Samuel Z. Goldhaber, MD; Christian T. Ruff, MD, MPH


December 04, 2013

This feature requires the newest version of Flash. You can download it here.

Samuel Z. Goldhaber, MD: Hello. This is Dr. Sam Goldhaber for the Clot Blog at the on Medscape, speaking to you from the American Heart Association Scientific Symposia in Dallas. Today it's a true pleasure to have Dr. Christian Ruff with me, co-principal investigator of the ENGAGE-AF trial with edoxaban, the largest-ever trial looking at stroke prevention and atrial fibrillation.[1] Christian, welcome to the Clot Blog.

Christian T. Ruff, MD, MPH: Thank you, Sam. I'm very excited to be with you this morning.

Dr. Goldhaber: We've been waiting for years to learn the results of this trial. Do you want to summarize for our and Medscape viewers what they should take away from this landmark trial?

Dr. Ruff: It's been quite a journey. As you know, ENGAGE-AF TIMI 48 is the largest of the 4 trials studying one of the novel oral anticoagulants (NOACs) vs warfarin for stroke prevention in atrial fibrillation. In the ENGAGE-AF trial, we enrolled 21,105 patients. And we randomly assigned them to either warfarin standard of care or 2 different doses of edoxaban: a high-dose 60 mg once daily or the low-dose 30 mg once daily. And importantly, with those 2 edoxaban doses, we incorporated a dose adjustment for clinical factors that increased the risk of bleeding: either a creatinine clearance l < 50 mL/min, a body weight ≤ 60 kg, or taking medications that inhibited the P-glycoprotein system.

Both dose arms included a dose reduction of 50% for patients with one of those risk factors for high drug exposure. So you would go from 60 mg to 30 mg or 30 mg to 15 mg. We enrolled a large amount of patients and followed them for a median duration of 2.8 years. Warfarin, which was the comparator arm, was actually used expertly in this trial. The median time to therapeutic range was 68.4%, which is a real credit to our investigators.

Dr. Goldhaber: Very impressive.

Dr. Ruff: And a lot of hard work on everybody's part. Both doses of edoxaban, the high and the low dose, were noninferior to warfarin for reducing stroke and systemic embolism. Of course, once we met noninferiority, we looked for superiority for both doses. Although there was a trend in the higher-dose arm (60 mg once daily), it did not reach statistical significance for superiority. The low dose was noninferior as well, but not superior.

We were most excited about the safety side with both doses; there was a dose-related dramatic decrease in major bleeding, in fatal and life-threatening bleeding, and specifically in intracranial hemorrhages, which, as you know, is one of the most devastating complications with anticoagulant therapy. Both doses in dose-related fashion are dramatically safer than warfarin used quite expertly.

Dr. Goldhaber: What about some of the secondary endpoints? I know you had a host of them such as cardiovascular or all-cause mortality.

Dr. Ruff: Right. We prespecified a number of secondary endpoints. And both doses, interestingly, decreased cardiovascular mortality -- by 15% in the low dose and 14% in the high dose. The low dose actually reduced all-cause mortality and the high dose just missed statistical significance (for reducing all-cause mortality).

It is interesting that both doses are effective, much safer than warfarin, and that both doses preserved cardiovascular mortality. In a lot of the key net clinical endpoints where we combined both serious efficacy events, such as stroke, systemic embolic event, cardiovascular mortality with major or life-threatening bleeding, and a whole host of secondary net clinical endpoints, there were dramatic reductions with both the high and low dose of edoxaban.

Dr. Goldhaber: And why do you think edoxaban is superior to warfarin for reducing cardiovascular mortality?

Dr. Ruff: It's a great question. Obviously, bleeding is part of the story. When you reduce life-threatening bleeding, when you reduce intracranial hemorrhage, when you reduce hemorrhagic stroke, clearly those are very serious complications that, obviously if you have them, they frequently end up being fatal bleeds or lead to life-threatening fatal bleeds.

But I think it's also more complicated. One of the things that we're doing in our analysis is diving into the data, because the relationship between bleeding and cardiovascular mortality may be a lot more complicated. People may have a bleed and it might not be a life-threatening bleed, but they may stop their anticoagulant therapy or their antiplatelet therapy. Down the line, that may predispose them to an increased risk for potentially fatal ischemic events that may not be directly causal to the bleed.

So, a lot of those exciting analyses are coming, but it is very reassuring that drugs that are very effective compared with warfarin used very well can be effective in reducing stroke but, very importantly, dramatically reduced bleeding and preserving a mortality benefit. In the end, those are the things I think patients and physicians care about when you prescribe an anticoagulant. You want it to be effective and you want it to be safe for patients, and you hope that you do see a mortality benefit because you want them to come back to you to see you in clinic at your next appointment.

Dr. Goldhaber: Now let's put this in a larger context. Released today is a meta-analysis in the Lancet of which you are first author, which takes (I believe) all the mega-trials with NOACs, stroke prevention, and atrial fibrillation and puts them together. What did you find?

