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Abstract

Background:

Initial regimen selection is critical for pulmonary arterial hypertension (PAH) management and survival. Since 2015, guidelines have recommended upfront combination therapy as the standard of care in newly diagnosed patients.

Objectives:

To highlight real-world treatment patterns and predictors of initial combination therapy.

Design:

Retrospective cohort analysis of U.S. administrative claims from 01 January 2013 (Optum’s de-identified Clinformatics^® Data Mart Database [CDM]) or 01 July/2015 (IQVIA PharMetrics^® Plus) through 30 September 2020.

Methods:

Patients initiating PAH medications (phosphodiesterase-5 inhibitors (PDE5i), soluble guanylate cyclase stimulators (SGCS), endothelin receptor antagonists (ERA), or prostacyclin analogues (PCY)) were identified and indexed on the first medication date. All PAH medications identified between index and 365 days post-index were identified and classified as PDE5i/SGCS/ERA monotherapy, PDE5i/SGCS + ERA dual therapy, or PCY-containing regimen. Treatment regimens were analyzed by index year, physician specialty, and among physician specialists associated with a Pulmonary Hypertension Care Center. Multivariable regression was conducted to identify patient characteristics predictive of the first-line regimen.

Results:

1754 (CDM) and 1107 (IQVIA PharMetrics Plus) met selection criteria. The most initiated first-line regimen was PDE5i/SGCS/ERA monotherapy (CDM: 61.2%; IQVIA PharMetrics Plus: 50.9%). The proportion of CDM patients initiating PDE5i/SGCS + ERA dual therapy increased from 13.1% in 2013 to 21.9% in 2019; for IQVIA PharMetrics Plus, PDE5i/SGCS + ERA dual therapy remained consistent (24.4% in 2015, 23.7% in 2019). More pulmonologists prescribed PDE5i/SGCS + ERA dual therapy (CDM: 30.2%; IQVIA PharMetrics Plus: 38.6%) than cardiologists (CDM: 18.3%; IQVIA PharMetrics Plus: 24.3%). PHCC patients were prescribed first-line dual therapy (35.7% vs 26.9%) and PCY-containing regimens (30.3% vs 21.7%) more frequently than non-PHCC patients, respectively. Females (vs males) were more likely to receive dual therapy and PCY-containing regimens; Black (vs White) patients were less likely to receive PCY-containing regimens.

Conclusion:

Additional research is needed to better understand barriers to optimal initial treatment regimen selection and to quantify the impacts of therapeutic delay.

Plain language summary

Use of combination treatment in patients with pulmonary arterial hypertension

Why was the study done?

Selecting the treatment approach for newly diagnosed pulmonary arterial hypertension (PAH) is critical for improving patient survival. Research has shown that patients newly diagnosed with PAH who are started on combination therapy experience less disease progression, hospitalization, and death, than those started on monotherapy. Thus, experts now recommend starting treatment in patients with newly diagnosed PAH using a combination of medications, but it is not clear if this is happening.

What did the researcher do?

Using two large databases, with data spanning from 2013-2020, this study explored the treatment approaches used for newly diagnosed patients with PAH and found patient factors that influenced treatment selection.

What did the researchers find?

In total, 1,754 and 1,107 patients were identified from each database. In both databases, more than one-half of patients started PAH treatment with one medication (61.2% and 50.9%). However, combination treatments did increase over time (from 13.1% in 2013 to 21.9% in 2019), and in the other database, dual therapy stayed at approximately 24% from 2015 to 2019. Females were more likely than males to receive dual therapy. Lung specialists and doctors at specialty care clinics were more likely to start patients on combination treatments.

What do the findings mean?

Even though clinical guidelines recommend starting PAH therapy using combination treatments, most patients are initiating therapy with only one medication.

Keywords

claims analysis combination drug therapy pulmonary arterial hypertension pulmonary medicine

Introduction

Pulmonary arterial hypertension (PAH) is a rare, chronic, incurable, and life-threatening condition characterized by thickening and rigidity of the pulmonary arteries.¹ In patients with PAH, the progressive elevation of pulmonary arterial pressure and pulmonary vascular resistance eventually leads to right heart failure and ultimately death.² In the 2015–2020 Pulmonary Hypertension Association Registry (PHAR), survival estimates of US patients enrolled within 6 months of initial PAH diagnosis were 91% and 81% after 1 and 3 years, respectively.³ While these rates are better than those previously observed from 2006 to 2009 in the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry; 1-, 3-, and 5-year survival rates of 85%, 68%, and 57% respectively), mortality in PAH remains high.^4,5

The initial PAH treatment strategy plays a key role in patient survival.³ Currently available medication classes for PAH include phosphodiesterase-5 inhibitors (PDE5i), soluble guanylate cyclase stimulators (SGCS), endothelin receptor antagonists (ERA), activin signaling inhibitors, and prostacyclin analogues (PCY).^6–10 Clinical guidelines recommend comprehensive risk assessment at PAH diagnosis to guide initial treatment selection with monotherapy, dual therapy, or even triple PAH therapy.^11–13 AMBITION, the first randomized clinical trial to highlight dual combination therapy with a PDE5i and ERA as an upfront treatment strategy, showed a significantly reduced risk of clinical failure (i.e., hospitalization, death, disease progression, or unsatisfactory long-term response) in patients initiated on dual therapy versus monotherapy.¹⁴

