Carvedilol or Propranolol in the Management of Portal Hypertension?

Transcription

1 Evidence Based Case Report Carvedilol or Propranolol in the Management of Portal Hypertension? Arranged by: dr. Saskia Aziza Nursyirwan RESIDENCY PROGRAM OF INTERNAL MEDICINE DEPARTMENT UNIVERSITY OF INDONESIA 2013

2 Introduction Development of bleeding gastroesophageal varices is a serious consequence of portal hypertension secondary to cirrhosis. Portal hypertension is the main complication of cirrhosis and is defined as an hepatic venous pressure gradient (HVPG) of more than 5 mmhg. Clinically significant portal hypertension is defined as HVPG of 10 mmhg or more. Development of gastroesophageal varices and variceal hemorrhage are the most direct consequence of portal hypertension. [1] An ideal treatment of portal hypertension would be one that is universally effective, safe, easy to administer, and cost effective. While such a treatment does not currently exist, there are several medical and surgical modalities available for primary prophylaxis of variceal hemorrhage. These therapies are aimed at achieving one of the following results: decreasing portal hypertension (eg, beta blockers, surgical portal decompression, or transjugular intrahepatic shunts); and directly treating the varices themselves (eg, variceal ligation). [2] Non selective beta blockers (eg, propranolol and nadolol) block the adrenergic dilatory tone in mesenteric arterioles resulting in unopposed alpha adrenergic mediated vasoconstriction and therefore a decrease in portal inflow. These are the only drugs recommended for prophylaxis against a first variceal hemorrhage. However, the report of increased mortality rates in patients with refractory ascites who received nonselective beta blockers has called their safety into question. [1] Although selective beta blockers also reduce portal venous pressure, the effect is not dramatic and their use remains to be validated in large scale clinical trials. Carvedilol, a non cardioselective vasodilating beta blocker, has also shown promise but has not been extensively studied. Carvedilol possesses both nonselective beta antagonist and alpha1 receptor antagonist activity. Given its combined mechanism of action, carvedilol presents a potential option for lowering portal pressures. Its effects on lowering portal pressures and its role in therapy are undefined. [3] 2

3 This evidence based case report is aimed to search any evidences for the management of portal hypertension using carvedilol compared to propranolol. Case Resume Male, 34 years old known to have hepatic cirrhosis with grade II esophageal varices and severe portal hypertension gastropathy, ascites, and history of hepatic encephalopathy. Patient was long known to have hepatitis B. He had already received propranolol for primary prophylaxis of variceal bleeding. Clinical query Does carvedilol has a better efficacy than propranolol in the management of portal hypertension? Methods In order to answer the question above, we conduct a searching in PubMed site by using three key words, which are carvedilol AND propranolol AND portal hypertension. Based on this search strategy, we found 14 articles. The schematic searching was stated below until we extracted 4 articles that matched our search. Figure 1. Flow chart of searching strategy 3

4 Critical Appraisal In appraising the studies, we were focusing on three aspects abbreviated as VIA, which consist of validity, importance, and applicability. The following are the critical appraisal for each of those aspects. Table 1. Articles to be Appraised No. Article Author Publication 1. Carvedilol or propranolol in portal hypertension? A randomized Hobolth L, Møller S, Grønbæk H, Roelsgaard K, Bendtsen F, Feldager Scand J Gastroenterol Apr comparison.[4] Hansen E. 2. Randomized comparison of long term carvedilol Bañares R, Moitinho E, Matilla A, García Pagán Hepatology Dec and propranolol administration in the treatment of portal hypertension in cirrhosis.[5] JC, Lampreave JL, Piera C, Abraldes JG, De Diego A, Albillos A, Bosch J. 3. Acute and 7 day portal pressure response to De BK, Das D, Sen S, Biswas PK, Mandal SK, J Gastroenterol Hepatol Feb carvedilol and propranolol in cirrhotics.[6] Majumdar D, Maity AK. 4. Carvedilol, a new nonselective beta blocker with intrinsic anti Alpha1 adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis.[7] Bañares R, Moitinho E, Piqueras B, Casado M, García Pagán JC, de Diego A, Bosch J. Hepatology Jul 4

