L‐ornithine L‐aspartate untuk pencegahan dan rawatan ensefalopati hepatik dalam pesakit yang mengalami sirosis
Abstract
Background
Hepatic encephalopathy is a common complication of cirrhosis and has high associated morbidity and mortality. The condition is classified as overt if it is clinically apparent or minimal if only evident though psychometric testing. The exact pathogenesis of this syndrome is unknown although ammonia is thought to play a key role. L‐ornithine L‐aspartate has ammonia‐lowering properties and may, therefore, benefit people with cirrhosis and hepatic encephalopathy.
Objectives
To evaluate the beneficial and harmful effects of L‐ornithine L‐aspartate versus placebo, no intervention, or other active interventions in people with cirrhosis and hepatic encephalopathy.
Search methods
We undertook electronic searches of The Cochrane Hepato‐Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS and Science Citation Index Expanded to December 2017 and manual searches of meetings and conference proceedings; checks of bibliographies; and corresponded with investigators and pharmaceutical companies.
Selection criteria
We included randomised clinical trials, irrespective of publication status, language, or blinding. We included participants with cirrhosis who had minimal or overt hepatic encephalopathy or who were at risk for developing hepatic encephalopathy. We compared: L‐ornithine L‐aspartate versus placebo or no intervention; and L‐ornithine L‐aspartate versus other active agents such as non‐absorbable disaccharides, antibiotics, probiotics, or branched‐chain amino acids.
Data collection and analysis
Two review authors, working independently, retrieved data from published reports and correspondence with investigators and pharmaceutical companies. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta‐analyses and presented the results as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed bias control using the Cochrane Hepato‐Biliary Group domains; we evaluated the risk of publication bias and other small trial effects in regression analyses; conducted subgroup and sensitivity analyses; and performed Trial Sequential Analyses. We determined the quality of the evidence using GRADE.
Main results
We identified 36 randomised clinical trials, involving at least 2377 registered participants, which fulfilled our inclusion criteria including 10 unpublished randomised clinical trials. However, we were only able to access outcome data from 29 trials involving 1891 participants. Five of the included trials assessed prevention, while 31 trials assessed treatment. Five trials were at low risk of bias in the overall assessment of mortality; one trial was at low risk of bias in the assessment of the remaining outcomes.
L‐ornithine L‐aspartate had a beneficial effect on mortality compared with placebo or no intervention when including all trials (RR 0.42, 95% CI 0.24 to 0.72; I2 = 0%; 19 trials; 1489 participants; very low quality evidence), but not when the analysis was restricted to the trials at low risk of bias (RR 0.47, 95% CI 0.06 to 3.58; 4 trials; 244 participants). It had a beneficial effect on hepatic encephalopathy compared with placebo or no intervention when including all trials (RR 0.70, 95% CI 0.59 to 0.83; 22 trials; 1375 participants; I2 = 62%; very low quality evidence), but not in the one trial at low risk of bias (RR 0.96, 95% CI 0.85 to 1.07; 63 participants). The analysis of serious adverse events showed a potential benefit of L‐ornithine L‐aspartate when including all randomised clinical trials (RR 0.63, 95% CI 0.45 to 0.90; 1 trial; 1489 participants; I2 = 0%; very low quality evidence), but not in the one trial at low risk of bias for this outcome (RR 0.83, 95% CI 0.15 to 4.65; 63 participants). The Trial Sequential Analyses of mortality, hepatic encephalopathy, and serious adverse events found insufficient evidence to support or refute beneficial effects. Subgroup analyses showed no difference in outcomes in the trials evaluating evaluating the prevention or treatment of either overt or minimal hepatic encephalopathy or trials evaluating oral versus intravenous administration We were unable to undertake a meta‐analysis of the three trials involving 288 participants evaluating health‐related quality of life. Overall, we found no difference between L‐ornithine L‐aspartate and placebo or no intervention in non‐serious adverse events (RR 1.15, 95% CI 0.75 to 1.77; 14 trials; 1076 participants; I2 = 40%). In comparison with lactulose, L‐ornithine L‐aspartate had no effect on mortality (RR 0.68, 95% CI 0.11 to 4.17; 4 trials; 175 participants; I2 = 0%); hepatic encephalopathy (RR 1.13, 95% CI 0.81 to 1.57); serious adverse events (RR 0.69, 95% CI 0.22 to 2.11); or non‐serious adverse events (RR 0.05, 95% CI 0.01 to 0.18). In comparison with probiotics, L‐ornithine L‐aspartate had no effect on mortality (RR 1.01, 95% CI 0.11 to 9.51); serious adverse events (RR 1.07, 95% CI 0.23 to 4.88); or changes in blood ammonia concentrations from baseline (RR ‐2.30 95% CI ‐6.08 to 1.48), but it had a possible beneficial effect on hepatic encephalopathy (RR 0.71, 95% CI 0.56 to 0.90). Finally, in comparison with rifaximin, L‐ornithine L‐aspartate had no effect on mortality (RR 0.33, 95% CI 0.04 to 3.03; 2 trials; 105 participants); hepatic encephalopathy (RR 1.06, 95% CI 0.57 to 1.96); serious adverse events (RR 0.32, 95% CI 0.01 to 7.42), or non‐serious adverse events (RR 0.32, 95% CI 0.01 to 7.42).
