**Transcript of Cyberseminar**

**Evidence Based Synthesis Program (ESP)**

**Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants for the Long-term Prevention and Treatment of Arterial and Venous Thromboembolism**

**Presenter:  Soheir Adam, M.D.**

**June 11, 2012**

**Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants for the Long-term Prevention and Treatment of Arterial and Venous Thromboembolism**

**June 11, 2012**

Moderator:  We are going to do a quick introduction.  We have two presenters today.  Our first presenter is Soheir Adam.  She is an Assistant Professor at Duke University, the Department of Medicine division of hematology.  Her hematology training was in London, England and her areas of interest include thrombosis, anticoagulation, thrombophilia, Sickle cell anemia and myeloproliferative neoplasms.  

Sorry, did I butcher that a little bit?  And she will be joined by John Williams, who is a Professor of Medicine at Duke University Medical Center, and a past recipient of the VA Health Services Career Development and a Robert Wood Johnson Foundation Generalist Faculty Scholar Awards.  And with that, Dr. Adam, can I turn it over to you?  

Dr. Soheir Adam:  Yes.  Thank you very much, Heidi.  Good afternoon, everyone, and thank you for being here today.  I would like if I may start with to start with short polls just to get an idea of your experience with more than anticoagulants and the number of patients in your practice who are currently on new oral anticoagulants. 

Moderator:  And the responses are coming in and we will give it just a few more seconds for a few more responses and then I will show the results on the screen.  And there are results.  And, Dr.  Adam, we did get a request if you could speak up a little bit.  

Dr. Soheir Adam:  Okay.  

Moderator:  Great, thank you.  

Dr. Soheir Adam:  So it seems that we have got an even, almost even split.  And some of you do have a lot of experience with new oral anticoagulants with more than twenty patients from those practices.  

So Vitamin K antagonists, especially Warfarin has been around for over fifty years.  And we do have a vast experience with Warfarin and find it to be highly effective in preventing recurrent CTEs and embolism, stroke and peripheral embolism in patients with atrial fibrillation and prosthetic heart values.

And largely it avoids of long-term side effects apart from bleeding and acidogenicity.  It’s an inexpensive drug with a once daily dosing schedule.  And it does have a specific antidote, Vitamin K, which may take awhile to reverse its action, but it does work.  And it’s also it’s important and I’m sure most of you are aware to remember that it inhibits also the natural oral anticoagulants likes protein C and S.  

The main limitation of Warfarin is its narrow therapeutic range, which means that it doesn’t take much to tip the balance toward thrombosis or bleeding once the line is crossed on either side of the range.  Additional limitations the need for regular monitoring using the INR and numerous interactions with food, drugs and herbal medicines, slow onset and offset of action as well as genetic contributions to dose variability which may complicate management. 

Another poll asking for your input on the biggest challenge that you face while managing patients on long-term anticoagulation, is it (1) lack of compliance; (2) drug interactions; (3) patients not getting tested as directed; (4) lack of communication or patient education; (5) patients not reporting relevant complications?  

Moderator:  Those responses are coming in.  I’ll give it a few more seconds before I close it.  Okay and there are your results.  

Dr. Soheir Adam:  Okay.  I see that most of the audience is suffering from lack of compliance of patients on long-term anticoagulation.  And I think this kind of reflects real-life experience for all of us.  

So why do we need an additional option if Warfarin is working so well and we have this long intimate experience with it?  Out of each one hundred North American patients with AF who do have an additional risk of stroke or for stroke, only one half are receiving Warfarin.  And of these only one half are adequately treated, which means that up to two million are inadequately treated or untreated.  And they may experience up to 100,000 strokes. 

Over the past years several specific inhibitors of coagulation proteins have been developed, and of these the anti Xa inhibitors including Rivaroxaban, Apixaban, Betrixaban and Edixaban, as well as the direct thrombin inhibitor, Dabigatran, which inhibits the free and clot bound thrombins have been developed. And some of them are already approved for use in atrial fibrillation and thromboprophylaxis. 

