Dear colleagues, welcome to this presentation, which is entitled 'Atrial fibrillation from risk prediction to clinical outcomes'. Over the next 15 minutes or so, we will be discussing some new findings on screening for atrial fibrillation, and on the efficacy and safety of non-vitamin K oral anticoagulants in preventing stroke in this patient group.We will do so in the context of the latest edition of the European guidelines for the management of atrial fibrillation.

In this slide, you see my conflicts of interest.

Now, when we start with a patient who is already known to have atrial fibrillation you all are familiar with the way to risk predict stroke and other events in this particular patient population. This is where you do the CHA2DS2-VASc score. This is well-known and I'm not going to dwell too much on this risk stratification tool.

The guideline writers, actually have taken this into consideration and this is a class 1A recommendation, to use the CHA2DS2-VASc score in every patient with established atrial fibrillation.

They go along and say: All anticoagulation is recommended in all patients with a CHA2DS2-VASc score of greater or equal than 2 in men, or greater and equal than 3 in women. In fact, as a 2A recommendation, they say: Even in patients with a CHA2DS2-VASc of 1 in men, 2 in female, you should always consider putting these patients on anticoagulation to prevent stroke and other major events in this group of patients.

Now, what about the question: Should we proactively screen for atrial fibrillation? In this cartoon, I have put different tools you could use for screening patients without known atrial fibrillation at this point in time. In the upper row, the second to the left, you have what the guideline writers recommend that is opportunistic pulse taking, resting ECG, or listening to the heart sounds. The others are all high-tech, high technology devices which are suitable to record the ECG either intermittently or as you can see in the lower row, to the far end to the right, the inner cardiac monitors or ILR as another abbreviation: Intracardiac Loop Recorders. In fact, you can see on the left hand side, there are more than 100,000 health apps already you could recommend to your patients with atrial fibrillation and you have a choice of more than 400 variable activity monitors. This of course, is beyond what we could actually take care of in the clinical setting but that is what is available.

I thought, that we go ahead and review briefly one of the largest studies on pro-active screening for atrial fibrillation in patients without known rhythm disorders. This is the Danish study called The LOOP Trial. More than 6,000 patients, none of them with known atrial fibrillation, were actually randomized in that study. They were all between 70 and 90 years of age and had one more additional stroke risk factor. As I said, they were randomized 1:3, to ILR or usual care and the minimum ILR length, documented AF length, were six minutes or longer so rather short episodes counted for detection of atrial fibrillation. That's important to remember. And the primary endpoint, of course, was stroke and systemic embolism. This was a carefully conducted study with a long follow-up as you can see of more than five years. So, on the flow diagram to the right, you can see that 1500 patients received actually an ILR and 4500 served as controls on usual care. Now, you can see again that in the ILR group, every third patient almost 500 patients were actually diagnosed with newly detected, atrial fibrillation. And the second point I would like to make is nearly all of them were actually subsequently treated with anticoagulants so very good adherence to the study protocol. That was three times as many patients newly detected with atrial fibrillation as in the usual care group, where the adherence to anticoagulation was equally good.

Now, what happened to these patients? What about the primary endpoint and the secondary endpoint? You can see that on this slide. Top row on the left, you can see the primary endpoint: all-cause stroke, systemic embolism. And you can see from the hazard ratio and the p-value there was actually no statistically significant difference between the ILR group, using this device to detect atrial fibrillation, and the usual care group. And if you go on and look at the secondary endpoints and that is the lower two and the one in the upper row on the right hand side you can see no significant difference, whatsoever. That was really a disappointment, actually.

The authors concluded from their studies that in individuals with stroke risk factors ILR was able to detect three times as many patients with atrial fibrillation than usual care would have done, and they went on to get anticoagulated. Despite this, there was no significant reduction in the risk of stroke or systemic embolism.

And that, of course, implies that not all atrial fibrillation episodes are probably worth screening for and not all detected atrial fibrillation merits anticoagulation. So, in these two issues, we desperately need more data and respective trials are currently undertaken to solve these two questions.

So, what did the guideline writers recommend? This is shown on this slide. Opportunistic screening is already implicated so if you see a patient for whatever reason in your office then you are to determine his pulse, if this patient is 65 or older.That's what the guidelines recommend to us. They also recommend that all patients with pacemakers or implantable defibrillators should get a regular screen for atrial high rate episodes as well. And then you have a 1B recommendation and this is actually simply saying: you need to have the infrastructure to discuss these findings with a patient, because otherwise you will end up, or the patient will end up being toppled by this finding. These abnormal results may cause anxiety. ECG misinterpretation may lead to overdiagnosis and overtreatment and the ECG may detect other abnormalities triggering invasive tests and so forth. So this is very important and the guideline writers have done a good job in pointing this out.

