What literature is there to support using Berinert for treatment of hereditary angioedema attacks vs. supportive care? How do outcomes compare between patients treated with Berinert and those treated with FFP?

Comment by InpharmD Researcher

There is a lack of literature directly comparing Berinert with supportive care alone for hereditary angioedema (HAE) attacks. Current guidelines consistently recommend prompt on-demand pharmacologic treatment of HAE attacks, with intravenous C1 inhibitor (C1-INH), including plasma-derived C1-INH products such as Berinert, considered a first-line option for HAE type 1/2 attacks. Early treatment has been associated with shorter time to symptom relief and shorter overall attack duration. In the absence of effective on-demand treatment, patients may require supportive measures such as IV fluids, antiemetics, narcotic pain medication, or intubation; however, morbidity is significantly higher when effective on-demand therapy is not administered (Table 1). Overall, available evidence supports on-demand treatment with intravenous C1-INH for HAE attacks, while direct comparative data versus supportive care alone are lacking.

A comprehensive literature search identified 3 practice guidelines, 3 tertiary sources, and 7 primary sources relevant to this inquiry.

Background

The international 2021 guidelines published by the World Allergy Organization (WAO) and European Academy of Allergy and Clinical Immunology (EAACI) recommend that all hereditary angioedema (HAE) attacks be considered for on-demand treatment, with treatment considered mandatory for attacks affecting or potentially affecting the upper airways. Early treatment improves outcomes, with earlier use of intravenous C1 inhibitor (C1-INH), ecallantide, or icatibant associated with shorter time to symptom resolution and shorter total attack duration. Because early treatment is facilitated by self-administration, patients with HAE type 1 or 2 (HAE-1/2) should be considered for home therapy and self-administration training. [1]

For HAE-1/2, recommended on-demand treatments of choice are intravenous C1-INH [Breinert® (CSL Behring) and Cinryze® (Takeda)], ecallantide, and icatibant. If these first-line therapies are unavailable, solvent detergent-treated plasma (SDP) is recommended; if SDP is unavailable, fresh frozen plasma (FFP) may be used where a safe supply exists as third-line treatment. The panel also notes that FFP may be used for short-term prophylaxis when intravenous plasma-derived C1-INH is unavailable; however, FFP is considered a second-line option because it is not as safe as intravenous plasma-derived C1-INH and carries a greater risk of blood-borne disease transmission and allosensitization. Antifibrinolytics such as tranexamic acid or androgens such as danazol are not recommended for on-demand treatment, as these agents provide no or only minimal benefit. For treatment of HAE in children and adolescents, ecallantide is considered first-line; C1-INH and icatibant can be used, with SDP preferred over FFP when both C1-INH and icatibant are unavailable, but all are considered second-line to ecallantide. [1]

Regarding C1-INH treatment, plasma-derived or recombinant C1-INH replaces the deficient or dysfunctional protein in HAE-1/2, increasing plasma C1-INH levels and helping regulate the cascade systems involved in bradykinin generation during attacks. Only intravenous administration of C1-INH is considered effective for on-demand treatment. Available plasma-derived products for on-demand treatment include Berinert® and Cinryze®, and recombinant C1-INH (Ruconest®) is also described as an option for acute attacks. Available plasma-derived C1-INH products are reported to have good safety and tolerability, with few adverse events reported and negligible risk of allergic reactions. [1]

For severe attacks involving the upper airway, laryngeal HAE attacks are considered medical emergencies and require rapid administration of an effective HAE on-demand medication along with preparation for airway management. In progressive upper-airway edema, early intubation or surgical airway intervention should be considered if respiratory compromise develops. Patients should also carry sufficient on-demand medication to treat at least two attacks at all times. Overall, the guideline emphasizes treatment of acute HAE attacks with on-demand medications and recommends FFP only when preferred on-demand therapies are unavailable and does not provide separate recommendations for supportive care alone. [1]

