Whats Lost is Lost, Why CRAB can sometimes mean CRAP

This German studies shows real life data that dimethyl fumarate is better than the CRAB drugs plus teriflunomide……So why are we still using them?

Comparative effectiveness of delayed-release dimethyl fumarate versus interferon, glatiramer acetate, teriflunomide, or fingolimod: results from the German NeuroTransData registry. Braune S, Grimm S, van Hövell P, Freudensprung U, Pellegrini F, Hyde R, Bergmann A; NTD Study Group.J Neurol. 2018 Oct 16. doi: 10.1007/s00415-018-9083-5. [Epub ahead of print]
BACKGROUND:Comparative effectiveness (CE) research allows real-world treatment comparisons using outcome measurements important to physicians/patients. This German NeuroTransData registry-based analysis compared delayed-release dimethyl fumarate (DMF) effectiveness with interferons (IFN), glatiramer acetate (GA), teriflunomide (TERI), or fingolimod (FTY) in patients with relapsing-remitting multiple sclerosis (RRMS) using propensity score matching (PSM).
METHODS:Data from registry patients aged ≥ 18 years with RRMS, ≥ 1 relapse, and Expanded Disability Status Scale (EDSS) assessment(s) after index therapy initiation underwent 1:1 PSM to match DMF with comparator populations baseline characteristics. Primary outcome measurement was time to first relapse (TTFR). Secondary outcome measurements included annualised relapse rate (ARR), proportion of patients relapse free at 12 and 24 months, time to index therapy discontinuation (TTD), and reasons for discontinuation. Exploratory analyses included time to 3- and 6-month EDSS confirmed disability progression (CDP). Non-pairwise censoring was the primary analysis method; pairwise censoring was the main sensitivity analysis method.
FINDINGS:Post-matched cohorts were well-balanced. By non-pairwise censoring, TTFR and ARR were significantly lower in DMF populations versus matched IFN, GA, and TERI, but there was no evidence of difference between DMF and FTY. TTD was similar between DMF and IFN, GA, and TERI, but significantly shorter versus FTY. Time to CDP generally showed no evidence of difference between DMF and comparator populations. Pairwise censored analysis results confirmed the non-pairwise censoring results.
INTERPRETATION:These results support previous CE studies in demonstrating relative improvement in real-world effectiveness with DMF versus first-line agents IFN, GA, and TERI, and similar effectiveness versus FTY.

OK I accept that there are merits for each agent and perhaps in Germany it means that the Neuros doesnt have to do any monitoring if people are on a certain drug, but looking at the ocrelizumab extension trial data presented at ECTRIMS and at the Ammerican Academy (see post two days ago) where they put people on beta interferon on ocrelizumab two years after other people started on ocrelizumab and when they looked at confirmed disability progression the damage was done. 

People on ocrelizumab did better during the trial and when switched they both progressed at the same rate saying that you can get the benefit still,  but what was lost in the first two years whilst on beta interferon, stayed lost. Why do we need more evidence to treat early and effectively?

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  • Early start of high-efficacy therapies improves disability outcomes over
    10 years

    At baseline, the mean(SD) EDSS was 2.3(1.3) vs 2.3(1.2) in the early vs late groups. At six years, the mean(SD) EDSS was 2.5(1.8) in the early group, compared to 3.4(1.7) in the late group (p< .001). This difference remained clinically (≥.5 EDSS steps) and statistically (p≤ .05) significant up to 10 years post disease onset.
    Conclusions: Patients with MS commencing high-efficacy immunotherapy early after disease onset accumulate less long-term disability compared to those exposed later in their disease. Those treated earlier had a more aggressive disease course initially, which was then mitigated by their early active management strategy. In patients with highly active MS, early high efficacy therapy is recommended.



  • Why are you still using them? I don’t know really – but thanks for the reminder – it’s amazingly frustrating from a patient perspective that we are not able to access new technologies.

    On a separate note – you haven’t drawn attention to the use of propensity score matching in this study. The expectation for registry based studies is for regression techniques to be used, the use of PSM is a very powerful tool (a bit like using statistical modelling to create a retrospective RCT) and makes it a higher level of evidence. Considering that this tool has been applied it is interesting that the results flatten the difference between between fingo/DMF. It’s a bit of a shame that the study is Biogen funded, the study looks robust but the results are very favourable for the funder =-/. Given the nominal cost, it would be nice to see this study repeated on the UK MS register on charity/academic funding.

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