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Non-Selective Beta-Blockers in Cirrhosis: Indications and Contraindications
1. Richard Moreau
Inserm U1149, Centre de Recherche sur l’Inflammation (CRI), Paris
UMR S_1149, Université Paris Diderot-Paris 7
DHU UNITY, Service d’Hépatologie, Hôpital Beaujon, APHP, Clichy
Laboratoire d’Excellence Inflamex, ComUE Sorbonne Paris Cité, Paris
Beta-bloquants non-sélectifs :
Indications et contre-indications
dans la cirrhose
Centre Hépato-Biliaire
Hôpital Paul-Brousse
Villejuif, 4 février 2015
2. Dr. Lebrec
We know that ... five
percent of [patients
admitted for variceal
bleeding] develop
hepatorenal syndrome.
Following total
paracentesis,
approximately 10
percent develop
hepatorenal syndrome.
3. AN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSION
Vasodilatation
splanchnique
Distortion de
l’angio-
architechure
hépatique
Veine
porte
Dans la cirrhose, une augmentation du débit
sanguin dans le territoire de la veine porte
maintient l’hypertension portale
Débit sanguin
augmenté
Blanchet et Lebrec. Eur J Clin Invest 1982.
4.
5. Découverte du propranolol comme premier traitement
pharmacologique de l’hypertension portale
Lebrec et al. Lancet 1980;2:180-2.
8. • Prophylaxie pré-primaire
• Prévention d’une première
hémorragie digestive
• Prévention de la récidive
hémorragique
• Effet sur la translocation
bactérienne
• Complications des β-bloquants
Sommaire
9. •All patients with cirrhosis should be
screened for varices at diagnosis
•No indication to use β-blockers to
prevent the formation of varices
•Underlying cause of liver disease should
be treated when possible
•HVPG measurement in the context of
RCTs
•Unmet need: non invasive biomarkers
Pre-primary Prophylaxis
Baveno V Recommendations
de Franchis and Baveno V Faculty. J Hepatol 2010; 53:762-8.
10. • Prophylaxie pré-primaire
• Prévention d’une première
hémorragie digestive
• Prévention de la récidive
hémorragique
• Effet sur la translocation
bactérienne
• Complications des β-bloquants
Sommaire
11. Estimated 1 Year Percentage
Probability of Bleeding
Class A Class B Class C
Red wale
marking Small Large Small Large Small Large
Absent 6 15 10 26 20 42
Mild 8 79 15 33 28 54
Severe 16 34 28 52 44 76
From NIEC. N Engl J Med 1988;319:983-9.
12. •Patients with small varices:
‒ Patients with red wale marks or CP class C
should be treated with nonselective
β-blockers.
‒ Patients without signs of increased risk may
be treated with nonselective β-blockers to
prevent progression of varices and bleeding.
Further studies are required to confirm their
benefit.
Prevention of the First Bleeding Episode
Baveno V Recommendations
de Franchis and Baveno V Faculty. J Hepatol 2010;53:762-8.
13. •Patients with medium-large varices:
‒ Use: either nonselective β-blockers or
endoscopic band ligation (EBL)
‒ Carvedilol is a promising alternative (TBC).
‒ Not recommended: shunt therapy, endoscopic
sclerotherapy, isosorbide mononitrate alone.
‒ Not recommended: nonselective β-blockers in
combination with Isosorbide-5-mononitrate,
spironolactone, or EBL.
Prevention of the First Bleeding Episode
Baveno V Recommendations
de Franchis and Baveno V Faculty. J Hepatol 2010; 53:762-8.
14. •Patients with gastric varices:
‒ No available data
‒ May be treated with
nonselective β-blockers.
Prevention of the First
Bleeding Episode
Baveno V Recommendations
de Franchis and Baveno V Faculty. J Hepatol 2010; 53:762-8.
15. • Prophylaxie pré-primaire
• Prévention d’une première
hémorragie digestive
• Prévention de la récidive
hémorragique
• Effet sur la translocation
bactérienne
• Complications des β-bloquants
Sommaire
16. •Secondary prophylaxis should
start ASAP from day 6 of the index
variceal episode.
•The start time of secondary
prophylaxis should be
documented.
Prevention of Re-bleeding
Baveno V Statement
de Franchis and Baveno V Faculty. J Hepatol 2010; 53:762-8.
17. •Best option: combination of nonselective
β-blockers & band ligation; results in lower
re-bleeding compared to either therapy alone.
•Patients with contra-indications or intolerance
to nonselective β-blockers:
‒ Use EBL
•Patients unable or unwilling to be treated with
EBL:
‒ Use nonselective β-blockers + isosorbide
mononitrate
Prevention of Re-bleeding
Baveno V Recommendations
de Franchis and Baveno V Faculty. J Hepatol 2010; 53:762-8.
18. EBL vs. β-Blockers
+ Isosorbide-5-Mononitrate
in the Prevention of Rebleeding
Rebleeding (%) Mortality (%)
β-Blockers EBL
Iso-5-Mm
β-Blockers EBL
Iso-5-Mm
Villanueva 1
33 49* 26 35
Lo 2
57 38* 13 25
Patch3
44 54 32 23
* Significantly different.