The 2020 US Hereditary Angioedema Association (HAEA) Medical Advisory Board guidelines provide similar recommendations, stating that patients should have ready access to effective on-demand medication and that a Food and Drug Administration (FDA)-approved on-demand HAE medication, including ecallantide, icatibant, plasma-derived C1-INH, or recombinant C1-INH, should be used as first-line treatment whenever possible. If FDA-approved on-demand therapies are unavailable, FFP may be used because it contains C1-INH, although its efficacy has not been evaluated in randomized trials or in direct, comparative studies against C1-INH therapies. The guideline also notes anecdotal reports of symptom worsening following FFP administration, possibly related to the presence of substrates involved in bradykinin generation, and recommends that airway precautions be maintained when FFP is used, particularly in patients with oropharyngeal or laryngeal involvement. Solvent detergent-treated plasma may represent a safer alternative because of its lower viral transmission risk. The guideline states that all HAE attacks are eligible for treatment regardless of swelling location or severity. In the absence of effective on-demand treatment, patients may require supportive measures such as IV fluids, antiemetics, narcotic pain medication, or intubation; however, morbidity is significantly higher when effective on-demand therapy is not administered (Table 1). For short-term prophylaxis, FFP may also be considered when plasma-derived C1-INH is unavailable and there is insufficient time to administer a course of anabolic androgens. [2]

A 2013 comprehensive document by the Joint Task Force on Practice Parameters (JTFPP), representing the American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI), addresses HAE, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor (ACE-I)–associated angioedema. The guideline notes that consensus United States and international guidelines recommend that all patients with HAE have access to an effective on-demand HAE-specific agent. It further states that evidence from double-blind, placebo-controlled, randomized clinical trials demonstrates the efficacy and safety of C1-INH concentrates, plasma kallikrein inhibitors, and bradykinin B2 receptor antagonists for acute HAE attacks. FFP is described as often effective in aborting acute HAE attacks; however, it may acutely exacerbate some attacks, and its use requires caution (strength of recommendation D). The guideline also states that epinephrine, corticosteroids, antihistamines, anabolic androgens, and antifibrinolytic agents are not recommended as reliable treatments for acute HAE attacks. Reinforcing other guidance documents, the panel mentions that, for short-term prophylaxis, FFP, C1-INH replacement, or short-term high-dose anabolic androgen therapy are identified as treatment options, whereas plasma-derived C1-INH is considered an effective and safe option for long-term prophylaxis. [3]

Available review articles do not present direct comparative outcomes data between C1-INH and FFP for acute HAE attacks. Rather, available literature describes C1-INH concentrate as the preferred treatment based on evidence from randomized, placebo-controlled trials demonstrating rapid symptom improvement, with many patients experiencing relief within 30 minutes and a favorable safety profile comparable to placebo. FFP is described as an alternative when C1-INH is unavailable. Although FFP has been used successfully to treat acute HAE attacks, the reviews note that it remains controversial because it contains kininogens and other substrates that may theoretically worsen HAE attacks. Compared with FFP, C1-INH is described as having a superior benefit and adverse effect profile and greater viral safety because of purification and pasteurization processes. [4], [5], [6]

Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-7 for your response.

