A better hope for irregular hearts- Dabigatran

2 days ago  the FDA approved the first new anticoagulant in fifty years, dabigatran  for stroke prevention in patients with non-valvular atrial fibrillation. Available in 75 & 150 mg to be taken twice daily. Dabigatran showed a better side effect profile compared to warfarin in the recently published  RE-LY trial in NEJM. This was a non inferiority trial with 18000 patients. Half received Dabigatran and half..coumadin. Primary outcome was stroke. Compared with Coumadin (warfarin), patients on Dabigatran had a 9% lesser incidence of stroke, and the risk of major bleeding each year was 2.71% with dabi ..and 3.36% per year with warfarin.The risk of hemorrhagic stroke also decreased significantly. These results has pushed FDA to approve this on the market. 


On top of all these benefits.....the one advantage that stands out...is the there is NO NEED TO CHECK BLOOD LEVELS. This is a great news for patients taking warfarin....but may be a bad news for the warfarin clinics!
What is the downside of Dabigatran?  The common side effect is GI intolerance. This was not a major issue in the trial. Second..it is expected to be 7-8 times costlier than warfarin (roughly around $6 -$9 / day). But given the amount spent on blood checks, clinic visits, lost work days, money spent on patients travelling to the clinics..........plus the reduction in complications.....Dabigatran might still prove to be a cost effective medication. Well...who knows........our clever Insurance companies might think differently.     But another important group of concerns are...that there is no antidote in case of a major bleeding ( but due to short half life..stopping the drug could be adequate). Also when to stop before surgeries..and when to restart? How to monitor if needed? Well ...the most reliable means of montoring seems to be activated partial thromboplastin time(aPTT) and Thrombin clottin time (TT).


How does it work? It is a prodrug..and is immediately  converted by a serum esterase to dabigatran, a potent, direct, competitive inhibitor of thrombin. It has an absolute bioavailability of 6.5%, 80% of the given dose is excreted by the kidneys, its serum half-life is 12 to 17 hours. It is approved by FDA at a dose of 150 mg bid. Lets wait and see if this would end the story for warfarin. 


Remember....a direct thrombin inhibitor called Ximelagatran was about to be released in Europe for the same indication as Dabigatran...but had to be withdrawn because of hepatotoxicity during its trials. This was not a great problem in the RE-LY trial. But this something to be aware of especially in the first few months of treatment.

combination of Aspirin,Plavix & Warfarin - how bad or how good?

I am sure you had come across those patients who had been on aspirin & warfarin ..or...plavix & warfarin...or rarely all three (either intentionally or by mistake!!). Well...a patient with CAD might benefit more from a antiplatelet...but may need warfarin for A.fib ....will he benefit from both? A recent article from Arch of Int Medicine tried to address these issues by calculating the risk of bleeding associated with each combination.
Lets look at the risk of stoke with A fib at 1 year...so the numbers from the above study would make more sense.

Risk of stroke with A fib - commonly assessed with CHADS2 score
CHADS score of 0,1,2,3,4,5 & 6 carries a 1 year stroke risk of ..roughly 2%,3%, 4%, 6%, 8%, 12% & 18% respectively.So we usually start treatment to prevent this thromboembolic risk by starting them on either antiplatelets or warfarin. This question about warfarin or no warfarin always pops up when we see a patient with A fib.

Now lets see the numbers from the above study where they looked at a cohort of 82,000 patients discharged with a diagnosis of Atrial fibrillation. During a follow up period of 3 years ..11%(13,000 pts) had a fatal or non-fatal bleeding.Having warfarin as the standard ..the hazard ratio for the above end point is as follows
For Aspirin alone - 0.93
for plavix alone - 1.06
for aspirin + plavix - 1.66
for aspirin + warfarin - 1.83
for plavix + warfarin - 3.08
for aspirin +plavix+warfarin - 3.70

Clearly this was something that was expected ..based on previous studies. The crude incidence rate of bleeding was 13% for plavix +warfarin, and 15% for triple therapy. So having these numbers ...gives a better idea for making a risk-benefit decision !! ...So ..whoever your pt is....aspirin+plavix+warfarin seems to be a bad combination!

what is it with Cranberry juice and warfarin!

Anticoagulation clinic!! - a place to advice patients about diet, and monitoring treatment closely. Today..I had a patient ask me about Cranberry and products ..and taking them with warfarin. Well..I didnt know the right answer. She has an aunt diagnosed with cancer..and she would like to take cranberry for its antioxidant/anticancer property. So ..I delved into some evidence.....
What does FDA say -  In 2006, FDA issued warning about a potential interaction between the two in raising the INR. This was based on a UK health committee's warning about the same interaction. The warning came after 12 reports of a suspected interaction!! (Just 12 reports...without any base??)


What is the mechanism of interaction - Warfarin  is a racemic mixture of the R- and S-enantiomers, with the S-enantiomer having 2-5 times more anticoagulant activity.It was proposed that some Flavinoids in Cranberry products might inhibit cytochrome P450 (CYP) 2C9, the enzyme responsible for the hepatic elimination of S-warfarin. But many studies have shown  no effect on CYP2C9(J of Exp Pharm 2010), although some questionable effect on the less important enzyme, CYP3A4(Drug Met & Dis 2009)


What does evidence say -  The same year as FDA put up the warning...the first randomised trial on this was published( J of Amer Diet Asssoc,2006). Just with 7 patients...taking 250cc of Cranberry juice /day......no difference in INR was found during 3 months duration. Another study in Clin Pharm in 2009 showed no difference in INR among warfarin pts taking 240cc/day of cranberry juice Vs placebo for 2 weeks.
A recent review in Amer J of Medicine concluded that no interaction exists between warfain and Cranberry products consumed in moderation (around 250cc/day). We don't know about excessive consumption though.
So, thats pretty much it......... SAFE to tahe warfarin and Cranberry products (may be < 300 cc/day). Anticoagulants like Dabigatran are on the horizon...which might have less interaction...and would be the way forward.