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Antivirales de acción directa para la hepatitis C crónica
Janus C Jakobsen, Emil Eik Nielsen, Joshua Feinberg, Kiran Kumar Katakam, Kristina Fobian, Goran Hauser, Goran Poropat, Snezana Djurisic, Karl Heinz Weiss, Milica Bjelakovic, Goran Bjelakovic, Sarah Louise Klingenberg, Jian Ping Liu, Dimitrinka Nikolova, Ronald L Koretz, Christian Gluud | 18 septiembre 2017

Respuestas clínicas Cochrane

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Temas

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 1

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

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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 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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Trial sequential analysis of the cumulative meta‐analysis of the effect of pentoxifylline on all‐cause mortality in participants with alcoholic hepatitis. The required information size of 1169 is calculated based on an a priori intervention effect of 20% (APHIS), a risk of type 1 error of 5%, and a power of 80%. The event rate in the control group is 39%, which is based on a meta‐analytic estimate of the control event rate of all the included trials. Although the cumulated z‐curve (blue curve) crosses the traditional boundary of 5% significance (horizontal red line), it does not cross the trial sequential monitoring boundary (red curve), implying that there is no firm evidence for an effect of 20% risk ratio reduction (RRR) when the cumulative meta‐analysis is adjusted for multiple testing on accumulating data.
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Figure 3

Trial sequential analysis of the cumulative meta‐analysis of the effect of pentoxifylline on all‐cause mortality in participants with alcoholic hepatitis. The required information size of 1169 is calculated based on an a priori intervention effect of 20% (APHIS), a risk of type 1 error of 5%, and a power of 80%. The event rate in the control group is 39%, which is based on a meta‐analytic estimate of the control event rate of all the included trials. Although the cumulated z‐curve (blue curve) crosses the traditional boundary of 5% significance (horizontal red line), it does not cross the trial sequential monitoring boundary (red curve), implying that there is no firm evidence for an effect of 20% risk ratio reduction (RRR) when the cumulative meta‐analysis is adjusted for multiple testing on accumulating data.

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Trial sequential analysis of the cumulative meta‐analysis of the effect of pentoxifylline on hepatic‐related mortality in participants with alcoholic hepatitis. The required information size of 1636 is calculated based on an a priori intervention effect of 20% (APHIS), a risk of type 1 error of 5% and a power of 80%. The event rate in the control group is 38%, which is based on a meta‐analytic estimate of the control event rate of all the included trials. Although the cumulated z‐curve (blue curve) crosses the traditional boundary of 5% significance (horizontal red line), it does not cross the trial sequential monitoring boundary (red curve), implying that there is no firm evidence for an effect of 20% risk ratio reduction (RRR) when the cumulative meta‐analysis is adjusted for multiple testing on accumulating data.
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Figure 4

Trial sequential analysis of the cumulative meta‐analysis of the effect of pentoxifylline on hepatic‐related mortality in participants with alcoholic hepatitis. The required information size of 1636 is calculated based on an a priori intervention effect of 20% (APHIS), a risk of type 1 error of 5% and a power of 80%. The event rate in the control group is 38%, which is based on a meta‐analytic estimate of the control event rate of all the included trials. Although the cumulated z‐curve (blue curve) crosses the traditional boundary of 5% significance (horizontal red line), it does not cross the trial sequential monitoring boundary (red curve), implying that there is no firm evidence for an effect of 20% risk ratio reduction (RRR) when the cumulative meta‐analysis is adjusted for multiple testing on accumulating data.

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Trial sequential analysis of the cumulative meta‐analysis of the effect of pentoxifylline on serum creatinine in participants with alcoholic hepatitis. The required information size of 252 is calculated based on an intervention effect of 0.25 (mg/dl) (APHIS), a risk of type 1 error of 5% and a power of 80%. The cumulated z‐curve (blue curve) crosses the trial sequential monitoring boundary implying that there is firm evidence for a beneficial effect of 0.25 (mg/dl) decrease in serum creatinine when the cumulative meta‐analysis is adjusted for multiple testing on accumulating data.
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Figure 5

Trial sequential analysis of the cumulative meta‐analysis of the effect of pentoxifylline on serum creatinine in participants with alcoholic hepatitis. The required information size of 252 is calculated based on an intervention effect of 0.25 (mg/dl) (APHIS), a risk of type 1 error of 5% and a power of 80%. The cumulated z‐curve (blue curve) crosses the trial sequential monitoring boundary implying that there is firm evidence for a beneficial effect of 0.25 (mg/dl) decrease in serum creatinine when the cumulative meta‐analysis is adjusted for multiple testing on accumulating data.