Subsequent smaller studies, like the phase IV OPTIMA trial, have shown improved cardiopulmonary hemodynamics and functional parameters in newly diagnosed patients with PAH treated with upfront combination therapy with a PDE5i and ERA.¹⁵ Some registry studies also indicate that this treatment approach is associated with improved patient survival.^3,16 In the PHAR, 1-year mortality was lower in patients treated with initial combination therapy versus monotherapy (7% vs 13%; p = 0.046).³ In the French Pulmonary Hypertension Registry (2006–2018), upfront triple combination therapy (that included parenteral PCY) in patients with severe PAH was associated with a higher 5-year survival rate (91%) versus dual (61%) or monotherapy (61%) (p < 0.001 vs both).¹⁶

Despite this evidence for benefit and existing guideline recommendations for upfront combination therapy for patients with PAH,^11–13 a number of real-world studies show that monotherapy, most often with a PDE5i, remains the most common initial treatment approach in patients with PAH.^17–19 Additional research is needed to identify specific factors that influence first-line treatment decision-making, both in general and in specialty treatment settings. In this study, we analyzed real-world initial treatment strategies in the management of patients with PAH and predictors of particular treatment strategies, such as monotherapy and combination therapy.

Methods

Study design and data source

We performed an analysis of real-world data using Optum’s de-identified Clinformatics^® Data Mart Database (CDM) and IQVIA PharMetrics^® Plus databases to identify patients who used any PAH medication (ERA, PCY, PDE5i, or SGCS) between 1 January 2013 (CDM) or 1 July 2015 (IQVIA PharMetrics Plus) through 30 September 2019 (identification period). The index date was defined as the date of the first medical or pharmacy claim for any PAH specific therapy during the identification period.

Both the CDM and IQVIA PharMetrics Plus databases contain de-identified, integrated, longitudinal data that includes adjudicated administrative claims for >65 million (CDM) and >170 million (IQVIA PharMetrics Plus) unique US patients. CDM includes members with commercial or Medicare Advantage health plans, while IQVIA PharMetrics Plus includes members with commercial, Medicare Advantage, Medicare Supplement Insurance, and Managed Medicaid health plans. For individuals aged ⩽65 years, IQVIA PharMetrics Plus data are representative of the national, commercially insured US population. No direct subject contact or primary collection of individual human subject data occurred. Study results are presented as aggregate analyses that omit subject identification; therefore, informed consent, ethics committee, or independent review board approval was not required. Moreover, this study used de-identified data that comply with the requirements of the Health Insurance Portability and Accountability Act (HIPAA). This manuscript was produced according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.²⁰

Selection criteria

To be included in the study, patients were required to have a medical or pharmacy claim for a PDE5i, SGCS, ERA, and/or PCY during the identification period and be ⩾18 years of age at index (Figure 1). To ensure that patients were being treated for PAH, patients must have had one inpatient or two outpatient medical claims in the 6-month pre-index period, separated by ⩾30 days, with a diagnosis of PH in any position (ICD-9-CM: 416.0, 416.8, 416.9 or ICD-10-CM: I27.0, I27.2, I27.20, I27.21, I27.29, I27.81, I27.83, I27.89, I27.9). Patients were required to have ⩾6 months of continuous enrollment pre-index and ⩾12 months of continuous enrollment post-index. Patients who used PDE5i, SGCS, ERA, or PCY in the 6-month pre-index period were excluded. In addition, PDE5i prescription claims that had a ⩽15-day supply were excluded, because these may have been claims for erectile dysfunction.²¹ Also excluded were patients with a chronic thromboembolic pulmonary hypertension (CTEPH) diagnosis in the 6-month pre-index period, because riociguat is indicated to treat both PAH and CTEPH.²² Finally, patients without a documented procedure code for right heart catheterization (RHC) in the 6-month pre-index period were excluded, as RHC is required to officially diagnose PAH.

Figure 1.

Study design.

Regimen classification

Patients were classified into primary treatment regimens by medication use occurring between the index date and 365 days post-index. Patients whose initial medication was only PDE5i or SGCS within this window were classified as PDE5i/SGCS monotherapy. Patients whose initial medication was only ERA or PCY within this window were classified as ERA monotherapy or PCY monotherapy, respectively. Patients whose initial medication was either a PDE5i or SGCS and an ERA within this window were classified as PDE5i/SGCS + ERA dual therapy. Finally, patients whose initial medication was a PCY in combination with PDE5i, SGCS, or ERAs within this window were classified as PCY combination therapy.

Outcomes

Patient demographic, clinical, and other baseline characteristics were measured in the pre-index period, including age, sex, geographic region, race, payer type, Quan-Charlson comorbidity index (Quan-CCI),²³ and cardiovascular comorbidities. Primary post-index treatment regimens were analyzed overall and stratified by index year to show first-line prescribing patterns over time.

In addition, physician specialties (cardiology or pulmonology) were identified to evaluate receipt of initial treatment regimen by specialty and affiliation with a Pulmonary Hypertension Care Center (PHCC). National Provider Identifiers (NPIs) were merged with the US Centers for Medicare & Medicaid Services’ National Plan and Provider Enumeration System to obtain physician taxonomy values. Taxonomy codes follow federal definitions from the National Uniform Claim Committee. NPIs were available in the IQVIA PharMetrics Plus database but not for the CDM database, which only provided taxonomy values. Using NPIs, prescribing physicians who are affiliated with a PHCC, either a Center of Comprehensive Care or Regional Clinical Program, were identified in the IQVIA PharMetrics Plus cohort. PHCCs were classified by identifying PH program physicians as listed on the Pulmonary Hypertension Association website.²⁴

Sensitivity analysis

Sensitivity analyses were conducted on a broader study population. This broader population sensitivity analysis helped to ensure that patients with PAH were not wrongly excluded due to restrictive selection criteria. To capture a broader patient sample, PDE5i prescription claims that had a ⩽15-day supply were added into the analysis, as were patients with a CTEPH diagnosis, and patients without a documented procedure code for RHC, both in the 6-month pre-index period.

