Amiodarone Is Not NICE

Posted on January 7, 2010
Filed Under Cardiology Topics, Gekkonian Rationing, General Rationing Issues |

As has been pointed out (pointedly) to DrRich, we do not have death panels in the United States. And indeed, considering that we’re not conducting military tribunals for Islamist terrorists who have tried  (or succeeded in)  killing and maiming as many of us as possible, it seems relatively unlikely that we’d assemble death panels (which sound even less due-process-friendly than military tribunals) for American patients.

What we will have, however, is a federally-mandated assembly, body, committee, commission, board, diet, parliament, or posse (but not a panel) of experts which will carefully evaluate all the objective clinical evidence regarding a particular medical treatment, and make “recommendations” to doctors about whether or when to use that treatment. The model which frequently has been offered up for our consideration, as we contemplate the workings of such a non-death-panel, is the British National Institute for Clinical Excellence, or NICE.

This being the case, it might be instructive to examine the preliminary decision made by NICE last week to disallow the use of the new antiarrhythmic drug, dronedarone (Multaq, Sanofi-Aventis) for British patients with atrial fibrillation (AF). Dronedarone is a long-awaited drug, painfully developed and tested over a very long period of time, as a potential replacement for the drug amiodarone (which, despite its many drawbacks, is the most commonly prescribed antiarrhythmic drug for AF).

AF is a common heart rhythm disturbance in the elderly and in patients with underlying heart disease. It can cause palpitations, dizziness, poor exercise tolerance and - because blood clots tend to form in fibrillating atria - often leads to stroke. Unfortunately, the antiarrhythmic drugs that are used to treat AF are either incompletely effective, or have potentially dangerous side effects, or both.

Indeed, as a group, antiarrhythmic drugs tend to be only moderately effective, and are toxic and poorly tolerated. Worse, one of the very nasty side effects sported by most antiarrhythmic drugs is the propensity to produce (paradoxically), sudden death from cardiac arrhythmias - a phenomenon we electrophysiologists like to call “proarrhythmia,” since this seems a less unnerving term than “sudden death.”

The reason amiodarone has become the most commonly used antiarrhythmic drug for AF is that it is measurably more effective than any of the other drugs, and better yet, tends not to cause proarrhythmia.

However, if Satan had wanted to invent an antiarrhythmic drug, he would have invented amiodarone. There are at least three features of amiodarone that render it diabolical.

First, as mentioned, the drug is obviously far more effective than other antiarrhythmic drugs, and does not cause proarrhythmia. So on its face, like most entrapping vices, it spins a certain appeal, one that lures doctors into using it far more blithely than they should.

Second, amiodarone has bizarre pharmacokinetics. Before it becomes fully effective, amiodarone needs to completely saturate the tissues of the body. During this “loading period,” which is generally several weeks in duration, large doses are typically used. Once the drug is deemed to be loaded, a relatively small daily maintenance dose can be used. This is because amiodarone is not excreted from the body like most drugs are, by the kidneys or the liver. Instead, amiodarone likes to stay in the cells “forever,” and for practical purposes you get rid of it only through the normal shedding of your body’s cells, such as skin cells and gut cells. This means that once you are loaded with the stuff, it’s a part of you for a long, long time - just about forever. (Amiodarone can still be detected in the blood for at least a year after the last dose.) Once you are on amiodarone, you’re on it.

And third, amiodarone has a unique and disturbing toxicity profile. Because it is stored in essentially every organ of the body, its side effects can affect almost any organ. And because amiodarone continues accumulating in your body as long as you continue taking it, the side effects can develop weeks, months, or even years after you begin the stuff. The side effects of amiodarone are almost too numerous to describe, but some of the more unique ones include:

And of course, given the drug’s extremely long excretion period, if any of these side effects should occur (and one or more of them occur in at least 25 - 30% of people who take the drug), you may be living with them (if indeed you remain alive) for quite a while.

As you can see, Beelzebub would be very proud.

When DrRich was a practicing electrophysiologist, his rule was to offer amiodarone only if the arrhythmia being treated was life-threatening or very disabling or disruptive to the patient’s life, and for which there were no other reasonable therapies, and only after a long, long talk about the potential risks. He has always been distressed that many of his cardiology colleagues appear to prescribe it so readily.

