Global Guidelines for the Care of Patients with Hereditary

Angioedema

World Allergy Organization

General AdvisorsWAO President Ruby Pawankar, Professor, Nippon Medical School, TokyoWAO Past President (Initiator of the guideline development)Richard Lockey, Professor of Medicine, University of South Florida

Steering Committee Chair: Timothy Craig, Professor of Medicine and Pediatrics, Penn State University

Members of the Steering committee:Emel Aygoren-Pursun, Professor of Medicine, University of FrankfurtKonrad Bork, Professor of Medicine, Johannes Gutenberg University MainzTom Bowen, Professor of Medicine, Universiy of CalgaryHenrik Boysen, Executive Director, HAEi-International Patient OrganizationMarco Cicardi, Professor of Medicine, University of MilanHenriette Farkas, Professor of Medicine, Semmelweis UniversityAnete Grumach, Faculty of Medicine, University of Sao PauloConnie Katelaris, Professor of Medicine, Allergy University of Western SyndneyHilary Longhurst, Consultant Immunologist, Barts and the London NHS Trust William R. Lumry, Professor of Medicine, University of Texas SouthwesternInmaculada Martinez-Saguer, Professor of Medicine, University of FrankfurtMarcus Maurer, Professor of Dermatology and Allergy, Charité - Universitätsmedizin BerlinBruce Ritchie, Professor of Medicine, University of AlbertaBruce Zuraw, Professor of Medicine, University of California San Diego

Pharmaceutical Supporters of the Guidelines in Alphabetical Order

• CSL Behring• Dyax• Shire• Viropharma

World Allergy Organization’s HAE Global Guidelines

• Objective: To develop a global approach for the management of patients with Hereditary Angioedema (HAE) so as to improve the quality of care delivered to patients with HAE globally, to increase the availability of HAE medications globally, and to encourage all physicians, patients, pharmaceutical companies and governments to ensure that patients with HAE are given similar access to therapies and care in an appropriate manner worldwide.

C1-esterase Inhibitor Protein (C1INH)

• Major inhibitor of several complement proteases (C1r, C1s, and mannose-binding lectin–associated serine protease [MASP] 1 and 2) and contact-system proteases (plasma kallikrein and coagulation factor XIIa) and a relatively minor inhibitor of the fibrinolytic protease plasmin and the coagulation protease factor XIa.

• C1-INH is deficient (type 1) or abnormal in function (type 2), but normal in type III HAE

C1-INH involved in 3 systems → C1-INH depletion

Kallikrein

HMW-K

Factor XII

Prekallikrein

Contact SystemContact System

C4C2

C1

Complement Complement SystemSystem

Increased vascular

permeability ANGIOEDEMA

C1-

INH

C1-

INH

C1-INH C1-INH C

1-IN

H

C

1-IN

H

C1-

INH

C1-

INH

Bradykinin

FibrinolyticFibrinolyticSystemSystem

Factor XIIa

Plasmin

Plasminogen

C1rs

C1-INH

Bradykinin is Responsible for the Angioedema associated with HAE

• Complement and contact plasma proteolytic cascades are activated with the potential to generate several vasoactive compounds.

• Bradykinin is generated through activation of the contact system• Bradykinin is the primary mediator of swelling • Plasma kallikrein and factor XII are normally inhibited by C1INH • Plasma kallikrein cleaves high molecular weight kininogen

Actin stress fibersVE-cadherin

Non stimulated

Stimulated

Increased vascular permeability

from Tiruppathi C, et al. Vascul Pharmacol. 2003;39:173-185.

How Does BK Cause Angioedema?

Suspect HAE when a patient presents with angioedema, especially if free of urticaria, that is unpredictable in onset, but frequently

follows a trigger such as trauma, and is associated with recurrent abdominal pain and upper airway swelling. (100% consensus)

Triggers for HAE• Estrogen• ACE-inhibitors• Trauma• Dental and surgical procedures• Stress• Infections• Menstruation• Pregnancy

HAE Attacks can Involve

• Face• Extremities• Upper airways• Gastrointestinal system • Genital-urinary system

Intestinal swelling during an Abdominal attach

Patients with suspicion of HAE and family members of patients with HAE should be screened so that

appropriate therapy can be available for treatment, especially since the first event may manifest in the upper airway and potentially may be fatal without

appropriate therapy. (100% consensus)• All patients with HAE should have an action plan.• Patients may be asymptomatic even later in life; however,

preparation is needed to have therapy available for procedures that can trigger HAE

• In order to be prepared, all patients with suspected HAE and all family members of patients diagnosed with HAE should be screened for at least C4 and if positive, they should have an action plan and 2 doses of on demand therapy.

