Why carry out this study? |
Patients with connective tissue disease associated with pulmonary arterial hypertension (CTD-PAH) form the largest PAH etiological subgroup after idiopathic/heritable PAH (I/HPAH). |
However, patient characteristics, treatment patterns, safety profile, and outcomes of patients with CTD-PAH (including patients with systemic sclerosis [SSc], systemic lupus erythematosus [SLE], and mixed connective tissue disease [MCTD]-PAH) newly initiating macitentan are not well understood. |
The OPUS/OrPHeUS studies provide detailed insight into real-world clinical practice and management of patients with CTD-PAH and its subgroups, with differing disease severities and comorbidity burdens. |
What was learned from the study? |
Macitentan was used as part of combination therapy in most patients with CTD-PAH; however, contrary to guideline recommendations, a considerable proportion remained on monotherapy therapy at follow-up. |
Outcomes were similar between patients with CTD-PAH and I/HPAH and there were no unexpected safety findings, supporting the safety and tolerability of macitentan, including as a combination therapy in patients with CTD-PAH. |
Digital Features
Introduction
Methods
OPUS and OrPHeUS Study Design
Monitoring and Ethical Approval
Observations and Assessments
Statistical and Other Analyses
Results
Study Population and Characteristics
I/HPAH, N = 2498 | CTD-PAH, N = 1192a | SSc-PAH, N = 708 | SLE-PAH, N = 159 | MCTD-PAH, N = 124 | |
---|---|---|---|---|---|
Age, median (Q1, Q3) years | 64 (53, 73) | 62 (52, 70) | 64 (55, 71) | 49 (38, 62) | 57 (48, 65) |
Female sex, n (%) | 1826 (73.1) | 1028 (86.2) | 603 (85.2) | 152 (95.6) | 109 (87.9) |
Race, n (%) | |||||
Black or African American | 390 (15.7) | 234 (19.9) | 96 (13.7) | 51 (32.7) | 38 (30.9) |
White | 1936 (77.9) | 844 (71.7) | 558 (79.7) | 82 (52.6) | 67 (54.5) |
Otherb | 159 (6.4) | 99 (8.4) | 46 (6.6) | 23 (14.7) | 18 (14.6) |
Missing | 13 (0.5) | 15 (1.3) | 8 (1.1) | 3 (1.9) | 1 (0.8) |
Ethnicity, n (%) | |||||
Hispanic or Latino | 252 (10.1) | 127 (10.7) | 60 (8.5) | 32 (20.1) | 19 (15.4) |
Not Hispanic or Latino | 2131 (85.7) | 1019 (85.7) | 624 (88.3) | 119 (74.8) | 96 (78.0) |
Unknown | 105 (4.2) | 43 (3.6) | 23 (3.3) | 8 (5.0) | 8 (6.5) |
Missing | 10 (0.4) | 3 (0.3) | 1 (0.1) | 0 | 1 (0.8) |
Time from diagnosis, n (%) | 2440 (97.7) | 1156 (97.0) | 688 (97.2) | 153 (96.2) | 116 (93.5) |
