University of Thessaly, Larissa, Greece

University of Thessaly, Larissa, Greece
2013 Joint meeting BNS-BSC NOACs (new oral anticoagulants): are we ready for a wide use after stroke? YES George Ntaios University of Thessaly, Larissa, Greece Dear colleagues, good morning. Please allow me first to thank Prof .. And Prof …. For their kind invitation to be here today with you and discuss about anticoagulant treatment in stroke patients. Also, I would like to thank them because they gave me the easy task, that is to support the NOAC, and they left the difficult task, to support warfarin to my opponent, Prof. Chatelain! Leuven, Belgium 23/11/2013

Disclosures Support to attend conferences: Bayer; Sanofi-Aventis; Pfizer; Lundbeck; Boehringer-Ingelheim; Galenica; Elpen; Bristol Myers Squibb. Honoraria: Quintiles; CHUV; Medtronic. Speaker fees: Sanofi Scholarships: European Stroke Organization; Hellenic Society of Atherosclerosis. Participation in trials National coordinator (Greece) for the ENOS trial. Sub-investigator (AMGEN, ).

And let me tell you first a few things about warfarin, that we all know…

Don’t forget my INR ! Warfarin is a great drug, but it has some problems. And perhaps the main limitation is that we need to measure INR every 3-4 weeks.

Target INR 2.5 (range 2-3) 20 Ischemic stroke 15
Intracranial hemorrhage Odds ratio 10 5 And this is because warfarin has a narrow therapeutic window. The higher the INR, the lower the stroke risk is. On the other hand however, the higher the INR, the higher the risk of hemorrhage. And the best compromise, is the area around 2.5, and this is why we measure the INR every few weeks, to target this value. 1.0 2.0 3.0 4.0 5.0 6.0 7.0 INR Courtesy of Patrik Michel, adapted from Hylek et al. NEJM 1996; 335:540-6

And very frequently, we need to change warfarin dose according to the measured INR. And as you know, there are many algorithms available to guide the physician and the patient to adjust the dose, like this one, this one, this one, this one, and this one…!

Baker W, et al. J Manag Care Pharm 2009;15:244-52
But despite these algorithms and despite the frequent INR measurements, the truth is that we don’t perform very well. This is a study where the investigators estimated the time within therapeutic range (or else, TTR) in various clinical settings. So, what they found was that in patients followed-up in anticoagulation clinics, the TTR is approximately 63%, whereas in commuity-based settings the TTR was only 55%. Cumulative Effect of Warfarin Management on the Proportion of Time Spent Within Therapeutic INR Range Baker W, et al. J Manag Care Pharm 2009;15:244-52

Active Clotting Factor
Why is it so difficult ? Inactive precursor Active Clotting Factor - Diet Reduced Vitamin K Oxidised Vitamin K Vitamin K oxide reductase But why is it so difficult to adjust INR? The answer lies in warfarin’s metabolism. In order to generate the procoagulant factors II, VII, IX and X, we need vitamin K, which needs to be oxidized. Our organism has an enzyme called vitK oxide reductase converts back vitamin K into its reduced form so that it can be used again. So, what warfarin does is to inhibit this enzyme, and thus inhibits the activation of the coagulation factors. And there are two enantiomers of warfarin, the S and the R enantiomers, of which the most important is the S enantiomer. These enantiomers are metabolized by some cytochromes in the liver. And it is these cytochromes which regulate the magnitude of the anticoagulant effect of warfarin. Unfortunately, there are many factors which modulate this catarract. And a major factor is diet! CYP1A1 CYP1A2 CYP3A4 CYP2C9 S R WARFARIN

As we know, there is a lot of vitK in green vegetables
As we know, there is a lot of vitK in green vegetables. So, if your patient wants to keep his INR steady, he should better consume steady amount of green vegetables. And there are tables available which can guide patients how to design his diet. I am afraid that there are not many patients using such tables….

Inactive precursor Active Clotting Factor - Diet - Drugs Reduced Vitamin K Oxidised Vitamin K Vitamin K oxide reductase Another major factor that modulates this catarract is drugs. Some drugs are metabolized in the liver cytochromes, which are the very same enzymes that also metabolize warfarin. And as a result, INRs may be higher or lower. CYP1A1 CYP1A2 CYP3A4 CYP2C9 S R WARFARIN