Clinical symptoms + Familial history

C4

Normal Low

Confirm C4 during attack

Normal

Consider HAE type III or AE due

to medications

C1INH level

Normal Low

HAE type I

C1q

Normal Low

Functional C1INH

Normal Low

HAE type II

Consider other causes of C4 consumption

AAE

DIAGNOSING HAE

Treatment of HAE

• Acute treatment of attacks (On Demand)• Short Term Prophylaxis (pre-procedural)• Long Term Prophylaxis (Suppression of attacks)

On Demand Therapies

• C1-esterase inhibitor (C1=INH)• Recombinant C1-INH (rcC1-INH)• Ecallantide• Icatibant• Fresh Frozen Plasma

Indications of C1-INH are partially off label and all plasma derived products can be used in place of

each other (100%)Berinert®

all types of attacks in adults, children, pregnant women also during breastfeeding. Dose is 20units/kg

Cinryze ® all types of attacks in adults, children, pregnant women also during breastfeeding. Dose is 1000 units

Cetor ® all types of attacks in adults, children, pregnant women also during breastfeeding. Dose is 1000 units

Use of C1-INH in HAERecommendation:• The risk versus benefits of C1INH favors benefits. Few adverse

events have been reported. All 3 products are equal in efficacy and adverse effect profile; however, the need for repeat dosing is less with the initial use of 20 units/kg. The risk is minimal, but absolute safety cannot be assumed since it is a human blood product. (100%)

• A natural product• Inhibits all cascade systems involved in the

generation of bradykinin• Its half-life is longer than those of other drugs for

AT; it rapidly reaches peak plasma concentration• Rapid onset of action• Lack of rebound angioedema• Effective in all types of attacks• Appears to be safe for children• Appears to be safe for pregnant women• Safe for home use • Minimal allergic reaction• No tachyphylaxis• Long (30 years of) clinical experience

• Expensive (but its price is not higher than those of other drugs except FFP)

• Potential risk for the transmission of other diseases and infective agents

• Intravenous administration• Frequent and repetitive use may

influence attack frequency and severity

• Off label administration of high doses is associated with thrombotic events

ADVANTAGES of C1-INH DRAWBACKS

Recommendation: For on demand therapy recombinant C1-INH appears to be equally

effective to plasma derived C1-INHDifferences between rcC1-INH and C1-INH• rcC1-INH half-life is 3 hours • Contains traces of rabbit antigen• Contraindicated in rabbit allergy• Unique polysaccharides are added to the protein during

production. Which shorten half life and may be allergenic• No human blood-borne disease associated with it

Recommendation: The recommended rcC1-INH dose for the routine treatment of acute attacks

is 50 U/kg body weight (100%)• Test for rabbit antibodies before using the rcC1-INH• Contains 2100 units per vial • concentration of 150 units/ml • treatment of acute attacks is 50 U/kg body weight • maximum of 4200 U (2 vials) for patients of or over 84kg body

weight • second injection may be given if the patient does not improve

satisfactorily after the first dose

• Inhibits all cascade systems involved in the generation of bradykinin

• Rapid onset of action• Lack of rebound angioedema• Effective in all types of attacks• Safe for children• Safe for pregnant women• Minimal allergic reaction• No tachyphylaxis• No viral transmission• Unlimited supply

• Expensive (but its price is not higher than those of other drugs except FFP)

• Potential risk for anaphylaxis• Intravenous administration• Potential, but not described, for

neutralizing antibodies and IgE to polysaccharide added to the protein

ADVANTAGES of rcC1-INH DRAWBACKS

Treatment of HAE: Icatibant

• Recommendation: Icatibant is effective for the treatment of HAE attacks at all locations with a dose of 30 mg SQ (100%)

• Recommendation: Repeat dosing of icatibant is necessary in up to 10% of attacks and 1% require a third dose to treat an HAE attack. (not voted)

