Abstract
BACKGROUND:
Current evidence supports risk-based treatment for pulmonary arterial hypertension (PAH) with an endothelin receptor antagonist and phosphodiesterase type 5 inhibitor as initial therapy for patients with low- and intermediate-risk PAH, and triple therapy with the addition of a parenteral prostacyclin for patients with high-risk PAH.
RESEARCH QUESTION:
What are the current treatment patterns for patients with newly diagnosed PAH in the Pulmonary Hypertension Association Registry (PHAR)?
STUDY DESIGN AND METHODS:
This analysis was performed in a prospectively collected cohort of patients with incident PAH diagnosed by right heart catheterization and enrolled in the PHAR between September 30, 2015, and February 14, 2024. The primary objective was to assess the guideline-recommended risk-based treatment approaches and their impact in the real world. All-cause mortality was compared across risk groups and between patients receiving monotherapy, dual therapy, and triple therapy for PAH across risk strata.
RESULTS:
There were 1,019 patients with incident PAH in the PHAR who received either initial monotherapy (n = 344, 33.8%), dual therapy (n = 557, 54.7%), or triple therapy (n = 118, 11.6%). Of 323 patients with complete data for risk classification who received initial monotherapy, 25.1% were low risk, 31.3% were intermediate risk, and 43.7% were high risk by Registry to Evaluate Early and Long-term PAH Disease Management Lite 2 risk score. For the 540 patients treated with initial dual therapy, 35.7% were low risk, 26.5% were intermediate risk, and 37.8% were high risk. Finally, among the 113 patients who received initial triple therapy, 31.9% were low risk, 28.3% were intermediate risk, and 39.8% were high risk. All-cause mortality was lowest for patients with low-risk PAH at baseline and highest for those with high-risk PAH at baseline across the entire cohort and for patients treated with initial monotherapy, dual therapy, or triple therapy.
INTERPRETATION:
This analysis highlights the underutilization of PAH therapies for patients with newly diagnosed PAH in this real-world patient population.
Keywords: mortality, pulmonary hypertension, REVEAL risk score, risk stratification, survival, treatment
Pulmonary arterial hypertension (PAH) is associated with elevated pulmonary vascular resistance, which often leads to right ventricular failure and death.1,2 Current expert recommendations and guidelines advise that initial therapy for newly diagnosed PAH should be based on risk stratification using a validated risk calculator such as the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) Lite 2 risk score at baseline, with the goal of achieving low-risk status on subsequent risk assessment.3–5 Initial dual combination therapy with a phosphodiesterase type 5 (PDE5) inhibitor and an endothelin receptor antagonist (ERA) is recommended for patients at low or intermediate risk, whereas initial triple combination therapy with the addition of a parenteral prostacyclin is recommended for patients at high risk.3–5
The Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial laid the foundation for the use of upfront dual combination with an ERA and a PDE5 inhibitor by demonstrating that initial dual combination therapy was associated with a 50% reduction in the risk for clinical failure (defined as events of death, PAH-related hospitalization, disease progression, or poor long-term clinical response) for patients with PAH compared with monotherapy with either a PDE5 inhibitor or an ERA.6 To date, only 1 randomized controlled trial has investigated upfront triple combination therapy with a PDE5 inhibitor, an ERA, and an oral prostacyclin, but it failed to meet the primary clinical end point of improvement in pulmonary vascular resistance compared with patients treated with a PDE5 inhibitor, ERA, and placebo combination.7 The strongest evidence to support initial triple combination therapy for patients with high-risk PAH was reported in a retrospective cohort study of patients in the French Pulmonary Hypertension Registry. It showed that patients with high-risk PAH treated with a triple combination therapy that included a parenteral prostacyclin had higher survival rates than those who received monotherapy or dual therapy.8
Despite these data and guidelines, real-world data from PAH registries have shown suboptimal treatment patterns. The Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European registry, reported that 80% of patients entering the registry between 2010 and 2019 were initiated on monotherapy; this fell to 75% in those diagnosed during 2019.9 A similar analysis from the French Pulmonary Hypertension Registry between 2006 and 2018 showed that 61% of patients were initiated on monotherapy at the time of diagnosis.8 Furthermore, the Swedish Pulmonary Arterial Hypertension Register found that 84% of patients newly diagnosed between 2008 and 2014 were initiated on monotherapy.10 Assessment of a US medical and pharmacy claims database, which represents a general PAH population rather than patients from expert centers, demonstrated similar results, with 78% of newly diagnosed patients initiating monotherapy.11
Previous reports have suggested physicians rarely use objective and validated assessments to determine PAH risks, relying instead on gestalt to make treatment decisions.12,13 Despite the availability of clear guideline-directed management and treatment strategies, long-term survival for patients with PAH in clinical practice remains poor14,15; therefore, early treatment based on guideline-directed recommendations may improve patient survival.
