Falsification of evidence on some NOACs

I was reading John Mandrola's latest post, which is on trust in science and medical experts, see


He refers to falsification of evidence in clinical trials. I looked up the original paper:


and this mentions two of the new anti-coags, Apixaban (Eliquis) and Rivaroxaban (Xarelto).

With Rivaroxaban, the FDA inspections apparently uncovered evidence of various transgressions, such as “systemic discarding of medical records,” unauthorized unblinding, falsification, and “concerns regarding improprieties in randomization.”

With Apixaban it was found that a clinical site in China taking part in a large trial of the drug had apparently altered patient records. If data from the patients at that site was excluded, the claim of a statistically significant mortality benefit disappeared. For this reason, among others, the FDA wrestled with whether it was appropriate to allow the manufacturer to claim a mortality benefit. None of this discussion appears in the literature. The claim for the mortality benefit, which has appeared in the literature since 2011 consistently relies on the full data set, including data from the site at which the research misconduct allegedly occurred.

There's so much money to be made out of new drugs, particularly the NOACs which people tend to remain on for life, I do wonder whether there isn't a requirement for more independent trials.

I'm not sure it would necessarily change the recommendations, but I'd like to know whether NICE were aware of this evidence before they made their recommendations on the NOACs. Perhaps this is something the AFA can investigate. We have to have confidence that the drugs regime operates in our favour, not that of Big Pharma.

26 Replies

  • I agree its a minefield.

  • Always remember - money doesn't talk, it swears. :(

  • Thanks for this very informative post. It will be interesting to see how advocates of apixaban respond, and whether such transgressions in science have been uncovered in the evaluation of other drugs for atrial fibrillation and stroke.

  • will be following this post! thank you

  • Profit over people rearing it's ugly head again!

  • I agree that drug trials should always be controlled by an independant body but do remember that trials are administered by doctors. Of course any massaging of statistics, intentional or accidental ISO be deplored.

    I worked for a drug company and it is the data the doctors submit that the companies use in their results. What used to happen, in the UK, is that the marketing budget was very large, approximately £10K per consultant, for sponsoring medical conventions, often in exotic resorts. That was in the 80's and 90's.

    My understanding is that the ethics of medical trials has somewhat improved at the same time as the marketing budgets have drastically reduced for pure economic reasons.

    It is very easy to condemn but what would you suggest instead? How would you finance trials? How would you finance R&D? Who would you make responsible for controlling trials?

    I do not see all drug companies as the nasty, greedy money grabbers they are often portrayed as, at the moment we need drug companies to make money in order to invest in research. The lack of new anti-biotics because they are a drug which people do not take long term is a case in point. I do however, have a strong moral reaction to the overcharging for basic drugs and the 'massaging' of the medical professions by excellent marketing techniques by the drug companies. I think more prevalent in the US than in the UK, and that is mainly due to the NHS and NICE.

    And I deplore unethical practice!

    As a sufferer of a rare, chronic condition I would love to believe there might, eventually be a cure rather than a treatment, but that isn't going to be in the interest of drug companies isit? Yet there is research going on in Europe (not UK) and in US, both are starting trials hopefully this year which will involve a course of 3 injections, if it works that is it! It is sponsored by a consortium of academic institutions, drug companies (plural) and charities.

    It is a a complicated and emotive issue and it wasn't until we had the Internet and were able to gain access to all these studies that we have become aware of these issues, so maybe it will also be the instrument of change as I think we are all much more cautious and suspicious than we were 20 years ago. But let's face I for one would say yes to anyone holding the golden pill saying 'take this and no more disease'.

    Sorry for long post, got into reflective mode.

  • That's a very good post, CDreamer and you raise some interesting points.

    The concern I have is that I see the same old names coming up all the time in trials. They are paid by the drugs companies, they run the trials and if there's any dissent in medical literature they immediately come down hard on the dissenter. I get the feeling that doctors who want to get on these very lucrative trials have to play along and promote the drugs so they are "seen to be on-side".

    I feel that the trials themselves are engineered to provide the required result. For instance in the trials of the NOACs, there was no comparison to extremely well controlled warfarin (TTR > 90%), because the results would not have been favourable.