Median (Q1, Q3) months | 7.0 (1.3, 36.8) | 6.3 (1.1, 35.1) | 7.9 (1.2, 38.7) | 6.0 (0.9, 44.3) | 4.6 (1.0, 27.8) |
≤ 6 months before macitentan initiation (incident), n (%) | 1154 (47.3) | 573 (49.6) | 325 (47.2) | 77 (50.3) | 61 (52.6) |
> 6 months before macitentan initiation (prevalent), n (%) | 1286 (52.7) | 583 (50.4) | 363 (52.8) | 76 (49.7) | 55 (47.4) |
WHO functional class, n (%) | 1383 (55.4) | 654 (54.9) | 380 (53.7) | 89 (56.0) | 68 (54.8) |
Ic | 117 (8.5) | 49 (7.5) | 28 (7.4) | 8 (9.0) | 2 (2.9) |
IIc | 419 (30.3) | 152 (23.2) | 90 (23.7) | 30 (33.7) | 10 (14.7) |
IIIc | 761 (55.0) | 412 (63.0) | 233 (61.3) | 46 (51.7) | 54 (79.4) |
IVc | 86 (6.2) | 41 (6.3) | 29 (7.6) | 5 (5.6) | 2 (2.9) |
Missing | 1115 (44.6) | 538 (45.1) | 328 (46.3) | 70 (44.0) | 56 (45.2) |
6-min walk distance, n (%) | 900 (36.0) | 454 (38.1) | 275 (38.8) | 62 (39.0) | 46 (37.1) |
Median (Q1, Q3) m | 289 (193, 375) | 279 (184, 362) | 274 (187, 360) | 344 (237, 397) | 286 (152, 362) |
Missing | 1598 (64.0) | 738 (61.9) | 433 (61.2) | 97 (61.0) | 78 (62.9) |
BNP/NT-proBNP risk category, n (%) | 813 (32.5) | 502 (42.1) | 293 (41.4) | 62 (39.0) | 55 (44.4) |
Lowd | 225 (27.7) | 113 (22.5) | 54 (18.4) | 17 (27.4) | 14 (25.5) |
Intermediated | 302 (37.1) | 187 (37.3) | 116 (39.6) | 19 (30.6) | 21 (38.2) |
Highd | 286 (35.2) | 202 (40.2) | 123 (42.0) | 26 (41.9) | 20 (36.4) |
Missing | 1685 (67.5) | 690 (57.9) | 415 (58.6) | 97 (61.0) | 69 (55.6) |
Relevant medical historye, n (%) | |||||
Hypertension | 929 (37.2) | 405 (34.0) | 251 (35.5) | 47 (29.6) | 35 (28.2) |
Obesity (BMI ≥ 30 kg/m2) | 851 (34.1) | 245 (20.6) | 128 (18.1) | 35 (22.0) | 21 (16.9) |
Anemiaf | 223 (8.9) | 166 (13.9) | 101 (14.3) | 27 (17.0) | 17 (13.7) |
Edemaf | 317 (12.7) | 156 (13.1) | 108 (15.3) | 14 (8.8) | 11 (8.9) |
Diabetes mellitus | 697 (27.9) | 153 (12.8) | 78 (11.0) | 18 (11.3) | 17 (13.7) |
Renal insufficiency | 196 (7.8) | 82 (6.9) | 54 (7.6) | 4 (2.5) | 12 (9.7) |
Hepatic comorbidities | 191 (7.6) | 77 (6.5) | 36 (5.1) | 17 (10.7) | 9 (7.3) |
≥ 1 commonly prescribed therapy, n (%) | 1910 (76.5) | 938 (78.7) | 565 (79.8) | 111 (69.8) | 98 (79.0) |
Diuretic | 1417 (56.7) | 673 (56.5) | 396 (55.9) | 79 (49.7) | 76 (61.3) |
Oxygen therapy | 890 (35.6) | 464 (38.9) | 285 (40.3) | 34 (21.4) | 50 (40.3) |
Anticoagulation agent | 767 (30.7) | 227 (19.0) | 133 (18.8) | 33 (20.8) | 24 (19.4) |
Calcium channel blocker | 377 (15.1) | 225 (18.9) | 161 (22.7) | 26 (16.4) | 12 (9.7) |
Treatment Patterns
