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Prevention of first esophageal variceal bleeding

In patients with small esophageal varices the risk of variceal bleeding is low, and data from 7 RCTS show that

it is not decreased by NSBBs (

Fig. 4.9). However, this low risk only applies to patients with compensated cirrho-

sis, since patients with decompensated cirrhosis and small varices, have a risk of bleeding close to patients with

compensated cirrhosis and large varices

[185]. Therefore, taking into account that in patients with compensated

cirrhosis NSBBs decrease the risk of decompensation, and that in patients with decompensated cirrhosis the risk

of bleeding is high and decreases with NSBBs, it is reasonable to apply NSBBs to all patients with small varices

in the absence of contraindications. Indeed, an individual patient metaanalysis has shown that the higher the

baseline risk of bleeding, the higher the absolute risk reduction of bleeding with NSBBs (

Table 4.5) [179].

In patients with medium large or large varices, with a much higher baseline risk of bleeding, a metaanalysis of

eight randomized-controlled trials (RCT) comparing NSBB versus no therapy/placebo

[152] has shown that

NSBBs are effective for the prevention of first variceal bleeding (from 24% to 15% after a median follow-up of

2 years). Furthermore, a metaanalysis of 19 RCTs comparing NSBB to endoscopic variceal ligation

[186] showed

that NSBB are as effective as EVL in good quality trials. Two trials compared EVL to carvedilol showing either a

greater efficacy of carvedilol

[187] or comparable efficacy [188]. Therefore either propranolol, nadolol, or carvedi-

lol can be used as first-line therapy to prevent a first variceal bleeding in patients with cirrhosis and medium to

large varices.

FIGURE 4.9 Beta-blockers and prevention of first bleeding in patients with small varices. Metaanalysis (previously unpublished) of

seven randomized trials comparing NSBBs with placebo providing data on the incidence of first variceal bleeding. NSBBs did not significantly

decrease the risk of first bleeding, that was very low in the control group (4%).

TABLE 4.5 Baseline risk of variceal bleeding and absolute risk reduction of bleeding achieved with nonselective beta-blockers

(NSBBs).

Risk in control (%) Risk on NSBBs (%) Absolute risk reduction of bleeding with NSBBs (%)

Medium/large varices

ChildPugh ,8

28 19 9

Medium/large varices

ChildPugh $ 8

44 24 20

In patients with more advanced cirrhosis (ChildPugh $ 8), the baseline risk of bleeding was higher, and the absolute risk reduction achieved with NSBBs was

greater.

Data from the individual patient meta-analysis by Poynard T, Cales P, Pasta L, Ideo G, Pascal JP, Pagliaro L, et al. Beta-adrenergic-antagonist drugs in the prevention of

gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-

Italian Multicenter Study Group. Nengl J Med. 1991;324(22):15321538.

54 4. Drugs at the crossroads of heart and liver

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Preventing esophageal variceal rebleeding

A metaanalysis that included 12 RCTs of NSBBs in secondary prophylaxis showed that NSBBs prevent rebleed-

ing and improve survival

[181]. Importantly, sensitivity analysis showed that the benefit of increased long-term sur-

vival was more pronounced in those with severe liver disease. Along these lines, a recent individual patient

metaanalysis comparing the combination of NSBBs 1 endoscopic variceal ligation (EVL) versus EVL alone to

prevent variceal rebleeding, showed that in patients with decompensated cirrhosis (ChildPugh B and C)

the addition of NSBBs to EVL improved both rebleeding and survival

[189]. This data underscores the impor-

tance of NSBBs in secondary prophylaxis, which are at very high risk of rebleeding.

Beta-blockers in acute on chronic liver failure

In a prospective observational study in 349 hospitalized patients with ACLF

[190] by Mookerjee et al., patients

on NSBBs had a reduced 28-day mortality (24 vs 34%, p 5 0.048 ). Of note, patients in the NSBBs group had lower

grades of ACLF, and the median propranol ol dose was relatively low (40 mg). Although the exact mechanism by

which NSBBs may improve outcomes is speculative, the authors proposed NSBBs reduced systemic inflamma-

tion. This association was also suggested in two recent studies

[191,192], in which patients admitted with decom-

pensated cirrhosis on NSBBs had a lower white cell count. Finally, a recent longitudinal mechanistic study

showed that NSBBs treatment, especially in ChildPugh C patients, achieved a decrease in inflammatory mar-

kers that was independent of the effect on portal pressure

[158]. However, the lack of a control group untreated

with NSBBs makes this study difficult to interpret.

A very recent randomized trial assessing the effects of carvedilol in acute on chronic liver failure has shown

that it might improve short-term survival, an effect that was not mediated by a decrease in the rate of variceal

bleeding, that was very low and similar in placebo and carvedilol groups

[178]. Interestingly, the beneficial

effects of beta-blockers were mainly mediated by a decrease in infections and kidney failure, again suggesting

potential nonhemodynamic effects of carvedilol in advanced cirrhosis.

Bleeding from gastric varices

The effects of NSBBs on bleeding from gastric varices, an infrequent complication in cirrhosis, are much less

certain. Evidence is limited to one RCT for primary prevention of bleeding and two RCTs for the prevention of

rebleeding.

In primary prevention, a small RCT compared NSBBs versus endoscopic obliteration with cyanoacrylate ver-

sus no treatment

[193], showing that endoscopic treatment was superior to NSBBs, with no differences in sur-

vival. In patients with previous bleeding, an RCT compared endoscopic obliteration with cyanoacrylate with

NSBBs for the prevention of rebleeding

[194], showing again superiority of endoscopy treatment, both in rebleed-

ing and survival. Finally, an RCT compared cyanoacrylate alone versus the combination of cyanoacrylate and

NSBBs and did not demonstrate a benefit for the addition of NSBBs

[195]. The scarcity of data and the lower effi-

cacy shown as compared to cyanoacrylate injection makes the role of NSBBs for gastric varices uncertain. Since

cyanoacrylate treatment is not available in many centers, NSBBs are still used for primary or secondary preven-

tion by many practitioners.

Beta-blockers for portal hypertensive gastropathy

Portal hypertensive gastropathy causes acute or chronic gastric bleeding and it is related to a marked dilata-

tion of the vasculature of the gastric mucosa and submucosa, together with an increased blood flow

[196].An

RCT showed lower rates of rebleeding with propranolol as compared to placebo

[183] and therefore NSBBs are

the first-line therapy in this context.

The concept of a therapeutic window of nonselective beta-blockers in decompensated cirrhosis

Soon after the first reports of propranolol in the treatment of varices, caution was raised regarding the poten-

tial of NSBBs to decrease cardiac output and put a patient with ascites at risk of hepatorenal syndrome

[197].

