Transcript slide kit di riferimento

Task Force
Documento sulla standardizzazione della
diagnosi e trattamento della tromboembolia
polmonare (TEP)
• Coordinatore: Massimo Pistolesi (Firenze)
• Esperto: Antonio Palla (Pisa)
• Segretario: Federico Lavorini (Firenze)
• Componenti della Task Force: Vitantonio Di Bello (Pisa), Maria Luisa De Rimini
(Napoli), Letizia Marconi (Pisa) , Gualtiero Palareti (Bologna), Raffaele Pesavento
(Padova), Domenico Prisco (Firenze), Massimo Santini (Pisa), Nicola Sverzellati
(Parma)
Incidenza
• Italia
60.000
nuovi casi/anno
• Francia
100.000 nuovi casi/anno
• G. B.
65.000
• USA
300.000 nuovi casi/anno
nuovi casi/anno
200
0
1969
1970
1971
1972
1973
1974
1975
1976
1977
1978
1979
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001(6 mesi)
2002
2003
2004
2005
2006
2007
2008
Urgenze per sospetta EP
250
EP confermate
EP non confermate
150
100
50
Distribuzione di frequenza di gravità della malattia embolica
in 690 pazienti consecutivi con diagnosi di EP
60
9,22 = 51,2%
PAZIENTI (n°)
50
40
30
20
10
0
5
10
SEGMENTI NON PERFUSI (n°)
15
Frequenza di embolia polmonare al momento
dell’autopsia,non riconosciuta in vita
•
•
•
•
•
•
•
•
•
•
Modan
Coon
Deganuto
Morpurgo
Goldhaber
Passarino
Rubinstein
Sperry
Morpurgo
Roulson
• Totale
(71)
(76)
(80)
(80)
(82)
(82)
(88)
(90)
(95)
(05)
62 %
84 %
81 %
80 %
70 %
91 %
68 %
65 %
89 %
60%
77 %
Criteri di utilità
sintomi
dispnea improvvisa,
dolore toracico
fattori predisponenti
segni RX
immobilizzazione prolungata
APD,
diaframma
segni ECG
Tneg
V1-V2,
I
R in
aVR
segni EGA
PaO2 std < 80 mmHg
segni di laboratorio
D-dimero
in pazienti esterni
Gas Exchange Abnormalities in PE
Hypoxemia;
Increased alveolar-arterial O2 tension gradient;
Hypocapnia;
Respiratory alkalosis.
Hypoxia and hypocapnia in PE are present in the
acute phase and may persist, according to the
degree of recovery, for months
Wilson JE et al J Clin Invest 1971.
Several mechanisms (VA/Q inequality, shunt, diffusion
limitatation, low mixed PvaO2) have been implicated, and
they vary according to the severity of PE, degree of
recovery, presence of previous cardiopulmonary
conditions and/or complications.
Pistolesi M et al l Eur Respir Mon 2004
Historically, PE has been characterised by VA/Q
mismatching in the affected lung zones and by an
increase in wasted ventilation, i. e. dead space.
DeNardo GL et al N Engl J Med s 1970.
"Regional ischemia results in airway constriction
in the same region…. which helps to achieve
matching of VA/Q "
"The decrease in wasted ventilation (ventilation
to unperfused and poorly perfused lung) helps
the patient but hinders the physician in the
diagnosis "
Comroe JH Circulation 1966.
Develpment of lung units with high VA/Q ratio is accompanied
by redistribution of ventilation away from these units; thus,
reduced or absent VA is present in the embolised regions.
Putative mechanisms:
- Bronchoconstriction mediate by hypocapnia (acute phase);
- Atelectasis related to alterated surfactant production;
- Obstruction and pulmonary infarction secondary to
insufficient blood flow.
Shunt, diffusion limitation and true alveolar dead space occur
in some patients but are generally insignificant
"Redistribution of ventilation and blood flow is characterised
by development of separate lung units with high VA/Q ratio
and lung units with low VA/Q ratio (Bimodal distribution)"
Giuntini C Q J Nucl Med 2001.
AFTER
Ventilation ( ) and
Pulmonary blood flow ( )
BEFORE
Log Ventilation-Perfusion ratio (MIGET)
The bimodal shape of VA and Q distributions observed
in the acute phase nearly
vanished after heparin
treatment
Santolicandro AM et al Am J Respir Crit Care Med 1995.
PE +
PaO2 (mmHg)
PaCO2 (mmHg)
PaO2st (mmHg)
PE -
65±13
68±18
(40-101)
(35-129)
32±4
34±5
(20-42)
(21-49)
53±16
59±18
(22-80)
(28-99)
p<0.02
p<0.0001
p<0.01
However, 75% of patients in whom PE was excluded
had PaO2 <75 mmHg and PaCO2 <36 mmHg
Geneva prediction rule
Recent surgery
2
Previous PE or DVT
2
Older age
2
Hypocapnia
2
Hypoxemia
2
Tachycardia
2
Platelike atelectasis
2
Hemidiaphragm
elevation
2
Low
500
400
PE absent
PE present
300
200
38%
100
≤4
Intermediate 5 to 8
High
Arch Intern Med 2001
10%
81%
0
low
intermediate
≥9
single center study (n=986), only outpatients
high
“With various combinations of Pa02≥80 mmHg,
PaC02≥35 mmHg, and P(A-a)02≤20 mmHg, PE could
not be excluded in more than 30% of patients with no
prior cardiopulmonary disease,…. and in more than
14% of patients with prior cardiopulmonary disease”.
“Evaluation of blood gas levels may contribute to the
formulation of a clinical suspicion, but are of insufficient
discriminant value to permit exclusion of the diagnosis
of PE”.