The objective of this analysis was to assess whether real-world treatment patterns align with guideline-directed treatment of incident PAH in a contemporary prospective PAH registry. We also explored the relationship of treatment patterns to survival as a hypothesis-generating assessment. Current guidelines recommend prompt referral to a pulmonary hypertension (PH) expert center for patients with suspected PAH.3 The Pulmonary Hypertension Association Registry (PHAR) collects data from expert care centers,16,17 and thereby offers valuable insights into real-world treatment patterns.
Study Design and Methods
The PHAR is a US-based, prospective, multicenter registry of adult and pediatric patients with PAH or chronic thromboembolic pulmonary hypertension (CTEPH) enrolled from participating PH care centers within 6 months of diagnosis;18 there are currently > 80 participating centers in the registry. Institutional review board approval was received for PHAR-related activities by the University of Pennsylvania institutional review board (No. FWA00004028), and informed consent was obtained from each patient before enrollment. Enrollment criteria have been previously described.18 Data are collected as part of patients’ routine clinical evaluation, with electronic case report forms completed for each baseline and follow-up visit (1 by the patient and 1 by the staff) and are entered in a deidentified manner by participating centers in a central database. Baseline demographic and clinical characteristics are recorded in the PHAR from the time of the initial right heart catheterization at enrollment and have been described elsewhere.15,18
This analysis included adult patients, ≥ 18 years of age, with incident PAH who were enrolled in the PHAR between September 30, 2015, and February 14, 2024. PAH was considered incident if the patient had been diagnosed with PAH for < 6 months and had not been treated with PH-specific medications for > 6 months before their first PH care center visit. Otherwise, they were considered as having prevalent PAH and were excluded. Patients with CTEPH or with no PH-specific medication recorded within 6 months of entering the registry were also excluded. The primary objective of this analysis was to compare initial PAH therapies by REVEAL Lite 2 risk categories. Medications were grouped by mechanism of action: nitric oxide (NO) pathway drug (PDE5 inhibitor or soluble guanylate cyclase [sGC]), ERA, or prostacyclin pathway agent (PPA). Sotatercept was not included in this study because it became commercially available after the enrollment period. The initial treatment strategy was defined as monotherapy (any single PH-specific therapy), dual therapy (any combination of 2 medications from unique medication classes), or triple therapy (any combination of 3 medications from unique medication classes). REVEAL Lite 2 risk category for baseline visits was determined based on the clinical data reported at the time of a patient’s first diagnostic right heart catheterization at an accredited PHAR center18,19; risk category for follow-up visits was determined using data from the day of the follow-up.
Secondary outcomes for this study included changes in REVEAL Lite 2 risk category from initial assessment to first follow-up, changes in practice patterns over 2 epochs (2015–2019 and 2020–2024), and all-cause mortality. First follow-up was defined as the first visit recorded in the PHAR. Sankey plots were used to qualitatively compare the movement of patients between risk groups from initial assessment to follow-up assessment. All-cause mortality was collected as per the PHAR protocol and was reported by the respective enrolling sites. Kaplan-Meier curves with log-rank tests were used to compare mortality between REVEAL Lite 2 risk groups for the combined patient cohort and for the those who received monotherapy, dual therapy, or triple therapy. Because this study was not designed to detect differences in mortality, the mortality analysis was hypothesis-generating. Baseline characteristics were summarized descriptively; the study was not powered to detect differences in outcomes between patient subgroups.
Analyses were performed using a patched R version 4.4.1 (Patched [2024-06-20 r86796 ucrt], R Foundation), which rectified issues with R Studio’s HTML viewer. Changes in REVEAL Lite 2 risk category from baseline were analyzed descriptively using Sankey diagrams to illustrate differences between initial treatment strategy groups. REVEAL Lite 2 data were classified as missing when at least 4 of the 6 REVEAL Lite 2 variables were not recorded, of which at least 2 were among the major prognostic variables (World Health Organization functional class [WHO FC], 6-minute walk distance, and B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide).19 Patients with these missing data or no follow-up visit were not included in the Sankey diagrams.