The ideal anticoagulant should have a wider and safer range of actions and with little thrombosis or bleeding.  Comparing the new oral anticoagulants to Warfarin they have a much shorter onset and offset of actions, but also lesser bioavailability.  

The dose is monitored by INR in case of a Warfarin and adjusted accordingly but in case of the newer anticoagulants they are given as fixed doses and monitoring is not required and can be challenging.  Renal excretion is the main group of elimination for Dabigatran and the newer anticoagulants, but it’s not the case for Warfarin. 

Drug interactions in the case of Warfarin are mainly through the CYP2C9 inhibiters and dietary Vitamin K, which is a long and inexhaustible list of drugs that interact with Warfarin.  In case of oral anticoagulants it’s mainly the P-glycoprotein inhibitors, and in the case of Rivaroxaban the CYP3A4 inhibitors as well. 

Drug reversal is possible in case of Warfarin with Vitamin K.  Fresh frozen plasma bypasses the low levels of Vitamin K depending on factors, and also other drugs are less like [inaudible] and compensate and recombinant VIIa can bypass the effects of Warfarin. 

Unfortunately with the new oral anticoagulants there are no specific antidotes, which may complicate bleeding while on therapy with these medications.  The FDA has approved Rivaroxaban Dabigatran for prevention of stroke in patients with atrial fibrillation and also for thromboprophylaxis in orthopedic surgery in the case of Rivaroxaban. 

Excuse me.  This diagram shows the relationship of the plasma concentration of Dabigatran through various coagulations assays, the most linear relationship being with [inaudible] clotting time, excuse me, which is unfortunately not readily available in all hospitals.  And this is a list of drugs that potentially interact with Dabigatran and Rivaroxaban through P-glycoprotein inhibition or CYP3A4 inhibition. 

While a specific antidote is not available for the new oral anticoagulants, other approaches to reversal of their action has been described like oral activated charcoal immediately after the injection, and also in case of Dabigatran hemodialysis, which can be achieved within two to three hours.  And recently 4-factor prothrombin complex has been successfully used to reverse Rivaroxaban and Dabigatran anticoagulation in healthy volunteers at a dose of 50 and it’s per kg. And it contained factors II, VII, IX and X. However it’s not available in the U.S. and it does have prothrombotic properties. 

The emergence of data on new oral anticoagulants has prompted the commission of this report by the VA looking at the comparative effectiveness of Warfarin and new oral anticoagulants for prevention and treatment of arterial and venous and thromboembolisms.  And I’m going to skip some of the details in the methodology section, but they are available on your slide handout.  And there will be some time for questions at the end of the presentation.  So in the interest of time I will not go through all the details.   

The first key question examined was for patients with AF chronic nonvalvular AF, what is the comparative effectiveness of a new oral anticoagulant versus Warfarin on stroke incidence, mortality, health-related quality of life and patient treatment experience.  We did not identify any studies on health-related quality of life or patient treatment experience. 

The second question was looking at the population with venous thromboembolism or the same outcomes.  Key questions three was to examine patients with mechanical heart valves on new oral anticoagulants and versus Warfarin.  And we did not identify any studies on mechanical heart valves.  

The fourth key question was looking at adverse effects of new oral anticoagulants compared to Warfarin and treatment.  In consultation with a master librarian we searched the main databases for relevant randomized controlled studies, and again I will not be going through the details of the inclusion, exclusion or the rest of the methodology, and the data was extracted by two independent reviewers and these agreements were resolved by the discussion and consent of or referred to a third reviewer.  

Quality was assessed using a standard approach as recommended by the AHRQ method manual for comparative effectiveness.  And these are the details of the data synthesis which I’ll not go through line by line, but again are available for questions at the end of the presentation.  

Strength of evidence have created a high, moderate, low or insufficient based on four domains, the risk of bias, consistency, directness and precision.  Our search identified three good quality randomized studies, six good quality randomized controlled studies, three on atrial fibrillation and three on venous thromboembolism. 

