Dabigatran

I have never liked the sight of blood, which is why the thought of anti-coagulants at first made me uneasy.  However, blood clots can pose a significant health risk.

Symptoms of blood clots depend on where the clot is.  In hospitals or airplanes, where the patient is less able to move around to keep blood flowing through their veins, there is a serious risk of blood clotting in the legs due to venous stasis, which could result in a DVT, or deep venous thromboembolism.  A blood clot that travels to the lungs is a pulmonary embolism, a blood clot that gets lodged in a coronary artery causes a myocardial infarction, and a blood clot that blocks a cerebral artery results in a stroke.  

Clots are a serious health risk.  A person with no baseline risk of clotting has no need for daily anti-coagulant therapy.  However, there are a number of disease states and conditions that increase a patient’s risk of a blood clot.  

Anti-platelet medications such as aspirin and clopidogrel reduce risk in patients with low baseline risks of blood clots.  However, certain conditions mandate stronger anti-coagulant therapy.

Atrial fibrillation is an arrhythmia that results in blood stasis in the heart when the electrical signaling in the heart prevent the heart from beating at a normal rhythm.  Patients with atrial fibrillation are at higher risks of clots, their risk is calculated from five of risk factors (the CHADS2 score).  For years, the only available oral anti-coagulant has been warfarin (brand Coumadin) which requires patients to be closely monitored by a physician for their INR, international normalized ratio or bleeding time.  The INR is kept within a specific range, usually 2-3 but it depends on the condition, lower INRs are associated with increased risk of clot whereas a high INR could result in a life threatening bleed.

Warfarin inhibits the production of vitamin K dependent clotting factors; it inhibits numerous clotting factors in the clotting cascade but its effects can be reversed by administration of vitamin K.  It is the only medication of its class and was first developed as a rat poison. 

Warfarin tablets are very inexpensive.  However, use of this medication requires a lot of monitoring and constant dosage adjustments.  Furthermore, if the patient changes the amount of vitamin K consumed within a week, the patient’s INR will change.  Additionally, the time to reach optimal clotting time is dependent on the half life of the clotting factors, and not on the medication.  Even after steady state has been reached, clotting factors that were produced before administration of warfarin will keep the INR low.  Approximately 5 days are needed before warfarin is showing its full effects, although the INR will start to increase after a few days of therapy.

A second class of anti-coagulants are the direct thrombin inhibitors (DTIs).  This class has been restricted to injection drugs until only recently.  The first of the class, lepirudin, is derived from hirudin, an anti-coagulant released by leeches to allow the continuous sucking of blood without clotting.   While there is no antidote for DTIs, they only inhibit one clotting factor making them a “cleaner” class of drugs. 

Dabigatran etexilate is the first oral direct thrombin inhibitor to be available on the market in the United States.  There are currently only two available doses on market: one for patients will normal renal function (150 mg twice daily) and a second for patients whose creatine clearance is below 30 mL/min (75 mg twice daily).  Monitoring of INR is not necessary.

Two major ground breaking trials were published comparing warfarin and dabigatran in venous thromboembolism treatment and as clot prophylaxis in patients with atrial fibrillation at the end of 2009 in the New England Journal of Medicine.

In a non-inferiority study by the RE-LY study group, over 18,000 patients with atrial fibrillation and a CHADS score of at least 1 were randomized to three treatment arms: 110 mg dabigatran twice daily, 150 mg dabigatran twice daily, or a warfarin dose titrated to a goal INR.  The warfarin arm was not blinded.  The patients were studied for 2 years until stroke or systemic embolism and the primary secondary outcome was major hemorrhage.  

Both doses of dabigatran were shown to be non-inferior to warfarin and the higher dose of dabigatran was shown to superior to warfarin.  There was a statistically significant reduced risk of hemorrhagic stroke with both doses of dabigatran compared to warfarin and less bleeding with the 110 mg twice daily dose of dabigatran than warfarin.  The risk of a major bleed with warfarin found within the RE-LY trial was found to be higher than the risk determined in prior studies.  The risk of major bleeding with warfarin determined in this study may have biased the results in favor of dabigatran.

The RE-COVER trial published in NEJM in 2009 compared the treatment of venous thromboembolism (VTE) by dabigatran compared with warfarin.  1274 patients were randomized to receive 150 mg dabigatran twice daily or warfarin titrated to an INR of 2-3.  Dabigatran was determined to be non-inferior to warfarin for treatment of a VTE with no statistically significant difference in bleeding.  However, more patients on dabigatran therapy experienced dyspepsia and were more likely to discontinue the study drug.

