Thursday, 16 July 2015

ClinicSpeak: trial of oral vs. intravenous steroids

Robbing Peter to pay Paul makes us all the poorer. #ClinicSpeak #MSBlog #MSResearch

"The following study below shows that treating MS relapses within 15 days of onset with high-dose oral methylprednisolone (MP) 1,000 mg x 3 days is not inferior to using the same dose intravenously. This is not surprising and confirms an earlier Danish Study showing MP 500 mg daily for 5 days was the same as 1,000 mg, or 1g, intravenously for 3 days. At Barts-MS we have been using the oral route in preference to the intravenous route for over a decade. We still use the IV route occasionally, for example if the person is an inpatient or if we are worried about the neuropsychiatric manifestations of steroids and want to assess the patient's mental state daily."

"Some facts about high-dose steroids for relapses. MP is not licensed for the treatment of relapses; they way we are using it is an off-label indication. All that high-dose MP does is speed-up the rate of recovery from a relapse and on average does not affect the final outcome of the relapse. In other words you will reach a recovery point ~14 days sooner with steroids compared to no steroids; however, at 6 months the outcome is similar whether or not you have received them or not. Please note high-dose steroids are not without side-effects and serious adverse events. We worry about hypertension, diabetes, acne, insomnia, weight gain, hypomania and mania. My biggest worry is avascular necrosis of the hip that is commoner than we realise. As I get older and accumulate more personal experience with AVN I get more conservative with the use of high-dose steroids. One of my latest is a patient who has bilateral AVN from steroid cover for his alemtuzumab infusions; he is in his early 30s and is will need bilateral total hip replacements."

"Interestingly, in a fee-for-service healthcare environment neurologists still prefer admitting MSers and using the IV route over the oral route; this way they can charge for seeing their patients daily and for the cost of giving an infusion. I am told this is the reason why infusion therapies do so well; you simply can't make enough money as a private neurologist unless you run a lucrative infusion service as well. I am told this is the main reason why Biogen canned their subcutaneous injection route for natalizumab. They have excellent data showing the same pharmacodynamics of the monthly subcutaneous route vs. the monthly intravenous route in terms of saturation of the binding sites of natalizumab on white blood cells and blood levels of the drug. I am told that market research data from the US indicated that neurologists would not be happy to see one of their revenue streams dry-up. Some neurologists in the US have so many MSers on natalizumab that they are referred to as the 'Tysabri Millionaires'. The same situation is occurring in the NHS; NHS Trusts make money from NHS England for giving infusions. The only difference in the NHS is that we are simply robbing Peter (NHS England) to pay Paul (Local NHS Trusts). No guessing who wants to maintain the status quo?"


Le Page et al. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients withmultiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. Lancet. 2015 Jun 26. pii: S0140-6736(15)61137-0. doi: 10.1016/S0140-6736(15)61137-0. [Epub ahead of print]

BACKGROUND: High doses of intravenous methylprednisolone are recommended to treat relapses in patients with multiple sclerosis, but can be inconvenient and expensive. We aimed to assess whether oral administration of high-dose methylprednisolone was non-inferior to intravenous administration.

METHODS: We did this multicentre, double-blind, randomised, controlled, non-inferiority trial at 13 centres for multiple sclerosis in France. We enrolled patients aged 18-55 years with relapsing-remitting multiple sclerosis who reported a relapse within the previous 15 days that caused an increase of at least one point in one or more scores on the Kurtzke Functional System Scale. With use of a computer-generated randomisation list and in blocks of four, we randomly assigned (1:1) patients to either oral or intravenous methylprednisolone, 1000 mg, once a day for 3 days. Patients, treating physicians and nurses, and data and outcome assessors were all masked to treatment allocation, which was achieved with the use of saline solution and placebo capsules. The primary endpoint was the proportion of patients who had improved by day 28 (decrease of at least one point in most affected score on Kurtzke Functional System Scale), without need for retreatment with corticosteroids, in the per-protocol population. The trial was powered to assess non-inferiority of oral compared with intravenous methylprednisolone with a predetermined non-inferiority margin of 15%. This trial is registered with ClinicalTrials.gov, number NCT00984984.

FINDINGS: Between Jan 29, 2008, and June 14, 2013, we screened 200 patients and enrolled 199. We randomly assigned 100 patients to oral methylprednisolone and 99 patients to intravenous methylprednisolone with a mean time from relapse onset to treatment of 7·0 days (SD 3·6) and 7·4 days (3·9), respectively. In the per-protocol population, 66 (81%) of 82 patients in the oral group and 72 (80%) of 90 patients in the intravenous group achieved the primary endpoint (absolute treatment difference 0·5%, 90% CI -9·5 to 10·4). Rates of adverse events were similar, but insomnia was more frequently reported in the oral group (77 [77%]) than in the intravenous group (63 [64%]).

INTERPRETATION: Oral administration of high-dose methylprednisolone for 3 days was not inferior to intravenous administration for improvement of disability scores 1 month after treatment and had a similar safety profile. This finding could have implications for access to treatment, patient comfort, and cost, but indication should always be properly considered by clinicians.

14 comments:

  1. Prof G, how many high dose steroid treatments does it take to experience bone problems. Is the risk the same oral or intravenous?

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    1. I'd like to know too, I haven't taken steroids more than 4 times in 20 years, but last 1 was by IV and since then I've developed bilateral hip pain that my GP doesn't think is arthritis etc!

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  2. This is a timely post - I'm just about to complete my final day of lemtrada (smooth sailing all the way so far) and methylpred has been given to me on all 5 days. Aside from this I've had no previous steroids.

