Melissa,

I understand your angst. We love to measure results and it puts us in an uncomfortable zone not to do so. Since we can't measure the effect of the treatment, we are unsure if it is working enough vs working too much.

Perhaps we should recognize that many other drugs used in medicine ultimately depend on the outcome e.g. birth control pills, cancer chemotherapy drugs etc.

Based on the RELY trial, the drug prevents more strokes and embolic events with the downside of increased GI bleeding. As one sage said "You can transfuse blood, but you can't transfuse brain".

Agree about cost, perhaps as other competitors come on the market over the next year, we will see it fall.

I like it :) 

RE-LY used the C-G formula with the actual weight to calculate GFR: not the MDRD estimation or 24 hour urine collections. The FDA used this data to formulate their recommendations.

Although PTT does not correlate well with ECT or dabigatran levels, at the extremes it is helpful. A trough level > 3x ULN is too high. A PTT in the control range (particularly 32 or less) indicates absence of effect (these statements are derived from the published FDA data). Unless renal function has significantly deteriorated, 5 days of waiting is not necessary.

 Also, who says that the trough is therapeutic after the first dose? Maybe this is good enough when converting from heparins, but I am not sure it is safe to cardiovert after just one dose of dabigatran and a normal TEE.

David and Ralph,

thanks for your comments.  I'm a bit uncomfortable at the extremes of age with C-G forumula though I understand your point.

I don't think there is an answer to your cardioversion question, merely conjecture I believe unless some subset analysis has been published?

Thanks

Melissa

Bleeding to Hb 6.0 in a 87 year old female on 150 bid with a creatinine of 0.8 (pharmacy directed dosing choice). BUT she was also taking aspirin without my knowledge. She's been on coumadin for years with NO bleeding. Within three weeks of switching to Pradaxa she has bled.

Running Gut.  I'm wishing for that 110 bid dose right about now.

Melissa

I wonder who will be the first to give 150mg in the AM, and 75mg in the PM in attempt to

split the difference between 150 bid, and 75 bid?

Add to the comfort and confidence of weekly patient self testing and your old friend warfarin almost becomes a new friend again. Better warfarin control and the ability to monitor compliance is a benefit you cannot have with any new agents. The increased testing frequency will provide you with fewer critical INR values which in turn results in decreased risk of major bleeding including ICH.

Alere Home Monitoring is one service company providing complete support for clinicians wishing to offer imrpoved INR control. Medicare reimbursed for weekly testing - warfarin is not only affordable but the benefit/risk ratio may make this 60 year old choice look pretty attractive.

George,

NO DATA for that, but I did it yesterday. (Guess I have about as much data for that as the FDA does for 75 bid though :)

Melissa

Gary,

I think you need to put up your disclosure right?

Melissa

Good day, Dr.Melissa Walton-Shirley,

I'm a cardiologist in Québec, Canada. Dabigatran has just received approval for refund 2 days ago, 2011-4-20, for NON VALVULAR AF, by the MEDICATION plan of the Quebec government. . But in a restricted fashion:   RESTRICTED ONLY FOR PATIENT :

1-ANTICOAGULATION IS NOT WITHIN THERAPEUTIC RANGE;

2-SURVILANCE OF ANTICOAGULATION WARFARINE  IS NOT POSSIBLE;

3-SURVILANCE OF ANTICOAGULATION WARFARINE  IS NOT AVAILABLE. 

 I agree only on the first restriction, since 10-40% INR are out of therapeutic range, i then keep for my dossier one print of a graft of the recent years of INR results, that prouves  me and the government that i comply to the restriction. 

But the restrictions 2+3 look to me very restrictive: seems wright only for hunter in wild forest... how do they know they have AF ?  

I also have one formula to complete, then e-mail or fax, give 5 days sample; and write one prescription.  And NO LAWYER HARASSEMENT IN CANADA ! Probably in 1 year, formula of exception will be replaced by a simple code; like Plavix code is CV 19. 

