Global Guidelines for the Care of Patients with Hereditary Angioedema

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Global Guidelines for the Care of Patients with
Hereditary Angioedema

• World Allergy Organization

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• General Advisors
• WAO President Ruby Pawankar, Professor, Nippon
  Medical School, Tokyo
• WAO 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 Frankfurt
• Konrad Bork, Professor of Medicine, Johannes
  Gutenberg University Mainz
• Tom Bowen, Professor of Medicine, Universiy of
  Calgary
• Henrik Boysen, Executive Director,
  HAEi-International Patient Organization
• Marco Cicardi, Professor of Medicine, University
  of Milan
• Henriette Farkas, Professor of Medicine,
  Semmelweis University
• Anete Grumach, Faculty of Medicine, University
  of Sao Paulo
• Connie Katelaris, Professor of Medicine, Allergy
  University of Western Syndney
• Hilary Longhurst, Consultant Immunologist, Barts
  and the London NHS Trust
• William R. Lumry, Professor of Medicine,
  University of Texas Southwestern
• Inmaculada Martinez-Saguer, Professor of
  Medicine, University of Frankfurt

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Pharmaceutical Supporters of the Guidelines in
Alphabetical Order

• CSL Behring
• Dyax
• Shire
• Viropharma

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World Allergy Organizations 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.

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C1-esterase Inhibitor Protein (C1INH)

• Major inhibitor of several complement proteases
  (C1r, C1s, and mannose-binding lectinassociated
  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

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C1-INH involved in 3 systems ? C1-INH depletion
Factor XIIa
Factor XII
C1-INH
C1
Contact System
C1-INH
Prekallikrein
Complement System
HMW-K
C4 C2
Kallikrein
C1rs
C1-INH
C1-INH
Plasminogen
C1-INH
Bradykinin
Plasmin
FibrinolyticSystem
Increased vascular permeability ? ANGIOEDEMA
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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

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How Does BK Cause Angioedema?
Increased vascular permeability
Actin stress fibers
VE-cadherin
Non stimulated
Stimulated
from Tiruppathi C, et al. Vascul Pharmacol.
200339173-185.
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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

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HAE Attacks can Involve

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

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Intestinal swelling during an Abdominal attach
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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.

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DIAGNOSING HAE
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Treatment of HAE

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

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On Demand Therapies

• C1-esterase inhibitor (C1INH)
• Recombinant C1-INH (rcC1-INH)
• Ecallantide
• Icatibant
• Fresh Frozen Plasma

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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

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Use of C1-INH in HAE

• Recommendation
• 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)

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ADVANTAGES of C1-INH
DRAWBACKS

• 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

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Recommendation For on demand therapy recombinant
C1-INH appears to be equally effective to plasma
derived C1-INH

• Differences 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

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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

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ADVANTAGES of rcC1-INH
DRAWBACKS

• 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

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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)

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Positives
Negatives

• 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

Cicardi et al NEJM 2010
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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)

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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

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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

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How Do the Newer Drugs Compare?
Drug Advantages Disadvantages Best use Status
Plasma-derived C1-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
Recombinant C1-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
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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

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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

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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
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Androgens as short term prophylaxis 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
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Advantages and disadvantages for C1-inhibitor for
short term prophylaxis
Advantages Disadvantages
Some evidence for efficacy Good 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
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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

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

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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)

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Anti-fibrinolytic use for chronic prophylaxis

• disadvantages

• advantages

• Inexpensive
• Availability

• Adverse effects
• Few data to support effectiveness
• Multiple daily dosing
• Unsure of status during pregnancy, lactation and
  pre-puberty

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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)

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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

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8.5 Monitoring while receiving treatment with
Androgens
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

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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)

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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

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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)

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Use of C1-INH for Chronic Prophylaxis

• Disadvantages

• Advantages

• Dose ranging studies are lacking
• Human plasma derived
• Breakthrough attacks occur despite 1000 units
  twice a week
• Intravenous dosing necessary
• Expensive

• Effective
• Few adverse events
• Long safety record from over 3 decades use in the
  EU

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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)

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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)

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Drugs to avoid in HAE

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

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8.8 screening summary
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
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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.

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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).

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Treatment of Children with HAE

• Drugs 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

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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)

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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

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Prophylaxis During Gestation and Lactation

• Elimination of Triggering FactorsThe measures
  for non-pregnant females apply.
• Drug Prophylaxis
• Chronic 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

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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

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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

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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

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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.