Results
Patient Baseline Characteristics and Treatments
At the time of this analysis, 2,877 patients with PAH or CTEPH were enrolled in the PHAR: 1,441 with incident disease, 1,404 with prevalent disease, and 32 with insufficient information to determine whether they had incident or prevalent disease (Fig 1). Of the 1,441 patients with incident PAH diagnoses eligible for the present analysis, 420 were excluded because they were < 18 years of age, had CTEPH, or did not receive PH-specific medications within 6 months of entering the registry (Fig 1). Sensitivity analyses for the 191 patients who were excluded for not receiving PH medications within 6 months of diagnosis showed no substantial differences compared with individuals included in the study regarding demographics, clinical characteristics, hemodynamics, and other baseline clinical testing (e-Tables 1, 2). A total of 1,021 patients were included in the final study population, of whom 769 (75.3%) were female and 794 (77.8%) identified as White (Table 1). Two patients who were classified as taking ≥ 4 drugs (due to switching between medications within a drug class [eg, ambrisentan to bosentan], recorded as receiving an additional drug) were excluded from further analyses by therapy strategy, leaving 1,019 patients in total. Idiopathic and connective tissue disease were the 2 leading PAH etiologies (43.1% and 30.2%, respectively). At the time of registry inclusion (ie, within 6 months of PAH diagnosis), the mean 6-minute walk distance ± SD was 328.5 ± 121.3 m, mean B-type natriuretic peptide ± SD was 288.6 ± 474.2 ng/L, and mean N-terminal pro B-type natriuretic peptide ± SD was 1,662.8 ± 4,616.7 ng/L (Table 2).
Figure 1 –
Flow diagram of the study design. CTEPH = chronic thromboembolic pulmonary hypertension; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; PHAR = Pulmonary Hypertension Association Registry.
TABLE 1 ].
Patient Demographic Characteristics Categorized Based on the Initial Therapy Selection
| Characteristic | Overall (N = 1,021a) | Monotherapy (n = 344) | Dual Therapy (n = 557) | Triple Therapy (n = 118) |
|---|---|---|---|---|
| Age | ||||
| Mean [SD], y | 55.0 [16.1] | 59.1 [14.9] | 54.1 [16.1] | 47.2 [15.8] |
| Sex | ||||
| Male | 252 (24.7) | 84 (24.4) | 153 (27.5) | 15 (12.7) |
| Female | 769 (75.3) | 260 (75.6) | 404 (72.5) | 103 (87.3) |
| Race | ||||
| Asian | 33 (3.2) | 12 (3.5) | 15 (2.7) | 6 (5.1) |
| Black | 114 (11.2) | 35 (10.2) | 67 (12.0) | 11 (9.3) |
| White | 794 (77.8) | 273 (79.4) | 425 (76.3) | 95 (80.5) |
| Otherb | 33 (3.2) | 11 (3.2) | 19 (3.4) | 3 (2.5) |
| Missing/unknown | 47 (4.6) | 13 (3.8) | 31 (5.6) | 3 (2.5) |
| Ethnicity | ||||
| Hispanic | 89 (8.7) | 26 (7.6) | 46 (8.3) | 17 (14.4) |
| Non-Hispanic | 892 (87.4) | 304 (88.4) | 494 (88.7) | 93 (78.8) |
| Missing/unknown | 40 (3.9) | 14 (4.1) | 17 (3.1) | 8 (6.8) |
| PAH diagnosis | ||||
| Idiopathic | 440 (43.1) | 137 (39.8) | 251 (45.1) | 51 (43.2) |
| Heritable | 34 (3.3) | 6 (1.7) | 20 (3.6) | 8 (6.8) |
| Drug-/toxin-induced | 116 (11.4) | 45 (13.1) | 59 (10.6) | 12 (10.2) |
| Connective tissue disease | 308 (30.2) | 109 (31.7) | 164 (29.4) | 34 (28.8) |
| HIV-related | 15 (1.2) | 5 (1.5) | 7 (1.3) | 3 (2.5) |
| Portopulmonary | 64 (6.3) | 30 (8.7) | 30 (5.4) | 4 (3.4) |
| Congenital heart disease | 38 (3.7) | 10 (2.9) | 23 (4.1) | 5 (4.2) |
| PVOD | 4 (0.4) | 2 (0.6) | 1 (0.2) | 1 (0.9) |
| Unknown/missing | 2 (0.2) | 0 (0.0) | 2 (0.4) | 0 (0.0) |
| BMI, kg/m2 | ||||
| Mean [SD] | 30.1 [7.9] | 30.0 [7.4] | 30.0 [7.8] | 30.9 [9.3] |
| Missing | 13 (1.3) | 3 (0.9) | 7 (1.3) | 3 (2.5) |
Data are presented as No. (%) or as otherwise indicated. PAH = pulmonary arterial hypertension; PVOD = pulmonary veno-occlusive disease.