Finally, i have access to newer and safer Tx.            

Louis-André Chartrand, md, frcp, cspq

Erin,

Here is what the "author means by 'ridiculous cost of Pradaxa':

Three prior auths on my desk on a Friday afternoon for Pradaxa. Though I appreciate the attributes of this medication, it's hard to stomach that individual Americans pays so much for new medications so the rest of the world can afford theirs.   None of the patients can afford the around $180.00/month cost. (Warfarin $6.00/month).  More often, the population utilizing "Pradaxa" live on a fixed income, as many are medicare aged patients. It is remeniscent of the same debacle we faced when Dronedarone came onto the market without the third party payer issues worked out. Lots of patients were started on Dronederone and still the hassles of trying to get the medication into the mouths of patients were daily for months. We were told NONE of this when we started prescribing and getting the patients onto the medication. Once on it, they need to be maintained and it was a nightmare. Now, the same with Pradaxa often.  

Added to the cost issue is the difficulty with getting it prior auth'd. I called the number given to me by the pharmacy to get it prior auth'd yesterday. The gentleman was nice enough but said I'd been given the wrong number. This was for some other medication authorization. My secretary ran to get the other two charts, I called both numbers left for those patients, again the wrong numbers.  I called the pharmacy back and by then, another pharmacist had come on duty.  He didn't know the correct number.  THEN, I just told my secretary to give the patient samples so we could supply her until Monday.  WE ONLY HAD 150 mg available .  So, I called the pharmacist back and he had mercy on the patients and gave her a week's supply until we could start the ad nauseum phone calls again on Monday.  

Patients on a fixed income  shouldn't have to choose between purchasing groceries or preventing a stroke.  I stand by the statement that the cost is ridiculous and by the way, the cost of "Plavix" is ridiculous as well.  

Melissa

George,

I've not been made aware of any hepatic issues with Dabigatran. Thanks for posting. So honorable of you to report it as many times, we are are bit lazy in our reporting of such events. GOOD FOR YOU!!!

Louis-Andre: I was not certain if you had to meet all three restrictions or just one?  It seems that everyone would meet number one since less than 50% of patients are fully anticoagulated at all times in several trials.  Good luck. Hope the year passes uneventfully until you can get it for your patients with less hassle. We are still dealing with Hassles down here in the good ole US of A!

Thanks for posting gentlemen!

Melissa

Per Melissa-Walton-Shirley's request - I am associated with Alere Home Monitoring - a company dedicated to improve the safety, practicality and quality of life for patients taking warfarin. We provide complete service for healthcare professionals including using medically certified patient trainders.

Our time in range for > 50,000 patient self testers is over 66% time in range and over 80% with a slight variance of .2 low, .5 high.

Medicare has issued special reimbursement codes for home INR testing. The G-codes reimburse physicians for training and interpretation of home test results and offset the cost of the monitor 100% for patients.

We believe the growing market can benefit from new and old treatments - for patients remaining on wararin, professionals have recommended high quality warfarin managment including patient self testing.

Resources for patients and professionals managing warfarin can be found at our non-promotional, non-commercial site: www.ptinr.com

GaryL

Melissa, 

Great discussion.  I appreciate you highlighting the importance of evaluating a patients ability to pay and insurance coverage.   If a patient cannot affort a medication and as a result they don't take it care is compromised.  Simple concept but very important.

A concern I have is anticoagulants in general are high-risk medications.  Despite decades of use we continue to have adverse drug events/med errors related to warfarin.  With dabigatran now on the market (and more to come in the near future) we have just added another oral anticoagulant to the "tool box" but I'm not sure we have done a good job anticipating potential adverse drug events or med errors.  One should anticipate an increase going from one oral anticoagulant to two.  I have had colleagues reporting patients accidentally taking both warfarin and dabigatran, inappropriate prescribing of enoxaparin with dabigatran, etc...  I fear that marketing may given patients and potentailly prescribers a false sense of security (no need to monitor, less bleeding). 