“None of the ABG data or prediction rules had sufficient
negative predictive value, specificity, or likelihood ratios
to be useful in the management of patients with
suspected PE”.
Evaluation of gas exchange parameters may allow the assessment
of functional recovery of patients, thus giving additional
information about the effect of therapy.
The enlargement of the right descending pulmonary artery and the
Westermark sign were significantly associated with a higher degree
of gas exchange impairment and with a more severe embolization.
Sensitivity
PETCO2 <36
Specificity
PPV
NPV
96.2
87.2
53.0
21.1
PETCO2 <36
92.3
+ Wells’ score >4
45.2
19.6
97.6
Gas exchange following PE is influenced by
numerous factors, often with contrasting effects, so
that arterial blood gas abnormalities are non-specific
and insensitive to the extent of embolization.
.
Arterial blood gas abnormalities have virtually no
predictive value in patients with suspected PE.
Serial measurements of arterial blood gases may be
of value in monitoring the resolution of PE in
response to anticoagulant therapy.
2006
Embolia polmonare
Strategie diagnostiche
Sospetto diagnostico
Probabilità clinica
D-dimero
Sviluppo di strategie
diagnostiche appropriate
e personalizzate
Studio circolazione
polmonare
• Angiografia CT
• Scintigrafia
Studio circolazione
venosa
• Ultrasuonografia
• Venografia CT
Embolia polmonare
Strategie diagnostiche
Sospetto diagnostico
Frequenza autoptica di EP non diagnosticata in vita
•
•
•
•
•
•
•
•
•
Modan
Coon
Deganuto
Morpurgo
Goldhaber
Passarino
Rubinstein
Sperry
Morpurgo
Media generale
(71)
(76)
(80)
(80)
(82)
(82)
(88)
(90)
(95)
62
84
81
80
70
91
68
65
89
%
%
%
%
%
%
%
%
%
77 %
Key messages
1. La TEP deve essere sempre sospettata ogni volta che un paziente
lamenti dispnea improvvisa, dolore toracico o deliquio non
altrimenti spiegabili.
2. In ogni paziente deve essere sempre quantificato il sospetto di
TEP mediante score clinici validati
3. Un valore di D-dimero normale associato a probabilità clinica
medio-bassa esclude la TEP; in caso di elevata probabilità clinica
il dosaggio del D-dimero non è utile.
4. Nei pazienti con probabilità clinica di TEP elevata è necessario
sempre confermare od escludere la malattia per mezzo di
tecniche di immagine polmonare (Q scan, angioTC)
5. In caso di discordanza tra probabilità clinica ed imaging (TC o Q
scan) è necessario eseguire ulteriori indagini
Key message 1
• La TEP è diagnosticata o sospettata in vita soltanto nel 20-30%
dei pazienti nei quali è stata dimostrata all’esame autoptico;
• Le difficoltà nel diagnosticare la TEP risiedono sia
nell’aspecificità dei sintomi (dispnea improvvisa, dolore toracico
o deliquio), sia nell’estrema variabilità di presentazione clinica
della malattia. L’embolia può manifestarsi in condizioni di quasi
completo benessere fino alla sincope e alla morte improvvisa.
• Questo riflette probabilmente l’ampio spettro di gravità della
malattia in termini di letto vascolare polmonare interessato dal
processo di embolizzazione.
Key message 2
Comparison between PISA and WELLS’ scoring systems
Male sex
Age 63-72
Age ≥ 73
DVT (ever)
Dyspnea (sudden-onset)
Chest pain
Hemoptysis
ECG signs (RV strain)
Focal oligemia
Amputation (hilar artery)
Consolidation (infarct)
0.81
0.59
0.92
0.69
1.29
0.64
0.89
1.53
3.86
3.92
3.55
Comparison between PISA and WELLS’ scoring systems
Male sex
Age 63-72
Age ≥ 73
DVT (ever)
Dyspnea (sudden-onset)
Chest pain
Hemoptysis
ECG signs (RV strain)
Focal oligemia
Amputation (hilar artery)
Consolidation (infarct)
0.81
0.59
0.92
0.69
1.29
0.64
0.89
1.53
3.86
3.92
3.55
Comparison between PISA and WELLS’ scoring systems
Male sex
Age 63-72
Age ≥ 73
DVT (ever)
Dyspnea (sudden-onset)
Chest pain
Hemoptysis
ECG signs (RV strain)
Focal oligemia
Amputation (hilar artery)
Consolidation (infarct)
0.81
0.59
0.92
0.69
1.29
0.64
0.89
1.53
3.86
3.92
3.55
Comparison between PISA and WELLS’ scoring systems
Male sex
Age 63-72
Age ≥ 73
DVT (ever)
Dyspnea (sudden-onset)
Chest pain
Hemoptysis
ECG signs (RV strain)
Focal oligemia
Amputation (hilar artery)
Consolidation (infarct)
0.81
0.59
0.92
0.69
1.29
0.64
0.89
1.53
3.86
3.92
3.55
Embolia polmonare
Probabilità clinica
PE present
800
PE absent
600
400
700
350
number of patients
500
600
300
400
500
250
400
300
200
300
150
200
200
100
100
100
0
50
low intermediate high
0
low intermediate high
0
low intermediate high
Wells
Geneva
Pisa
n=1239
mostly outpatients
n=986
only outpatients
n=750
mostly inpatients
Embolia polmonare
Probabilità clinica
JAMA 1936
About 50% of patients with proven acute PE have
ECG findings of acute cor pulmonale.