I/HPAH, N = 2498 | CTD-PAH, N = 1192 | SSc-PAH, N = 708 | SLE-PAH, N = 159 | MCTD-PAH, N = 124 | |
---|---|---|---|---|---|
PAH-specific therapies prior to macitentan initiation | |||||
No previous PAH therapy, n (%) | 965 (38.6) | 377 (31.6) | 221 (31.2) | 55 (34.6) | 33 (26.6) |
≥ 1 previous PAH therapy, n (%) | 1533 (61.4) | 815 (68.4) | 487 (68.8) | 104 (65.4) | 91 (73.4) |
PDE5i | 1206 (48.3) | 662 (55.5) | 396 (55.9) | 85 (53.5) | 69 (55.6) |
ERA | 417 (16.7) | 203 (17.0) | 133 (18.8) | 24 (15.1) | 18 (14.5) |
Bosentan | 280 (11.2) | 126 (10.6) | 82 (11.6) | 19 (11.9) | 10 (8.1) |
Ambrisentan | 144 (5.8) | 78 (6.5) | 52 (7.3) | 5 (3.1) | 8 (6.5) |
i.v./s.c. prostanoid | 305 (12.2) | 142 (11.9) | 87 (12.3) | 22 (13.8) | 15 (12.1) |
Inhaled prostanoid | 142 (5.7) | 95 (8.0) | 62 (8.8) | 13 (8.2) | 11 (8.9) |
sGC stimulator | 105 (4.2) | 40 (3.4) | 23 (3.2) | 3 (1.9) | 8 (6.5) |
Oral prostanoid | 59 (2.4) | 30 (2.5) | 18 (2.5) | 2 (1.3) | 2 (1.6) |
Investigational druga | 5 (0.2) | 2 (0.2) | 2 (0.3) | 0 | 0 |
PAH-specific therapies ongoing at macitentan initiation | |||||
No concomitant PAH-specific therapy, n (%) | 1021 (40.9) | 410 (34.4) | 250 (35.3) | 58 (36.5) | 36 (29.0) |
≥ 1 concomitant PAH-specific therapy, n (%) | 1477 (59.1) | 782 (65.6) | 458 (64.7) | 101 (63.5) | 88 (71.0) |
ERAb | 64 (2.6) | 16 (1.3) | 9 (1.3) | 4 (2.5) | 1 (0.8) |
PDE5i | 1197 (47.9) | 670 (56.2) | 397 (56.1) | 87 (54.7) | 70 (56.5) |
i.v./s.c. prostanoid | 305 (12.2) | 136 (11.4) | 81 (11.4) | 20 (12.6) | 15 (12.1) |
Inhaled prostanoid | 122 (4.9) | 88 (7.4) | 56 (7.9) | 11 (6.9) | 10 (8.1) |
sGC stimulator | 108 (4.3) | 39 (3.3) | 24 (3.4) | 3 (1.9) | 7 (5.6) |
Oral prostanoid | 56 (2.2) | 26 (2.2) | 15 (2.1) | 3 (1.9) | 1 (0.8) |
Investigational druga | 5 (0.2) | 1 (0.1) | 1 (0.1) | 0 | 0 |
Kaplan–Meier estimates for time to additional PAH-specific therapy, % (95% CL)c | |||||
Monotherapy to combination therapy | |||||
Patients receiving monotherapy at macitentan initiation, n | 1044 | 412 | 253 | 58 | 35 |
Patients who escalated therapy up to 1 year | 31.8 (28.7, 35.1) | 39.2 (34.3, 44.5) | 40.0 (33.8, 46.9) | 17.0 (9.2, 30.2) | 48.3 (32.1, 67.5) |
Patients who escalated therapy up to 2 years | 40.7 (36.9, 44.6) | 49.4 (43.7, 55.3) | 49.7 (42.6, 57.3) | 31.4 (18.7, 49.7) | 53.5 (36.2, 72.9) |
Double to triple therapy | |||||
Patients receiving double therapy at macitentan initiation, n | 1118 | 595 | 336 | 79 | 71 |