While there is a role for dabigatran in care I think it should be used with the same level of caution as any other anticoagulant.  I think your post helps to raise awareness with some of these concerns.   

Hi Connie - you might find this of interest.

Regards - Ken Croll

Thanks Brian.  I am hopeful the kinks will get ironed out. It took about three months with Dronederone. Same kind of thing here.

Melissa

Dear Dr. Shirley,

In Japan, an authority for anticoagulation treatment told us that new OAT drug, Dabigatran,has light and shadow.

As you might be aware, actually from the results of RE-LY, Dabigatran reduces the bleeding complication comparing Wrafarin, and no interaction with any food, espacially VK inducers(Natto, soybeans based food is quite tradittional and popular in Japan).

But, Dabigatran does not have any antidote, any monitoring way, has any possibility of MI, and has frequent gastrointenstinal bleeding. Further more, the capsule of Dabigatoran is bid huge for the elderly people in Japan. It causes difficulty in swallowing it. And, the authority pointed out that patients always forget intake drugs and tell a lie, "I abosolutely take drugs along with your indication, doctor". At this case, the docotor does not have any ruler like PT-INR. Doctors,also patients do,can not have any infomation of the efficacy of Dabigatran.

I guess it is not happy for both.

Noboru Saito

let me add another small area of concern:

I've now had 2 patients presenting with bleeding (one GI, the other hematuria) on pradaxa 150mg BID with normal renal function. Both patients had a history of CHF, with valvular disease but relatively preserved LV function. Both patients arrived at the hopsital off Warfarin for >4 weeks, with a "therapeutic INR". both had evidence of at least mild congestive hepatopathy. I suspect there was underlying INR elevation that may have made them "auto-anticoagulate" off warfarin, and then became more susceptble to bleeding by adding full dose pradaxa. Suspect further that their INR adjustment on warfarin took into account this hepatopathic effect of dosing. I haven't seen this reported, and I've sent this comment to the R&D of the company for comment. Just a thought, that in our CHF patients being converted from warfarin to pradaxa,  perhaps checking an INR one week after initiation of therapy, we might avoid "over-anticoagulation" and potential bleeding.

Dr Donato J. Arguelles FACC 

A couple of comments/questions from the inpatient pharmacist's perspective. The 87 yo female with scr of 0.8, Was CRCL calculated using 0.8 or 1? actual body weight or corrected?

As for potential surgery patients you can look at aPTT to get a qualitative idea of how anticoagulated a person is, for example we use <40 as cutoff for LP or Epidural placement. This can be used for all direct thrombin inhibitors.   

Your 150/75 dosing is interesting at if crcl is between 30-50.

Bryan

 WN,

I think common sense must apply here.  Higher CHADS2VASC scores in my opinion should be admitted. Why take a chance? 

Melissa

There is one point which is not often addressed , and when someone ealrier rand my bell with "you can transfuse blood, you can't transfuse brain.

But sometimes you wish you could "exfuse" blood. 

Re-Ly patients fared  better  or not worse on dabigatran than on coumadin.

Hopefully:

-  only patients such as those included will be started on dabigatran,

-  and  real life will confirm Re-Ly so that it wont' be a re-lie (sorry, too tempting)

Yet, the emergency physician in me sees a different population in the ED than that included in the Re-Ly trial: 

- bleeding patients (trauma / non trauma)

- intracranial haemorrhages (which also happen on dabigatran)

- patients in need of statim emergency surgery

In those patients in case they are on coumadin,  prothrombin complex (PC)  would revert them within minutes to a normal INR without any proven risk for thrombosis (unlike factor VII) . PC is largely used in Europe.

Dabigatran has been marketed without the antidote being available , in addition to being marketed without an assesment test kit. 