S1
PISA-PED Am J Respir Crit Care Med 1999
Q3
T3
Embolia polmonare
Westermark’s
sign (1938)
Radiografia del torace
Hampton’s
sign (1940)
Fleischner’s
sign (1962)
At least one of these findings was identified in 75% of 202 patients with proven PE
and in only 1% of 298 patients with PE excluded at angiography PISA-PED Am J
Respir Crit Care Med 1999
Embolia polmonare
Radiografia del torace
Embolia polmonare
Radiografia del torace
Embolia polmonare
Radiografia del torace
Embolia polmonare
Radiografia del torace
Embolia polmonare
Radiografia del torace
Embolia polmonare
Radiografia del torace
Embolia polmonare
Radiografia del torace
Embolia polmonare
Review
Probabilità clinica
2008
Embolia polmonare
D-dimero
Sospetto diagnostico
Probabilità clinica
D-dimero
Embolia polmonare
Strategie diagnostiche
Sospetto diagnostico
Probabilità clinica
D-dimero
Sviluppo di strategie
diagnostiche appropriate
e personalizzate
Studio circolazione
polmonare
• Angiografia CT
• Scintigrafia
Studio circolazione
venosa
• Ultrasuonografia
• Venografia CT
Embolia polmonare
Stein PD et al. 2007
Strategie diagnostiche
Embolia polmonare
Strategie diagnostiche
Stein PD et al. Controversies in diagnosis of pulmonary embolism.
Clin Appl Thromb Hemost 2011
Embolia polmonare
Angiografia CT
Embolia polmonare
Angiografia CT
Embolia polmonare
Angiografia CT
Embolia polmonare
Angiografia CT
Embolia polmonare
Angiografia CT
Embolia polmonare
Angiografia CT
“multidetector CT angiography has fullfilled
the conditions to replace pulmonary
angiography as the reference standard for
diagnosis of acute pulmonary embolism”
Embolia polmonare
Stein PD et al. 2007
Strategie diagnostiche
Embolia polmonare
Strategie diagnostiche
Embolia polmonare
Strategie diagnostiche
Embolia polmonare
Strategie diagnostiche
Embolia polmonare
Scintigrafia da perfusione
Sensitivity and Specificity of
Perfusion Scintigraphy Combined
with Chest Radiography for Acute
Pulmonary Embolism in PIOPED II
HD Sostman, M Miniati, A Gottschalk, F Matta, PD Stein, M Pistolesi
Embolia polmonare
Scintigrafia da perfusione
Predictive Values of Perfusion Scan
Compared with CT angiography (n=889)
Test
PPV
NPV
Not
diagnostic
PISA-PED
(Q scan)
85%
96%
0%
CT
angiography
86%
95%
6%
Key message 3
• I risultati del dosaggio del D-dimero sono
influenzati dalla metodica utilizzata; i cut-offs
spesso differiscono fra i vari ospedali e tra le varie
tipologie di pazienti
• Il dosaggio di D-dimero deve essere effettuato
mediante una metodica formalmente validata per
questa diagnostica.
Key message 4
Per l’ampia diffusione, pronta disponibilità ed elevata accuratezza
diagnostica, la TC multidetettore è la tecnica di riferimento per la
conferma/esclusione della malattia.
La scintigrafia polmonare da perfusione (Q scan) rappresenta una
metodica altrettanto valida per la conferma/esclusione della malattia.
L’esame dovrebbe essere sempre refertato come: Q scan +, Q scan -, Q
scan non diagnostico.
In presenza di TC positiva per TEP si consiglia di eseguire Q scan entro 2472 ore per ottenere un valutazione riproducibile di sede ed estensione dei
deficit perfusori da utilizzare nel follow-up. La TC non è raccomandata nel
follow-up.
L’ecocardiogramma rappresenta l’esame diagnostico di prima scelta nei
pazienti con condizioni emodinamiche instabili. Inoltre, riveste un ruolo
importante per la valutazione prognostica e l’impostazione delle decisioni
terapeutiche.
Angio TC
• Ridurre l’esposizione alle radiazioni:
– Sistemi di controllo automatico di modulazione della dose
– Ridurre il kilovoltaggio (100-80 Kv) ed il mezzo di
contrasto (60-80 ml)
– Scansione limitata (arco aortico-base cuore) soprattutto
nei pazienti giovani
– Estendere (dopo 2 minuti) la scansione agli arti inferiori
e/o addome solo in casi selezionati (es. sospetta embolia
neoplastica, trombosi iliaca isolata )
Pazienti con allergia e/o insufficienza renale
• Se eco negativa, allergia o insuff renale lieve o
moderata: angio-TC previa preparazione, basso kVp
(es.70 mL) con poco mezzo di contrasto
• Se eco negativa, allergia o insuff renale severa:
scintigrafia perfusionale
Remy-Jardin M et al, Radiology 2007
Probabilità clinica e TC
• In pazienti con prob. clinica bassa-intermedia:
• vpn TC 96%-89%
• vpp TC 58%-92%
• In pazienti con prob. clinica alta:
• vpn TC 60%
• vpp TC 96%
Stein PD et al, NEJM 2006
Fattori prognostici TC
• Score estensione dei difetti di riempimento embolici
(maggiore o minore del 50%)
• Alterazioni cardiache devono essere segnalate:
– Rapporto VD/VS > 1
– Inversione del setto interventricolare
– Allargamento dell’atrio destro
– Reflusso del mdc nelle vene sovraepatiche
– Dilatazione marcata di vena cava (sup o inf) e seno coronarico
Embolia polmonare
Strategie diagnostiche
21) Sostman et al. Journal of Nuclear Medicine 2008
Respirology (2012) 17, 180–184
Inclusion criteria:
resting mean pulmonary artery pressure greater than 25 mm Hg in the
setting of normal or reduced cardiac output and a normal capillary wedge
pressure; confirmation of the extent of CTEPH by examination of
specimens excised during PEA
Respirology (2012) 17, 180–184
Q Scan
• No mdc (I.Ren. , Allergie)
• Riproducibilità
• Ripetibilità
•SPECT
•SPECT/CT
Follow-up
Quantizzazione
Dosimetria bassa
Embolia polmonare
Scintigrafia da perfusione
Embolia polmonare
Stein PD et al.