However, none of the RCTs comparing NSBBs with placebo showed a safety signal either on survival or kidney

function in most cases, patients with refractory ascites. This question was further emphasized after the publica-

tion of two key observational studies, showing worse outcomes in patients on NSBBs with refractory ascites

[198], SBP [199] or alcohol-associated hepatitis [200]. This led to the concept of a therapeutic window for NSBBs

55The concept of a therapeutic window of nonselective beta-blockers in decompensated cirrhosis

I. Liver and heart

https://t.me/medicina_free

[201], and to several subsequent studies, mostly retrospective, which showed conflicting results. Two different

metaanalysis of these observational studies showed no association between NSBBs a nd mortality in patients with

refractory ascites but with significant heterogeneity

[202,203]. Furthermore, the above-mentioned RCT comparing

initiation of carvedilol (vs placebo) in patients with AoCLF, which are at the end of the spectrum of cirrhosis

severity showed a decreased 28-day mortality, with additional benefits, somewhat unexpectedly, on the incidence

of AKI. Of note, carvedilo l was started at 3.125 mg BID, and was carefully uptitrated to a maximum of 12.5-mg

BID, provided that SBP did not decrease below 90 mmHg and HR was maintained above 55 bpm.

A very recent study

[165] addressed in detail the differences in effects of NSBBs on hemodynamics between

patients with diuretic responsive ascites and those with diuretic refractory ascites. As opposed to patients with

diuretic responsive ascites, treatment with NSBBs decreased renal perfusion pressure below the critical threshold

for autoregulation (65 mmHg) in 55% of the patients. A major finding of this study was that while the decrease

in systolic function with NSBBs was mild in patients with responsive ascites, it was much more pronounced in

patients with refractory ascites (

Fig. 4.10). This suggests that in patients with refractory ascites the increase in car-

diac output is highly dependent on sympathetic activation, and hence the major neg ative inotropic effect of

NSBBs.

FIGURE 4.10 Changes in left ventricular systolic function (assessed by the ejection intraventricular pressure differences of EIVPD) (A)

and renal perfusion pressure (RPP) (B) after 4 weeks on NSBBs in patients with diuretic responsive ascites and diuretic refractory ascites.

In patients with refractory ascites there was a marked reduction in systolic function with NSBBs, while this was not the case in patients with

nonrefractory ascites. In addition, in patients with refractory ascites NSBBs reduced RPP below 65 mmHg in 55% of the patients. Source:

Reproduced with permission from Tellez L, Ibanez-Samaniego L, Perez Del Villar C, Yotti R, Martinez J, Carrion L, et al. Non-selective beta-blockers impair

global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites. J Hepatol 2020;73:14041414.

56 4. Drugs at the crossroads of heart and liver

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A question arises on how to identify patients in which NSBBs might do harm. A recent study [204] showed

that patients with a low left ventricular stroke work index (LVSWI) on NSBBs have increased waitlist mortality,

but this measurement is unfeasible in day-to-day practice. Arterial pressure might be a much simpler biomarker

to determine when the therapeutic window for NSBBs closes. This was assessed in a prospective observational

study

[205] showing that a MAP , 65 mmHg, but not SBP or AoCLF, defined a threshold below which NSBBs

did not have benefit on transplant-free survival. Similar results were observ ed using a systolic blood pressure of

90 mmHg

[206] which is recommended in current guidelines as a threshold for dose reduction or discontinuation

of NSBBs

[137,207,208].

Table 4.6 summarizes practical recommendations for the use of NSBBs in patients with decompensated

cirrhosis.

Summary and current recommendations

NSBBs have shown beneficial effects in placebo-controlled trials across the natural history of cirrhosis. NSBBs

require titration and the use of fixed doses of NSBBs is discouraged

[209]. In addition, a need for dose reduction

might be predicted in patients treated with propranolol who develop progressive liver insufficiency (as occurs,

e.g., in patients with alcoholic hepatitis), and in patients treated with nadolol that develop kidney failure, inde-

pendently of the cause. In patients with advanced circulatory dysfunction (i.e., refractory ascites) NSBBs might

do harm, since they might markedly decrease cardiac output and renal perfusion pressure (

Fig. 4.11). Systolic

blood pressure is an excellent biomarker to determine when the dose of NSBBs needs to be decreased or when

they need to be disconti nued. The indiscriminate discontinuation of NSBBs in all patients with refractory ascites

or SBP is not warranted and would deprive patients from the hemodynamic and nonhemodynamic benefits of

these drugs.

Practice guidelines from the American Association for the Study of Liver Diseases

[176] recommend that in

patients with cirrhosis and refractory ascites, NSBBs (propran olol, nadolol) should be used cautiously with close

monitoring of blood pressure, serum sodium, and serum creatinine. NSBBs should be reduced/discontinued if a

patient with refractory ascites develops systolic blood pressure ,90 mmHg, hyponatremia , 130 mEq/L or AKI.

Re-initiation of NSBB should be considered after these abnormal parameters return to baseline values following

resolution of the precipitant; in such cases, dose should be re-titrated, starting at the lowest dose. The consensus

also makes emphasis on the need to reassess the risks/benefits of NSBB periodically on each patient, as contrain-

dications may be absent when the therapy is initiated but may appear later. The guidelines additionally suggest

avoiding doses of more than 160 mg in the case of propranolol or 80 mg when using nadolol in patients with

refractory ascites and SBP

[176]. Although one RCT has shown a benefit of carvedilol in patients with acute on

TABLE 4.6 Recommendations for the use of NSBBs in patients with decompensated cirrhosis.

Patients on beta-blocker treatment for primary or secondary prophylaxis of variceal bleeding

• NSBBs require careful titration (up and down). Fixed doses are discouraged.

• In patients with adverse effects/intolerance consider a decrease in the dose or NSBB before discontinuing the treatment.

• Reassess the risks/benefits of NSBBs periodically on each patient, as contraindications may be absent when the therapy is initiated but

may appear later.

• Monitor closely sodium, blood pressure, and creatinine in patients with refractory ascites.

• There is no need to discontinue NSBBs in case of patients with refractory ascites and/or SBP if there is no evidence of severe circulatory

dysfunction (MAP .65 mmHg, SBP .90 mmHg, absence of hyponatremia, absence of functional kidney failure).

Discontinue/reduce NSBBs

• In case of circulatory dysfunction in patients with refractory ascites (MAP ,65 mmHg or SBP ,90 mmHg, hyponatremia ,130 mEq/L or

acute kidney injury).

• Temporarily hold NSBBs in patients with bleeding or septic shock.

After discontinuation/reduction of NSBBs

• Re-initiation/up-titration of NSBBs should be considered after evidence of circulatory dysfunction is over and after resolution of the

precipitant. Dose should be re-titrated, starting at the lowest dose.

• In case NSBBs cannot be resumed, consider alternative treatment. In patients on primary prophylaxis: switch to EVL. In patients on

secondary prophylaxis: continue with EVL and consider TIPS when indicated.

57Summary and current recommendations

I. Liver and heart

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chronic liver failure, carvedilol has a stronger hypotensive effect than traditional NSBBs [173] and should be

used with great caution in patients with advanced cirrhosis until confirmatory trials verify these benefits.