And in the case of atrial fibrillation one of the three, each of the three studies as compared Dabigatran, Apixaban and Rivaroxaban to adjusted through Warfarin.  In the case of VTE two of the randomized controlled studies compared with Rivaroxaban to adjusted dose Warfarin, or deep vein thrombosis and PE. And the third study compared Dabigatran to adjusted-dose Warfarin. 

And the main outcome by diagnosis showed that in atrial fibrillation the risk of all cause mortality and hemorrhagic stroke were both significantly lower in the new oral anticoagulants group compared to adjusted-dose Warfarin.  In the case of venous thromboembolism there was no difference in the main outcomes between the new oral anticoagulant treatment groups and the adjusted-dose Warfarin.  

So the sense of evidence was high in the case of all cause mortality with eight fewer deaths per 1,000 patients associated with the new oral anticoagulant treatment compared to Warfarin treatment.  And the risk of hemorrhagic stroke was also lower in then new oral anticoagulants with four fewer hemorrhagic strokes per 1,000 patients in the new oral anticoagulants.  And the strength of evidence was moderate. 

Looking at adverse events we analyzed the outcomes by treatment group.  So we looked at direct thrombin and [sintafaris], mainly Dabigatran in this case as the only available oral direct thrombin inhibitor currently.  And we looked at the Factor Xa inhibitors and the adverse outcomes in this treatment group.  

The rate for fatal bleeding was found to be significantly lower and the Factor Xa inhibitors compared to adjusted-dose Warfarin, as well as the overall risk when combining both treatment groups compared to adjusted-dose Warfarin.  The risk of major bleeding was lower with new oral anticoagulants.  However, the confidence interval included no effects. 

The risk of gastrointestinal bleeding was increased with the bigger trend compared to Xa inhibitors, but overall it was not different from adjusted-dose Warfarin.  Myocardial infarction the risk was increased with Dabigatran compared to Factor Xa inhibitors, but again there was no difference overall between two treatment groups combining Dabigatran and Factor Xa inhibitors. 

Discontinuation due to adverse events was higher with the new oral anticoagulants, but the confidence interval improved.  There’s no effect.  In a subgroup analysis ,which we will discuss a little bit later on, discontinuation due to adverse events was higher with Dabigatran compared to Factor Xa inhibitors.  

And the risk of liver dysfunction declined as elevation of liver enzymes more than three times the upper limit of normal was not different in both treatment groups.  And the sense of evidence was moderate in the case of fatal bleeding with the risk of fatal bleeding being lower with the new oral anticoagulants with a ratio of 0.60 and the risk difference of one fewer death per 1,000 patients. 

And in the case of myocardial infarction this was not different with new oral anticoagulants collectively compared to adjusted-dose Warfarin.  However, a subgroup analysis identified the risk as the risk ratio as 1.35 in case of Dabigatran compared to Factor Xa inhibitors. 

Looking at the observational studies, we identified numerous reports on bleeding with Dabigatran.  Risk factors included age over seventy-five years and renal impairment, as well as concomitant thrombolytic therapy.  Some of these cases had fatal outcomes.  We also identified two cases of treatment failure in which thrombolytic therapy was successfully used.  

The RELY study was the second largest study we included in our report.  It was a three-arm study looking at two doses of Dabigatran compared to adjusted-dose Warfarin.  Forty percent of the patients were above the age of seventy-five years.  And this group of patients was found to have a higher risk of extracranial, but not intracranial bleeding when treated with Dabigatran 150 milligrams compared to adjusted-dose Warfarin.  

However, the lower dose of 110 milligrams was not found to be superior to the higher dose of 150 milligrams in this age group, which led the FDA to conclude that dose modification in the elderly based on the results of the RELY study was unnecessary.  The greatest benefit of the higher dose of Dabigatran was observed in those below the age of sixty-five.  