Statistical analysis

Descriptive statistics were used for all demographic and clinical characteristics, with continuous variables described using means and standard deviations (SD), and categorical variables described using frequencies and percentages. Cochran-Armitage tests with two-sided p-values were used to assess the statistical significance of trends over time in receipt of regimens comprising PDE5i/SGCS/ERA monotherapy, PDE5i/SGCS + ERA dual therapy, or a PCY-containing regimen (PCY monotherapy or PCY combination therapy) and were stratified by prescriber specialty (cardiologists/pulmonologists). Multivariable log binomial regression was used to identify baseline characteristics predictive of patients initiating regimens. Each model was adjusted for pre-index age, sex, geographic region, Quan-CCI (continuous), select comorbidities, prescriber specialty, and all-cause hospitalization. Race and insurance coverage type (commercial and Medicare Advantage) were further included for the CDM cohort analysis. All analyses were conducted using Statistical Analysis Software (Version 9.4 or higher; Cary, NC: SAS Institute, Inc., 2011)

Results

Demographic and clinical characteristics

A total of 17,312 and 75,087 patients who used any PAH medication were identified from the CDM and IQVIA PharMetrics Plus databases, respectively. After applying selection criteria, 1754 and 1107 were included in the CDM and IQVIA PharMetrics Plus cohorts (Figure 2).

Figure 2.

Patient attrition.

In general, similar findings were observed for both databases. Table 1 shows demographic and clinical characteristics for both patient cohorts at index, as well as the most prevalent comorbidities for each cohort. In the CDM database, mean (SD) patient age ranged from 64.5 (12.5) to 69.5 (11.3) years, depending on initial therapy. Most patients were White. In the IQVIA PharMetrics Plus database, mean (SD) patient age ranged from 55.4 (11.8) to 62.2 (10.6) years. In both cohorts, most patients were female, the largest proportion resided in the geographic South, and the majority of patients (59.6%–88.7%) had a Quan-CCI ⩾2. The most common comorbidities were congestive heart failure (41.5%–75.5%) and Systemic Hypertension (61.0%–76.9%).

Table 1.

Patient demographic and clinical characteristics at index.

Characteristic	CDM (N = 1754)					IQVIA PharMetrics Plus (N = 1107)
	PDE5i or SGCS monotherapy	ERA monotherapy	PDE5i/SGCS + ERA	PCY monotherapy	PCY combination therapy	PDE5i or SGCS monotherapy	ERA monotherapy	PDE5i/SGCS + ERA	PCY monotherapy	PCY combination therapy
N (%)	953 (54.3)	121 (6.9)	362 (20.6)	53 (3.0)	265 (15.1)	469 (42.4)	94 (8.5%)	313 (28.3%)	26 (2.3%)	205 (18.5)
Age (years), mean ± SD	67.4 ± 11.8	67.6 ± 11.7	66.2 ± 11.9	69.5 ± 11.3	64.5 ± 12.5	57.4 ± 12.8	55.4 ± 11.8	55.7 ± 11.9	62.2 ± 10.6	55.5 ± 12.3
18–39 years, n (%)	25 (2.6)	<5	13 (3.6)	<5	14 (5.3)	50 (10.7)	13 (13.8)	41 (13.1)	1 (3.9)	24 (11.7)
40–64 years, n (%)	310 (32.5)	>5	114 (31.5)	>5	112 (42.3)	295 (62.9)	65 (69.2)	214 (68.4)	17 (65.4)	147 (71.2)
65+ years, n (%)	618 (64.9)	80 (66.1)	235 (64.9)	38 (71.7)	139 (52.5)	124 (26.4)	16 (17.0)	58 (18.5)	8 (30.8)	34 (16.6)
Sex, female, n (%)	534 (56.0)	90 (74.4)	263 (72.7)	38 (71.7)	203 (76.6)	234 (49.9)	66 (70.2)	217 (69.3)	16 (61.5)	149 (72.7)
Region, n (%)
Northeast	88 (9.2)	14 (11.6)	29 (8.0)	10 (18.9)	15 (5.7)	58 (12.4)	10 (10.6)	51 (16.3)	6 (23.1)	27 (13.2)
Midwest	204 (21.4)	32 (26.5)	60 (16.6)	17 (32.1)	64 (24.2)	140 (29.9)	21 (22.3)	75 (24.0)	7 (26.9)	55 (26.8)
South	439 (46.1)	42 (34.7)	179 (49.5)	19 (35.9)	129 (48.7)	173 (36.9)	45 (47.9)	128 (40.9)	12 (46.2)	98 (47.8)
West	222 (23.3)	33 (27.3)	94 (26.0)	7 (13.2)	57 (21.5)	93 (19.8)	18 (19.2)	57 (18.2)	1 (3.9)	25 (12.2)
Race, n (%)
White	576 (60.4)	84 (69.4)	213 (58.8)	35 (66.0)	170 (64.2)	NA	NA	NA	NA	NA
Black	170 (17.8)	25 (20.7)	73 (20.2)	<5	38 (14.3)	NA	NA	NA	NA	NA
Hispanic	84 (8.8)	<5	35 (9.7)	<5	27 (10.2)	NA	NA	NA	NA	NA
Quan-CCI, mean ± SD	3.64 ± 2.02	2.78 ± 1.77	3.11 ± 1.84	3.79 ± 2.27	3.30 ± 1.74	3.63 ± 1.91	2.56 ± 1.82	3.04 ± 2.00	3.54 ± 1.92	3.20 ± 1.80
Quan-CCI, n (%)
0–1	168 (17.6)	38 (31.4)	89 (24.6)	6 (11.3)	48 (18.1)	73 (15.6)	38 (40.4)	85 (27.2)	6 (23.1)	46 (22.4)
2–3	313 (32.8)	51 (42.2)	135 (37.3)	22 (41.5)	113 (42.6)	185 (39.5)	31 (33.0)	129 (41.2)	10 (38.5)	85 (41.5)
4+	472 (49.5)	32 (26.5)	138 (38.1)	25 (47.2)	104 (39.3)	211 (45.0)	25 (25.6)	99 (31.6)	10 (38.5)	74 (36.1)
2022 ESC/ERS guideline¹² cardiovascular comorbidities, n (%)
Atrial fibrillation	393 (41.2)	32 (26.5)	71 (19.6)	16 (30.2)	61 (23.0)	162 (34.5)	12 (12.8)	35 (11.2)	5 (19.2)	27 (13.2)
CHF	663 (70.0%)	54 (44.6%)	194 (53.6%)	40 (75.5%)	172 (64.9%)	339 (72.3%)	39 (41.5%)	145 (46.3%)	16 (61.5%)	124 (60.5%)
CAD	483 (50.7)	49 (40.5)	103 (28.5)	23 (43.4)	90 (34.0)	189 (40.3)	16 (17.0)	69 (22.0)	6 (23.1)	46 (22.4)
Diabetes	416 (43.7)	47 (38.9)	123 (34.0)	22 (41.5)	85 (32.1)	173 (36.9)	21 (22.3)	70 (22.4)	5 (19.2)	47 (22.9)
Hypertension	733 (76.9)	86 (71.1)	253 (69.9)	34 (64.2)	200 (75.5)	342 (72.9)	58 (61.7)	191 (61.0)	16 (61.5)	129 (62.9)
Obesity	246 (25.8)	19 (15.7)	88 (24.3)	8 (15.1)	74 (27.9)	103 (22.0)	21 (22.3)	63 (20.1)	5 (19.2)	53 (25.9)

