Primary Pulmonary Hypertension Mortality Trends and Demographic Disparities in the United States, 2018–2024

1. Introduction

Pulmonary hypertension is a group of disorders defined by a mean pulmonary artery pressure greater than 20 mm Hg. [1] PAH is further subdivided into: (1.1) idiopathic PAH, (1.2) heritable PAH, (1.3) drug- and toxin-induced PAH, (1.4) PAH associated with connective tissue disease, HIV infection, portal hypertension, congenital heart disease, and schistosomiasis, (1.5) PAH long-term responders to calcium channel blockers, (1.6) PAH with overt features of venous/capillary involvement (pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis), and (1.7) persistent pulmonary hypertension of the newborn. [1]

Patients often manifest as exertional dyspnea and progress to severe complications such as right heart failure. Echocardiogram shows an elevated RVSP or reduced TAPSE, which suggests right-sided overload. The diagnosis of PAH requires right heart catheterization demonstrating a mean pulmonary artery pressure (mPAP) >20 mmHg, pulmonary artery wedge pressure (PAWP) ≤15 mmHg, and pulmonary vascular resistance (PVR) >2 Wood units (WU) per the 2022 ESC/ERS guidelines. The PVR threshold was lowered from ≥3 WU to >2 WU, reflecting evidence that the upper limit of normal PVR is approximately 2 WU and that values above this threshold carry independent prognostic significance. However, it should be noted that clinical trial evidence supporting PAH-specific therapies was established using the prior hemodynamic criteria (mPAP ≥25 mmHg and PVR ≥3 WU), and the clinical significance of the expanded hemodynamic zone (PVR 2–3 WU) remains under investigation [2,3,4].

PAH is rare disorder with an incidence of about 2.4 cases and a prevalence of 15 cases per 1 million per French registry [5]. The US counterpart shows a similar incidence of 2.0 cases and a prevalence of 10.6 cases per 1 million adults [6]. Historically, it has been seen in female gender at birth. The NIH registry (1981–1985) reported a mean age at diagnosis of 36 years, whereas the REVEAL registry (2006–2009) reported a mean age of 50 years, reflecting improved survival and later-onset disease recognition [6,7].

Five-year survival has improved from 34% in 1991 to approximately 60% in 2015 with the advent of combination therapy. Currently approved therapies target three biological pathways: the nitric oxide–cGMP pathway (sildenafil, tadalafil, riociguat), the endothelin pathway (bosentan, ambrisentan, macitentan), and the prostacyclin pathway (epoprostenol, treprostinil, selexipag). Sotatercept, an activin signaling inhibitor, was approved by the FDA in March 2024 as the first therapy with a novel mechanism of action in over a decade [8].

Persistent demographic disparities have been documented across all prior surveillance studies. Kang et al. found that non-Hispanic Black individuals experienced consistently higher age-adjusted PH mortality rates, with an average age-adjusted PH mortality rate of 7.9 per 100,000 that increased by 1.9% per year from 1999 to 2019 [8]. This was further strengthened by Parikh et al., who provided a mechanistic link, demonstrating that Black patients with incident PH had greater right ventricular dysfunction. However, in the same study, matching for insurance led to non-significance based on race HR 2.06 (95% CI, 1.18–3.44) to HR 1.74 (95% CI, 0.84–3.32), suggesting more social than genetic disparities [9]. GBD 2021 analysis found that 62% of prevalent PAH cases worldwide were female, yet the PVRI GoDeep meta-registry identified a male survival disadvantage (adjusted HR 1.36, 95% CI 1.23–1.50), suggesting that while more women develop PAH, men with PAH die sooner, more particularly in White race [10]. This CDC-based analysis uses the updated database from 2018 to 2024 to study the demographic disparities, including gender, race, and geographic location [11].

2. Materials and Methods

Study Design and Data Source

This was a retrospective, population-based cross-sectional study of mortality trends and demographic disparities in primary pulmonary hypertension (PPH) in the United States from 2018 to 2024. Mortality data were obtained from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) Underlying Cause of Death database, 2018–2024, Single Race series. This database compiles information from all death certificates filed in the 50 states and the District of Columbia. The underlying cause of death, defined by the World Health Organization as “the disease or injury which initiated the train of morbid events leading directly to death,” was used for case identification.

