Development and evaluation of a predictive algorithm for unsatisfactory response among patients with pulmonary arterial hypertension using health insurance claims data

Figures & data

Figure 1. Study design. Abbreviations. ERAs, endothelin-receptor antagonists; PAH, pulmonary arterial hypertension; PDE5is, phosphodiesterase type 5 inhibitors.

Table 1. Unsatisfactory clinical response during the at-risk period.

Components^a	Study sample
	N = 4781
(1) Initiation of a treatment indicated for PAH that was not part of the treatment regimen initiated on the index date, n (%)^b	932 (19.5%)
Agent(s) newly initiated, n (%)
ERA	340 (7.1%)
Ambrisentan	181 (3.8%)
Macitentan	115 (2.4%)
Bosentan	44 (0.9%)
PDE5i	329 (6.9%)
Tadalafil	197 (4.1%)
Sildenafil	60 (1.3%)
PPA	229 (4.8%)
Treprostinil	137 (2.9%)
Selexipag	61 (1.3%)
Iloprost	22 (0.5%)
Epoprostenol	11 (0.2%)
Riociguat	37 (0.8%)
(2) ≥1 PAH-related or heart failure-related hospitalization or ER visit, n (%)^c	2611 (54.6%)
(3) PAH-related or heart failure-related death, n (%)^d	933 (19.5%)
(4) Lung transplant or atrial septostomy, n (%)^e	24 (0.5%)
(5) Initiation of chronic oxygen therapy, n (%)^f	602 (12.6%)
Composite outcome
Any component	3169 (66.3%)
Duration of at-risk period (months), mean ± SD [median]	22.3 ± 23.7 [14.0]

Abbreviations. ER, emergency room; ERAs, endothelin-receptor antagonists; PAH, pulmonary arterial hypertension; PDE5is, phosphodiesterase type 5 inhibitors; PPA, prostacyclin pathway agent.

^aComponents were measured during the at-risk period. The at-risk period was defined as the period spanning from the index date until the earliest of the end of data availability, end of continuous healthcare plan enrollment, or death.

^bThe list of medications indicated for PAH included ERAs, PDE5is, PPA: prostacyclin pathway agents, and riociguat. The treatment regimen initiated on the index date was defined based on the agents received within the first 60 days of the index date.

^cPAH-related or heart failure-related hospitalization or ER visit was defined based on a diagnosis for PAH (ICD-9-CM: 416.0, 416.8; ICD-10-CM: I27.0, I27.20, I27.21, I27.89) or right heart failure (ICD-9-CM: 428.0; ICD-10-CM: I50.81) recorded in a medical claim in an inpatient or ER setting.

^dPAH-related or heart failure-related death was defined as having a diagnosis for PAH (ICD-9-CM: 416.0, 416.8; ICD-10-CM: I27.0, I27.20, I27.21, I27.89) or right heart failure (ICD-9-CM: 428.0; ICD-10-CM: I50.81) within 30 days of the date of death.

^eLung transplant was defined based on a lung or lung lobe transfer procedure (ICD-9-PCS: 33.5x, 33.6; ICD-10-CM: 0BYC, 0BYD, 0BYF, 0BYG, 0BYH, OBYJ, 0BYK, 0BYL, 0BYM; CPT: 32851, 32852, 32853, 32854, 33935). Atrial septostomy was defined based on an atrial septostomy procedure (ICD-9-PCS: 35.4x; ICD-10-PCS: 02QA4ZZ, 02QA3ZZ, 02QA0ZZ, 02B50ZZ, 02B53ZZ, 02B54ZZ; CPT: 92992, 92993, 33735, 33736, 33737).

^fInitiation of chronic oxygen therapy was defined based on medical claims for oxygen therapy (HCPCS: E0424, E0425, E0430, E0431, E0433, E0434, E0435, E0439, E0440, E0441, E0442, E0443, E0444, E0445, E0447, E0455, E1356, E1357, E1358, E1390, E1391, E1392, K0738, K0740, K0741, K0742, K0671, S8120, S8121), excluding claims recorded in inpatient or ER settings. It was further required that patients do not have a medical claim for oxygen therapy during the baseline period to be considered as initiating chronic oxygen therapy.

Figure 2. Sample selection flowchart. Abbreviations. CTEPH, chronic thromboembolic pulmonary hypertension; ERAs, endothelin-receptor antagonists; PAH, pulmonary arterial hypertension; PDE5is, phosphodiesterase type 5 inhibitors; PPA, prostacyclin pathway agent. Notes: 1. The index regimen was defined as the treatment initiated on the index date, along with any other treatment indicated for PAH initiated within a 60-day window after the index date.

