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May 16, 2012 10:50 EDT
RE-LY: An obituary for Warfarin?
I told an elderly patient last week that “in our lifetime” we might just see a drug that would take the place of Warfarin. Her eyes sparkled at the thought. I could imagine her vision of freedom. No more monthly treks to our clinic to roll the dice. Like all Warfarin users, she gambles every 4 weeks for a 30-day respite from blood checks. So often, the players are disappointed, but there is hope today with the new direct thrombin inhibitor Dabigatran.
Warfarin dosing is like witchcraft. The starting dose is a total stab in the dark. 300-pound men take 1.0 mg/day and 88-pound women require 12 mg/day. The high dose in our clinic currently is 20 mg/day in a gentleman with an ostomy. Both physicians and patients hate Warfarin and all the hoopla that goes along with it. Without it, scores of humans would be dead of embolic stroke and prosthetic heart valves would have been as useless as DaVinci's helicopter grounded for centuries for lack of fuel.
I had already decided NOT to get my hopes up. I was stung by Ximelegatran due to transaminase issues. I was teased by the clopedigrel and aspirin combination pronounced “less effective” than Warfarin, and I do mean a lot less effective. Idraparanux failed with too much bleeding and was sub-q in trial, which would never compete with Warfarin. There always seems to be a snag and thus it’s been a long good-bye for Warfarin since my first hint of optimism.
Re-Ly gave us cause for hope again. The trial design was ample. It answered all of the basic safety questions. The right dose was fairly obvious to me, but the researchers are still haggling a bit. Bleed rates were less than Warfarin at the 110-bid dose. It did well with aspirin. Some unanswered questions include its application in the valvular a-fib patients and of course, the Holy Grail (s) of all anticoagulants: prosthetic valve patients and pregnant women.
With the birth of a new technology comes the death of the one that preceded it and the entire community of support that has kept it alive. I’m hoping to eulogize my Coumadin clinic soon. I want all of my Protime gals to spend their time shopping , and the guys? .... I hope they can tee off at 8 am instead of signing the clipboard at our front desk. Fingers will be less sore, money will be saved and time will be better spent without Warfarin.
Born via patent in 1948 a product of sweet clover tainted with Penicillin Mold and Aspergillus that fermented coumarol into Dicoumarol, Warfarin killed thousands of head of cattle before it found application. The massive hemorrhaging it produced was later applied to rodent control. It surfaced as a savior of hopeless victims of stroke risk who could tolerate it and a harbinger of death and disability for those who couldn’t.
From the shear inconvenience alone of utilizing Warfarin, thanks to at least one of the new thrombin inhibitors coming down the pike, I hope I can soon say:
May Warfarin rest in peace.
"Consent the stent" campaign--long overdue!
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All natural? $15 billion worth sold annually
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Comments
Amen.
You are spot on.
Warfarin despite it's tremendously advantegous role in thousands of patients all these decades has always been an extremely slippery customer.
A replacement has long been overdue.
Good review!
Just a minor correction. I think you meant to refer to DaVinci's Helicopter, not Rembrandt's.
Regards,
Mohamed Rahman
Mohamed,
When I went to bed last night, I suspected I had written Rembrandt's name. Don't know why I did that. I've actually seen Davinci's burial site, his helicopter drawings, etc. I'm blaming everything I did yesterday on jet lag!!! Thanks for reading AND the correction!!!
Melissa
Mohammed,
Thanks so much for your correction. I've actually seen DaVinci's burial site, toured one of the castles he designed and have seen his drawings (of that helicopter!) I'm blaming everything I did yesterday on jetlag!!
Thanks for reading!!!
Melissa
I had to laugh at your quote that "money will be saved." I have a feeling dabigatran will be several orders of magnitude more expensive than warfarin (even including monitoring) to the point where many patients who could benefit from it will not have access. This is a multi-billion dollar drug, and the pharma guys plan on milking that cow for all its worth.
I propose another possibility: warfarin and INR monitoring will continue to coexist with dabigatran, at least until Medicare starts regulating drug costs as it does physician charges and hospital charges. Perhaps dabigatran will be reserved for some warfarin patients: the ones in whom warfarin is unpredictable or ineffective. I would propose that this is the minority of patients.
Perhaps you or some other enterprising cardiologist would even take the liberty of performing a clinical trial, comparing dabigatran in patients with VKORC polymorphisms, with warfarin in patients without these mutations. Now that would be interesting.