    As Dr John says, Cochrane Collaboration researchers discovered in 2012 that industry-sponsored clinical trials produced favorable results more often than independent studies.

    Another suggestion is that all trials, favourable and unfavourable, are published. Most trials, particularly unfavourable, do not get published. This would help reduce the cost of research at drugs companies.

    A possible answer is an independent body that is paid for by the drugs companies themselves. Trials cost a huge amount of money anyway, so instead of a drugs company paying and running trials themselves, the independent body would be paid to do the same. An alternative would be an independent body to appoint staff to trials and oversee the results and publication.

    Don't get me wrong, I'm not against drugs companies per se, just against some of the practices and conflicts of interest that exist. I think resolving these would benefit everyone, not least drugs companies themselves who could see reduction in the cost of R&D.

  • Agree with everything you said, it really comes down to the motivation and the intent of the people who work in these organisations and unfortunately they are not always in the interest of the majority.

  • This is very similar to the discussion that's been going on about sugar in the last few days where it has been alleged that the industry has been attempting to influence scientists and the medical profession. Very difficult for the layman to know who to trust.

  • Absolutely, but don't ignore the power of voicing our concerns, it really does help to change things.

  • Some months ago, there was a post and following thread along the lines that most people are OK on warfarin and that the demand for NOACs was an invention of the drug companies. Moreover, because the NOACs are more expensive, we should all put up with warfarin.

    I read and understand all (most of) the above but I would be very reluctant to take a retrograde step back to a drug that didn't suit me in many ways.

    This sort of thing has been going on for years. As an ex-medical secretary of 40+ years ago, I remember that medical reps were always trying to get to see the consultants and sending them free gifts.

    It needs a few whistleblowers but sadly there is news just this week about what happens to those in the NHS.

  • I think it's fair enough that you should stay with your NOAC. Some people like myself do very well on warfarin, others like you do less well and an NOAC is a good development for you.

    What concerns me is that some NOAC supporters are saying everyone should be on them, which I don't believe to be true. I believe the effectiveness of an anti-coagulant is all about control of the level of the drug in the body. The NOACs have the advantage that there is less variability from diet etc. Warfarin has the advantage that it's effectiveness can be easily measured, unlike the NOACs. The balance is shifted towards the NOAC for you as you are not stable on warfarin. The effectiveness is shifted towards warfarin for me as I am so stable.

    The one thing that would shift the balance towards the NOACs is if they develop a simple measure of their effectiveness for individuals along the lines of a Coaguchek monitor.

    On your second point, my father was and my wife is a doctor so I have seen first hand the work of the drugs reps. I am surrounded by pens and pads for this, that and the other. But the falsification of data in trials is in a different category altogether, it's effectively stealing money from us on false pretences. Hopefully NHS whistleblowers will get better protection in the future.

  • One of the things that comes out time and time again on this forum is that what suits one patient doesn't suit another, so ideally there should always be a choice of treatments.

    ACs are odd in some ways as unlike many medications, they are not a cure and don't even alleviate any symptoms. Like many people, I was on aspirin for many years and never had a stroke. Maybe I was lucky. But then I was assessed as low risk anyway.

    Lack of measurement doesn't worry me, just as it didn't when I was on aspirin. NOACs have only been around for a few years so there isn't a great body of evidence about their efficacy. However, I haven't heard many, if any, stories of people having strokes using them.

    I don't have scientific training but my understanding is that because of the way NOACs work in the body, measurement of effectiveness isn't possible in the same way that it is for warfarin. Indeed, the lack of need for constant checking is one of the main attractions for NOACs. I know there is at least one doctor at my surgery who will not prescribe NOACs because of the lack of measurement.

    Agree that falsifying data is in a different category, if indeed this is what happened.However, I would hate to think that there was any underlying motive to push us all back to warfarin. I might have to disagree with you on this one as I think that NOACs with all the freedoms involved are the way forward. Even if I had been stable on Warfarin, I would have been pushing for something else.

  • You're right that one of the apparent advantages of NOACs is that they don't need constant monitoring. However controversial research from the makers of dabigatran have shown that the level in the body can vary as much as 5 fold. This research was apparently hushed up and is at the centre of court cases in the States of people suing the manufacturers after they got strokes.

