Barts-MS rose-tinted-odometer: ★
This week I was asked by two patients independently of each other who had delayed access to treatment if this could explain why they now have secondary progressive MS. In parallel, I had a meeting with a friend yesterday, who was the primary driver of the 21-year interferon-beta follow-up survival study (see below), who said that to him this was the most convincing data to support the early treatment paradigm in MS.
In summary, trial subjects in the pivotal original interferon-beta-1b study who had delayed access to interferon-beta-1b because they were randomised to receive placebo were 50% less likely to be alive at 21 years compared to study subjects with early access to treatment. Was this due to the impact of interferon-beta on MS or some other confounding factor? In the 69 pwMS for whom information on the relationship of death to MS was available 78% were judged to have died from MS-related complications. This tells us that IFN-beta increases your life expectancy by reducing MS-related complications that can cause death in the future. The latter include swallowing problems that are associated with aspiration pneumonia, urinary dysfunction that lead to urinary tract infections and septicaemia, immobility and pressure sores, falls and fractures, to name the most common causes of premature death in pwMS.
You need to remember that this was a placebo-controlled study and the subjects on placebo were switched to active treatment after 3 years, with some subjects having to wait up to 5 years (trial recruitment was from June 1988 to May 1990; with placebo-treated subjects given free commercial supply as of October 1993). What this study shows is that delaying access to treatment by just 3-5 years has a major impact on long-term outcomes.
Please note that apart from suicide most pwMS get to EDSS 10 or death as a result of MS by passing through EDSS stages 2, 4, 6 (stick), 8 (wheelchair/bed). So my answer to these patients was yes your delayed access to DMTs in the early 2000s is almost certainly the reason why you now have secondary progressive MS and are disabled.
Please note this there is now overwhelming evidence from other controlled trials and real-life data to support the interferon-beta 21-year mortality data. In fact, the debate about early treatment and MS outcomes is so widely accepted that it has now has shifted from early access to DMTs to early access to highly effective DMTs, i.e. flipping the pyramid. It is clear that pwMS who are treated with more effective DMTs first-line do so much better than those who are asked to wait (watchful waiting) or are escalated gradually up the DMT ladder (slow escalation). This is why, despite us designing the early treat-2-target NEDA trial, our centre couldn’t participate in the trial comparing maintenance-escalation vs. flipping the pyramid. We simply don’t have equipoise; in other words, we don’t think it is ethical to randomise patients to a treatment arm that is less effective and hence will result in poorer long-term outcomes and probably poorer long-term survival. This is why it is our current clinical practice to offer pwMS who have active disease and are eligible under the NHSE algorithm for treatment access to highly effective treatment first-line.
We are so convinced about the early treatment that we are doing the ATTACK-MS trial, which will explore if access to the highly effective treatment natalizumab, 2 months earlier than what happens in routine practice, improves outcomes. Yes, we will be randomising patients before they have finished the MS diagnostic pathway to treatment vs. delayed access, i.e. only 2 months later when they have a definitive diagnosis of MS. We anticipate that the ATTACK-MS study will activate the MS community to treat the MS brain as we treat the brain in stroke. Forget about years, every day, week or month for the untreated MS brain is like every second, minute or hour in the non-perfused brain of a person having a stroke.
Yes, in MS time really is brain and by delaying access to DMTs and potentially highly effective DMTs is unacceptable in the modern era of treating MS. The data below not only supports the maxim “Time is Brain” but “Time is Life“, why would anyone wait to treat someone with active MS knowing this?
Goodin et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology. 2012 Apr 24;78(17):1315-22.
Objective: To examine the effects of interferon beta (IFNβ)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments.
Methods: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNβ-1b 250 μg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary.
Results: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNβ-1b 250 μg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNβ-1b 250 μg-treated patients (46.0% among IFNβ-1b 50 μg-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect.
Conclusions: There was a significant survival advantage in this cohort of patients receiving early IFNβ-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNβ-1b benefit on all-cause mortality.
Classification of evidence: This study provides Class III evidence that early treatment with IFNβ-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis.
Goodin et al. Cause of death in MS: long-term follow-up of a randomised cohort, 21 years after the start of the pivotal IFNβ-1b study. BMJ Open. 2012 Nov 30;2(6).
Objectives: Compared with controls, multiple sclerosis (MS) patients die, on average, 7–14 years prematurely. Previously, we reported that, 21 years after their participation in the pivotal randomised, controlled trial (RCT) of interferon β-1b, mortality was reduced by 46–47% in the two groups who received active therapy during the RCT. To determine whether the excessive deaths observed in placebo-treated patients was due to MS-related causes, we analysed the causes-of-death (CODs) in these three, randomised, patient cohorts.
Design: Long-term follow-up (LTF) of the pivotal RCT of interferon β-1b.
Setting: Eleven North American MS-centres participated.
Participants: In the original RCT, 372 patients participated, of whom 366 (98.4%) were identified after a median of 21.1 years from RCT enrolment.
Interventions: Using multiple information sources, we attempted to establish COD and its relationship to MS in deceased patients.
Primary outcome: An independent adjudication committee, masked to treatment assignment and using prespecified criteria, determined the likely CODs and their MS relationships.
Results: Among the 366 MS patients included in this LTF study, 81 deaths were recorded. Mean age-at-death was 51.7 (±8.7) years. COD, MS relationship, or both were determined for 88% of deaths (71/81). Patients were assigned to one of nine COD categories: cardiovascular disease/stroke; cancer; pulmonary infections; sepsis; accidents; suicide; death due to MS; other known CODs; and unknown COD. Of the 69 patients for whom information on the relationship of death to MS was available, 78.3% (54/69) were adjudicated to be MS related. Patients randomised to receive placebo during the RCT (compared with patients receiving active treatment) experienced an excessive number of MS-related deaths.
Conclusions: In this long-term, randomised, cohort study, MS patients receiving placebo during the RCT experienced greater all-cause mortality compared to those on active treatment. The excessive mortality in the original placebo group was largely from MS-related causes, especially, MS-related pulmonary infections.
If you are interested you can watch my presentation from last year’s ACTRIMS-ECTRIMS meeting during which I make the case for flipping the pyramid. Please note the ATTACK-MS study paradigm takes this concept of time is brain even further. Do you agree with this approach?
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.