References

[1] Rang HP. The receptor concept: pharmacology’s big idea. Br J Pharmacol. 2006;147(Suppl 1):S916.

[2] Pollak PT, Bouillon T, Shafer SL. Population pharmacokinetics of long-term oral amiodarone therapy. Clin Pharmacol Ther 2000;67

(6):64252.

[3] Myers RP, Cerini R, Sayegh R, Moreau R, Degott C, Lebrec D, et al. Cardiac hepatopathy: clinical, hemodynamic, and histologic charac-

teristics and correlations. Hepatology 2003;37(2):393400.

[4] Babatin M, Lee SS, Pollak PT. Amiodarone hepatotoxicity. Curr Vasc Pharmacol 2008;6(3):22836.

[5] Moctezuma-Velazquez C, Kalainy S, Abraldes JG. Beta-blockers in patients with advanced liver disease: has the dust settled? Liver trans-

plantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation.

Society. 2017;23(8):105869.

[6] Oryan A, Bemani E, Bahrami S. Emerging role of amiodarone and dronedarone, as antiarrhythmic drugs, in treatment of leishmaniasis.

Acta Trop 2018;185:3441.

[7] Xanthopoulos A, Starling RC, Kitai T, Triposkiadis F. Heart failure and liver disease: cardiohepatic interactions. JACC Heart Fail 2019;7

(2):8797.

[8] Mujovi

c N, Dobrev D, Marinkovi

c M, Russo V, Potpara TS. The role of amiodarone in contemporary management of complex cardiac

arrhythmias. Pharmacol Res 2020;151:104521.

[9] Murray KT. Why amiodarone is better: another piece of the puzzle. J Cardiovasc Electrophysiol 2009;20(7):81112.

[10] Nattel S. Drugs to promote sinus rhythm reversion and maintenance in atrial fibrillationwhy amiodarone is better. Cardiovasc Drugs

Ther 2003;17(1):56.

[11] Mackenzie C, Syed J, Pollak PT, Koren G. Falling between the cracks: a case of amiodarone toxicity. CMAJ. 2011;183(12):13937.

[12] Hussain N, Bhattacharyya A, Prueksaritanond S. Amiodarone-induced cirrhosis of liver: what predicts mortality? ISRN Cardiol

2013;2013:617943.

[13] Charlier R, Marcovici J, Deltour G, Henaux F, Binon F, Hosslet A. [Studies in the benzofuran series. V. Alkyl-hydroxybenzoyl-

benzofurans with analgesic activity]. Arch Int Pharmacodyn Ther 1962;139:23446.

[14] Shah P, Westwell AD. The role of fluorine in medicinal chemistry. J Enzyme Inhib Med Chem 2007;22(5):52740.

cirrhosis pro

ression

NSBBs

Mean arterial pressure

Threshold for renal

hypoperfusion and AKI

with and without NSBBs

FIGURE 4.11 Simplified representation of the progressive deterioration in cirrhosis hemodynamics and potential effects of nonselec-

tive beta-blockers (NSBBs) in advanced cirrhosis. Cirrhosis is characterized by a progressive decrease in systemic vascular resistance, mainly

due to splanchnic vasodilation. This is compensated by an increase in cardiac output that initially maintains mean arterial pressure. When the

increase in cardiac output cannot further compensate for vasodilation, severe circulatory dysfunction ensues with hypotension, decreased

renal perfusion pressure, and acute kidney injury. NSBBs interfere with the expected increase in cardiac output, especially in the more

advanced stages. This is partly compensated by an increase in systemic vascular resistance, but which may shift the threshold for significant

kidney hypoperfusion to the right. This would be signaled by a decrease in arterial pressure.

58 4. Drugs at the crossroads of heart and liver

I. Liver and heart

https://t.me/medicina_free

[15] Charlier R, Delaunois G, Bauthier J, Deltour G. [Research on the benzofuran series. XL. Anti-arrhythmic properties of amiodarone].

Cardiol. 1969;54(2):8390.

[16] Charlier R. Cardiac actions in the dog of a new antagonist of adrenergic excitation which does not produce competitive blockade of adre-

noceptors. Br J Pharmacol 1970;39(4):66874.

[17] Plomteux G, Heusghem C, Ernould H, Vandeghen N. Long-term hepatic tolerance of amiodarone in the clinic. Eur J Pharmacol 1969;8

(3):36976.

[18] Dreifus LS, Ogawa S. Quality of the ideal antiarrhythmic drug. Am J Cardiol 1977;39(3):4668.

[19] Rosenbaum MB, Chiale PA, Kaski JC, Elizari MV. Is amiodarone an ideal antiarrhythmic drug? Pacing Clin Electrophysiol 1984;7(2):2725.

[20] Flanagan RJ, Storey GC, Holt DW. Rapid high-performance liquid chromatographic method for the measurement of amiodarone in blood

plasma or serum at the concentrations attained during therapy. J Chromatogr 1980;187(2):3918.

[21] Pollak PT, Carruthers SG, Freeman DJ. Simplified liquid-chromatographic assay of amiodarone and desethylamiodarone after solid-

phase extraction. Clin Chem 1986;32(5):8903.

[22] Pollak PT, Shafer SL. Use of population modeling to define rational monitoring of amiodarone hepatic effects. Clin Pharmacol Ther

2004;75(4):34251.

[23] Rotmensch HH, Belhassen B, Swanson BN, Shoshani D, Spielman SR, Greenspon AJ, et al. Steady-state serum amiodarone concentra-

tions: relationships with antiarrhythmic efficacy and toxicity. Ann Intern Med 1984;101(4):4629.

[24] Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, et al. Mortality and morbidity in patients receiving encainide,

flecainide, or placebo. the cardiac arrhythmia suppression Trial. N Engl J Med 1991;324(12):7818.

[25] Akiyama T, Pawitan Y, Greenberg H, Kuo CS, Reynolds-Haertle RA. Increased risk of death and cardiac arrest from encainide and flecai-

nide in patients after non-Q-wave acute myocardial infarction in the Cardiac Arrhythmia Suppression Trial. CAST Investigators. Am J

Cardiol 1991;68(17):15515.

[26] Farre

J, Romero J, Rubio JM, Ayala R, Castro-Dortico

s J. Amiodarone and “primary” prevention of sudden death: critical review of a

decade of clinical trials. Am J Cardiol 1999;83(5B):55D63D.

[27] Kochiadakis GE, Igoumenidis NE, Marketou ME, Solomou MC, Kanoupakis EM, Vardas PE. Low-dose amiodarone vs sotalol for sup-

pression of recurrent symptomatic atrial fibrillation. Am J Cardiol 1998;81(8):9958.

[28] Singh BN, Singh SN, Reda DJ, Tang XC, Lopez B, Harris CL, et al. Amiodarone vs sotalol for atrial fibrillation. N Engl J Med 2005;352

(18):186172.

