Evaluating the Data: What Recent Clinical ... -...

View this activity online at:medscape.org/spotlight/anticoagulants or

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Evaluating the Data: What Recent Clinical Trials Can Teach Us About Preventing Atrial Fibrillation-Related Stroke CMEBruce D. Lindsay, MDKeith A. A. Fox, MB, ChB John H. Alexander, MD, MHS Gregory Y. H. Lip, MD

The Cleveland Clinic Foundation Center for Continuing Education acknowledges an educational grant for support of this activity from:

Bristol-Myers Squibb and Pfizer, Inc.

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Evaluating the Data: What Recent Clinical Trials Can Teach Us About Preventing Atrial Fibrillation-Related Stroke CME

This transcript is being provided for your reference. To participate in the CME activity visit:

medscape.org/spotlight/anticoagulants ortheheart.org/spotlight/anticoagulants

CME released: 09/23/201Valid for credit through: 09/22/2012

Target AudienceThis program is intended for cardiologists, primary care physicians, internists, neurologists, and allied healthcare professionals who manage patients with atrial fibrillation (AF).

GoalThe goal of this activity is to educate clinicians on the clinical trial results for currently available anticoagulant agents and those in development for stroke prevention for patients with AF.

Learning ObjectivesUpon completion of this activity, participants will be able to:

1. Review recent clinical trial data of oral anticoagulants for the prevention of stroke and systemic embolism

2. Evaluate the potential of the novel oral anticoagulants to manage and reduce stroke

3. Implement changes in approach based on recent American Heart Association/American Stroke Association stroke prevention guidelines Credits Available

Accreditation StatementsThe Cleveland Clinic Foundation Center for Continuing Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Cleveland Clinic Foundation Center for Continuing Education designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity

Instructions for Participation and CreditTo participate in this internet activity: (1) review the target audience, learning objectives, and author disclosures; (2) study all of the educational content online; (3) take the post-test and/or complete the evaluation; (4) view/print certificate. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 70% on the post-test. Estimated time of completion: 30 minutes

Authors and Disclosures

Author(s)

Bruce D. Lindsay, MDSection Head Clinical Cardiac Electrophysiology Cleveland Clinic Foundation Cardiovascular Medicine Cleveland, OhioBruce D. Lindsay, MD, has disclosed no relevant financial relationships.

Keith A. A. Fox, MB, ChBProfessor of CardiologyCentre for Cardiovascular ScienceUniversity of Edinburgh Edinburgh, United Kingdom

Keith A. A. Fox, MB, ChB, has disclosed the following relevant financial relationships:

medscape.org/spotlight/ anticoagulants or theheart.org/spotlight/anticoagulants

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Served as a consultant and independent contractor for: Bayer HealthCare Pharmaceuticals; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

John H. Alexander, MD, MHSAssociate Professor of MedicineDivision of Cardiovascular MedicineDuke University Medical CenterDuke Clinical Research InstituteDurham, North CarolinaJohn H. Alexander, MD, MHS, has disclosed the following relevant financial relationships:Served as a consultant and member of advisory committee or review panel for: Bristol-Myers Squibb Company; Ortho-McNeil-Jannsen Pharmaceuticals; Pfizer Inc.

Gregory Y. H. Lip, MDConsultant CardiologistProfessor of Cardiovascular MedicineUniversity of BirminghamCentre for Cardiovascular SciencesCity HospitalBirmingham, United KingdomGregory Y. H. Lip, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Boehringer Ingelheim Pharmaceuticals, Inc.; sanofi-aventis; Bayer HealthCare Pharmaceuti-cals; Merck & Co., Inc.; Astellas Pharma, Inc.; Portola Pharmaceuticals, Inc.; BIOTRONIK, Inc.; AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Pfizer IncServed as a speaker or a member of a speakers bureau for: Boehringer Ingelheim Pharmaceuticals, Inc.; sanofi-aventis; Bayer HealthCare Pharmaceuticals; Bristol-Myers Squibb Company; Pfizer Inc.

Activity Director and Reviewer Katherine J. Hoercher, RNSenior Director of Special ProgramsKaufman Center for Heart FailureHeart and Vascular InstituteCleveland Clinic Cleveland, Ohio

Katherine J. Hoercher, RN, has disclosed no relevant financial relationships.

Editor(s)Javier F. Negrón, PhDScientific Director, Medscape, LLC

Javier F. Negrón, PhD, has disclosed no relevant financial relationships.