CAD, coronary artery disease; CCI, Charlson comorbidity index; CHF, congestive heart failure; ERA, endothelin receptor antagonists; ERS, European Respiratory Society; ESC, European Society of Cardiology; NA, not available; PCY, prostacyclins; PDE5i, phosphodiesterase-5 inhibitors; PVD, peripheral vascular disease; SGCS, soluble guanylate cyclase stimulators.

First-line regimens

In descending order, over the 365-day classification window, the most common initial treatment regimens in the CDM cohort were PDE5i or SGCS monotherapy (953 (54.3%)), PDE5i or SGCS + ERA dual therapy (362 (20.6%)), PCY combination (265 (15.1%)), ERA monotherapy (121 (6.9%)), and PCY monotherapy (53 (3.0%)). The most common initial treatments in the IQVIA PharMetrics Plus cohort were PDE5i or SGCS monotherapy (469 (42.4%)), PDE5i or SGCS + ERA dual therapy (313 (28.3%)), PCY combination (205 (18.5%)), ERA monotherapy (94 (8.5%)), and PCY monotherapy (26 (2.3%)). Medication use analyses conducted using 90- and 180-day classification windows showed largely similar results to the 365-day window (Supplemental Figure 1).

As shown in Figure 3, in both cohorts and throughout the study period, PDE5i/SGCS monotherapy comprised the largest proportion of initial treatment regimens (CDM: 49.0%–64.2%; IQVIA PharMetrics Plus: 35.9%–46.1%). A lower percentage of patients received PDE5i/SGCS + ERA dual therapy (CDM: 13.1%–23.3%; IQVIA PharMetrics Plus: 23.7%–30.5%), PCY combination therapy (CDM: 8.7%-20.7%; IQVIA PharMetrics Plus: 16.1%–22.9%), ERA monotherapy (CDM: 3.3%–11.9%; IQVIA PharMetrics Plus: 6.5%–13.3%), or PCY monotherapy (CDM: 1.5%–5.5%; IQVIA PharMetrics Plus: 0.0%–6.1%). The trend PDE5i/SGCS + ERA dual therapy was statistically significant for CDM (p < 0.001) but not significant for IQVIA PharMetrics Plus (p = 0.9375). Trends for PDE5i/SGCS/ERA monotherapy or PCY-containing regimens were statistically significant for both CDM and IQVIA PharMetrics Plus.

Figure 3.

First-line regimens over time.

Multivariable regression

Patients with PAH initiating a primary treatment regimen in 2013 were less likely to receive PDE5i/SGC + ERA dual therapy (CDM: relative risk (RR) 0.59 (95% CI: 0.38–0.93)) compared to 2019 (Table 2). No differences were observed for subsequent years for CDM and IQVIA PharMetrics Plus. Patients were also less likely to receive PCY-containing regimens in earlier years until 2017 for CDM and 2015 for IQVIA PharMetrics Plus. Females were more likely than males to receive PCY-containing regimens (CDM: RR 1.60 (95% CI: 1.26–2.04); IQVIA PharMetrics Plus: RR 1.44 (95% CI: 1.11–1.87)). In the CDM cohort, Black patients were less likely than White patients to receive PCY-containing regimens (RR 0.65 (95% CI: 0.48–0.90)).