[29] Vamos M, Hohnloser SH. Amiodarone and dronedarone: an update. Trends Cardiovasc Med 2016;26(7):597602.

[30] Piccini JP, Hasselblad V, Peterson ED, Washam JB, Califf RM, Kong DF. Comparative efficacy of dronedarone and amiodarone for the

maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiology 2009;54(12):108995.

[31] Dan GA, Martinez-Rubio A, Agewall S, Boriani G, Borggrefe M, Gaita F, et al. Antiarrhythmic drugs-clinical use and clinical decision

making: a consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC)

Working Group on Cardiovascular Pharmacology, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society

(APHRS) and International Society of Cardiovascular Pharmacotherapy (ISCP). Europace. 2018;20(5):731 2an.

[32] Harris L, McKenna WJ, Rowland E, Krikler DM. Side effects and possible contraindications of amiodarone use. Am Heart J 1983;106

(4 Pt 2):91623.

[33] Brien JF, Jimmo S, Brennan FJ, Ford SE, Armstrong PW. Distribution of amiodarone and its metabolite, desethylamiodarone, in human

tissues. Can J Physiol Pharmacol 1987;65(3):3604.

[34] Sapp JL, Wells GA, Parkash R, Stevenson WG, Blier L, Sarrazin JF, et al. Ventricular tachycardia ablation vs escalation of antiarrhythmic

drugs. N Engl J Med 2016;375(2):11121.

[35] Pourbaix S, Berger Y, Desager JP, Pacco M, Harvengt C. Absolute bioavailability of amiodarone in normal subjects. Clin Pharmacol Ther

1985;37(2):11823.

[36] Goldschlager N, Epstein AE, Naccarelli G, Olshansky B, Singh B. Practical guidelines for clinicians who treat patients with amiodarone.

Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med 2000;160(12):17418.

[37] Bartalena L, Bogazzi F, Braverman LE, Martino E. Effects of amiodarone administration during pregnancy on neonatal thyroid function

and subsequent neurodevelopment. J Endocrinol Invest 2001;24(2):11630.

[38] Haffajee CI, Love JC, Canada AT, Lesko LJ, Asdourian G, Alpert JS. Clinical pharmacokinetics and efficacy of amiodarone for refractory

tachyarrhythmias. Circulation. 1983;67(6):134755.

[39] Fogoros RN, Anderson KP, Winkle RA, Swerdlow CD, Mason JW. Amiodarone: clinical efficacy and toxicity in 96 patients with recur-

rent, drug-refractory arrhythmias. Circulation. 1983;68(1):8894.

[40] Bouvy ML, Heerdink ER, Hoes AW, Leufkens HG. Amiodarone-induced thyroid dysfunction associated with cumulative dose.

Pharmacoepidemiol Drug Saf 2002;11(7):6016.

[41] Vassallo P, Trohman RG. Prescribing amiodarone: an evidence-based review of clinical indications. JAMA. 2007;298(11):131222.

[42] McCarthy TC, Pollak PT, Hanniman EA, Sinal CJ. Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associ-

ated with peroxisome proliferator-activated receptor-alpha target gene activation. J Pharmacol Exp Ther 2004;311(3):86473.

[43] Lewis JH, Ranard RC, Caruso A, Jackson LK, Mullick F, Ishak KG, et al. Amiodarone hepatotoxicity: prevalence and clinicopathologic

correlations among 104 patients. Hepatology. 1989;9(5):67985.

[44] Pollak PT, You YD. Monitoring of hepatic function during amiodarone therapy. Am J Cardiol 2003;91(5):61316.

[45] Teng W, Shan Z, Teng X, Guan H, Li Y, Teng D, et al. Effect of iodine intake on thyroid diseases in China. N Engl J Med 2006;354

(26):278393.

[46] Camargo RY, Tomimori EK, Neves SC, Ileana GSR, Galrao AL, Knobel M, et al. Thyroid and the environment: exposure to excessive

nutritional iodine increases the prevalence of thyroid disorders in Sao Paulo, Brazil. Eur J Endocrinol 2008;159(3):2939.

[47] Mussig K, Thamer C, Bares R, Lipp HP, Haring HU, Gallwitz B. Iodine-induced thyrotoxicosis after ingestion of kelp-containing tea.

J Gen Intern Med 2006;21(6):C1114.

59References

I. Liver and heart

https://t.me/medicina_free

[48] Cairns JA, Connolly SJ, Roberts R, Gent M. Randomised trial of outcome after myocardial infarction in patients with frequent or repeti-

tive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators.

Lancet 1997;349(9053):67582.

[49] Bedrossian CW, Warren CJ, Ohar J, Bhan R. Amiodarone pulmonary toxicity: cytopathology, ultrastructure, and immunocytochemistry.

Ann Diagn Pathol 1997;1(1):4756.

[50] Siddoway LA. Amiodarone: guidelines for use and monitoring. Am Fam Physician 2003;68(11):218996.

[51] Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deedwania PC, et al. Amiodarone in patients with congestive heart failure and

asymptomatic ventricular arrhythmia. Survival trial of antiarrhythmic therapy in congestive heart failure. N Engl J Med 1995;333

(2):7782.

[52] Finnegan MJ, Faragher EB. Amiodarone and chronic lung fibrosis. Postgrad Med J 1985;61(716):4979.

[53] Ruzieh M, Moroi MK, Aboujamous NM, Ghahramani M, Naccarelli GV, Mandrola J, et al. Meta-analysis comparing the relative risk of

adverse events for amiodarone vs placebo. Am J Cardiol 2019;124(12):188993.

[54] Chang CC, Petrelli M, Tomashefski Jr. JF, McCullough AJ. Severe intrahepatic cholestasis caused by amiodarone toxicity after with-

drawal of the drug: a case report and review of the literature. Arch Pathol Lab Med 1999;123(3):2516.

[55] Bravo AE, Drewe J, Schlienger RG, Krahenbuhl S, Pargger H, Ummenhofer W. Hepatotoxicity during rapid intravenous loading with

amiodarone: description of three cases and review of the literature. Crit Care Med 2005;33(1):12834.

[56] Giannattasio F, Salvio A, Varriale M, Picciotto FP, Di Costanzo GG, Visconti M. Three cases of severe acute hepatitis after parenteral

administration of amiodarone: the active ingredient is not the only agent responsible for hepatotoxicity. Ann Ital Med Int 2002;17

(3):1804.

[57] Masi S, de Clety SC, Anslot C, Detaille T. Acute amiodarone toxicity due to an administration error: could excipient be responsible? Br J

Clin Pharmacol 2009;67(6):6913.

[58] Jones DB, Mullick FG, Hoofnagle JH, Baranski B. Reye’s syndrome-like illness in a patient receiving amiodarone. Am J Gastroenterol

1988;83(9):9679.

[59] Reyniers JP, Machado EA, Farkas WR. Hepatotoxicity of chemically-defined diets containing polysorbate-80 in germfree and conven-

tional mice. Prog Clin Biol Res 1985;181:914.