Content Reviewer:Nafeez Zawahir, MDCME Clinical Director, Medscape, LLC

Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

All other planners, CME staff, and content reviewers, have no relevant financial relationships to disclose.

DisclaimerThe information in this educational activity is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient’s medical condition. The viewpoints expressed in this CME activity are those of the authors/faculty. They do not represent an endorsement by The Cleveland Clinic Foundation. In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this CME activity.

In accordance with the Standards for Commercial Support issued by the Accreditation Council for Continuing Medical Education (ACCME), The Cleveland Clinic Foundation Center for Continuing Education requires resolution of all faculty conflicts of interest to ensure CME activities are free of commercial bias.

The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on www.theheart.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

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Bruce D. Lindsay, MD: Hello. My name is Bruce Lindsay, and I head the section in electrophysiology and pacing at the Cleveland Clinic. We’re joined today as a panel to evaluate the data of recent clinical trials and what they can teach us about atrial fibrillation-related stroke.

Evaluating the Data: What Recent Clinical Trials Can Teach Us About Preventing AtrialFibrillation-Related Stroke CMEIntroduction: Stroke is a significant concern for patients with atrial fibrillation, contributing to morbidity, mortality, and overall disease burden. Despite its proven benefits, anticoagulant therapy for stroke prevention in patients with atrial fibrillation is widely underutilized and inappropriately applied. Identifying patients at risk for stroke and prescribing anticoagulant therapy accord-ing to risk level are areas for improvement in the management of atrial fibrillation. Limitations of traditional therapies have led to exploration of alternative oral anticoagulants for stroke prevention in atrial fibrillation. Emerging data support the use of new oral anticoagulants -- that exhibit linear kinetics and do not require routine international normalized ratio monitoring -- for stroke prevention in atrial fibrillation. Join Drs. Lindsay, Lip, Fox, and Alexander as they discuss recent anticoagulant trials in the preven-tion of atrial fibrillation-related stroke.


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I’m joined today by my colleagues, Dr. Gregory Lip, he is from the University of Birmingham; Dr. Keith Fox, University of Edinburgh; and Dr. John Alexander from Duke.

To put all of this in perspective, stroke is the most common and devastating complication of atrial fibrillation, and the all-cause stroke rate in patients with atrial fibrillation is about 5% per year. Atrial fibrillation is an independent risk factor for stroke, and there is about a 5-fold increased risk for stroke in patients who have atrial fibrillation. It probably accounts for about 15% of all strokes, and it increases with age, which is a problem in our societies because we have an aging population. That risk persists even in asymptomatic patients.

Now, the biggest problem, as shown in the figure, that we have here is that the therapeutic window for warfarin is extremely narrow. As we all know, we have to keep the international normalized ratio (INR) between 2 and 3, but if it’s subtherapeutic the risk for stroke increases, and if it’s supratherapeutic the risk for bleeding complication increases.

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Now, we are here today among other things to talk about some of the alternatives to warfarin and some of the new trials that have been done. The alternatives include apixaban, rivaroxaban, and dabigatran. Apixaban and rivaroxaban target factor Xa, and dabigatran is a direct thrombin inhibitor. Apixaban and dabigatran are both administered twice a day. One of the potential advantages of rivaroxaban is it can be administered just once a day, and the half-life of these agents is in the range of 9-17 hours. Rivaroxaban is probably a little bit shorter in half-life, somewhere in the range of 5-9 hours, though a bit longer in the elderly. Renal metabolism is about 33% for apixaban and 25% for rivaroxaban but 80% for dabigatran. For patients who have renal failure, dabigatran requires some special consideration. In contrast, hepatic metabolism is higher for the other 2 agents, about 67% for apixaban and 75% for rivaroxaban.

There have been several interesting trials that we’re going to talk about today, and they include AVERROES, which was a study of apixaban compared with aspirin. ARISTOTLE, which is breaking today, is apixaban vs warfarin. Dr. Alexander will be talking about that. ROCKET AF, which was rivaroxaban compared with warfarin, Dr. Fox will be talking about that; and RE-LY, which was dabigatran and warfarin, Dr. Lip will be discussing that.


