• Treating 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, improving overall quality of life.

Pulmonary arterial hypertension (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 — taking a single medication for a certain disease or health condition — 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. Known as vasodilators, these medications have been shown to reduce PAH symptoms and prevent other complications such as right heart failure.

Common PAH medications used in combination therapy include:

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

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.

Currently available PAH medications and their effects include:

• Phosphodiesterase-5 (PDE-5) inhibitors — Block the enzyme PDE-5 from working to increase nitric oxide (NO) levels, which helps widen the blood vessels in your lungs
• Soluble guanylate cyclase (sGC) stimulators — Stimulate the enzyme sGC to help widen blood vessels
• Endothelin receptor antagonists (ERAs) — Block the protein endothelin, 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

Who Is a Candidate for Combination Therapy?

The medications prescribed by your doctor vary depending on the severity of your PAH. If you’re currently taking a single PAH medication and you haven’t seen improvement in your symptoms, your doctor may prescribe a second medication to help lower your blood pressure in a different way. This is known as sequential combination therapy.

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 (ESC/ERS) 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:

• World Health Organization (WHO) functional class — Measures the severity of your PAH symptoms
• Six-minute walk test (6MWT) — Measures how far you’re able to walk in six minutes; your oxygen levels are also measured during the test
• Levels of certain blood markers, such as brain natriuretic peptide (BNP) — 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 had any previous PAH treatment and are considered high risk are recommended to start combination therapy with a parenteral (injection or infusion) or intravenous (IV) prostacyclin analog.

Dual Therapy Medication Combinations

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

In more severe cases of PAH, prostacyclin medications may be added into dual or triple combination therapy for added effects.

Several clinical trials have studied sequential dual therapy. In these studies, participants started on medication and added another or a placebo (fake 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.

Two clinical trials have also studied the benefits of beginning two PAH treatments at the same time (known as initial combination therapy) compared to a single treatment. One large study found that participants who started both ambrisentan and tadalafil saw more improvement than those taking only ambrisentan or tadalafil alone.

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 six-minute walk distance (6MWD).

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 being held in your body)

Interestingly, research shows that some side effects are just as common in monotherapy 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 49,000 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 to manage your PAH? Share your experience in the comments below, or start a conversation by posting on your Activities page.