Makes me shiver. Well  all haemorrhages eventually stop , don't they ? But I'll have a hard time to c onvince my ICU fellow to admit the dabigatran-ised patient for dialysis. 

On the other hand I'd be happy to start anticoagulation with "just one pill" for my DVT / PE patients, when allowed to....

I noted a comment above about the questionable safety of giving one dose of dabigatran before cardioversion after TEE.  There is a subset analysis of the RELY trial that was published in Circulation, 2011;123:131-136 looking at patients who were cardioverted on dabigatran vs. warfarin.  The data did not look at patients receiving just one dose of dabigatran before cardioversion- it looked at those on dabigatran <3 wks/>3wks.   The results showed a very low stroke rate after cardioversion in all 3 groups (D110, D150, warfarin)- not powered to show statistical difference.  It also showed that patient's had no difference in stroke rate if treated empirically with dabigatran for 3 weeks and cardioverted, regardless of TEE. 

Given that dabigatran requires no bridge, what would be the difference between a lovenox bridge + warfarin vs. empiric dabigatran?  I cardioverted a patient on Friday- he was sent out on lovenox + warfarin over the weekend, but the housestaff forgot to tell the social worker that the patient could not afford the copay on the lovenox.  The patient returned to clinic today- no lovenox, and an INR of 1.  I think I would have preferred to battle the insurance company for the pre-auth for the dabigatran on Friday, and sent the patient out on a reliable dose of dabigatran (plus I have pradaxa copay cards from the reps to help cut down the cost to my patients for now).

Crystal

We have received a sorrowful and tragic report that a patient was dead who took Dabigatran.

And, several patients went back from Dabigatran to Warfarin because of gastrointensitinal symptom and hematuria.

I guess, it is useful or vital that  physicians use Wrafarin, Dabigatran and other Xas for different occasions. 

own pradaxa for about two monts 150 mg and plavix

my rectum hurt so bad i coud not set down.now i take one of the pradaxa a day now i can set down

Mary,

Pradaxa is not FDA approved for use in patients with a mechanical valve. Please rediscuss this issue with your cardiologist.

Melissa

Hi Melissa

I am a pharmacist in New Zealand.  We have had Pradaxa available (fully funded) for about three months now.  It is very unusual here to have a new drug, especially one at this price, to be granted full funding to the general population on entry into the New Zealand drug market.  The normal process is for it to be available to a very select group of patients via specialists applying for funding.

Hence, it has been prescribed with some gusto.  Just in the last week it has had some negative media attention here, leading to a few of my patients changing back to Warfarin.

The media have reported two fatalities and a number of hospital admissions with GI bleeds.  The two fatalities were in elderly patients who were not transitioned correctly from Warfarin to Dabigatran.

There is growing concern that the elderly are more likely to suffer from GI bleeds from Dabigatran, even when following guidelines regarding renal function.  My understanding is, there is a small study underway at Auckland Hospital and that the recommendations of this will provide prescribing guidelines relating to age.  

As new information becomes available, I will endeavour to post it

Candy,

Thanks so much for your post.  I think the issue with bleeding is those patients who've been on warfarin for a gazillion years who've never really achieved a therapeutic INR for any length of time. Suddenly, with Dabi, there is no question. You are getting the full monty, hence bleeding occurrs. It's a stress test for the gut.  

By the way, do you guys have the 110 dose available there?

Melissa

Hi Melissa

Yes, we do have the 110 dose, which is for patients over 80 years old and those with moderate renal function.

We also have the 75mg, but as yet I haven't dispensed any.

Hello

I have been on chemotherapy for metastatic bladder cancer to my liver since 6/2011

Just 3 days ago diagnosed with Deep Vein Thrombosis behind my knee.

My oncologist initiated Pradaxa dose 75 mg twice daily.

I have one kidney.  Currently undergoing 24 hour uring for GFR study to see if I can tolerate a higher typical 150 Mg. BID regime.