Table 2. Baseline characteristics.

	Study sample	Patients without outcome	Patients with outcome
Patient characteristics^a	N = 4781	N = 1612	N = 3169	P-value
Demographics
Age, mean ± SD [median]	67.8 ± 12.7 [69.0]	67.2 ± 12.8 [68.0]	68.1 ± 12.6 [70.0]	<.05
Age group, n (%)				<.05
18–29 years old	53 (1.1%)	20 (1.2%)	33 (1.0%)
30–39 years old	93 (1.9%)	30 (1.9%)	63 (2.0%)
40–49 years old	261 (5.5%)	102 (6.3%)	159 (5.0%)
50–59 years old	718 (15.0%)	247 (15.3%)	471 (14.9%)
60–69 years old	1275 (26.7%)	460 (28.5%)	815 (25.7%)
70–79 years old	1464 (30.6%)	468 (29.0%)	996 (31.4%)
80–89 years old	917 (19.2%)	285 (17.7%)	632 (19.9%)
Female	2800 (58.6%)	777 (48.2%)	2023 (63.8%)	<.001
Insurance type, n (%)				<.001
Exclusive provider organization	190 (4.0%)	77 (4.8%)	113 (3.6%)
Health maintenance organization	1100 (23.0%)	242 (15.0%)	858 (27.1%)
Indemnity	156 (3.3%)	39 (2.4%)	117 (3.7%)
Point-of-service	1037 (21.7%)	435 (27.0%)	602 (19.0%)
Preferred provider organization	318 (6.7%)	93 (5.8%)	225 (7.1%)
Other	1980 (41.4%)	726 (45.0%)	1254 (39.6%)
Geographic region, n (%)				<.001
Midwest	949 (19.9%)	272 (16.9%)	677 (21.4%)
Northeast	454 (9.5%)	169 (10.5%)	285 (9.0%)
South	2162 (45.3%)	775 (48.1%)	1387 (43.8%)
West	1210 (25.3%)	394 (24.5%)	816 (25.8%)
Time between first observed PAH diagnosis and the index date (months), mean ± SD [median]	5.2 ± 3.9 [4.2]	5.8 ± 3.9 [5.3]	4.9 ± 3.9 [3.7]	<.001
Treatment regimen^e as of the index date, n (%)
Monotherapy	4318 (90.3%)	1497 (92.9%)	2821 (89.0%)	<.001
PDE5i	3483 (72.9%)	1309 (81.2%)	2174 (68.6%)	<.001
Sildenafil	2656 (55.6%)	1012 (62.8%)	1644 (51.9%)	<.001
Tadalafil	827 (17.3%)	297 (18.4%)	530 (16.7%)	.153
ERA	835 (17.5%)	188 (11.7%)	647 (20.4%)	<.001
Ambrisentan	374 (7.8%)	88 (5.5%)	286 (9.0%)	<.001
Bosentan	274 (5.7%)	38 (2.4%)	236 (7.4%)	<.001
Macitentan	187 (3.9%)	62 (3.8%)	125 (3.9%)	.931
Combination therapy	463 (9.7%)	115 (7.1%)	348 (11.0%)	<.001
Quan-Charlson comorbidity index^b, mean ± SD [median]	3.9 ± 2.2 [4.0]	3.6 ± 2.2 [3.0]	4.1 ± 2.2 [4.0]	<.001
Medical encounters, mean ± SD [median]
All-cause hospital admissions	1.5 ± 2.0 [1.0]	1.2 ± 1.7 [1.0]	1.6 ± 2.0 [1.0]	<.001
PAH-related outpatient visits^c	5.6 ± 7.8 [4.0]	5.0 ± 8.2 [3.0]	5.9 ± 7.5 [4.0]	<.001
Cardiologist visits	9.7 ± 13.6 [6.0]	8.8 ± 13.6 [5.0]	10.1 ± 13.6 [6.0]	<.01
Pulmonologist visits	4.8 ± 7.1 [3.0]	3.7 ± 5.6 [2.0]	5.3 ± 7.7 [3.0]	<.001
PAH-related procedures, n (%)
Echocardiography	2111 (44.2%)	585 (36.3%)	1526 (48.2%)	<.001
RHC	1258 (26.3%)	309 (19.2%)	949 (29.9%)	<.001
Comorbidities, n (%)
Cardiomegaly	2092 (43.8%)	632 (39.2%)	1460 (46.1%)	<.001
Chronic obstructive pulmonary disease	2597 (54.3%)	810 (50.2%)	1787 (56.4%)	<.001
Connective tissue disorder	640 (13.4%)	184 (11.4%)	456 (14.4%)	<.01
Diabetes mellitus	2128 (44.5%)	675 (41.9%)	1453 (45.9%)	<.01
Pulmonary fibrosis	976 (20.4%)	241 (15.0%)	735 (23.2%)	<.001
Renal disease	1837 (38.4%)	560 (34.7%)	1277 (40.3%)	<.001
Thyroid disorders	1350 (28.2%)	412 (25.6%)	938 (29.6%)	<.01
Valvular disease	2886 (60.4%)	960 (59.6%)	1926 (60.8%)	.432
Symptoms, n (%)
Dyspnea	4241 (88.7%)	1349 (83.7%)	2892 (91.3%)	<.001
Chest pain	1942 (40.6%)	535 (33.2%)	1407 (44.4%)	<.001
Lower limb edema	1684 (35.2%)	467 (29.0%)	1217 (38.4%)	<.001

