Deans' stroke musings

Changing stroke rehab and research worldwide now.Time is Brain!Just think of all the trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 493 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It's quite disgusting that this information is not available from every stroke association and doctors group.
My back ground story is here:

Thursday, March 2, 2017

Masters of Neurology: Avoiding MS Treatment Failure

Where is the exact same CME for stroke, since stroke rehab is a complete failure at 10% full recovery? Or is your neurologist and stroke hospital OK with that fucking 90% failure rate? And doing nothing to get better resaults? MS got from 90% disability in the 90s to being able to prevent lots of disability today. If MS can do this, stroke can do it also. It will require leadership and a stroke strategy.
Timothy Vollmer, MD, on treatment failure rates among first- and second-generation MS drugs

Timothy Vollmer, MD, of the University of Colorado Anschutz Medical Campus, spoke with MedPage Today at the European Committee for Treatment and Research in Multiple Sclerosis annual meeting in September, where he presented several posters on treatment failure rates for first- and second-generation disease-modifying drugs in MS. Two full posters may be downloaded by clicking here and here.
Following is a transcript of his remarks.
The issue that led to these reports was a concept that we've been working on for a number of years called "Maximizing Lifelong Brain Health in MS." By that, we mean using these disease-modifying therapies to try to minimize injury in the brain as early in the disease course as we can, as well as helping patients to adopt a healthy lifestyle such as a good, healthy diet to avoid diabetes, hypertension, and other diseases that further increase disability in MS and also to help them adopt an active lifestyle because we know that exercise improves function in multiple sclerosis.
This concept of maximizing lifelong brain health comes out of a growing concept called "neurological reserve." In multiple sclerosis, about 90% of new lesion formation in the brain is actually clinically silent at the time that it occurs. The brain is compensating for this injury, and the injury actually is leading to not only demyelination, but also loss of neurons and accelerated shrinkage of the brain, or loss of brain volume.
The ability of the brain to compensate for that injury, that subclinical injury where the patient actually feels like they're functioning normally and they don't notice any loss in function, is neurological reserve.
The capacity to compensate for subclinical injury, however, is limited and there's a growing consensus in the field that the cause of the progressive phase of MS actually may be the point where the brain has used up that neurological reserve and now it doesn't have neurological reserve to buffer for the subclinical disease activity. At that point, it's also unmasked by the effects of aging. We begin to have our brain shrink, all of us, at around age 35, and yet we don't notice the effects of aging usually until later in life. So preserving brain volume in early disease for MS patients is not only important for the MS disability. It's also important to minimize the age-related changes that we're all going to suffer as we go forward.
We now have 14 FDA-approved disease-modifying therapies, therapies that can decrease the inflammatory attack on the brain and potentially decrease disability and relapses. We're going to have a 15th drug approved presumably in the next few months called ocrelizumab.
So in thinking about these 15 drugs as we go forward, it's important to use terminology that we can all share so we understand what we're talking about. So to do this, I propose that we consider the early therapies as the first-generation, first-line drugs. These are a half dozen agents or so that were approved by the FDA for first-line use. Of course, the early ones were the interferons that included Betaseron, Avonex, Rebif, Plegridy. Then obviously, the glatiramer acetates, Copaxone and Glatopa.
We also placed in this category teriflunomide or Aubagio, because it has very similar effects on efficacy and similar tolerability issues. So that's the first-generation drugs. They began to emerge in the early 1990s, and most were in the marketplace by the early 2000s.
More recently, though, there's been another class of first-line drugs that are referred to as the second-generation drugs that have been increasing their marketshare throughout the world. This includes dimethyl fumarate, which is Tecfidera. Fingolimod, which is Gilenya, and natalizumab, which is Tysabri. Ocrelizumab, which will be called Ocrevus, I believe, will be the fourth member of the second-generation, first-line drugs.
There is a third group of drugs that's really important for us to understand where they fit, and these are the third-line agents as approved by the FDA. In the United States, there's alemtuzumab, which is called Lemtrada, daclizumab, which is Zinbryta, and mitoxantrone, all approved for use in MS, but they're considered drugs to be used only when patients have failed multiple other first-line drugs. So these are not the drugs that we're talking about today. We're talking about the first-generation and the second-generation first-line drugs.
The question that we were trying to address is identifying strategies that allow you to do a better job of selecting the right disease-modifying therapy for the individual patient to try to minimize progression of disease, also minimize tolerability and safety issues, and to avoid treatment failure.