I see notes herein discussing severaly variations of dosing from 150 mg in morning and 75mg in evening.

I also see a note indicating a 110 mg capsule exists.

 Is that so?    My doctor is pretty bright but I do want to be educated about this serious 

matter and discuss with him.

Thank you 

Wayne Quinn                Seattle Washington USA   ( I am a registered nurse so felt okay blogging on here) 

Wayne,

All health care providers, researchers and industry are welcome here as long as identities are posted and posts aren't repetitively argumentative. Welcome!

However, we cannot advise individuals regarding individual health care. I will make a general statement that the 110 mg bid dose was not approved by our FDA. It is available in many other countries. Amazingly, the 75 mg bid dose was, and in my opinion, a glaring error of ommission. I also check GFR's though  the RELY trial did not dose patients based on actual GFR measurements but rather estimated GFR's. 

I encourage you to sit down with your physician and discuss the rely trial which was approved for non-valvular afib patients. This  med class has also been studied extensively for DVT prophylaxis.  I've not used it in patients with established DVT or PE. I utilize warfarin for that diagnosis.

Melissa

More fatalities, please see this link:

http://www.stuff.co.nz/national/health/5717410/Pradaxa-deaths-probed

I'm one of those that switched from Coumadin to Pradaxa....Now I'm having second thoughts because of dosage. I see info about 75mg & 110mg's caps but my Cardio guy says not available....

I'm one of those patients that less is more and with dosage @ 150MG TWICE A Day I'm bleeding,and I'm having dizzy spells.....I'm scared.....going for GI stuff and then don't know what I'll do????

Dr. Melissa.

 I'm wondering what you have heard, if anything, regarding the interaction of Pradaxa and Multaq. I am on both meds, and recently read a vague report regarding the increase of serum levels of Pradaxa up to 1.7-2 times the levels without the Multaq. I've seen nothing else about this, but it's very worrisome to me. I keep having wierd side effects on this combo of meds and am trying to decipher what the cause is. My doctors currently don't know of reports of similar side effects (well some, like the terrible GI stuff) but I'm also having bad nightmares, am tired and brain fogged, forgetful, and like my IQ dropped about 30 points all of the time and am unsteady on my feet and just feel plain weird.

 Thanks. I'm not asking your medical advice about what to do, just curious if you've seen anything. 

Trev,

So far, this interaction is acknowledged but I don't think we currently understand if it is translating into clinical bleeding. I don't think I have anyone on that combination currently but the option has come up several times in conversation. I avoid the combination for now but am happy to hear others' opinion/experiences. Anyone from industry is also welcome to bring us up to speed and address the Canadian guidelines/recommendation as well, which vary from ours ocassionally. 

Melissa

Hello again Melissa et al....

 Almost 2 months on the Pradaxa 75 mg. BID for the several DVT's behind knee.

Totally asymptomatic regarding pain/swelling/redness etc. at this time thankfully.

No apparent side effects.   My MD was indeed aware "somewhat" of the RELY study 

aforementioned.  With a Creatinine of 1.8 and an estimated GFR of 40  this dosing became his 

choice for me.

I am very pleased as a patient with the simplicity of all of this  ie.  no INR's  or blood  draws

whatsoever.   I do have however a very grave concern about the clear lack of "antidote"

should a trauma or significant bleed should occur.   Taking the chances.   

While looking over the internet I did stumble upon a Minnesota emergency room physician who did

a YOUTUBE piece on "what if your patient is in significant bleed on Pradaxa and gets to the ER"

Worth a look. I trust you are aware of these limited options.  Vitamin K clearly out.

Thrombin and Factor 7  a good choice. Dialysis.   I unfortunately cannot locate that educational video as I 

look back.  It was pretty informative.

Again I am a patient here making comments from my lay perspective.  So far a very happy 

reciever of the Pradaxa option but also a bit fearful for "lack of proven antidote" in emergency 

situation.   Thank You.   