Case Identification

Deaths attributable to primary pulmonary hypertension were identified using the International Classification of Diseases, Tenth Revision (ICD-10) code I27.0 (Primary pulmonary hypertension) listed as the underlying cause of death. This code corresponds to WHO Group 1 (PAH) and was selected to maximize specificity for PAH-attributable mortality, consistent with prior CDC WONDER–based analyses of pulmonary hypertension.

Outcome Measures

The primary outcome was the age-adjusted mortality rate (AAMR) per 100,000 population, standardized to the 2000 U.S. standard population using the direct method. Secondary outcomes included absolute annual death counts, crude mortality rates per 100,000 population, and mortality rate ratios with 95% confidence intervals for demographic comparisons.

Demographic Variables

Deaths were stratified by the following variables as recorded on the death certificate: - Sex: Female and male.

- Race: Deaths were classified using the Single Race 6 categories as recorded on the death certificate: White, Black or African American, Asian, Native Hawaiian or Other Pacific Islander, American Indian or Alaska Native, and More than one race. Race of the decedent was reported by the funeral director as provided by an informant, most often the surviving next of kin, or, in the absence of an informant, based on observation. Cells with fewer than 10 deaths were suppressed per CDC confidentiality standards; consequently, reliable rate estimates were limited to White and Black or African American decedents, with Asian subgroup rates flagged as unreliable per NCHS convention.

- Census Region: Northeast (Region 1), Midwest (Region 2), South (Region 3), and West (Region 4), as defined by the U.S. Census Bureau.

Statistical Analysis

Analysis 1 - Sex Disparities: Deaths grouped by sex, with aggregate AAMR comparison and female-to-male mortality rate ratio.

Analysis 2 - Racial Disparities: Deaths grouped by Single Race 6 categories, with AAMR comparison across groups.

Analysis 3 - Temporal Trend: Deaths grouped by calendar year (2018–2024), with annual AAMR to assess temporal trends. The estimated compound annual growth rate (CAGR) was calculated as [(AAMRfinal / AAMRinitial)^(1/n) − 1] × 100, where n is the number of intervals. The year-over-year percent change in death counts was calculated for each consecutive pair of years.

Analysis 4 - Geographic Disparities: Deaths grouped by U.S. Census Region.

Mortality rate ratios were calculated by dividing the AAMR of the comparison group by the AAMR of the reference group. For rate ratios, 95% confidence intervals were calculated using exact Poisson methods.

All confidence intervals for age-adjusted rates were calculated using the gamma method as implemented by CDC WONDER. Cells with fewer than 10 deaths were suppressed per CDC confidentiality standards and were excluded from rate calculations. Rates based on fewer than 20 deaths were flagged as statistically unreliable per NCHS convention. All analyses were performed using CDC WONDER query tools.

3. Results

From 2018 to 2024, a total of 1831deaths were attributed to primary pulmonary hypertension (ICD-10 I27.0) as the underlying cause of death in the United States. The overall age-adjusted mortality rate for the full period was 0.06 per 100,000 population.

Analysis 1 - Sex Disparities

Women accounted for 69.5% of all PPH deaths during the study period, with an aggregate female-to-male mortality rate ratio of 8:1. The aggregate AAMR was 0.08 per 100,000 for females and 0.04 per 100,000 for males.

Table 1. Mortality by Sex (2018-2024).

Sex	Deaths	Population	Crude Rate (per 100,000)	Age-Adjusted Rate	% of Total
Female	1,272	1,176,300,483	0.11	0.08	69.5%
Male	559	1,148,797,782	0.05	0.04	30.5%
Total	1,831	2,325,098,265	0.08	0.06	100%

Table 1. Mortality by Sex (2018-2024).

Sex	Deaths	Population	Crude Rate (per 100,000)	Age-Adjusted Rate	% of Total
Female	1,272	1,176,300,483	0.11	0.08	69.5%
Male	559	1,148,797,782	0.05	0.04	30.5%
Total	1,831	2,325,098,265	0.08	0.06	100%

Analysis 2 - Racial Disparities

Table 2. Mortality by Race (2018-2024).

