by Phyllis Hanlon, Contributing Writer

When researchers conduct clinical trials, they usually look for evidence that a drug works effectively and is safe. These trials are conducted in a structured setting with a very carefully selected group of patients.  Most trials cannot explore the way a drug will work in the real world and require more assessment.

Ambrisentan (Letairis®) – is an oral medication called an endothelin receptor antagonist. It is frequently used in pulmonary arterial hypertension (PAH) treatment. Clinical studies showed that the drug improved the six minute walk distance (6MWD), presented a low risk of injury to the liver and was generally well tolerated. By 2015, ambrisentan was frequently used around the world. But when the drug was approved, there was a limited amount of safety data available. So an international team of researchers conducted the VoLibris Tracking (VOLT) Study to look at the safety profile of ambrisentan in treating PAH.

The authors reviewed data collected from 115 centers in 15 countries over a three year period. They identified 998 patients who had taken ambrisentan between June 2008 and May 2011 and were considered a population that could be monitored for drug safety (the “safety population”). Two hundred thirty-eight patients had PAH associated with connective tissue disease (PAH-CTD) and 220 had not received any therapy for their PAH before enrolling in the study.

All patients were assessed during their routine clinical care; recorded characteristics included:

  • History of their PAH
  • Cause of PAH (idiopathic, heritable, associated)
  • World Health Organization Functional Class (WHO-FC)
  • All previous therapies used for PAH
  • Estimation of creatinine clearance (measures how well the kidneys are functioning)
  • Alanine aminotransferase (ALT) levels (enzyme used as a biomarker for liver health)
  • Aspartate aminotransferase (AST) levels (enzyme used as a biomarker for liver health)
  • Hemoglobin (protein that transports oxygen in the blood) and hematocrit (volume of blood cells compared to total volume of blood) levels

During each follow-up visit to the center, researchers recorded other medications patients might be taking and their health status. Most important, the authors looked at any adverse events related to ambrisentan, specifically liver injury, swelling in the arms or legs, heart failure, anemia, low blood pressure and possible hypersensitivity.

Any serious adverse events from the time the patients enrolled in the study to 30 days after taking the last dose of ambrisentan, as well as abnormal vital signs, scans and lab results, were noted. All adverse events were closely watched until they resolved or the patient stabilized. The study also collected if patients stopped using ambrisentan due to these adverse events.

At the beginning of the trial period, 845 patients (85 percent) were taking 5 mg daily ambrisentan and 105 patients (15 percent) were taking 10 mg daily. During the course of the study period, the patients could switch from another medication to ambrisentan; they could also have ambrisentan added onto the PAH-targeted therapies they were already taking. By the end of the study period, 632 patients (63 percent) and 363 patients (36 percent), respectively, were taking 5 mg and 10 mg daily.

A total of 827 patients (83 percent) reported at least one adverse event; 429 (43 percent) were considered mild to moderate and 377 (38 percent) were viewed as serious. The most common adverse events included:

  • Edema (swelling in the lower limbs due to fluid accumulation)
  • Shortness of breath
  • Anemia
  • Heart failure
  • Hospitalization one or more times

Of those patients who were hospitalized, 7 patients (2 percent) experienced a negative reaction, which might have been related to ambrisentan, and 10 patients (3 percent) were judged to be hospitalized due to another PAH treatment. Negative reactions prompted 167 patients (17 percent) to discontinue taking ambrisentan.

One of the goals of the study was to ensure that patients taking ambrisentan were not at increased risk of liver injury due to taking the drug. Doctors did blood work as needed to check for signs of liver injury, measuring ALT and AST levels. They found that taking ambrisentan did not significantly cause increased signs of liver injury compared to what would be expected in this population in general.

During the review period, 213 patients died: 69 from heart problems, including heart failure and right ventricular failure.

Patients with PAH associated with connective tissue diseases (PAH-CTD) and patients with PAH who had not received ambrisentan prior to this study had similar medical profiles and characteristics as the PAH treatment group when they enrolled in the trial. Results for these two groups were also similar to those found in the overall “safety population.”

The authors pointed out that this study did not have a comparison group and did not make allowances for the two different ambrisentan doses. Also, the PAH-CTD and PAH patients taking ambrisentan for the first time comprised a small group. Despite these minor limitations, the VOLT study demonstrated no new safety issues for patients taking ambrisentan in more real life situations compared to the original study.

Studies of this nature (called “post-marketing” or Phase 4 studies) are important, according to the authors, because the typical PAH patient profile is changing. More patients are older, more obese and often have more than one medical condition. However, they reported that, despite these issues, prognosis is better, possibly because there is more awareness of the disease, and ways to diagnose and treat it have improved. Having good data about the safety of treatments for PAH will benefit all patients.

Each PH patient is different. It is essential that you talk to your own doctor about what treatment options are best for you. For more information on finding a doctor or an accredited care center, visit


VOLT study demonstrated no new safety issues for patients taking ambrisentan in real life situations.

According to authors, “post-marketing” studies are important because the typical PAH patient profile is changing.