Brief summary
In this study, patients who had their liver removed due to liver cancer or biliary tract disease were included. The patients were randomly divided into 2 groups, with one group receiving carnitine for 2 weeks, while the other group received no additional intervention. After the surgery, a slightly shorter hospital stay was observed for the patients who received carnitine. No significant differences were found regarding postoperative complications or the frequency of liver failure. The authors provide little information about the study procedure, leaving some methodological questions unanswered.
In dieser Studie wurden Patienten eingeschlossen, denen die Leber aufgrund einer Leberkrebs- oder Gallenwegserkrankung entfernt wurde. Die Patienten wurden zufällig in 2 Gruppen eingeteilt, wovon eine Gruppe über 2 Wochen Carnitin erhielt und die andere Gruppe erhielt keine zusätzliche Maßnahme. Nach der OP zeigte sich ein leicht kürzerer Krankenhausaufenthalt für die Patienten, die Carnitin erhielten. In Hinsicht auf Komplikationen nach der OP oder der Häufigkeit des Leberversagens konnten keine bedeutsamen Unterschiede gefunden werden. Die Autoren geben wenig Informationen über den Ablauf der Studie, so dass einige methodische Fragen offenbleiben.
Study Design
| Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies
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Prospective
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| Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals
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Monocentric
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| Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties
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No
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| Is randomized
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Yes
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| Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control
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No
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| Number of arms
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2
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Study characteristics
| Inclusion criteria
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Preoperative contrast-enhanced computed tomography was available within 30 days of the scheduled surgery.
Criteria for hepatectomy included:
- Absence or controllability of ascites.
- Serum total bilirubin level ≤2 mg/dL (no patients required diuretics for ascites)
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| Exclusion criteria
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- Previous liver surgery.
- Body weight loss >10% during the 6 months before surgery.
- Presence of distant metastases.
- Seriously impaired function of vital organs due to respiratory, renal, or heart disease.
- Biliary cancer, due to the need for biliary resection, bilioenteric anastomosis, and lymphadenectomy during hepatectomy for this condition.
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| N randomized
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208
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| Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.
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ITT Analysis
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| Specifications on analyses
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ITT analysis not specified, but no drop-out occured.
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| Countries of data collection
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Japan
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| LoE Level of evidence
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Level 2 Oxford 2011
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| Outcome timeline Data collection times
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Baseline: 2 weeks before surgery
T1: After surgery
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Characteristics of participants
| Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.
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Curative
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| Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included
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Gastrointestinal Cancers - Liver Cancer
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| Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis
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NI
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| Specifications on cancer stages
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NI
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| Comorbidities
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Comorbidity with hepatitis B (n=73), hepatitis C (n=104), alcohol (n=95), and non-alcoholic steatohepatitis (n=24)
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| Current cancer therapies
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Surgery
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| Specifications on cancer therapies
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Hepatectomy (n=30 bisegmentectomy or extended hepatectomy, n=69 segmentectomy, and n=109 subsegmentectomy)
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| Previous cancer therapies
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NI
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| Gender
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Mixed
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| Gender specifications
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Intervention arm 67%, control arm 67.6% male
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| Age groups
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Adults (18+)
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| Age groups specification
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Age (mean ± SD): intervention arm 73 ± 9.8 years, control arm 73 ± 10.7 years
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Arms
| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment
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Intervention
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| Number of participants (arm) N randomized
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102
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| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date
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0
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| Drop-out reasons
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NA
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| Intervention
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L-Carnitine
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| Dosage and regime
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Oral, 30 mg/kg body weight for 2 weeks before surgery
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| One-time application
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No
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| Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.
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14
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| Side effects / Interactions
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Authors: “L-carnitine was well tolerated by all patients.”
No differences in mortality as of March 2018.
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| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment
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Passive control
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| Number of participants (arm) N randomized
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106
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| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date
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0
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| Drop-out reasons
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NA
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| Intervention
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No further intervention
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| Dosage and regime
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NA
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| One-time application
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No
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| Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.
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14
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| Side effects / Interactions
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Authors: “L-carnitine was well tolerated by all patients.”
No differences in mortality as of March 2018.
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Outcomes
Postoperative morbidity/ complications
| Outcome type As specificed by the authors
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Primary
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| Outcome specification
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Classification according to Clavien-Dindo, 50-50 criteria (Prothrombin time < 50% and bilirubin level > 50 µmol/L on the 3rd and 5th postoperative days are associated with an increased risk of postoperative mortality), posthepatic liver failure (PHLF)
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| Type of measurement
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Blood Test
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| Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
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After Surgery:
- No significant differences between the intervention arm and the control arm in the frequency of postoperative complications, including bile leakage, pleural effusion, respiratory insufficiency, perihepatic abscess, and postoperative ileus.