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Trial sequential analysis of the cumulative meta‐analysis of the effect of pentoxifylline on serum bilirubin in participants with alcoholic hepatitis. The trial sequential monitoring boundary is not calculated because the actual information size is less than 1% of the information size required. This is calculated based on an intervention effect of 1.00 (mg/dl) suggested by the one trial with low risk of bias.
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Figure 6

Trial sequential analysis of the cumulative meta‐analysis of the effect of pentoxifylline on serum bilirubin in participants with alcoholic hepatitis. The trial sequential monitoring boundary is not calculated because the actual information size is less than 1% of the information size required. This is calculated based on an intervention effect of 1.00 (mg/dl) suggested by the one trial with low risk of bias.

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Trial sequential analysis of the cumulative meta‐analysis of the effect of pentoxifylline on levels of TNF in participants with alcoholic hepatitis. The required information size of 318 is calculated based on an intervention effect of 4.00 pg/ml, suggested by the one trial with low risk of bias (LBHIS) (Akriviadis 2000), a risk of type 1 error of 5% and a power of 80%. The cumulated z‐curve (blue curve) does not cross the trial sequential monitoring boundary implying that there is no firm evidence for a potentially harmful effect of 4.00 pg/ml when the cumulative meta‐analysis is adjusted for multiple testing on accumulating data.
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Figure 7

Trial sequential analysis of the cumulative meta‐analysis of the effect of pentoxifylline on levels of TNF in participants with alcoholic hepatitis. The required information size of 318 is calculated based on an intervention effect of 4.00 pg/ml, suggested by the one trial with low risk of bias (LBHIS) (Akriviadis 2000), a risk of type 1 error of 5% and a power of 80%. The cumulated z‐curve (blue curve) does not cross the trial sequential monitoring boundary implying that there is no firm evidence for a potentially harmful effect of 4.00 pg/ml when the cumulative meta‐analysis is adjusted for multiple testing on accumulating data.

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Comparison 1 All‐cause mortality, pentoxifylline versus control, Outcome 1 Mortality using the fixed effect model.
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Analysis 1.1

Comparison 1 All‐cause mortality, pentoxifylline versus control, Outcome 1 Mortality using the fixed effect model.

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Comparison 1 All‐cause mortality, pentoxifylline versus control, Outcome 2 Mortality using the random effects model.
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Analysis 1.2

Comparison 1 All‐cause mortality, pentoxifylline versus control, Outcome 2 Mortality using the random effects model.

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Comparison 1 All‐cause mortality, pentoxifylline versus control, Outcome 3 Mortality according to risk of bias.
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Analysis 1.3

Comparison 1 All‐cause mortality, pentoxifylline versus control, Outcome 3 Mortality according to risk of bias.

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Comparison 2 Hepatic‐related mortality, Outcome 1 Hepatic‐related mortality using fixed‐effect model.
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Analysis 2.1

Comparison 2 Hepatic‐related mortality, Outcome 1 Hepatic‐related mortality using fixed‐effect model.

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Comparison 2 Hepatic‐related mortality, Outcome 2 Hepatic‐related mortality using the random‐effects model.
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Analysis 2.2

Comparison 2 Hepatic‐related mortality, Outcome 2 Hepatic‐related mortality using the random‐effects model.

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Comparison 3 Sensitivity analysis, all‐cause mortality, Outcome 1 Mortality.
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Analysis 3.1

Comparison 3 Sensitivity analysis, all‐cause mortality, Outcome 1 Mortality.

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Comparison 4 Hepatic‐related morbidity, pentoxifylline versus control, Outcome 1 Variceal bleeding.
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Analysis 4.1

Comparison 4 Hepatic‐related morbidity, pentoxifylline versus control, Outcome 1 Variceal bleeding.

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Comparison 5 Biochemical parameters, pentoxifylline versus control, Outcome 1 Serum creatinine.
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Analysis 5.1

Comparison 5 Biochemical parameters, pentoxifylline versus control, Outcome 1 Serum creatinine.

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Comparison 5 Biochemical parameters, pentoxifylline versus control, Outcome 2 Serum bilirubin.
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Analysis 5.2

Comparison 5 Biochemical parameters, pentoxifylline versus control, Outcome 2 Serum bilirubin.

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Comparison 6 Post‐hoc outcome measures, TNF levels, Outcome 1 Tumour necrosis factor.
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Analysis 6.1

Comparison 6 Post‐hoc outcome measures, TNF levels, Outcome 1 Tumour necrosis factor.