Dr. Ruff: It's a unique opportunity. Obviously we now have 4 factor-specific new -- or maybe not so new -- oral anticoagulants in atrial fibrillation. There have been over 71,000 patients randomly assigned to one of these 4 landmark trials. We took the opportunity with the release of the ENGAGE-AF study to combine all of those patients and do a comprehensive meta-analysis to try to better understand where the NOACs fit in the therapeutic arsenal for stroke prevention.

We found that, overall, if you add all the trials and look at NOACs as a class, they significantly reduce stroke and systemic embolism. That benefit was primarily driven by reductions in hemorrhagic stroke. And that doesn't mean that, as a class, the agents are not effective for ischemic stroke, because, as you know, warfarin is very effective for reducing ischemic stroke by approximately 65%-70%.

But the primary benefit -- there seems to be something different about these drugs with bleeding in the brain. When you look at them as a class, they significantly reduce fatal bleeding. They significantly reduce intracranial hemorrhage and significantly reduce hemorrhagic stroke.

We did see that, as a class, there is some excess for gastrointestinal bleeding. But again, those bleeds appear not to be leading to fatal bleeding because we see these dramatic reductions in the serious types of bleeding.

One of the things that we did with the meta-analysis, which I think is unique, is that all of these trials are obviously very well powered for their primary endpoints. They included 14,000-21,000 patients. But we know that there are many vulnerable groups of patients enrolled in these trials that are potentially underrepresented: the very elderly, the VKA naive patients who are at risk for both bleeding and stroke when using a new anticoagulant, patients with renal dysfunction and prior history of stroke. Each individual trial really can't definitively answer the question if that drug or this class of drug is safe in these high-risk patients, because they simply don't have enough patients.

But by combining the 4 trials, we were able to look at a whole host of vulnerable subgroups, both on the efficacy and safety side. And very reassuringly, across all of the different groups for efficacy, there was a significant benefit for the new anticoagulants vs warfarin.

Dr. Goldhaber: Tell us about the effect on myocardial infarction in the meta-analysis.

Dr. Ruff: In the meta-analysis, there were very similar effects to warfarin. There's been this controversy that there may be a potential difference with warfarin and that there may be more myocardial infarctions with some of the agents or potentially the class.

We found, very convincingly, that the rates of myocardial infarction were very similar to those with warfarin, and there was no excess in risk.

Dr. Goldhaber: And what about cardiovascular mortality and all-cause mortality in the meta-analysis?

Dr. Ruff: It's a great question, Sam. Although the individual trials differ slightly, whether they're technically significant for cardiovascular mortality or all-cause mortality... In the meta-analysis, when you combine the data, you see very robustly that, as a class, these agents significantly reduce all-cause mortality by approximately 10%. So it's very reassuring that these results are very consistent.

There may be important differences between the agents anytime you combine data that you don't assess for. But I think that there are many similarities with these drugs. They're more similar than they are different, and, very reassuringly, these drugs are effective. These drugs are very safe. And they're very effective and very safe in patients who are at high risk for both stroke and bleeding.

Dr. Goldhaber: And now can we circle back to edoxaban? Let's talk about edoxaban in a broader context, because we have the largest-ever study in deep vein thrombosis and pulmonary embolism with Hokusai-VTE.[2] My final question for you is, what is your overall perspective? Maybe you can talk a little bit about Hokusai-VTE and ENGAGE-AF and how you put them all together, addressing the spectrum of cardiovascular thrombosis.

Dr. Ruff: Now that's a terrific question. This is an exciting time for all of us in this field, where we have many different options now potentially and where we have had warfarin for over half a century. As you mentioned, edoxaban completed the largest venous thromboembolism (VTE) treatment, a future prevention for recurrent events, and now the ENGAGE-AF study. Between those 2 studies, we now have shown that edoxaban in the Hokusai-VTE study, which used the 60-mg dose, dose-adjusted for patients with high drug exposure, was shown to be very effective and as effective as standard therapy for prevention of recurrent VTE, and also significantly safer on the bleeding side.

Importantly, we saw that there was very good efficacy in high-risk pulmonary embolism patients who have right ventricular dysfunction. I think that was a very reassuring sign, now in both trials, that a dose of edoxaban is very effective in reducing thrombotic events, both on the venous side and the arterial side. But when we prescribe an anticoagulant, which is one of the most dangerous drugs we use in clinical practice, the fact that in both disease areas that edoxaban showed significant safety benefit is reassuring. With reductions in all types of bleeding, I think it's very effective.

All things being equal, a once-a-day medication is preferable to patients and clinicians. I'm very reassured by the 2 large trials in both VTE and atrial fibrillation which showed that edoxaban once daily against very effective warfarin standard of care is very effective for reducing VTE and stroke in atrial fibrillation, and also very safe with respect to the bleeding that we care about, the severe life-threatening fatal bleeding. And, importantly, it preserves mortality, particularly cardiovascular mortality in the atrial fibrillation population.

We're very excited about the results. It's early days, but we think that edoxaban should clearly join the ranks. It's a very effective, safe, and convenient option potentially for patients with these 2 diseases.

Dr. Goldhaber: Christian, congratulations on these multiple successes. This is Dr. Sam Goldhaber, signing off from the Clot Blog.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.