Diagnostic and Therapeutic Management of Hereditary Angioedema Due to C1-Inhibitor Deficiency

The Italian Experience

Mauro Cancian


Curr Opin Allergy Clin Immunol. 2015;15(4):383-391. 

In This Article


Since the first international consensus conference on C1-INH-HAE management in 2003,[42] guidelines and position papers were regularly released to reflect progress in therapy and results from clinical and observational studies.[43–45] The last expert panel recommendations and an extensive review on the different strategies and drugs available for C1-INH-HAE were published in 2014.[46,47]

Acute attacks can be treated by C1-INH replacement, inhibition of plasma kallikrein or blockade at the BK-B2r (Fig. 2), whereas attenuated androgens and infusion of plasma-derived C1-INH concentrate (pd-C1-INH) may be used both for short-term and long-term prophylaxis[44–47] (Table 1).

Figure 2.

Pathophysiology of C1-INH-HAE and site of action of targeted drugs. Black circle, plasma-derived or humanrecombinant C1-INH concentrate; gray circle, Ecallantide; gray square, Icatibant. HMWK, high molecular weight kininogen.

There is a widespread agreement on therapeutic goals (reduce mortality and morbidity; prevent recurrence of attacks; improve quality of life) as well as on the opportunity to provide all patients with at least two doses of drug available at home for treating an acute attack, to train them for self-administration and to encourage a prompt treatment of attacks.[44–46]

Nevertheless, different approaches to the time for switching from on-demand to long-term prophylaxis are present among HAE experts.[44]

Acute Attacks (On-demand Therapy)

Three C1-INH concentrates (Berinert, Cinryze, Ruconest) and the BK-B2r antagonist Icatibant are at present licensed in Italy to treat acute attacks, whereas we have no direct experience with the kallikrein inhibitor Ecallantide[48] that is not approved in Europe. All mentioned medications were shown to be highly more effective than placebo – or tranexamic acid for Icatibant – in randomized, double-blind, placebo-controlled clinical trials. No head-to-head trials compared the relative efficacy of these drugs.


Berinert is a plasma-derived, pasteurized and nanofiltered C1-INH concentrate[49] which is available in Italy from 2003 (a concentrate from Immuno Baxter had been previously marketed in our country between 1985 and 2003). In the past, we used to prescribe fixed doses of intravenous 500 U for peripheral and abdominal attacks – or overall in the pediatric population – and 1000 U or higher amounts for the facial and laryngeal ones.[12] Although this strategy was shown to be effective in clinical practice,[50] based on the results of the IMPACT-1 and IMPACT-2 studies,[51,52] Berinert is at present licensed for self-administration with a weight-based dosage of 20 U/kg in the treatment of all types of attacks in adults and children.


Cinryze is a heat-treated, nanofiltered C1-INH product purified from human plasma and marketed in Italy from 2013. Cinryze may be self-administered on acute episodes of HAE in adults and children as an intravenous infusion at the fixed dose of 1000 U followed by additional 1000 U if no effect is obtained after 1 h.[53,54] Given that the efficacy of C1-INH replacement seems to be dose-dependent and correlates with peak plasma levels,[55] this may explain why in the acute attack-treatment clinical trial for Cinryze marketing authorization most of the participants required a second injection of the study drug.[53] Unlike Europe, Cinryze is approved for prophylaxis but not for on-demand therapy in the United States.


Ruconest (conestat alfa, Rhucin) is a human recombinant C1-INH (hr-C1-INH) extracted from the milk of transgenic rabbits. Two separate phase III randomized, placebo-controlled trials were conducted in Europe (with a 100 U/Kg) and in North America (with 100 U/kg or 50 U/kg): the 50 U/kg dose proved to be effective in most acute attacks, with only around 10% of the patients needing a second infusion.[56] Thus, Ruconest is licensed (in Italy since 2012) for management of acute attacks in adults by a healthcare professional, with a posology of 50 U/kg up to 84 kg body weight and of one intravenous injection of 4200 U for heavier individuals. Rabbit sensitivity should be ruled out before drug administration.


Icatibant (Firazyr), a synthetic, selective BK-B2r antagonist, has been available in Italy since 2009 as prefilled syringes containing 30 mg of drug to be self-injected subcutaneously for treatment of acute attacks in C1-INH-HAE adult patients. Two parallel phase III studies, FAST-1 (in the United States) and FAST-2 (in Europe and Israel), respectively, against placebo and tranexamic acid assessed efficacy to obtain relief of symptoms in acute HAE attacks. As the endpoint was initially reached just in FAST-2, Icatibant was licensed in Europe starting from 2008.[57] Another similar trial, FAST-3, showing Icatibant to be significantly superior to placebo was necessary for FDA approval given in 2011.[58] Probably because of the short plasma half-life, approximately 10% of patients require a further dose for recurrence of symptoms.