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In aggregate, these trials include more than 56,000 patients, and the reason for that is warfarin has been pretty effective over the years so it takes a lot of patients to show these differences. In ROCKET AF, more than 80% of the patients had a CHADS2 score greater than 3, and the other trials were down in the 30% range. Participants’ median age was around 70 or so, but what is also interesting in these trials is no matter how carefully we try to regulate the INR, the time in therapeutic range (TTR) was about 55%-68%. That speaks to the difficulty in regulating warfarin. At this point, I’d like to turn to Dr. Lip, and he’ll discuss some of the trials including RE-LY and AVERROES. Dr. Lip?

Gregory Y. H. Lip, MD: Thank you. The first clinical trial of these new anticoagulants to be published and presented was the RE-LY trial, and RE-LY when it was first presented essentially changed the landscape of how we approach stroke prevention in atrial fibrillation. This is a trial comparing the oral direct thrombin inhibitor dabigatran vs warfarin, and this was done in a PROBE design, a prospective, randomized, open, blinded-endpoint evaluation. Patients were randomly assigned to warfarin or dabigatran so they knew they were either taking warfarin or dabigatran, but both doses of dabigatran were given in a blinded manner.

We can see from the Kaplan-Meier curves that dabigatran 110 mg twice a day was noninferior to warfarin for the primary endpoint of stroke and systemic embolism. However, for the 150-mg, twice-daily dose of dabigatran it showed superiority compared with warfarin with 35% less stroke and systemic embolism compared with warfarin. This was a very important result, certainly when it was first published and presented 2 years ago. This was the first time that we had seen one of the new anticoagulants showing superiority to warfarin. It was long considered that warfarin was hard to beat in terms of preventing strokes in atrial fibrillation.

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Turning to the safety aspects from the RE-LY trial, these are summarized on this slide. If you look at bleeding -- and first it concentrated particularly on major bleeding because that is a particularly hard endpoint -- if you compare dabigatran 110 mg vs warfarin there was 20% fewer major bleeds, which was significant. From the efficacy aspect, 110 mg twice a day was noninferior to warfarin and was therefore associated with 20% fewer major bleeds. In terms of the 150-mg dose, there was no significant difference to warfarin in terms of major bleeds. Therefore with the 150-mg dabigatran dose there was superior efficacy in preventing stroke and systemic embolism and no significant difference in the major bleed rate. Both doses of dabigatran had significantly fewer life-threatening major bleeds compared with warfarin. Another important result on the safety aspect is that both doses of dabigatran also showed significantly fewer intracranial hemorrhages compared with warfarin, and of course intracranial hemorrhage is the most feared complication related to warfarin therapy. Here we see with the oral direct thrombin inhibitors significantly fewer intracranial hemorrhages at both doses compared with warfarin.

In terms of gastrointestinal major bleed, there was a slight excess in the 150-mg arm of the trial, which was statistically significant. One result that did cause a bit of discussion was the rate of myocardial infarction because this was numerically increased in both doses of dabigatran compared with warfarin. This was not statistically significant, but still there was a numerical but nonstatistically significant increase in myocardial infarction events in dabigatran-treated patients compared with warfarin. Much has been debated about whether this is largely a protective effective of warfarin or whether this was a bad effect of dabigatran, but it is more likely considered to be a protective effect of warfarin.

Dr. Lindsay: Why do you think warfarin might be protective if this is really a statistically significant trend at least? Why would warfarin be more protective, do you think, than dabigatran?

Dr. Lip: Various mechanistic hypotheses have been put forward, and it is perhaps related to multiple coagulation pathways being affected by warfarin compared with dabigatran, which only targets thrombin. You also see this pattern in some of the other studies comparing warfarin with a new anticoagulant or a warfarin comparator. Certainly this was seen in the SPORTIF III trial, which compared warfarin vs the older direct thrombin inhibitor ximelagatran. There were numerically fewer myocardial infarctions in the warfarin-treated patients compared with ximelagatran. This was also seen in the AMADEUS trial comparing warfarin with the indirect factor Xa inhibitor idraparinux. Quite interestingly in the ACTIVE trial where warfarin was compared with aspirin/clopidogrel combination therapy, there was also numerically fewer myocardial infarction events in the warfarin-treated patients compared with aspirin/clopidogrel.

Dr. Lindsay: That’s interesting. I don’t think we talk about that much, but it seems to be a fairly consistent trend.

Keith A. A. Fox, MB, ChB: There’s another trial with dabigatran more recently that has suggested at least a trend for increased myocardial infarction with dabigatran.

