therapy.

Discover helpful strategies for making your PAH medications more affordable.

If you’re newly diagnosed with PAH and haven’t had any treatment yet, you’ll likely be started on combination therapy. The European Society of Cardiology/European Respiratory Society has created guidelines for PAH treatments. The recommendations for which medications to prescribe and when to start them depend on different aspects of your PAH and overall health status, like:

• Your World Health Organization (WHO) functional class — This measures how severe your PAH symptoms are.
• Results of your 6-minute walk test — During the test, your oxygen levels are checked as you walk for six minutes. The distance you walk in that time is called your 6-minute walk distance (6MWD).
• Your levels of certain blood markers, such as brain natriuretic peptide — These markers show how hard the right side of your heart is working to pump blood.

These factors help determine your risk group and estimate your one-year mortality risk (risk of dying in one year). People who are at low or intermediate risk are recommended to start dual combination therapy with two oral medications.

People who haven’t received PAH treatment before and are considered high risk should start combination therapy with a prostacyclin analog given through injection or infusion. This medication can be administered either into the vein or under the skin and helps widen your blood vessels and improve blood flow.

Dual Therapy Medication Combinations

Before beginning a combination therapy, your doctor will discuss your treatment options with you. They’ll determine which medications are best for your case. Common oral combination therapies include ERAs with PDE-5 inhibitors or ERAs with sGC stimulators.

If PAH 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. Studies show that combination therapy significantly reduces the worsening of PAH. Examples of sequential combinations studied for dual therapy include:

• ERA plus prostacyclin medication
• PDE-5 inhibitor plus prostacyclin medication
• ERA plus sGC stimulator
• ERA plus PDE-5 inhibitor

The order in which these medications are prescribed has also been studied in reverse. For example, studies have investigated treatment with an ERA first, then adding a prostacyclin medication — they’ve also studied participants starting a prostacyclin medication first, then adding an ERA.

Several clinical trials have looked at starting two PAH treatments together (known as initial combination therapy) versus adding one drug to another. However, it’s important to note that only two studies focused on starting combination therapy from the beginning. The others examined adding one drug to an existing treatment. Additionally, the Triton study, which compared three drugs at once to two, did not show any benefit.

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

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

Studies show that dual therapy helps improve PAH symptoms by lowering your mean pulmonary arterial pressure (blood pressure in your lungs’ arteries). Many people also see improvements in their exercise capacity and 6MWD from the 6-minute walk test.

Side Effects of Combination Therapy

Taking multiple medications to treat PAH can increase your risk of side effects. Because these medications widen blood vessels to help lower blood pressure, you may experience more side effects or adverse events than you would from taking only one medication. Side effects can include:

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

Interestingly, research shows 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 53,000 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? Have you noticed a significant difference in your symptoms as a result? Share your experience in the comments below, or start a conversation by posting on your Activities page.