• Ease of Use• Rapid to Administer• Appear to have good safety profile

•Not blood product•Not immunogenic

• Alternative to C1 inhibitor• Ideal for self administration• May address problem of delays in

accessing treatment• Not Intravenous

• Short half life-probably not suitable for prophylaxis

• Need for repeat dosing• Not currently

recommended for pregnant women or children

• No action on other systems regulated by C1 inhibitor

• Pain and burning at injection site

Positives Negatives

Cicardi et al NEJM 2010

Treatment of HAE: Ecallantide

• Recommendation: Ecallantide at 30 mg SQ can be used to treat HAE attacks at all locations (100%)

• Recommendation: Self injection of ecallantide should be avoided secondary to a small, but real risk of anaphylaxis (100%)

Treatment of HAE: Ecallantide

• Allergic reactions occur in approximately 3% of patients that receive ecallantide.

• IgG and IgE antibodies are produced against ecallantide, but the IgG does not appear to be neutralizing.

• Approved in the USA to be giving at home by a health care provider equipped and trained to treat anaphylaxis

Recommendation: Fresh Frozen Plasma should only be used for on-demand therapy when other medications are

not available (100%)

• action- replaces C1-INH• indication- not indicated unless no other treatments are available• method- 2 units for adults, weight based for children• adverse events – anaphylaxis, worsening of HAE, viral transmission• positives and negatives- negatives out-weigh positives and FFP

should be avoided if other therapies are available

How Do the Newer Drugs Compare?Drug Advantages Disadvantages Best use Status

Plasma-derivedC1-INH

• Extensive clinical experience

• Corrects the fundamental defect

• long half-life

• Infectious risk• Needs IV access• Limited supply

• Acute attacks• Short-term• Long-term

prophylaxis• Prodromes

• Berinert P: approved for attacks

• Cinryze: approved for prophylaxis and attacks

• Cetor approved for attacks

RecombinantC1-INH

• Corrects the fundamental defect

• No human virus risk

• Scalable supply

• Needs IV access• Short half-life• Potential for

allergic reactions

• Acute attacks• Short

prophylaxis• Prodrome?

• Rhucin: used for attacks

Ecallantide • More potent than C1-INH

• No infectious risk• Subcutaneous

administration

• Antibodies may cause allergic reaction or neutralization

• Short half-life

• Acute attacks in office or by HCP in home

• Kalbitor approved for administration by HCP for attacks

Icatibant • No infectious risk

• Stable at room temperature

• Subcutaneous

• Short half-life• Local pain or

irritation

• Home treatment of acute attacks

• Firazyr: used for attacks

Short-term or pre-procedural therapy: Indication

• Prior to some surgeries; especially– dental/ intraoral surgery– where intubation is required– major surgery

• To cover periods of high risk for attacks– increased likelihood of attack– increased consequence of attack

Evidence limited to case reports/ small series – recommendation based on expert opinion

Short term prophylaxis for lower risk procedures

• For lower risk procedures, or where safe prophylactic agents are not available, prophylaxis may be omitted

• the patient should be aware of the risk of and have a management plan for attacks, which are more likely to occur after surgery. – Two doses of C1 inhibitor, ecallantide or icatibant should be

immediately available.• [100% agreement. Observational/ case series]

Short-term or pre-procedural therapy: Attenuated Androgens - REGIMEN

Document Recommendation Alternative Children Duration

UK Consensus 2005

Danazol 200-600 mg

Stanozolol 2-6 mg od

Danazol

300mg od

5 days before, 2 days after procedure

International (Canadian/

Hungarian) Consensus 2010

Danazol 2.5-10mg/kg//day: max 600 mg /

Stanozolol 4-6 mg od

5 days before, 2 days after procedure

Farkas 2010 Danazol 600mg

4 days before and after procedure

Doses are based on expert opinion: not evidence-based

Androgens as short term prophylaxis

Advantages Disadvantages

Ease of use

Well tolerated in short term (usually)

Have been used in children without problem

Have been used in pregnancy (3rd trimester) without problem

Low cost

Broad availability

Perceived inferior efficacy to C1 inhibitor

Need to start several days prior to procedure

Concern of side effects, but minimal

Not suitable for most children

Not suitable for most pregnant women and during breast feeding

Unavailable in some countries

Advantages and disadvantages for C1-inhibitor for short term prophylaxis

Advantages Disadvantages

Some evidence for efficacyGood theoretical rationale for use 

Intravenous

Well tolerated  

Lack of availability in some countries

Treatment of choice in children and pregnancy 

Cost

May give additional doses if swellings occur

Therapies not to be used for short term prophylaxis

• The following are not recommended:– Plasma (FFP/SDP)*. (only if no other therapies are

available)– Icatibant– Ecallantide– Methyl testosterone

• Probably effective.– Ruconest/ Rhucin

• [100% agreement except for plasma (75% agreement). Expert opinion]