    AVN hasn't been mentioned to me as a complication, is it something I should be pushing to have monitored? Or is it unlikely in the absence of previous steroid exposure?

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  3. Is there a correlation between steroid use and brain atrophy? I have taken oral steroids once before for my MS.

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  4. From the ONTT trial...

    "The investigators found that within the first two years, MS developed in 7.5 percent of the intravenous group, 14.7 percent of the oral corticosteroid group, and 16.7 of the placebo group.

    Moreover, participants with abnormal brain scans benefitted most from the intravenous corticosteroids. Thirty-six percent of patients in the placebo group who had two or more brain lesions developed MS within two years compared to 16 percent of those in the intravenous group."

    If I was having my first bout of optic neuritis, I'd be pretty keen to go for IV steroids if it offers a greater than 55% reduction in the probability of developing MS within 2 years, as indicated here.

    As to the question of IV vs oral:
    "The researchers also found that oral corticosteroids alone are ineffective in treating optic neuritis, and that treatment with these drugs can actually increase a person’s risk for future attacks of optic neuritis."

    Thoughts?

    Source: National Institute of Eye Heatlh, https://nei.nih.gov/news/pressreleases/onttpressrelease

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  5. Also, does the advice not to bother with steroids not go somewhat against your theory on the inflammatory penumbra? Surely the quicker you suppress inflammation, the better?

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    1. Matt, the question we are asking is does Prof G have any information on the use of steroids and bone health. We would probably still need them, but when we see our orthopaedic doctors we can present them with a better history.

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    2. Hey Anon.

      Cheers - hope Prof G provides the answers you need.

      I'm asking a very different question though, and I equally hope Prof G or MD will answer this, as it is important for CIS/MS'ers.

      Question is three-fold:

      1) The ONTT trial (well-respected, reasonably well powered, frequently referenced study) showed that IV steroids, taken on a first relapse of Optic Neuritis, reduce the probability of developing MS within 2 years by more than half. The flavour of the commentary provided in the original post is that there is no long-term benefit in taking IV steroids in most cases. This directly contradicts the conclusions of the ONTT study, so I'm interested on the Barts' team viewson this, and what data informs it. It's an important point as, if you have a first bout of ON, you'd read the above and think steroids are not worth the risk ("All that high-dose MP does is speed-up the rate of recovery from a relapse and on average does not affect the final outcome of the relapse" - Prof G). But in actual fact, by following that advice, you'd be effectively increasing your risk of developing MS in the next 2 years by more than 55% (according to the better powered ONTT study) - which is a massive jump in probability which presumably most patients would wish to avoid.

      2) The same study showed that oral corticosteroids (which Prof G is recommending over IV) are not effective in treating relapses of ON, and actually increase a person's risk of future attacks of ON. Again, if this is true, it needs to be made clear - because nobody wants another attack of ON (or a higher chance of developing MS in the next 2 years).

      3) The blog often talks of the importance of stopping inflammation early, and of getting in ahead of the inflammatory penumbra. If that is true, then presumably there is, in fact, a benefit of rapid access to IV steroids. The study quoted in the original post is for patients who've relapsed in the last 15 days. From the commentary on the LINGO trial, this is likely to be too late to impact nerve damage as it's missed the penumbra, so perhaps we need to be careful as to what conclusions are drawn from it.

      I'm not saying IV steroids are risk free, and I'm not saying Prof G is wrong (he's the expert). I'm just interested in the Barts' team philosophy on this, and what data informs it, as anyone reading the original article cold would deduce that IV steroids are risky, without any real benefit in most cases - which is teh polar opposite of what the ONTT data seem to suggest.

      As an MS patient myself, on the balance of the available data, if I had an attack of ON I would want IV steroids as soon as I could feasibly get to the hospital (though it would be good to understand the statistical risks associated with it).

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    3. Well argued comment but I am going to pass on answering this clinical question, I can not talk from experience in humans. The effect in animals is that if it stops attacks then it is limiting the accumulation of damage........and base on the penumbra I would argue that we should be doing more than just giving steroids if they are not controlling disease and this would be obvious test bed to see if phenytonin is reallyneuroprotecting.

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    4. I always push for steroids. None of my neuros have ever convinced me that the bone loss issue is as bad as me tripping and falling and then breaking bones without the steroids. Another case of robbing Peter (my long term bone health) to pay Paul (not tripping over my feet on the subway and hairline cracking my femur again.)

      Until I had MS, I had never so much as hairline fractured a finger.

      It would be nice to see a longitudinal study comparing bone loss v. fall risk in MSers using steroids. Normally not into such boring non-cure type studies, but I'd volunteer for it if you could use Americans.

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    5. I resisted steroids unless I thought there was no other answer. I've had a couple of intravenous high dose Prednisolone, ACTH and oral steroids. I had not gone through the menopause until my fifties. I have osteoporosis in my vertebrae and hips. I don't know if there is any connection. I now have SPMS and I'm falling over and ended up having xrays to see the damage done. Taking steroids does not stop you falling over. I'm due to go to get treatment on Saturday for a nasty shoulder injury. We need to know if there is a connection, that's not saying we stop using steroids.

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  6. Wow this post raises all sorts of ethical questions. Fascinating really. I remember thinking the branded bag covering my infusion slightly distasteful at the time. The term cash cow came to my mind albeit I remain a grateful one.

    Re steroids, I'm not a fan. I always feel out of sorts while on them.

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  7. I'm curious about ACTH as an alternative to steroids. Why is this not offered with the NHS for relapses? Well it's never been offered to me and I have a very hard time on steroids. Is it cost?

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    1. I was on ACTH in the 70s for two weeks. It is a steroid and it comes with all the side effects, I won't name them, but not nice.

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