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.

When are treatments equivalent? Dr. John Mandrola and I disagree (a little bit) ....

A few months ago, Dr. John Mandrola, a prolific web-based author who opines on a variety of health related matters, especially those that are heart rhythm related, published the above piece at Medscape Cardiology.

The NOACS are four Novel Oral AntiCoagulant drugs (dabigatran, rivaroxaban, apixaban, and edoxaban) that challenge the well established status quo, warfarin, for the prevention of stroke in patients with a heart rhythm disorder called atrial fibrillation (AF). I've written about AF and the rationale for OACs in this blog here and here. Compared to warfarin, some of these drugs have been shown to prevent strokes (related mostly to clots) without increasing (and in some cases decreasing) the risk of bleeding. The combination of these 2 feats is amazing since they tend to oppose each other. The occasion of Dr. Mandrola’s opinion piece was the recent publication of two meta-analyses of the NAOC drugs versus warfarin: huge superstudies performed by pooling the data from 4 large randomized trials comparing each individual NOAC with warfarin.

I like Dr. Mandrola: I follow him on twitter and I always try to read his work. While I agree with much of what he writes, I cannot agree with his conclusion that the new oral anticoagulants (NOACs) are "equivalent to warfarin", nor that they are "grossly overvalued".

If you or a loved one has atrial fibrillation, this may be of interest to you, but it will be a bit technical. You'll get a chance to see how docs consider high quality data.

Here's a link to his article, which includes links to the relevant meta-analyses of the NOAC drugs. In case you can't get into the article (registering at Medscape with an email address is required and probably worth it), here and here are links to those studies, but I'll only be discussing the first one.

See you in a few days with my thoughts on the matter.

What doctors and anti-vaxxers have in common: Part 2

When I openly pose the post-vaccine fever scenario, most people consider it more likely than not that the vaccine caused the fever. That is, most people think the chance that the vaccine caused the fever is > 50%. Almost every medical student in a group of 20 that I was teaching a few weeks ago thought that. After all, fever is a well-recognized side effect of vaccine injections and your child was perfectly fine until a few days after the injection. Who wouldn’t reasonably conclude that the vaccine likely caused the fever?

Notice that by focusing responses on 1-49%, I set the question up to give you a better chance at being correct than they were but still, nobody got the question right. Don't worry. You are in good company. For now, just remember the feeling you had when you made your choice.

Back in the 80’s, investigators were concerned that combining mumps, measles, and rubella vaccines into one (MMR) might increase the risk of side effects, so some doctors in Finland did an ingenious study to determine what was not just temporally associated with vaccine injection, but caused by vaccine injection.

They studied 581 pairs of twins and randomly gave the MMR injection to one of the twins and a placebo injection to the other. Then, so as to not deprive the children that got a placebo injection of the vaccine's proven benefits, three weeks later, they gave each twin the opposite of what they had earlier received. Parents, who were blinded (they didn’t know when the kids were getting the placebo or the MMR injection), were instructed to vigilantly check for fever and a variety of other potential side effects after each injection.

In the first 6 days after placebo injection, 17% of children had a fever. That’s the background frequency of fever in vaccine-age children, and it's pretty high, huh? On the other hand, in the first 6 days after MMR injection, 17.2% of children got a fever. The difference - 0.2% - is what can be causally attributed to the active ingredients in the vaccine.

Conclusion: >99% of fevers that occur in the first week after MMR injection have nothing to do with the vaccine at all. 

However, we are very likely to erroneously attribute the fever to the vaccine. We do this because we have a powerful intuition that leads us to identify a causal relationship when 2 events that could possibly be causally related follow each other in time. We are mistaking what is merely possible for what is probable. Unfortunately, children develop mysterious illnesses like MS, autism, epilepsy, hepatitis, arthritis, etc. with regular frequency. Sometimes, those illnesses will appear fairly soon after getting a vaccination, and that’s when that intuition of ours can do some serious damage. That same intuition does damage when mysterious conditions like these disappear -as they often spontaneously do- after interventions that have no effect on the disease like prayer, acupuncture, chiropractic neck manipulations, homeopathic remedies, etc. Only randomized controlled trials can sort this stuff out.

Imagine once again your son who got a fever early after the MMR injection, only now, he is a healthy 18-year-old man who was spared the ravages of mumps, measles, and rubella. At any point in his upbringing, would you have ever had cause to stop and be thankful for the vaccine? How could you? You’d have had no way of knowing whether your child would have contracted one of these illness had he not been vaccinated!

See what’s happening here? The way that we experience life offers us no way to identify the situation where a vaccine prevents a horrible illness or death. On the other hand, we have a tendency to erroneously attribute adverse events to vaccines when they follow each other in time. Remember how you felt about your child's fever after MMR vaccine? Parents considering whether to vaccinate their children can anticipate the regret that they will experience if their child does develop an illness like autism afterwards, but they cannot anticipate the relief that they cannot experience when their child is spared a vaccine-preventable illness. Anti-vaxxers are much more likely to anticipate the former type of regret than the latter because they tend to overestimate the risks of vaccines and underestimate their benefits. Our intuitions erroneously set vaccines up to be unattractive. 