Efficacy of on-demand treatment in reducing morbidity in patients with hereditary angioedema due to C1 inhibitor deficiency
Design	Prospective observational study N= 227
Objective	To evaluate the efficacy of on-demand treatment in reducing morbidity in patients with hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency
Study Groups	All patients (N= 227)
Inclusion Criteria	Patients with diagnosis of C1-INH-HAE based on family and/or personal history of recurrent angioedema and laboratory levels of C1-INH <50% of normal
Exclusion Criteria	Not specified
Methods	Data were derived from yearly patient diaries collected between 2009 and 2014. Per guideline-based routine care, all patients had home access to on-demand treatment and were advised to treat attacks at symptom onset. Approved on-demand therapies in Italy during the study period included plasma-derived C1-INH (Berinert, Cinryze), icatibant, and recombinant human C1-INH; however, this report included only Berinert and icatibant data, as Cinryze and Ruconest use was minimal after later market approval. Diaries captured attack onset and resolution, location, severity, treatment used and timing, and any need for medical assistance or hospitalization.
Duration	January 2009 to August 2014
Outcome Measures	Reduction in attack duration and morbidity; frequency of on-demand treatment use; self-administration rates; need for second treatment
Baseline Characteristics		All patients (N= 227)
	Female	63%
	C1-INH-HAE type I	90%
	Age, years (IQR)	43 (29–54)
	Abbreviations: IQR, interquartile range. Sixty-two patients were receiving long-term prophylaxis with attenuated androgens (n= 48) or tranexamic acid (n= 14).
Results	Among 227 patients who returned diaries, 4244 attacks were reported, with a mean attack frequency of 10.5 per year; attacks were most often peripheral (46%) or abdominal (34%), and 3% were laryngeal. Half of attacks received on-demand treatment, with use ranging from 89% of laryngeal attacks to 37% of peripheral attacks; self-administration occurred in 59% of pdC1-INH-treated attacks and 93% of icatibant-treated attacks. Median attack duration was 11.5 hours with pdC1-INH and 8 hours with icatibant, compared with 38 hours for tranexamic acid-treated attacks and 45 hours for untreated attacks. For pdC1-INH, attacks treated within 2 hours lasted 6 hours versus 13 hours when treated after 4 hours (p< 0.0001), and a second treatment within 48 hours was used in 24 attacks (1.9%). More than 70% of attacks treated on demand resolved within 24 hours compared with fewer than 25% of untreated attacks, and on-demand treatment was estimated to reduce time spent with angioedema symptoms by 78%.
Adverse Events	Not assessed.
Study Author Conclusions	This study provides evidence that on-demand treatment is effective in reducing disease-related morbidity. The use of on-demand treatment in Italy has increased up to 50% of attacks in the last years, reflecting a better adherence to international guidelines.
Critique	The study provides supportive evidence for the effectiveness of on-demand treatment in reducing morbidity, but lacks an active control group. Additional limitations include the absence of randomization and the potential for reporting bias from patient diaries.

Table 1 References:
[7] Zanichelli A, Mansi M, Azin GM, et al. Efficacy of on-demand treatment in reducing morbidity in patients with hereditary angioedema due to C1 inhibitor deficiency. Allergy. 2015;70(12):1553-1558. doi:10.1111/all.12731

Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks
Design	Randomized, double-blind, placebo-controlled study N= 125
Objective	To compare the efficacy of pasteurized C1 esterase inhibitor (C1-INH) concentrate (Berinert, CSL Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema (HAE)
Study Groups	Placebo (n= 42) C1-INH 10 U/kg (n= 39) C1-INH 20 U/kg (n= 43)
Inclusion Criteria	Patients at least 6 years of age with laboratory-confirmed C1-INH deficiency (type I or II HAE) treated within 5 hours of an acute moderate to severe abdominal or facial attack
Exclusion Criteria	History of hypersensitivity to C1-INH concentrates, acquired angioedema, other types of angioedema, abdominal pain not associated with C1-INH deficiency, habitual use of narcotics, or use of pain medication during a current attack
Methods	Patients received a single intravenous infusion of either C1-INH (Berinert) at a dose of 10 or 20 U/kg, or placebo. Patients were observed for a minimum of 4 hours after treatment. Rescue medication was available if needed. Viral safety assessment was performed before and up to 12 weeks after treatment.
Duration	August 2005 to December 2007
Outcome Measures	Primary: Time from start of treatment to onset of symptom relief Secondary: Time to complete resolution of all HAE symptoms, proportion of patients with worsened intensity of symptoms between 2 and 4 hours after treatment, number of vomiting episodes within 4 hours
Baseline Characteristics		Placebo (n= 42)	C1-INH 10 U/kg (n= 39)	C1-INH 20 U/kg (n= 43)
	Female	28 (66.7%)	26 (66.7%)	30 (69.8%)
	Age, years	31.5 ± 13.57)	33.1 ± 12.77	34.6 ± 14.91
	BMI, kg/m2	25.3 ± 6.00	26.7 ± 5.29	27.0 ± 5.57
	Type I HAE	38 (90.5%)	35 (89.7%)	35 (81.4%)
	Type II HAE	4 (9.5%)	3 (7.7%)	8 (18.6%)
	Intensity of baseline HAE attack Moderate Severe	26 (61.9%) 16 (38.1%)	32 (82.1%) 7 (17.9%)	27 (62.8%) 16 (37.2%)
	Abbreviations: BMI, body mass index.
Results		Placebo (n= 42)	C1-INH 10 U/kg (n= 39)	C1-INH 20 U/kg (n= 43)	p-value
	Time to onset of symptom relief, hours (median [range])*	1.5 (0.20-24.00)	1.2 (0.17-24.00)	0.5 (0.17-24.00)	0.0025
	Time to complete resolution of symptoms, hours (median [range])**	7.8 (0.33-1486.17)	20.0 (0.47-1486.17)	4.9 (0.47-1486.17)	0.0237
	Proportion with worsened intensity of symptoms (2-4 hours)	13 (31.0%)	8 (20.5%)	2 (4.7%)	0.0014
	Number of vomiting episodes within 4 hours	0.8 ± 2.59	0.2 ± 0.77	0.1 ± 0.41	0.0329
	Time to onset of symptom relief was set to 24 hours if the patient received rescue study medication or analgesics, antiemetics, open-label C1-INH, or fresh frozen plasma after 4 hours. The numbers of patients with values set to 24 hours were as follows: placebo, 17/42 (40.5%); C1-INH 10 U/kg, 11/39 (28.2%,); C1-INH 20 U/kg, 6/43 (14.0%). *Irrespective of use of rescue study medication or analgesics, antiemetics, open-label C1-INH, or fresh frozen plasma before onset of symptom relief. Missing values were set to maximum time to complete resolution (ie, 1,486 hours).
Adverse Events	C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus. Adverse events were less frequent with C1-INH 20 U/kg compared to placebo, particularly for gastrointestinal disorders.
Study Author Conclusions	C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief.
Critique	The study's strengths include its randomized, double-blind, placebo-controlled design and the clear demonstration of efficacy for the 20 U/kg dose. However, the study was limited by its relatively small sample size and the rare nature of the disease, which may affect the generalizability of the findings. Additionally, the efficacy of the 10 U/kg dose was not statistically significant compared to placebo, highlighting the need for further research to optimize dosing.

Table 2 References:
[8] Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol. 2009;124(4):801-808. doi:10.1016/j.jaci.2009.07.017

Novel Use of Fresh Frozen Plasma in Treating Hereditary Angioedema: A Success Story From Pakistan
Design	Case Report
Case presentation	A 30-year-old accountant was admitted to Aga Khan University Hospital's emergency department with severe bronchospasm, respiratory distress, and angioedema following a minor facial injury. Despite immediate treatment with intravenous steroids, adrenaline, and antihistamines, his condition deteriorated, resulting in cardiorespiratory arrest. After successful cardiopulmonary resuscitation (CPR), he was intubated and transferred to the intensive care unit (ICU) with a diagnosis of hereditary angioedema. Fresh frozen plasma (FFP) was administered every six hours, effectively resolving his symptoms over an 18-hour period without any transfusion-related adverse reactions. His low C4 complement level prior to FFP transfusion confirmed the diagnosis. He was extubated on Day 3 and shifted to a step-down unit before being transferred to a general ward for monitoring, where he and his family were educated on avoiding triggers and the importance of early hospital visits in case of symptom recurrence. Discharged on Day 5, he was prescribed danazol for prophylaxis and scheduled for follow-up care in the clinic.
Study Author Conclusions	In the absence of targeted therapies, fresh frozen plasma is a viable and effective alternative for the acute management of hereditary angioedema in resource-limited settings.