[60] Rhodes A, Eastwood JB, Smith SA. Early acute hepatitis with parenteral amiodarone: a toxic effect of the vehicle? Gut. 1993;34(4):5656.

[61] Gluck N, Fried M, Porat R. Acute amiodarone liver toxicity likely due to ischemic hepatitis. Isr Med Assoc J 2011;13(12):74852.

[62] Loke YK, Derry S, Aronson JK. A comparison of three different sources of data in assessing the frequencies of adverse reactions to amio-

darone. Br J Clin Pharmacol 2004;57(5):61621.

[63] Svensson EM, Acharya C, Clauson B, Dooley KE, Karlsson MO. Pharmacokinetic interactions for drugs with a long half-life—evidence

for the need of model-based analysis. AAPS J 2015;18(1):1719.

[64] McCord JM. The evolution of free radicals and oxidative stress. Am J Med 2000;108(8):6529.

[65] Di Meo S, Venditti P. Evolution of the knowledge of free radicals and other oxidants. Oxid Med Cell Longev 2020;2020:9829176.

[66] Vereckei A, Blazovics A, Gyorgy I, Feher E, Toth M, Szenasi G, et al. The role of free radicals in the pathogenesis of amiodarone toxicity.

J Cardiovasc Electrophysiol 1993;4(2):16177.

[67] Jaeschke H, Ramachandran A. Oxidant stress and lipid peroxidation in acetaminophen hepatotoxicity. React Oxyg Species 2018;5

(15):14558.

[68] Yamamoto T, Kikkawa R, Yamada H, Horii I. Investigation of proteomic biomarkers in in vivo hepatotoxicity study of rat liver: toxicity

differentiation in hepatotoxicants. J Toxicol Sci 2006;31(1):4960.

[69] Wu Q, Ning B, Xuan J, Ren Z, Guo L, Bryant MS. The role of CYP 3A4 and 1A1 in amiodarone-induced hepatocellular toxicity. Toxicol

Lett 2016;253:5562.

[70] Segawa M, Ogura J, Seki S, Itagaki S, Takahashi N, Kobayashi M, et al. Rapid stimulating effect of the antiarrhythmic agent amiodarone

on absorption of organic anion compounds. Drug Metab Pharmacokinet 2013;28(3):17886.

[71] Serviddio G, Bellanti F, Vendemiale G, Altomare E. Mitochondrial dysfunction in nonalcoholic steatohepatitis. Expert Rev Gastroenterol

Hepatol 2011;5(2):23344.

[72] Yasuda SU, Sausville EA, Hutchins JB, Kennedy T, Woosley RL. Amiodarone-induced lymphocyte toxicity and mitochondrial function.

J Cardiovasc Pharmacol 1996;28(1):94100.

[73] Grieco A, Forgione A, Miele L, Vero V, Greco AV, Gasbarrini A, et al. Fatty liver and drugs. Eur Rev Med Pharmacol Sci 2005;9

(5):2613.

[74] Stravitz RT, Sanyal AJ. Drug-induced steatohepatitis. Clin Liver Dis 2003;7(2):43551.

[75] Fromenty B, Fisch C, Labbe G, Degott C, Deschamps D, Berson A, et al. Amiodarone inhibits the mitochondrial beta-oxidation of fatty

acids and produces microvesicular steatosis of the liver in mice. J Pharmacol Exp Ther 1990;255(3):13716.

[76] Honegger UE, Zuehlke RD, Scuntaro I, Schaefer MH, Toplak H, Wiesmann UN. Cellular accumulation of amiodarone and desethylamio-

darone in cultured human cells. Consequences of drug accumulation on cellular lipid metabolism and plasma membrane properties of

chronically exposed cells. Biochem Pharmacol 1993;45(2):34956.

[77] Spaniol M, Bracher R, Ha HR, Follath F, Krahenbuhl S. Toxicity of amiodarone and amiodarone analogues on isolated rat liver mitochon-

dria. J Hepatol 2001;35(5):62836.

[78] Kaufmann P, Torok M, Hanni A, Roberts P, Gasser R, Krahenbuhl S. Mechanisms of benzarone and benzbromarone-induced hepatic tox-

icity. Hepatology. 2005;41(4):92535.

[79] Lewis JH, Mullick F, Ishak KG, Ranard RC, Ragsdale B, Perse RM, et al. Histopathologic analysis of suspected amiodarone hepatotoxic-

ity. Hum Pathol 1990;21(1):5967.

[80] Elving LD, Hoefnagels WH, Van Haelst UJ, Griffioen G, Janssens AR, Ruiter DJ. Amiodarone hepatotoxicity. Neth J Med 1986;29

(10):3037.

[81] Singhal A, Ghosh P, Khan SA. Low dose amiodarone causing pseudo-alcoholic cirrhosis. Age Ageing 2003;32(2):2245.

60 4. Drugs at the crossroads of heart and liver

I. Liver and heart

https://t.me/medicina_free

[82] Raja K, Thung SN, Fiel MI, Chang C. Drug-induced steatohepatitis leading to cirrhosis: long-term toxicity of amiodarone use. Semin

Liver Dis 2009;29(4):4238.

[83] Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathol 2009;62(6):48192.

[84] Kodavanti UP, Mehendale HM. Cationic amphiphilic drugs and phospholipid storage disorder. Pharmacol Rev 1990;42(4):32754.

[85] Jain D, Bowlus CL, Anderson JM, Robert ME. Granular cells as a marker of early amiodarone hepatotoxicity. J Clin Gastroenterol

2000;31(3):2413.

[86] Simon JB, Manley PN, Brien JF, Armstrong PW. Amiodarone hepatotoxicity simulating alcoholic liver disease. N Engl J Med 1984;311

(3):16772.

[87] Poucell S, Ireton J, Valencia-Mayoral P, Downar E, Larratt L, Patterson J, et al. Amiodarone-associated phospholipidosis and fibrosis of

the liver. Light, immunohistochemical, and electron microscopic studies. Gastroenterology 1984;86(5 Pt 1):92636.

[88] Shepherd NA, Dawson AM, Crocker PR, Levison DA. Granular cells as a marker of early amiodarone hepatotoxicity: a pathological

and analytical study. J Clin Pathol 1987;40(4):41823.

[89] Yap SH, Rijntjes PJ, Moshage HJ, Croes H, Jap PH. Amiodarone-induced lysosomal inclusions in primary cultures of human hepato-

cytes. Gastroenterology. 1987;92(1):2723.

[90] Lullmann H, Lullmann-Rauch R, Wassermann O. Drug-induced phospholipidoses. II. Tissue distribution of the amphiphilic drug chlor-

phentermine. CRC Crit Rev Toxicol 1975;4(2):185218.

[91] Somani P, Bandyopadhyay S, Klaunig JE, Gross SA. Amiodarone- and desethylamiodarone-induced myelinoid inclusion bodies and

toxicity in cultured rat hepatocytes. Hepatology. 1990;11(1):8192.

