Acetyl‐L‐carnitine for patients with hepatic encephalopathy

Arturo J Martí‐Carvajal; Christian Gluud; Ingrid Arevalo‐Rodriguez; Cristina Elena Martí‐Amarista

doi:10.1002/14651858.CD011451.pub2

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Figure 1

Study flow diagram for 10 August 2018.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Trial Sequential Analysis of five trials comparing acetyl‐L‐carnitine versus placebo on blood ammonium levels in participants with hepatic encephalopathy.

Trial Sequential Analysis of five trials comparing acetyl‐L‐carnitine versus placebo on blood ammonium levels in participants with hepatic encephalopathy based on the diversity‐adjusted required information size (DARIS) of 406 participants. This DARIS was calculated based upon a mean relevant difference of 10 mg; a variance of 263; an alpha (α) of 1.25%; and a beta (β) of 10%. The cumulative Z‐curve (blue line) crossed the conventional alpha of 1.25% (green line) after three trials. This implies that there is not a random error. The cumulative Z‐curve (blue line) surpassed the continuous alpha‐spending boundary (monitoring efficacy boundary) after four trials. Presently, 95.3% (387/406) of the DARIS has been obtained.

Malaguarnera 2011b measured twice blood ammonium level with mild or moderate hepatic encephalopathy.

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Analysis 1.1

Comparison 1 Acetyl‐L‐carnitine versus placebo, Outcome 1 Quality of life (SF‐36 scale; 0 to 100, higher score is better).

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Analysis 1.2

Comparison 1 Acetyl‐L‐carnitine versus placebo, Outcome 2 Non‐serious adverse events.

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Analysis 1.3

Comparison 1 Acetyl‐L‐carnitine versus placebo, Outcome 3 Non‐serious adverse events (sensitivity analysis by missing data).

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Analysis 1.4

Comparison 1 Acetyl‐L‐carnitine versus placebo, Outcome 4 Fatigue (the Wessely and Powell test).

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Analysis 1.5

Comparison 1 Acetyl‐L‐carnitine versus placebo, Outcome 5 Blood ammonium levels.

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Analysis 1.6

Comparison 1 Acetyl‐L‐carnitine versus placebo, Outcome 6 Blood ammonium levels (sensitivity analysis according to missing data).

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Summary of findings for the main comparison. Acetyl‐L‐carnitine compared with placebo for patients with hepatic encephalopathy