Two patients received ≥ 4 drugs, representing a switch within a class (eg, ambrisentan to bosentan).
Other indicates multiracial or race not otherwise specified.
TABLE 2 ].
Patient Hemodynamics and Other Key Variables at Baseline Categorized by the Initial Therapy Selection
| Variable | Overall (N = 1,021a) | Monotherapy (n = 344) | Dual Therapy (n = 557) | Triple Therapy (n = 118) |
|---|---|---|---|---|
| RAP, mm Hg | ||||
| Mean [SD] | 10.0 [6.7] | 8.9 [5.7] | 10.4 [7.3] | 10.9 [6.5] |
| Missing | 24 (2.4) | 11 (3.2) | 10 (1.8) | 3 (2.5) |
| mPAP, mm Hg | ||||
| Mean [SD] | 49.1 [13.3] | 44.7 [13.4] | 50.0 [12.3] | 57.4 [12.9] |
| Missing | 10 (1.0) | 3 (0.9) | 6 (1.1) | 1 (0.9) |
| PCWP, mm Hg | ||||
| Mean [SD] | 10.7 [5.6] | 10.7 [5.6] | 10.5 [4.7] | 12.2 [8.9] |
| Missing | 36 (3.5) | 9 (2.6) | 23 (4.1) | 4 (3.4) |
| CO, L/min | ||||
| Mean [SD] | 4.2 [1.4] | 4.5 [1.5] | 4.1 [1.3] | 3.8 [1.5] |
| Missing | 47 (4.6) | 17 (4.9) | 27 (4.9) | 3 (2.5) |
| CI, L/min/m2 | ||||
| Mean [SD] | 2.2 [0.7] | 2.4 [0.7] | 2.2 [0.7] | 2.0 [0.7] |
| Missing | 56 (5.5) | 23 (6.7) | 28 (5.0) | 5 (4.2) |
| PVR, Wood units | ||||
| Mean [SD] | 10.4 [5.6] | 8.5 [4.9] | 11.0 [5.7] | 13.3 [5.7] |
| Missing | 79 (7.7) | 26 (7.6) | 45 (8.1) | 8 (6.8) |
| 6-minute walk distance, m | ||||
| Mean [SD] | 328.5 [121.3] | 310.9 [118.2] | 342.7 [122.5] | 314.6 [117.0] |
| Missing | 188 (18.4) | 62 (18.0) | 104 (18.7) | 21 (17.8) |
| BNP or NT-proBNP | ||||
| No | 59 (5.8) | 27 (7.9) | 26 (4.7) | 6 (5.1) |
| Yes | 858 (84.0) | 280 (81.4) | 481 (86.4) | 95 (80.5) |
| BNP, ng/L | ||||
| BNP, mean [SD] | 288.6 [474.2] | 333.6 [542.4] | 248.4 [318.4] | 335.3 [745.6] |
| log(BNP), mean [SD] | 4.9 [1.3] | 5.0 [1.4] | 4.8 [1.3] | 5.0 [1.3] |
| Missing | 456 (44.7) | 144 (41.9) | 261 (46.9) | 50 (42.4) |
| NT-proBNP, ng/L | ||||
| NT-proBNP, mean [SD] | 1,662.8 [4,616.7] | 1,627.8 [3,042.5] | 1,741.0 [5,622.9] | 1,303.3 [1,940.7] |
| log(NT-proBNP), mean [SD] | 6.3 [1.5] | 6.4 [1.5] | 6.3 [1.4] | 6.1 [1.6] |
| Missing | 520 (50.9) | 190 (55.2) | 272 (48.8) | 57 (48.3) |
| Creatinine, mg/dL | ||||
| Mean [SD] | 1.0 [0.5] | 1.0 [0.4] | 1.0 [0.5] | 0.9 [0.3] |
| Missing | 24 (2.4) | 8 (2.3) | 13 (2.3%) | 3 (2.5) |
| eGFR, mL/min/1.73 m2 | ||||
| Mean [SD] | 79.6 [26.4] | 75.6 [25.2] | 80.5 [26.8] | 87.1 [26.0] |
| Missing | 24 (2.4) | 8 (2.3) | 13 (2.3) | 3 (2.5) |
Descriptive statistics were calculated without imputing missing data. Data are presented as No. (%) or as otherwise indicated. BNP = B-type natriuretic peptide; CI = cardiac index; CO = cardiac output; eGFR = estimated glomerular filtration rate; mPAP = mean pulmonary arterial pressure; NT-proBNP = N-terminal pro B-type natriuretic peptide; PCWP = pulmonary capillary wedge pressure; PVR = pulmonary vascular resistance; RAP = right arterial pressure.