All these drugs are effective for on-demand therapy, with specific limitations and potential adverse effects (Table 2). Plasma-derived products need continuous surveillance for their infectivity potential, but no case of blood-borne infection has been reported for pd-C1-INHs currently available for HAE since their presence on the market.[59,60] Thus, in the ITACA opinion the therapeutic approach should be tailored mostly by the ability of patients to self-infuse drugs and by the individual frequency of treatment effectiveness versus rebounds with different therapies. Attitude to self-administration, not yet approved for Ruconest, is particularly relevant allowing early on-demand treatment and to maintain personal safety without affecting day-to-day life.[61–63] Costs of an effective treatment are similar for the different drugs, and some patients may have alternative therapies, e.g. both a C1-INH concentrate and Icatibant, available at home to treat different kinds of attacks with the drug that they have experienced to be more effective in a particular situation. Fresh frozen plasma, which contains not only C1-INH but also potential substrate for bradykinin generation, should only be used if targeted therapies are not available and reserved for life-threatening attacks.[45,46]

Long-term Prophylaxis

In patients with frequent attacks and in whom on-demand therapy is inadequate to achieve adequate control of the disease, regular therapy to prevent episodes of angioedema should be considered. Attenuated androgens or pd-C1-INH can be prescribed in Italy for long-term prophylaxis (LTP), whereas we no longer recommend the off-label use of antifybrinolitic agents because randomized trials supporting their efficacy are lacking and clinical benefits are highly variable and limited to restricted numbers of patients. Given that angioedema attacks may even occur during routine prophylaxis, all patients must have available on-demand therapy at home.

Attenuated Androgens

Attenuated androgens have been used in Italy, where danazol is licensed for treatment of hereditary angioedema, since the 1970s and was shown to be very effective in preventing C1-INH-HAE attacks.[64–67] Their use is, however, contraindicated until after puberty as well as in pregnant or breast-feeding women, and may be limited by the many potential adverse effects. Weight gain, hypertension, dyslipidemia, mood disorders, acne, cholestasis and sporadic cases of hepatic adenoma have been reported in both sexes, whereas virilization, changes in libido and menstrual irregularities are among the most common side-effects in the female sex.[65–70] As adverse effects are dose-dependent, danazol intake should not exceed 200 mg per day and be adjusted to the minimal effective dose. Patients on androgen LTP must be monitored for blood pressure and screened at regular intervals by complete blood count, urine analysis, lipid panel, liver function and upper abdomen ultrasound.

Plasma-Derived C1-Inhibitor

Although Berinert has long been used in Europe for routine prophylactic treatment,[60] Cinryze is at present the only C1-INH concentrate approved for this specific purpose.[47] Italian health authorities authorize LTP in HAE patients intolerant or refractory to prior danazol therapy and with need for on-demand treatment at least four times a month over 3 consecutive months. Intravenous infusion of 1000 U every 3 to 4 days was shown to reduce the number and severity of attacks in both randomized and open-label studies,[53,54,71,72] but subsets of patient may require dose and/or interval adjustment to optimal control. Cinryze-associated thrombotic events, probably related to indwelling venous catheter rather than to the drug itself, have been reported during routine prophylaxis in a few patients with hereditary angioedema.[73]

The first issue when considering LTP for hereditary angioedema is how to identify patients who need this approach. An effort to establish objective criteria to assess the inadequacy of on-demand therapy before shifting to routine prophylaxis did not achieve unanimous agreement.[44] LTP is usually initiated whenever on-demand treatment fails in reverting patients to a satisfactory quality of life, there are no specific contraindications and in physicians' opinion the expected benefits are more relevant than the potential risks.

The decision to use one over the other therapeutic option should be individualized and take into account data on drug efficacy and overall adverse effects, ease of use for individual persons and costs, which are significantly higher for Cinryze than for danazol. Based on scientific evidence, the above-mentioned concerns and clinical experience, the Italian network for HAE feels that danazol may still be considered the first-line long-term prophylactic treatment for adult patients responsive to low doses (50–200 mg daily), in whom androgenic effects are not perceived as relevant and having no evidence of metabolic, behavioural or hepatic complications. Unlike the past, when LTP was usually started with high doses of androgens (e.g. danazol 600 mg daily),[12,65–69] in our experience the current posology is well tolerated by most patients and does not produce significant adverse effects as assessed by periodic monitoring. Approximately 20% of the Italian C1-INH-HAE patients are at present on LTP with danazol, and 1% with pd-C1-INH, respectively.

Short-term Prophylaxis

Although most of HAE attacks occur spontaneously, it is well known that local trauma, stress and surgical procedures may trigger angioedema. Physicians and patients are frequently concerned about the risk of swelling associated with upper airway manipulation, including dental care, but even minor procedures can induce angioedema anywhere from few to many hours later. Thus, depending on the kind of procedure and on patients' history of previous HAE attacks in similar conditions, a course of short-term prophylaxis (STP) may be planned when appropriate.[44,45,46]

The efficacy of STP with pd-C1-INH has been evaluated by retrospective studies[74,75] on dental procedure or irrespective of the type of surgery and shown to be dose-dependent. Both Berinert and Cinryze are licensed in Italy for preprocedural prophylaxis, and we suggest infusing the recommended dose of 1000 units about 1–2 h before the procedure.

Danazol may be considered an alternative to pd-C1-INH for STP, but needs to start 5 days before and continued 2–3 days after the procedure (2.5–10 mg/kg/day, maximum 600 mg/day in adults and 300 mg/day in children).

As breakthrough attacks may still occur with preprocedural prophylaxis, on-demand treatment must be always available as rescue therapy. Finally, although scientific evidence is lacking in selected cases we suggest STP also on stressful life experiences or when travelling in areas with limited health resources.

Concluding Remarks

In the past 10 years innovative drugs have been licensed for the treatment of C1-INH-HAE and from application trials we learned more also about the pd-C1-INH that we had used for a long time. However, no comparative study among targeted therapies for this rare disease has been conducted so far and the numbers of patients referring to a single physician are usually small. The efforts by the Italian network for C1-INH-HAE to pool clinical data of patients and share clinical experience help to improve and homogenise the management of the disease in the real world.