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?”
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.