[92] Guigui B, Perrot S, Berry JP, Fleury-Feith J, Martin N, Metreau JM, et al. Amiodarone-induced hepatic phospholipidosis: a morphologi-

cal alteration independent of pseudoalcoholic liver disease. Hepatology. 1988;8(5):10638.

[93] Somani P, Simon VA, Temesy-Armos PN, Gross SA, Didio LJ. Amiodarone-associated changes in human neutrophils. Am J Cardiol

1986;57(8):66672.

[94] Neuschwander-Tetri BA. Fatty liver and the metabolic syndrome. Curr Opin Gastroenterol 2007;23(2):1938.

[95] Mendez-Sanchez N, Arrese M, Zamora-Valdes D, Uribe M. Current concepts in the pathogenesis of nonalcoholic fatty liver disease.

Liver Int 2007;27(4):42333.

[96] Umetani K, Kodama Y, Nakamura T, Mende A, Kitta Y, Kawabata K, et al. High prevalence of paroxysmal atrial fibrillation and/or

atrial flutter in metabolic syndrome. Circ J 2007;71(2):2525.

[97] Nicolaou VN, Papadakis JE, Karatzis EN, Dermitzaki SI, Tsakiris AK, Skoufas PD. Impact of the metabolic syndrome on atrial size in

patients with new-onset atrial fibrillation. Angiology. 2007;58(1):215.

[98] Mirbagheri SA, Rashidi A, Abdi S, Saedi D, Abouzari M. Liver: an alarm for the heart? Liver Int 2007;27(7):8914.

[99] Athyros VG, Mikhailidis DP, Liberopoulos EN, Kakafika AI, Karagiannis A, Papageorgiou AA, et al. Effect of statin treatment on renal

function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syn-

drome: a subgroup analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. Nephrol Dial Transpl

2007;22(1):11827.

[100] Richer M, Robert S. Fatal hepatotoxicity following oral administration of amiodarone. Ann Pharmacother 1995;29(6):5826.

[101] Puli SR, Fraley MA, Puli V, Kuperman AB, Alpert MA. Hepatic cirrhosis caused by low-dose oral amiodarone therapy. Am J Med Sci

2005;330(5):25761.

[102] Mattar W, Juliar B, Gradus-Pizlo I, Kwo PY. Amiodarone hepatotoxicity in the context of the metabolic syndrome and right-sided heart

failure. J Gastrointestin Liver Dis 2009;18(4):41923.

[103] Pollak PT. How toxic is amiodarone to the liver? J Gastrointestin Liver Dis 2010;19(1):1113.

[104] Robinson K, Mulrow JP, Rowland E, McKenna WJ. Long-term effects of amiodarone on hepatic function. Am J Cardiol 1989;64(1):956.

[105] Heger JJ, Prystowsky EN, Jackman WM, Naccarelli GV, Warfel KA, Rinkenberger RL, et al. Clinical efficacy and electrophysiology dur-

ing long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 1981;305(10):53945.

[106] Waxman HL, Groh WC, Marchlinski FE, Buxton AE, Sadowski LM, Horowitz LN, et al. Amiodarone for control of sustained ventricular

tachyarrhythmia: clinical and electrophysiologic effects in 51 patients. Am J Cardiol 1982;50(5):106674.

[107] McGovern B, Garan H, Kelly E, Ruskin JN. Adverse reactions during treatment with amiodarone hydrochloride. Br Med J 1983;287

(6386):17580.

[108] Morady F, Sauve MJ, Malone P, Shen EN, Schwartz AB, Bhandari A, et al. Long-term efficacy and toxicity of high-dose amiodarone

therapy for ventricular tachycardia or ventricular fibrillation. Am J Cardiol 1983;52(8):9759.

[109] Raeder EA, Podrid PJ, Lown B. Side effects and complications of amiodarone therapy. Am Heart J 1985;109(5 Pt 1):97583.

[110] Anastasiou-Nana MI, Anderson JL, Nanas JN, Lutz JR, Smith RA, Anderson KP, et al. High incidence of clinical and subclinical toxicity

associated with amiodarone treatment of refractory tachyarrhythmias. Can J Cardiol 1986;2(3):13845.

[111] Pollak PT, Sharma AD, Carruthers SG. Relation of amiodarone hepatic and pulmonary toxicity to serum drug concentrations and super-

oxide dismutase activity. Am J Cardiol 1990;65(18):118591.

[112] Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, et al. Updated definitions of healthy ranges for serum alanine ami-

notransferase levels. Ann Intern Med 2002;137(1):110.

[113] Kum LCC, Chan WWL, Hui HHY, Wong GWM, Ho SSS, Sanderson JE, et al. Prevalence of amiodarone-related hepatotoxicity in 720

Chinese patients with or without baseline liver dysfunction. Clin Cardiol 2006;29(7):2959.

[114] Huang C-H, Lai Y-Y, Kuo Y-J, Yang S-C, Chang Y-J, Chang K-K, et al. Amiodarone and risk of liver cirrhosis: a nationwide, population-

based study. Ther Clin Risk Manag 2019;15:10312.

[115] Podrid PJ. Amiodarone: reevaluation of an old drug. Ann Intern Med 1995;122(9):689700.

[116] Rigas B, Rosenfeld LE, Barwick KW, Enriquez R, Helzberg J, Batsford WP, et al. Amiodarone hepatotoxicity. A clinicopathologic study

of five patients. Ann Intern Med 1986;104(3):34851.

[117] Goldman IS, Winkler ML, Raper SE, Barker ME, Keung E, Goldberg HI, et al. Increased hepatic density and phospholipidosis due to

amiodarone. Am J Roentgenol 1985;144(3):5416.

61References

I. Liver and heart

https://t.me/medicina_free

[118] Beuers U, Heuck A. Iodine accumulation in the liver during long-term treatment with amiodarone. J Hepatol 1997;26(2):439.

[119] Kannan R, Sarma JS, Guha M, Venkataraman K. Tissue drug accumulation and ultrastructural changes during amiodarone administra-

tion in rats. Fundam Appl Toxicol 1989;13(4):793803.

[120] Colunga Biancatelli RML, Congedo V, Calvosa L, Ciacciarelli M, Polidoro A, Iuliano L. Adverse reactions of amiodarone. J Geriatr

Cardiol 2019;16(7):55266.

[121] Ohyama K, Nakajima M, Suzuki M, Shimada N, Yamazaki H, Yokoi T. Inhibitory effects of amiodarone and its N-deethylated metabo-

lite on human cytochrome P450 activities: prediction of in vivo drug interactions. Br J Clin Pharmacol 2000;49(3):24453.

[122] Elsherbiny ME, El-Kadi AOS, Brocks DR. The metabolism of amiodarone by various CYP isoenzymes of human and rat, and the inhibi-

tory influence of ketoconazole. J Pharm Pharm Sci 2008;11(1):14759.