    I don't think there was any motive to push people back onto warfarin. Indeed I understand the falsification of the data was to improve the apparent performance of the NOAC against warfarin.

    I'm not sure I agree about your point on greater freedom with NOACs. For some people that is the case. However on warfarin I eat what I want, and I have a very varied diet. I have stoped the hazardous activity I used to do (hockey) but I'd have had to do that on the NOACs anyway. I don't see any advantage to the NOACs over warfarin. Indeed for me warfarin has a number of advantages such as if I forget a dose I can just take it when I remember, it can be tested so that I can ensure it is optimally in range, I have a stroke risk less than the NOACs, I don't have to stop it for any minor procedures and it can be reversed rapidly.

    However, as you say, it's horses for courses and for this particular horse, warfarin's currently the best!

  • Mm. One of the things that worries me about warfarin is the need to vary dose to achieve INR in desirable range. One hears of people on huge doses and yet we are told that it doesn't matter, only the INR matters. Doesn't seem right to me - on a par with people having huge concentrations of Dabigatran. Presumably if the Dabigatran level was measured, it would not necessarily equate to how efficient it was at preventing strokes in an individual, just as is the case with warfarin.

    Another problem with Warfarin is that in many people, INR levels change quite quickly. If INR testing is infrequent, someone can be out of range for quite a long period.

    This started out as a discussion about scientists allegedly falsifying evidence. Reading to the bottom of the article, the FDA criticises its own role in supervising some drugs trials. Scientists work largely by a system of peer review. They assume that the rest of us are incapable of understanding their work and I'm afraid that some doctors are guilty of this too.

    As a layman, there seem to be two key things: that all methods of AC should carry the same stroke prevention/bleeding risk (given that this may vary between individuals) and that no harm is done in respect of effects on the body. Not enough attention has been given to this latter point in my opinion.

    Glad that there is no hidden agenda to push us all back to warfarin! Just as a matter of interest, I would quite like to know if there are many people who choose to go back to warfarin after being on NOAC and how many are now being offered NOACS as a first choice?

  • Not so with the dose. With warfarin you actually measure it's effectiveness in stopping clots forming directly. For instance with an INR of 2, that means blood takes twice as long to clot. You can't do that with the NOACs.

    The amount of warfarin you take is irrelevant. So someone with a larger than average dose might take 15 mg. But you take 150mg twice daily with dabigatran! But if you're older you only take 75mg! On the other hand you take 10mg p.d. of Apixaban. It doesn't matter what the dose is, it how it affects you individually that matters.

    I agree about doctors assuming that ordinary mortals don't have sufficient comprehension to understand their work. It's arrogance which comes in all fields requiring specialist knowledge - I've seen it in my own sphere.

    I'd like to know the answer to your final question!

  • I don't think the amount of a drug you take can ever be irrelevant. You can't compare say 10 mg of one drug with 10 mg of something completely different.

    Warfarin has a much larger number of interactions with other drugs than NOACs. When I was prescribed Warfarin, I was even told that it didn't really go with two other drugs that I was taking but that I should take it anyway. There's more than INR to be considered.

  • But at least you know there's an inreaction with warfarin. It's been around such a long time that any interactions are known about and can be easily measured. The NOACs just haven't been around long enough to find out all the interactions, and in any case you wouldn't know if there was an interaction anyway as you can't measure it!

    But we seem to have got totally off topic, I think we'll just have to agree to disagree about warfarin, though we do agree that something needs doing about drug development to make it more transparent and in the best interests of patients.

  • My Doctor did not prescribe anything initially as she wanted the EP to decide which of the NOACs to use (as she believed he would want NOACs rather than Warfarin). Saw the EP the next week and he said to have Apixaban (5mg twice per day). That was in September 2014. In November had a cardioversion and achieved NSR for about 10 days before reverting back to persistent AF (24/7). In the first week of January was changed over to Warfarin in preparation for having a catheter ablation. The dose seems to be a regular topic and I am having 2mg Sat and Sun and 3mg the rest of the week (I am 6ft). My INR is swinging from 4.4 to 1.8 - last week 3.1 so far from stable after 6 weeks!!!

  • Hi Mark

    I have just, belatedly, caught up with your post.

