Patient age contributes to significant differences in the characteristics and etiology of pulmonary arterial hypertension seen in randomized, controlled trials, including more frequent connective tissue disease–associated disease in older patients, according to a post-hoc analysis of trials.
Additionally, older age was associated with worse baseline functional status, worse outcomes in the 6-minute walk distance, and an overall reduced response to treatment, while hemodynamic severity was higher in younger patients.
“Although registry data have shown that idiopathic PAH [pulmonary arterial hypertension] is increasingly recognized in older populations, our analysis shows that idiopathic etiology was less frequent in the older group. In contrast, CTD [connective tissue disease]–associated PAH accounted for a higher proportion of PAH etiology in the oldest age group,” wrote Jonathan A. Rose of Case Western Reserve University, Cleveland, and his colleagues (Chest. 2016;149[5]:1234-44. doi: 10.1016/j.chest.2015.11.008).
The researchers analyzed seven multicenter, randomized, double-blind, placebo-controlled treatment trials for PAH conducted by United Therapeutics and one open-label extension study that involved following patients being treated with subcutaneous treprostinil for 4 additional years. Data from the open-label extension trial and one of the trials were combined and reported as one trial. All trials excluded patients with a history of left-sided heart disease, pulmonary artery wedge pressure (PAWP) greater than 15 mmHg, or pulmonary vascular resistance (PVR) less than 3 Woods units. The researchers categorized the 2,627 patients included in the trials in the following three age groups: 50 years or younger, 51-64 years, and 65 years or older.
Between 53% and 74% of patients in all trials across all age groups had idiopathic PAH, but older patients comprised a significantly smaller proportion of the patients with idiopathic PAH in three of the trials (P = .004) and a significantly higher percentage of the patients with CTD-associated PAH in all of the trials (P less than .001). Across the trials, CTD-associated PAH occurred in 15%-21% of patients 50 years or younger, 25%-40% of those aged 51-64 years, and 27%-49% of those aged 65 years or older.
From baseline to the end in three of the studies, a smaller change in the 6-minute walk distance was seen in older patients and a higher proportion of older patients had an overall decrease in total 6-minute walk distance. Older age remained associated with this outcome measure when only data from treatment-naive patients or the subgroup of patients with CTD-associated PAH were included.
The association between age and lower baseline functional status was observed in four of the trials; A lower proportion of patients in the oldest age group were classified as being of the World Health Organization functional classes I and II, with 9%-32% of patients aged 65 years or older, 10%-33% in those aged 51-64 years, and 16%-43% of those aged 50 years or younger.
Hemodynamic severity was among the areas in which older patients performed better than younger patients, with the oldest age group having lower baseline mean pulmonary artery pressure (mPAP) and PVR in the two trials that measured hemodynamics.
“The difference in the clinical function and hemodynamics in older patients may reflect different mechanisms of disease. Older patients may have diminished cardiopulmonary reserve, and similar degrees of hemodynamic severity manifest with a larger functional impairment. Alternatively, additional comorbidities in older patients may contribute to a larger extent, and clinical function may not be as directly related to hemodynamic severity,” according to the researchers.
Mortality was generally small in these studies and not significantly different among age groups, except for in the open-label extension study of Subcutaneous Infusion of Treprostinil in Patients with PAH (SC-TRE) and the Study of Intravenous Remodulin in Patients in India with PAH (TRUST) trials, which were combined and reported on as one trial (P = .0004).
Nausea was the only adverse effect found to be associated with age in more than one trial, and the relationship between it and age in two trials were inconsistent. While a higher incidence of nausea was found in the oldest age group in the Oral Treprostinil as Monotherapy for the Treatment of Pulmonary Arterial Hypertension (FREEDOM-M) trial (P = .03), a lower incidence of nausea was found in the oldest age group in the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) trial (P = .02).
The analysis was supported by a grant from the National Institutes of Health. Two of the authors, Jody M. Cleveland and Youlan Rao, Ph.D., reported being employees of United Therapeutics, while Dr. Omar A. Minai, another author of the report, serves on the scientific advisory board of United Therapeutics. The other authors declared no conflicts.