2007
Strategie diagnostiche
Embolia polmonare
Review
Stein PD et al.
Strategie diagnostiche
2008
Embolia polmonare
Strategie diagnostiche
A
Am J Roentgenol
2008
CONCLUSION. We believe that the 10% PE positivity rate represents
overuse of CTA as a screening rather than diagnostic test. This
practice equates with ineffective resource utilization, increased
health care costs, and unnecessary radiation and contrast exposure.
Embolia polmonare
Strategie diagnostiche
Condizioni che possono costituire
controindicazioni relative od assolute
all’impiego dell’angiografia CT
• gravidanza
•
giovane età, specialmente nel sesso femminile
•
allergia ai mezzi di contrasto
•
insufficienza renale
Embolia polmonare
Strategie diagnostiche
Low/Intermediate clinical probability
D-dimer < 500µg
D-dimer > 500µg
PE ruled out
Venous US
positive
positive
treatment
negative
Perfusion scan
CTA, MRI,
Serial venous US, Echocardiography
PE +
PE-
<10%
negative
PE ruled out
Embolia polmonare
Strategie diagnostiche
High clinical probability
Venous US
positive
negative
Perfusion scan
treatment
PE ruled out
PE +
PE<2%
positive
CTA, MRI,
Serial venous US, Echocardiography
negative
Embolia polmonare
Strategie diagnostiche
Stein PD et al. Controversies in diagnosis of pulmonary embolism.
Clin Appl Thromb Hemost 2011
Embolia polmonare
Strategie diagnostiche
Stein PD et al. Controversies in diagnosis of pulmonary embolism.
Clin Appl Thromb Hemost 2011
Embolia polmonare
Strategie diagnostiche
Stein PD et al. Controversies in diagnosis of pulmonary embolism.
Clin Appl Thromb Hemost 2011
Embolia polmonare
Strategie diagnostiche
Stein PD et al. Controversies in diagnosis of pulmonary embolism.
Clin Appl Thromb Hemost 2011
Profilassi: key messages
Profilassi primaria è profilassi del tromboembolismo venoso
(TEV)
Profilassi secondaria è connessa con il problema della terapia
e della sua durata
La gestione della profilassi del TEV deve avvalersi di
protocolli scritti e condivisi a livello del singolo ospedale
eventualmente adattando alla realtà locale linee guida o
raccomandazioni di Società scientifiche
Il tipo di profilassi deve essere individualizzato valutando
contemporaneamente il rischio tromboembolico relativo alla
condizione e quello emorragico di base e indotto dai farmaci
antitrombotici
Profilassi: criticità
Restano da definire metodi validati per stabilire il
rischio trombo embolico e quello emorragico nel
singolo paziente
La durata della profilassi ottimale in pazienti in cui
persistano a lungo condizioni a rischio non è ben
definita
Le linee guida per la profilassi dovrebbero essere
non solo elaborate e diffuse ma anche
implementate
Le
corrette
modalità
di
profilassi
antitromboembolica nei pazienti non ricoverati
restano da definire
Follow-up
Obiettivi: individuazione di pazienti con ipertensione
polmonare post-TEP; valutazione sospensione terapia
anticoagulante
Follow-up da effettuare dopo 6 mesi ed al momento della
valutazione per la sospensione del trattamento.
Comprensivo di:
-visita;
- gas ematici;
- Q scan;
- Ecodoppler venoso
- Ecocardiogramma
FOLLOW-UP
1 mese
•Visita
•EGA
•SPP
6 mesi
•Visita
• EGA
•SPP
•EDV
•Ecocardiografia
1 anno
• Visita
• EGA
• SPP
• EDV se TVP residua
• Ecocardiografia se
alterata
• Valutazione stato
trombofilico
• Valutazione
sospensioneproseguimento TAO
Annualmente
•Visita
•SPP se alterata
•EDV se TVP
residua
•Ecocardiografia
se alterata
Problemi con EBPM
Indicazioni terapeutiche differenti
Dosi diverse a secondo del prodotto
Prodotti diversi disponibili negli ospedali
Incerta la necessità di monitoraggio in specifiche
condizioni cliniche (pediatria, gravidanza, obesità)
Difficilmente disponibile il test anti-Xa
Non completamente neutralizzabile
Durata prevenzione secondaria
3 mesi se:
- TEV secondaria a fattore transitorio
Almeno 3 mesi ma da valutare se a
tempo indefinito:
- TEV idiopatiche (non provocate)
Fasi della terapia della TEP non
“emodinamica”
Iniziale 5/7 g
EBPM
Lungo termine 3 m
Fondap.
AVK
ENF
NAO
(AVK,
(EBPM)
NAO)
Prevenzione secondaria
Indefinita ?
