Background
Methods
Study design
Eligibility criteria
Data analysis
Results
Patient demographics and attack characteristics
Overall (N = 225) | US (n = 56) | Canada (n = 51) | Germany (n = 45) | Australia (n = 35) | UK (n = 24) | Italy (n = 14) | |
---|---|---|---|---|---|---|---|
Follow-up duration (y), mean ± SD | 5.5 ± 4.2 | 5.2 ± 4.0 | 7.0 ± 4.2 | 5.6 ± 3.4 | 5.9 ± 5.9 | 5.0 ± 2.3 | 1.3 ± 1.2 |
Year of index date, n (%)a | |||||||
2008 or earlier | 37 (16.4) | 5 (8.9) | 17 (33.3) | 9 (20.0) | 6 (17.1) | 0 | 0 |
2009–2011 | 52 (23.1) | 20 (35.7) | 9 (17.6) | 8 (17.8) | 8 (22.9) | 7 (29.2) | 0 |
2012–2014 | 56 (24.9) | 8 (14.3) | 19 (37.3) | 13 (28.9) | 7 (20.0) | 6 (25.0) | 3 (21.4) |
2015–2017 | 69 (30.7) | 18 (32.1) | 6 (11.8) | 13 (28.9) | 12 (34.3) | 10 (41.7) | 10 (71.4) |
2018 or later | 11 (4.9) | 5 (8.9) | 0 | 2 (4.4) | 2 (5.7) | 1 (4.2) | 1 (7.1) |
Age at index date, mean ± SDa | 36.8 ± 15.6 | 34.0 ± 12.9 | 35.7 ± 16.6 | 42.3 ± 15.8 | 32.1 ± 14.0 | 41.7 ± 17.6 | 38.0 ± 16.0 |
Female sex, n (%) | 141 (62.7) | 39 (69.6) | 35 (68.6) | 27 (60.0) | 18 (51.4) | 16 (66.7) | 6 (42.9) |
Race/ethnicity, n (%) | |||||||
White | 194 (86.2) | 52 (92.9) | 51 (100.0) | 27 (60.0) | 32 (91.4) | 22 (91.7) | 10 (71.4) |
Otherb | 7 (3.1) | 4 (7.1) | 0 | 0 | 3 (8.6) | 0 | 0 |
Unknown | 24 (10.7) | 0 | 0 | 18 (40.0) | 0 | 2 (8.3) | 4 (28.6) |
Type of HAE, n (%) | |||||||
Type 1 | 203 (90.2) | 46 (82.1) | 49 (96.1) | 40 (88.9) | 31 (88.6) | 23 (95.8) | 14 (100.0) |
Type 2 | 22 (9.8) | 10 (17.9) | 2 (3.9) | 5 (11.1) | 4 (11.4) | 1 (4.2) | 0 |
Family history of HAE, n (%) | |||||||
Yes | 160 (71.1) | 46 (82.1) | 33 (64.7) | 27 (60.0) | 24 (68.6) | 20 (83.3) | 10 (71.4) |
No | 38 (16.9) | 8 (14.3) | 13 (25.5) | 8 (17.8) | 2 (5.7) | 3 (12.5) | 4 (28.6) |
Unknown | 27 (12.0) | 2 (3.6) | 5 (9.8) | 10 (22.2) | 9 (25.7) | 1 (4.2) | 0 |
Comorbidities, (%)c | |||||||
Any comorbidities | 105 (46.7) | 29 (51.8) | 34 (66.7) | 12 (26.7) | 17 (48.6) | 9 (37.5) | 4 (28.6) |
Allergy or anaphylaxisd | 36 (16.0) | 8 (14.3) | 18 (35.3) | 2 (4.4) | 7 (20.0) | 0 | 1 (7.1) |
Metabolice | 25 (11.1) | 10 (17.9) | 6 (11.8) | 3 (6.7) | 4 (11.4) | 2 (8.3) | 0 |
Psychiatricf | 25 (11.1) | 9 (16.1) | 8 (15.7) | 1 (2.2) | 6 (17.1) | 1 (4.2) | 0 |