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Table 1. Fisher's exact test

Outcome measure

Type of data

Pentoxifylline group

Control group

Statistical test

P value

Hepatic encephalopathy

Dichotomous

9/50 (18%)

13/52 (25%)

Fisher’s exact test

0.133

Withdrawals due to adverse events

Dichotomous

7/50 (14%)

1/52 (2%)

Fisher’s exact test

0.026
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Table 1. Fisher's exact test
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Table 2. Student's t‐test

Outcome measure

Type of data

Pentoxifylline group

Control group

Statistical test

T value

P value

Blood urea nitrogen

Continuous

Mean 23
SD 28

Mean 38
SD 36

Student’s T test

2.3426

0.021131

Prothrombin time

Continuous

Mean 5
SD 3

Mean 5
SD 2

Student’s T test

0

1
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Table 2. Student's t‐test
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Table 3. Adverse events reported in Akriviadis 2000

Occurrence of adverse event as reported by Akriviadis et al

Pentoxifylline

Control

Transient diarrhoea

4

2

Epigastric discomfort or pain with or without vomiting

13

5

Severe gastrointestinal symptoms and headache

3

0

Diarrhoea

1

0

Epigastric pain

1

0

Severe headache

1

0

Generalised skin rash

1

0

Headache and gastrointestinal symptoms

0

1

Urinary tract infection

1

0

Spontaneous bacterial peritonitis

3

4

Cryptococcal septicaemia

1

0

Bronchopneumonia

1

0

Pneumonia

0

1

Staphylococcal bacteraemia

0

1

Necrotising pancreatitis

0

1

Intracranial bleeding

1

0

Vaginal bleeding

1

0

Posttraumatic epidural haematoma

1

0

Total

33

15
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Table 3. Adverse events reported in Akriviadis 2000
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Table 4. Lost to follow‐up reported in Akriviadis 2000

Reason for loss to follow‐up

Pentoxifylline

Control

Data collected

Participant dropped out

1

0

None, participant excluded from analysis.

Incomplete regimen and/or incomplete follow‐up appointment

4

3

No data collected due to missed appointments, but mortality at 2 and 6 months follow‐up was assessed.

Treatment withdrawal due to adverse events

7

1

Adverse events and mortality at 2 and 6 months follow‐up were assessed.

Total

12

4
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Table 4. Lost to follow‐up reported in Akriviadis 2000
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Comparison 1. All‐cause mortality, pentoxifylline versus control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality using the fixed effect model Show forest plot

5

336

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.46, 0.89]

2 Mortality using the random effects model Show forest plot

5

336

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.47, 0.90]

3 Mortality according to risk of bias Show forest plot

5

336

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.46, 0.89]

3.1 Low risk of bias

1

102

Risk Ratio (M‐H, Fixed, 95% CI)

0.52 [0.29, 0.92]

3.2 High risk of bias

4

234

Risk Ratio (M‐H, Fixed, 95% CI)

0.71 [0.48, 1.07]
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Comparison 1. All‐cause mortality, pentoxifylline versus control
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Comparison 2. Hepatic‐related mortality

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Hepatic‐related mortality using fixed‐effect model Show forest plot

3

182

Risk Ratio (M‐H, Fixed, 95% CI)

0.40 [0.22, 0.71]

2 Hepatic‐related mortality using the random‐effects model Show forest plot

3

182

Risk Ratio (M‐H, Random, 95% CI)

0.43 [0.22, 0.85]
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Comparison 2. Hepatic‐related mortality
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Comparison 3. Sensitivity analysis, all‐cause mortality

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality Show forest plot

5

672

Risk Ratio (M‐H, Fixed, 95% CI)

0.65 [0.52, 0.82]

1.1 Mortality, sensitivity analysis with all missing mortality data survived

5

336

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.46, 0.89]

1.2 Mortality, sensitivity analysis with all missing mortality data died

5

336

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.48, 0.91]
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Comparison 3. Sensitivity analysis, all‐cause mortality
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Comparison 4. Hepatic‐related morbidity, pentoxifylline versus control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Variceal bleeding Show forest plot

2

132

Risk Ratio (M‐H, Fixed, 95% CI)

2.18 [0.42, 11.32]
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Comparison 4. Hepatic‐related morbidity, pentoxifylline versus control
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Comparison 5. Biochemical parameters, pentoxifylline versus control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Serum creatinine Show forest plot

2

124

Mean Difference (IV, Fixed, 95% CI)

‐1.00 [‐1.14, ‐0.87]

2 Serum bilirubin Show forest plot

2

124

Mean Difference (IV, Fixed, 95% CI)

‐1.55 [‐5.10, 2.00]
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Comparison 5. Biochemical parameters, pentoxifylline versus control
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Comparison 6. Post‐hoc outcome measures, TNF levels

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tumour necrosis factor Show forest plot

2

124

Mean Difference (IV, Fixed, 95% CI)

4.04 [1.59, 6.48]
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Comparison 6. Post‐hoc outcome measures, TNF levels
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