1
N Engl J Med 2001;345:647-55; 2
Gastroenterology 2002;
123:728-34; 3
Gastroenterology 2002;123:1013-9.
First authors
19. Prevention of Recurrent Bleeding
My own Conclusions
β-blockers and band ligation must be
used.
The combination of β-blockers and
nitrates cannot be recommended
but more trials are needed.
20. • Prophylaxie pré-primaire
• Prévention d’une première
hémorragie digestive
• Prévention de la récidive
hémorragique
• Effet sur la translocation
bactérienne
• Complications des β-bloquants
Sommaire
22. • Prophylaxie pré-primaire
• Prévention d’une première
hémorragie digestive
• Prévention de la récidive
hémorragique
• Effet sur la translocation
bactérienne
• Complications des β-bloquants
Sommaire
23. Traitement de l’ascite
Ascite
modérée Ascite
volumineuse
Ascite
réfractaire
• Paracentèses
répétées
+ albumine***
• TIPS
• Transplant. Hép.
Restriction Na
+ Tt Diurétique
progressif
(spironolactone*
+ furosémide**)
Paracentèse
+ Albumine IV***
+ Diurétiques
*Max: 400 mg/j. **Max: 160 mg/j. ***solution à 20 %, 8 g/L d’ascite évacuée.
European Association for the Study of the Liver. J Hepatol 2010;53:397-417.
24. Sestré et al. Hepatology 2010; 52:1017-22.
Poor Prognosis of Patients with Refractory Ascites
25. Sersté et al. Hepatology 2010; 52:1017-22.
Deleterious Effects of β-Blockers on Survival in
Patients with Cirrhosis and Refractory Ascites
26. Variable HR (95% CI) P value
Child-Pugh Score 1.43 (1.28 to 1.60) <0.0001
Refractory ascites category
Diuretic-resistant 1
Diuretic intractable
Serum sodium <125 mmol/L 2.11 (1.34 to 3.34) 0.001
Serum creatinine > 1.5 mg/dL 1.46 (0.92 to 2.29) 0.1
Beta-blocker therapy 2.04 (1.31 to 3.18) 0.0016
Frequency of large-volume
paracentesis
1.42 (1.25 to 1.61) <0.0001
Independent Predictors of Death in
174 Patients with Refractory Ascites
Sersté et al. J Hepatol 2012;57:274-80.
27. Conséquences de la paracentèse
Paracentèse évacuatrice
Ginès et al. Gastroenterology 1996;111:1002-10.
Dysfonction circulatoire (hypotension)
Récidive d’ascite
Hyponatrémie
Syndrome hépatorénal
Décès
28. Sersté et al. J Hepatol 2011;55 :794-9.
Avant arrêt Après arrêt
Fréquence cardiaque pendant la paracentèse,
avant et après arrêt des β-bloquants
29. Sersté et al. J Hepatol 2011;55 :794-9.
Rénine plasmatique pendant la paracentèse,
avant et après arrêt des β-bloquants
Avant arrêt Après arrêt
30. Nonselective β-Blockers Increase Risk of
Death in Patients with Cirrhosis and SBP
Mandorfer et al. Gastroenterology 2014;146:1680-90.
HR=0.75 (0.581-0.968); P=0.027 HR=1.58 (1.098-2.274); P=0.014
31. Nonselective β-Blockers Increase Risk for HRS
and AKI in Patients with Cirrhosis and SBP
Mandorfer et al. Gastroenterology 2014;146:1680-90.
32. Increased Risk of AKI in Patients with Severe Alcoholic
Hepatitis Receiving β-blockers
Sersté et al.
Liver Int 2015;
in press
33. Deleterious Effects of β-Blockers on
Exercise Capacity in 10 Patients with
Portopulmonary Hypertension
Provencher et al. Gastroenterology 2006;130:120-6
On
β-blockers
2 months
after
cessation of
β-blockers
P value
Heart rate
(beats/min)
66 ± 2 81 ± 10 <0.01
6-min walk
test (m)
338 ± 79 417 ± 54 0.01
34. • Dans le cirrhose, les β-bloquants sont
efficaces pour la prévention des hémorragies
digestives.
• Les β-bloquants pourraient diminuer la
translocation bactérienne intestinale.
• Les β-bloquants semblent avoir des effets
délétères chez les malades avec une ascite
réfractaire, les malades avec une SBP ou une
HAA ou une hypertension artérielle
pulmonaire.
Conclusions
My talk will be divided into 5 parts.
- Definitions
- Pathophysiology
- Prognosis
- Management
─ Infection
─ Organ failures
- Prevention
My talk will be divided into 5 parts.
- Definitions
- Pathophysiology
- Prognosis
- Management
─ Infection
─ Organ failures
- Prevention
Refractory ascites is associated with high mortality rate.
We recently studied the predictors of death in a prospective cohort of 174 patients with refractory ascites.
The independent predictors of death were the CP score, the use of beta-blockers, the frequency of LVP and the category of refractory ascites.
As you know, refractory ascites may be diuretic resistant or diuretic intractable. Ascites is diuretic intractable when hyponatremia or renal failure preclude the use of diuretics.
As you can see the fact to have diuretic intractable ascites due to hyponatremia was associated with a poor prognosis.
Finally, please note that the MELD score was not predictor of death in our series. This findings confirms that RA is an exception to MELD.