Cardiovascularg | 22 (9.8) | 5 (8.9) | 5 (9.8) | 4 (8.9) | 4 (11.4) | 3 (12.5) | 1 (7.1) |
Gastrointestinalh | 20 (8.9) | 2 (3.6) | 13 (25.5) | 0 | 3 (8.6) | 1 (4.2) | 1 (7.1) |
Canceri | 9 (4.0) | 0 | 6 (11.8) | 1 (2.2) | 1 (2.9) | 1 (4.2) | 0 |
Autoimmunej | 3 (1.3) | 0 | 1 (2.0) | 2 (4.4) | 0 | 0 | 0 |
Treatment patterns
n (%) | Overall (N = 545) | US (n = 140) | Canada (n = 112) | Germany (n = 74) | Australia (n = 103) | UK (n = 116) |
---|---|---|---|---|---|---|
Yes | 421 (77.2) | 112 (80.0) | 58 (51.8) | 45 (60.8) | 90 (87.4) | 116 (100) |
C1-INH: Berinert® | 257 (61.0) | 20 (17.9) | 55 (94.8) | 42 (93.3) | 52 (57.8) | 88 (75.9) |
Intravenous | 249 (96.9) | 20 (100) | 47 (85.5) | 42 (100) | 52 (100) | 88 (100) |
Subcutaneousa | 8 (3.1) | 0 | 8 (14.5) | 0 | 0 | 0 |
Icatibant | 99 (23.5) | 60 (53.6) | 1 (1.7) | 3 (6.7) | 33 (36.7) | 2 (1.7) |
C1-INH: Cinryze® | 51 (12.1) | 24 (21.4) | 0 | 0 | 1 (1.1) | 26 (22.4) |
Androgens | 7 (1.7) | 2 (1.8) | 2 (3.4) | 0 | 3 (3.3) | 0 |
Ecallantide | 4 (1.0) | 4 (3.6) | 0 | 0 | 0 | 0 |
Fresh frozen plasma | 3 (0.7) | 2 (1.8) | 0 | 0 | 1 (1.1) | 0 |
No | 54 (9.9) | 11 (7.9) | 6 (5.4) | 27 (36.5) | 10 (9.7) | 0 |
Unknown | 70 (12.8) | 17 (12.1) | 48 (42.9) | 2 (2.7) | 3 (2.9) | 0 |
n (%) | Overall (N = 225) | US (n = 56) | Canada (n = 51) | Germany (n = 45) | Australia (n = 35) | UK (n = 24) | Italy (n = 14) |
---|---|---|---|---|---|---|---|
Patients with any LTP usea | 121 (53.8) | 34 (60.7) | 33 (64.7) | 13 (28.9) | 19 (54.3) | 21 (87.5) | 1 (7.1) |
Plasma-derived C1-INH | |||||||
Berinert® | 31 (25.6) | 2 (5.9) | 17 (51.5) | 4 (30.8) | 7 (36.8) | 1 (4.8) | 0 |
Intravenous | 25 (20.7) | 2 (5.9) | 14 (42.4) | 1 (7.7) | 7 (36.8) | 1 (4.8) | 0 |
Subcutaneousb | 8 (6.6) | 0 | 4 (12.1) | 4 (30.8) | 0 | 0 | 0 |
Cinryze® | 36 (29.8) | 21 (61.8) | 6 (18.2) | 7 (53.8) | 0 | 2 (9.5) | 0 |
Haegarda® | 9 (7.4) | 9 (26.5) | 0 | 0 | 0 | 0 | 0 |
Androgen therapy | |||||||
Danazol | 65 (53.7) | 15 (44.1) | 19 (57.6) | 2 (15.4) | 11 (57.9) | 18 (85.7) | 0 |
Stanozolol | 7 (5.8) | 3 (8.8) | 1 (3.0) | 0 | 3 (15.8) | 0 | 0 |
Oxandrolone | 3 (2.5) | 0 | 0 | 0 | 1 (5.3) | 2 (9.5) | 0 |