Two patients received ≥ 4 drugs, representing a switch within a class (eg, ambrisentan to bosentan).
For initial PAH therapy, 344 patients (33.8%) received monotherapy, 557 (54.7%) received dual therapy, and 118 (11.6%) received triple therapy (Fig 2). Patients receiving monotherapy were older than those receiving dual or triple therapy (mean age, 59.1, 54.1, and 47.2 years, respectively) (Table 1). Of patients on monotherapy, 238 (69.2%) received an NO pathway drug (PDE5 inhibitor or sGC), 53 (15.4%) received a parenteral PPA, 50 (14.5%) received an ERA, and 3 (0.9%) received a nonparenteral PPA (Table 3). Among those on dual therapy, 536 (96.2%) received an NO pathway drug (PDE5 inhibitor or sGC) and 397 (71.3%) received an ERA (Table 3). Triple therapy consisted of NO pathway agent (n = 117, 99.2%), ERA (n = 117, 99.2%), and PPA (parenteral: n = 80, 67.8%; nonparenteral: n = 36, 30.5%) combination. Comparing initial prescribing patterns over time, more patients in the first study epoch (2015–2019) received monotherapy than those in the second epoch (2020–2024) (35% vs 30%, P = .02), whereas the proportion of patients who received triple combination therapy went up over time (21% vs 14%, P < .01) (e-Table 3). The proportion of patients who received dual combination therapy remained constant over time (50% vs 49%, P = .47).
Figure 2 –
Treatment patterns at baseline. The analysis included 1,019 patients. Percentages may not add up to 100% due to rounding.
TABLE 3 ].
Pulmonary Arterial Hypertension-Specific Therapy Class at Baseline
| Variable | Monotherapy (n = 344) | Dual Therapya (n = 557) | Triple Therapya (n = 118) |
|---|---|---|---|
| ERA | 50 (14.5) | 397 (71.3) | 117 (99.2) |
| NO pathway agent (PDE5 inhibitor or sGC) | 238 (69.2) | 536 (96.2) | 117 (99.2) |
| Parenteral PPA | 53 (15.4) | 136 (24.4) | 80 (67.8) |
| Nonparenteral PPA | 3 (0.9) | 44 (7.9) | 36 (30.5) |
Data are presented as No. (%). ERA = endothelin receptor antagonist; NO = nitric oxide; PDE5 = phosphodiesterase type 5; PPA = prostacyclin pathway agent; sGC = soluble guanylate cyclase.
Patients receiving dual or triple therapy may have received > 1 agent in a therapy class.
Baseline data on WHO FC were available for 966 patients: 59 (6.1%) were WHO FC I, 359 (37.2%) were WHO FC II, 492 (50.9%) were WHO FC III, and 56 (5.8%) were WHO FC IV (Fig 3). Of the 59 patients who were WHO FC I, 15 (25.4%) received initial monotherapy, 40 (67.8%) received dual therapy, and 4 (6.8%) received triple therapy (Fig 3). Of the 359 patients who were WHO FC II, 108 (30.1%), 207 (57.7%), and 44 (12.3%) received monotherapy, dual therapy, and triple therapy, respectively. Similarly, the distribution of monotherapy, dual therapy, and triple therapy for those who were WHO FC III was 170 (34.6%), 268 (54.5%), and 54 (11.0%), respectively (Fig 3). Finally, for the patients who were WHO FC IV, 24 (42.9%) received initial monotherapy, 21 (37.5%) received dual therapy, and 11 (19.6%) received triple therapy (Fig 3).