Dr. Lip: Indeed this is one of the venous thromboembolism trials.

Dr. Fox: A venous thromboembolism trial with long-term follow-up, yes indeed.

Dr. Lindsay: Thank you for clarifying that.


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Dr. Lip: Moving on now in terms of the trials in the order they were published or presented certainly in terms of publication, the next trial I will cover is the AVERROES trial. AVERROES is a trial where patients had either refused warfarin or were deemed to have failed warfarin in a sense of having difficulty maintaining warfarin monitoring or keeping it in the target INR range, either from the patient perspective or from the physician perspective that the patient was not suitable for warfarin. In our everyday clinical practice, the physician would reach for aspirin to treat these patients. In AVERROES, therefore, this was a comparison of the oral factor Xa inhibitor, apixaban, an anticoagulant, vs aspirin, and this trial was stopped early due to very clear superiority of apixaban over aspirin in terms of preventing stroke and systemic embolism, which was their primary endpoint. As can be seen from these Kaplan-Meier plots, it was a 55% reduction in the primary endpoint of stroke and systemic embolism.

Dr. Lindsay: That was quite a striking finding when it came out, and it certainly raises questions about some of these other drugs that are coming along the line. Well, we finish our evaluation of AVERROES and then move on to --

Dr. Fox: What if we just ask what kind of effect would you have expected for warfarin against aspirin?

Dr. Lip: Well, this is what we would expect in a sense that even if you look at the older trials or even one of the more contemporary trials, the BAFTA trial where elderly patients were randomly assigned to warfarin or aspirin, we clearly saw again over 50% reduc-tion in stroke.

Dr. Fox: A strong effect, yes.

John H. Alexander, MD, MHS: Greg, when I’m treating these patients, I usually reach for aspirin, but at 325 mg a day. In AVERROES there was a wide range of dosing options with I believe a majority of people getting on the lower end of aspirin doses.

Dr. Lip: That is correct. The treating trialist could choose anything between 81 and 324 mg. In terms of looking at the different doses of aspirin regimens, the P value of interaction was not significant. In any case, the data for aspirin are not terribly strong either, and as you say if you reach for 325 mg, it is on the basis of one trial, the SPAF1 trial, which has major problems.

Dr. Alexander: Yeah.

Dr. Lindsay: Maybe you could comment on the compliance with taking the drug and how often people were able to stay on it during the trial.

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Dr. Lip: Indeed in the AVERROES trial there are 2 other aspects. You have raised one of them, but I started by also saying in terms of the safety aspect, one of the important observations in the AVERROES trial was when you look at major bleeding there was no significant difference between apixaban, an anticoagulant, vs aspirin. The rate of intracranial hemorrhage with apixaban was also not significantly different from that seen with the aspirin-treated patients, and that in a sense was consistent with what we saw in the BAFTA trial as well. In the elderly patients treated with warfarin or aspirin, the rate of major hemorrhage was not significantly different in BAFTA between warfarin and aspirin-treated patients, nor was the intracranial hemorrhage rate. The other aspect of AVERROES is tolerability. If you look at tolerability in terms of permanent discontinuations, apixaban, the anticoagulant, was actually better tolerated than aspirin because the rates of permanent discontinuations, 17.9% per year with apixaban and 20.5% per year with aspirin, this translates to 12% fewer discontinuations with apixaban compared with aspirin.

Dr. Lindsay: That’s an important point because if we look ahead with these drugs, if somebody is on warfarin you can at least measure and get some assessment of whether they are taking the warfarin. With all of the other drugs we will be discussing today, to the best of my knowledge so far there is no way of measuring their effect for clinical regulation, and so we have to rely on what the patients are telling us as to whether they can take it.

Dr. Lip: Well, not yet, but there are anti-Xa assays that are available.

Dr. Lindsay: They are working on it.

Dr. Lip: They’re actually available in some countries.

Dr. Alexander: They’re not widely available because there are no Xa agents widely available being used in chronic therapy now. I expect we’ll see them.

Dr. Fox: But in some countries, they’ve standardized across the country so there is the same anti-Xa assay across the country.

Dr. Lindsay: We haven’t seen that in the United States yet, but that will probably be coming. Then I think that will be key because if you’re going to cardiovert somebody, it does raise the question of what do you do if you don’t have a measure to determine whether they have been taking it?