Tranexamic acid | 15 (12.4) | 0 | 5 (15.2) | 0 | 7 (36.8) | 2 (9.5) | 1 (100.0) |
Ruconest® | 1 (0.8) | 1 (2.9) | 0 | 0 | 0 | 0 | 0 |
Lanadelumab | 11 (9.1) | 7 (20.6) | 0 | 4 (30.8) | 0 | 0 | 0 |
Overall (N = 121) | US (n = 34) | Canada (n = 33) | Germany (n = 13) | Australia (n = 19) | UK (n = 21) | Italy (n = 1) | |
---|---|---|---|---|---|---|---|
Patients with any dose modification | 42 (34.7) | 15 (44.1) | 13 (39.4) | 2 (15.4) | 4 (21.1) | 8 (38.1) | 0 |
Patients with any up-dosinga | 30 (24.8) | 10 (29.4) | 13 (39.4) | 0 | 2 (10.5) | 5 (23.8) | 0 |
Berinert® | n = 31 | n = 2 | n = 17 | n = 4 | n = 7 | n = 1 | n = 0 |
Dose modification | 8 (25.8) | 0 | 6 (35.3) | 0 | 2 (28.6) | 0 | NA |
Up-dosing | 8 (25.8) | 0 | 6 (35.3) | 0 | 2 (28.6) | 0 | NA |
Cinryze® | n = 36 | n = 21 | n = 6 | n = 7 | n = 0 | n = 2 | n = 0 |
Dose modification | 13 (36.1) | 12 (57.1) | 1 (16.7) | 0 | NA | 0 | NA |
Up-dosing | 9 (25.0) | 8 (38.1) | 1 (16.7) | 0 | NA | 0 | NA |
Danazol | n = 65 | n = 15 | n = 19 | n = 2 | n = 11 | n = 18 | n = 0 |
Dose modification | 21 (32.3) | 4 (26.7) | 6 (31.6) | 1 (50.0) | 2 (18.2) | 8 (44.4) | NA |
Up-dosing | 13 (20.0) | 2 (13.3) | 6 (31.6) | 0 | 0 | 5 (27.8) | NA |
Tranexamic acid | n = 15 | n = 0 | n = 5 | n = 0 | n = 7 | n = 2 | n = 1 |
Dose modification | 3 (20.0) | NA | 3 (60.0) | NA | 0 | 0 | 0 |
Up-dosing | 3 (20.0) | NA | 3 (60.0) | NA | 0 | 0 | 0 |
Lanadelumab | n = 11 | n = 7 | n = 0 | n = 4 | n = 0 | n = 0 | n = 0 |
Dose modification | 1 (9.1) | 0 | NA | 1 (25.0) | NA | NA | NA |
Up-dosing | 0 | NA | 0 | 0 | NA | NA | NA |
LTP reduces HAE attack rate
Overall (N = 131) | US (n = 34) | Canada (n = 42) | Germany (n = 17) | Australia (n = 19) | UK (n = 12) | Italy (n = 7) | |
---|---|---|---|---|---|---|---|
Annual attack rate | |||||||
Mean ± SD | 20.2 ± 16.9 | 21.8 ± 17.5 | 17.4 ± 17.0 | 25.6 ± 13.5 | 17.8 ± 14.8 | 23.4 ± 24.7 | 17.5 ± 9.7 |
Median (range) | 14.1 (0, 84.1) | 15.9 (0, 72.0) | 11.9 (0.3, 79.3) | 24.0 (4.0, 52.2) | 14.0 (2.0, 52.2) | 11.8 (0.3, 84.1) | 13.8 (6.0, 33.2) |
Received LTPa | 79 (60.3) | 22 (64.7) | 28 (66.7) | 6 (35.3) | 11 (57.9) | 11 (91.7) | 1 (14.3) |
Annual attack rate | |||||||
Mean ± SD | 20.8 ± 18.9 | 26.9 ± 19.1 | 14.6 ± 13.2 | 35.4 ± 13.8 | 12.9 ± 15.2 | 25.0 ± 28.3 | 9.7 ± |