Figure 3 –
WHO functional class at baseline according to therapy. Data were available for 966 of 1,019 patients (data were missing for 53 patients); the n values shown exclude patients with missing data. Percentages were calculated based on a denominator excluding missing data. Percentages may not add up to 100% due to rounding. WHO = World Health Organization.
PAH Risk: Baseline to Follow-Up
Baseline data on REVEAL Lite 2 risk status were available for 976 patients. Of these, 310 (31.8%) had low-risk PAH, 276 (28.3%) had intermediate-risk PAH, and 390 (40.0%) had high-risk PAH (Fig 4A). In the low-risk category, 193 patients (62.3%) received dual therapy at baseline, whereas 81 (26.1%) received monotherapy. There was a similar distribution of therapy type at baseline among patients with intermediate-risk and high-risk status: 143 (51.8%) and 204 (52.3%), respectively, received dual therapy and 101 (36.6%) and 141 (36.2%), respectively, received monotherapy (Fig 4A).
Figure 4 –
A, B, Distribution of patients at baseline. A, Patients classified by REVEAL Lite 2 scores as low, intermediate, or high risk and stratified by therapy. B, Patients receiving monotherapy, dual therapy, or triple therapy and stratified by REVEAL Lite 2 categories. Data for REVEAL Lite 2 risk score were available for 976 of 1,019 patients (data were missing for 43 patients); the n values shown exclude patients with missing data. Percentages were calculated based on a denominator excluding missing data. Percentages may not add up to 100% due to rounding. REVEAL = Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management.
When considering the distribution of REVEAL Lite 2 risk scores by therapy type (data were available for 976 patients), of 323 patients receiving monotherapy, 81 (25.1%) had low-risk PAH, 101 (31.3%) had intermediate-risk PAH, and 141 (43.7%) had high-risk PAH (Fig 4B). Of patients receiving dual (n = 540) or triple therapy (n = 113), 193 (35.7%) and 36 (31.9%), respectively, were low risk; 143 (26.5%) and 32 (28.3%), respectively, were intermediate risk; and 204 (37.8%) and 45 (39.8%), respectively, were high risk (Fig 4B).
Change in REVEAL Lite 2 risk category at first follow-up was evaluated in 725 patients (those with missing data for REVEAL Lite 2 reassessment or no follow-up visit were not included). At first follow-up (approximately 6 months), a higher proportion of patients receiving dual or triple therapy were low-risk status (203 [50.9%] patients and 39 [49.4%] patients, respectively) compared with those receiving monotherapy (95 patients [38.5%]) (Fig 5). Among patients who were high risk at baseline, 43 (38.7%) receiving monotherapy improved to intermediate risk or low risk at follow-up; this was the same for 87 patients (52.4%) receiving dual therapy and 12 (37.5%) receiving triple therapy (Fig 5). For patients with intermediate-risk PAH at baseline, 34 (43.0%), 48 (47.5%), and 13 (56.5%) receiving monotherapy, dual therapy, and triple therapy, respectively, improved to low-risk status; 19 (24.1%), 13 (12.9%), and 1 (4.3%), respectively, worsened to high-risk status (Fig 5). Among those who were low risk at baseline, 9 (15.8%), 20 (15.2%), and 3 (12.5%) receiving monotherapy, dual therapy, and triple therapy, respectively, worsened to intermediate or high risk (Fig 5).
Figure 5 –
A-C, Changes in REVEAL Lite 2 risk category by initial treatment strategy: (A) monotherapy, (B) dual therapy, and (C) triple therapy. Patients with missing REVEAL Lite 2 risk data or no follow-up visit were excluded. Percentages may not add up to 100% due to rounding. BL = baseline; FU = follow-up; REVEAL = Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management.
All-Cause Mortality
After 8 years of follow-up, all-cause mortality was lowest in patients with low-risk REVEAL Lite 2 scores and highest in those with high-risk scores (P < .0001) (Fig 6). The difference in mortality between risk groups was statistically significant among patients receiving monotherapy (P = .024) (Fig 7A) and those receiving dual therapy (P < .0001) (Fig 7B), but not among those receiving triple therapy (P = .071) (Fig 7C).
Figure 6 –
A, B, All-cause mortality overall (A) and by REVEAL Lite 2 risk category (B). REVEAL = Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management.
Figure 7 –
A-C, All-cause mortality by initial therapy and REVEAL Lite 2 risk category. A, Patients receiving monotherapy at baseline, (B) patients receiving dual therapy at baseline, and (C) patients receiving triple therapy at baseline. REVEAL = Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management.