Authors' conclusions
The results of this review suggest a possible beneficial effect of L‐ornithine L‐aspartate on mortality, hepatic encephalopathy, and serious adverse events in comparisons with placebo or no‐intervention, but, because the quality of the evidence is very low, we are very uncertain about these findings. There was very low quality evidence of a possible beneficial effect of L‐ornithine L‐aspartate on hepatic encephalopathy, when compared with probiotics, but no other benefits were demonstrated in comparison with other active agents. Additional access to data from completed, but unpublished trials, and new randomised placebo‐controlled, double‐blind clinical trials are needed.
PICO
Plain language summary
L‐ornihtine L‐aspartate untuk pesakit hati kronik dan ensefalopati hepatik (pengurangan fungsi otak)
Latar belakang
Sirosis adalah penyakit hati yang kronik. Pesakit yang menghidapi sirosis biasanya akan mengalami ensefalopati hepatik, satu komplikasi yang menyebabkan pengurangan fungsi otak. Sesetengah pesakit yang menghidapi sirosis menunjukkan ciri‐ciri klinikal gangguan fungsi otak yang jelas seperti menghadapi kesukaran dalam pertuturan, keseimbangan dan menjalankan fungsi harian; mereka dikatakan mengalami ensefalopati hepatik yang ketara; perubahan yang dialami mungkin tidak lama, mungkin berulang atau mungkin berlanjutan dalam tempoh yang panjang. Pesakit sirosis yang lain pula mungkin tidak menunjukkan perubahan klinikal yang ketara tetapi beberapa aspek fungsi otak mereka seperti tumpuan dan kebolehan untuk melakukan tugasan yang kompleks didapati terjejas bila diuji; mereka dikatakan menghidapi ensefalopati hepatik minimum. Punca pesakit mengalami ensefalopati hepatik adalah kompleks, tetapi pengumpulan toksin dari usus dalam darah, terutamanya satu sebatian yang dipanggil amonia memainkan peranan yang penting. L‐ornithine, L‐aspartate menurunkan paras amonia darah dan ia mungkin mempunyai kesan bermanfaat dalam pesakit yang mengalami ensefalopati hepatik atau mencegah mereka daripada mengalaminya.
Soalan ulasan
Kami mengkaji penggunaan L‐ornithine L‐aspartate yang diberikan melalui mulut (oral) atau ke dalam vena melalui titisan cecair (intravena) untuk pencegahan dan rawatan ensefalopati hepatik dengan menilai kajian klinikal di mana pesakit sirosis diperuntukkan rawatan secara rawak dengan L‐ornithine L‐aspartate kepada sulih yang tidak aktif (plasebo) atau tanpa rawatan, atau ubat lain untuk penyakit ini seperti laktulosa, probiotik dan rifaximin. Kami memasukkan pesakit sirosis yang mengalami ensefalopati hati ketara atau minimum atau yang berisiko untuk menghidapi komplikasi ini.
Tarikh carian
Disember 2017.
Sumber pembiayaan kajian
Enam daripada 36 kajian klinikal rawak yang kami sertakan tidak menerima pembiayaan atau sebarang sokongan lain daripada syarikat farmaseutikal. Tujuh belas kajian menerima bantuan kewangan daripada syarikat farmaseutikal dan tiga lagi menerima L‐ornithine L‐aspartate atau plasebo tidak aktif secara percuma; tiada maklumat pembiayaan dalam 10 kajian selebihnya.
Ciri‐ciri kajian
Kami memasukkan 33 kajian klinikal rawak yang membandingkan L‐ornithine L‐aspartate dengan plasebo tidak aktif atau tanpa rawatan dan enam kajian klinikal rawak yang membandingkan L‐ornithine L‐aspartate dengan rawatan anti‐ensefalopati lain; beberapa kajian memasukkan lebih daripada satu perbandingan. Lima daripada kajian tersebut menguji L‐ornithine L‐aspartate untuk pencegahan ensefalopati hepatik manakala 30 kajian menguji penggunaannya sebagai rawatan untuk pesakit ensefalopati hepatik akut, kronik atau minimum. Tempoh rawatan berbeza antara tiga ke 35 hari dalam kajian yang menguji sediaan intravena (purata lapan hari) dan antara tujuh ke 180 hari dalam kajian yang menguji sediaan oral (purata 30 hari).
Hasil utama
Analisis kami menunjukkan L‐ornithine L‐aspartate mungkin mengurangkan kematian, memperbaiki ensefalopati hepatik dan mencegah kesan sampingan yang serius berbanding plasebo atau tanpa rawatan tetapi ia tidak mempunyai kesan bermanfaat tambahan apabila dibandingkan dengan penggunaan ubat‐ubat lain yang digunakan untuk mencegah dan merawat penyakit ini.
Kualiti bukti
Bukti yang diperolehi adalah sangat lemah, oleh itu kami tidak yakin bahawa L‐ornithine L‐aspartate berguna untuk mencegah atau merawat ensefalopati hepatik dalam pesakit sirosis. Banyak kajian belum diterbitkan, oleh itu belum melalui proses semakan yang teliti dan banyak kajian yang telah diterbitkan menerima bantuan daripada industri farmaseutikal yang boleh menyisipkan unsur bias. Sehubungan itu, lebih banyak maklumat diperlukan sebelum kepentingan L‐ornithine L‐aspartate untuk mencegah dan merawat ensefalopati hepatik dapat ditentukan.