Dr. Lip: One important point to perhaps emphasize is that you may not be able to have assays that do the same like an INR that we do for warfarin in terms of trying to use that as a measure of how intense an anticoagulant is and to use that to dose adjust. Nonetheless, even relatively simple assays such as the activated partial thromboplastin time, for example, can be used to measure an anticoagulant effect in a patient taking dabigatran.

Dr. Lindsay: Are there any other key points that you would like to make, Dr. Lip? If not, I’d like to move ahead to discussing the ROCKET AF trial. Dr. Fox?


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Dr. Fox: Thanks, Bruce. The ROCKET AF trial was a double-blind, double-dummied design in 14,200 patients, and the aim was to achieve noninferiority compared with warfarin. In the curve that we’re seeing here, you can see that the hazard ratio is 0.79 in favor of rivaroxaban showing that while patients were on treatment -- because the first analysis was the on-treatment analysis -- that it indeed achieved its aim of noninferiority. When we looked at the whole intent-to-treat (ITT) population that included both the time on treatment and the time after treatment, and that in total was another 117 days, then not surprisingly the curves were close together, and it did not achieve superiority in the ITT population.

It may be worthwhile to look at the time on treatment shown in the left-hand panel, which is while they’re receiving the blinded treatment vs events that occur after early discontinuation, and it’s not surprising that the 2 curves are almost superimposed. On the right-hand side, they are very small numbers later on so they aren’t really different.

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When we look at the treatment effect by category, you can see that in the per-protocol population there is clearly evidence that it meets noninferiority, again very similar results if you look at the whole safety population and also achieves superiority while on treatment. The ITT population achieved the aim of noninferiority, and up to the end of treatment it was superior. There were some differences in design across the trials, and that’s why I think it’s helpful to discuss it. Maybe we were very cautious about how we analyzed and presented ROCKET because it included both the on-treatment time and the post-treatment time.

Dr. Lindsay: I’d like to come back to some of the comments about trial design maybe after we’ve had a chance to review all of the studies because that always becomes a factor in trying to interpret these data. But go ahead and make your other points.

Dr. Fox: There are a whole number of things that we have to look at in each of the trials, and you already commented, for example, about the center time and therapeutic range, and that is an important issue.

Dr. Lindsay: A very practical issue.

Dr. Fox: A very practical issue, but it wasn’t measured in the same way in the different trials. In ROCKET there were no blanking periods say in the first 7 days or when people stopped therapy, so the result that you get is not necessarily going to be the same across the trials where the other trials adopted a blanking period. I think we need a straight playing field where we can look at, analyze, and understand the data, and I think that is going to help us.


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Here we show very clearly one of the things that’s happened, which is that at the end of the trial, during the transition when the patients came to the end of the trial, if they were on warfarin actually they remained almost horizontal rather than dipping down. In the rivaroxaban arm, you can see we were very cautious about transitioning them to warfarin, and that resulted in a small number of events, excessive events, in the rivaroxaban arm.

Dr. Lindsay: It does raise the point that as the patients are being transitioned from these drugs, probably most of the time from warfarin to whatever these new agents are, but sometimes in the reverse, there will be a body of experience that we will have to build up in how to do that safely.

Dr. Fox: Absolutely, and that’s why we present here the on-treatment effects, a different number of events in the rivaroxaban arms vs the warfarin arms in favor of rivaroxaban, and off-treatment there was a small excess. I think we were too cautious about that transition.

Dr. Lindsay: We have an exciting trial that got presented today. Let’s go ahead and run through that. Dr. Alexander will run through that with us.

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Dr. Alexander: Thanks, Bruce. I’m really thrilled to be able to share and discuss with you guys the ARISTOTLE data. These results were just presented this morning by my colleague, Chris Granger, and I had the opportunity to participate in the steering committee of ARISTOTLE. Like all of these other trials, and actually most similar to the ROCKET AF trial, ARISTOTLE was a large, 18,000-patient, blinded trial in patients with atrial fibrillation and at least 1 additional risk factor for stroke. It’s a similar population to RE-LY. Patients were randomized to either apixaban 5 mg twice a day, a factor X inhibitor, or warfarin that was adjusted by blinded INR like in the ROCKET AF trial. The primary endpoint was stroke, both ischemic and hemorrhagic stroke, or systemic embolism.