Median (range) | 13.9 (0, 84.1) | 20.7 (0, 72.0) | 11.6 (0.3, 52.2) | 30.0 (24.0, 52.2) | 5.6 (1.1, 52.2) | 12.0 (0.3, 84.1) | 9.7 (9.7, 9.7) |
Did not receive LTPa | 52 (39.7) | 12 (35.3) | 14 (33.3) | 11 (64.7) | 8 (42.1) | 1 (8.3) | 6 (85.7) |
Annual attack rate | |||||||
Mean ± SD | 20.3 ± 16.8 | 14.1 ± 14.7 | 23.4 ± 24.4 | 20.2 ± 10.3 | 22.9 ± 14.3 | 43.0 ± | 18.7 ± 10.1 |
Median (range) | 15.7 (0.3, 79.3) | 9.4 (0.9, 48.2) | 15.7 (0.3, 79.3) | 24.0 (4.0, 36.0) | 23.8 (2.0, 52.2) | 43.0 (43.0, 43.0) | 18.9 (6.0, 33.2) |
HAE attack rate (N = 131) | ||
---|---|---|
IRR (95% CI) | P-value | |
Treatment type | ||
Any LTP (ref: no LTP) | 0.90 (0.84–0.96) | 0.002 |
Baseline covariates | ||
Male sex (ref: female) | 0.94 (0.88–1.00) | 0.043 |
Age at HAE diagnosis (per 10 years) | 1.03 (1.01–1.05) | 0.001 |
HAE attacks before index date (ref: < median) | 1.67 (1.57–1.77) | < 0.001 |
Country of residence (ref: US) | ||
Canada | 0.76 (0.70–0.81) | < 0.001 |
Germany | 0.91 (0.83–1.01) | 0.075 |
Australia | 0.85 (0.78–0.92) | < 0.001 |
UK | 0.86 (0.76–0.97) | 0.014 |
Italy | 0.48 (0.37–0.63) | < 0.001 |
Family history of HAE (ref: no family history) | 1.27 (1.17–1.37) | < 0.001 |
Type 1 HAE (ref: type 2 HAE) | 0.81 (0.75–0.88) | < 0.001 |
Any preexisting comorbidity (ref: no preexisting comorbidity) | 1.13 (1.07–1.20) | < 0.001 |
Previous misdiagnosis (ref: no previous misdiagnosis) | 0.83 (0.75–0.91) | < 0.001 |
LTP discontinuation
Overall (N = 225) | US (n = 56) | Canada (n = 51) | Germany (n = 45) | Australia (n = 35) | UK (n = 24) | Italy (n = 14) | |
---|---|---|---|---|---|---|---|
Patients who discontinued LTP | n = 76 | n = 26 | n = 25 | n = 4 | n = 15 | n = 6 | n = 0 |
Intolerable adverse drug reaction(s) | 22 (28.9) | 4 (15.4) | 7 (28.0) | 0 | 7 (46.7) | 4 (66.7) | – |
Medication not effective | 17 (22.4) | 3 (11.5) | 8 (32.0) | 1 (25.0) | 5 (33.3) | 0 | – |
Discontinued access to medication | 10 (13.2) | 6 (23.1) | 1 (4.0) | 0 | 3 (20.0) | 0 | – |
Inconvenient route of administration | 9 (11.8) | 6 (23.1) | 3 (12.0) | 0 | 0 | 0 | – |
Fear of potential adverse drug reaction(s) | 8 (10.5) | 1 (3.8) | 7 (28.0) | 0 | 0 | 0 | – |