Alcohol (acute and chronic) Allopurinol Aminodarone Aminoglutethimide
Abciximab Acetaminophen Alcohol (acute and chronic) Allopurinol Aminodarone Aminoglutethimide Amobarbital Anabolic steroids Aspirin Azathioprine Butabarbital Butalbital Carbamazepine Cefoperazone Cefotetan Cefoxitin Ceftriaxone Chenodiol Chloral hydrate Chloramphenicol Chlorpropamide Chlorthalidone Cholestyramine Cimetidine Ciprofloxacin Clarithromycin Clofibrate Corticotropin Cortisone Coumadin Cyclophosphamide Danazol Dextran Dextrothyroxine Diazoxide Diclofenac Dicloxaxillin Diflunsial Disulfram Doxycycline Erythromycin Ethacrynic acid Ethchlorvynol Fenoprofen Fluconazole Fluorouracil Gemfibrozil Glucagon Glutethimide Griseofulvin Haloperidol Halothane Heparin Ibuprofen Ifosamide Indomethacin Influenza virus vaccine Itraconazole Ketoprofen Ketorolac Levamisol Levothyroxine Liothyronine Lovastatin Mefenamic Meprobamate Methimazole Methyldopa Methylphenidate Methylsalicylate Miconzale Metronidazole Miconazole Moricizine HCl Nafcillin Nalidixic acid Naproxen Neomycin Norfloxacin Ofloxacin Olsalazine Omeprazole Oxaprozin Oxymetholone Paraldehyde Paroxetine Penicillin G Pentobarbital Pentoxifylline Phenobarbital Phenylbutazone Phenytoin Piperacillin Piroxicam Prednisone Primidone Propafenone Propoxyphene Propranolol Propylthiouracil Phytonadione Quinidine Quinine Ranitidine Rifampin Secobarbital Sertaline Simvastatin Spironolactone Stanozolol Streptokinase Sucralfate Sulfamethizole Sulfamethoxazole Sulfinpyrazone Sulfisoxazole Sulindac Tamoxifen Tetracycline Thyroid hormone Ticacillin Ticlopidine t-PA Tolbutamide Trazodone Trimethoprim-sulfamethoxazole Urokinase Valproate Vitamin C Vitamin E And here is a list with drugs which interact with warfarin… oh sorry, and this…. And this….and this….. And this! Quite a lot, aren’t they? So, ideally, your patient should have such a list with him and anytime that a physician prescribes a drug to him, he should check if this drug is included here, and of course he should visit you to ask what he should do with his warfarin dose…. And if you think that this will only happen rarely, please have a look at some of these drugs… aspirin …….ranitidine

Inactive precursor Active Clotting Factor - Diet - Drugs - Polymorphisms Reduced Vitamin K Oxidised Vitamin K Vitamin K oxide reductase Another factor which modulates this catarract is the polymorphisms of these enzymes. And depending on the polymorphism of the enzyme, your patient may need higher doses of warfarin, or lower, to reach the ideal INR. CYP1A1 CYP1A2 CYP3A4 CYP2C9 S R WARFARIN

Estimated warfarin daily dose (mg) based on patient age and genotype
Age (years) CYP2C9*1 CYP2C9*2 CYP2C9*3 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 6.5 (2.9, 10.2) 6.3 (2.7, 9.9) 6.0 (2.5, 9.6) 5.8 (2.2, 9.3) 5.5 (2.0, 9.0) 5.3 (1.8, 8.8) 5.0 (16, 8.5) 4.8 (1.3, 8.2) 4.5 (1.1, 7.9) 4.3 (0.9, 7.7) 4.0 (0.6, 7.4) 3.8 (0.4, 7.2) 3.5 (0.9, 6.9) 3.3 (-0.2, 6.7) 3.0 (-0.5, 6.5) 5.8 (1.9, 9.8) 5.6 (1.8, 9.4) 5.3 (1.6, 9.0) 5.1 (1.5, 8.7) 4.8 (1.3, 8.3) 4.6 (1.1, 8.0) 4.3 (1.0, 7.7) 4.1 (0.8, 7.4) 3.8 (0.5, 7.1) 3.5 (0.3, 6.8) 3.3 (0.1, 6.5) 3.0 (-0.2, 6.3) 2.8 (-0.5, 6.0) 2.5 (-0.8, 5.8) 2.3 (-1.1, 5.6) 5.5 (1.3, 9.8) 5.3 (1.2, 9.4) 5.0 (1.1, 9.0) 4.8 (1.0, 8.6) 4.5 (0.8, 8.3) 4.3 (0.7, 7.9) 4.0 (0.5, 7.5) 3.8 (0.3, 7.2) 3.5 (0.1, 6.9) 3.3 (-0.1, 6.6) 3.0 (-0.3, 6.4) 2.8 (-0.6, 6.1) 2.5 (-0.8, 5.9) 2.3 (-1.1, 5.7) 2.0 (-1.5, 5.5) And this is a table reporting the estimated warfarin daily dose of your patient depending on his age and his polymorphisms, So, for example, your 70-year old patient would need 4mg of warfarin daily if he has the first polymorphism, but only 3 mg if he has the last polymorphism. Thrombosis & Anticoagulation Research Group

“… lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes …” And the FDA recommended in 2007 that “….”. Which of course means that we know the polymorphisms of our patients. Which means that we, as treating physicians, order this examination before we start warfarin in our patient. And let me share my little secret with you: I never ordered any polymorhism in my atrial fibrillation patients despite this FDA recommendation. And I am curious, how many of you in this hall did you ever order this examination? Noone…? OK, so now it is our little secret… ! FDA 2007

45.2% 45.4% Kimmel, et al. NEJM 2013, online early
But the truth is that until recently, we were not really sure that we have to take into consideration these polymorphisms. 3 days ago, there were 3 randomized trials published in the NEJM trying to answer this question. So, in the first trial, they compared the TTR between patients with genotype-guided warfarin dosing and patients with the usual warfarin dosing. So, what they found was that there was no difference: the TTR was exactly the same: 45.2% vs 45.4%! Kimmel, et al. NEJM 2013, online early

61.6% 60.2% Verhoef, et al. NEJM 2013, online early
In the second trial, the results were again the same: no difference between the genotype-guided group and the control group Verhoef, et al. NEJM 2013, online early

67.4% 60.3% Pirmohamed, et al. NEJM 2013, online early
However, the third trial did show a difference, which was however small: 67% vs 60%. So, as we conclude from these trials, there is probably no benefit of using genotyping to guide warfarin dose, and even in case that there is a benefit, this is small, especially considering the cost of this examination. Pirmohamed, et al. NEJM 2013, online early

Anti-VKAs’ limitations
Narrow therapeutic window Frequent INR monitoring Frequent dose adjustments Unpredictable dose response Drug and food interactions Slow onset/offset of action So, as we see, warfarin has a number of limitations like …….

And unfortunately, these limitations are exactly the reason why warfarin is so underused. As we see in this recent study, the proportion of eligible patients who were receiving warfarin is not more than 50%. Almost half of all eligible atrial fibrillation patients are not anticoagulated! Baker W, et al. J Manag Care Pharm 2009;15:244-52

So, it is no wonder that the medical community was looking for a better drug than warfarin. And if you want to know how long we were looking for a better drug, please have a look at this publication by someone Dr Link who asks if we can look forward ……. And if you wonder who is this Dr Link, please let me tell you that he is the Professor Link who discovered…. warfarin!!!

Anti-VKAs’ limitations
Narrow therapeutic window Frequent INR monitoring Frequent dose adjustments Unpredictable dose response Drug and food interactions Slow onset/offset of action And fortunately, at last, we now have some better choices than warfarin, that do not have these limitations.

And we all know these new drugs
And we all know these new drugs. It is dabigatran supported by the RE-LY trial, rivaroxaban supported by ROCKET-AF, and apixaban supported by ARISTOTLE trial. We all know these trials very well, so I will not get into details. And since last Tuesday, we have a new drug, edoxaban, supported by the ENGAGE trial published in the NEJM three days ago.

Guigliano, et al. NEJM 2013, online first
Given that this is a very recent publication, I will briefly present the key findings of this trial. It was a non-inferiority trial of two doses of edoxaban versus warfarin. Both doses were shown to be non-inferior to warfarin in the endpoint of stroke or systemic embolism. Guigliano, et al. NEJM 2013, online first

Guigliano, et al. NEJM 2013, online first
Also, both edoxaban doses were associated with lower risk for major bleeding. Guigliano, et al. NEJM 2013, online first

Rivaroxaban Apixaban Edoxaban Dabigatran Acenocoumarol Warfarin
What is the their mechanism of action? As we know, warfarin inhibits the vitK-dependent coagulation factors, that is II, VII, IX and X. Dabigatran is a direct thrombin inhibitor, whereas rivaroxaban and apixaban inhibit the activated X factor.

Now , please let me focus on the specific population that we discuss today, i.e. patients with atrial fibrillation and previous stroke. We did a subgroup meta-analysis of these 3 trials focusing on this specific population.