Race	Deaths	Crude Rate	Age-Adjusted Rate	% of Total
White	1,527	0.09	0.06	83.4%
Black or African American	235	0.07	0.10	12.8%
Asian	47	0.03	Unreliable	2.6%
Native Hawaiian or Other Pacific Islander	Suppressed	—	—	—
American Indian or Alaska Native	Suppressed	—	—	—
More than one race	11	0.02	Unreliable	0.6%
Total	1,831	0.08	0.06	100%

Table 2. Mortality by Race (2018-2024).

Race	Deaths	Crude Rate	Age-Adjusted Rate	% of Total
White	1,527	0.09	0.06	83.4%
Black or African American	235	0.07	0.10	12.8%
Asian	47	0.03	Unreliable	2.6%
Native Hawaiian or Other Pacific Islander	Suppressed	—	—	—
American Indian or Alaska Native	Suppressed	—	—	—
More than one race	11	0.02	Unreliable	0.6%
Total	1,831	0.08	0.06	100%

Among racial groups, White individuals accounted for the largest share of PPH deaths (1,527 deaths; 83.4%), followed by Black or African American individuals (221 deaths; 12.1%), Asian individuals (17 deaths; 0.9%), and Other/Suppressed groups (66 deaths; 3.6%). Black individuals had both the highest crude rate (0.11 per 100,000) and the highest age-adjusted mortality rate (0.10 per 100,000), compared with White individuals (crude rate 0.10; AAMR 0.06 per 100,000). The Black-to-White AAMR ratio was approximately 1.67:1. The Asian subgroup AAMR was flagged as statistically unreliable per NCHS convention due to small death counts. Rates for American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and More than one race subgroups were suppressed per CDC confidentiality standards (<10 deaths).

Analysis 3- Temporal Trend

Annual PPH deaths declined monotonically from 344 in 2018 to 199 in 2024, representing a 42.2% reduction in absolute death counts over seven years. The AAMR decreased from approximately 0.10 per 100,000 in 2018 to 0.06 per 100,000 in 2024, an estimated 40% decline in the population-adjusted rate. The estimated compound annual rate of change was approximately −9.3%. The largest single-year decline occurred between 2022 and 2023 (244 to 200 deaths; −18.0%), followed by a plateau into 2024 (200 to 199 deaths; −0.5%).

Table 3. Mortality by Year, 2018–2024.

Year	Deaths	Population	Crude Rate	AAMR
2018	344	327,167,434	0.11	0.10
2019	314	328,239,523	0.10	0.10
2020	276	329,484,123	0.08	0.08
2021	254	331,893,745	0.08	0.07
2022	244	333,287,557	0.07	0.07
2023	200	334,914,895	0.06	0.06
2024	199	340,110,988	0.06	0.06

Table 3. Mortality by Year, 2018–2024.

Year	Deaths	Population	Crude Rate	AAMR
2018	344	327,167,434	0.11	0.10
2019	314	328,239,523	0.10	0.10
2020	276	329,484,123	0.08	0.08
2021	254	331,893,745	0.08	0.07
2022	244	333,287,557	0.07	0.07
2023	200	334,914,895	0.06	0.06
2024	199	340,110,988	0.06	0.06

Analysis 4 Geographic Disparities

Census Region	Female Deaths	Male Deaths	Total Deaths	Crude Rate (per 100,000)	% of Total
Northeast	158	67	225	0.06	12.3%
Midwest	230	89	319	0.07	17.4%
South	513	277	790	0.09	43.1%
West	371	126	497	0.09	27.1%
Total	1,272	559	1,831	0.08	100%

The above table shows that the southern regions bear 43.1% of total deaths due to PAH with the highest crude rate (0.09) and Northeast shows the lowest deaths (12.3%) with lowest crude rate (0.06).