Table 3 References:
[9] Sabeen Ahmed A, Fayyaz S. Novel Use of Fresh Frozen Plasma in Treating Hereditary Angioedema: A Success Story From Pakistan. Cureus. 2020;12(8):e9669. Published 2020 Aug 11. doi:10.7759/cureus.9669

Effect of fresh frozen plasma infusion on hospital length of stay for patients with hereditary angioedema
Design	Retrospective analysis using the 2021 Nationwide Inpatient Sample N= 441
Objective	To study the effect of FFP infusion on hospital length of stay for patients with hereditary angioedema
Study Groups	FFP infusion (n= 29) Non-FFP infusion (n= 412)
Inclusion Criteria	Patients with hereditary angioedema identified using ICD-10 code D84.1 from the 2021 Nationwide Inpatient Sample
Exclusion Criteria	Not explicitly stated, but implied exclusion of patients without hereditary angioedema or those not receiving FFP infusion
Methods	Data from the 2021 Nationwide Inpatient Sample were analyzed using a Bayesian additive regression tree model to assess factors contributing to length of stay. The model included covariates such as age, gender, race, income, region, payer, severity, mortality risk, cost, Charlson Comorbidity Index (CCI), ER admission, FFP infusion, total procedures, and specific comorbidities
Duration	Data from the year 2021
Outcome Measures	Primary: Hospital length of stay Secondary: Not specified
Baseline Characteristics		FFP infusion (n= 29)	Non-FFP infusion (n= 412)
	Female	70%	Not specified
	White	58.5%	Not specified
	Age 40-64	38.5%	Not specified
Results		Mean LOS for FFP	Mean LOS for Non-FFP
	Respiratory disease	Higher	Lower
	Cardiovascular disease	Higher	Lower
	Urticaria	Higher	Lower
Adverse Events	Not explicitly detailed, but FFP infusion was associated with increased length of stay in patients with respiratory, cardiovascular disease, or urticaria, suggesting potential exacerbation of these conditions.
Study Author Conclusions	Caution is recommended when using FFP for hereditary angioedema patients, especially those with respiratory, cardiovascular disease, or urticaria, as it may increase hospital length of stay. Personalized treatment plans prioritizing C1-inhibitor therapy over FFP are advised.
Critique	The study provides valuable insights into the impact of FFP on hospital length of stay for hereditary angioedema patients. However, the small sample size of FFP-treated patients and the retrospective design may limit the generalizability of the findings. Additionally, the study relies on administrative data, which may lack clinical details necessary for comprehensive analysis.

Table 4 References:
[10] Khalid S, Hitch AT. Effect of Fresh Frozen Plasma Infusion on Hospital Length of Stay for Patients With Hereditary Angioedema. J Health Econ Outcomes Res. 2025;12(2):1-10. Published 2025 Jul 9. doi:10.36469/001c.141171

Fresh frozen plasma for on-demand hereditary angioedema treatment in South Africa and Iran
Design	Retrospective, multicenter folder or patient registry review in 6 South African and 1 Iranian centers N= 43 patients (176 acute swelling episodes)
Objective	To evaluate the efficacy and safety of on-demand plasma treatment of acute hereditary angioedema (HAE) in two low- and middle-income countries (LMICs)
Study Groups	Treated with fresh frozen plasma, FFP (n= 98 episodes) Treated without FFP (n= 78 episodes)
Inclusion Criteria	Known HAE patients who experienced acute swelling episodes necessitating emergency room attendance in South Africa and Iran
Exclusion Criteria	Not specified
Methods	In South Africa, folders of known HAE patients at 6 independent treatment centers were reviewed. In Iran, HAE patients detailed in an Iranian HAE registry were reviewed. Additionally, in South Africa HAE patients treated in the private healthcare sector were contacted via email and asked to provide any information available regarding any acute swelling episodes of HAE treated with FFP. Data collected included site of angioedema, timing and amount of FFP administered, time-to-resolution, hospital length of stay, and adverse events.
Duration	2001 to 2017
Outcome Measures	Primary: Resolution of acute swelling episodes Secondary: Time-to-resolution, adverse events, hospital length of stay
Baseline Characteristics		Total (N= 43)	South Africa (n= 27)	Iran (n= 16)
	Females:males	30:13	18:9	12:4
	Mean age, years	29 ± 15	26 ± 16	34 ± 12
	HAE type diagnosed - Type 1, n (%)	35	26	9
	HAE type diagnosed - Type 2, n (%)	7	0	7
	HAE type diagnosed - Unknown, n (%)	1	1	0
	Median first dose of FFP, mL	400 (280 to 560)	280 (280 to 560)	400 (200 to 1000)
Results		Total (N= 176 episodes)	South Africa (n= 81)	Iran (n= 95)
	Number of episodes treated with FFP	98 (56%)	44 (54%)	54 (57%)
	Median time from admission to FFP infusion in hours (IQR)	2 (0.5–3.0)	3 (2–5)	1 (0.3–2.5)
	Median first dose of FFP, mL (IQR)	400 (280-560)	280 (280-560)	400 (200-1000)
	Median time-to-resolution in hours (IQR)	4 (2–12)	9.3 (5–12.3)	2 (0.5–2.5)
	Median length of stay at hospital in hours (IQR) with FFP	12 (5–36)	36 (24–72)	5 (4–9)
Adverse Events	Five transfusion reactions occurred, with one case of anaphylaxis and no deaths; giving an adverse reaction rate of 5%.
Study Author Conclusions	Plasma (fresh-frozen) remains the only available effective on-demand treatment for acute HAE in many countries. FFP is effective and safe, but time-to-resolution is slower and adverse events are more frequent than published data on targeted therapies. Overall healthcare cost of FFP approaches that of targeted therapies when hospitalization is prolonged.
Critique	The study provides valuable data on the use of FFP in LMICs where targeted therapies are unavailable. However, the retrospective design and differences in healthcare settings between South Africa and Iran may limit the generalizability of the findings. Additionally, the lack of direct comparison with targeted therapies limits the ability to fully assess the relative efficacy and safety of FFP.