[123] van Opstal JM, Schoenmakers M, Verduyn SC, de Groot SH, Leunissen JD, van Der Hulst FF, et al. Chronic amiodarone evokes no torsade

de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome. Circulation. 2001;104(22):27227.

[124] Boutitie F, Boissel JP, Connolly SJ, Camm AJ, Cairns JA, Julian DG, et al. Amiodarone interaction with beta-blockers: analysis of the

merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial)

databases. The EMIAT and CAMIAT Investigators. Circulation. 1999;99(17):226875.

[125] Gill J, Heel RC, Fitton A. Amiodarone: an overview of its pharmacological properties, and review of its therapeutic use in cardiac

arrhythmias. Drugs. 1992;43(1):69110.

[126] Stelfox HT, Ahmed SB, Fiskio J, Bates DW. Monitoring amiodarone’s toxicities: recommendations, evidence, and clinical practice. Clin

Pharmacol Ther 2004;75(1):11022.

[127] Kundrotas LW, Clement DJ. Serum alanine aminotransferase (ALT) elevation in asymptomatic US Air Force basic trainee blood donors.

Dig Dis Sci 1993;38(12):214550.

[128] Burgess C, Blaikie A, Ingham T, Robinson G, Narasimhan S. Monitoring the use of amiodarone: compliance with guidelines. Intern

Med J 2006;36(5):28993.

[129] Mahmarian JJ, Smart FW, Moye LA, Young JB, Francis MJ, Kingry CL, et al. Exploring the minimal dose of amiodarone with antiar-

rhythmic and hemodynamic activity. Am J Cardiol 1994;74(7):6816.

[130] Hirakawa K, Abe K, Ayabe Y, Nishimura M. [Analysis of increased hepatic density during chronic amiodarone therapy]. Nihon Igaku

Hoshasen Gakkai Zasshi 2003;63(5):2214.

[131] Shenasa M, Vaisman U, Wojciechowski M, Denker S, Murthy V, Akhtar M. Abnormal abdominal computerized tomography with amio-

darone therapy and clinical significance. Am Heart J 1984;107(5 Pt 1):92933.

[132] Laukamp KR, Lennartz S, Hashmi A, Obmann M, Ho V, Große Hokamp N, et al. Iodine accumulation of the liver in patients treated

with amiodarone can be unmasked using material decomposition from multiphase spectral-detector CT. Sci Rep 2020;10(1):6994.

[133] Mudalel ML, Dave KP, Hummel JP, Solga SF. N-acetylcysteine treats intravenous amiodarone induced liver injury. World J

Gastroenterol 2015;21(9):281619.

[134] Akbay E, Erdem B, U

nlu

A, Durukan AB, Onur MA. Effects of N-acetyl cysteine, vitamin E and vitamin C on liver glutathione levels

following amiodarone treatment in rats. Kardiochir Torakochirurgia Pol 2019;16(2):8892.

[135] Agoston M, Orsi F, Feher E, Hagymasi K, Orosz Z, Blazovics A, et al. Silymarin and vitamin E reduce amiodarone-induced lysosomal

phospholipidosis in rats. Toxicology. 2003;190(3):23141.

[136] Scuntaro I, Kientsch U, Wiesmann UN, Honegger UE. Inhibition by vitamin E of drug accumulation and of phospholipidosis induced

by desipramine and other cationic amphiphilic drugs in human cultured cells. Br J Pharmacol 1996;119(5):82934.

[137] de Franchis R, Baveno VIF. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk

and individualizing care for portal hypertension. J Hepatol 2015;63(3):74352.

[138] Cohn JN, Khatri IM, Groszmann RJ, Kotelanski B. Hepatic blood flow in alcoholic liver disease measured by an indicator dilution tech-

nic. Am J Med 1972;53(6):70414.

[139] Kotelanski B, Groszmann R, Cohn JN. Circulation times in the splanchnic and hepatic beds in alcoholic liver disease. Gastroenterology.

1972;63(1):10211.

[140] Lebrec D, Nouel O, Corbic M, Benhamou JP. Propranolola medical treatment for portal hypertension? Lancet. 1980;2(8187):1802.

[141] Lebrec D, Poynard T, Hillon P, Benhamou JP. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrho-

sis: a controlled study. N Engl J Med 1981;305(23):13714.

[142] Bosch J, Groszmann RJ, Shah VH. Evolution in the understanding of the pathophysiological basis of portal hypertension: how changes

in paradigm are leading to successful new treatments. J Hepatol 2015;62(1 Suppl):S12130.

[143] Feu F, Bordas JM, Luca A, Garcia-Pagan JC, Escorsell A, Bosch J, et al. Reduction of variceal pressure by propranolol: comparison of the

effects on portal pressure and azygos blood flow in patients with cirrhosis. Hepatology. 1993;18(5):10829.

[144] Mills PR, Rae AP, Farah DA, Russell RI, Carter DC. Comparison of three adrenoceptor blocking agents in patients with cirrhosis and

portal hypertension. Gut. 1984;25:738.

[145] Hillon P, Lebrec D, Muyoz C, Jungers M, Goldfarb G, Banhamou JP. Comparison of the effects of a cardioselective and a nonselective

beta-blocker on portal hypertension in patients with cirrhosis. Hepatology. 1982;2:52831.

[146] Kroeger RJ, Groszmann RJ. Effect of selective blockade of beta 2-adrenergic receptors on portal and systemic hemodynamics in a portal

hypertensive rat model. Gastroenterology. 1985;88(4):896900.

[147] Villanueva C, Albillos A, Genesca J, Abraldes JG, Calleja JL, Aracil C, et al. Development of hyperdynamic circulation and response to

beta-blockers in compensated cirrhosis with portal hypertension. Hepatology. 2016;63(1):197206.

[148] Abraldes JG, Iwakiri Y, Loureiro-Silva MR, Haq O, Sessa WC, Groszmann RJ. Mild increases in portal pressure upregulate VEGF and

eNOS in the intestinal microcirculatory bed leading to vasodilatation and the hyperdynamic circulation. J Hepatol. 2005;42((Suppl.2):27A.

[149] Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, et al. Beta-blockers to prevent gastroesophageal varices in

patients with cirrhosis. N Engl J Med 2005;353(21):225461.

[150] Bhutta AQ, Garcia-Tsao G. The role of medical therapy for variceal bleeding. Gastrointest Endosc Clin N Am 2015;25(3):47990.

62 4. Drugs at the crossroads of heart and liver

I. Liver and heart

https://t.me/medicina_free

[151] Villanueva C, Albillos A, Genesca J, Garcia-Pagan JC, Calleja JL, Aracil C, et al. Beta blockers to prevent decompensation of cirrhosis in

patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.

Lancet. 2019;393(10181):1597608.

[152] D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. SeminLiver Dis

1999;19(4):475505.

[153] Groszmann RJ, Bosch J, Grace ND, Conn HO, Garcia-Tsao G, Navasa M, et al. Hemodynamic events in a prospective randomized trial

of propranolol vs placebo in the prevention of a first variceal hemorrhage [see comments]. Gastroenterology. 1990;99(5):14017.

