TRAF interacting protein

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Welcome to the Best of ESC Annual Meeting 2012. It will be the highlights of our meeting that you are going to see and to discuss, but that allows me to introduce a new concept called ESC Congress 365. The “Best of” is the first step for the re-purposing of the scientific content of the annual meeting of the ESC for all those of you who could not attend Munich, and you will have ample opportunities through different media to see the Best of the content of the Munich 2012. Once again, welcome to the Best of Munich. A programme supported by AstraZeneca and SERVIER in the form of an unrestricted educational grant. It is a great pleasure to welcome you, my name is Keith FOX and I am current chair of the European Society of Cardiology Congress Programme Committee and together with my colleague and co-moderator Barbara CASADEI, we bring you an expert panel for the Best of ESC 2012. The 2012 meeting in Munich has just finished, but we have here selected a group of highlights from the studies and ideas that would challenge your practice. This 60-minute programme is really very straight forward, it is an interactive programme and it is designed to present some short video reports from the highlights that have been selected by our expert panel, and then we are going to discuss those highlights and also interact with you, the audience, to answer your questions and present some questions to you. So our 5 European experts here are: Jeroen BAX, from The Netherlands, Helmut GOHLKE, from Germany, Kurt HUBER, from Austria, Steen KRISTENSEN, from Denmark, and Christophe LECLERCQ from France. Welcome. And finally, not least, let me introduce Ricardo FONTES-CARVALHO from Portugal who is going to have the difficult job of moderating all your questions. We move right on to the very first topic, and this covers platelet inhibition and anticoagulation and we are going to present 2 important clinical trials to you that were presented as ESC Hot Lines. The first of these is Trilogy-ACS with clopidogrel compared to prasugrel in the context of non-revascularised acute coronary syndrome patients. The second trial is the WOEST study and this compared single versus dual anti-platelet therapy, for people who are anti-coagulated and undergoing stent implantation. More than 9,000 patients with acute coronary syndrome managed without revascularisation were enrolled in TRILOGY-ACS and were randomised to receive, on top of aspirin, either 75 mg daily of clopidogrel or 10 to 5 mg daily of prasugrel. The median follow-up was 17 months. We hypothesised that prasugrel would reduce the time to the 1st event of cardiovascular death, MI or stroke and what we found is that although there was a 2% absolute difference in favour of prasugrel, it did not achieve statistical significance. Actually, we found no increased rate in serious bleeding, no increased rate in fatal bleeding for a duration of therapy that has been much longer than previously studied. In the WOEST trial, 573 patients who were already receiving oral anticoagulants and undergoing coronary stenting, were randomised to either double therapy with additional clopidogrel only or triple therapy with additional clopidogrel and aspirin on top of oral anticoagulant therapy. At one year in the triple therapy group, 44.9% of patients suffered at least one bleeding event. In the double therapy group, the incidents of bleeding were significantly lower with an overall rate of 19.5%. As expected, clopidogrel and oral anticoagulants cause less bleeding than triple antithrombotic therapy. Also the secondary endpoint was met and we see that there is no excess of thrombotic and thromboembolic events and there is even a significantly lower rate of all-cause mortality in that double therapy group. And I am going to turn to our expert panel and we’ll maybe start with Steen KRISTENSEN. So we know from the earlier trials that prasugrel is more effective, particularly in intervention contexts, than clopidogrel and yet this hasn’t worked. Steen, why do think this is? Yes that’s true, to me that was a bit surprising and I think the answer is of course that we don’t know why. Guesses could be that maybe an earlier randomisation of the patients might have, we would have more events in the beginning just after an ACS and maybe we lose some of these benefits there, and another possibility could be that the patients that are studied are not really all high-risk patients. OK, so not all high-risk patients. Kurt you have a lot of experiences in intervention and this sort of patients post ACS, but they are a group who not intervened upon, either because they got diffuse disease or they do not have suitable lesions, what is your experience of this group? Well, usually we believe that these patients have a high risk to have another ischaemic event in the follow-up and we have also seen this in the TRILOGY patients that the events were there, and it was an event driven study. On the other hand, if we compare the data with other trials with primarily conservatively treated patients like the PLATO trial, the comparator, the clopidogrel group, had a much higher mortality rate, double as high, 8% versus 4% now in TRILOGY. So there is some difference in the kind of event and I think mortality is a very strong trigger and so I personally think that although there were a lot of events, the group in total was not really high-risk, and you could also indirectly discuss this because, for example, in PLATO about 40% of patients were switched to a primarily not a conservative treatment, were switched to intervention, it was only 7% in the TRILOGY trial, which is good for the trial but might show indirectly that patients had not the high-risk we expected. Or it could indicate that they selected the patients appropriately who were not suitable for revascularisation. This is also a possibility. Steen, what about the people who had more than one event? Yes, there an effect was actually found with the stronger therapy but again this is subgroup analysis and we should be careful about it. Christophe LECLERCQ you have got a lot of experience with this field as well and we have seen that the curves appear to diverge after a year, is this a play of chance or is this, do you think, a real effect? Well, once again we don’t know, it could be a play of chance, it could be also that in this high-risk population perhaps events will come later than one year and I think that a longer follow-up for these patients could be interesting. But it sounds, Jeroen, as though the take-home message for the clinician here is we don’t have evidence to substitute prasugrel for clopidogrel in people who are on a conservative strategy where intervention is not considered appropriate, is that also your interpretation? I think that is very correct. That is indeed the take-home message as it stands now based on this data that