Le linee guida attualmente
esistenti per la terapia
dell’HAE
PERCHÈ TRATTARE L’HAE?
• Malattia potenzialmente letale
• Inabilità durante gli attacchi
• Bassa qualità di vita
Perchè non trattare l’HAE?
• Gli attacchi potenzialmente letali sono meno del 5%
• Gli attacchi non determinano inabilità permanente
• Pazienti per la maggior parte asintomatci
CRITICITÀ NEL TRATTAMENTO
DELL’HAE
• Variabilità nella frequenza dei sintomi:
• da paziente a paziente
• nei diversi periodi della vita
• Variabilità nella severità dei sintomi
• Lunghezza del trattamento
FINALITÀ DEL TRATTAMENTO
DELL’HAE
• Eliminare la mortalità
• Ridurre il tempo durante il quale un paziente soffre
per un attacco di HAE
STRATEGIE TERAPEUTICHE
PER L’HAE E PROBLEMI SPECIFICI
• Prevenire gli attacchi
• Trattare i pazienti quando stanno bene
• Trattare i pazienti per tutta la vita
• Ridurre la durata degli attacchi
• Non aspettare a trattare un’attacco di HAE
• Variabilità nella risposta
INDICAZIONI AL
TRATTAMENTO
• Valutazione della severità della malattia
• Misurare la lunghezza degli attacchi
• Misurare la frequenza degli attacchi
• Identificare la strategia ottimale
• Efficacia dei trattamenti
• Facilità di somministrazione dei farmaci
RISULTATI DEL TRATTAMENTO
• Misurare l’efficacia
• Risultati riportati dai pazienti
• Durata degli attacchi
• Ospedalizzazione
• Inabilità/complicanze
• Misurare gli effetti collaterali
• Strategie specifiche per l’HAE
HAE Treatment Guidelines
Consensus Meeting
Gargnano 2010
Criteri di valutazione
dell’HAE
Agostoni et al 2004
J ALLERGY CLIN IMMUNOL
PROPOSTE DAL MEETING
DI GARGNANO 2010
• Sistemi per registrare i dati degli attacchi da parte
dei pazienti
• Facili da completare e inviare
• Valutazione della severità
• Valutazione della durata
• Sistemi di registrazione dei dati per i medici
• Unico datbase
• Punteggio automatico
DISEASE SCORING
Gargnano 2010
ATTACK RECORDING
• Starting of symptoms
• Day and hour
• Location of the attack
• Performance status
• I have no limitations
• I can do my activities, but with limitations
• I can not do my activities
• I went/called the physician
• I was admitted to the hospital
• Days/hours
• Medication
• Type
• Day and hour
• Resolution of symptoms
• Day and hour
QUALITY OF LIFE QUESTIONNAIRE
• At yearly follow up
mild
moderate
severe
Trattamento dell’attacco
acuto nell’HAE
14
BOWEN ET AL J ALLERGY
CLIN IMMUNOL 2004
BOWEN ET AL AACI, 2010
We recommend treating attacks as early as possible
Trattamento dell’attacco
acuto nell’HAE
Evidence based data
16
TRATTAMENTO DEGLI ATTACCHI
ACUTI: STUDI MULTICENTRICI,
RANDOMIZATI, IN DOPPIO CIECO
Study name *
First
author
Year
Journal
Drug class
Drug
Controls
CINRYZE
Zuraw
2010
NEJM
C1-inhibitor
Cynrize
placebo
68
yes
IMPACT1
Craig
2009
J Allergy Clin
Immunol
C1-inhibitor
Berinert #
placebo
85
yes
RHUCIN100
Zuraw
2010
J Allergy Clin
Immunol
C1-inhibitor
Rhucin #
placebo
58
yes
FAST-1
Cicardi
2010
NEJM
Bradykinin B2 receptor
Icatibant
antagonist
placebo
56
no
FAST-2
Cicardi
2010
NEJM
Bradykinin B2 receptor
Icatibant
antagonist
Tranexamic
acid
74
yes
EDEMA3
Cicardi
2010
NEJM
Kallikrein inhibitor
Ecallantide
placebo
72
yes
2010
Ann Allergy
Asthma
Immunol
Kallikrein inhibitor
Ecallantide
placebo
96
yes
EDEMA4
Levy
* name used in this systematic review
# only most effective dosage considered
§ patients included in this systematic review
n included stat
patients § sign
INIZIO DEL MIGLIORAMENTO DEI SINTOMI
GRAFICO RIASSUNTIVO DELLE EVIDENZE CLINICHE
Median time to the onset of symptoms relief
Ratio treatment/control
Kallikrein inhibitor
FAST-2
FAST-1
Pooled - Bradykinin receptor antagonist
RHUCIN100
IMPACT1
Pooled - C1-inhibitor
0,0
0,1
0,2
0,3
0,4
0,5
Ratio T/C
0,6
0,7
0,8
0,9
1,0
The lower the ratio, the better the treatment
Confronto indiretto: non ci sono differenze tra i diversi trattamenti
RISOLUZIONE COMPLETA DEI SINTOMI
FIGURA RIASSUNTIVA DELLE EVIDENZE
Median time to complete resolution of symptoms
Ratio treatment/control
FAST-2
FAST-1
Pooled - Bradykinin receptor antagonist
RHUCIN100
IMPACT1
CINRYZE
Pooled - C1-inhibitor
0,0
0,2
0,4
0,6
0,8
1,0
The lower
1,2 the ratio, the better the treatment
Ratio T/C
Confronto indiretto: non ci sono differenze tra i diversi trattamenti
TRATTAMENTO IN ACUTO
GARGNANO 2010
• All patients diagnosed with HAE due to C1-INH deficiency
should have available at home:
• C1-INH (pd 3000 units, rh 4200 units)
or
• Ecallantide (60 mg)
or
• Icatibant (60 mg)
• Patients should be trained for self administration
• All attacks are eligible for treatment as soon as they are
recognized
• Any of the above drug can be used for any location
• Any location can be treated at home
• Hospital recommended upon risk of laryngeal involvement
Profilassi degli attacchi
acuti di HAE
21
Agostoni et al
J ALLERGY CLIN IMMUNOL 2004
• Long-term prophylactic treatment is
indicated for patients with many harmful and
disturbing edema episodes, usually patients
with more than 1 attack per month. Longterm prophylaxis may be performed with
attenuated androgens, antifibrinolytic
agents, and C1-INH concentrate.