Patients who escalated therapy up to 1 year | 13.9 (11.8, 16.4) | 22.8 (19.2, 26.9) | 20.7 (16.3, 26.1) | 24.2 (15.5, 36.5) | 23.6 (14.6, 36.8) |
Patients who escalated therapy up to 2 years | 22.0 (18.9, 25.5) | 31.3 (26.9, 36.2) | 28.7 (23.2, 35.2) | 27.0 (17.4, 40.3) | 36.4 (23.7, 53.0) |
Safety and Tolerability
I/HPAH, N = 2498 | CTD-PAH, N = 1192 | SSc-PAH, N = 708 | SLE-PAH, N = 159 | MCTD-PAH, N = 124 | |
---|---|---|---|---|---|
Observed exposure, median (Q1, Q3) months | 14.0 (5.1, 29.2) | 15.8 (5.6, 29.0) | 15.5 (5.9, 30.5) | 18.7 (5.6, 30.2) | 14.5 (6.2, 27.8) |
Patients who discontinued, n (%) | 1071 (42.9) | 485 (40.7) | 303 (42.8) | 57 (35.8) | 39 (31.5) |
Due to a non-hepatic AE | 434 (17.4) | 194 (16.3) | 134 (18.9) | 20 (12.6) | 16 (12.9) |
Due to an HAE | 5 (0.2) | 7 (0.6) | 5 (0.7) | 1 (0.6) | 1 (0.8) |
Not due to an AE/HAE | 465 (18.6) | 182 (15.3) | 95 (13.4) | 30 (18.9) | 12 (9.7) |
Missing reason | 167 (6.7) | 102 (8.6) | 69 (9.7) | 6 (3.8) | 10 (8.1) |
AEs (OPUS only), n | 1240 | 554 | 339 | 78 | 40 |
Patients with ≥ 1 AE, n (%) | 979 (79.0) | 460 (83.0) | 292 (86.1) | 62 (79.5) | 30 (75.0) |
Most common AEs (≥ 10% in any group), n (%) | |||||
Dyspnea | 273 (22.0) | 140 (25.3) | 99 (29.2) | 17 (21.8) | 8 (20.0) |
Headache | 143 (11.5) | 70 (12.6) | 41 (12.1) | 13 (16.7) | 5 (12.5) |
Peripheral edema | 129 (10.4) | 65 (11.7) | 43 (12.7) | 5 (6.4) | 6 (15.0) |
Dizziness | 90 (7.3) | 59 (10.6) | 38 (11.2) | 7 (9.0) | 5 (12.5) |
Pneumonia | 104 (8.4) | 59 (10.6) | 37 (10.9) | 7 (9.0) | 5 (12.5) |
Fatigue | 103 (8.3) | 57 (10.3) | 43 (12.7) | 5 (6.4) | 1 (2.5) |
Anemia | 90 (7.3) | 55 (9.9) | 38 (11.2) | 8 (10.3) | 2 (5.0) |
Nausea | 121 (9.8) | 51 (9.2) | 29 (8.6) | 6 (7.7) | 4 (10.0) |
Edema | 94 (7.6) | 50 (9.0) | 36 (10.6) | 7 (9.0) | 5 (12.5) |
Hypoxia | 68 (5.5) | 50 (9.0) | 31 (9.1) | 5 (6.4) | 4 (10.0) |
Cough | 84 (6.8) | 50 (9.0) | 29 (8.6) | 7 (9.0) | 5 (12.5) |
Aggravated condition | 87 (7.0) | 47 (8.5) | 34 (10.0) | 8 (10.3) | 1 (2.5) |
Chest pain | 83 (6.7) | 39 (7.0) | 28 (8.3) | 3 (3.8) | 5 (12.5) |
Exertional dyspnea | 48 (3.9) | 31 (5.6) | 17 (5.0) | 6 (7.7) | 5 (12.5) |
Vomiting | 57 (4.6) | 29 (5.2) | 14 (4.1) | 6 (7.7) | 4 (10.0) |
Pyrexia | 41 (3.3) | 28 (5.1) | 14 (4.1) | 4 (5.1) | 4 (10.0) |
Productive cough | 32 (2.6) | 27 (4.9) | 17 (5.0) | 3 (3.8) | 5 (12.5) |
Peripheral swelling | 60 (4.8) | 25 (4.5) | 15 (4.4) | 2 (2.6) | 5 (12.5) |
AESIs (OPUS only), n | 1240 | 554 | 339 | 78 | 40 |
