Table 1. EVDAS analysis: Reported characteristics in ACEi angioedema cases and ACEi controls and comparative analysis of ACEi angioedema cases versus ARBs and aliskiren angioedema cases.
| EVDAS analysis | Characteristics ACEi angioedema cases and ACEi controls | ACEi angioedema cases versus ACEi controls | ACEi angioedema cases versus ARBs angioedema cases k | ACEi angioedema cases versus aliskiren angioedema cases l | ||||
|---|---|---|---|---|---|---|---|---|
| ACEi angioedema cases (n = 3,194; 22.9%) | ACEi controls (n = 10,773; 77.1%) | unadjusted OR [+/- 95% CI] | logistic regression OR [+/- 95% CI] | unadjusted OR [+/- 95% CI] | logistic regression OR [+/- 95% CI] | unadjusted OR [+/- 95% CI] | logistic regression OR [+/- 95% CI] | |
| patient demographics | ||||||||
| mean age (median) [years] a | 66.8 (68.0) | 67.1 (69.0) | - | 1.0 [0.9–1.1] | - | 1.0 [0.9–1.2] | - | 1.1 [0.7–1.6] |
| female | 47.2% (1,506) | 48.6% (5,239) | 0.9 [0.9–1.0] | 1.0 [0.9–1.1] | 0.6 [0.5–0.8]* | 0.7 [0.6–0.9]* | 0.5 [0.4–0.8]* | 0.6 [0.4–0.9]* |
| male | ||||||||
| unknown | 50.6% (1,617) | 49.4% (5,323) | ||||||
| 2.2% (71) | 2.0% (211) | |||||||
| patients history | ||||||||
| smoker b | 2.1% (66) | 2.4% (255) | 0.9 [0.7–1.1] | 0.8 [0.6–1.1] | 1.0 [0.6–1.9] | 0.8 [0.4–1.5] | 1.6 [0.4–6.7] | 1.3 [0.3–5.7] |
| allergy c | 4.3% (137) | 2.1% (228) | 2.1 [1.7–2.6]* | 1.8 [1.4–2.3]* | 0.6 [0.4–0.9]* | 0.8 [0.5–1.1] | 0.3 [0.5–0.2]* | 0.4 [0.2–0.8]* |
| urticaria | 0.5% (17) | 0.1% (9) | 6.4 [2.8–14.4]* | 3.5 [1.4–8.4]* | 0.5 [0.2–1.2] | 0.5 [0.2–1.3] | - | - |
| angioedema d | 4.0% (129) | 0.1% (9) | 50.3 [25.6–99.1]* | 36.8 [18.5–73.3]* | 1.1 [0.7–1.9] | 1.1 [0.7–1.8] | 1.0 [0.4–2.4] | 1.4 [0.5–3.8] |
| comorbidities e | ||||||||
| renal disorders | 4.5% (144) | 6.4% (694) | 0.7 [0.6–0.8]* | 0.6 [0.5–0.8]* | 2.5 [1.4–4.5]* | 1.9 [1.1–3.5]* | 1.2 [0.5–2.7] | 0.9 [0.2–2.2] |
| diabetes | 10.2% (325) | 11.2% (1,206) | 0.9 [0.8–1.0] | - | 1.4 [1.0–1.9] | - | 0.9 [0.5–1.4] | - |
| asthma | 2.3% (74) | 1.3% (137) | 1.8 [1.4–2.4]* | 1.7 [1.2–2.3]* | 0.9 [0.5–1.6] | 0.9 [0.5–1.7] | 0.4 [0.2–0.9]* | 0.5 [0.2–1.1] |
| malignant tumors | 4.0% (127) | 4.3% (462) | 0.9 [0.8–1.1] | 0.9 [0.7–1.1] | 1.4 [0.8–2.2] | 1.1 [0.7–1.8] | 1.6 [0.6–4.3] | 1.8 [0.5–5.9] |
| thyroid disorders | 2.6% (82) | 2.8% (306) | 0.9 [0.7–1.2] | 0.9 [0.7–1.2] | 0.8 [0.5–1.3] | 0.8 [0.5–1.3] | 0.6 [0.3–1.2] | 0.6 [0.3–1.5] |
| administered ACEi f | ||||||||
| ramipril | 37.4% (1,195) | 45.3% (4,884) | 0.7 [0.7–0.8]* | 1.2 [1.0–1.4] | - | - | - | - |
| enalapril | 28.2% (902) | 21.8% (2,346) | 1.4 [1.3–1.5]* | 1.9 [1.6–2.3]* | - | - | - | - |
| perindopril | 16.1% (514) | 15.6% (1,676) | 1.0 [0.9–1.2] | 1.4 [1.2–1.7]* | - | - | - | - |
| lisinopril | 13.1% (419) | 10.2% (1,096) | 1.3 [1.2–1.5]* | 2.0 [1.6–2.5]* | - | - | - | - |
| comedication g | ||||||||
| β-blockers | 22.7% (725) | 30.3% (3,259) | 0.7 [0.6–0.7]* | 0.8 [0.7–0.9]* | 1.4 [1.1–1.7]* | 1.1 [0.9–1.4] | 1.3 [0.9–2.0] | 1.1 [0.7–1.9] |
| diuretics | 21.9% (700) | 34.5% (3,715) | 0.5 [0.5–0.6]* | 0.5 [0.4–0.6]* | 1.2 [0.9–1.4] | 1.0 [0.8–1.2] | 0.9 [0.6–1.3] | 0.8 [0.5–1.2] |
| calcium antagonists | 17.5% (558) | 16.9% (1,817) | 1.0 [0.9–1.2] | 1.1 [1.0–1.2] | 1.4 [1.1–1.9]* | 1.1 [0.8–1.4] | 0.6 [0.4–0.8] | 0.4 [0.3–0.6]* |
| ARBs | 4.0% (127) | 4.8% (518) | 0.8 [0.7–1.0] | 0.8 [0.7–1.0] | - | - | ||
| acetylsalicyclic acid | 19.9% (636) | 20.7% (2,235) | 0.9 [0.9–1.0] | 1.1 [1.0–1.2] | 2.0 [1.5–2.5]* | 1.4 [1.1–1.8]* | 1.6 [1.0–2.5] | 1.5 [0.9–2.6] |
| analgesics h | 11.4% (365) | 13.6% (1,469) | 0.8 [0.7–0.9]* | 0.8 [0.7–0.9]* | 1.3 [1.0–1.8]* | 1.1 [0.8–1.6] | 1.9 [1.0–3.6] | 2.6 [1.2–5.7]* |
| antidiabetics i | 10.1% (322) | 12.8% (1,376) | 0.8 [0.7–0.9]* | 0.8 [0.7–0.9]* | 1.0 [0.7–1.3] | 1.2[0.9–1.8] | 1.2 [0.7–2.0] | 1.6 [0.8–3.2] |
| DPPIVi | 2.1% (67) | 2.2% (232) | 1.0 [0.7–1.3] | 0.9 [0.6–1.2] | 0.7 [0.4–1.1] | 0.5 [0.3–0.9]* | 0.5 [0.2–1.3] | 0.6 [0.2–1.8] |