In any case it is no wonder that a substitute for amiodarone has been long sought - a drug that is as effective as amiodarone, that still has minimal proarrhythmia, and does not have the bizarre toxicity profile of amiodarone.

For years, hope has been high for dronedarone, whose chemical structure is very similar to amiodarone’s. As it turns out, however, dronedarone is an imperfect substitute. While the new drug appears to have amiodarone’s low proarrhythmia potential, and while it thankfully has none of amiodarone’s unique side effects (and indeed, appears to be quite well tolerated), dronedarone is not as effective as amiodarone.

Still, it has a decided advantage over amiodarone (much less toxicity) and over other antiarrhythmic drugs (low proarrhythmia), so in many patients who have AF it seems like it might be worth a try. It might not be effective in as many patients as amiodarone, but for those patients in whom it is effective, well, it’s effective. And if it doesn’t work well enough, you can always switch to something else.

Indeed, that’s how antiarrhythmic drugs ought to be used most of the time. Pick a drug that seems to provide the best available balance between effectiveness and side effects for a given patient and try it. If it is ineffective or causes problems, stop it and move to the next one. The more antiarrhythmic drugs that are available, the better the chance of eventually finding an adequate choice for your patient. (It is worth pointing our that once you try amiodarone, however, you are done with this trial-and-error strategy - once you are on amiodarone, you are, for practical purposes, always on amiodarone.)  In any case, the appropriate choice of an antiarrhythmic drug, as in many areas of medicine, can only be made on an individual basis, and not on a population basis.

But alas, this is not how a Clinical Effectiveness Tribunal like NICE works. These Diets of Medical Quality will only look at the average response to a therapy within a population of patients and, seeing (for instance) that dronedarone may only treat 40% of AF patients effectively while amiodarone treats 60%, will deem dronedarone to be insufficiently effective to justify its additional expense. (Read NICE’s “appraisal document” on dronedarone for yourself.) NICE has determined that amiodarone is a suitable choice for the treatment of atrial fibrillation, and that there is no need for a drug like dronedarone (or, presumably, any new drug that trades a bit of efficacy for a toxicity profile that is much less extravagant than that of amiodarone).

Old-fashioned physicians like DrRich, who might reason, “An initial trial of dronedarone would likely spare 40% of my AF patients from having to be exposed to the horrific toxicities of amiodarone, so perhaps it’s worth a try,” are hopelessly and irredeemably of low quality, and aren’t worth bothering over.

And as for the Smurfs and Smurfettes on amiodarone, despite their breathing difficulties, unsteady gaits, inability to see at night, and severe skin photosensitivities which preclude their Florida or Arizona vacations, at least their anguish over not being allowed a viable and available alternative will be temporary. For the drug companies, seeing how a Posse of Clinical Excellence operates, will take the only logical business step remaining to them and severely curtail their development of drugs aimed at offering incremental improvements over the current choices.

There will be no alternatives to agonize over, and everyone will be happy. This, DrRich thinks, is the plan.

Comments

7 Responses to “Amiodarone Is Not NICE”

  1. #1 Dinosaur on January 7th, 2010 9:33 am

    Why do you assume that the actions and conclusions of one group of lamebrains in a given country will be automatically duplicated elsewhere? Or are you saying that every physician needs to peruse all the relevant literature for every single indication and come up to his/her own conclusions about the best course of action for a given clinical scenario (which I try to do, though guidelines and the work of assorted consensus groups help me out by giving me a starting point)?

    Tell you what, DrRich: Why don’t we put *you* in charge of the panel helping the rest of us decide how to treat complex arrhythmias. Or do you find the entire idea of experts pooling their knowledge and sharing it with the rest of us unpalatable?

  2. DrRich on January 7th, 2010 10:09 am

    #1D,

    As much as I’d like to accept your nomination to become the czar of arrhythmias, I’m much too busy pointing out the shortcomings of all the other aspects of American medicine to concentrate solely on this one topic. Alas, there’s just not enough of me to go around.

    Further, I do not find the idea of experts pooling their knowledge and sharing it to be unpalatable. In fact, it’s often indispensable.

