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Vutrisiran (Amvuttra): CADTH Reimbursement Recommendation: Indication: For the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin-mediated amyloidosis [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2024 Feb.
| Outcome and follow-up | Patients (studies), N |
Relative effect
(95% CI) | Absolute effects (95% CI) | Certainty | What happens | ||
|---|---|---|---|---|---|---|---|
|
Patisiran
(within-study of the HELIOS-A trial) |
Vutrisiran
(HELIOS-A trial) | Difference | |||||
| Neurologic impairment | |||||||
| Percent of patients with PND score 1. “improvement” 2. “no change” 3. “worsened” Follow-up: 18 months | 164 (1 RCT) | NR | 1. | || || || | 2. | || || || | 3. | || || || | | 1. | || || || | 2. | || || || | 3. | || || || | | 1. | || || || | 2. | || || || | 3. | || || || | | 1. Lowd,f,h,i 2. Very lowe,f,h,i 3. Very lowe,f,h,i | Vutrisiran may result in more patients with a PND score of “improvement” when compared with patisiran. The evidence is very uncertain about the effects of vutrisiran on the PND scores of “no change” and “worsened” vs. patisiran. There is some uncertainty about the clinical importance of the estimates. |
| mNIS+7: LS mean (SE) change from baseline (0 [best] to 304 [worst]) Follow-up: 18 months | 148 (1 RCT) | NR | 1.53 | 0.06 (SE to 1.48) | −1.46 (−7.36 to 4.43) | Moderatea,f,i | Vutrisiran likely results in little to no difference in mNIS+7 when compared to patisiran. There is some uncertainty about the clinical importance of the estimates. |
| Functional impairment | |||||||
| R-ODS score: LS mean (SE) change from baseline (48 [best] to 0 [worst]) Follow-up: 18 months | 151 (1 RCT) | NR | −1.3 | −1.2 (SE to 0.5) | 0.1 (−2.0 to 2.2) | Moderateb,f,i | Vutrisiran likely results in little to no difference in R-ODS scores when compared to patisiran. |
| HRQoL | |||||||
| Norfolk QoL-DN score: mean (SE) change from baseline (−4 [best] to 136 [worst]) Follow-up: 18 months | 149 (1 RCT) | NR | −0.8 | −2.5 (SE to 1.8) | −1.6 (−8.6 to 5.4) | Moderatec,f,i | Vutrisiran likely results in little to no difference in Norfolk QoL-DN score when compared to patisiran. |
| Serum TTR | |||||||
| Serum transthyretin: percent change from baseline, median Follow-up: 12 months (month 6 to month 18) | 160 (1 RCT) | NR | | || || || | | | || || || | (NR) | 5.28 (1.17 to 9.25) | Highg | Vutrisiran results in little to no clinically important difference (i.e., a noninferior effect) for serum TTR when compared to patisiran. |
| Harms | |||||||
| Mortality Follow-up: 18 months | 164 (1 RCT) | NR | | || || || | | | || || || || || || || || || || || | | | || || || || || || || || || || || || || || || | | Very lowd,f,h,j | The evidence is very uncertain about the effects of vutrisiran on mortality vs. patisiran. |
CI = confidence interval; COMPASS 31 = Composite Autonomic Symptom Score 31; HRQoL = health-related quality of life; LS = least squares; mNIS+7 = modified Neuropathy Impairment Score +7; NA = not applicable; Norfolk QoL-DN = Norfolk Quality of Life–Diabetic Neuropathy; NR = not reported; PND = polyneuropathy disability; RCT = randomized controlled trial; R-ODS = Rasch-built Overall Disability Score; SD = standard deviation; SE = standard error; vs. = versus.
Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the following footnotes.
Imprecision was not rated down. The was no known minimal important difference and the clinical expert consulted by CADTH could not estimate a threshold of a clinically important difference. The CADTH team judged the point estimate and entire CI to suggest little to no difference.
Imprecision was not rated down. No known threshold was identified but according to the clinical expert consulted by CADTH for the review, a 4-point difference between groups in R-ODS score could be considered clinically meaningful. The between-group difference and lower and upper bounds of the 95% CI did not meet the threshold, suggesting little to no difference.
Imprecision was not rated down. A threshold of 8.8 was identified in the literature. The between-group difference and lower and upper bound of the 95% CI did not meet the threshold, suggesting little to no difference.
Rated down 1 level for serious imprecision. There is no known threshold and the clinical expert consulted by CADTH could not provide a threshold of important difference, so the null was used. The CADTH team judged that the point estimate for the between-group difference as well as the upper bound of the 95% CI were likely to include an important benefit, while the lower bound of the 95% CI suggested little to no difference.
Rated down 2 levels for very serious imprecision. There is no established minimal important difference and the clinical expert consulted by CADTH could not provide a threshold of important difference. In the absence of a known threshold, the null was used. The CADTH review team judged that the point estimate for the between-group difference was unlikely to include an important effect; however, the upper and lower bounds of the 95% CI for difference between groups suggested a possibility of both benefit and harm.
Rate down 1 level for serious risk of bias due to the analyses being post hoc and not part of the protocol and may have been chosen among many potential analyses of the data.
Imprecision was not rated down. The clinical expert consulted by CADTH could not provide a threshold of important difference. The noninferiority margin set out in the HERLIOS-A trial was used as the threshold. The CADTH review team judged that the point estimate and both the lower and upper boundaries of the 95% CI of the between-group comparison suggested little to no difference; the 95% CI excluded the noninferiority margin (10%).
This analysis was not part of the sponsor's statistical analysis plan and was requested by CADTH to facilitate a certainty of evidence appraisal.
There was a risk of bias due to open-label study design and the subjective nature of the outcome. The open-label study design may have biased measurement scores due to knowledge of assigned treatment, although the direction of potential bias is unclear. HELIOS-A implemented integrity strategies for the mNIS+7 and Norfolk QoL-DN measures to mitigate any potential bias. CADTH review team did not rate down for risk of bias, as it was believed that rating down 1 time due to the post hoc nature of the analyses was adequate to account for risk of bias concerns.
Rated down 1 level for serious indirectness due to insufficient duration of follow-up for the outcome according to clinical expert input.
From: Vutrisiran (Amvuttra)
Copyright © 2024 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
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