Acetyl‐L‐carnitine compared with placebo for patients with hepatic encephalopathy
Patient or population: patients with covert or overt hepatic encephalopathy Settings: inpatient or outpatient Intervention: acetyl‐L‐carnitine Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Acetyl‐L‐carnitine
All‐cause mortality	See comment	See comment	Not estimable	0 (0 trials)	See comment	No trial reported this outcome
Quality of life (general health at 90 days) SF‐36 scale Scale from 0 to 100 Follow‐up: 90 days	Mean quality of life in the control groups was 67.1 points	Mean quality of life in the intervention groups was 6.20 lower (9.51 to 2.89 lower)^a	‐	67 (1 trial^b)	⊕⊝⊝⊝ very low^c,d	Physical functioning Mean difference (MD) 7.90 (95% confidence interval (CI) 4.49 to 11.31) Role limitations due to physIcal problems MD 9.60 (95% CI 5.77 to 13.43) Bodily pain MD 1.80 (95% CI ‐2.78 to 6.38) Vitality MD 2.80 (95% CI ‐0.11 to 5.71) Social functioning MD 2.90 (95% CI 0.44 to 5.36) Role of limitations due to emotional problems MD 4.80 (95% CI 1.45 to 8.15) General mental health perceptions MD 3.10 (95% CI 0.64 to 5.56)
Serious adverse events	See comment	See comment	Not estimable	0 (0 trials)	See comment	No trial reported this outcome
Fatigue Mental fatigue in moderate‐grade hepatic encephalopathy Wessely and Powell test Scale from 0 to 10 Follow‐up: 90 days Physical fatigue Wessely and Powell test from 0 (no fatigue) to 16 (highest possible fatigue)	Mean mental fatigue in the control groups was 5.8 points	Mean fatigue in the intervention groups was 0.40 higher (0.21 lower to 1.01 higher)	‐	121 (1 trial^e)	⊕⊝⊝⊝ very low^c,d	Mental fatigue in mild‐grade hepatic encephalopathy Mean difference (MD) ‐0.80 (95% confidence interval (CI) ‐1.48 to ‐0.12) Physical fatigue in moderate‐grade hepatic encephalopathy MD ‐0.20 (95% CI ‐0.92 to 0.52) Physical fatigue in mild‐grade hepatic encephalopathy MD 0.20 (95% CI ‐0.72 to 1.12) MD was assessed with fixed‐effect or random‐effects models
Non‐serious adverse events Follow‐up: 90 days	25 per 1000^f	63 per 1000 (17 to 231)	RR 2.51 (0.68 to 9.22)	246 (2 trials^b,e)	⊕⊝⊝⊝ very low^g,h
Days of hospitalisation	See comment	See comment	Not estimable	0 (0 trials)	See comment	No trial reported this outcome
Blood ammonium levels Follow‐up: 90 days	Mean blood ammonium levels in the control groups was 7.6 mg/dL	Mean blood ammonium levels in the intervention groups was 13.06 lower (17.24 to 8.99 lower)	‐	387 (5 trials^b,e)	⊕⊕⊝⊝ low^g,i
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio; SF‐36: Short Form‐36.
GRADE Working Group grades of evidence. High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aFor mental health domain. ^bCovert hepatic encephalopathy. ^cDowngraded one level for limitations in design and execution: trial assessing this outcome has high risk for allocation and confusion biases. ^dDowngraded two levels for imprecision: small sample size leading to wide confidence intervals. ^eOvert hepatic encephalopathy. ^fAssumed risk is based on risks for the control group in the meta‐analysis (2.6%). ^gDowngraded one level for limitations in design and execution: both trials assessing this outcome have high risk for allocation and confusion biases. We did not downgrade quality rating for risk of bias due to missing data because results show robustness to each of the imputation strategies. See Analysis 1.3 and Analysis 1.6. ^hDowngraded two levels for imprecision: small sample size and very low rate of adverse events leading to wide confidence intervals. ⁱDowngraded one level for inconsistency: 59% with fixed‐effect or random‐effects model.

Summary of findings for the main comparison. Acetyl‐L‐carnitine compared with placebo for patients with hepatic encephalopathy

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Table 1. Impact of acetyl‐L‐carnitine on quality of life in patients with hepatic encephalopathy

Domain (SF‐36 scale; 0 to 100, higher score is better)	Mean difference (95% CI)	Ratio of means (95% CI)
Physical functioning	7.90 (4.49 to 11.31)	1.12 (1.07 to 1.18)
Role limitations due to physIcal problems	9.60 (5.77 to 13.43)	1.15 (1.09 to 1.21)
Bodily pain at 90 days	1.80 (‐2.78 to 6.38)	1.03 (0.96 to 1.10)
General health at 90 days	‐6.20 (‐9.51 to ‐2.89)	0.91 (0.86 to 0.96)
Vitality at 90 days	2.80 (‐0.11 to 5.71)	1.05 (1.00 to 1.10)
Social functioning at 90 days	2.90 (0.44 to 5.36)	1.05 (1.01 to 1.08)
Role limitations due to emotional problems at 90 days	4.80 (1.45 to 8.15)	1.08 (1.02 to 1.13)
General mental health perceptions at 90 days	3.10 (0.64 to 5.56)	1.05 (1.01 to 1.09)
SF‐36: Short Form‐36. Malaguarnera 2011a.

Table 1. Impact of acetyl‐L‐carnitine on quality of life in patients with hepatic encephalopathy

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Table 2. Adverse events reported in each trial

Trial	Adverse events
Malaguarnera 2006	"No side effects were observed in our study series"
Malaguarnera 2008	"In the group treated with acetyl‐L‐carnitine, one patient complained of nausea, two of slight headache and two of abdominal pain. In the placebo group, one patient complained of diarrhoea and one of moderate headache. Nobody withdrew from the planned treatment"
Malaguarnera 2011a	Researchers did not report on adverse events
Malaguarnera 2011b	"Three patients in the acetyl‐L‐carnitine group (1 with mild hepatic encephalopathy and 2 with moderate hepatic encephalopathy) withdrew from the study because of abdominal pain. One patient in the placebo group withdrew from the study because of headache. In the placebo group, we observed occasional abdominal pain, cramping, diarrhoea, and flatulence. At follow‐up 1 mo after treatment ended, 2 patients in the acetyl‐L‐carnitine group and 5 patients in the placebo group experienced moderate hepatic encephalopathy"
Malaguarnera 2011c	Researchers did not report on adverse events