• All of these medications are associated with
potential adverse effects, limiting their use
as standard, life-long prophylactic treatment.
GOMPELS ET AL.
CLIN EXP IMMUNOL 2005
• The regimen for each affected individual should be guided by
the severity of the disease. Frequent attacks of peripheral
angio-oedema (extremities, trunk), although unpleasant
andannoying, are not dangerous and may not require
(contingent upon the patient’s judgement) long-term
prophylaxis.
• Long-term prophylaxis with C1 INH may be necessary in
patients where tranexamic acid or steroids are not effective, not
tolerated or contraindicated. This may include those with
underlying thromboembolic disease or during pregnancy. Prior
to recommending regular therapy, access to C1 inhibitor for
acute attacks should be optimized, by home therapy training if
necessary. In exceptional cases where thisapproach does not
provide sufficient symptom control, regular C1 inhibitor
infusions of 500–1000 U twice weekly may be required.
BOWEN ET AL.
ALLERGY, ASTHMA
& CLIN IMMUNOL, 2010
• Consider long-term prophylaxis with
antifibrinolytics, attenuated androgens, or
pdC1INH if more than one severe event per
month occurs and if a treatment for acute
attacks is not sufficiently effective or is not
available.
• It should be noted that: the number of events
per year does not predict severity of the next
event nor whether the first or next event will
be an airway event.
CRAIG ET AL.
ANN ALLERGY ASTHMA
IMMUNOL, 2009
Profilassi degli attacchi
acuti di HAE
Evidence based data
26
PROFILASSI DEGLI ATTACCHI
Controls
N°
included
patients
cross-over
design
p <0.05
Aminocaproic
placebo
5
yes
yes
AFs
tranexamic
placebo
12
yes
yes
NEJM
androgen
danazol
placebo
9
yes
yes
1977
Ann
Int Med
androgen
methyltest
placebo
4
yes
yes
2002
JACI
heparin
heparin
placebo
15
yes
no
placebo
6
yes
yes
placebo
22
yes
yes
First
author
Year
Journal
Drug class
Drug
Frank
1972
NEJM
AFs
Sheffer
1972
NEJM
Gelfand
1976
Sheffer
Weiler
Waites
1996
NEJM
vaporC1 inhibitor heated C1
inhibitor
Zuraw
2010
NEJM
C1 inhibitor C1inhibitor
Study Id
METANALISI
DEI DIVERSI STUDI CLINICI
7.0
Drug
RR (95% CI)
6.0
Aminocaproic
acid
0.095 ^
(0.025-0.356)
5.0
Tranexamic
acid
0.308 §
(0.195-0.479)
Pooled
0.204
(0.068-0.611)
Danazol
0.023 ^
(0.003-0.162)
Methyltestoren
e
0.054 §
(0.013-0.163)
Pooled
0.044
(0.017-0.114)
C1 inhibitor
0.491 §
(0.395-0.607)
4.0
3.0
2.0
1.0
0.0
0.00
Better0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
Relative risk Drug vs Placebo
Red: Androgen;
Blu: Antifibrinolytics;
Green: C1 inhibitor
Beware heterogeneity!
^
attacks per cycle
§ attacks per month
PROFILASSI DEGLI
ATTACCHI ACUTI
GARGNANO 2010
Long term prophylaxis
• Should be considered when optimized on demand therapy fails
for a documented reason as for example:
• > 24 days with angioedema per year
or
• >12 severe attacks per year
• Drugs
• androgens
• >16 year
• no pregnancy
• C1-INH
• when androgens contraindicated/not
accepted/>200 mg danazol daily.
• Doses should be titrated individually (usually two
infusions of 1000 U. per week)