Wednesday, 19 March 2014

Cause of death on interferon-beta

What evidence is there for stating "Time is Brain"? #MSBlog #MSResearch

"In view of the post today showing that there is no obvious change in cancer risk I think it is time to revisit the 21-year follow-up of the pivotal interferon-beta-1b (Betaseron/Betferon) study."

"Did you know that a delay in access to interferon-beta-1b reduces your chances of being alive at 21 years by about 50%? This fact is amazing. How is interferon-beta doing this? Is is it due to its impact on MS or is it doing it via another mechanism, for example reducing your chances of dying from cancer or heart disease? To explore this the investigators' looked at the causes of death in those who had died before the census at 21 years. Surprise, surprise in the 69 MSers for whom information on the relationship of death to MS was available 78% were judged to have died from MS-related complications. This is telling you that IFN-beta is increasing 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, etc. 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 waiting 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. It is interesting that nobody listening to my debate clocked this fact last Saturday. If they had they may have voted for early treatment."


"The other thing to register is that if this impact on survival can occur with IFNbeta-1b, which is only a moderately effective agent, what would happen with a high-efficacy DMT?"

"This data supports the maxim "Time is Brain" or "Time is Life", Why would anyone wait to treat someone with active MS knowing this data?"

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.


CoI: multiple

13 comments:

  1. Do you reckon copaxone is similarly effective?

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    1. Re: "Do you reckon copaxone is similarly effective?"

      Yes, I think this is due a treatment effect and therefore is not specific to interferon.

      Delete
  2. "Mean age-at-death was 51.7 (±8.7) years."

    That seems significantly younger than 7-14 years prematurely.

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    1. Re: "That seems significantly younger than 7-14 years prematurely."

      This is the age of the MSers who died. When the other MSers who are alive die the average will increase. MS reduces life expectancy by ~10 years. In some this will much larger than this and in others less than this.

      Delete
  3. Prof G,

    Perhaps I'm an outlier, but survival isn't as important to me as it appears to be to you / other researchers. I had a good life until MS came along in my late 30s. The treatment I'm on has kept the relapses at bay, but I still have deficits from earlier relapses e.g. walkign not great, pain... I would rather have 5 years of the pre-MS me that another 20 years like this. Quality over quantity for me. Only a focus on the repair of the CNS is of interest to me now. It's a pity that with the highly effective treatments available / nearly available, there hasn't been a shift in MS research to repair. One game of tennis would do me, or a long walk in the country etc. But the thought of never having these opportunities again is the most disheartening part of this disease. I'm not asking for much e.g. 23% improvement in my deficits. But it looks like repair is considered way to difficult to even start thinking about.

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    1. Re: "Only a focus on the repair of the CNS is of interest to me now."

      There are a large number of groups working on repair. We just need to keep things in perspective and not overhype repair claims. What is important is that when we use highly active treatment early on in the course of the disease a significant number notice spontaneous improvement; in other words spontaneous recovery occurs without any additional therapies. Hence the need to treat early and if possible to use highly-active treatments early.

      Delete
  4. Is this data robust, given the numbers involved?

    If so, are we saying that the UK's "let's wait 50 years and then try to work out how to treat MS" may not be in the person with MS's best interests?

    Would I be right or wrong in my impression that the UK has one of the most conservative approaches to the treatment of this disease in the entire western world?

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    1. Re: "Is this data robust, given the numbers involved?"

      Yes, it is robust. The study nearly had 100% case ascertainment. Death is also a very hard outcome and was confirmed in most subjects by looking at the death certificate.

      The be honest this is one of the best studies in the field. Well done to the team for completing it.

      Delete
    2. Re: "Would I be right or wrong in my impression that the UK has one of the most conservative approaches to the treatment of this disease in the entire western world?"

      Yes, almost the most conservative. In Europe we are 3rd from the bottom; only Poland and Romania did worse when it came to access to DMTs.

      Delete
  5. "81 deaths were recorded. Mean age-at-death was 51.7 (±8.7) years."

    Isn't it time to consider the fact that MS is a fatal disease? A number of these people were in their 40s. Doesn't seem to fit with the claim that life expectancy is only 8-10 years lower in people with MS.

    The MS neurology / MS research worlds should hang their heads in shame. Firstly, for not making any breakthrough in the last 60 years (I'm talking the basic stuff like identifying the cause / a cure, and secondly, for treating this disease as a minor illness with ineffective therapies, when it was actually a fatal / disabling / very life-shortening disease!

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    1. I have to agree with you that the effects of this disease have be woefully underplayed. It has done patients absolutely no good at all.

      If MS was a disease that caused its cognitive and physical disability suddenly rather than gradually it would be a different story - say if in a 65 year old it caused the same level of disability suddenly as an average 65 year old MSer has accumulated over the previous 30 years or so, a lot more would have been done about it. I know that I would far prefer to be in the sudden onset at 65 camp rather than being potentially miserable for years beforehand, but we can't choose this - unless the drugs really do work, and I would like to have that choice, though NICE/the NHS seem to want to deprive us of it.

      Delete
  6. I don't mind a bit of over-hype. Your commitment to the newly diagnosed / yet to be diagnose if commendable. I hope the early highly effective treatment deliver the goods for these patients. If only there was the equivalent of you for those with established disease i.e. those where highly effective treatments are not an option. What about a repair hard approach? The strategy is to give those with established disease the maximum chance of recovery of some deficits. Combo of neuroprotective agent, stem cell injection, and a drug which stimulates axon growth / remyelination. Oh, I forget,. The trials and licensing would take at least 15-20 years. If you ever get ill, make sure it doesn't fall within the remit of a neurologist!

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    1. Re: "The trials and licensing would take at least 15-20 years. If you ever get ill, make sure it doesn't fall within the remit of a neurologist!"

      Outside of HIV, cancer and some orphan diseases there are no short cuts when it comes to drug development. I do admit neurologists, in particular UK neurologists, are bit slow when it comes to adoption.

      Delete

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