Summary of findings 2. Diflunisal compared to placebo for people with transthyretin‐familial amyloid polyneuropathy (TTR‐FAP).
| Diflunisal compared to placebo for people with transthyretin‐familial amyloid polyneuropathy (TTR‐FAP) | ||||||
| Patient or population: people with TTR‐FAP Setting: outpatient Intervention: diflunisal Comparison: placebo | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with placebo | Risk with diflunisal | |||||
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Disability due to FAP progression (expressed as the change in Kumamoto Score) Scale from: 0 (normal) to 102 (worst disease severity). Follow‐up: 24 monthsa |
The mean baseline Kumamoto Score in the placebo group was 16.7 points. The mean change from baseline in the placebo group was an increase (worsening) of 8.0 points. |
The mean change in Kumamoto Score in the diflunisal group was 4.90 points lower (better) than in the placebo group (7.89 points lower to 1.91 points lower). | ‐ | 130 (1 RCT) | ⊕⊕⊝⊝ Lowb | MCID not provided nor reported in the literature. Diflunisal probably slightly decreases disability due to FAP progression compared to placebo. |
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Severity of peripheral neuropathy (expressed as the change in NIS+7) Scale from: 0 (normal) to 270 (total impairment) Follow‐up: 24 monthsa |
The mean baseline NIS+7 score in the placebo group was 59.0 points. The mean change from baseline in the placebo group was an increase (worsening) of 26.3 points. |
The mean change in NIS+7 score in the diflunisal group was 18.10 points lower (better) than in the placebo group (26.03 points lower to 10.17 points lower). | ‐ | 130 (1 RCT) | ⊕⊕⊝⊝ Lowb | MCID detectable by neuromuscular experts is 2 NIS+7 points according to the international Peripheral Nerve Society (PNS 1995). Diflunisal probably slightly reduces the worsening of peripheral neuropathy compared to placebo. |
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Quality of life (expressed as the change in SF‐36 physical component score) Scale from: 0 (worst possible quality of life) to 100 (best possible quality of life) Follow‐up: 24 monthsa |
The mean baseline SF‐36 QOL score (physical component) in the placebo group was 34.8 points. The mean change from baseline in the placebo group was a decrease (worsening) of 4.9 points. |
The mean change in SF‐36 QOL score (physical component) in the diflunisal group was 6.10 points higher (better) than in the placebo group (2.56 points higher to 9.64 points higher). | ‐ | 130 (1 RCT) | ⊕⊝⊝⊝ Very lowc |
MCID proposed in the SF‐36v2 2011 is 2 points on the physical component summary. QOL (physical status) may decline slightly less with diflunisal than placebo. |
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Quality of life (expressed as the change in SF‐36 mental component score) Scale from: 0 (worst possible quality of life) to 100 (best possible quality of life). Follow‐up: 24 monthsa |
The mean baseline SF‐36 QOL score (mental component) in the placebo group was 46.5 points. The mean change from baseline in the placebo group was a decrease (worsening) of 0.9 points. |
The mean change in SF‐36 QOL score (mental component) in the diflunisal group was 4.40 points higher (better) than in the placebo group (0.19 points lower to 8.99 points higher). | ‐ | 130 (1 RCT) | ⊕⊝⊝⊝ Very lowd | MCID proposed in the SF‐36v2 2011 is 3 points on the mental component summary. Quality of life (mental status) may decline slightly less with diflunisal than placebo. |
| Number of participants who died during the trial Follow‐up: 24 monthsa | Study population | RR 0.46 (0.15 to 1.41) | 130 (1 RCT) | ⊕⊝⊝⊝ Very lowe | There is evidence that there may be fewer deaths among people treated with diflunisal | |
| 14 per 100 | 6 per 100 (2 to 19) | |||||
| Number of dropouts due to adverse events Follow‐up: 24 monthsa | Study population | RR 2.06 (0.39 to 10.87) | 130 (1 RCT) | ⊕⊝⊝⊝ Very lowe | Diflunisal may increase the number of dropouts due to adverse events. | |
| 6 per 100 | 11 per 100 (3 to 36) | |||||
| Number of participants experiencing at least one severe adverse event Follow‐up: 24 monthsa | Study population | RR 0.77 (0.18 to 3.32) | 130 (1 RCT) | ⊕⊝⊝⊝ Very lowe | Diflunisal may have no clear effect on the number of participants experiencing at least one severe adverse event. | |
| 6 per 100 | 5 per 100 (1 to 20) | |||||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FAP: familial amyloid polyneuropathy; MCID: minimum clinically important difference; NIS+7: Neuropathy Impairment Score plus 7 nerves test; QOL: quality of life; RCT: randomised clinical trial; RR: risk ratio; SD: standard deviation; SF‐36: 36‐Item Short‐Form Health Survey; TTR: transthyretin. | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect. | ||||||
aEnd of the study. bWe downgraded the certainty of evidence by one level for risk of bias (high risk of attrition bias in the single RCT included in this comparison) and by one level for serious imprecision. cWe downgraded the certainty of evidence by one level for risk of bias (high risk of attrition bias in the single RCT included in this comparison), by one level for serious imprecision and by one level for serious indirectness (data regarding QOL provided for SF‐36 physical and mental components separately). dWe downgraded the certainty of evidence by one level for risk of bias (high risk of attrition bias in the single RCT included in this comparison), by one level for serious imprecision (CI includes the possibility of both harms and benefits) and by one level for serious indirectness (data regarding QOL provided for SF‐36 physical and mental components separately and mechanisms by which this intervention would affect QOL are not direct). eWe downgraded the certainty of evidence by one level for risk of bias (high risk of attrition bias in the single RCT included in this comparison) and by two levels for very serious imprecision (small event numbers and CI includes the possibility of both harms and benefits).