Focus on Second-Generation Drugs
So, in thinking about this particular problem, though, we already have a lot of data that has shown that, in general, the second-generation first-line drugs are superior to the first generation. So that's not really a key question in modern medicine today. The key question is distinguishing between those members of the second-generation disease-modifying therapies, and as a result, we've been looking back at our experience with these agents -- which has been substantial over the last eight years -- and looking at their outcomes.
So we looked at a treatment failure definition, which means that the patient discontinued one of these four agents in the second-generation group either because of lack of efficacy, safety issues, or tolerability issues, or any other issue that took them off the drug. We looked out to a little less than three years of follow up in over 200 patients per group.
What we found was that in one abstract we presented the comparison of natalizumab (Tysabri) to fingolimod (Gilenya) and dimethyl fumarate (Tecfidera). What we found is, in general, the treatment failure rate of patients on Tysabri was actually pretty high. It was in the mid-20s, and most of those were related to safety issues with the patients developing evidence of an infection of the virus called JC Virus, which can cause a very serious brain infection in patients on Tysabri. If we looked at discontinuations for Tysabri that were not related to the development of JC positivity, then the treatment failure rate was around 10% or a little bit less.
For Gilenya or fingolimod, the discontinuation rate was also in the mid-20s, and that was for a combination of factors. It included lack of efficacy, but also some tolerability issues and some access issues. But again, the treatment failure rate over two years roughly was about 22%.
Then with dimethyl fumarate or Tecfidera, the treatment failure rate was even higher, between 27% to 35% depending on exactly how you measured it. Again, it was a mixture of factors that led to discontinuation of the treatment, but the main one was actually tolerability. Patients were discontinuing the medication because of the side effect profile.
This is an important issue for us as we move forward, because from a medical, cost-effective standpoint, the discontinuation of these very expensive medications after a year or two is basically a lost opportunity. These drugs cost around $70,000 in average wholesale price per year, per patient. There's a substantial investment by the American healthcare system in these drugs, and we're trying to identify best strategies to minimize the sort of wasted investment in a drug that patients are not going to remain on.
Benefits of Infusions
We're continuing this work and looking, again, at a group of drugs that include ocrelizumab, which are called the anti-CD20 monoclonal antibodies. This is a class of drugs that have actually been around since 1996, when rituximab first emerged for use in lymphomas, rheumatoid arthritis, and lupus. We've used this drug extensively in MS as well, both here and in Sweden. Ocrelizumab is a newer version of rituximab and we hope will be approved by the FDA within the next few months.
This class of drugs is a little bit different than the other three classes I've talked about. So Gilenya and Tecfidera are oral medications. Gilenya is taken once a day as an oral tablet. Tecfidera is taken twice a day as two capsules. Tysabri or natalizumab is a once-a-month IV infusion. Then ocrelizumab and rituximab are twice-a-year IV infusion.
We're trying to address the issues of safety and efficacy, because there actually is significant, comparative data on these drugs in that sense, but we also want to look at patient tolerability. What are the aspects of the use of these agents that patients really find attractive?
Our experience to date, although we haven't published this yet, is that the twice-a-year IV infusions are actually very acceptable to patients. Part of the reason is that even taking oral medication once a day has a downside. One is just remembering to do it on a day-to-day basis when you have a busy lifestyle, but the other issue is for many of our patients, taking that pill reminds them that they have MS on a daily basis and that adds to their stress that they experience during the day.
So Tysabri or natalizumab is attractive to patients. They only deal with it once a month. It's a highly effective drug, and outside of the JC issue associated with this infection of the brain called PML, it is a very tolerable drug. In general, our patients who are on that drug prefer that over the orals. That might even be more so with the anti-CD20s, rituximab and ocrelizumab, where it's only twice a year.
It actually leads to a possibility in the treatment of MS where for patients who have little disability that are treated early in the disease course maybe only have to deal with the disease twice a year. They come in. They see us. We do the safety assessments. They get their infusion and they're basically done for six months.
So this is a potential revolution in the treatment of MS. We've moved from a disease in the early 1990s that had a chance of disabling a patient between 70% and 90% in terms of significant disability, life-altering disability, to an era where we now have 15 agents, several of which are highly effective agents, and may be able to completely prevent disability progression in the majority of patients.
