Friday, April 18, 2014

Novel Oral Anticoagulants: The Truth is in the Details

The clever and delightful Dr. John Mandrola thinks that the NOACs, four Novel Oral AntiCoagulant drugs (dabigatran, rivaroxaban, apixaban, and edoxaban), are equivalent to the status quo, warfarin, and have therefore been over-hyped and grossly overvalued. I'm going to try to change his mind. My statements, like his, will apply to the types of non-valvular AF patients enrolled in the large randomized controlled trials of the 4 NOACs vs warfarin that have recently been meta-analysed: CHADS2 score > 1-2, followed for around 2 years.

Death cuts through all of the individual potential benefits (reduced ischemic stroke and bleeding including intracerebral bleeding) and harms (increased GI bleeding) that these drugs might cause and is of obvious interest as an outcome to patients. So to keep things short and simple, I'm going to focus on what the meta-analysis by Ruff et al indicates about the risk of death on warfarin vs a NOAC.

What proportion of patients on warfarin died in the randomized clinical trials (RCTs)? 2,245 out of 29,221, for a death rate of 7.7%.

What proportion of patients on a NOAC died in the RCTs? 2,022 out of 29,292, for a death rate of 6.9%.

Dr. Mandrola seems to emphasize what Bogaty and Brophy have called the number needed to treat needlessly (NNTN). In this case, that 0.8% absolute reduction in the risk of death means that 124 patients (out of 125) would needlessly be treated with a NOAC for they’d be alive even if they had taken warfarin; none of those 124 would derive a mortality benefit from NOAC use compared to warfarin. Expressed as a percentage (124/125), we can obtain what Bogaty and Brophy call the index of therapeutic impotence (ITI), which for NOACs compared to warfarin is 99.2%. Madrola writes:

"In the outcomes that matter to the patient who sits across from us, the two classes of drugs perform nearly identically—that is, if you count greater than 99% the same . . . It simply means they are clinically equivalent to warfarin. And, therefore, at the current premium, these drugs are grossly overvalued."

But here's the rub: 1 out of 125 people would be dead if they had taken warfarin rather than a NOAC.

The 0.8% absolute reduction in the risk of death is a small difference, to be sure, but a key message is that this small difference is very real. The statistical power of a meta-analysis including almost 60,000 people is high enough to detect such a difference with a high degree of confidence (p=0.003).

So when it comes to life or death, are you into details? If you are, then you must conclude that the NOACs are life saving drugs. Though the number of lives saved by using NOACs seems small, since millions of North Americans have AF, NOAC use may save thousands of lives a year compared to warfarin.

When it comes to primary prevention – interventions to protect people from some harm that they've never experienced - details like that are really important. When you consider that most people who will take these drugs will never have a stroke anyways, it becomes especially clear that the physician’s directive to first do no harm is paramount. The bar for recommending a primary preventative therapy must be extremely high. The NOACs reach up towards that bar just a little bit higher than does warfarin.

Even if you’re not into details and you think that “99% the same” just is the same*, NOACs do not require frequent blood testing and they have far fewer interactions with other drugs and foods. Warfarin is such a difficult drug to effectively use that warfarin clinics have cropped up all over North America and Europe and all that they do is regularly monitor and advise patients of warfarin dose requirements. The cost of these clinics is not to be ignored. Furthermore, the state of the art in warfarin therapy seems to be having patients test and/or manage their warfarin dose at home with kits and blood strips that also add to the cost of therapy; patients randomized to home monitoring have a lower risk of dying. NOACs don’t require any of this. That benefit alone easily prevents the conclusion that they are equivalent to warfarin and certainly deserves a fair bit of hype. It is believed that these challenges associated with warfarin use at least partly explain why physicians under prescribe OAC therapy to eligible AF patients, so I think that drug companies directly marketing to AF patients might well be a very good thing in this case.

If NOACs were the same price as warfarin, this would be a no-brainer and few would dare say that they are equivalent to warfarin. So the only remaining question is what one might be willing to pay for this small but real benefit. In Canada (and remember, Americans can buy the same drugs from reputable Canadian pharmacies at low Canadian prices on-line), it seems that NOACs cost about $120/month, while warfarin might cost around $10/month. The difference is $3.66/day, which is the cost of a diaper, a gallon of gasoline, or a hot beverage at Starbucks, so you be the judge of whether NOACs are "grossly overvalued".

A more difficult question is whether NOACs are cost-effective. That is, if one considers the costs of caring for stroke and bleed patients, monitoring the use of warfarin with blood tests, and the different drug costs, what is the price of saving a life with a NOAC vs warfarin? Medical economists answer this question by determining the cost of a quality adjusted life year (QALY) gained by a particular treatment. This gets complicated, but this, this, and this study among many others suggest that NOACS are cost-effective compared to warfarin, so Mandrola's assertion that they are “grossly overvalued” isn't at all obvious.

Here's a thought experiment: imagine a world where the NOACs are the status quo in use at their current prices and warfarin is the new drug on the block, hyped as being equivalent but dirt cheap. Does anybody really think that warfarin, supported by the same data that Dr. Mandrola and I seem to disagree about, along with all of its challenges would ever get approved and accepted by clinicians on the basis of being an inexpensive alternative? I doubt it.

Dr. Mandrola's math and mine are the same, and he's right that this way of looking at treatment differences based on absolute rather than relative risks provides important insights. We agree that patients should be informed of differences in costs and high stakes outcomes and make their own decisions. We agree that the devil is in the details, but from my perspective, that devil is warfarin. It's almost as effective as the NOACs but the small difference is real and it affects life and death. While warfarin  is cheap, NOACs are better and they provide value to many people that is very likely (especially in the case of certain NOACs) cost effective. 

I wonder if Dr. Mandrola still stands by his earlier conclusions ...

*Try telling that to Serbia's Milorad Cavic, whom Michael Phelps beat by a thousandth of a second to win his record-tying seventh Olympic gold medal in the 100 meter butterfly. With less than a metre to go, Phelps trailed Cavic, whose fingers were gliding inches away from gold. But Phelps' last half stroke made the difference as his arms flew around and out-touched his competitor. Phelps did the exact same thing in the same event 4 years earlier, winning gold over fellow American, Ian Crocker by just 4 thousands of a second.

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