Dabigatran has been shown to be a safe alternative to warfarin in the treatment of VTE and in prevention of clots in atrial fibrillation.  There is less monitoring involved, making it ideal to health care professionals but patients should be monitored for compliance due to the high incidence of dyspepsia.  Although it is more expensive, it would be interesting to see in a pharmacoeconomic analysis if the cost of the drug is offset by reduced cost of monitoring.

References:

Baetz BE et al.  Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases.  Pharmacotherapy 2008; 28(11): 1254- 1373.  Accessed at http://www.medscape.com/viewarticle/583856 on 11/10/2010.

Medi C et al.  Stroke risk and antithrombotic strategies in atrial fibrillation.  Stroke 2010; 41: 2705-2713.

Ezekowitz MD et al.  The evolving field of stroke prevention in patients with atrial fibrillation.  Stroke 2010; 41(suppl 1): S17-S20.

Connolly SJ et al.  Dabigatran versus warfarin in patients with atrial fibrillation.  The New England Journal of Medicine 2009; 361(12): 1139- 1151.

Camm AJ.  The RE-LY study: randomized evaluation of long-term anticoagulant therapy: dabigatran vs. warfarin.  European Heart Journal 2009; 30: 2554- 2555.

Gericke CA.  RE-LY study (dabigatran vs. warfarin in atrial fibrillation)- a call for caution.   European Heart Journal E-letter; published November 26, 2009.  Available at http://eurheartj.oxfordjournals.org/content/30/21/2554.extract/reply#ehj_el_95

Schulman S et al.  Dabigatran versus warfarin the the treatment of acute venous thromboembolism.  The New England Journal of Medicine 2009; 361(124): 2342- 2352.

Mzungu / Mafrika

Jumapili 26 septemba

KiSwhili word of the day is wimbo. Song.

Back in Mombasa and I already have my ticket to Tanga. I didn’t really want to come back, but I don’t think Lamu to Tanga was possible, and I had a really great day anyway.

The bus ride was miserable but at least I prepared myself for it. I was in the VERY back and everytime we went over a pot hole I flew out of my seat almost over the chair in front of me. The guy next to me kept getting so angry at the bus driver and calling him lazy and all kinds of names. The reality was the road was in bad condition and we had shitty seats.

As soon as I arrived in Mombasa, I just wanted to walk around. I walked to Fort Jesus and was debating paying to go in when this guy started talking to me and he is a tour guide but wasn’t pushy and really knew the facts. He wanted to show me around... How much? He told me he would show me the city and I could decide after how much to pay him.

Sweet.

Fort Jesus is built on the highest part of Mombasa, 17 meters above sea level, on the coast. It is shaped like Jesus on the cross. The Portugese had a weird sense of humor. It was built in 1497 (?) and the walls are a meter thick. After Vasco de Gama was turned away from Mombasa the first time, the Portugese came back later and settled in here.

There is also an expensive club next to it. Only for people with big pockets. Like Brangelina. I asked if Brangelina had ever come. My guide, Harrison, said no, but they frequent Diani Beach (south of Mombasa) and are apparently very loud.

In the bedroom.

I would have been surprised if he had said otherwise.

Old town in Mombasa had similar architecture to Lamu, with large mahogany doors with shackles carved into them. I noted that it was weird the Arabs made such beautiful carvings to symbolize something so immoral and depressing, but Harrison responded that slavery to the Arabs WAS beautiful; it was a very lucrative business.

I also saw the old ferry port, a Mosque for Indian Muslims, and a Hindu temple. Mombasa is mostly Christian and Muslim with some Hindus and very few Rastafaris. Harrison is rastafari: one man, one woman, peace and love. They pray to Haile Sallassie because, one year, during a drought in Jamaica, Haile Sallassie came to Jamaica and as soon as the plane landed, it began to rain. When Harrison prays, he prays to "Ja". I asked him why he calls his god "Ja". It sounds cool when you're stoned.

When we were leaving the Hindu temple I saw this really cool looking night club so we went over to have a beer and just talked.

Of course he was very curious to know how many children I wanted.

Zero.

Little Chi Chi is enough for me. And I can only think about finishing school and starting my career.

School can wait! But you must have babies now to bring you blessings and happiness!

Which of course is the opposite of American/Western thinking. BABIES can wait. But Harrison already has 4 children by different baby-mamas. He says when he gets married he wants to have 14 children because his father had 10 and he must have more than his father. He asked me if I would like to make a little zebra with him. I politely declined.