Patient noncompliance | 3 (3.9) | 0 | 2 (8.0) | 0 | 1 (6.7) | 0 | – |
Drug–drug interactions | 2 (2.6) | 0 | 0 | 2 (50.0) | 0 | 0 | – |
Drug–concomitant disease interactions | 2 (2.6) | 0 | 0 | 0 | 2 (13.3) | 0 | – |
Othera | 17 (22.4) | 4 (15.4) | 10 (40.0) | 1 (25.0) | 1 (6.7) | 1 (16.7) | – |
Unknown | 7 (9.2) | 4 (15.4) | 1 (4.0) | 1 (25.0) | 0 | 1 (16.7) | – |
Berinert® | n = 9 | n = 2 | n = 6 | n = 1 | n = 0 | n = 0 | – |
Inconvenient route of administration | 2 (22.2) | 0 | 2 (33.3) | 0 | – | – | – |
Medication not effective | 1 (11.1) | 1 (50.0) | 0 | 0 | – | – | – |
Patient noncompliance | 1 (11.1) | 0 | 1 (16.7) | 0 | – | – | – |
Othera | 5 (55.6) | 1 (50.0) | 3 (50.0) | 1 (100) | – | – | – |
Cinryze® | n = 17 | n = 15 | n = 1 | n = 1 | n = 0 | n = 0 | – |
Discontinued access to medication | 6 (35.3) | 6 (40.0) | 0 | 0 | – | – | – |
Inconvenient route of administration | 6 (35.3) | 6 (40.0) | 0 | 0 | – | – | – |
Medication not effective | 3 (17.6) | 2 (13.3) | 1 (100) | 0 | – | – | – |
Othera | 1 (5.9) | 1 (6.7) | 0 | 0 | – | – | – |
Unknown | 3 (17.6) | 2 (13.3) | 0 | 1 (100) | – | – | – |
Danazol | n = 32 | n = 6 | n = 12 | n = 2 | n = 8 | n = 4 | – |
Intolerable adverse drug reaction(s) | 17 (53.1) | 3 (50.0) | 6 (50.0) | 0 | 5 (62.5) | 3 (75.0) | – |
Fear of potential adverse drug reaction(s) | 7 (21.9) | 1 (16.7) | 6 (50.0) | 0 | 0 | 0 | – |
Medication not effective | 5 (15.6) | 0 | 3 (25.0) | 1 (50.0) | 1 (12.5) | 0 | – |
Drug–drug interaction(s) | 2 (6.3) | 0 | 0 | 2 (100) | 0 | 0 | – |
Discontinued access to medication | 2 (6.3) | 0 | 0 | 0 | 2 (25.0) | 0 | – |
Inconvenient route of administration | 1 (3.1) | 0 | 1 (8.3) | 0 | 0 | 0 | – |
Drug–concomitant disease interaction(s) | 1 (3.1) | 0 | 0 | 0 | 1 (12.5) | 0 | – |
Othera | 9 (28.1) | 1 (16.7) | 7 (58.3) | 0 | 1 (12.5) | 0 | – |
Unknown | 3 (9.4) | 1 (16.7) | 1 (8.3) | 0 | 0 | 1 (25.0) | – |
Stanozolol | n = 6 | n = 2 | n = 1 | n = 0 | n = 3 | n = 0 | – |
Intolerable adverse drug reaction(s) | 2 (33.3) | 1 (50.0) | 0 | – | 1 (33.3) | – | – |
Discontinued access to medication | 2 (33.3) | 0 | 1 (100) | – | 1 (33.3) | – | – |
Medication not effective | 1 (16.7) | 0 | 0 | – | 1 (33.3) | – | – |
