Decisions, decisions ...

Almost three years ago, I accidentally discovered that I have severe aortic heart valve regurgitation (leaking). The only treatment for this problem is surgery, the timing of which is somewhat controversial because we lack the highest quality evidence - multiple randomized controlled rials - addressing that question. Nevertheless, there is reasonable evidence suggesting that the time to operate was not then, and I have been grateful for the three pretty normal years that followed. Unfortunately, it appears that that time has come now.

My left ventricle has shown subtle signs of ongoing dilatation on serial cardiac MRI examinations and that volumetric increase was quite clear on my most recent images. Delaying operation has some benefits that seem largely static with the passage of time while the risk of adverse outcomes increases. The recent dilatation in my ventricle suggests that I'm probably at or near the inflection point of the curve relating the risks and benefits of waiting. It's impossible to know for sure, but I've always wanted to err on the side of operating little bit sooner rather than later if an error had to occur. Accordingly, I am going to wait no longer; my surgery is being planned for early in the new year. But no sooner is that question answered to a satisfactory degree that another question arises: what operation should I have?

The Options

Mechanical valve replacement
This option refers to surgically replacing my aortic valve with one made out of pyrolytic carbon discs that tilt open and closed. The advantage of mechanical valves is that they are very durable. There is probably an 80-90% chance that a mechanical valve will last me the rest of my life. The disadvantage of mechanical valves is that they are foreign material, and the body tends to form blood clots on foreign material exposed to the blood stream. If a blood clot formed on the tilting discs, it could prevent the discs from opening or closing properly. The valve could become severely blocked, impairing the flow of blood out of my heart, and causing a life threatening situation. Alternatively, the clot could break free and travel through just the right blood vessels leading to my brain, causing a stroke. To minimize these clot-related risks, an anticoagulant medication called warfarin is indefinitely required. Because warfarin interacts with changes in diet, liver function, and many medications, regular blood testing to determine the adequacy of anticoagulation are indefinitely required. Thankfully, I could perform these tests at home, about once a week, for the rest of my life. Despite good control of my use of warfarin, I'd probably be facing a 25% life time risk of life-threatening bleeding in the worst case scenario, or enough bleeding to require a blood transfusion in the best. So while there's probably a 75% chance of not having a major bleed, mundane human experiences like a bonk on the head, a car accident, or a bleeding ulcer could all pose serious risks to my well-being.

There are a couple of other considerations regarding mechanical valves. Firstly, they make an audible clicking sound when they close. Sometimes it's loud enough to hear in a quiet room when standing next to someone with a mechanical valve. You can check out what the click sounds like here. Some people are bothered by a sound that they can never get away from, while others get used to it and still others find it soothing or comforting. I'm not sure how I would handle the perpetual click, but I do know that if I can hear my watch ticking on my night table, I can't sleep until I put it away. Secondly, ultrasound examinations of the blood vessels of people with mechanical valves often reveal little specks flying around in the blood stream. These are thought to represent very small blood clots or bubbles, and since they are flying around all over the place, some go to the brain. There is some evidence that patients with relatively high numbers of these tiny emboli have deficits on detailed neurocognitive testing (such as memory defecits). It is unpleasant to speculate that a mechanical valve could lead to early onset dementia. Some biological valves (see below) are associated with these micro emboli, too, though they seem more common among people with mechanical valves.

Biological valve replacement
This option refers to surgically replacing my aortic valve with a new one made out of biologic material from a cow or pig heart. The tissue is treated so as to not invoke an immune rejection response. The advantage of biological valves is that they do not require anticoagulants after the first 3-6 months post-op. The major bleeding risk is therefore about half of that observed with mechanical valves. The downside of biological valves is that they wear down over time and that rate of structural deterioration is fastest in younger patients. A biological valve would be expected to last 10-15 years before requiring replacement surgery, so there is a very high chance that I'd have to have a second open heart operation to replace a biological valve in my lifetime, perhaps, even a third. While the risk of bleeding is lower over those years, the risk of the second surgery is probably double the risk of the initial surgery (though we're still talking about relatively low risks), and if a third operation is required, the risk seems to really increase significantly. Plus, each operation also carries a risk of neurocognitive decline just from being on cardiopulmonary bypass for a few hours. Open heart surgery is basically the mother of all operations, taking 8-12 weeks from which to recover. Nobody wants to have to undergo it more than once if they don't have to...

