Stroke prevention: a less bitter pill?

Stroke is one of the three most common causes of death in North America.   A while back, we briefly discussed some of the causes of stroke, including a heart rhythm problem called atrial fibrillation (afib).  Afib is a very common problem, affecting over 2 million North Americans.  It becomes more common with age.  In afib, the normal flow of electricity through the heart is disturbed.  Before we discuss it  in a little more detail, we’d better take a look at how the heart’s electrical system works.

Normally, a pacemaker near the top of the heart called the sinoatrial (SA) node sets the rhythm for each heartbeat.  It sends an electrical signal through the top chambers to a choke point between the top and bottom chambers called the atrio-ventricular (AV) node.  From there, the electrical signal spreads through the main pumping chambers of the heart, causing the muscles to contract.

1) SA node; 2) AV node

On an EKG, like the one below, the bump at the purple arrow (the p-wave) represents the discharge of the SA node.  The larger blip (the QRS complex) represents the electricity flowing through the ventricles.

What would happen if the the SA node decided not to fire?  Each point in the conduction system has its own pacemaker which can serve as a backup.  The SA node generally fires at about 60-90 beats per minute.  If it fails to fire, the AV node can kick in at about 40-60 beats per minute.  If the AV node fails, the ventricles can fire at about 20-40 beats per minute.  These low heart rates can usually keep you alive, but not much else.

In atrial fibrillation, the SA node stops firing regularly and instead, electrical signals discharge chaotically.  Some of the signals make it to the AV node, and some don’t, so instead of a nice, regular rhythm, the heart often beats in an “irregularly irregular” rhythm.  Since the SA node isn’t working properly, the top chamber (the atrium) flops around instead of pumping cleanly, and the relatively stagnant blood in the fibrillating atrium can form clots.  The top tracing in the EKG above is typical for atrial fibrillation: the p-waves are rapid and varied, and the QRS’s don’t march out regularly.

Which brings us back to strokes, and preventing them.  Afib is a major cause of stroke.  As clots form in the floppy atrium, they can shoot into the main chamber of the heart, and then to the brain.  Depending on a number of factors, the risk of stroke in people with afib is about 5% per year.  This risk is cut significantly with drugs that prevent blood clotting.  The classic drug is warfarin (Coumadin).  Warfarin interferes with vitamin K, preventing blood from clotting normally.  Even when used properly, warfarin increases the risk of bleeding, for example from a stomach ulcer or from a burst blood vessel in the brain, but this risk is usually balanced by the stroke-preventing effect.

Warfarin is a pain to use.  A dose takes 2-3 days to kick in, and the only way to measure the effect is with frequent blood testing.  Foods containing vitamin K interfere with it, as do many different medications.  If levels are too low, the stroke risk goes up, and if they are too high, the bleeding risk goes up.  It is a “messy” drug.

For a number of years, an alternative has been available in Europe.  Under the generic name Dabigatran, it is dosed twice daily and requires none of the blood monitoring needed for warfarin.  It also has fewer drug and food interactions.  It is also horribly expensive.  Warfarin generally costs under $15 per month, while Dabigatran can cost that much per day.

These costs are tricky, though.  The overall cost of warfarin is more than just the pill; it is the care for patients who have complications, and the frequent blood testing.  A recent study in the Annals of Internal Medicine examined the cost-effectiveness of warfarin and Dabigatran and found that depending on pricing (of course), the two treatments can be equally cost-effective.  But not to the consumer, at least not yet.

Unless insurance companies are willing to price dabigatran based on money they will save on complications and blood testing, few patients will be willing to pay for the drug.  As it stands, the consumer sees the price of the drug at the pharmacy checkout line, and there is one clear winner.  Many insurance companies farm out their prescription coverage; the prescription company won’t save money from fewer tests and has no reason to lower the drug price.

If our health care system continues a shift toward outcomes-based pay, this will change.  Until then, it may be a while before Dabigatran makes it big in the U.S.

References

Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation (2006). ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Circulation, 114 (7) DOI: 10.1161/CIRCULATIONAHA.106.177292

Freeman JV, Zhu RP, Owens DK, Garber AM, Hutton DW, Go AS, Wang PJ, & Turakhia MP (2010). Cost-Effectiveness of Dabigatran Compared With Warfarin for Stroke Prevention in Atrial Fibrillation. Annals of internal medicine PMID: 21041570

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8 Comments

  1. Dianne

     /  November 21, 2010

    It’s about time. DTIs have been “just around the corner” in the US for a ridiculous amount of time. I’m curious to see whether they’ll have any anti-tumor properties. Thrombin inhibition, by various routes, does seem to inhibit metastasis in mice.

  2. Daniel J. Andrews

     /  November 21, 2010

    Maybe a very silly question, but would low levels of aspirin have a similar preventative effect?? Or better phrased, since aspirin isn’t prescribed, why isn’t it as effective as Wayfarin?

  3. Dave

     /  November 21, 2010

    $15 a day!? That would be $450 a month! I just checked online pharmacies and it is less than half that. Where does your information come from?

    • From usual sources, and not from random googling of online pharmacies, but drug prices are quite variable.

  4. Schwa

     /  November 21, 2010

    Dr. Lipson, you wrote,

    “In atrial fibrillation, the AV node stops firing regularly and instead, electrical signals discharge chaotically.”

    I think you mean that the SA node stops firing regularly. I mean, the AV node also misbehaves in Afib, but that’s a consequence of the atrial electrical chaos, and not directly related to stroke?

    Re: aspirin vs. warfarin

    Aspirin prevents the synthesis of thromboxane in platelets, so it inhibits platelet aggregation. Warfarin inhibits the synthesis of a bunch of different clotting factors, so you never get formation of the fibrin net that catches platelets and offers a site for aggregation in the first place. That is, of course, an extreme case where you’ve gotten enough warfarin to shut down coagulation completely; in reality doses are titrated to reduce spotaneous clot formation while allowing some coagulation after injury. Aspirin doesn’t really work that way, since it’s an irreversible inhibitor of cyclooxygenases, so it’s either on or off, and even when on it’s not quite beefy enough. Of course, since they work by different mechanisms, you can combine aspirin and warfarin for a more pronounced effect.

    • Thanks for the proof-reading.

      Aspirin does reduce the risk of stroke in afib, but is significantly less effective than warfarin, depending on the patient’s stroke risk, age, etc.

  5. Coincidentally, I start reading up about the whole EKG cycle, along with the QRS complex and the Q-T interval and all that stuff, about a week ago, on one of my periodic Wikipedia deep dives. Absolutely fascinating stuff, but unfortunately I am impaired by the fact that I am squeamish about the circulatory system for some reason. No, not squeamish about blood — I can get a pretty bad cut and just be like, “Oops, that sucks, better patch that up.” It’s visualizing the circulatory system itself that trips me out. I actually started to feel dizzy reading this post and had to stop!

    It’s a really unfortunate hangup, because I was finding that stuff fascinating until I had to stop reading it. Oh well 😦

  6. D. C. Sessions

     /  November 23, 2010

    Thank you very much for this. As it happens, Afib runs in the family (seems to have skipped me, fortunately) so a good backgrounder is extremely valuable.

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