The main results of the trial were that on all-cause stroke or systemic embolism, apixaban resulted in a 21% reduction relative to warfarin that was statistically significant for superiority. Like the rivaroxaban program, ARISTOTLE was designed as a noninferiority trial. Actually, all of these programs were designed before RE-LY was published, and nobody expected any trial, any drug to beat warfarin.

Dr. Lindsay: I think it speaks to how well warfarin has worked over the years. It has done pretty well.


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Dr. Alexander: Absolutely, and so this effect on all-cause stroke was driven mostly by a reduction in hemorrhagic stroke. There’s a large reduction, about a 50% reduction in hemorrhagic stroke with apixaban compared with warfarin. On ischemic stroke and uncertain stroke, because there’s a small number of strokes in which you aren’t able to define whether they are hemorrhagic or ischemic, there was essentially no difference with apixaban compared with warfarin. So apixaban is equally effective to warfarin at preventing ischemic stroke and much safer, and I think that is something we want to come back to because it’s something that I see as a common theme among all of these drugs. We did look at myocardial infarction, and there was no increase in myocardial infarction. There was a trend toward a lower rate of myocardial infarction differentiating it from the thrombin-inhibitor trials.

And then this reduction in stroke coupled with the lower rate of major bleeding that we saw in the trial overall resulted in a borderline statistically, .047, reduction in all-cause mortality. The different trials, I think, just waffle around the P value of .05. ARISTOTLE ended up just on the right side of it, but all of these trials that are reducing stroke and reducing bleeding are benefitting our patients.

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In total, the ARISTOTLE trial demonstrated a 21% reduction in stroke or systemic embolism, a 31% reduction in major bleeding, and an 11% reduction in all-cause mortality. For those of us who have trouble remembering data and numbers, this is really con-venient because it’s 11, 21, and 31. As I said, Chris Granger presented these data just this morning. They are hot off the press, and we’re really excited about them.

Dr. Lindsay: I think as we put all of this together and look at these trials, it’s a very consistent theme. Certainly these drugs are not inferior to warfarin. There is some evidence that they have some benefits to warfarin. I think the question is, as they become more readily available, how are we going to use them? There have been throughout these trials exclusion criteria that do separate out some of the patients we’re currently treating with warfarin. So they didn’t include patients with mechanical valves. We’ll have to learn how to use them appropriately in people who have renal failure, and they’re not included in dialysis patients right now. I guess on a practical standpoint, one of the things we struggle with in the United States is that these drugs are expensive. If you look at a cost-effectiveness analysis, dabigatran looks pretty good with that, but it depends in the United States at least on how your insurance is because the total cost might be better but if you’re the one that’s paying that cost, then it may not be better for you as an individual. How does that compare in England, for example?


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Dr. Fox: The cost issue is important, and I think it is also important that the cost of the drugs is coming out of one pocket but the cost of having a stroke and long-term care is coming out of another pocket.

Dr. Lindsay: INR monitoring is often coming out of a third pocket.

Dr. Alexander: When you compare budgets, you have to bring them all together.

Dr. Fox: These are hard things to balance, but you’ve raised the issue of renal dysfunction. I presented this morning the results of the big cohort, prospective cohort in ROCKET AF with renal dysfunction, those with moderate renal dysfunction, so it’s above 30 mL/minute in creatinine clearance. We reduce the dose of rivaroxaban to 15 mg for that, and the bottom line result is it’s consis-tent with the overall trial. That’s the bottom line result. It’s very interesting. There’s a lot of consistency of several things between the apixaban trial and the ROCKET trial in terms of the hazard ratios are identical and so on, identical. You had a more powered trial, a bigger trial.

Dr. Alexander: We have some number, 50 more events or so, and that P value crosses the bound of statistical significance.

Dr. Fox: One difference that is in favor of apixaban is actually the bleeding. Both of us showed decreased fatal bleeds and intrace-rebral bleeds.

Dr. Alexander: Yes.

Dr. Fox: But overall the reduction in bleeding is a very interesting and I think potentially important result in the ARISTOTLE trial.

Dr. Lindsay: Let me ask you this, and maybe we can go around the table on this. Let’s assume that these drugs were all approved, which is not quite the case, at least for us in the United States. The question is how you decide which patients you would put on these. For example, as I see patients, if they are doing well on warfarin and their INRs have been easy to regulate, I typically just leave them on warfarin unless they feel strongly about it in different ways. Sometimes patients will say to me even if that has been easy to manage that they don’t like having to modify their diet or they’re always concerned about some drug interaction. All of these are well-known problems with warfarin that don’t seem to be an issue with these newer drugs.