- Classification according to Clavien-Dindo: Morbidity was 10.4% in the control arm and 6.9% in the intervention arm; 7 patients (6%) in the control arm and 3 patients (3%) in the intervention arm had at least one severe complication (Grade III-V), with no significant difference between the groups.
- 50-50 criteria: 6 patients (6%) in the control arm and 2 patients (2%) in the intervention arm, with no significant difference between the groups.
- PHLF: 12 patients (11%) in the control arm and 6 patients (6%) in the intervention arm, with no significant difference between the groups.
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| Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
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NA
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
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| Bias arising from the randomization process
|
?
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| Bias due to deviation from intended intervention (assignment to intervention)
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?
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
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?
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| Bias in measurement of the outcome
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?
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| Bias in selection of the reported result
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?
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| Other sources of bias
|
?
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| Overall RoB judgment
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?
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Length of hospital stay
| Outcome type As specificed by the authors
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Primary
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| Outcome specification
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NA
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| Type of measurement
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Observation
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| Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
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Slightly significant shorter stay in the intervention arm compared to the control arm: Median stay was 12 days (range, 5-144 days) in the control arm and 10 days (range, 7-157 days) in the intervention arm, p=0.048. The length of stay in the intensive care unit was 1 day (range, 0-1 days) in both arms.
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| Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
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NA
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
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| Bias arising from the randomization process
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?
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| Bias due to deviation from intended intervention (assignment to intervention)
|
?
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
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?
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| Bias in measurement of the outcome
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?
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| Bias in selection of the reported result
|
?
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| Other sources of bias
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?
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| Overall RoB judgment
|
?
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Mortality rate
| Outcome type As specificed by the authors
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Primary
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| Outcome specification
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NA
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| Type of measurement
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Observation
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| Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
|
NI
|
| Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
|
One death occurred 62 days post-operation in the control arm (segmentectomy) due to bleeding from esophageal varices 2 weeks after surgery, followed by multi-organ failure. No other surgical mortalities or readmissions related to the surgery were reported.
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
|
| Bias arising from the randomization process
|
?
|
| Bias due to deviation from intended intervention (assignment to intervention)
|
?
|
| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
|
?
|
| Bias in measurement of the outcome
|
?
|
| Bias in selection of the reported result
|
?
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| Other sources of bias
|
?
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| Overall RoB judgment
|
?
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Funding and Conflicts of Interest
| Funding
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This work was supported by grants from the K ¯ochi Organi-zation for Medical Reformation and Renewal. Dr. TakehiroOkabayashi is the guarantor of this work, had full access to allthe data in the study, and takes responsibility for the integrityof the data and the accuracy of the data analysis.
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| Conflicts of Interest
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According to authors no conflict of interest.
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Further points for assessing the study
Sample
| Power analysis performed
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?
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| - Sample size corresponds to power analysis
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?
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| - Reasons for insufficient sample size based on power analysis
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?
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| If no power analysis performed: at least moderate sample size (n >= 30 per arm)
|
?
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| Ethnicity mentioned
|
?
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Alternative Explanation
| Other explanations for an effect besides the investigated intervention
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?
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| - Possibility of attention effects
|
?
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| - Possibility of placebo effects
|
?
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| - Other reasons
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?
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Statistics
| Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing
|
?
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| Correction for multiple testing
|
?
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| Measurement of compliance
|
?
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| Consistent reporting in numbers (figures, flowchart, abstract, results)
|
?
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| Comprehensive and coherent reporting
|
?
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| Cross-over
|
?
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| - Sufficient washout period
|
?
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| - Tested for carry-over effects
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?
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| - Tested for sequence effects
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?
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Interpretation of results
| Effect sizes reported (clinical vs. statistical significance)
|
?
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| Side effects systematically recorded
|
?
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| Side effects considered in result interpretation
|
?
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| Ethics votum
|
?
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Additional Notes
PRO:
- Ethical approval obtained.
- Large sample size.
- Study registered.
- Baseline comparison conducted.
- Power analysis performed.
CONTRA:
- No description of the randomization process.
- Financial support was initially not disclosed, but later indicated.
- Open design.
- PHLF: Table in article shows n=5 in the control arm, but text reports n=6.
- No information on the treatment of the control group.
- No control for multiple testing.