Ntaios G, et al. Stroke 2012; 43: 3298-3304
Let’s have a look at the results: approximately 15 hundred patients with a follow up of approximately 2 years, and a TTR of approximately 60%. Ntaios G, et al. Stroke 2012; 43:

For the endpoint of stroke or systemic embolism, there was a significant difference of 15% in favor of the new oral anticoagulants. Ntaios G, et al. Stroke 2012; 43:

But for the endpoint of ischemic stroke (or else: non-hemorrhagic stroke), there was absolutely no difference. Ntaios G, et al. Stroke 2012; 43:

On the conrary, for the endpoint of hemorrhagic stroke, there was a 56% reduction with NOACs compared to warfarin! Ntaios G, et al. Stroke 2012; 43:

Regarding safety, there was no difference in the risk of gastrointestinal hemorrhage… Ntaios G, et al. Stroke 2012; 43:

But there was a significant difference in favor of the new oral anticoagulants for the endpoint of major bleeding. Ntaios G, et al. Stroke 2012; 43:

The difference in mortality was barely significant in favor again of the new oral anticoagulants,… Ntaios G, et al. Stroke 2012; 43:

Finally, there was absolutely no difference in the risk of myocardial infarction. So, the conclusion of this subgroup meta-analysis is that these new drugs are better than warfarin not because they are more effective to prevent a stroke recurrence, but because they are safer and will not cause intracranial and major hemorrhage as often as warfarin. Ntaios G, et al. Stroke 2012; 43:

Now, someone would tell you that these drugs are expensive
Now, someone would tell you that these drugs are expensive. And they are! They are expensive. But we already have good studies published in high-impact journals like Stroke, Neurology, Annals of Internal Medicine, which conclude that these drugs are cost-effective.

NOAC’s limitations (?) Patients with renal function impairment
Patients with mechanical valves Can not monitor drug effect and titrate dose No specific antidote Their short half-life makes them dangerous in non-adherent patients Not better than warfarin for high TTRs Now, there are some facts about the new oral anticoagulants that someone could present as limitations. And the first one is that you need to be careful in patients with renal function impairment. And that is true, there are specific recommendations how to use these drugs in patients with renal failure. You need to first calculate creatinine clearance, and then adjust the dose. if we don’t do this and our patient bleeds, it is not the drug’s fault, it is our fault because we didn’t follow the recommendations. Then, mechanical valves is not an indication for these drugs. The recently published RE-ALIGN trial showed that in these patients, warfarin is better. So, it is clear, don’t use these drugs in patients with mechanical valves – but actually this is not what we discuss in this debate, we discuss secondary stroke prevention. Then, someone may tell you that it is a disadvantage that you can not monitor the anticoagulant effect. Well, I don’t remember many people complaining that you can not monitor the effect of aspirin or clopidogrel for clinical practice. This is not a disadvantage, it is advantage that you don’t need to monitor the effect. Then, there is criticism that there is no specific antidote for these drugs like vitK is for warfarin. Well let me just remind us that you need to wait for more than 12 hours for vitK to reverse warfarin’s effect. But if you can wait for 12 hours in a bleeding patient, then probably this seems rather minor hemorrhage, doesn’t it? So, if it a minor hemorrhage that can wait for 12 hours for warfarin’s reversal, it can perhaps also wait 12 hours until the levels of these new oral anticoagulants start to significantly decline because of their short half life. On the other hand, if this is a major, an urgent bleeding on warfarin, you probably will not wait 12 hours for vitK and you will immediately administer coagulation factors like prothrombin complex. But this is not a specific antidote for warfarin either. So, for major urgent bleedings in patients with oral anticoagulants, you may simply administer coagulation factors, like you do with warfarin. We have some related studies: prothrombin complex was shown to reverse the anticoagulant effect of rivaroxaban, but it was not succesful to reverse the anticoagulant effect of dabigatran. Of course, we still need more studies in different doses and larger populations. But at the bottomline, does it really matter if we don’t have a specific antidote for the new oral anticoagulants? Let me answer that, no, it doesn’t matter. Please have a look at this study which was recently published in Circulation, and which compared the bleeding outcomes in the dabigatran trials. So, as we see, patients who bled on oral anticoagulants had lower 30-days mortality than patients who bled on warfarin. So, it seems that despite the lack of a specific antidote, bleeding on oral anticoagulants has a better outcome than bleeding on warfarin. Then, someone may notice that their short half-life makes them dangerous in patients with poor adherence. Well, of course, warfarin is also dangerous for a patient with poor adherence. But please let me say that usually poor adherence is not our patient’s fault, but rather our fault because we didn’t spend enough time with him to discuss and explain what atrial fibrillation is and how dangerous it is, how important anticoagulation is for him, and how important good adherence is. Then, someone may tell you that these drugs are not better than warfarin for high TTRs, that is for patients whose time within therapeutic range is satisfactory. And this is true really! Eerenberg, et al. Circulation 2011; 124:1573-9 Majeed, et al. Circulation 2013; 128:

Wallentin L, et al. Lancet 2010; 376:975–83
This graph comes from subgroup analysis of the RE-LY according to the TTR. So, in patients with a low TTR (i.e. <…), dabigatran 150 was definitely superior. The effect was somehow diminished in patients with a bit higher TTRs (figure 2 and 3), and was abolished for patients with extremely high TTR, i.e. above 72%. Wallentin L, et al. Lancet 2010; 376:975–83

Wallentin L, et al. Lancet 2010; 376:975–83
Similarly, for the endpoint of major bleeding, warfarin was definitely worse than the new oral anticoagulants in patients with low TTRs (figure 1 and 2), but for patients with high TTRs the two drugs were equal. So, yes, the two options seem equivalent when the TTRs are high. Wallentin L, et al. Lancet 2010; 376:975–83

But I am sorry, high TTR is not what happens in real life. In real life, TTRs are much lower. We saw this graph before. Even in anticoagulation clinics, the TTR is just 63%, whereas in the community setting, the TTR is only 55%. Baker W, et al. J Manag Care Pharm 2009;15:244-52

NOAC’s limitations (?) Patients with renal function impairment
Patients with mechanical valves Can not monitor drug effect and titrate dose No specific antidote Their short half-life makes them dangerous in non-adherent patients Not better than warfarin for high TTRs Bleeding rates in real-life were higher than in RCTs Finally, someone may tell you that in real life, the bleeding rates with these new oral anticoagulants are higher than in the RCTs.

As we see, Australia has issued a bleeding warning about dabigatran reporting that bleeding rates were higher than expected.

And this was also the case for Japan that had issued a strong warning to physicians of potentially deadly bleeding with these new drugs.

So, then the FDA initiated a Safety Review to investigate this issue.

“We believe that the large number of reported cases of bleeding associated with dabigatran provides a salient example of stimulated reporting.” And what was the conclusion of this safety review? You may read the conclusion in the New England Editorial by Mary Southworth from the FDA, who says that this large number ….., and than bleeding rates….., and that finally, they believe that dabigatran provides an important ….. “Bleeding rates associated with dabigatran are not higher than those with warfarin, a finding that is consistent with the results of RE-LY.” “We believe that dabigatran provides an important health benefit when used as directed.” Southworth M, et al. NEJM 2013; 368:1272-4

The same also here in Europe: The European Medicines Agency in 2012 concluded that the latest available data are consistent with the known risks of bleeding!

NOAC’s limitations vs. Warfarin
Reduce stroke or systemic embolism Reduce ICH Reduce major hemorrhage Steady dose Limited drug & no food interactions No INR monitoring Novel oral anti-coagulants So, to summarize, the new oral anticoagulants are definitely a better choice than warfarin because they …….

THIS IS ALREADY HAPPENING !
NOACs (new oral anticoagulants): are we ready for a wide use after stroke? YES THIS IS ALREADY HAPPENING ! So, the answer to our debate is yes, we are ready for wide use of the new oral anticoagulants after stroke. And actually, not only we are ready, but this is already happening!

Kirley K, et al. Circ Cardiovasc Qual Outcomes. 2012;5:615-621
This is from a recent publication from the U.S. showing the national anticoagulation treatment visits during the recent years. This line shows that anticoagulation visits keep constant. But let’s see what is happening since 2010 when dabigatran was launched. Dabigatran visits are rapidly increasing, whereas warfarin visits are rapidly declining. Kirley K, et al. Circ Cardiovasc Qual Outcomes. 2012;5:

Exactly the same findings are reported from Canada, where as we see with the red colour, dabigatran prescriptions are sharply increasing since 2010 and now approach approximately 20%. Xu J, et al. CMAJ 2013

And please let me close this presentation with an imaginary scenario: let’s turn back time and imagine that in 1939, Prof Link hadn’t discovered warfarin but dabigatran, rivaroxaban, apixaban and edoxaban. And these were the drugs that we were using all these decades. And then, in 2010, a new drug came around called warfarin. And let’s imagine that you are the FDA. And let’s imagine that the company which owns warfarin, comes to you, the FDA, asking for your approval. So, they tell you that you know, we have a new drug, a very good drug. Of course, they say, it causes more bleedings, and there are some food interactions, and there are some drug interactions, and you have to measure INR every 3 weeks, and you have to adjust the dose very frequently, but, but, but…. We are cheaper! You, the FDA, would you give your approval to such a drug? Just think it over… Thank you! NOAC…

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