AVK
NAO
Immediata anticoagulazione
QUANDO
• Appena fatta la diagnosi di TEP
• Anche in attesa di diagnosi se alta
probabilità clinica
• Dopo aver escluso controindicazioni
assolute agli anticoagulanti
Farmaci anticoagulanti ad
azione immediata
QUALI
• EBPM (1 scelta)
• Fondaparinux
• Nuovi Anticoagulanti Orali (NAO)
• ENF se:
IR (< 30ml clearence creatinina)
previste prossime manovre invasive o
chir.
possibile trombolisi
Terapia iniziale della TEP
• EBPM s.c., 100 UI / kg / 12 ore oppure:
• Fondaparinux 7,5 mg s.c./24 ore (peso 50-100 Kg)
per almeno 5 giorni
In alternativa
(paziente da monitorare, ins. renale)
ENF e.v (bolo 5000 UI seguito da infusione
continua per mantenere APTT 1.5-2.5)
• Sospendere ENF o EBPM dopo non meno di 5 gg
ed almeno 2 gg con INR > 2.0 (range terapeutico =
2.0-3.0)
Terapia iniziale della TEP
Come paziente ambulatoriale, se possibile
(Grado 1C) o da ricoverato, se necessario
(Grado 1A)
In caso di EBPM si sconsiglia il
monitoraggio routinario mediante
determinazione del livello di anti-Xa (Grado
1A)
Problemi con l’uso di LMWH
• Indicazioni “legali” diverse
• Dosi diverse a secondo del prodotto
• Prodotti diversi disponibili negli ospedali (e
•
•
•
•
variabili)
Incerta la necessità di monitoraggio in
specifiche condizioni cliniche (pediatria,
gravidanza, obesità, ecc)
Difficilmente disponibile il test anti-Xa
Non completamente neutralizzabile
Possibile HIT
Durata della prevenzione secondaria
3 mesi se:
- TEV secondaria a fattore transitorio
Almeno 3 mesi ma da valutare se a
tempo indefinito:
- TEV idiopatiche (non provocate)
Nuove terapie
Strategic targets : Xa et IIa
New Anticoagulants
PARENTERAL
ORAL
TTP889
FIXai
FIXab
TFPI (tifacogin)
NAPc2
VIIai
TF/VIIa
X
Rivaroxaban
Apixaban
Edoxaban
Razaxaban
Betrixaban
YM 150 / LY517717
DU176B / PRT054021
IX
VIIIa
IXa
Va
AT
SSR123781
SSR128428
AVE 5026
Org 42675
IIa
Fibrinogen
Idrabiotaparinux
DX-9065a
Otamixaban
Xa
II
Ximelagatran
Dabigatran
TGN 255
Odiparcil
(via GAGs)
Flovagatran (p)
APC (drotrecogin alfa)
sTM (ART-123)
Fibrin
Flovagatran
Pegmusirudin
Peg Hirudin
Desiruidin
The Big Four
• Dabigatran – Pradaxa  Boehringer
– Approved in Europe : Orthopedic surgery
– Approved in Usa : AF
– Approval in European market: Exp. Spring 2012 AF 2013VTE
• Rivaroxaban – Xarelto  Bayer Schering
– Approved in Europe: Orthopedic surgery
– Pending app in USA: AF maybe Orthop surg
– Approving in Europe: Spring 2012 AF 2013 VTE
• Apixaban – Eliquis  BMS-Pfizer
– Approved in Europe: Orthopedic surgery
– Submitted in USA: Orthopedic surgery
– VTE studies (Amplify/Amplify ext) stop recruitment: end 2011;
publication 2012 – approval VTE 2014?
• Edoxaban – Daichi Sankyo
– VTE study (Hokusai) stop recruitment: early 2012 – approval ?
Clinical pharmacology of apixaban,
rivaroxaban and dabigatran
Apixaban1
Rivaroxaban2
Dabigatran3
Mechanism of
action
Direct factor Xa
inhibitor
Direct Factor
Xa inhibitor
Direct thrombin
inhibitor
Absolute
availability
~50%
80–100%
6.5%
Route of
administration
Oral
Oral
Oral
Pro-drug
No
No
Yes
Food effect
No
No
No
Renal clearance
~27%
~33 %
85%
Mean half-life (t1/2)
~12 h
7–11 h
14–17 h (patients)
Tmax
3-4 h
2–4 h
0.5–2 h
1. Apixaban SmPC 2011
2. Rivaroxaban SmPC 2011
3. Dabigatran SmPC 2011
No head-to-head comparisons between apixaban, rivaroxaban and dabigatran have been performed in a
randomised clinical trial setting. The information in this table is based on the SmPCs for apixaban,
rivaroxaban and dabigatran. Please refer to the SmPCs for further information.
Embolia Polm
Dabigatran
Rivaroxaban
Idrobiotaparinux
Terapia
Immediata
No
Si
No
Efficacia
Non inferiore
Sfiora super(TVP) Non inferiore
Sicurezza
Superiore
HR0.71
Non inferiore
(TVP)
Superiore
HR 0.67
Emorragie magg.
Non Inferiore
-
v.Sotto
composito?
Emorragie NMRil
Superiore
HR 0.63
-
Superiore
0.70
Effetti collater +++ Dispepsia
-
-
Altri effetti
-
No
> Eventi CV acuti
HR
Embolia Polm
Dabigatran
Rivaroxaban
Idrobiotaparinux
Studio Extension
Si
Si
No
Efficacia
Sup HR 0.08/Non
Infer HR1.44
Superiore
HR 0.18
-
-
-
Sicurezza (emorr.) inferiore HR 2.9
Non Infer. HR
0.71
Emorragie magg.
Sfiora Superiorità Non inferiore
HR 0.52
0,7% vs 0%
-
Emorragie NMRil
-
Inferiore
5,4% vs 1,2%
-
-
-
Si (in uno dei 2 st) -
-
Effetti collater +++ IMA
Nuovi anticoagulanti - PROS
• efficaci nella prevenzione del TEV in chirurgia ortopedica, nella terapia
della TVP ( EP), nella fibrillazione atriale
•Nella terapia del TEV rivaroxaban/apixaban/edoxaban sostituiscono
completamente la terapia classica.
