Heterogeneity of treatment response to beta-blockers in the treatment of portal hypertension: A systematic review

Figures

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  FIGURE 1. Illustration of the concept of increased variability in the outcome measure with a heterogeneous treatment response. A homogeneous effect assumes the same effect occurred in all patients and thus, the lines in the middle panel are parallel. In this case, the HVPG variability at the end of the study (represented by the blue distribution) is comparable between the treatment group and the placebo group. If the treatment induces a heterogeneous response, the lines are no longer parallel (lower panel), and the variability of the HVPG at the end of the study would be greater in the treatment group as compared with the control group. Further details and a more thorough data simulation are provided in Supplemental Data 1, http://links.lww.com/HC9/A657.

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  FIGURE 2. Forest plot showing VR of the 19 study arms (in 18 studies) comparing the effects of beta-blockers versus placebo (or control) on portal pressure. Studies are summarized in Table 1. Values of VR below 1 indicate a greater variability in the final HVPG in the control than in the treatment group. Values over 1 indicate a greater variability in the final HVPG in the treatment group. A VR significantly greater than 1 would support that beta-blocker treatment has a heterogeneous patient-to-patient effect on HVPG (a patient-by-treatment interaction), whereas a VR not significantly different from 1 (as found in the present study) would support the notion that the average decrease in HVPG observed with beta-blockers can be assumed to apply to all patients. Abbreviation: BB, beta-blockers; nCont, number of patients assessed in the control group; nBB, number of patients assessed in the beta-blocker group; Days, duration of treatment in days; Route, route of administration; VR, variability ratio.

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  FIGURE 3. Funnel plot showing the VR at outcome between treatment and control arms with the 19 comparisons. Vertical axis indicates the precision of the estimate of the VR (estimated by the SE), with points inside the triangle indicating the 95% most probable. The 2 points outside of the triangle correspond to the 2 studies identified in the text as being outliers.1920 Points on the right indicate higher outcome variability for the treated individuals, as expected if there is heterogeneity in treatment effects. Points on the left correspond to lower variability in the treatment arm, which implies a more homogenous response after treatment. The vertical dashed line corresponds to the pooled VR. The distribution of the studies was symmetrical, suggesting that the study-to-study variation in the VRs occurred by chance. Abbreviation: VR, variability ratio.

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  FIGURE 4. Forest plot showing VR of the 6 studies outlined in Table 2 comparing carvedilol and propranolol. Values of VR below 1 indicate a greater variability in the final HVPG in the propranolol than in the carvedilol group. Values over 1 indicate a greater variability in the final HVPG in the carvedilol group. There was no evidence of different variabilities in the final HVPG between the groups. nProp, number of patients in the propranolol group. Abbreviation: nCarv, number of patients assessed in the carvedilol group; Days, duration of treatment; VR, variability ratio.

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  FIGURE 5. Forest plot showing VR of the 3 studies comparing the effects of statins versus placebo on portal pressure. Studies are summarized in Table 3. As shown in the plot, there was no evidence of greater variability in the statins group, which argues against a treatment-by-patient interaction. Abbreviation: VR, variability ratio.