Abbreviations. AIDS, Acquired immunodeficiency syndrome; ER, emergency room; HIV, Human immunodeficiency virus; ERAs, endothelin-receptor antagonists; PAH, pulmonary arterial hypertension; PDE5is, phosphodiesterase type 5 inhibitors; PH, pulmonary hypertension; RHC, right heart catheterization.

^aUnless specified otherwise, characteristics were measured during the baseline period (i.e. 12-month period prior to the index date).

^bQuan et al. [41].

^cPAH-related is defined as having at least one diagnosis code for PAH (ICD-9-CM: 416.0, 416.8; ICD-10-CM: I27.0, I27.20, I27.21, I27.89) or right heart failure-related (ICD-9-CM: 428.0; ICD-10-CM: I50.81) recorded on a medical claim in an inpatient or ER setting.

Figure 3. Top 20 most important risk factors based on random survival model algorithm. Abbreviations. PAH, pulmonary arterial hypertension; RHC, right heart catheterization.

Table 3. Algorithm performance at key time points.

Concordance of the model is 0.732
Key time point	Sensitivity	Specificity	PPV	NPV
3 months	0.41	0.89	0.45	0.88
6 months	0.65	0.75	0.51	0.84
9 months	0.75	0.64	0.57	0.80
12 months	0.82	0.55	0.62	0.78
15 months	0.87	0.48	0.67	0.77
18 months	0.90	0.43	0.71	0.75
21 months	0.93	0.40	0.74	0.74
24 months	0.94	0.37	0.77	0.73
3 years	0.96	0.29	0.86	0.62
4 years	0.97	0.23	0.92	0.47
5 years	0.98	0.16	0.95	0.29

Abbreviations. NPV, negative predictive value; PPV, positive predictive value.

Table 4. Simplified risk score.

Risk factors in the prior 12 months	Points
Healthcare resource utilization
≥4 PAH-related outpatient visits	8
≥1 pulmonologist visits	6
≥1 hospitalization for any cause	5
Diagnosis
Dyspnea	5
Pulmonary fibrosis	2
Chest pain	1
≥3 months since treatment initiation	−10
Risk score range^a	−10–27
C-statistic (training set)	0.645
C-statistic (validation set)	0.668

^aRisk score is calculated as the sum of the points for each risk factor for given patient.

Figure 4. Kaplan-Meier curves for unsatisfactory response by risk groups.

Table 5. Predicted risk of an unsatisfactory response for hypothetical patient profiles.

Risk factors in the prior 12 months	Case 1	Score	Case 2	Score	Case 3	Score
Healthcare resource utilization
PAH-related outpatient visits	2 visits	0	3 visits	0	6 visits	8
Pulmonologist visits	0 visit	0	1 visit	6	2 visits	6
Hospitalization for any cause	0 visit	0	1 visit	5	2 visits	5
Diagnosis
Dyspnea	Yes	5	Yes	5	No	0
Pulmonary fibrosis	No	0	Yes	2	No	0
Chest pain	No	0	Yes	1	No	0
Time since treatment initiation	5 months	−10	12 months	−10	1 month	0
Total score	−5		9		19
Risk group	Low		Medium		High

Quan H, Li B, Couris CM, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173(6):676–682.

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Data availability statement

The data that support the findings of this study are available from Optum, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Any researchers interested in obtaining the data used in this study can access database through Optum, under a license agreement, including the payment of appropriate license fee.