And so it is with physicians and oral anticoagulants (OAC’s). Bleeding events are fairly common. Whenever somebody experiences a bleeding event on an OAC, they and the doctors tasked with treating the bleeding blame the OAC. The reality is that most bleeding events that happen while on an OAC would have happened otherwise: just as only 0.2% of fevers early after the MMR injection were caused by it, only 0.2-0.3% of bleeds /yr are caused by the OAC. But physicians can anticipate the regret that they will experience when they prescribe an OAC to a person with atrial fibrillation (AF) who then develops a bleeding event. The finger of blame will point to the OAC and the physician who prescribed it. Unfortunately, nobody ever returns to the prescribing physician to pat them on the back and thank them for the stroke that they and the OAC prevented because, just like the case of mumps that your son avoided, there is no way to recognize a stroke that would otherwise have happened. Doctors' intuitions erroneously set OACs up to be unattractive.

Just as there is evidence that anti-vaxxers overestimate the risk of vaccines, so is there evidence that physicians overestimate the risks of OACs, exaggerating  their anticipated regret over prescribing one.

Our ancestors evolved on an African Savannah with no pressures to select for intuitions that address the types of complicated primary prevention questions posed by vaccination and OAC use in AF. It seems that we did evolve intuitions that lead us to readily identify patterns and infer causal relations where there often isn't one. On the whole, this rudimentary heuristic has done well to protect us from certain kinds of dangers, but, as Sam Harris has written, “we have flown the perch built for us by evolution”. If we are to make advances with complex questions, we simply have to recognize when our intuitions lead us astray, and they regularly do, whether we are specialized physicians or lay people. None of us are spared the consequences of irrationality. It is a struggle we all must recognize and participate in.

If you are faced with complex decisions like vaccinating or taking an OAC, I hope that you are most heavily weighing the evidence from RCTs. If you aren't, then I hope that you are seeking the involvement of people who are. Otherwise, you're just being irrational.

What doctors and anti-vaxxers have in common: Part 1

A few years ago, a Canadian neurologist reviewed the case of every patient admitted to 12 Ontario hospitals  with a stroke between 2003 and 2007. He only studied patients with a heart rhythm disorder called atrial fibrillation (AF) because AF is known to cause blood clots inside the heart that can get pumped out and block a brain artery causing strokes. There is an abundance of clear evidence: people who suffer from AF can dramatically reduce their risk of stroke by taking oral anticoagulants (OACs) that prevent intracardiac clots from forming. These medications are to be avoided in people with bleeding problems, but otherwise, the majority of people with AF ought to take one.

Gladstone discovered something shocking: after excluding patients with bleeding risks, only 40% of people with AF who suffered a stroke were on an OAC when all of them ought to have been, and three quarters of them were under-treated. The data was even more staggering for patients with AF who were admitted with their second stroke – a situation where it ought to be blatantly obvious that an OAC is needed: only 57% of people were being treated and two thirds of them were undertreated. Overall, only about 15% of patients with AF were appropriately treated with an OAC. The conclusion was sobering: if these patients had been appropriately treated, the majority of these strokes could have been prevented.

Of course, part of the responsibility for not being on OACs rests with patients who decide not to take one, but this is one study among many that indicate that physicians around the world routinely under-prescribe OACs to people with AF. Is it because AF is rare and doctors just don’t know about the opportunity to prevent strokes by prescribing OACs? Consider that AF is the most common arrhythmia in adults and that you and everybody you know and love has a 1 in 4 chance of developing it at some point in life. Plus, it’s responsible for 20% of all strokes. Is it because the risks and benefits are unclear? Absolutely not: as I mentioned earlier, over 10 randomized trials done around the world by different investigators involving thousands of patients have all shown the same consistent results: at the cost of a small (0.3%/yr)increase in the risk of bleeding, OACs reduce the risk of stroke by around 65%.

So why are doctors not doing the obvious and prescribing these drugs?

What's the anti-OAC body count at today?

In my next blog entry, I’ll explain the situation, but first, I want you to consider the following common scenario: 

You have a young child who has been perfectly well until he receives a combined vaccine injection for mumps, measles, and rubella (MMR). Around 3-6 days after the shot, your son develops some irritability and he feels hot; his temperature is 38.9 degrees C. You give him some acetaminophen and in an hour, he defervesces and perks up. How likely do you think it is that the vaccine injection caused his fever?

(A) > 50%
(B) 31-50%
(C) 21-30%
(D) 11-20%
(E) 1-10%
(F) < 1%?

Don't Google it. Close your eyes and visualize the situation and try to be as honest as you can. You and your spouse are probably going to bring this very question up when the fever develops. What are you going to say? Tell us by anonymously voting in the poll on the right. (Poll now down.)

(Go to Part 2, and the answer)