Table 5 References:
[11] Wentzel N, Panieri A, Ayazi M, et al. Fresh frozen plasma for on-demand hereditary angioedema treatment in South Africa and Iran. World Allergy Organ J. 2019;12(9):100049. Published 2019 Oct 12. doi:10.1016/j.waojou.2019.100049

Hereditary angioedema with normal C1 inhibitor: clinical characteristics and treatment response with plasma-derived human C1 inhibitor concentrate (Berinert®) in a French cohort
Design	Retrospective analysis of data from the French Cohort BeRinert Angiœdème (COBRA) registry N= 28
Objective	To report the clinical characteristics of patients with hereditary angioedema (HAE) with normal C1-INH (with F12 gene mutation; FXII-HAE) or of unknown origin (U-HAE), and their response to Berinert®
Study Groups	FXII-HAE (n= 11) U-HAE (n= 17)
Inclusion Criteria	Patients with normal C1-INH antigenic level and function, refractoriness to high-dose antihistamines, F12 gene mutation for FXII-HAE, and a positive family history for U-HAE
Exclusion Criteria	Not specified
Methods	Data were analyzed from the COBRA registry, which describes the long-term efficacy and safety of human C1 INH concentrate and follows patients for up to 10 years. Patients received plasma-derived human C1-INH concentrate (Berinert®) for documented angioedema attacks. Efficacy was assessed based on symptom improvement time after treatment initiation. No control group was included.
Duration	Data from 2007 to February 2016
Outcome Measures	Primary: Symptom improvement time after Berinert® administration Secondary: Complete resolution of symptoms, safety of Berinert®
Baseline Characteristics		All patients (N = 28)	Efficacy analysis set (n = 21)
	Sex, Female, n (%)	24 (85.7%)	19 (90.5%)
	Mean age (years)	27.0 ± 10.7	27.6 ± 10.0
	Mean age at first attack (years)	19.8 ± 9.8	20.7 ± 8.7
	Mean age at diagnosis (years)	23.7 ± 9.9	24.1 ± 9.0
	Family history of HAE, n (%)	24	18
	Females receiving oral contraceptives, n (%)	16	12
Results		Efficacy analysis set (n = 21)
	Number of attacks treated	78
	Mean time between attacks (weeks)	17.3 ± 3.2
	Number of attacks per patient, n (%) 1 2 3 4 ≥ 5	8 (38.1) 6 (28.6) 2 (9.5) 2 (9.5) 3 (14.3)
	Median number of attacks treated per anatomical location Abdominal Laryngeal Facial	25 12 6
	Efficacy assessment of Berinert® was available for 38 of 78 documented Berinert®-treated attacks; 22 improved within 60 minutes of treatment initiation, nine within 60-180 minutes, four after 180 minutes, and three showed no improvement.
Adverse Events	No severe or serious adverse effects were reported
Study Author Conclusions	Data to date suggest that Berinert® may be a safe and efficacious treatment option for the majority of HAE patients.
Critique	The study provides valuable insights into the treatment of FXII-HAE and U-HAE with Berinert®, but is limited by its retrospective design and small sample size. The lack of a control group and prospective analysis for all patients may affect the robustness of the findings. However, given the rarity of the condition, the study offers important information on treatment feasibility.