Discussion
In this analysis of real-world prospective registry data from the PHAR, we found significant deviations in current prescribing practices from the evidence-based standards for treating PAH. We expected that most patients with newly diagnosed low- or intermediate-risk PAH by REVEAL Lite 2 risk score would receive initial dual therapy. Although this was true for approximately one-half of the patients in those risk groups, one-quarter of the low-risk patients and one-third of the intermediate-risk patients were undertreated, receiving only monotherapy. Furthermore, we thought patients with high-risk PAH would receive triple therapy, but this was the case for only 12% of these patients. In fact, the proportion of patients receiving triple therapy was similar across all 3 risk groups. Overall, 12% of patients with low- and intermediate-risk PAH were overtreated with triple therapy, which is inconsistent with recommendations. Furthermore, these results show that there are a number of patients with PAH (26% of low-risk status, 37% of intermediate-risk status, and 88% of high-risk status) who are not optimally treated based on current treatment guideline recommendations.3 Regarding treatment strategy and clinical outcomes, a higher proportion of patients in the total cohort who received initial dual or triple therapy had low-risk REVEAL Lite 2 status after 6 months, compared with those who received initial monotherapy. Furthermore, patients classified as high risk at baseline were more likely to improve their risk status if they received dual therapy compared with monotherapy. When we evaluated all-cause mortality, survival correlated with risk group: patients with low-risk PAH had lower all-cause mortality than those with intermediate- and high-risk PAH, across the entire cohort and among those receiving monotherapy or dual therapy. We did not see the same differences among patients receiving triple therapy, likely due to the small numbers of patients receiving triple therapy across all risk groups, rather than an actual treatment effect of one treatment strategy or another. Nevertheless, our study shows an underutilization of therapy in high-risk patients, which may lead to worsening of risk status and poor outcomes, as supported by previous studies.19,20
Comparing our findings with previous studies, the proportions of patients in our study receiving monotherapy (33.8%), dual therapy (54.7%), or triple PAH therapy (11.6%) are similar to those reported in Chang et al 15 from their 2022 analysis of the PHAR (30%, 43%, and 13% on monotherapy, dual therapy, and triple therapy, respectively, with 14% receiving no therapy). However, when comparing our findings with those from European registries, the percentage of patients in the PHAR who received initial monotherapy is much lower. The pan-European Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) study and the French Pulmonary Hypertension Registry found that 80% and 61% of patients with PAH, respectively, were initiated on monotherapy.8,9 These differences likely reflect the changes in the evidence and standards for treating patients over the past 2 decades. COMPERA enrolled patients in 2010 to 2018 and the French Pulmonary Hypertension Registry in 2006 to 2018, whereas the practice-changing AMBITION trial was published in 201521,22 and the European Society of Cardiology and European Respiratory Society guidelines for diagnosing and treating PAH were updated in the same year.6 Indeed, US-based claims data from similar time periods report that 91% to 95% of patients with PAH were prescribed monotherapy between 2010 and 2017.23–25
A more contemporary US claims-based study looking at practice patterns for treating PAH in 2021 and 2022 reported differences in the proportions of patients receiving monotherapy, dual therapy, and triple therapy depending on whether medications were prescribed at PHA-accredited centers or high-volume centers vs nonaccredited, non-high-volume institutions.26 Of the patients seen at PHA-accredited centers, 72% received monotherapy, 21% received dual therapy, and 8% received triple therapy26; these numbers are very different to those observed in this study’s overall cohort. Although there are differences in the time periods for data collection, these contrasting results seem to indicate that there may be important differences between the overall population of patients treated at PHA centers and the patients who consent to enroll in the PHAR.
Survival of patients with PAH varying depending on disease severity is consistent with prior reports.19,20 However, we did not see the differences in survival by treatment strategy that have been reported by some authors. In the Chang et al15 study of treatment-naive patients with PAH enrolled in the PHAR between 2015 and 2020, those with PAH receiving any combination therapy (ie, dual, triple) had better survival than those on monotherapy at 2 year, but not at 2 or 3 years. A study of the French Pulmonary Hypertension Registry found that high-risk patients with PAH who received initial triple therapy, particularly regimens including a parenteral prostanoid, had improved survival vs those who received dual therapy or monotherapy.8 For patients at intermediate risk, better survival was also associated with more intensive therapies.8 Some of the differences between our findings and the results of these 2 studies may be explained, in part, by the differing methodologies. The prior PHAR study analyzed patients receiving dual or triple therapy as 1 combined group, whereas we analyzed patients receiving either dual or triple therapy as 2 unique groups. The French Pulmonary Hypertension Registry study used propensity score matching to correct for confounding factors between different treatment strategies, which we were unable to do within the scope of our study design.