We talked about birth control. He said a lot of women in Kenya used the shot (which does not protect against HIV) but said it is frowned upon if a woman does not have many children; it is like being selfish. Comments on condom use, "Why would you eat a banana with the peel still on? It can be done, but isn't better to remove the peel first?" Again I reminded him that eating it with the peel on is better than getting HIV, herpes, HPV, and other STIs but he replied that if you are sleeping with a boyfriend/girlfriend you do not have to worry.

I wanted to ask him how many times he'd been tested. My bets are on zero.

It was interesting. Also because of the amount of corruption in Kenya, the only thing that guarantees you a job is knowing someone at the top, so why bother with school? Family has much more significance in East African culture, so it is only natural that people would want to have large families and start earlier, even though it does not make sense from my cultural perspective.

Harrison also talked about he does not understand wazungu who come to East Africa and get stressed out. You are on vacation. Why are you stressed? He said that wazungu would not endure one day of what an African endures. From the moment a baby leaves its mother, everyday is a struggle to survive. But you know you can survive this day because look at how many days you have already survived this far.

I talked about how many people in the U.S. are depressed. I think part of it is we are told to work hard in school so we can get a good job and be able to afford the American lifestyle, but sooner or later many people just figure out its all just crap. Harrison said even the poorest person is able to laugh and enjoy himself no matter what because he knows what is important. He has life, family, friends. While I couldn't agree with Harrison that I should make a zebra with him immediately, I really value what he said about family.

We finished the Tuskers and parted. I gave him 500 KSH for the tour, but he told me the thing he appreciated most was just having the beer with me.

Beautiful.

Good Snorkeling

Jumamosi 25 septemba

KiSwahili word of the day is "baharini". The ocean.

I drank too much last night and am now preparing myself for a day in the sun on a boat with Captain Happy.

3 other girls from my hotel also paid Omar Shariff the deposit for snorkeling, but counted their losses and are going with someone else. So my American friend and I decided we would ask Omar Shariff if he could go in place of the girls.

As soon as I get to the ferry port and ask Omar Shariff, he flips out. FLIPS OUT. He's yelling about all kinds of things. I said the girls said it was ok for the other American to go in their place so he drags me across the port looking for the girls and we find them as they are getting onto their boat.

I felt awful for them! Seeing this horrible angry stinking Omar Shariff coming at them yelling about how it was rude to promice this and asks if they said what I had told him.

One of the girls nervously looks at me and says, "yes"

"OK THEN IT IS FINE!" Omar Shariff yells and turns around and we walk back to the boat. Whew!

So there are 5 wazungu on the boat: Myself, my American friend, 2 German girls, and a photographer. And 2 sailors. The photographer was great. He is originally from Australia but has lived in Fiji and California (holla) and for the past 14 months has been driving around the continent of Africa taking pictures of tribes in their traditional clothing. He is is Lamu because he is waiting for his Ethiopian visa (which is really easy to get IF you fly into Addis on Ethiopian airline which is owned by the sultan... if not, it is damn near impossible to get).

So we pull up to this spot near another island that is brown with silt from mangrove trees and the captain says "I think here we make good snorkeling". I can't even see my hand under the water. So we are given "fishing poles" which are blocks of wood with fishing line tied around and a hook and weight on the end and sit for some minutes trying to catch fish. The water is so murky the fish probably can't even see the bait.

So we move to another location. Slightly better, but still the water is really murky. "Ok I think here we make for snorkeling".

The photographer inquires about a house boat in the distance. It is a hotel. Bar? Yes.

He immediately jumps ship and starts swimming.

Is he going to the bar?

Just a few meters before he reaches it, I jump in after him, swim to the house boat and he helps pull me up onto it.

Did you bring any money? He asks.

No, did you?

No.

Well, we tried. We hung out for a while and talked then swam back to the boat. The water was warm but part of me was completely panicked about sharks and crocodiles the whole time, especially because I couldn't see under the water.

We finally ended up at the beach across from Shela and played in the waves. I watched Omar, the captain's helper, prepare the food. Then we all got back onto the boat and the captain put up a sun shade for us.

"For you, not for me" he says.

"Well, you certainly have a lot of pigment. But supposedly we are all from Africa... I guess if you don't use it you lose it..." the photographer replies.

After eating we went back to Amu port. Even though I didn't snorkel, I really enjoyed the boat ride. We passed a house or shop near the water with all these 8x10 inch windows but every single one was broken. We asked about it, and the captain said these French people lived there who hated locals walking by their house (even though the house is on the main walkway) and are always giving the locals trouble about whatever issues so one night, a bunch of people came and broke all the windows a few weeks ago. So funny!