Tuesday, September 15, 2009

Plavix (clopidogrel), step aside, and prasugrel (Effient), watch your back: Ticagrelor proves that some "me-too" drugs are truly superior

Another breakthrough is reported in last week's NEJM: http://content.nejm.org/cgi/content/abstract/361/11/1045 . Wallentin et al report the results of the PLATO trial showing that ticagrelor, a new reversible inhibitor of P2Y12 is superior to Plavix in just about every imaginable way. Moreover, when you compare the results of this trial to the trial of prasugrel (Effient, recently approved, about which I blogged here: http://medicalevidence.blogspot.com/2007/11/plavix-defeated-prasugrel-is-superior.html ), it appears that ticagrelor is going to be preferable to prasugrel in at least 2 ways: 1.) a larger population can benefit (AMI versus just patients undergoing PCI); and 2.) less bleeding, which may be a result of reversible rather than irreversible inhibition of P2Y12.

I will rarely be using either of these drugs or Plavix because I rarely treat AMI or patients undergoing PCI. My interest in this trial and that of prasugrel stems from the fact that in the cases of these two agents, the sponsoring company indeed succeeded in making what is in essence a "me-too" drug that is superior to an earlier-to-market agent(s). They did not monkey around with this non-inferiority trial crap like anidulafungin and gefitinib and just about every antihypertensive that has come to market in the past 10 years, they actually took Plavix to task and beat it, legitimately. For this, and for the sheer size of the trial and its superb design, they deserve to be commended.

One take-home message here, and from other posts on this blog is "beware the non-inferiority trial". There are a number of reasons that a company will choose to do a non-inferiority trial (NIT) rather than a superiority trial. First, as in the last post (http://medicalevidence.blogspot.com/2009/09/theres-no-such-thing-as-free-lunch.html ) running a NIT often allows you to have your cake and eat it too - you can make it easy to claim non-inferiority (wide delta) AND make the criterion for superiority (of your agent) more lenient than the inferiority criterion, a conspicuous asymmetry that just ruffles my feathers again and again. Second, you don't run the risk of people saying after the fact "that stuff doesn't work," even though absence of evidence does not constitute evidence of absence. Third, you have great latitude with delta in a NIT and that's appealing from a sample size standpoint. Fourth, you don't actually have to have a better product which might not even be your goal, which is rather to get market share for an essentially identical product. Fifth, maybe you can't recruit enough patients to do a superiority trial. The ticagrelor trial recruited over 18,000 patients. You can look at this in two ways. One is that the difference they're trying to demonstrate is quite small, so what does it matter to you? (If you take this view, you should be especially dismissive of NITs, since they're not trying to show any difference at all.) The other is that if you can recruit 18,000 patients into a trial, even a multinational trial, the problem that is being treated must be quite prevalent, and thus the opportunity for impact from a superior treatment, even one with a small advantage, is much greater. It is much easier and more likely, in a given period of time, to treat 50 acute MIs and save a life with ticagrelor (compared to Plavix - NNT=50=[1/0.02]) than it is to find 8 patients with invasive candidiasis and treat them with anidulafungin (compared to fluconazole; [1/.12~8]; see Reboli et al: http://content.nejm.org/cgi/reprint/356/24/2472.pdf ), and in that latter case, you're not saving one life but rather just preventing a treatment failure. Thus, compared to anidulafungin, with its limited scope of application and limited impact, a drug like ticagrelor has much more public health impact. You should simply pay more attention to larger trials, there's more likely to be something important going on there. By inference, the conditions they are treating are likely to be a "bigger deal".

Of course, perhaps I'm giving the industry too much credit in the cases of prasugrel and ticagrelor. Did they really have much of a choice? Probably not. Generally, when you do a non-inferiority trial, you try to show non-inferiority and also something like preferable dosing schedules, reduced cost or side effects. That way, when the trial is done (if you have shown non-inferiority), you can say, "yeah, they have basically the same effect on xyz, but my drug has better [side effects, dosing, etc.]". Because of the enhanced potency of prasugrel and ticagrelor, they knew there would be more bleeding and that this would cause alarm. So they needed to show improved mortality (or similar) to show that that bleeding cost is worth paying. Regardless, it is refreshing to see that the industry is indeed designing drugs with demonstrable benefits over existing agents. I am highly confident that the FDA will find ticagrelor to be approvable, and I wager that it will quickly supplant prasugrel. I also wager that when clopidogrel goes generic (soon), it will be a boon for patients who can know that they are sacrificing very little (2% efficacy compared to ticagrelor of prasugrel) for a large cost savings. For most people, this trade-off will be well worth it. For those fortunate enough to have insurance or another way of paying for ticagrelor, more power to them.