Table 2.

Results of multivariable regression analyses.*

Characteristic	CDM			IQVIA PharMetrics Plus
Characteristic	PDE5i/SGC + ERA dual therapy	PDE5i/SGC/ERA monotherapy	PCY-containing regimen	PDE5i/SGC + ERA dual therapy	PDE5i/SGC/ERA monotherapy	PCY-containing regimen
	RR (95% CI)	RR (95% CI)	RR (95% CI)	RR (95% CI)	RR (95% CI)	RR (95% CI)
Index year (ref: 2019)
2013	0.59 (0.38–0.93)	1.17 (1.07–1.27)	0.40 (0.25–0.65)	–	–	–
2014	0.75 (0.51–1.10)	1.14 (1.04–1.25)	0.50 (0.33–0.75)	–	–	–
2015	0.93 (0.66–1.30)	1.09 (1.00–1.19)	0.51 (0.35–0.76)	1.10 (0.75–1.62)	1.09 (0.94–1.27)	0.61 (0.40–0.93)
2016	0.77 (0.55–1.07)	1.08 (1.00–1.16)	0.67 (0.48–0.95)	1.37 (0.98–1.92)	1.02 (0.88–1.18)	0.73 (0.52–1.04)
2017	0.99 (0.74–1.34)	1.04 (0.96–1.12)	0.83 (0.62–1.13)	1.43 (1.01–2.02)	1.01 (0.87–1.17)	0.72 (0.50–1.02)
2018	0.92 (0.68–1.26)	1.02 (0.94–1.10)	0.95 (0.71–1.28)	1.35 (0.95–1.92)	0.98 (0.84–1.13)	0.85 (0.60–1.21)
Age, years, (ref: 65+)
18–39 years	1.15 (0.68–1.94)	1.03 (0.89–1.19)	0.60 (0.37–0.97)	0.76 (0.54–1.07)	0.98 (0.84–1.15)	1.38 (0.87–2.20)
40–64 years	1.11 (0.99–1.39)	1.01 (0.95–1.07)	0.78 (0.61–0.99)	0.89 (0.70–1.14)	1.02 (0.93–1.12)	0.97 (0.71–1.33)
Sex, female (ref: male)	1.21 (0.99–1.49)	0.93 (0.89–0.98)	1.60 (1.26–2.04)	1.13 (0.91–1.39)	0.88 (0.80–0.95)	1.44 (1.11–1.87)
Region (ref: west)
Midwest	0.74 (0.55–0.99)	1.00 (0.94–1.06)	1.35 (1.01–1.81)	0.78 (0.59–1.03)	1.01 (0.91–1.13)	1.47 (0.97–2.24)
Northeast	0.88 (0.62–1.26)	1.00 (0.92– 1.08)	1.11 (0.74–1.68)	1.07 (0.81–1.43)	0.90 (0.77–1.03)	1.58 (1.00–2.52)
South	0.97 (0.77–1.21)	0.99 (0.94 –1.05)	1.21 (0.92–1.58)	0.86 (0.67–1.11)	0.96 (0.86–1.08)	1.77 (1.19–2.64)
Race (ref: White)
Black	1.23 (0.97–1.55)	1.02 (0.96–1.08)	0.65 (0.48–0.90)	–	–	–
Hispanic	1.12 (0.82–1.52)	0.99 (0.91–1.08)	0.98 (0.70–1.36)	–	–	–
Insurance, commercial (ref: Medicare Advantage)	0.96 (0.75–1.24)	1.00 (0.94–1.06)	1.03 (0.80 –1.34)	–	–	–
Quan-CCI (continuous)	1.05 (0.99–1.24)	1.00 (0.98–1.01)	0.97 (0.90–1.05)	1.05 (0.99–1.12)	0.98 (0.95–1.01)	0.98 (0.90–1.06)
Atrial fibrillation	0.62 (0.48–0.80)	1.08 (1.03–1.13)	0.70 (0.55–0.91)	0.60 (0.42–0.84)	1.22 (1.11–1.34)	0.63 (0.44–0.90)
Congestive heart failure	0.93 (0.73–1.18)	0.98 (0.92–1.04)	1.39 (1.03–1.86)	0.66 (0.41–0.85)	1.12 (1.00–1.27)	1.18 (0.85–1.65)
Coronary artery disease	0.72 (0.58–0.90)	1.05 (1.01–1.10)	0.83 (0.66–1.03)	1.00 (0.78–1.29)	1.07 (0.97–1.18)	0.77 (0.57–1.03)
Diabetes	0.97 (0.79–1.19)	1.02 (0.98–1.07)	0.85 (0.68–1.06)	0.94 (0.74–1.20)	1.07 (0.97–1.19)	0.76 (0.56–1.02)
Hypertension	1.05 (0.85–1.30)	0.98 (0.93–1.04)	1.22 (0.95–1.56)	1.01 (0.82–1.23)	1.02 (0.92–1.14)	0.81 (0.63–1.05)
Obesity	0.89 (0.68–1.17)	1.05 (0.99–1.11)	0.71 (0.53–0.96)	0.97 (0.76–1.23)	0.98 (0.88–1.10)	1.16 (0.88–1.53)
Patients with any all-cause hospitalization (ref: No pre-index hospitalization)	0.72 (0.57–0.91)	1.03 (0.97–1.09)	1.14 (0.89–1.45)	0.91 (0.71–1.16)	0.98 (0.88–1.08)	1.35 (1.00–1.81)
Cardiologists	1.50 (1.18–1.90)	0.96 (0.91–1.00)	1.16 (0.90–1.48)	1.27 (1.00–1.61)	0.94 (0.85–1.03)	1.05 (0.80–1.38)
Pulmonologists	2.09 (1.66–2.64)	0.90 (0.86–0.95)	1.06 (0.84–1.35)	1.77 (1.43–2.20)	0.82 (0.74–0.90)	0.95 (0.73–1.24)

