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. 2022 Jun;19(6):952-961.
doi: 10.1513/AnnalsATS.202110-1139OC.

Secular and Regional Trends among Pulmonary Arterial Hypertension Clinical Trial Participants

Jeff Min  1 , Dina H Appleby  2 , Robyn L McClelland  3 , Jasleen Minhas  1 , John H Holmes  2 , Ryan J Urbanowicz  2 , Steven C Pugliese  1 , Jeremy A Mazurek  1 , K Akaya Smith  1 , Jason S Fritz  1 , Harold I Palevsky  1 , Jude Moutchia Suh  2 , Nadine Al-Naamani  1 , Steven M Kawut  1   2
Affiliations

Secular and Regional Trends among Pulmonary Arterial Hypertension Clinical Trial Participants

Jeff Min et al. Ann Am Thorac Soc. 2022 Jun.

Abstract

Rationale: The population of patients with pulmonary arterial hypertension (PAH) has evolved over time from predominantly young White women to an older, more racially diverse and obese population. Whether these changes are reflected in clinical trials is not known. Objectives: To determine secular and regional trends among PAH trial participants. Methods: We performed a pooled cohort analysis using harmonized data from phase III clinical trials of PAH therapies submitted to the U.S. Food and Drug Administration. We used mixed-effects linear and logistic regression to assess regional differences in participant age, sex, body habitus, and hemodynamics over time. Results: A total of 6,599 participants were enrolled in 18 trials between 1998 and 2013; 78% were female. The mean age of participants in North America, Europe, and Latin America at the time of study start increased by 2.09 (95% confidence interval [CI], 0.67-3.51), 1.62 (95% CI, 0.24-3.00), and 4.75 (95% CI, 2.29-7.21) years per 5 years, respectively (P = 0.01). Body mass index at the time of study start increased by 0.72 kg/m2 per 5 years (95% CI, 0.44-0.99; P < 0.001) across all regions. Eighty-five percent of participants in early studies were non-Hispanic White, but this decreased over time to 70%. Ninety-seven percent of Asians and 74% of Hispanics in the sample were recruited from Asia and Latin America. Conclusions: Patients enrolled in more recent PAH therapy trials are older and more obese, mirroring the changing epidemiology of observational cohorts. However, these trends varied by geographic region. PAH cohorts remain predominantly female, presenting challenges for generalizability to male patients. Although the proportion of non-White participants increased over time, this was primarily through recruitment in Asia and Latin America.

Keywords: clinical trial participants; pooled cohort analysis; pulmonary arterial hypertension; secular trends.

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Figures

Figure 1.
Figure 1.
Participant (A) geographic region, (B) race, (C) sex, and (D) disease etiology over time. Data are displayed as cumulative counts (top) and overall percentage of participants (bottom) over time. AUS = Australia; CA = Canada; CHD-PH = pulmonary arterial hypertension associated with congenital heart disease; CTD-PH = pulmonary arterial hypertension associated with connective tissue disease; IPAH = idiopathic pulmonary arterial hypertension; ISR = Israel; Other = includes all other group I etiologies; US = United States.
Figure 2.
Figure 2.
Participant age at study enrollment over time. Data were calculated using mixed-effects linear regression. AUS = Australia; CA = Canada; ISR = Israel; Pinteract = P value for region × time interaction; Pregion = P value for differences by region; US = United States.
Figure 3.
Figure 3.
Probability of male sex among participants over time. Data were calculated using mixed-effects logistic regression. AUS = Australia; CA = Canada; ISR = Israel; Pinteract = P value for region × time interaction; Pregion = P value for differences by region; US = United States.
Figure 4.
Figure 4.
Participant (A) body mass index and (B) probability of obesity over time. Data were calculated using mixed-effects (A) linear and (B) logistic regression. AUS = Australia; CA = Canada; ISR = Israel; Pregion = P value for differences by region; Pslope = P value for change over time; US = United States.
Figure 5.
Figure 5.
Entry hemodynamic parameters over time. (A) RAP, (B) mPAP, (C) PCWP, (D) CI, and (E) PVR. Data were calculated using mixed-effects linear regression with multivariable adjustment for age, sex, body mass index, pulmonary arterial hypertension etiology, and whether background therapy was allowed. AUS = Australia; CA = Canada; CI = cardiac index; ISR = Israel; mPAP = mean pulmonary arterial pressure; PCWP = pulmonary capillary wedge pressure; Pinteract = P value for region × time interaction; Pregion = P value for differences in mean hemodynamic parameter by region; Pslope = P value for change in mean hemodynamic parameter over time; PVR = pulmonary vascular resistance; RAP = right atrial pressure; US = United States.
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