• Recommendation: Chronic Prophylaxis is indicated when on demand therapy fails to improve the quality of life of a patient with HAE (100%)

Chronic Prophylaxis: Anti-fibrinolytics

• Recommendation: Anti-fibrinolytics are have little benefit, have adverse events and are not indicated for use in prophylaxis of HAE (65%)

• Recommendation: The minority recommended use in pre-puberty children for HAE prophylaxis (35%)

• Recommendation: Avoid use of anti-fibrinolytics during pregnancy and lactation (80%)

Anti-fibrinolytic use for chronic prophylaxis

advantages• Inexpensive• Availability

disadvantages• Adverse effects• Few data to support

effectiveness• Multiple daily dosing• Unsure of status during

pregnancy, lactation and pre-puberty

Chronic Prophylaxis: Androgens• Recommendation: Androgens are effective to control the

symptoms of HAE, but secondary to the potential adverse effects the dose should not exceed Danazol 200 mg a day or an equivalent dose of an alternate androgen and the dose should be reduced to the least effective dose (100%)

• Recommendation: Androgens should be avoided during pregnancy, lactation and in most children before puberty (100%)

Monitoring for adverse events when using androgens for Chronic Prophylaxis (100%)

Before use and every 6 months:• Fasting lipid profile• Liver function studies and biochemistry • Complete blood cell count• Urinalysis• Alfa-fetal protein

Before use and every 12 months:• abdominal liver ultrasonography

Before Follow up

Liver Functional Tests Every 6 months

Lipid profile Every 6 months

Urine analysis Every 6 months

Abdominal ultrasound Once/year

Alpha fetoprotein Every 6 months

CBC Every 6 months

8.5 Monitoring while receiving treatment with Androgens

Use of C1-INH for chronic prophylaxis

• Recommendation: C1-INH that is human plasma derived can be used at 1000 units IV twice a week to suppress HAE attacks. Doses as low as 500 units may be effective in some and others may require greater than 1000 units. (100%- rating A)

• Recommendation: Human derived C1-INH products should be equally effective, but the shorter half-life of recombinant C1-INH may limit its use for chronic prophylaxis (90%)

Dosing C1-INH for Chronic Prophylaxis

• The approved dose is 1000 units twice a week.• At this dose breakthrough attacks are not infrequent• Higher doses and more frequent dosing may be necessary to

prevent breakthrough attacks.• Optimal dosing of C1-INH for chronic use has not yet be determined

Use of C1-INH for Chronic Prophylaxis

• Recommendation: Before starting C1-INH hepatitis B, C, HIV and parvovirus titers should be obtained and monitored on a yearly basis (100%)

• Recommendation: Upon prescribing C1-INH hepatitis B and A vaccine series should be started (no vote)

• Recommendation: Because of the risk of thrombosis with central lines indwelling central lines and catheters should be avoided when administered C1-INH for chronic prophylaxis (100%)

Use of C1-INH for Chronic Prophylaxis

Advantages• Effective• Few adverse events• Long safety record from over 3

decades use in the EU

Disadvantages• Dose ranging studies are

lacking• Human plasma derived• Breakthrough attacks occur

despite 1000 units twice a week

• Intravenous dosing necessary• Expensive

Preventive and long term care of the patient with HAE

• Recommendation: All patients with HAE should have at least an annual assessment by an HAE specialist. (100%)

• Recommendation: All patients with HAE should have an action plan and product available to treat an attack of HAE. (100%)

Preventive and long term care of the patient with HAE

• All HAE patients have a potential for receiving human blood products. Because of this all HAE patients should be screened as early as possible for Hepatitis B and C and HIV. In addition, vaccination for Hepatitis B and possibly A should be stressed. Annual assessment for infections with hepatitis and HIV are suggested. (100%)

Drugs to avoid in HAE

• Estrogen birth control• Estrogen hormone replacement• ACE-inhibitors for blood pressure, CHF and other diseases• Agreement: 100%