Dr. Fox: So, Bruce, this patient comes into your office and says, well, Dr. Lindsay, thank you for telling me that I’m doing really well and I’m well-controlled on warfarin. But I’ve been looking at the Internet, and I see that this same cohort have gone into various other trials with reduced rates of intracerebral bleeding. Is this important, doctor?

Dr. Lindsay: It’s an interesting point because these are statistical differences, but what I’ve generally told patients is that there are differences in populations here, but when you apply it to an individual, those risks are pretty small. So I look at it as being compa-rable.

Dr. Alexander: The stroke risks in the trials are 2% a year or less, right, so 98% of patients do okay.

Dr. Lindsay: They’re doing okay.

Dr. Alexander: But you don’t know which are the 2%.

Dr. Lindsay: Well, of course you don’t. But if cost is an issue for them, and it is at least right now for most of them, that can be a big burden for an uncertain gain. For me it has to do more with how they are managing on warfarin, whether it has been difficult to regulate or whether they have a strong preference from whatever they’ve heard. How do you handle that, Greg?

Dr. Lip: Cost is clearly an issue, and as has been discussed, there is a tendency to directly compare the costs of a new drug vs the cost of warfarin, which doesn’t cost very much at all. The wider picture is obviously monitoring and inconvenience, certainly in the United Kingdom where a lot of anticoagulation monitoring is centralized either in warfarin clinics or the patient going up to the GP and having to take time off. Also, then there are other aspects in terms of the possibility of superiority of the new drugs in reducing strokes and more importantly intracranial hemorrhage, where if an intracranial hemorrhage occurs the mortality is extremely high and morbidity is great. I agree with the point you made that I think an initial batch of patients, most suitable for the new drugs would be those difficult to either attend for monitoring or those we have difficulty keeping within an adequate INR therapeutic range. What will be a real challenge to all of us is the newly diagnosed atrial fibrillation patient who needs anticoagu-lation therapy, and once they’ve done their research on the Internet or wherever, they are going to say I would really much like to be on this new drug.

Dr. Lindsay: There is maybe even a more practical issue here, and that is there are a lot of patients who just aren’t treated. I think many family practitioners are busy. They find it difficult to regulate warfarin, so either they treat them with aspirin or unfortunately often with nothing.

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Dr. Fox: The registries across Europe have shown this significant proportion of patients, maybe a third of high-risk patients with CHADS2 of 2 or more, who are currently either on nothing.

Dr. Lindsay: Nothing.

Dr. Fox: Or some of them are on aspirin.

Dr. Lindsay: So these new drugs may reduce the threshold of getting started on some effective agent, which is not reflected in the studies because they are a very different population.

Dr. Lip: That sort of thing you need to look at either real-world analyses, but I’ll start on making a point. Even a recent Markov decision model published by Mark Eckman, modeling the impact of new drugs by balancing the relative hazard of stroke vs the relative hazard of intracranial hemorrhage, concluded that we should be treating with a newer anticoagulant therapy which gives us a lower annual stroke rate of 0.9% per year. Also, in terms of how the approach has been in Europe with the new guidelines, if you want to look at the net clinical benefit, the net clinical benefit balancing stroke vs intracranial hemorrhage is only negative at a CHA2DS2-VASc score of 0 because they are so low risk.

Dr. Lindsay: Keith, maybe we can close by having you comment on your thoughts on special populations. For example, I don’t think there’s much experience in children or at least limited experience with these drugs. I doubt that they have been used in pregnancy. I’m not sure what the concerns are for that, and perhaps certain minority groups haven’t been included in some of these trials. Could you comment on that?

Dr. Fox: There are challenges in how you translate these trials out into practice, and I think that the population of patients that knock on our doors most who are interested in the new drugs are actually some of the valve patients and of course prosthetic valves, they’ve been excluded, and perhaps moving into the aortic bioprosthetic valve first in order to be cautious might be one of the ways to go.


Pg.19

Dr. Lindsay: I’d like to thank the panel. I think this was a great discussion and all of the data that you put together. I think there is yet a lot of study to be done with these drugs as we look at these special populations and how they’ll be used. But I think we see a clear future for these drugs, and in many cases replacing warfarin in day-to-day management of patients who are at risk for stroke from atrial fibrillation.

Thank you very much.

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