Patients with ≥ 1 AESI of edemaa, n (%) | 344 (27.7) | 168 (30.3) | 116 (34.2) | 18 (23.1) | 13 (32.5) |
Patients with ≥ 1 AESI of anemia/hemoglobin decreaseb, n (%) | 122 (9.8) | 72 (13.0) | 53 (15.6) | 10 (12.8) | 2 (5.0) |
I/HPAH, N = 2498 | CTD-PAH, N = 1192 | SSc-PAH, N = 708 | SLE-PAH, N = 159 | MCTD-PAH, N = 124 | |
---|---|---|---|---|---|
HAE | |||||
Patients with ≥ 1 HAE, n (%) | 196 (7.8) | 92 (7.7) | 59 (8.3) | 12 (7.5) | 9 (7.3) |
Incidence rate, per person-year (95% CL)a | 0.05 (0.05, 0.06) | 0.05 (0.04, 0.06) | 0.05 (0.04, 0.07) | 0.05 (0.03, 0.08) | 0.05 (0.03, 0.10) |
HAESI | |||||
Patients with ≥ 1 HAESI, n (%) | 108 (4.3) | 47 (3.9) | 27 (3.8) | 8 (5.0) | 6 (4.8) |
Incidence rate, per person-year (95% CL)a | 0.03 (0.02, 0.04) | 0.03 (0.02, 0.03) | 0.02 (0.02, 0.03) | 0.03 (0.02, 0.06) | 0.03 (0.02, 0.08) |
Liver enzyme elevations | |||||
Patients with ALT/AST ≥ 3 × ULN, n (%) | 64 (2.6) | 35 (2.9) | 24 (3.4) | 3 (1.9) | 4 (3.2) |
Incidence rate, per person-year (95% CL)a | 0.02 (0.01, 0.02) | 0.02 (0.01, 0.03) | 0.02 (0.01, 0.03) | 0.01 (0.004, 0.03) | 0.02 (0.01, 0.06) |
Patients with ALT/AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN, n (%) | 8 (0.3) | 3 (0.3) | 2 (0.3) | 0 | 1 (0.8) |
Incidence rate, per person-year (95% CL)a | 0.002 (0.001, 0.004) | 0.002 (0.001, 0.005) | 0.002 (0.0004, 0.007) | 0 (0, NE) | 0.01 (0.001, 0.040) |
Hospitalization and Survival
I/HPAH, N = 2498 | CTD-PAH, N = 1192 | SSc-PAH, N = 708 | SLE-PAH, N = 159 | MCTD-PAH, N = 124 | |
---|---|---|---|---|---|
Patients with ≥ 1 hospitalization, n (%) | 1114 (44.6) | 579 (48.6) | 350 (49.4) | 66 (41.5) | 63 (50.8) |
Incidence rate, per person-year (95% CL) | 0.42 (0.39, 0.46) | 0.45 (0.40, 0.50) | 0.44 (0.38, 0.51) | 0.34 (0.25, 0.47) | 0.56 (0.39, 0.80) |
Kaplan–Meier estimates of freedom from hospitalizationa, % (95% CL) | |||||
Free from hospitalization at 1 year | 60.3 (58.1, 62.4) | 59.3 (56.1, 62.3) | 60.2 (56.2, 64.1) | 63.7 (54.9, 71.3) | 53.4 (43.2, 62.5) |
Free from hospitalization at 2 years | 45.3 (42.8, 47.8) | 43.4 (39.9, 46.8) | 42.6 (38.1, 47.1) | 54.4 (44.9, 62.9) | 38.5 (27.5, 49.3) |
Free from hospitalization at 30 monthsb | 40.5 (37.9, 43.1) | 38.8 (35.2, 42.4) | 37.2 (32.6, 41.8) | 49.5 (39.4, 58.8) | 35.9 (24.8, 47.2) |
Number of deaths, n (%) | 365 (14.6) | 191 (16.0) | 128 (18.1) | 15 (9.4) | 15 (12.1) |
Incidence rate, per person-year (95% CL) | 0.10 (0.09, 0.11) | 0.10 (0.09, 0.12) | 0.11 (0.09, 0.13) | 0.05 (0.03, 0.09) | 0.08 (0.05, 0.14) |