Tests Androgens Plasmin inhibitors

Plasma derived C1INH/ Plasma

Liver Functional Tests

Q 6 mth Q 6 mth

Lipid profile Q 6 mth

Renal function Q 6 mth

Urine analysis Q 6 mth Q 6 mth

Abdominal ultrasound Q 12 mth

Alpha fetoprotein Q 6 mth

CPK Q 6 mth

Eye pressure Q 6 mth

Thrombophilia tests? At start of therapy

Serology for HIV, hepatitis B, C, E,

Parvovirus

Start of therapy and every year

8.8 screening summary

Why Children with HAE are Unique Teachers and health care personnel responsible for the child at

school should be informed in writing of the diagnosis.

Special medication and an action plan for emergency treatment should be made available at home, at school, and field trips.

A proportion of attacks can be prevented through appropriate counseling and lifestyle modifications aimed at eliminating triggering factors.

Stigmatization by peers is more frequent in children, than in adults.

Treating attacks of HAE

• C1-INH concentrate is effective and safe.

• Probably the best dose should be based on 20 units/kg since other weight based dosing is not available

• No experience is as yet available with the pediatric use of the innovative drugs (bradykinin receptor B2 antagonist, kallikrein inhibitor, recombinant C1-INH concentrate).

Treatment of Children with HAEDrugs and the indications for their use are the same as in adults.

Short-Term Prophylaxis (STP) • Short term use of androgens is tolerated well.• Preferred pre-procedural treatment is with C1-inhibitor.• FFP can be utilized, but only in cases C1-inhibitor is not available.

Chronic Prophylaxis• In severe cases uncontrolled by on demand therapy of acute attacks chronic

prophylaxis may be necessary • C1-inhibitor prophylaxis is preferred in children• Androgens can be used, but toxicity often exceeds benefits and should be

reserved only in severe uncontrolled cases where other therapies are not available.

• Anti-fibrinolytics have minimal efficacy, but may be tried in children

Treatment during Gestation and Lactation

• Recommendation: Because of the lack of safety data with icatibant and ecallantide and the toxicity of androgens and antifibrinolytics during pregnancy, C1INH is the preferred drug during pregnancy and lactation.

• (100% expert opinion)

On-Demand Therapy during Gestation and Lactation

• C1-inhibitor is the preferred therapy. Presently, until further information is available the dose would be 20 units/kg (majority). Minority opinion is 500 or 1000 units for an attack (minority opinion)

• FFP (heat treated) can be substituted if C1-inhibitor is not available, but risk is greater than with C1-inhibitor

• Anti-fibrinolytics should be avoided• No data are available for eccalantide or icatibant and both should

be avoided until safety data exists

Prophylaxis During Gestation and Lactation

Elimination of Triggering FactorsThe measures for non-pregnant females apply.

Drug ProphylaxisChronic prophylaxis: • Pd C1-INH concentrate is thought to be safe and effective during both pregnancy

and lactation. • Anti-fibrinolytics are not recommended to use during pregnancy. AFs cross the

placenta. They are not teratogenic in animals, but are excreted into breast milk. These drugs are not recommended during breastfeeding.

• Androgens are not recommended, as these drugs cross the placenta. They cause masculinization of the female fetus, placental insufficiency, and fetal growth retardation. No mutagenicity has been shown in animal models. Excretion into breast milk is unknown, but androgens should be avoided during lactation.

• Heat-treated fresh frozen plasma (FFP): Only limited data exist on the use of FFP during pregnancy. Use only if no C1-inhibitor is available

Home Therapy

• Recommendation: Patients with HAE should be encouraged to provide self care and home care to allow early, effective and cost effective care

• Agreement: 100%• A evidence

Action Plans

• Recommendation: All patients with HAE should have an acute action plan to include location to acquire care, therapies available or in possession, dose and route of administration

• Agreement: 100%

World Wide Access to Therapies

• Recommendation: Associations, doctors, patients, health care providers, and pharmaceutical companies should petition to have therapies available world wide for all patients with HAE.

• Agreement: 100%

Summary

• This short slide set and the document and comprehensive slide set that accompanies it are intended for the better dissemination of the care and treatment of patients with HAE. These slides are available on the WAO website to be used for self learning, patient care and teaching. Feel free to use them.