And there is gastrointestinal bleeding was increased, which could be attributable to the lower bioavailability which increases the concentration of the active drug in the stools.  Discontinuation of drug due to and of the drug to adverse events was higher in the Dabigatran treatment arm compared to Warfarin.  And the main reason for discontinuation was GI symptoms.  And again GI symptoms could be related to Tartaric acid which is necessary for absorption and included in Dabigatran composition, as well as the high concentration of the active drug in the colon.  

The ROCKET-AF study comparing Rivaroxaban to adjusted-dose Warfarin did conclude that Rivaroxaban treatment was associated with an increased risk of gastrointestinal bleeding, which meant that patients with inflammatory bowel disease, angiodysplasia and diverticulosis may experience deterioration while on Dabigatran and Rivaroxaban treatment. 

The sub analysis of myocardial infarction associated with Dabigatran treatment included—and it was a systematic review including seven randomized controlled studies.  Two of them were on AF, three on thromboprophylaxis in orthopedic surgery and one on acute coronary syndrome.  

Three of the randomized controlled studies included for comparing Dabigatran to adjusted-dose Warfarin.  The systematic review concluded that Dabigatran was associated with a higher risk for MI event control treatments with a risk ratio of 1.32. 

3,781 reports were associated with Dabigatran treatment in 2011 according to the FDA reports earlier this year.  More than 2,300 were bleeding episodes.  Almost 300 were cases of acute renal failure.  654 were strokes and more than 500 deaths, as well as fifteen cases of suspected liver failure.  

Most of these adverse events were reported in the elderly patient population, which led to the FDA issuing the recommendation to re-evaluate the dose in elderly patients.  Also in the case of Rivaroxaban the FDA reported that post-treatment and discontinuation events were higher with Rivaroxaban compared to adjusted-dose Warfarin, which could be attributed to sub therapeutic INR when transitioning from Warfarin to Rivaroxaban. 

So new oral anticoagulants are considered viable options for patients on long-term anticoagulation.  However, the benefits compared to adjusted-dose Warfarin are more evident at centers where there is more control of Warfarin treatment.

Ambulatory patients and those with renal failure are especially at a higher risk of bleeding and may need dose adjustment.  Also thus far there are no head-to-head direct comparisons for the new oral anticoagulants.  And long-term adverse effects of these medications are yet to be evaluated. 

The FDA has issued reports on bleeding complications in both Dabigatran and Rivaroxaban.  They were found to be cost effective, especially in patients with a high CHADS2 score and atrial fibrillation, but not cost saving.  

In atrial fibrillation new oral anticoagulants were superior to adjusted-dose Warfarin for some clinical outcomes, including mortality and hemorrhagic stroke.  And in venous thromboembolism the outcomes were similar in both treatment groups. 

And adverse events such as fatal bleeding were lower with Factor Xa inhibitor treatment.  And discontinuation due to adverse events was found to be higher with Dabigatran treatment.  [The nay spell] however be a role for Warfarin in specific populations based on these findings.  

Elderly patients above the age of seventy-five,  and those with creatinine clearance less than thirty, and patients with mechanical heart valve where new oral anticoagulants were not evaluated, and those with gastrointestinal disease may experience exacerbation of their disease or deterioration of their disease when on oral anticoagulants.  

Most importantly patients should not be switched to the new oral anticoagulants due to non-compliance because the INR is a kind of a forced compliance.  INR monitoring is a forced compliance and it helps ensure that the patients stay within the desired therapeutic range.  

Finally, I would appreciate your feedback with answering this question.  Thank you very much for your attention.  

Moderator:  And responses are coming in.  We’ll give it a few more seconds here.  And also just a reminder to our audience, if you have finished up with the poll question here, please take this opportunity to submit any questions in using the Q&A pane.  

We’ll be getting to questions very shortly here.  So it will be good to have a few of those queued up before we get started.  The Q&A is located on the dashboard on the right-hand side of your screen.  Just click on that orange arrow.  It’s collapsed against the side of your monitor.  

Okay.  And let me just launch the results here.  There are your survey, your poll results there.  

Dr. Soheir Adam:  Okay.  Thank you very much.  [Inaudible]. 