Adjusting for age, sex, region, race (CDM only), line of business (CDM only), Quan-CCI (continuous), select comorbidities, prescriber specialty, and presence of a pre-index hospitalization.

Bolded values represent p < 0.05.

CCI, Charlson comorbidity index; CI, confidence interval; PCY, prostacyclins; ref, reference; RR, relative risk.

Patients with comorbid atrial fibrillation were more likely to initiate on PDE5i/SGC/ERA monotherapy (CDM: RR 1.08 (95% CI: 1.03–1.13); IQVIA PharMetrics Plus: RR 1.22 (95% CI: 1.11–1.34)). Patients with congestive heart failure were more likely to initiate on a PCY-containing regimen (CDM: RR 1.39 (95% CI: 1.03–1.86)), though this was not observed in the IQVIA PharMetrics Plus cohort. Cardiologists were more likely to prescribe PDE5i/SGC + ERA dual therapy compared to other specialties (CDM: RR 1.50 (95% CI: 1.18–1.90); IQVIA PharMetrics Plus: RR 1.27 (95% CI: 1.00–1.61)). An even higher effect size was observed for pulmonologists prescribing PDE5i/SGC + ERA dual therapy (CDM: RR 2.09 (95% CI: 1.66–2.64); IQVIA PharMetrics Plus: RR 1.77 (95% CI: 1.43–2.20)) compared to other specialties.

Specialist practice patterns

Table 3 shows the breakdown of initial treatment regimens by physician specialty prescriber and index year. In the CDM cohort, PDE5i/SGCS/ERA monotherapy was used by 63.3% (415/656) and 50.5% (338/669) of patients prescribed PAH therapy by cardiologists and pulmonologists, respectively. PDE5i/SGC + ERA dual therapy was used by 120 (18.3%) and 202 (30.2%) and PCY-containing regimens were used by 121 (18.5%) and 129 (19.3%) patients prescribed PAH therapy by cardiologists and pulmonologists, respectively. There was a significant trend for PDE5i/SGCS/ERA monotherapy and PCY-containing regimens among patients prescribed PAH therapy by cardiologists and pulmonologists.

Table 3.

First-line regimens by provider specialty and affiliation with PHCC.

Provider specialty	2013	2014	2015	2016	2017	2018	2019	All	p-Value
Optum–cardiologists
PDE5i/SGC/ERA monotherapy	59 (83)	58 (75)	50 (60)	65 (63)	74 (65)	63 (56)	46 (48)	415 (63)	<0.01
PDE5i/SGC + ERA dual therapy	7 (10)	11 (14)	19 (23)	21 (20)	18 (16)	25 (22)	19 (20)	120 (18)	0.10
PCY-containing regimen	5 (7)	8 (10)	15 (18)	17 (17)	21 (19)	24 (21)	31 (32)	121 (18)	<0.01
Optum–pulmonologists
PDE5i/SGC/ERA monotherapy	43 (67)	43 (54)	45 (57)	64 (58)	49 (34)	56 (49)	38 (48)	338 (51)	0.00
PDE5i/SGC + ERA dual therapy	14 (22)	23 (29)	23 (29)	24 (22)	58 (41)	31 (27)	29 (36)	202 (30)	0.06
PCY-containing regimen	7 (11)	13 (16)	11 (14)	22 (20)	36 (25)	27 (24)	13 (16)	129 (19)	0.05
IQVIA–cardiologists
PDE5i/SGC/ERA monotherapy	–	–	32 (65)	50 (63)	45 (54)	38 (45)	19 (46)	184 (54)	0.01
PDE5i/SGC + ERA dual therapy	–	–	8 (16)	19 (24)	23 (28)	24 (28)	8 (20)	82 (24)	0.43
PCY-containing regimen	–	–	9 (18)	11 (14)	15 (18)	23 (27)	14 (34)	72 (21)	0.01
IQVIA–pulmonologists
PDE5i/SGC/ERA monotherapy	–	–	35 (52)	41 (34)	40 (37)	34 (36)	25 (43)	175 (39)	0.42
PDE5i/SGC + ERA dual therapy	–	–	21 (31)	50 (42)	44 (41)	40 (42)	17 (29)	172 (39)	0.89
PCY-containing regimen	–	–	11 (16)	28 (24)	23 (22)	21 (22)	16 (28)	99 (22)	0.27

ERA, endothelin receptor antagonists; PCY, prostacyclins; PDE5i, phosphodiesterase-5 inhibitors; SGCS, soluble guanylate cyclase stimulators.