Table 6 References:
[12] Bouillet L, Boccon-Gibod I, Gompel A, et al. Hereditary angioedema with normal C1 inhibitor: clinical characteristics and treatment response with plasma-derived human C1 inhibitor concentrate (Berinert) in a French cohort. Eur J Dermatol. 2017;27(2):155-159. doi:10.1684/ejd.2016.2948

Fresh Frozen Plasma for the Treatment of Hereditary Angioedema Acute Attacks
Design	Retrospective analysis of medical records and literature review in China N= 13
Objective	To determine the safety and efficacy of fresh frozen plasma (FFP) infusion for the treatment of hereditary angioedema (HAE)
Study Groups	All patients (N= 13)
Inclusion Criteria	Patients diagnosed with HAE receiving FFP infusion at Peking Union Medical College Hospital based on 2010 international HAE consensus definition, and patients reported in the literature (through Pubmed)
Exclusion Criteria	Patients with angioedema caused by allergen or medicine; non-English publications
Methods	Retrospective review of medical records and literature. Data collected included patient demographics, body location of HAE attacks, FFP infusion dose, time to improvement, time to complete remission, complications, C1 inhibitor activity, and outcomes. C1 inhibitor (C1INH) activity in FFP was 60,000. Normal range of C1INH activity was 60,000-100,000.
Duration	2004 to 2010
Outcome Measures	Safety and efficacy of FFP infusion for acute HAE attacks, time to symptom improvement, time to complete remission, C1INH activity changes
Baseline Characteristics		All patients (N= 13)
	Mean age, years	30 ± 17
	Male sex, n (%)	7 (53.8%)
	HAE type I, n (%)	5 (38.5%)
	HAE type II, n (%)	1 (7.7%)
	HAE type unknown, n (%)	7 (53.8%)
Results		All patients (N= 13)
	Mean dose of FFP infusion, mL	586 ± 337
	Mean time to improvement, minutes	49 ± 19
	Median time to complete remission, hours	3.3 (2.0, 12.0)
	Mean remission time without FFP, hours	61.7 ± 27.0
	There was no significant difference between male and female patients in the dose of FFP infusion (581±259 vs. 519±451 mL, p=0.209). The FFP dosage was lower in the laryngeal edema group (375±128 vs. 657±256 mL, p=0.016). There were 2 cases of C1INH activity in the literature. After 400 mL of FFP, C1INH activities in both patients increased from 10,000 to 26,500 and from 16,000 to 25,000, respectively.
Adverse Events	Symptoms improved in all cases except 1 due to transfusion reaction. Rash, fever, and chilling occurred in 1 case, considered an allergic reaction to FFP. Abdominal pain worsened in 2 cases initially but resolved within 1.5 to 2.5 hours.
Study Author Conclusions	FFP seems to be safe and effective for acute attacks of HAE.
Critique	The study provides evidence of FFP's efficacy in treating acute HAE attacks, but the small sample size and retrospective design limit the generalizability of the findings. The reliance on literature data may introduce variability in treatment protocols and outcomes. Additionally, the lack of comparator therapies limits generalizability to real-world practices for acute HAE attacks.

Table 7 References:
[13] Tang R, Chen S, Zhang HY. Fresh frozen plasma for the treatment of hereditary angioedema acute attacks. Chin Med Sci J. 2012;27(2):92-95.