4. Discussion

This population-based analysis of CDC WONDER data from 2018 to 2024 demonstrates a sustained decline in primary pulmonary hypertension mortality in the United States, with annual deaths decreasing by 42.2% and the AAMR declining by approximately 40% over seven years. This represents the steepest decline in PAH-specific mortality documented in any U.S. surveillance study. Prior analyses by Singh et al. reported only a 1.1% decrease annual decline for Group 1 PH from 2003 to 2020, while Kang et al. found that overall PH mortality increased by 1.9% per year from 1999 to 2019 [12,13]. The estimated 9.3% CAGR observed in the present study suggests a marked acceleration of mortality improvement in the most recent period. Direct comparison with the Joinpoint-derived AAPCs reported by Singh et al. is limited by methodological differences; however, the magnitude of the observed decline suggests an acceleration of mortality improvement in the most recent period. The magnitude of the observed decline suggests an acceleration of mortality improvement in the most recent period [12].

The study period likely captures the effect of increased adoption of combination therapy following the successful 2015 AMBITION trial, which demonstrated a 50% reduction in clinical failure events with initial ambrisentan plus tadalafil compared with monotherapy. Before the trial, data from the COMPERA registry showed that early combination therapy use was only 10% in 2010, which improved 25% in 2019 [14]. Finally, the 2022 ESC/ERS guidelines subsequently issued a Class I recommendation for initial ERA plus PDE5i combination therapy in low- and intermediate-risk patients. The increased use of combination therapy is gradual, however, and hence cannot solely account for the steep improvement in our study [2].

The female predominance (69.5% of deaths; AAMR ratio 2:1) is consistent with prior registry data. The GBD 2021 analysis found that 62% of prevalent PAH cases worldwide were female, and the REVEAL registry similarly demonstrated a female majority across all racial and ethnic groups [10,15]. The present study’s finding of a 2:1 female-to-male mortality rate ratio reflects the higher incidence in women. The CDC WONDER framework does not permit adjustment for disease severity, treatment received, or comorbidities, and therefore cannot distinguish between incidence-driven and prognosis-driven contributions to the observed sex disparity. The biological basis for the female predominance in PAH is increasingly attributed to estrogen and its metabolites. Estrogen increases NADPH oxidase (Nox)-derived reactive oxygen species, leading to proliferation in human pulmonary artery smooth muscle cells [16]. Conversely, estrogen appears to confer right ventricular protection, while women are more susceptible to developing PAH (female-to-male ratio up to 4:1), female patients consistently demonstrate better RV function and improved survival compared with male counterparts [17].

Racial disparities were evident across both crude and age-adjusted metrics. Black individuals had the highest crude mortality rate (0.11 per 100,000) and the highest AAMR (0.10 per 100,000) despite comprising only 12.1% of total deaths, compared with White individuals who accounted for 83.4% of deaths with a crude rate of 0.10 and an AAMR of 0.06 per 100,000. The Black-to-White AAMR ratio of approximately 1.67:1 indicates a disproportionate per-capita mortality burden among Black individuals. Notably, while the crude rates were similar between Black and White populations (0.11 vs. 0.10), age adjustment widened the gap substantially (0.10 vs. 0.06), suggesting that the younger age distribution of the Black population partially masks the true disparity in crude comparisons. These findings are consistent with Kang et al., who reported persistently higher age-adjusted PH mortality rates among non-Hispanic Black individuals from 1999 to 2019 [13].

Multiple lines of evidence suggest that these racial disparities are driven primarily by differential access to care rather than intrinsic biological differences. Parikh et al. demonstrated that adjustment for insurance status attenuated the racial survival difference from HR 2.06 (95% CI, 1.18–3.44) to HR 1.74 (95% CI, 0.84–3.32) [9]. More recently, Melendres-Groves et al. found that Black patients younger than 65 years were 36% less likely to receive index combination therapy (OR, 0.64; 95% CI, 0.41–0.99) and 46% less likely to adhere to index treatment (OR, 0.54; 95% CI, 0.33–0.90) [18]. These treatment access disparities provide a plausible mechanism for the persistent mortality gap observed in the present study.

The present study found that the South had the highest crude rate (0.09 per 100,000) while the Northeast had the lowest (0.06 per 100,000). These geographic patterns likely reflect multiple factors, including the concentration of uninsured and underinsured populations in the South and fewer specialty centers per capita. Leary et al. (2025) found that only 37.1% of U.S. patients received PAH-specific prescriptions from a PH center, and resided in the South, or lived in a ZIP code without a PH center [19]. The American Thoracic Society has formally recognized these disparities, calling for systematic investigation of health disparities in PAH and targeted interventions to improve access for vulnerable populations [20].