    I have a lot of time for NICE. In my opinion they take great care in their evaluation of drugs before approval (or rejection). My local CCG has been refusing the use of NOACs for the past twelve months and as a consequence I studied all documents in the NICE appraisal and was very impressed with the scope of their evaluation. Many outside bodies were consulted during the evaluation.

    Eventually my CCG capitulated and agreed that patients choice of drug should be paramount once all the pros and cons of each drug has been looked at. We have to remember that it is usually the patient who decides.

    We should also remember that around 10 years of trials have taken place prior to approval and, in general, the drug companies do us proud -where would we be without them? Should we still carry on with a drug that has been on the market for 40 years when new better (or equal) medication is available? There are diatery restrictions with Warfarin despite some people stating otherwise.

    I will acknowledge that there is some degree of risk with new drugs but simply to say that because a drug has been on the market for 40 years it should continue to be used does not, to me, make much sense.

    Lets always remember that patients have the final choice and there is a wealth of information out there both from professionals (I had several discussions with my EP and haematologist) and search engines such as Google.

    Take care

  • Hi Bridges4,

    Thanks for your well thought out reply. I fully agree that we need the drugs companies to develop new drugs. I also agree that warfarin needs a replacement. What I'm not so sure about is that the NOACs are as good as they could be. I think you're right, they're roughly on a par with warfarin, better in some circumstances and worse in others.

    I remember back to when I first heard about them. I was very excitied and thought they would be overwelmingly better. In the event I've stuck with warfarin as better the devil you know. NOACs could be better if they had monitoring as warfarin does. But that would remove their major selling point, that they don't need monitoring!

    I've worked in Financial Services for the last 30 odd years and I've seen dramatic changes in that time in standards, compliance, risk analysis and treating customers fairly. The apparent evidence I outlined above about fraudulent trial results, lack of transparency and lack of care for clients indicates that the drugs companies still have a way to go.


  • I'm late to this post, but want to add my two cents on this topic.

    At one point during my treatment, I was advised by my cardiologist, "Warfarin is difficult for a patient to manage, and it requires a ton of testing. Best to go with Eliquis because it is easy." My EP agreed.

    After being on it for several months, I started to have repeated nose bleeds. They told me not to worry because they were treatable. Then my eye started to bleed. Then I had "other" bleeding, which I'd rather not describe because it was graphic and quite scary.

    Headed to the hospital because I couldn't control it. Found out there was NO antidote! I just had to bleed until the drug left my system. They NEVER told me that was possible!

    I'm off Eliquis, but they put me on 325 mg of aspirin a day and nothing else. After reading posts and getting advice from others (thanks Bob and Mark), I'm going to talk to my EP about warfarin.

    I need to know that I have some protection against clots and stroke, but I am not comfortable using drugs for which there is no antidote. Therefore, warfarin seems to be the better choice for me.

    Again...just my two cents.

  • It's funny you mention that because I've had some slight nose bleeds while on Eliquis.Usually in the morning and while exercising. I thought maybe it was the weather or dryness in my house. My bleeding is nothing compared to what you've been through. I've mentioned this to both my cardiologist and my EP. Both of them said nothing about it at all.My understanding is this is a side effect of the drug and should be reported to the physician. So I did and what happened.Nothing!!

  • The ER doc was upset that my doc did not take me off eliquis when the nosebleeds began. It can cause significant internal bleeding in some folks. I'm still not sure what my plan should be because my favorite foods are fresh spinach and grapefruit and those might be a problem with warfarin. So confusing!

  • I take Vit K2 which stabilises my INR and means I can eat pretty much what I want. In the last week I've been working in Edinburgh and Aberdeen. I had French one night, Turkish/Kurdish another with a spinach accompaniment and Korean the final night, plus plenty of broccoli since then, plus grapefruit and muesli for breakfast. I use a Coaguchek monitor so I can see exactly what's happening, my INR yesterday was 2.6. So warfarin doesn't have to mean a boring diet. But as PeterWh says, some people can't stabilise on warfarin.

  • If you have the same amount of spinach each day then it probably won't matter about being on warfarin. However if you end up being very sensitive to warfarin as I am then it might. Giving up some things for health reasons is I believe a minor irritation rather than making things worse

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