If we go further. Let's turn to the clinical outcomes. What you see here is a TEE recording with a large embolism in the LAA of this patient. And needless to say, if such an embolism is resolving and flowing away then this patient will have a major sequela from it.

So stroke prevention in atrial fibrillation is priority number one. No question. What can we do with the new anticoagulants? Or we should say non-vitamin K oral anticoagulants. There were four pivotal studies and one extremely well conducted meta-analysis, which I'm showing here. These four trials, all in all randomized more than 70,000 patients. And you can see that the point estimates for the NOACs point to the left of the line of unity indicating that NOACs are clearly superior, without differences between the NOACs, compared to warfarin.

There's a 20% risk reduction and no heterogeneity between the various drugs. This is the other side of the coin. This is major bleeding. And here you can see, there are somewhat heterogeneous results observed because two NOACs, dabigatran and rivaroxaban, are no different from warfarin in terms of bleeding risk, whereas the other two, apixaban and edoxaban have point estimates, which are clearly left to the line of superiority. So these two are actually better than warfarin in terms of avoiding bleeding events.

I thought we would discuss at the very end one very recent study. And this study tries to answer the question: Can we safely anticoagulate very old patients with additional risk factors? This is a so-called real world study from Taiwan. The author's collected data on 7,300 patients, who were older than 90 years, and who had in addition either history of intracranial bleeds, GI bleeds or chronic kidney disease. At the lower end of this flow chart, you can see that there were roughly 5,000 patients where the physician said: We are not anti-coagulating these patients. The risk is too high. There were 670 patients who, despite the risk, received Warfarin and 1700 patients who, despite the risk, were treated with NOACs. You can also see that the NOACs were very often administered in reduced dosages, which is a finding what you would expect if you look at the risk profile of this population.

These are the results. The primary endpoint was net clinical benefit. That is the risk of ischemic stroke, inter-cranial bleed, major bleeding events or mortality. What do you see on this slide? At the top in red, you can see what happened to very old patients who had chronic kidney disease. You can see without oral anticoagulation, that's the default strategy. That's one on the risk scale. If you compare that to warfarin, you can see that warfarin actually had a higher risk than doing nothing in these patients with chronic kidney disease. NOACs, on the other hand, either taken together or taken separately, let to a point estimate to the left of the line of unity. So these drugs were clearly superior in terms of avoiding the primary end points compared to warfarin and also compared to doing nothing in terms of anticoagulation. Very similar findings for patients with a history of intracranial hemorrhage, in purple. Very similar findings for patients with a history of GI bleed in green. And in the lower part of the figure you can see if you mix together all risk factors exactly the same pattern comes through here.

Finally, the author's went on and carefully propensity score matched these patients 1-to-1 and that yielded also interesting findings. At the top you can see again the comparison without oral anticoagulation versus Warfarin. No risk difference. You can see the point estimates are just below each other. The second one in blue is NOACs versus not anticoagulated. You see a 30% risk reduction for the primary endpoint in favor of NOACs. And below you can see in green NOACs versus warfarin and again you have more than 30% risk reduction for patients treated with NOACs compared to warfarin.

What does this reflect in the guidelines? In the guidelines you have this famous AF 3 step anticoagulation pathway. Very briefly, step one is identify low risk patients, who do not need anticoagulation. Who do not need aspirin as well. Step two is: consider the CHA2DS2–VASc score and the HAS-BLED score and make your plan for this individual patient. And if the CHA2DS2–VASc score is elevated then you should go on and treat these patients with oral anticoagulants. And that is step number three, obviously. And here it says that NOACs are generally recommended as first-line therapy for oral anticoagulation. And I want to emphasize this because I think it is very important.

Ladies and gentlemen, in summary, therefore, opportunistic screening by pulse taking or ECG rhythm strip is indicated in all subjects older than 65 years of age. More advanced screening methods for atrial fibrillation are available. But here we need further studies because their clinical yield is questionable, at least for broader populations, as I have shown in the LOOP-study. Patients with established AF should be risk stratified by means of the CHA2DS2–VASc score. And finally, anticoagulation using NOACs has indeed revolutionized stroke prevention in subjects with atrial fibrillation.

Thank you very much for your attention.

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