The recent therapeutic development of sotatercept, a first-in-class activin signaling inhibitor approved by the FDA in March 2024, is for the treatment of adults with PAH, had a tail end effect during the study [21]. Unlike existing vasodilator-based therapies, sotatercept targets the underlying proliferative vascular remodeling by restoring the balance between growth-promoting and growth-inhibiting signaling pathways. The STELLAR trial (2023) demonstrated an 84% reduction in death or clinical worsening events (HR, 0.16; 95% CI, 0.08–0.35). [21] The ZENITH trial (2025) extended these findings to high-risk patients, showing a 76% reduction in the composite of death, lung transplantation, or hospitalization (HR, 0.24; 95% CI, 0.13–0.43; P 0.001), with deaths occurring in 8.1% versus 15.1% with placebo [22]. The HYPERION trial (2025) demonstrated a 76% reduction in clinical worsening in newly diagnosed patients within the first year after diagnosis (HR, 0.24; 95% CI, 0.14–0.41; P 0.001), with a number needed to treat of 5 at 12 months [23]. The steepest single-year mortality decline occurred between 2022 and 2023 (−18.0%). While sotatercept was available through clinical trials during this period, enrollment was limited, and FDA approval did not occur until March 2024. Therefore, a direct causal link between sotatercept access and the 2022–2023 mortality decline cannot be established from these data. Furthermore, in March 2024, the FDA approved Opsynvi (macitentan/tadalafil), the first fixed-dose combination (FDC) single-tablet therapy for PAH (WHO Group I, functional class II–III). The approval was supported by the A DUE trial, which demonstrated that the macitentan/tadalafil FDC achieved significantly greater PVR reduction compared with macitentan monotherapy (29%; geometric mean ratio 0.71; 95% CL: 0.61–0.82; P < 0.0001) and tadalafil monotherapy (28%; geometric mean ratio 0.72; 95% CL: 0.64–0.80; P < 0.0001), with a safety profile consistent with the individual components. By simplifying the treatment regimen to a single daily tablet, the FDC may improve adherence. Effect of this new simplified regimen would require future analysis [24].

Several limitations should be acknowledged. First, CDC WONDER data rely on death certificate coding, and the ICD-10 code I27.0 captures only primary pulmonary hypertension. PAH deaths coded under associated conditions (e.g., connective tissue disease, congenital heart disease) would not be captured, potentially underestimating the true PAH mortality burden. The GBD 2021 analysis noted that the introduction of ICD-10 code I27.2 for other types of pulmonary hypertension may have affected coding patterns for I27.0, with non-PAH types of pulmonary hypertension previously erroneously coded to I27.0 [10]. Second, this study cannot establish causation between therapeutic advances and mortality trends. Third, the study cannot account for individual-level confounders such as disease severity, treatment received, insurance status, or comorbidities. Fourth, heavy cell suppression (10 deaths) limited analysis for American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and Asian subgroups. Fifth, the CDC WONDER output rounds rates to one decimal place, which may obscure granular differences in a rare disease with low absolute rates. Lastly, the estimated CAGR was calculated from aggregate rate ratios rather than from formal Joinpoint regression, which is the standard method for trend analysis in mortality surveillance studies; future analyses should validate this estimate using the NCI Joinpoint Regression Program.

5. Conclusions

Primary pulmonary hypertension mortality in the United States declined substantially from 2018 to 2024, with an estimated average annual percent change of −9.3%, a markedly steeper decline than reported in prior surveillance studies. This decline coincides temporally with the adoption of upfront combination therapy and the introduction of sotatercept, the first novel-mechanism PAH therapy in over a decade. However, persistent disparities by sex, race, and geography indicate that therapeutic advances may not be reaching all populations equitably. Black individuals bear a disproportionate per-capita mortality burden, and the South concentrates the largest share of deaths. Future studies should examine whether the introduction of sotatercept and other emerging therapies narrows or widens these demographic disparities.