• Minore o uguale rischio emorragico
• Soprattutto con dabigatran e idrobiotaparinux
• Rivaroxaban: eccesso di sanguinamento (Magellan)
• Apixaban: eccesso di sanguinamento (Appraise 2)
• Nessun monitoraggio
•Disponibilità di dosaggi testati per anziani e IRC moderata
• Dabigatran ( per gli altri prob. non necessarie)
Nuovi anticoagulanti orali - CONS
•Relativ. Pochi dati sulla tossicità epatica – per molti escrezione renale
•Possibili sorprese dalla farmacovigilanza: studi limitati a 6-12 mesi max
•Mancano dati sulla sicurezza /efficacia nelle popolazioni speciali:
• Grandi geronti, oncologici, obesi, chirurgici, valvolari, bridging ecc
•Compliance/sottostima sintomi da eccesso di sicurezza del paziente
•Gravidanza (tossicità riproduttiva negli animali)
• non dotati di antidoto ( cmq dializzabili) (Novoseven? Compl. Protr? In
corso studi preliminari) – manca un test di attività per l’emergenza e durante
emorragia – NB: idrobiotaparinux ha l’antidoto (avidina)
Riflessioni
• I costi andranno valutati da rigorose analisi farmacoeconomiche
ma senza demonizzazioni strumentali e dovranno anche tenere
conto dei costi del monitoraggio della terapia attuale e della
qualità di vita dei pazienti.
•Il problema della “demedicalizzazione” della terapia
anticoagulante esiste certamente ma non deve essere sovrastimato
eccessivamente
Riflessioni
Rivoluzione relativamente lenta? Cfr ACCP 2012
•Evitare scelte sbagliate che rallentino lo loro
introduzione nella pratica clinica
• Gli anticoagulanti tradizionali resteranno nel
prontuario ancora per molti anni
• I pazienti che traggono il massimo beneficio
dalla terapia classica non dovrebbero
sospenderla per i nuovi farmaci?
International, multicenter study
aimed at assessing the efficacy and safety of TNK
versus placebo in patients with
acute pulmonary embolism,
normal blood pressure
and right ventricle overload
TNK o placebo
singolo bolo
30-50 mg sec P.C.
UHF:
80UI/KG
+18UI/Kg/h
LMWH dopo 48 ore
RE-COVERTM Trial Design
Singledummy
period
Warfarin
placebo
Double-dummy period
(1274 pts)
Dabigatran etexilate 150 mg bid
Warfarin placebo
30 days
follow up
Objective
confirmation
of VTE
Dabigatran etexilate placebo bid
72 h
Warfarin
Initial parenteral
therapy
E R
E= enrolment
R= randomization
Until INR ≥2.0 at
two consecutive
measurements
(8-11 days)
Warfarin
(INR 2.0–3.0)
(1265 pts)
6 months
End of treatment
NEJM Dec 2009
Cumulative Risk of Recurrent Venous Thromboembolism or Related Death during 6 Months of
Treatment among Patients Randomly Assigned to Dabigatran or Warfarin.
Dabigatran: 2.4%
Warfarin: 2.1%
HR 1.10 (0.65-1.84), p<0.001 for non-inferiority criteria
Schulman S et al. N Engl J Med 2009;361:2342-2352.
Cumulative Risks of a First Event of Major Bleeding and of Any Bleeding among Patients
Randomly Assigned to Dabigatran or Warfarin.
Dabigatran: 16.9%
Warfarin: 21.9%
HR 0.71(0.59-0.85)
Dabigatran: 1.6%
Warfarin: 1.9%
HR 0.82(0.45-1.48)
Schulman S et al. N Engl J Med 2009;361:2342-2352.
Significant reduction in major / clinically
relevant bleeds
HR 0.63 (95% CI: 0.47–0.84)
p=0.002
9,0
for superiority
8,0
Percentage
7,0
37% RRR
8.8%
6,0
5,0
5.6%
4,0
3,0
2,0
1,0
0,0
Dabigatran etexilate 150 mg bid
71 / 1273
Warfarin
111 / 1266
RELY
• PE accounts for 30% of the study population
• Mean age 55 yo, 95% white, >90% with CrCl >50
• Only ~5% of patients have cancer
• First dose of dabigatran was only given after median of 9
days after parenteral anticoagulation, giving rise to the
question of the effectiveness of dabigatran monotherapy
in acute setting
• Dabigatran group has more dyspepsia(2.9% vs 0.6%)
and discontinuation of drugs (9% vs 6.8%)
Schulman S et al. N Engl J Med 2009;361:2342-2352.
RE-SONATE Trial
[O-MO-037] DABIGATRAN VERSUS PLACEBO FOR EXTENDED
MAINTENANCE THERAPY OF VENOUS THROMBOEMBOLISM
the RE-SONATE Study Group
METHODS
Patients with VTE who had completed 6-18 months of anticoagulant therapy
were randomized, using a double-blind design, to treatment with dabigatran 150
mg twice daily or with placebo for an additional period of 6 months. Patients
with a clear indication for continued anticoagulation were not eligible. The
primary efficacy outcome was the frequency of recurrent symptomatic VTE and
related deaths at the end of the planned treatment period. The principal safety
outcome was time to the first major bleeding. Additional outcomes included
clinically relevant bleeding events, deaths and cardiovascular events.
Modified - ISTH 2011 Kyoto
RE-SONATE Trial – ISTH 2011 Kyoto
Recurrent VTE occurred in 3 (0.4%) of 681 patients treated with dabigatran and
37 (5.6%) of 662 patients treated with placebo (hazard ratio [HR] 0.08; 95%
confidence interval [CI], 0.02 to 0.25; P<0.0001). There were 2 patients with
major bleeds (0.39%), both gastrointestinal, requiring transfusion, on treatment
with dabigatran. None occurred in patients receiving placebo (95% CI, 0.04 to
1.05; P=0.5). Clinically relevant bleeding occurred in 36 patients (5.3%) on
treatment with dabigatran and in 12 patients (1.8%) on placebo (HR 2.9; 95%
CI, 1.5 to 5.6; P=0.001). Cardiovascular events were observed in 3 patients
(0.4%) on treatment with dabigatran and in 2 patients (0.3%) on placebo. In the
safety on-treatment analysis, there were no deaths in the dabigatran group and
1 unexplained death in the placebo group and there were 30 severe adverse
events in each of the two treatment groups.