Moderator:  I’m sorry, Dr. Adam, I didn’t hear that.  

Dr. Soheir Adam:  I said I’d be happy to answer any questions and also Dr. Williams is available now to answer your questions.  

Moderator:  Fantastic.  We do have a couple of questions that have come in here.  The first one we have, is there any precaution or recommendation to use Pradaxa in hital hernia patients?  

Dr. Soheir Adam:  If you want, Marie, I can’t hear you.

Moderator:  It says here hital, H-I-T-A-L hernia patients.  

Dr. Soheir Adam:  H-I?

Moderator:  H-I-T-A-L. 

Dr. John Williams:  I suspect that’s hiatal hernia.  

Moderator:  It very well could be.  I’m not a subject expert.  I apologize for everything I put in here.  

Dr. Soheir Adam:  Oh that thing, okay, okay, well not to my knowledge, not to my knowledge.  And I would say that the experience with Dabigatran, you’re talking about Dabigatran, right, the question is about Dabigatran?  

Moderator:  That I’m not sure, most likely but I’m not positive.  

Dr. Soheir Adam:  Okay.  So I’m not aware of any precautions with hiatal hernias.  

Dr. John Williams:  And we are doing a separate review of the agents, this is John Williams, in patients for the prevention of venous thromboembolism in patients undergoing total hip and total knee replacement. That will be out later this fall, so certainly in this calendar year.  And we’ll be comparing the newer agents to low [melotorate] Heparin to Warfarin and other strategies for preventing venous thromboembolism.  

Dr. Soheir Adam:  Right.  And so currently only Rivaroxaban is approved for thromboprophylaxis, primary thrombophylaxis in orthopedic surgery.  And there is of course some off label used, but as far as FDA approval only Rivaroxaban is approved, but we’ll be looking like John just mentioned at all the available trials on new oral anticoagulants [inaudible].  

Moderator:  Great.  Thank you.  We also had one of our attendees write in saying that he has forty patients on the therapy and has never had a patient complain about the GI disturbance.  So there’s another viewpoint on that there.  

Dr. Soheir Adam:  And that’s great.  And I should just mention that the mechanism for a GI disturbance is still very speculative.  We do think that the drug is available in the active form in the GI, which kind of exacerbates the GI symptoms, but having said that in our practice also we do have a lot of patients with no problems whatsoever while on the oral anticoagulants, the new oral anticoagulants.  They do not have any GI symptoms.  

Moderator:  Okay.  Thank you.  And we’ll to the next question here, the next question.  Is there a biologic reason to suspect different effects in patients with valvular heart disease?

Dr. Soheir Adam:  To suspect?  All right, can you repeat the question?  

Moderator:  Is there a biologic reason to suspect different effects in patients with valvular heart disease?

Dr. Soheir Adam:  Well these patients have been—well it’s basically first all it has been approved, or these drugs are approved for non-valvular atrial fibrillation.  So the question is there any biologic, are there any biological reasons.  We don’t have enough experience in valvular disease with these new oral anticoagulants.  And it’s always important to remember that they act in a totally, just by a totally different mechanism compared to Warfarin.  

So while Warfarin kind of inhibits the activation of the oxidation of the Vitamin K dependent of factors, these drugs are specific inhibitors of single coagulation proteins which may mean that you will have much more interactions at other levels of the coagulation [cap As].  And we don’t know whether they would be as effective in preventing thrombosis for strokes in patients with valvular disease because we don’t have a lot of experience with them so far. 

Dr. John Williams:  And this is John Williams.  The—if the—the question is also thinking about patients who have undergone a valve replacement.  Currently these drugs are not approved for that indication.  We know that it’s being used off label in some instances for anticoagulation in patients who’ve had mechanical heart valve for example because the FDA has been getting adverse event reports including thrombosed valves. 

There is an ongoing clinical trial that is looking at the comparative effectiveness of newer oral anticoagulants, and I don’t recall which one right off the bat, compared to adjusted-dose Warfarin in patients with mechanical heart valves.  So those data will be forthcoming, but that trial is underway. 