The king is dead, long live the king.
InteractMD.com
Appreciate all of your comments and are all points well taken. I, too am concerned about how expensive Dabigatran will be as it comes out the gate. We'll see if the pharmaceutical industry will be smart enough to take the market with competitive dosing or isolate itself amongst the elite patients who can afford anything they need. Only time will tell.
As for MI risk, it was a small signal and not statisically significant and hopefully that is the way it will stay.
Melissa
I am A Guatemalan Cardiologist, Dabigatrán hasn't reached us yet. local Boehringer Ingelheim warriors say it´s beeing released according to FDA approval, and local beaurocratic sliding. I think this is a great molecule, and the possibility of seeing warfarin stepping down in our country is feasable only if prices with warfarin are cost/effective anything but similar. I doubt that very much, since many or probably most warfarin users in our country are on the low side of the economical bench. But nevertheless I think it is about time, we all have something else besides the coumarol derivates. I hope the dabigatran prosthetic valve issue is resolved in the following months or years.
Nice article, keep on trucking !!
Mario Lambour MD.
Mario,
thanks so much for your post. I have several friends who are nurses who totally love Guatemala. Saw some beautiful pictures of your country just last week.
I believe the enthusiasm is justified. I'd use it in a heart beat (especially if it's irregularly irregular! )
Melissa
Sure, RE-LY will cost much more than Coumadin, but its use will offset the thousands of dollars per year for each patient's INR testing -- not to mention the cost of people's time and inconvenience of testing. If the economics didn't make sense then I think the manufacturer would face push-back.
As for the safety of RE-LY, I think the jury will be out until around 50,000 patients have tried it, just in case there are rare adverse events. Remember, warfarin has been time-tested by millions of patients.
In case anyone is still tracking this dialogue, I thought I would point out that we have a fairly extensive critique of the RE-LY study on ClotCare.org at http://www.clotcare.com/dabigatran_vs_warfarin.aspx Also discussed in that posting are recent studies that have improved anticoagulation management through INR self-testing and automated online management. This approach allows patients to test their INR at home, while traveling, or anywhere; and online management required less than 10 minutes of clinician time to manage 4 "virtual clinic visits" per month. In 2 of 3 such studies, the INR time in range improved to approximately 80% - which is substantially better than the to 50% of warfarin-treated patients in the RE-LY trial (see next paragraph).
Also, information recently presented by L. Wallentin (see wallentin, L. www.theheart.org/article/1046957.do) examines event rates based on the patient's individual time in the therapeutic range (ITTR). If one compares the data presented by Wallentin with the findings in the original publication, it appears that the 50% of warfarin-treated patients whose INRs were in range more than 67% of the time actually had fewer events than did patients in either dabigatran group. It would appear that the composite endpoint of stroke, systemic embolism, MI, PE, death, and major bleeding was 5.3% per year in the top 50% of warfarin-treated patients, but was much higher at 11.9%/yr for the bottom 25% of the warfarin treated patients whose INRs were in range < 53% of the time. The composite even rates were 7.09 %/yr and 6.91%/yr in the 110 mg and 150 mg dabigatran groups, respectively. Those number would suggest that the number needed to treat to prevent one major event compared to the bottom 25% of warfarin-treated patients would be 15 for warfarin-treated patients with a ITTR > 67%, 21 for the 110 mg dabigatran regimen, and 20 patients for the 150 mg dabigatran regimen. It would appear, therefore, that well-managed warfarin (individual time in range > 67%) was better than either dabigatran arm.
Perhaps the ease and efficiency of INR self-testing with automated online management together with the remarkable improvement in INR control will allow us to improve patient outcomes, reduce health care cost, and cancel the warfarin funeral.
Henry,
I think Coumadin will still be the only option for many for quite some time. Still yet, you never know a compound until it's been on the American market for about 2 years and we might learn of issues that haven't quite made it to the forefront during clinical trials with the direct thrombin inhibitors. However, if you had a choice between just swallowing a pill or sticking your finger once or more per week and then swallowing a pill after checking an algorithm, which would you prefer?
The problem is that even tracking daily INR's in the hospital setting, one day it will be 1.7 and the next 2.5 and even after holding it, the next 3.2 for some folks.
I think I'll pick out the casket and a few favorite songs just in case! HA!
Seriously, I get your point and an excellent one and thanks for posting!
Melissa