In the IQVIA PharMetrics Plus cohort, 54.4% (184/338) of patients were prescribed PDE5i/SGC/ERA monotherapy among patients prescribed a PAH therapy by cardiologists; 24.3% (82/338) were prescribed PDE5i/SGC + ERA dual therapy, and 21.3% (72/338) were prescribed PCY-containing regimens. Among patients prescribed PAH therapy by pulmonologists, 39.2% (175/446), 38.6% (172/446), and 22.2% (99/446) were prescribed PDE5i/SGCS/ERA monotherapy, PDE5i/SGC + ERA dual therapy, and PCY-containing regimens, respectively. There was a significant trend for PDE5i/SGCS/ERA monotherapy and PCY-containing regimens among patients prescribed PAH therapy by cardiologists, but only for PDE5i/SGCS/ERA monotherapy for pulmonologists.

Furthermore, in the IQVIA PharMetrics Plus cohort, PDE5i/SGCS/ERA monotherapy was used by 34.0% (83/244) of PHCC-affiliated patients and 51.4% (500/973) of non-PHCC-affiliated patients. PDE5i/SGC + ERA dual therapy (35.7% (87/244) vs 26.9% (262/973)) and PCY-containing regimens (30.3% (74/244) vs 21.7% (211/973)) were both higher for PHCC-affiliated patients compared to non-PHCC-affiliated patients, respectively.

Sensitivity analysis

After applying the less-specific selection criteria in the extended population sensitivity analysis, there were 3093 patients in the CDM cohort and 1907 in the IQVIA PharMetrics Plus cohort. As shown in Supplemental Figure 2, PDE5i/SGCS monotherapy comprised the largest proportion of initial treatment regimens (CDM: 58.1%–66.2%; IQVIA PharMetrics Plus: 46.6%–54.4%). A lower percentage of patients received PDE5i/SGCS + ERA dual therapy (CDM: 11.1%–19.5%; IQVIA PharMetrics Plus: 19.2%–25.2%), PCY combination therapy (CDM: 7.4%–14.8%; IQVIA PharMetrics Plus: 14.7%–17.5%), ERA monotherapy (CDM: 4.2%–12.0%; IQVIA PharMetrics Plus: 6.3%–11.4%), or PCY monotherapy (CDM: 1.4%–3.7%; IQVIA PharMetrics Plus: 1.5%–5.0%) as initial treatment.

Discussion

In this longitudinal evaluation of two large administrative claims databases, most patients with newly diagnosed PAH initiated treatment with PDE5i/SGCS/ERA monotherapy (61.2% in the CDM cohort and 50.9% in the IQVIA PharMetrics Plus cohort). These results were consistent across both databases, for commercial and Medicare Advantage populations, and within sensitivity analyses conducted on a broader patient population with PAH (PDE5i/SGCS/ERA monotherapy, CDM: 71.5%; IQVIA PharMetrics Plus: 60.9%). Our findings indicate that prescribing patterns may have been affected by the 2015 publication of the AMBITION study¹⁴ and subsequent clinical guideline updates.²⁵ Specifically, from a pre- and post-AMBITION perspective, a moderately increased use of PDE5i/SGCS + ERA dual therapy was apparent post-2015. However, this trend plateaued and stabilized, and PDE5i/SGCS/ERA monotherapy remained the primary first-line PAH treatment through the end of study follow-up in 2020.

The current findings are consistent with published data from other large, real-world, administrative claims studies.^{17–19,26,27} In a retrospective study, Burger et al (2018) identified patients with PAH (N = 3908) from the Truven Health MarketScan Commercial and Medicare Supplemental Databases (2010–2014) and found that 95.1% initiated treatment with monotherapy, typically a PDE5i (77.8%). Notably, over 90% of this cohort was indexed prior to the publication of the AMBITION study and updates to treatment guidelines.²⁶ Similarly, Studer et al (2019) performed a retrospective US administrative claims study using the CDM Research Database (2010-2015), which included patient data for commercial and Medicare health plans. Of 1637 patients with PAH, the vast majority (93.8%) initiated treatment with monotherapy, most commonly with a PDE5i (70.0%).¹⁹ An update to that analysis, which extended the study period to 2018 (N = 1878), found that the percentage of patients with PAH initiating monotherapy remained largely unchanged, at 90.8%, with 64.1% starting treatment with a PD5Ei. However, when examined by cohort year, the proportion of patients using initial combination therapy increased from 5.7% in 2012–2013 to 13.0% in 2015–2017.¹⁸ Last, a similar study, Pizzicato et al.,¹⁷ used US commercial claims data from the HealthCore Integrated Research Database^® (2015–2020) to describe treatment patterns in patients with PAH. A total of 78.8% of patients received first-line monotherapy, with one-half (51.7%) receiving PDE5i monotherapy.¹⁷