| mTORi | 1.3% (42) | 0.2% (18) | 8.0 [4.6–13.8]* | 8.9 [4.9–16.4]* | 4.3 [1.0–17.9] | 2.8 [0.7–12.0] | - | - |
| fibrinolytics | 1.2% (38) | 0.1% (9) | 14.4 [7.0–29.8]* | 16.3 [7.5–35.1]* | 7.8 [1.1–57.2]* | - | - | - |
| seriousness criteria j | ||||||||
| serious | 88.8% (2,836) | 73.9% (7,965) | 2.8 [2.5–3.1]* | 3.3 [2.9–3.7]* | 1.8 [1.5–2.3]* | 1.8 [1.4–2.3]* | 0.3 [0.1–0.6]* | 0.3 [0.1–0.9]* |
| death | 1.6% (52) | 2.7% (288) | 0.6 [0.4–0.8]* | - | 2.7 [1.0–7.4] | - | 0.6 [0.2–1.8] | - |
| life-threatening | 15.5% (496) | 5.9% (632) | 2.9 [2.6–3.3]* | - | 2.2 [1.6–2.9]* | - | 14.2 [3.5–57.4]* | - |
| hospitalization | 50.7% (1,619) | 45.6% (4,909) | 1.2 [1.1–1.3]* | - | 2.3 [1.9–2.8]* | - | 5.4 [3.5–8.3]* | - |
| disabling | 0.8% (27) | 2.4% (262) | 0.3 [0.2–0.5]* | - | 0.3 [0.2–0.5]* | - | 0.7 [0.2–2.8] | - |
*OR = 1 is not included; OR > 1 reported more often in ACEi angioedema cases; OR < 1 reported more often in ACEi controls, ARBs angioedema cases, alisiren angioedema cases
a age unknown: ACEi angioedema cases: 179 cases (5.4% of cases), ACEi controls: 717 cases (6.7% of cases).
b refers to current smoking at the time of the reported ADR. Former smokers were classified as non-smokers.
c the term "allergy" refers to a reported allergy and the occurrence of any allergic and hypersensitivity reactions reported in the history of the patient.
d urticaria was analyzed based on the HLT "urticarias". The term "angioedema" summarizes previous angioedema or swellings coded in the SMQ "angioedema (narrow)" reported in the history of the patient.
e suitable hierarchical levels of the MedDRA terminology were chosen for analysis of the reported patients’ comorbidities. The term "renal disorders" was identified using the SMQs "acute renal failure" and "chronic kidney disease"; "diabetes": SMQ "hyperglycaemia/new onset diabetes mellitus"; "asthma": SMQ "asthma/bronchospasm"; "malignant tumors": SMQ "malignant tumours"; "thyroid disorders": SMQ "thyroid dysfunction".
f the four ACEi monosubstances most frequently reported as "suspected/interacting" are tabulated. The relative number of ADR reports specifying one of the remaining ACEi (not listed) as "suspected/interacting" was lower than 2%. One ADR report may contain more than one ACEi as "suspected/interacting" drug substance. Thus, the number of reported ACEi exceeds that of the ADR reports.
g the analysis of the most frequently reported and most relevant comedications refers to monosubstances and combination products of the tabulated drug substances and/or drug classes and corresponds to the ATC classification. All drugs co-reported to the "suspected/interacting" ACEi were assessed as concomitant, regardless of whether they had been reported as "suspected", "interacting" or "concomitant".
h deviating from the ATC-code, the analysis concerning "analgesics" also includes ADR reports in which ibuprofen and/or diclofenac were listed as suspected/interacting or concomitant drug. We excluded ADR reports in which acetylsalicyclic acid was listed as suspected/interacting or concomitant drug. The number of ADR reports in which acetylsalicyclic acid was used concurrently were analyzed separately.
i deviating from the ATC-code, we excluded ADR reports in which a DPPIVi was listed as suspected/interacting or concomitant drug in the analysis concerning "diabetics". The number of ADR reports in which DPPIVi was used concurrently was analyzed separately.
j one ADR report may yield information about more than one seriousness criterion, therefore, the number of reported seriousness criteria exceeds that of the ADR reports.
k 44 cases which were included in ACEi angioedema cases and ARBs angioedema cases were excluded.
l 6 cases which were included in ACEi angioedema cases and aliskiren angioedema cases were excluded.