Drug–concomitant disease interaction(s) | 1 (16.7) | 0 | 0 | – | 1 (33.3) | – | – |
Unknown | 1 (16.7) | 1 (50.0) | 0 | – | 0 | – | – |
Oxandrolone | n = 1 | n = 0 | n = 0 | n = 0 | n = 1 | n = 0 | – |
Medication not effective | 1 (100) | – | – | – | 1 (100) | – | – |
Tranexamic acid | n = 10 | n = 0 | n = 5 | n = 0 | n = 3 | n = 2 | – |
Medication not effective | 6 (60.0) | – | 4 (80.0) | – | 2 (66.7) | 0 | – |
Intolerable adverse drug reaction(s) | 3 (30.0) | – | 1 (20.0) | – | 1 (33.3) | 1 (50.0) | – |
Patient noncompliance | 2 (20.0) | – | 1 (20.0) | – | 1 (33.3) | 0 | – |
Fear of potential adverse drug reaction(s) | 1 (10.0) | – | 1 (20.0) | – | 0 | 0 | – |
Othera | 1 (10.0) | – | 0 | – | 0 | 1 (50.0) | – |
Ruconest® | n = 1 | n = 1 | n = 0 | n = 0 | n = 0 | n = 0 | – |
Othera | 1 (100) | 1 (100) | – | – | – | – | – |
Healthcare resource utilization
Patients with any HRU episodes, N (%) Annual rate, mean ± SD [median] | Overall (N = 225) | US (n = 56) | Canada (n = 51) | Germany (n = 45) | Australia (n = 35) | UK (n = 24) | Italy (n = 14) |
---|---|---|---|---|---|---|---|
HRU visits (any reason) | 137 (60.9) 4.4 ± 9.0 [2.2] | 23 (41.1) 3.5 ± 4.4 [2.1] | 50 (98.0) 4.3 ± 12.0 [2.2] | N/A | 34 (97.1) 5.9 ± 9.1 [2.5] | 24 (100) 4.0 ± 4.5 [2.6] | 6 (42.9) 1.8 ± 1.8 [1.1] |
Routine HAE-related outpatient visits | 128 (93.4) 2.3 ± 4.2 [1.6] | 21 (91.3) 1.7 ± 2.2 [1.0] | 45 (90.0) 1.8 ± 1.1 [1.5] | N/A | 33 (97.1) 3.4 ± 7.4 [1.6] | 24 (100) 2.6 ± 2.8 [1.9] | 5 (83.3) 1.5 ± 1.9 [0.7] |
HAE attack-related visits | 70 (51.1) 2.8 ± 10.2 [0.7] | 12 (52.2) 0.8 ± 1.1 [0.4] | 30 (60.0) 3.9 ± 15.2 [0.8] | N/A | 19 (55.9) 2.3 ± 3.8 [1.0] | 8 (33.3) 2.7 ± 3.4 [0.7] | 1 (16.7) 2.9 ± [2.9] |
Emergency room visits | 53 (38.7) 1.3 ± 1.8 [0.7] | 8 (34.8) 0.6 ± 0.7 [0.2] | 23 (46.0) 1.0 ± 1.2 [0.8] | N/A | 17 (50.0) 1.9 ± 2.4 [0.7] | 5 (20.8) 2.1 ± 2.7 [0.7] | 0 NA |
Hospitalizations | 12 (8.8) 1.1 ± 2.3 [0.3] | 0 NA | 5 (10.0) 0.2 ± 0.1 [0.1] | N/A | 4 (11.8) 2.4 ± 3.8 [0.6] | 3 (12.5) 1.0 ± 1.2 [0.4] | 0 NA |
Outpatient visitsa | 32 (23.4) 3.5 ± 14.8 [0.3] | 7 (30.4) 0.7 ± 1.3 [0.2] | 15 (30.0) 6.3 ± 21.6 [0.3] | N/A | 4 (11.8) 0.4 ± 0.4 [0.4] | 5 (20.8) 1.7 ± 2.3 [0.7] | 1 (16.7) 2.9 ± [2.9] |