Dr. Soheir Adam:  Right.  There are some risks we will gain now for this trial and it’s the first trial to evaluate the new oral anticoagulants in patients with mechanical valves.  

Dr. John Williams:  And I guess I would add one other caution.  Even in patients with non-valvular afib where we have I think pretty good data about how the drugs work, is that the duration of follow up at its most lengthy is two years.  Many of these patients are going to be on the agents for much longer than that.  And I think we should all stay tuned to the long-term follow-up studies that look at things like the less common adverse effects, the experience for patients who are managed on these drugs outside of clinical trials, which tend to have more homogenous samples because of their selection criteria and sometimes better follow up because they’re involved in studies than patients who may be more adherent and more both to taking the medication and to follow up.  

Moderator:  Great.  Thank you.  The next question that we received, are there data on the use of the newer agents in poorly compliant patients?

Dr. Soheir Adam:  The short answer is no.  And as you have seen the randomized controlled trials that were included had very strict inclusion and exclusion criteria.  And some of the therapeutic OCTR, the CTR value were like lower than sixty percent in some of the trials.  And this was with a lot of control and very strict selection inclusion criteria.  So the answer is no.  

And my clinical experience is that patients who are non-compliant on Warfarin will not be compliant on the new oral anticoagulants because with Warfarin we do have the INR to keep everybody in check, and we will no or recognize in our non-compliant patients and help by adjusting the dose or bringing them back more frequently to the anticoagulant clinic, while in the case of new oral anticoagulants the first evidence of non-compliance may well be a stroke that the patient presenting with a stroke or DVT.  So there is no way to monitor compliance in case of new oral anticoagulants this far, thus far.  

Moderator:  Great.  Thank you.  Okay, the next question that we have, have you looked into off-label uses of the NOACs?  Is it being used for treatment of VPEs?

Dr. Soheir Adam:  Actually yes.  And we do have a few patients who are on off the label or on with off-label indications and are using new oral anticoagulants.  And most of the time this is because the patient is aware of the availability of the oral anticoagulant and they request specifically to be started on them, or if they have like a host of all other drugs that could be interacting with Warfarin and it’s very difficult to adjust their doses while on these other medications. 

So yes it is being used for treatment of VTE and PE, unlike John mentioned, in some cases also with mechanical valves.  Also in primary prophylaxis we are for specific surgery it has been used and they are being used currently.  

Moderator:  Great.  Thank you.  The next question that we have, are you planning pharmacoepidemiologic studies within the VA population?  I’m not sure what the formulary alternatives are.  

Dr. Soheir Adam:  Okay, John, you want to answer this question?

Dr. John Williams:  So our group is not specifically looking at that or planning to do that, although I think the VA clinical databases give us a unique opportunity for those kinds of studies.  So if that’s something someone on the phone call is interested in doing I think it’s a great idea and I would encourage you to pursue it, but no our group does not have plans along those lines. 

Moderator:  Okay.  And that person sent in a follow-up question.  Will our workup for suspected thrombophilia in patients with recurrence be affected?  Will the same panel of tests be relevant?

Dr. Soheir Adam:  So this is for a patient presenting with idiopathic thromboembolism, or idiopathic VTE.  I’m assuming this is the question.  

Moderator:  I can only give you what I’ve got.  If—

Dr. Soheir Adam:  Okay.  

Moderator:  —the questioner wants to send in additional information that would be great, but yes.  

Dr. Soheir Adam:  Based on that yes. 

Moderator:  They said today yes.  

Dr. Soheir Adam:  Okay.  So yes for the idiopathic venous thromboembolism we usually have a panel of sets for underlying thrombophilia.  And usually some of these sets cannot be done at presentation, but in the case of new oral anticoagulants.  And if you are talking about adherence and if you’re talking about ease of administration of that and you think that we’re going to be using the oral anticoagulants much more than we are using [long molecular] weights Heparin and transitioning the patients to Warfarin because of suspected underlying thrombophilia, I don’t think it’s going to be different.  