ADVERSE REACTIONS

  Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The RE-LY study provided safety information on the use of two doses of Pradaxa and warfarin [see Clinical Studies (14)]. The numbers of patients and their exposures are described in Table 1. Limited information is presented on the 110 mg dosing arm because this dose is not approved.

Drug Discontinuation in RE-LY

The rates of adverse reactions leading to treatment discontinuation were 21% for Pradaxa 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of Pradaxa were bleeding and gastrointestinal events (i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea).

Bleeding [see Warnings and Precautions (5.1)]

Table 2 shows the number of patients experiencing serious bleeding during the treatment period in the RE-LY study, with the bleeding rate per 100 patient-years (%). Major bleeds fulfilled one or more of the following criteria: bleeding associated with a reduction in hemoglobin of at least 2 grams per deciliter or leading to a transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding). A life-threatening bleed met one or more of the following criteria: fatal, symptomatic intracranial bleed, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.

The risk of major bleeds was similar with Pradaxa 150 mg and warfarin across major subgroups defined by baseline characteristics, with the exception of age, where there was a trend towards a higher incidence of major bleeding on Pradaxa (hazard ratio 1.2, 95% CI: 1.0 to 1.4) for patients ≥75 years of age.

There was a higher rate of major gastrointestinal bleeds in patients receiving Pradaxa 150 mg than in patients receiving warfarin (1.6% vs. 1.1%, respectively, with a hazard ratio vs. warfarin of 1.5, 95% CI, 1.2 to 1.9), and a higher rate of any gastrointestinal bleeds (6.1% vs. 4.0%, respectively).

Gastrointestinal Adverse Reactions

Patients on Pradaxa 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs. 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer).

Hypersensitivity Reactions

In the RE-LY study, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in <0.1% of patients receiving Pradaxa.

7  DRUG INTERACTIONS

The concomitant use of Pradaxa with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided [see Clinical Pharmacology (12.3)].

P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran [see Clinical Pharmacology (12.3)]. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone.

In patients with moderate renal impairment (CrCl 30-50 mL/min), consider reducing the dose of Pradaxa to 75 mg twice daily when administered concomitantly with the P-gp inhibitor dronedarone or systemic ketoconazole. The use of P-gp inhibitors (verapamil, amiodarone, quinidine, and clarithromycin) does not require a dose adjustment of Pradaxa. These results should not be extrapolated to other P-gp inhibitors [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

The concomitant use of Pradaxa and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) should be avoided [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

8  USE IN SPECIFIC POPULATIONS

  Pregnancy

There are no adequate and well-controlled studies in pregnant women.

Dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 times the human exposure at maximum recommended human dose [MRHD] of 300 mg/day based on area under the curve [AUC] comparisons) prior to mating and up to implantation (gestation Day 6). Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition. Although dabigatran increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat, it did not induce major malformations in rats or rabbits.

  Labor and Delivery

Safety and effectiveness of Pradaxa during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using Pradaxa in this setting [see Warnings and Precautions (5.1)].

Death of offspring and mother rats during labor in association with uterine bleeding occurred during treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times the human exposure at MRHD of 300 mg/day based on AUC comparisons).

  Nursing Mothers

It is not known whether dabigatran is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Pradaxa is administered to a nursing woman.

  Pediatric Use

Safety and effectiveness of Pradaxa in pediatric patients has not been established.

  Geriatric Use

Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups [see Warnings and Precautions (5), Adverse Reactions (6.1), and Clinical Studies (14)].

  Renal Impairment

Renal function should be assessed by calculating the CrCl prior to initiation of treatment with Pradaxa. While on treatment, renal function should be assessed in clinical situations which may be associated with a decline in renal function. In patients with a CrCl <50 mL/min or >75 years of age, renal function should be assessed at least once a year.