Mechanical and biological valves compared:
Both mechanical and biological prosthetic heart valves carry a similar and, thankfully, very small risk of becoming infected (endocarditis). This is a serious complication, often requiring redo surgery to remove the infected valve and replace it with a new one. At the end of the day, when these valves have been compared in people over 55, the risk over time of stroke is the same, though mechanical valves require anticoagulants for that to be the case. Survival has seemed pretty much the same, too. With a mechanical valve, the risk of bleeding is spread out over time, while with a biological valve, the risk is concentrated at those times when the valve degenerates and re-operation is required. However, there have been no randomized trials comparing mechanical and biological valves in people in their 40's, so the bottom line is that nobody can provide any confident information about how someone like me ought to expect to fare with either. All one can do is make an educated guess based on trials involving older patients and the best guess of some experts is a mechanical valve, while for others, its a biological one. (Hmmm, an interesting and important disagreement.)

Valve Repair: There is a small chance (estimated at 20-30%), that my aortic valve could be surgically repaired. This would mean that the surgeon could, if the tissues are strong and the valve leaflets long enough, artfully put in some carefully places sutures that would re-align the leaflets and make them close well again. Like a biological valve, repair would have the advantage of not requiring anticoagulants, but more importantly, it would not be associated with an increased risk of infection because no foreign material is involved. The coolest thing about a repair is that while prosthetic valves just palliate the problem, a repair could potentially cure it. The downside of a repair is that its longevity would be unknown. It could last my lifetime, but it could also fail within 2 years and require redo surgery that soon. One estimate is a 20% chance of needing a second operation at or before 10 years. The trouble with these estimates is that the cause of my valve leak isn't known; the usual conditions that cause it have been excluded. Maybe I have weak connective tissues and a repair would be destined to fail again just as my original valve did?

What am I going to do?
Well, I've made a choice, but it's not like I feel very confident about it. I remain open to new evidence and other opinions. At this moment in time, I'm planning to have a surgeon who is very experienced with aortic valve repair - and there are not that many in the world - make a judgement call in the OR: if he thinks that there is a good chance for a durable repair, that is my #1 choice. If he feels otherwise, my second choice is a mechanical valve. The On-X aortic valve has recently been shown to be as safe with less aggressive anticoagulation (INR 1.5-2 rather than 2-3) and therefore less bleeding, so I have asked my surgeon to use this valve if it comes to that.

Repair is attractive because of the lower risk of endocarditis, and because it represents a chance to be normal again. I'm willing to risk something for that, but not much. If the surgeon thinks my tissues are not up to the job of providing me with a lasting competent aortic valve, then I would prefer erring on the side of implanting a mechanical prosthesis. Why mechanical? Because while survival of patients with mechanical and biological valves has been similar in trials of older patients, my suspicion is that there will be a survival advantage in younger patients because the risk of bleeding - the major risk of a mechanical valve over biological - is lower in young patients. Plus, I'm choosing a valve that likely requires less intensive anticoagulation than has traditionally been required, and I would monitor my anticoagulation at home. All of these things should help to reduce the risk of bleeding with a mechanical valve during young years when a biological valve would be undergoing relatively rapid structural deterioration. Also, I somehow feel more comfortable taking my chances with anticoagulants, which I can to some extent control, than with watching and waiting for the clock to tick down to a second big operation. (That doesn't seem like a particularly rational consideration, but I'm with David Hume, whom I must quote at every opportunity: "Reason is, and ought only to be the slave of the passions, and can never pretend to any other office than to serve and obey them.")

I wish that there was an ongoing randomized controlled trial comparing mechanical and biological valves in 40 year-olds with long term follow up. I would gladly participate in such a trial and let the study make that decision for me. Unfortunately, and for reasons that are really unclear to me, no such study is underway, nor, to my knowledge, even being planned. It would seem to be so easy to do, and it's a question that's important to many thousands of people like me around the world. Too bad.

So that's likely going to be my roll of the dice. I'll probably end up with a mechanical valve and the best case scenario is that it never gets infected (95% chance), that I have no major bleeding while on warfarin (75% chance), that I get used to the click and even come to like it (? chance), and that it lasts me a long life (80-90% chance) without major neurocognitive decline (? chance). Of course, this discovery has forced me to rethink the concept of a long life: my average life expectancy is probably somewhere around 65* while it ought to be well over 70. And while it would be nice to make it to 75, doing so with cognitive dysfunction represents a particularly unattractive scenario to me. Hopefully, safer alternatives to warfarin will become available for use with mechanical valves in my lifetime.

But like I said, I'm open to other perspectives. Please share your thoughts in the comments below. Would you take a chance at valve repair? Would your back-up plan be a biological valve with a high chance of a second operation, or a mechanical valve with the life-long use of warfarin? How would you roll the dice if you were in my shoes?


*Martijn W.A. van Geldorp , W.R. Eric Jamieson , A. Pieter Kappetein , Jian Ye , Guy J. Fradet , Marinus J.C. Eijke... Patient outcome after aortic valve replacement with a mechanical or biological prosthesis: Weighing lifetime anticoagulant- related event risk against reoperation risk. The Journal of Thoracic and Cardiovascular Surgery Volume 137, Issue 4 2009 881 - 886.e5

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.