Table 2. Adverse events reported in each trial

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Table 3. Impact of acetyl‐L‐carnitine on fatigue (the Wessely and Powell test)

Type of fatigue by hepatic encephalopathy

Fatigue

(the Wessely and Powell test)^b,c

Mean difference

(95% CI)

Ratio of means

(95% CI)

Mental fatigue in people with mild hepatic encephalopathy (0 (no fatigue) to 10 (highest possible))^a

‐0.80

(‐1.48 to ‐0.12)

0.88

(0.78, to 0.98)

Mental fatigue in people with moderate hepatic encephalopathy (0 (no fatigue) to 10 (highest possible))^a

0.40

(‐0.21 to 1.01)

1.07

(0.97 to 1.18)

Physical fatigue in people with mild hepatic encephalopathy (0 (no fatigue) to 16 (highest possible))^a

0.20

(‐0.72 to 1.12)

1.02

(0.93 to 1.13)

Physical fatigue in people with moderate hepatic encephalopathy (0 (no fatigue) to 16 (highest possible))^a

‐0.20

(‐0.92 to 0.52)

0.98

(0.90 to 1.06)

^aMalaguarnera 2011b.
^bWessely 1989.
^cChalder 1993.

Table 3. Impact of acetyl‐L‐carnitine on fatigue (the Wessely and Powell test)

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Table 4. Impact of acetyl‐L‐carnitine on blood ammonium levels in patients with hepatic encephalopathy

Type of hepatic encephalopathy	Acetyl‐L‐carnitine sample size	Placebo sample size	Blood ammonium levels
Type of hepatic encephalopathy	Acetyl‐L‐carnitine sample size	Placebo sample size	Mean difference, mg/dL (95% CI)	Ratio of means (95% CI)
Mild hepatic encephalopathy^a	31	30	‐13.00 (‐18.17 to ‐7.83)	0.81 (0.74 to 0.88)
Moderate hepatic encephalopathy^a	30	30	‐11.30 (‐19.05 to ‐3.55)	0.88 (0.80 to 0.96)
Hepatic coma^b	13	11	‐4.10 (‐10.77 to 2.57)	0.94 (0.85 to 1.04)
Minimal hepatic encephalopathy^c,d Subtotal (95% CI)	60	55	‐21.90 (‐32.84 to ‐10.96)	0.66 (0.53 to 0.81)
	33	34	‐16.70 (‐21.21 to ‐12.19)	0.72 (0.65 to 0.79)
	93	89	‐17.46 (‐21.63 to ‐13.28) I²= 0%	0.70 (0.64 to 0.77) I²= 0%
Severe hepatic encephalopathy^e	30	30	‐13.80 (‐20.78 to ‐6.82)	0.86 (0.79 to 0.93)
Total (95% CI)	197	190	‐13.06 (‐17.24 to ‐8.89) I²= 59%	0.82 (0.75 to 0.89) I²= 78%
^aMalaguarnera 2011b. ^bMalaguarnera 2006. ^cMalaguarnera 2008. ^dMalaguarnera 2011a. ^eMalaguarnera 2011c.

Table 4. Impact of acetyl‐L‐carnitine on blood ammonium levels in patients with hepatic encephalopathy