    What I find “unpalatable” is the idea of experts pooling their knowledge on a therapy and, based on the mean response to that therapy in a large population of patients, removing the option of applying that therapy to any patients whatsoever (essentially making it illegal for doctors to prescribe it). When (as in the example I’ve used here) a substantial minority of the population could have achieved substantial medical benefit from the banned therapy, a) patients will suffer unnecessary harm, and b) innovation will be forcibly stifled. (Would you put yo’ mama on amiodarone? NICE would.)

    Finally, I am not assuming that the U.S. will automatically adopt the specific policies promulgated by NICE. What we will adopt (I fear) are the methodologies used by NICE, i.e., rationing healthcare based solely on cost, but disguising the cost-based rationing with lots of scientific palaver to make it look completely objective.

    Rich

  3. Jupe on January 7th, 2010 5:15 pm

    I would totally nominate Dr Rich for membership on our US death panel, for what it’s worth. :)

    Dr Rich, is there a chance you’re being a little overly cynical about NICE in this instance?

    They flat-out say:

    “In addition, the Committee considered that there was substantial uncertainty about the beneficial effect of dronedarone on all-cause mortality. It noted the main driver of cost effectiveness was mortality benefit and when this was removed the costs per QALY gained were extremely high (over £1 million). The Committee concluded that the use of dronedarone in people with a CHADS2 score of 4 or more (in addition to standard baseline therapy) for the treatment of atrial fibrillation could not be considered to be a cost-effective use of NHS resources.”

    This is overt, transparent rationing, isn’t it? If there’s evidence they’re not correctly interpreting the all cause mortality data, then yeah, that would imply something sinister. Is there a case to be made that they are?

    Also, if I’m not mistaken, you can buy “non-NICE-approved drugs” out of pocket in the UK. What would be the objective of removing that freedom in the US?

  4. DrRich on January 7th, 2010 6:16 pm

    Jupe,

    I don’t anticipate being on a death panel, only before one.

    I have no problem with a rationing board (like NICE) deciding what the collective is and is not willing to pay for my individual healthcare, as long as: a) they ration transparently and by a publicly vetted set of rationing rules, and b) I’m permitted to buy any non-approved care I desire with my own money. I agree that NICE comes a lot closer to criterion “a” than anything we’re likely to put together in the U.S. But my understanding is that, while you can buy non-NICE-approved drugs with your own money, if you do so you are no longer eligible for ANY healthcare through the NHS, which effectively precludes patients from actually doing so in the vast majority of cases. This provision remains controversial, and I believe it is under active reconsideration. http://www.findingdulcinea.com/news/health/May-June-08/British-Doctors–Patients-Fight-for-Right-to-Buy-Costly-Medicines.html

    Rich

  5. Jupe on January 7th, 2010 7:17 pm

    Woah. I had no idea.
    If they were to fix that, would you consider the UK system ok?

  6. DrRich on January 8th, 2010 8:35 am

    Jupe,

    No, I would not consider it OK, but it would be a step in a needed direction. I have described my ideal healthcare system (given that rationing is unavoidable) in detail elsewhere. The ideal system not only permits people to spend their own money, but also relies and encourages them to do so as a major step in reducing the amount of necessary rationing.

    The problem I have with progressives/liberals is that they actively discourage this necessary step, and would like to render it illegal. (”Single payer,” after all, means single payer. If I’m allowed to contribute my own funds to my own healthcare, that’s at least two payers.)

    Rich

  7. Hal Dall, MD on January 8th, 2010 6:07 pm

    The criteria used in rationing decisions are critical. If “cost effectiveness” is the rationale, how is it measured? As noted above, NICE explains the “main driver of cost effectiveness was mortality benefit” although lip service is made about quality of life.

    Apparently dronedarone gives minimal “mortality benefit” compared to amiodarone, so the quality of life improvement is discounted as unworthy of NHS funding.

    DrRich, note that NHS’ “top-up” policy was changed last November http://www.telegraph.co.uk/health/3255806/NHS-patients-will-be-allowed-to-pay-for-private-top-up-care-says-Alan-Johnson.html and http://www.englemed.co.uk/08/08nov052.php

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