People with a serious illness such as pulmonary hypertension (PH) must form a partnership with their health care providers to effectively manage the disease in a way that enhances quality of life. Two recent clinical trials related to World Health Organization (WHO) Group 1 PH (pulmonary arterial hypertension, or PAH) – the SERAPHIN and GRIPHON trials – included an assessment of adverse events, such as worsening disease and hospitalization. A group of international researchers took the findings from these trials one step further; they conducted their own study of the data to better understand the connection between morbidity (the state of the disease) and mortality (likelihood of dying) in patients with PAH.
Vallerie V. McLaughlin, M.D.; Kim A. Eagle M.D., endowed professor of cardiovascular medicine at the University of Michigan, a Pulmonary Hypertension Association (PHA)-accredited Center of Comprehensive Care; and a group of global scientists examined the findings from the two PAH trials. The SERAPHIN trial involved 742 patients with various forms of PAH. Some patients were given a placebo (sugar pills) and others received macitentan. In the GRIPHON trial, 1,156 patients with characteristics similar to those enrolled in the SERAPHIN study received either a placebo or selexipag. In both trials, patients also were able to take other medications, Dr. McLaughlin noted.
The authors examined data on adverse events (defined by each trial in the chart below), which were taken at landmark time points of three, six and 12 months after the start of each of the studies.
Definition of adverse events in the SERAPHIN trial:
Definition of adverse events in the GRIPHON trial:
Worsening of PAH including all of the following:
15 percent decrease in six-minute walking distance (6MWD).
Worsening of PAH symptoms such as signs of right heart failure or change to a higher WHO functional class (FC).
Need for additional PAH treatment
Beginning treatment with intravenous (into the vein) or subcutaneous (under the skin) prostanoids
Worsening of PAH including both of the following:
15 percent decrease in 6MWD.
Change to a higher WHO FC or the need for additional PAH treatment.
Beginning prostanoid therapy or long-term oxygen therapy.
Balloon atrial septostomy.
The authors found that patients who experienced one of the above adverse events were at higher risk of death than those who did not. They also stated that the risk of death was higher for those who experienced an event earlier in the study (within three months vs. within six months vs. within 12 months) and that this risk decreased as time went on.
The authors noted that the SERAPHIN and GRIPHON trials looked only at disease worsening related to PAH and not to other, non-PAH, causes. However, the results still indicate an association between disease progression and an increased risk of dying, which reinforces the recommendation to begin intense therapy to prevent deterioration.
After examining the data in both trials, the authors agreed with previous findings that adverse events caused worsening disease and were associated with an increased risk of death. They emphasized that “…preventing morbidity events is of the utmost importance for patients with PAH…” and they highly recommended using an intensive treatment approach, which might include the use of more than one PAH drug. The authors added that their findings also might be a critical part in designing future trials related to PAH. Specifically, future studies may produce more detailed and useful results if they are long-term as compared with the shorter studies.
Actelion Pharmaceuticals Ltd. provided funding for the referenced study. Actelion Pharmaceuticals did not provide PHA funding or writing assistance for this article.