CONCLUSIONS
Extended treatment with dabigatran was associated with a 92% relative risk
reduction for recurrent VTE and a low risk for major bleeding.
RE-MEDY TRIAL
[O-TH-033] DABIGATRAN OR WARFARIN FOR EXTENDED
MAINTENANCE THERAPY OF VENOUS THROMBOEMBOLISM
Sam Schulman et al.
METHODS
Patients with VTE who had initially received 3 to 12 months of
anticoagulant therapy were randomized, using a double-blind design, to
treatment with dabigatran 150 mg twice daily or with warfarin (to maintain
an international normalized ratio of 2.0 to 3.0) for an additional period of 6
to 36 months. The primary efficacy outcome was the frequency of recurrent
symptomatic VTE and related deaths at the end of the planned treatment
period. Safety outcomes were bleeding events, acute coronary syndromes
and other adverse events.
Modified - ISTH 2011 Kyoto
RE-MEDY TRIAL
RESULTS
Recurrent VTE occurred in 26 (1.8%) of 1430 patients treated with dabigatran and
18 (1.3%) of 1426 patients treated with warfarin (hazard ratio [HR] 1.44; 95%
confidence interval [CI], 0.78 to 2.64; P=0.03 for the pre-specified non-inferiority
margin). There were 13 major bleeds (0.9%) in patients on treatment with
dabigatran and 25 (1.8%) in patients on treatment with warfarin (HR 0.52; 95% CI,
0.27 to 1.01). Any bleeding occurred in 277 patients (19%) on treatment with
dabigatran and in 373 patients (26%) on warfarin (HR 0.71; 95% CI, 0.61 to 0.83).
Acute coronary syndromes were observed in 13 patients (0.9%) on treatment with
dabigatran and in 3 patients (0.2%) on warfarin (P=0.02). There were 17 deaths in
the dabigatran group and 19 deaths in the warfarin group; other adverse events
were also similar with the two treatments.
CONCLUSIONS
Dabigatran was as effective as warfarin in the extended treatment of VTE.
Dabigatran was associated with a reduced risk for bleeding but an increased
incidence of acute coronary events.
Modified - ISTH 2011 Kyoto
Rivaroxaban
• Einstein PE: in corso di analisi e pubblic
• Inizio terapia immediato
• Einsten DVT:
– Efficacia: sfiora la superiorità
– Sicurezza: simile
• Pazienti oncologici: 8%
Study design
Confirmed
symptomatic DVT
or PE completing
6 or 12 months of
rivaroxaban or VKA
in EINSTEIN VTE
program
Confirmed
symptomatic DVT
or PE completing
6 or 12 months
of VKA
Treatment period of 6 or 12 months
~53%
N=1,197
Rivaroxaban 20 mg od
R
Day 1
~47%
EINSTEIN Extension Trial ID: NCT00439725
Placebo
30-day observational period
Randomized, double-blind, placebo-controlled,
event-driven (n=30), superiority study
Primary efficacy outcome analysis
(time to first event)
Cumulative event rate (%)
10
Number needed to treat
to prevent 1 primary
efficacy outcome: 15
9
8
7
Placebo
(n=594)
HR=0.184; p<0.0001
95CI (0.086-0.391)
RRR=82%
6
5
4
3
2
Rivaroxaban
(n=602)
1
0
0
30
60
90
Rivaroxaban 602
590
583
573
552
503
482
171
138
132
114
92
81
Placebo
582
570
554
521
467
444
164
138
133
110
93
85
Number of
subjects at risk
594
ITT population
120 150 180 210 240 270
Time to event (days)
300 330 360
Principal safety outcome:
major bleeding
Placebo
(n=590)
Rivaroxaban
(n=598)
0
4 (0.7%)*
Bleeding contributing to death
0
0
Bleeding in a critical site
0
0
Gastrointestinal bleeding
0
3 (0.5%)
Menorrhagia
0
1 (0.2%)
Major bleeding
Associated with fall in
hemoglobin
≥2 g/dL and/or transfusion
• Number needed to harm: approximately
139
*p=0.11
Safety population
Other outcomes
Placebo
(n=590)
Rivaroxaba
n
(n=598)
7 (1.2%)
32 (5.4%)*
Urogenital/uterus
2 (0.3%)
12 (2.0%)
Nasal
1 (0.2%)
8 (1.3%)
Rectal/anal
2 (0.3%)
6 (1.0%)
Skin
2 (0.3%)
4 (0.7%)
Ear
0
1 (0.2%)
Gastrointestinal
0
1 (0.2%)
Surgical site
0
1 (0.2%)
Clinically relevant non-major
bleeding
Safety population; some patients experienced more than one event.
*p<0.01
IDRABIOTAPARINUX
Sviluppata forma biotinilata
Antidoto : Avidina ricombinante e.v.