One of the unique findings of our analysis is the potential relationship between prescribing patterns and physician specialty and PHCC affiliation. A higher proportion of pulmonologists’ patients were prescribed dual therapy with PDE5i/SGCS + ERA (CDM: 30.2%; IQVIA PharMetrics Plus: 38.6%) compared to cardiologists’ patients (CDM: 18.3%; IQVIA PharMetrics Plus: 24.3%). When the overall data were further analyzed by whether prescribers were affiliated with a PHCC, prescribers were more likely to prescribe PDE5i/SGCS + ERA dual therapy and PCY-containing regimens compared to non-PHCC-affiliated prescribers. It is interesting to note that PHCCs are about 70% pulmonologist-led, with the remainder largely cardiologist-led. Initial PAH treatment strategy based on physician specialty and among patients seen by specialty care centers is not adequately researched in the US. However, results of the current study are consistent with results from a 200 to 2018 evaluation of PHCC care, which showed a higher rate of PDE5i + ERA dual therapy use between PHCC- and non-PHCC-treated patients (30.1% vs 14.0%; p < 0.001). It is possible that these differences in PAH management strategies between PHCC and non-PHCC-affiliated physicians reflect increased treatment guideline compliance among PHCC physicians,²⁸ as well as greater awareness of emerging clinical trial data supporting new or alternative treatment strategies. Current US guidelines recommend that patients with PAH be managed at PHCC sites,¹² and clinical research has shown that patients treated in specialty centers have improved survival (hazard ratio, 0.68; p < 0.012) and fewer hospitalizations (incidence ratio, 0.54; p < 0.001) compared to patients not treated in specialty centers.²⁸

This study also identified key factors associated with therapeutic initiation. Prescribers appear to be more cautious in patients with comorbid atrial fibrillation, opting for PDE5i/SGC monotherapy regimens. A lesser proportion of patients with comorbid congestive heart failure received ERA monotherapy or PDE5i/SGCS + ERA dual therapy compared to other regimens, potentially to avoid fluid retention and worsening of edema. Furthermore, subgroup analyses and guideline updates have cautioned management of patients with comorbidities; however, a balance must be achieved between PAH severity at initial presentation and cardiopulmonary comorbidities.²⁹ Females were more likely to receive PDE5i/SGCS + ERA dual therapy and PCY-containing regimens relative to males. In addition, Black patients were less likely to receive PCY-containing regimens relative to White patients. This racial disparity may be due to the fact that Black patients systematically experience greater obstacles to accessing equitable health care,³⁰ which may affect their ability to obtain therapies such as prostacyclins.^30,31

Strengths and limitations

Study limitations of note are associated with the use of administrative claims databases, which are designed for billing and research purposes. The accurate identification of patients with PAH (vs other forms of PH) using administrative claims is challenging, and it is possible that patients with PH types other than Group 1 (PAH) were captured in this sample. To minimize this limitation, additional selection criteria were applied (beyond ICD-9-CM and ICD-10-CM codes), including the use of PAH-specific medications and documented RHC, and the exclusion of patients with CTEPH and/or erectile dysfunction. This approach was more stringent than similar retrospective studies,^17–19 but still provided an adequate sample size, and was in alignment with previous studies validating claims-based algorithms for PAH.^26,32 Reflecting another common, potential limitation of retrospective database studies, it was possible that patients with claims for PAH medications did not actually use the medication, despite filling the prescription. Also not accounted for were overlaps in patient-days’ supply, which may have accounted for some misclassification of patient drug-switching, and would have led to an underestimate of monotherapy use. Finally, for the prescriber specialty analysis, we were unable to observe PCY prescribing practices because prescriber information utilized specialty pharmacy information/NPI rather than original prescriber NPIs. However, few patients were initiated on PCY monotherapy, and PCY dual and triple therapy patients were classified using the prescribers on their PDE5i, SGCS, and/or ERA prescriptions.

It is likely that the more recently published 2019, 2022, and 2024^11–13 PAH management guidelines will shift future and ongoing first-line treatment strategies, potentially leading to improved long-term patient survival. Compared to guidelines available during most of this study’s data collection period (American College of Chest Physicians (2014); European Society of Cardiology/European Respiratory Society guidelines (2015)),^25,33 the updated guidelines include more compelling evidence in favor of initial combination therapy, as well as additional specific, recommended first-line drug combinations.^11–13

It should be noted that practical barriers exist to implementing PDE5i/SGCS + ERA dual therapy. These include the risk of additive side effects with multiple medications and the need to manage these effects promptly and effectively. Maintaining adherence to complex regimens is also a challenge. It is increasingly recognized that regimens must be individualized according to the patient’s specific disease etiology, comorbidities, concomitant medications, lifestyle, and preferences. Expert care centers, where experienced specialist physicians and multidisciplinary teams are available, can help balance the risk-benefit of PDE5i/SGCS + ERA dual therapy, overcome treatment barriers, and optimize treatment outcomes.³⁴

Conclusion

Despite AMBITION and subsequent updates to clinical guidelines indicating the superiority of first-line PAH treatment with PDE5i/SGCS + ERA dual therapy, this analysis of two large, real-world administrative claims databases found that most patients with newly diagnosed PAH continue to receive initial monotherapy. Importantly, PDE5i/SGCS + ERA dual therapy was more commonly prescribed as upfront therapy when patients were treated in a specialty care center. Additional research is needed to better understand barriers to optimal initial treatment regimen selection and to quantify the impacts of therapeutic delay.

Supplemental Material

sj-docx-1-tar-10.1177_17534666251390070 – Supplemental material for Real-world use of initial combination treatment in the management of pulmonary arterial hypertension

Supplemental material, sj-docx-1-tar-10.1177_17534666251390070 for Real-world use of initial combination treatment in the management of pulmonary arterial hypertension by Sandeep Sahay, Megan Sisk, Andrew Nelsen, Benjamin Wu and John Ryan in Therapeutic Advances in Respiratory Disease

Footnotes

Acknowledgements

Medical writing support was provided by Caitlin Rothermel MA, MPH, and Naseem Bazargan, MPH of MedLitera.

Declarations

ORCID iD

Benjamin Wu

Supplemental material

Supplemental material for this article is available online.

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