No dose adjustment of Pradaxa is recommended in patients with mild or moderate renal impairment [see Clinical Pharmacology (12.3)]. Reduce the dose of Pradaxa in patients with severe renal impairment (CrCl 15-30 mL/min) [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Dosing recommendations for patients with CrCl <15 mL/min or on dialysis cannot be provided.

Adjust dose appropriately in patients with renal impairment receiving concomitant P-gp inhibitors [see Warnings and Precautions (5.3), Drug Interactions (7), and Clinical Pharmacology (12.3)].

10  OVERDOSAGE

Accidental overdose may lead to hemorrhagic complications. There is no antidote to dabigatran etexilate or dabigatran. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with Pradaxa, and investigate the source of bleeding. Dabigatran is primarily excreted in the urine and shows low plasma protein binding. Therefore, dabigatran can be dialyzed with the removal of about 60% of drug over 2 to 3 hours; however, data supporting this approach are limited. Consider surgical hemostasis or the transfusion of fresh frozen plasma or red blood cells. There is some experimental evidence to support the role of activated prothrombin complex concentrates (e.g., FEIBA), or recombinant Factor VIIa, or concentrates of coagulation factors II, IX or X; however, their usefulness in clinical settings has not been established. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used. Measurement of aPTT or ECT may help guide therapy [see Clinical Pharmacology (12.2)].

Good Evening Melissa

Re: Intracranial Haemorrhage et al

It is very interesting to look at the four studies done on the new oral anticoagulants (Sportif V, RE-LY, Rocket AF and Aristotle).  Sportif V (ximelagatran vs. warfarin) was a North American trial. The intracranial bleeding rate in the warfarin arm of the study was very low: only 2 out of 1,962 patients in 1.67 years (0.06%/yr).  Ximelagatran was taken off the market and Sportif V has been omitted from most of the discussions on the new oral anticoagulants.

The subsequent trials (RE-LY, Rocket AF and Aristotle) were switched from a North American to an international forum (39-45 countries) and all of a sudden the intracranial haemorrhage rates in the warfarin arms became 6-8 times that experienced in Sportif V's warfarin arm.

Including countries with high death rates from hypertension, high rates of intracranial haemorrhage, patients taking asa and clopidogrel in addition to poor warfarin control systems created a significant bias against warfarin in these studies.  

Our "old buddy" warfarin is probably still our best and safest option provided we do a better job of monitoring INR's (time in therapeutic range of >80%), which can be accomplished using point of care testing and computerized warfarin dosing systems (e.g. INR Online - New Zealnad).  Perhaps the right answer is to use these new tools with warfarin instead of throwing out a cheap, effective, reversible drug, not dependent on renal clearance, and whose degree of anti-coagulation and patient compliance can all be accurately measured.  We should not forget that the recommendation in favour of dabigatran from the American College of Chest Physicians (ACCP), is Grade 2B not 1A.

For the sake of better clinical science, we need to gather real world, North American data on all of the new oral anticoagulants vs. warfarin at varying levels of INR control including time in therapeutic range of >80% from our stroke registries.   

Warfarin can only come out better with improved control.  The RE-LY study's sensitivity analysis published in the Lancet Vol. 376, Issue 9745, pages 975-983, 18 September 2010, demonstrates this clearly, as warfarin is superior to dabigatran 150 mg at TTR's >72.6% for non-haemorrhagic stroke and systemic embolism.  

With this analysis in mind, the serious doubts about the reported intracranial haemorrhage rates in the North American context as mentioned, the lack of monitoring tests, the lack of a reversal agent, the additional costs of the drug, renal clearance testing, blood bank products and dialysis for cases of haemorrhage, the advantages of dabigatran boil down to convenience.  This being said, perhaps we should wait until the ACCP can support dabigatran with a Grade 1A recommendation before abandoning warfarin.

Murray Trusler, MD 

P.S. The intracranial haemorrhage rate for dabigatran 150 mg in RE-LY was 0.1%/yr.

M.