[154] Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodes J, Bosch J. Hemodynamic response to pharmacological treatment of portal

hypertension and long-term prognosis of cirrhosis. Hepatology. 2003;37(4):9028.

[155] Villanueva C, Aracil C, Colomo A, Hernandez-Gea V, Lopez-Balaguer JM, varez-Urturi C, et al. Acute hemodynamic response to beta-

blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding. Gastroenterology. 2009;137(1):11928.

[156] Thalheimer U, Bosch J, Burroughs AK. How to prevent varices from bleeding: shades of greythe case for nonselective beta blockers.

Gastroenterology. 2007;133(6):202936.

[157] Giannelli V, Lattanzi B, Thalheimer U, Merli M. Beta-blockers in liver cirrhosis. Ann Gastroenterol 2014;27(1):206.

[158] Jachs M, Hartl L, Schaufler D, Desbalmes C, Simbrunner B, Eigenbauer E, et al. Amelioration of systemic inflammation in advanced

chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes. Gut. 2020;70(9):175867.

[159] Niazi M, Abraldes JG. Can we add the history of the nonoperative therapy of varices to other success chapters of modern medicine?

Clin Liver Dis 2020;16(Suppl 1):7382.

[160] Garcia-Tsao G, Grace ND, Groszmann RJ, Conn HO, Bermann MM, Patrick MJ, et al. Short-term effects of propranolol on portal venous

pressure. Hepatology. 1986;6(1):1016.

[161] Turnes J, Hernandez-Guerra M, Abraldes JG, Bellot P, Oliva R, Garcia-Pagan JC, et al. Influence of beta-2 adrenergic receptor gene poly-

morphism on the hemodynamic response to propranolol in patients with cirrhosis. Hepatology. 2006;43(1):3441.

[162] Bai W, Al-Karaghouli M, Stach J, Matheson G.J, Abraldes J.G. Test-retest reliability of hepatic venous pressure gradient and impact on

trial design: a study in 289 patients from the control groups of 20 randomized trials. medRxiv. 2020. Available from:

https://doi.org/

10.1101/2020.12.07.20245464

[163]

Shukla R, Kramer J, Cao Y, Ying J, Tansel A, Walder A, et al. Risk and predictors of variceal bleeding in cirrhosis patients receiving pri-

mary prophylaxis with non-selective beta-blockers. Am J Gastroenterol 2016;111(12):177887.

[164] Tandon P, Saez R, Berzigotti A, Abraldes JG, Garcia-Pagan JC, Bosch J. A specialized, nurse-run titration clinic: a feasible option for

optimizing beta-blockade in non-clinical trial patients. Am J Gastroenterol 2010;105(9):191721.

[165] Tellez L, Ibanez-Samaniego L, Perez Del Villar C, Yotti R, Martinez J, Carrion L, et al. Non-selective beta-blockers impair global circula-

tory homeostasis and renal function in cirrhotic patients with refractory ascites. J Hepatol 2020;73:140414.

[166] Taegtmeyer AB, Haschke M, Tchambaz L, Buylaert M, Tschopl M, Beuers U, et al. A study of the relationship between serum bile acids and

propranolol pharmacokinetics and pharmacodynamics in patients with liver cirrhosis and in healthy controls. PLoS One 2014;9(6):e97885.

[167] Riddell JG, Harron DW, Shanks RG. Clinical pharmacokinetics of beta-adrenoceptor antagonists: an update. Clin Pharmacokinet

1987;12(5):30520.

[168] Banares R, Moitinho E, Matilla A, Garcia-Pagan JC, Lampreave JL, Piera C, et al. Randomized comparison of long-term carvedilol and

propranolol administration in the treatment of portal hypertension in cirrhosis. Hepatology. 2002;36:136773.

[169] Forrest E, Stanley A, Hayes P. CarvedilolA new nonselective beta blocker. Hepatology. 2000;31(3):80911.

[170] Reiberger T, Ulbrich G, Ferlitsch A, Payer BA, Schwabl P, Pinter M, et al. Carvedilol for primary prophylaxis of variceal bleeding in cir-

rhotic patients with haemodynamic non-response to propranolol. Gut. 2012;62(22):163141.

[171] Forrest EH, Bouchier IA, Hayes PC. Acute haemodynamic changes after oral carvedilol, a vasodilating beta-blocker, in patients with cir-

rhosis. JHepatol 1996;25(6):90915.

[172] Rasool MF, Khalil F, Laer S. Optimizing the clinical use of carvedilol in liver cirrhosis using a physiologically based pharmacokinetic

modeling approach. Eur J Drug Metab Pharmacokinet 2016.

[173] Sinagra E, Perricone G, D’Amico M, Tine F, D’Amico G. Systematic review with meta-analysis: the haemodynamic effects of carvedilol

compared with propranolol for portal hypertension in cirrhosis. Aliment Pharmacol Ther 2014;39(6):55768.

[174] Bosch J, Garcia-Tsao G. Pharmacological vs endoscopic therapy in the prevention of variceal hemorrhage: and the winner is.

Hepatology. 2009;50(3):6747.

[175] Longacre AV, Imaeda A, Garcia-Tsao G, Fraenkel L. A pilot project examining the predicted preferences of patients and physicians in

the primary prophylaxis of variceal hemorrhage. Hepatology. 2008;47:16976.

[176] Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis and manage-

ment. AASLD practice guidance. Hepatology. 2016;65(1):31035.

[177] Ripoll C, Augustin S, Reiberger T, Moreau R, Salerno F, Albillos A, et al. Effect of current therapies aimed at preventing variceal

rebleeding on other complications of cirrhosis. Portal Hypertension VI. Springer; 2016. p. 3339.

[178] Kumar M, Kainth S, Choudhury A, Maiwall R, Mitra LG, Saluja V, et al. Treatment with carvedilol improves survival of patients with

acute-on-chronic liver failure: a randomized controlled trial. Hepatol Int 2019;13(6):80013.

[179] Poynard T, Cales P, Pasta L, Ideo G, Pascal JP, Pagliaro L, et al. Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal

bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four random-

ized clinical trials. Franco-Italian Multicenter Study Group. Nengl J Med 1991;324(22):15328.

[180] Conn HO, Grace ND, Bosch J, Groszmann RJ, Rodes J, Wright SC, et al. Propranolol in the prevention of the first hemorrhage from eso-

phagogastric varices: a multicenter, randomized clinical trial. The Boston-New Haven-Barcelona Portal Hypertension Study Group.

Hepatology. 1991;13(5):90212.

[181] Bernard B, Lebrec D, Mathurin P, Opolon P, Poynard T. Beta-adrenergic antagonists in the prevention of gastrointestinal rebleeding in

patients with cirrhosis: a meta-analysis. Hepatology. 1997;25(1):6370.

63References

I. Liver and heart

https://t.me/medicina_free

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