5 Table 2. VIA of the Studies Criterion Article Validity Importancy Applica bility Hobolth, et al [4] Randomised all patients accounted for at its conclusion Blinding Equal Treatment The groups are similar at the start of the trial Relative Risk Reduction (RRR) RRR = (CER EER) / CER Absolute Risk Reduction (ARR) ARR = CER - EER Number needed to treat (NNT) NNT = 1 / ARR ,32-0, Patient similarity impact on Important patient Bañares, et al [5] , De, et al [6] ,03-0, Moitinho, et al [7] ,78-0, Result In Hobolth, et al, HVPG decreased by 19.3 ± 16.1% (p < 0.01) and by 12.5 ± 16.7% (p < 0.01) in the carvedilol and propranolol groups, respectively, with no signicant difference between treatment regimens (p = 0.21). Although insignificant, an acute decrease in HVPG of 12% was the best cut off value to predict long term HVPG response to propranolol when using ROC curve analysis. This randomized study showed that carvedilol is at least as effective as propranolol on HVPG after longterm administration. Furthermore, a predictive value of an acute propranolol test on HVPG could not be confirmed.[4] Study from Bañares, et al compared the HVPG reduction and safety of long term carvedilol and propranolol. Fifty one cirrhotic patients were randomly 5

6 assigned to receive carvedilol (n = 26) and propranolol (n = 25). Hemodynamic measurements and renal function were assessed at baseline and after 11.1 ± 4.1 weeks. Carvedilol caused a greater decrease in HVPG than popranolol ( 19 ± 2% vs. 12 ± 2%; P <.001). The proportion of patients achieving an HVPG reduction >20% or <12 mm Hg was greater after carvedilol (54% vs. 23%; P <.05). Carvedilol, but not propranolol caused a significant decrease in mean arterial pressure (MAP) ( 11 ± 1% vs. 5 ± 3%; P =.05). In conclusion, carvedilol has a greater portal hypotensive effect than propranolol in patients with cirrhosis. However, its clinical applicability may be limited by its systemic hypotensive effects.[5] In De, et al, with carvedilol, 11/18(61.1%) and 11/17(64.7%) patients responded acutely and after 7 days, respectively, while 9/18(50%) and 10/16(62.5%) did so to propranolol. However, HVPG reduction (percent) by carvedilol was not superior to that by propranolol either acutely (27.67 ± compared to ± 27.40, P = 0.6) or after 7 days (28.2 ± compared to ± 20.15, P = 0.6). With carvedilol, the acute HVPG response (P < 0.001) and responder status (P = 0.018) were good predictors of the response after 7 days, but were weak predictors in the case of propranolol (0.1 > P > 0.05 and P = 0.059, respectively). On carvedilol, only one patient (with ascites) developed symptomatic systemic hypotension with oliguria. In conclusion, carvedilol is a relatively safe, effective portal hypotensive agent, both acutely and over 7 days, but not superior to propranolol, at least in Indians. The acute hemodynamic response seems promising in predicting long term response.[6] In Moitinho, et al, thirty five cirrhotic patients had hemodynamic measurements before and after the random administration of carvedilol (n = 14), propranolol (n = 14), or placebo (n = 7). Carvedilol markedly reduced HVPG, from19.5 ± 1.3 to 15.4 ± 1mmHg(PF.0001). This HVPG reduction was greater than after propranolol ( 20.4 ± 2 vs ± 2%, P F.05). Moreover, carvedilol decreased HVPG greater than 20% of baseline values or to I12 mm Hg in a greater proportion of patients (64% vs. 14%, P F.05). Both drugs caused similar reductions in hepatic and azygos blood flows, suggesting that the greater HVPG decrease by carvedilol was because of reduced hepatic and portocollateral resistance. Propranolol caused greater reductions in heart rate and cardiac 6

7 output than carvedilol, whereas carvedilol caused a greater decrease in mean arterial pressure ( 23.1 vs. 11%, P <.05). Thus, carvedilol has a greater portal hypotensive effect than propranolol in patients with cirrhosis, suggesting a greater therapeutic potential. However, it causes arterial hypotension, which calls for careful evaluation before its long term use.[7] Conclusion Carvedilol is a relatively safe, effective portal hypotensive agent, but its superiority to propranolol was still debatable. However, its clinical applicability may be limited by its systemic hypotensive effects. To determine whether carvedilol is superior to propranolol, long term comparative trials of carvedi lol and propranolol with both bleeding and mortality as outcome measures are required. Such trials should include HVPG measurements. References 1. Bari, K. and G. Garcia Tsao, Treatment of portal hypertension. World J Gastroenterol, (11): p D'Amico, G., et al., Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology, (5): p Hemstreet, B.A., Evaluation of carvedilol for the treatment of portal hypertension. Pharmacotherapy, (1): p Hobolth, L., et al., Carvedilol or propranolol in portal hypertension? A randomized comparison. Scand J Gastroenterol, (4): p Banares, R., et al., Randomized comparison of long term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis. Hepatology, (6): p De, B.K., et al., Acute and 7 day portal pressure response to carvedilol and propranolol in cirrhotics. J Gastroenterol Hepatol, (2): p Banares, R., et al., Carvedilol, a new nonselective beta blocker with intrinsic anti Alpha1 adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis. Hepatology, (1): p