Sperimentazioni
EQUINOX : 757 pz Idrabiotap VS idrap : <
emorragie
BOREALIS –AF : interrotto il reclutamento a
ca 3000 pz/ 6000 previsti per motivi di
marketing
CASSIOPEA: pubblicato
idrabiotaparinux + LMWH vs VKA treatment of PE and
prevention of VTE N = 3200
US 50 sites 355 pts
Clinical study Assessing SSR126517E
Injections Once-weekly in Pulmonary
Embolism therapeutic Approach
On behalf of the CASSIOPEA Investigators
Idrabiotaparinux – Cassiopea results – ISTH 2011
Study Design (double blind, double dummy)
3m
6m
Enox ≥ 5 d
Idrabiotaparinux
SSR126517E
Obs
Placebo
Placebo Warfarin
Warfarin
Idrabiotaparinux
Enox ≥ 5 d SSR126517E
6-month stratum
3-month stratum
Obs
Placebo Warfarin
3m
Any Heparin
< 36 hours before
randomization
3m
R
6m
Enox ≥ 5 d
3m
Placebo
PlaceboIdrabiotaparinux
SSR126517E
Warfarin
Enox ≥ 5 d
Placebo
Placebo
Idrabiotaparinux
SSR126517E
Obs
Obs
6-month stratum
3-month stratum
Warfarin
3m
3m
Idrabiotaparinux dose was 3 mg sc once a week
Patients with severe renal insufficiency : one dose of 3 mg and then 1.8 mg sc once a week
Idrabiotaparinux – Cassiopea results – ISTH 2011
Primary efficacy outcome analysis
Randomized population (3 months – both strata)
Idrabiotaparinux
(n=1,599)
Warfarin
(n=1,603)
n (%)
34 (2.1)
n (%)
43 (2.7)
5 (0.3)
18 (1.1)
Non-fatal PE
13 (0.8)
9 (0.6)
Fatal PE/unexplained death where
PE cannot be ruled out
16 (1.0)
16 (1.0)
First symptomatic recurrent VTE
Recurrent DVT
0.50
0
0.79
1.25
1.00
Odds ratio
Idrabiotaparinux
superior
2.00
Idrabiotaparinux
non-inferior
Idrabiotaparinux
inferior
p<0.0001 for non-inferiority
127
Idrabiotaparinux – Cassiopea results – ISTH 2011
Efficacy results
Kaplan-Meier cumulative incidence of PE/DVT (fatal or not)
in the combined 3-month and 6-month period - Randomized population
5
Idrabiotaparinux
Warfarin
Cumulative incidence (%)
4
3
2
Hazard ratio: 0.77
95% CI: 0.51 to 1.17
1
0
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190
Number at Risk
Time since randomization (days)
Idrabio 1599
1556
1530
1517
1200
1194
1172
Warfarin 1603
1565
1535
1518
1190
1185
1174
Idrabiotaparinux – Cassiopea results – ISTH 2011
Primary safety outcome analysis
Randomized population (3 months – both strata)
Idrabiotaparinux
(n=1,599)
n
Warfarin
(n=1,603)
(%)
n
(%)
Clinically relevant bleedings
Patients with event
0.49
0
72 (4.5)
0.67
Odds ratio
106 (6.6)
0.91
1.00
Idrabiotaparinux
superior
P=0.0098 for superiority
(two-sided)
Idrabiotaparinux
inferior
129
Idrabiotaparinux – Cassiopea results – ISTH 2011
Bleeding results
Kaplan-Meier cumulative incidence of clinically relevant bleeding in
the combined 3-month and 6-month period - Randomized population
Cumulative incidence (%)
15
Idrabiotaparinux
Warfarin
10
End of
enoxaparin
5
Hazard ratio: 0.70
95% CI: 0.54 to 0.91
0
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190
Number at Risk
Time since randomization (days)
Idrabio 1599
1526
1492
1471
1150
1136
1113
Warfarin 1603
1505
1470
1452
1146
1132
1109
Idrabiotaparinux – Cassiopea results – ISTH 2011
Efficacy results
Kaplan-Meier cumulative incidence of PE/DVT (fatal or not)
up to the end of study - Randomized population
10
Idrabiotaparinux
Warfarin
9
Hazard ratio : 0.49
95% CI: 0.35 to 0.70
Cumulative incidence (%)
8
7
6
5
4
3
2
1
End of treatment
0
0
Number at Risk
Idrabio 1599
Warfarin1603
60
1530
1535
120
180
240
Time since randomization (days)
1494
1461
1124
1478
1450
1105
300
360
1023
982
933
895
Idrabiotaparinux – Cassiopea results – ISTH 2011
Bleeding results
Kaplan-Meier cumulative incidence of clinically relevant
bleeding up to the end of study - Randomized population
Cumulative incidence (%)
15
Idrabiotaparinux
Warfarin
Hazard ratio : 0.79
95% CI: 0.62 to 1.00
10
5
End of treatment
0
0
Number at Risk
Idrabio 1599
Warfarin1603
60
1492
1470
120
180
240
Time since randomization (days)
1438
1395
1066
1418
1375
1057
300
360
967
951
878
872
Idrabiotaparinux – Cassiopea results – ISTH 2011
Pradaxa®/dabigatran etexilate
Drug Facts
• Pregnancy Category : C
• Lactation: Excretion in breast milk
unknown/use caution
Xarelto®/rivaroxaban
Special Populations
• Pregnancy
– No adequate data of use in pregnant women
– Animal studies have shown reproductive toxicity
and evidence that rivaroxaban crosses the
placenta
– Use is contraindicated
• Lactation
– No data of use in breast-feeding women
– Animal data shows evidence that rivaroxaban is
secreted into milk
– Use in contraindicated
Pradaxa®/dabigatran etexilate
Monitoring Parameters
• Activated Partial Thromboplastin Time
(aPTT): values >2.5 time control may
indicate overanticoagulation
• Ecarin Clotting Test (ECT) if available
• Thrombin Time (TT)
• CBC with differential
• Bleeding
Xarelto®/rivaroxaban
Monitoring Parameters
• CBC w/differential, periodically
• Renal function and Hepatic function, periodically
• Signs and symptoms of bleeding
• Prothrombin time (PT) – not used in major
clinical trials, but may be appropriate for certain
populations (eg. renal insufficiency, hepatic
impairment, low body weight, extreme obesity);
correlates well with rivaroxaban concentrations