I don’t think it’s going to change because so we think that the thrombophilia screening isn’t an idiopathic VTE, should not be used or should not be conducted unless there are specific indications like for example of strong familiar history or a young patient presenting with first thrombosis in absence of and risk factor or an identifiable risk factor, also patients who do not have any previous history of previous [stemic], I’m sorry, they do not have an underlying risk factor whether transient or otherwise should be investigated, but I don’t think we will change our protocols for investigation of these patients.  

Moderator:  Okay, thank you.  The next question that we have here, which anticoagulant would you use in a 54-year-old female patient with thrombophilia who has widely fluctuating INRs and is a vegetarian?

Dr. Soheir Adam:  That’s an excellent question.  So if this patient presented with an idiopathic VTE and their INR is widely fluctuating, I would actually consider Rivaroxaban because of well the fluctuating INR is going to be a problem to maintain here on long-term Warfarin.  We have had very good experience with Rivaroxaban even with off-label uses.  It’s quite stable.  The dose is usually there’s not with any multiplications and the side effects or adverse events are very few.  

Moderator:  Great.  Thank you.  And I’m going to apologize before asking this last question.  There are words in here I do not know how to pronounce, so please bear with me.  When an interacting drug such as Ketoconazole is ordered for a patient on Dabigatran, is dose adjustment of Dabigatran recommended?

Dr. Soheir Adam:  Actually it is recommended not to be given concomitantly with Dabigatran, Ketoconazole.  And this is the current recommendations not to give them concomitantly because basically those adjustments were not found to be a practical way of approaching this.  So the recommendation currently is not to give them concomitantly with each other, and also the same applies for Rivaroxaban.  

Moderator:  Great.  Thank you so much.  And that does conclude our questions for today’s session.  Dr. Adams, Dr. Williams, do either of you have any final remarks you’d like to say before we close up here?

Dr. Soheir Adam:  Thank you very much.  John, would you like to add anything?

Dr. John Williams:  I guess I would add a couple of things.  One is that we briefly described that these drugs were determined to be cost effective, but not cost saving.  They do cost more compared to adjusted-dose Warfarin.  The differences between the new drugs and adjusted-dose Warfarin disappear or get smaller at locations where you are able to deliver very high quality adjusted-dose Warfarin therapy. 

I guess the other caution I would add is that when we did our subgroup analyses for example looking at myocardial infarction, our GI bleeding rate between the Factor Xa and direct [promin] inhibitors that those are indirect comparisons across studies.  And they could be confounded by differences in the study population or differences in the way the trials are executed.  So I wouldn’t take those to the bank just yet.  I would think about them as exploratory analyses that certainly give me some cause for concern about Dabigatran versus some of the Factor Xa inhibitors, but in no way a definitive finding at this point.  And I think that’s all I wanted to add.  

Dr. Soheir Adam:  And I would concur with John’s remarks.  And I would say that the experience is quite limited at this time with the longest period of follow up being only two years with these drugs.  And there is still a place for Warfarin in management of patients on long-term anticoagulation, especially in those subsets such as the elderly, and those with renal failure and the non-compliant patients which have been if they were on anticoagulants and then disappear from clinic for a few months.  

So it’s early days yet and they should be carefully evaluated.  And while clinical experience is growing we still are learning some new data about these drugs every day.  Thank you very much for your attention. 

Moderator:  Wonderful.  Thank you so much, Dr. Adams, for taking this time to put this together and to present for us today.  And thank you, Dr. Williams, for joining us for the Q&A.  For our audience thank you so much for joining us today.  We appreciate you taking time out of your schedules. 

And as you leave today’s session you should have a survey pop up on your screen when you leave.  If you could take a few moments to fill that out we love getting your feedback.  We definitely listen to you we have for our current sessions and definitely for planning our future sessions.  

Thank you, everyone, for joining us today and we hope that you join us for a future HSR&D cyberseminar.  Thank you and this concludes today’s HSR&D cyberseminar.  Thank you.  

**[End of Recording]**