  1. As a patient who is also very concerned with health care costs, I wonder how you, as a physician, decide what to prescribe in a case like this.

    The New England Journal of Medicine article termed the difference between Ticagrelor and Plavix "significant," although I read that as meaning that there was a "statistically" significant difference, not that it was a difference that would be significant in terms of treatment.

    Is a 2% difference in efficacy enough medically to warrant writing scripts for Ticagrelor versus generic clopidogrel given what will undoubtedly be a major cost difference, REGARDLESS of whether the patient has insurance or not?

    From a public policy perspective, should insurance pay for a much more expensive drug which has a 2% greater efficacy in a single, albeit large, study?

    I would argue, both as a patient and someone concerned with the public policy of health care, that a 2% difference is not enough to warrant paying a what is likely to be a truly "significant" difference in price and as a matter of policy, physicians, insurance companies and public health care funding agencies should not script or pay for drugs with so little difference.

    In terms of "choice," I have no problem with anyone buying the more expensive drug using their own money, but think physicians, insurance and governmental agencies should not treat a 2% difference as being sufficient to warrant a major price difference.

    Just my opinion.

  2. Mr, Murray -

    Thanks for your comments.

    You do beg the question of what difference WOULD be clinically significant enough to warrant prescribing a more expensive drug.

    When you have put a number to that difference, would you mind providing examples of therapies that have achieved a difference as great or greater than that which you numbered?

    After you run this exercise, I think you might find that 2% is not so meager as you suggest, at least on a relative scale. And if you continue to believe that it is, you may be compelled to forego many if not most therapies in modern medicine.

    Note also that, from an economic perspective, it is not just the probability (2%) but also the value (mortality, decrease in symptoms, etc) that counts when trying to determine the utility of a therapy.

    Thanks again for your comments.


  3. While I think I understand your response, even for high value, ie, mortality, outcomes, I would still think that a 2% absolute difference in outcomes probably doesn't warrant a substantial price difference, at least for those like me with Scotish blood. I would certainly pay more than the 2% price difference. Probably 10%, or the 16% represented by the improvement in odds ratio, but there is an upper threshold even when the value is improved mortality.

    To me, 2% may well be noise, even if it is statistically significant. I would think it less likely that say a 10% difference is the result of some undetected confounding factor and likely to survive repeated testing. For example, we know that there are poor metabolizers of clopidogrel. I would think it more than possible that the small observed difference in outcomes might be the result of those with the wrong alleles being over-represented in the PLATO study and if they are under represented in the next study, the results again will be skewed in the other direction. That's a lot less likely to be the case were the observed difference 10% rather than just 2%.

    On a personal basis, I can probably plot out a curve that shows my tolerance for increased price as a function of improved outcome so there is no single number that determines this. Maybe this is multiple curves since, as you point out, there are different values in determining the utility of a therapy.

    I wouldn't want to deny anyone the ability to purchase a new drug that the FDA has determined to be safe and efficacious or limit a physician's ability to prescribe whatever medicine he or she deems best, but in terms of public health policy, I would think that there should be 'substantial' clinical benefit, not just statistical significance, before we pay for it collectively through insurance or a government program. Clearly, defining 'substantial' is not easy.

    In keeping with the objectives of your blog, it would seem that my question is completely secondary to the issues you are raising about the validity of evidence coming from clinical trials. We have to get that right before we can even begin to look at the cost-benefit question.

    But, as long as that issue is driven by the need of pharmaceutical companies to be profitable, it is hard to picture how to prevent profitability, rather than science driving the outcome of trials.

    I see in the case of PLATO that many articles tout the 16% improvement in odds, not the 2% absolute difference and would assume the marketing departments are busy making sure that is the way the study is presented. Even with the most scientifically valid studies, marketing departments can spin gold out of dross should the numbers not agree with marketing objectives.