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Comparison 1. Acetyl‐L‐carnitine versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life (SF‐36 scale; 0 to 100, higher score is better) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1 Physical functioning	1	67	Mean Difference (IV, Random, 95% CI)	7.90 [4.49, 11.31]
1.2 Role limitations due to physIcal problems	1	67	Mean Difference (IV, Random, 95% CI)	9.60 [5.77, 13.43]
1.3 Bodily pain at 90 days	1	67	Mean Difference (IV, Random, 95% CI)	1.80 [‐2.78, 6.38]
1.4 General health at 90 days	1	67	Mean Difference (IV, Random, 95% CI)	‐6.20 [‐9.51, ‐2.89]
1.5 Vitality at 90 days	1	67	Mean Difference (IV, Random, 95% CI)	2.80 [‐0.11, 5.71]
1.6 Social functioning at 90 days	1	67	Mean Difference (IV, Random, 95% CI)	2.90 [0.44, 5.36]
1.7 Role limitations due to emotional problems at 90 days	1	67	Mean Difference (IV, Random, 95% CI)	4.80 [1.45, 8.15]
1.8 General mental health perceptions at 90 days	1	67	Mean Difference (IV, Random, 95% CI)	3.10 [0.64, 5.56]
2 Non‐serious adverse events Show forest plot	2	246	Risk Ratio (M‐H, Random, 95% CI)	2.51 [0.68, 9.22]

3 Non‐serious adverse events (sensitivity analysis by missing data) Show forest plot	2		Risk Ratio (Random, 95% CI)	Subtotals only

3.1 Available case analysis	2		Risk Ratio (Random, 95% CI)	2.50 [0.68, 9.16]
3.2 Best‐case scenario	2		Risk Ratio (Random, 95% CI)	0.97 [0.28, 3.40]
3.3 Worst‐case scenario	2		Risk Ratio (Random, 95% CI)	4.93 [1.48, 16.47]
3.4 Gamble‐Hollis analysis	2		Risk Ratio (Random, 95% CI)	2.57 [0.48, 13.74]
3.5 Informative missingness odds ratio (OR = 2)	2		Risk Ratio (Random, 95% CI)	2.51 [0.69, 9.17]
4 Fatigue (the Wessely and Powell test) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 Mental fatigue in people with mild hepatic encephalopathy (0 (no fatigue) to 10 (highest possible))	1	61	Mean Difference (IV, Random, 95% CI)	‐0.80 [‐1.48, ‐0.12]
4.2 Mental fatigue in people with moderate hepatic encephalopathy (0 (no fatigue) to 10 (highest possible))	1	61	Mean Difference (IV, Random, 95% CI)	0.40 [‐0.21, 1.01]
4.3 Physical fatigue in people with mild hepatic encephalopathy (0 (no fatigue) to 16 (highest possible))	1	61	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.72, 1.12]
4.4 Physical fatigue in people with moderate hepatic encephalopathy (0 (no fatigue) to 16 (highest possible))	1	61	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.92, 0.52]
5 Blood ammonium levels Show forest plot	5	387	Mean Difference (IV, Random, 95% CI)	‐13.06 [‐17.24, ‐8.89]

5.1 Mild hepatic encephalopathy	1	61	Mean Difference (IV, Random, 95% CI)	‐13.00 [‐18.17, ‐7.83]
5.2 Moderate hepatic encephalopathy	1	60	Mean Difference (IV, Random, 95% CI)	‐11.30 [‐19.05, ‐3.55]
5.3 Hepatic coma	1	24	Mean Difference (IV, Random, 95% CI)	‐4.10 [‐10.77, 2.57]
5.4 Minimal hepatic encephalopathy	2	182	Mean Difference (IV, Random, 95% CI)	‐17.46 [‐21.63, ‐13.28]
5.5 Severe hepatic encephalopathy	1	60	Mean Difference (IV, Random, 95% CI)	‐13.80 [‐20.78, ‐6.82]
6 Blood ammonium levels (sensitivity analysis according to missing data) Show forest plot	5		Mean Difference (IV, Random, 95% CI)	Subtotals only

6.1 Complete case analysis	5	327	Mean Difference (IV, Random, 95% CI)	‐13.40 [‐18.31, ‐8.48]
6.2 Strategy 1	5	342	Mean Difference (IV, Random, 95% CI)	‐12.88 [‐17.69, ‐8.06]
6.3 Strategy 2	5	342	Mean Difference (IV, Random, 95% CI)	‐14.70 [‐20.23, ‐9.16]
6.4 Strategy 3	5	342	Mean Difference (IV, Random, 95% CI)	‐14.06 [‐19.50, ‐8.62]
6.5 Strategy 4	5	342	Mean Difference (IV, Random, 95% CI)	‐13.79 [‐18.99, ‐8.58]

Comparison 1. Acetyl‐L‐carnitine versus placebo

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