If we can figure out how to use these drugs in the optimal way, we can potentially and dramatically improve health outcomes. We want to decrease health-related costs, and improve the cost effectiveness of the way that we use these drugs in general clinical practice.
Best Supportive Care
Our role in the disease is primarily supportive, how to treat symptoms the best we can, try to support the patients as they move through the different disability stages that occur in MS. In 1993, interferon beta was approved, interferon beta-1b, which is Betaseron, and that began the modern treatment era. Those therapies were very important advances, but they only had a modest impact on the disease course, about a 30% reduction in attacks, MS attacks per year and a relatively modest effect from disability progression.
But since then, we've had, as I said, now approaching 15 therapies approved in this space, and they vary widely in terms of their effectiveness, their tolerability, and their safety profiles. So treating MS right now is relatively complex because you have to know a lot about the therapies and a lot about the risk factors associated with those therapies to be able to select the best agent for the individual patient that maximizes safety and also maximizes efficacy.
In the world right now, the treatment of MS is quite random. It's unfortunate because there's undoubtedly better strategies embedded in there that if we understood them we could use them to improve outcomes and decrease health-related costs.
The area that I've been active in is trying to help the world to understand that escalation therapy, which is the generally mandated approach to MS, is not the optimal strategy. By escalation therapy, I mean that in the United States, as well as in most other countries, the healthcare systems actually enforce on physicians a need to use the older therapies first and wait for patients to fail those therapies before they're allowed to use the newer-generation drugs.
I'm not really quite sure why they think that is important. Because if you actually look at the data, the newer drugs are just as safe, if not safer. They're better tolerated and they're more effective. But nevertheless in the United States, 58% of all patients that are on a disease-modifying therapy are on that first generation of drugs. Unfortunately, those drugs have very little impact on rate of new lesion formation and rate of brain volume loss.
The reason I mention rate of brain volume loss is because how fast you're losing brain volume in early life is a very strong predictor of how much disability you're going to have in later life. So my patients truly understand that losing brain volume is not a good thing, and yet the first-generation therapies have a very minor effect on that particular aspect of the disease.
So we've been discussing the strategy of optimizing therapy by evaluating the patient for risk factors for adverse events related to therapies, and then using that to select the best therapy in the second-generation drugs to minimize further disease activity and try to maximize outcomes, in other words, maximize lifelong brain health in these patients.
That's beginning to catch on in the world. There's more centers that treat patients the way we do, and it's being discussed at the national and the international levels and the professional associations. I think that over the next four or five years we'll be going through a major revolution, just like we did rheumatoid arthritis and diabetes where they learned to treat early with highly effective therapies to really have a big impact on the disease ultimately for everybody's sake.
Pivot Point in MS
I think we're at a pivot point in MS, which is potentially revolutionary because it has the potential for fundamentally changing what's going to happen to the next generation of patients who develop MS. In our experience here at the Rocky Mountain MS and at the University of Colorado, we have over 3,000 patients. We have 10 clinicians and we all treat the same way. We follow algorithms based on the data to identify the best treatment for an individual patient based on their biological characteristics.
We've been doing this for eight years. Our patients that we catch in very early disease, which is newly diagnosed patients, if we put them on these second-generation, highly effective therapies, it's very common for them to come back after a year or two and say they don't feel like they have MS anymore, and we don't see any evidence of the MS progression on the MRI, and most of their symptoms, particularly the most common symptoms – which are fatigue, depression, and cognitive problems – tend to resolve in these patients.
Those symptoms seem to be related to inflammation. So we have a lot of evidence right now that's really suggesting that for the majority of patients, if we can treat them early enough with the right one of these second-generation drugs to maximize safety, we really can potentially fundamentally change the course of the disease where they don't have to anticipate disability in the future. They can anticipate living a normal life and doing normal things. So MS is probably the most treatable neurological disease in neurology today because of these advances that we've had over the last 20 years.
For a description of this CME program, please click here.
Vollmer disclosed financial relationships with Acorda, Biogen, Novartis, Questcor, Teva, Sanofi, XenoPort, Daiichi Sankyo, EMD Serono, Genzyme, Jensen Research, Eli Lilly, Ono Pharmaceuticals, Orasi Software, and Roche.

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