There are some limitations to this study. First, there is some difficulty in defining the incident PAH population in the PHAR because patients may have been diagnosed with PAH in the community before being referred to a PHA care center. As such, it is possible that before their initial visit recorded in the PHAR, patients may have already been initiated on therapy with adjustments made—either intensification or reduction—based on their response to a therapy or adverse effects. Second, due to the periodic reporting of data to the PHAR by individual study sites, medication initiation and stop dates were inferred based on the timing of data entry and mortality data may be affected by patients lost to follow-up. We could not validate these reports at an individual level because of the anonymity of the data used in this study. Third, comorbid conditions are not captured in the PHAR; therefore, we were unable to analyze why physicians may have deviated from the evidence-based standards of care for their patients. Finally, there was a reduction in enrollment due to the COVID-19 pandemic; therefore, data from the cohort in this study may not fully reflect more recent trends in prescribing and patient survival.
In conclusion, we have reported that a number of patients with newly diagnosed PAH in the PHAR are undertreated compared with the current evidence-based standards of care. Patients with low-, intermediate-, and high-risk PAH had significant differences in survival and these were not affected by treatment strategy.
Interpretation
This analysis provides insights into current treatment patterns at expert centers in the United States. It highlights the underutilization of PAH therapies for patients with newly diagnosed PAH.
Supplementary Material
Additional information: The e-Tables are available online under “Supplementary Data.”
Take-Home Points.
Research Question:
What are the current treatment patterns for patients with newly diagnosed pulmonary arterial hypertension (PAH) in the Pulmonary Hypertension Association Registry (PHAR)?
Results:
In patients with incident PAH in the PHAR, 26% of low-risk status, 37% of intermediate-risk status, and 88% of high-risk status by Registry to Evaluate Early and Long-term PAH Disease Management Lite 2 risk score received therapies inconsistent with current guideline recommendations.
Interpretation:
Real-world data indicate that there are substantial deviations in clinical practice from the current guidelines for treating patients with incident PAH.
Acknowledgments
Role of sponsors:
The sponsor provided funding for the study, medical writing support, and publication charges.
Funding/Support
This work was supported by the National Heart, Lung, and Blood Institute [Grants F32HL170482, T32HL007534 to S. L. K.] and the Pulmonary Fibrosis Foundation PFF Scholars Program (S. L. K.). Sponsorship for this study and publication charges were funded by Johnson & Johnson (Titusville, NJ). Medical writing support was provided by Mary Greenacre, PhD, on behalf of Twist Medical and was funded by Johnson & Johnson.
Financial/Nonfinancial Disclosures
The authors have reported to CHEST the following: A. R. T. participated in advisory panels for Merck and Janssen. S. C. M. is a consultant for Actelion/Janssen, Aerovate, Merck, and United Therapeutics; and has received research support from the NHLBI, Department of Defense, and Scleroderma Foundation. C. J. P. and G. G. R. are employees of Johnson & Johnson. S. S. is a consultant for Merck, United Therapeutics, Keros, and Liquidia; is a member of the end point adjudication committee for GSK; is a chair and member of DSMB for NIH-funded trials; is an advisor for the American Lung Association; and has received research support to institute from United Therapeutics, Gossamer Bio, Respira, Keros Therapeutics, and Pulmovant. None declared (S. L. K., N. K., K. W., H. C.).
ABBREVIATIONS:
- COMPERA
Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension
- CTEPH
chronic thromboembolic pulmonary hypertension
- ERA
endothelin receptor antagonist
- NO
nitric oxide
- PAH
pulmonary arterial hypertension
- PDE5
phosphodiesterase type 5
- PH
pulmonary hypertension
- PHAR
Pulmonary Hypertension Association Registry
- PPA
prostacyclin pathway agent
- REVEAL
Registry to Evaluate Early and Long-Term PAH Disease Management
- sGC
soluble guanylate cyclase
- WHO FC
World Health Organization functional class
Footnotes
Part of this article has been presented at the Annual Meeting of the American Heart Association, November 11–13, 2023, Philadelphia, Pennsylvania.
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