we have. I just wanted to catch up on the WOEST results, this is an area where we don’t have a lot of evidence and this is obviously a concern. So this is a study that shows a reduction in minor to moderate bleeds, no difference in intra-cranial bleeds in patients on triple therapy versus double therapy. Only about 500 patients, not really powered to show non-superiority between the two treatments, is this enough to change our practice? I think it is a great trial and I think that the trial give us some new information that is really important, on the other hand, I would like to see more studies in this field. It is true that the study was primarily powered to local bleeding and also minimal bleeding, I am not saying that these are not important because sometimes we actually stop our antithrombotic therapy when we have a minimal bleeding, so it is a very nice trial. And also it showed, a bit surprisingly, as a secondary endpoint, a reduction in mortality. So it is a very interesting trial, I will say though that we will probably start using warfarin and clopidogrel in several of our patients, but I don’t think in all patients; I think we have to read the paper carefully, there might be some subgroups, for example STEMI patients that were not included in this trial. Kurt, I know that you have been very concerned about the fact that some of the durations of treatment might well have been longer than recommended in some of the guidance documents. Yes, in the WOEST trial especially the patients who received drug-eluting stents were treated for 12 months with triple therapy, this is a bit against the recommendations we have from two recently published position papers, one from Europe, 2010, and one from North America, 2011, where stable patients should be treated with triple therapy if they receive drug-eluting stents for 3 up to 6 months only, so a 12-month term of triple therapy could well explain the very high bleeding complication risk and eventually shorter treatment would have shown different results. Even if that was mainly, as Barbara says, more minor or more moderate bleeding, there is a relationship between that and outcomes and other studies have shown that. There are also a lot of GI bleeds and we have no information on the gastric protection in these patients, do you think that might have affected that? You know that might have been exaggerated. Well, that is a big hypothesis but we have to look into this, there are not enough patients I think to really get a clear answer about this. But one of the interesting findings is that if you get rid of aspirin and only do antithrombotic therapy with a vitamin K antagonist and clopidogrel you get some very interesting results and this would be also very interesting for study planning for the future, for example in ACS patients with atrial fibrillation, we don’t know exactly what to do with these patients but dual therapy could be extremely important and so far it was very difficult not to use aspirin with respect to ethics commissions who wouldn’t allow such trials. So watch this space for the future and maybe aspirin will not automatically be included. It is extremely important. Now Ricardo, do we have questions from the audience at the moment? Yes Keith, actually we are having a lot of questions, a lot of people from all over the world asking questions. I will start with a comment that I think is the aim of this session, it comes from Morocco and says that “The fun with knowledge is to share it”, and I think this an important comment. Then the 1st question that I would like to ask is about the question of subgroup analysis on patients taking PPIs in the TRILOGY trial, if there is evidence for an interaction with the clopidogrel and then we have a question on the WOEST also. Who’s going to tackle the PPIs? Well I can do that. So we have some controversial data showing that clopidogrel might be inhibited in its action in patients who are on proton pump inhibitors but not all trials show the same. Now this is an interesting finding because now it seems that prasugrel treated patients benefit more than clopidogrel treated patients which indirectly could again show that clopidogrel is sort of inhibited by proton pump inhibitors, but it is also only hypothesis and it is a subgroup analysis but very interesting findings. So, we’ve got a lot more questions coming, but we need to be fair to the other topics, so let’s move right ahead with the next topic. To the next topic, that is pertinent to arrhythmias and atrial fibrillation where new anticoagulants are to replace warfarin in the guidelines and this has prompted an update of the guideline this year, in addition we will discuss some issues on the implementation of genetic testing in patients at risk with sudden cardiac death. We recommend in the new guideline to utilise the CHADS–VASc score rather than the CHADS 2 score and the reason for that is that we think that there is a better separation of patients as to their risk of stroke or systemic embolism. There is actually only one place for aspirin and that is if a patient refuses to take any form of oral anticoagulation. The updated guidelines clearly state that you can use either vitamin K antagonists or factor II inhibitor or factor Xa inhibitor. The guideline writers recommend that one of the new agents; either dabigatran, rivaroxaban or apixaban should be preferred over vitamin K antagonists in the majority of patients. The field of inherited arrhythmias and predisposition to sudden cardiac death has now evolved to a quite mature stage. Polymorphism in iron channels, in protein deregulated calcium and also in protein that so far are still of unknown significance do contribute to the predisposition to sudden cardiac death. So we are really fast approaching the clinical introduction of these markers, that of course by themselves will not be enough to predict who is at risk, but put together with the clinical variants may help the clinicians identify the patients at higher risk of sudden cardiac death. You have heard a bit about the guidelines and I have got a question for Christophe and it is about the low end of the CHADS–VASc score, those with a score of 0, what do the guidelines say, Christophe? I think that the guidelines first mention that to assess the risk of embolism we should use now the CHADS–VASc score and not the CHADS score, that is the first message and the main message also is that for patients with a CHADS–VASc score of 0, there is no indication for any anticoagulation or even any thrombotic therapy so this patient with a CHADS–VASc score of 0 should not receive anything to prevent embolism. And they may not be better off on aspirin as we have heard, they may be bleeding risks. Exactly, because there is no evidence that aspirin will decrease the risk of embolism, which is very low, but we know that aspirin will increase the risk of bleeding. So now I want just to put a general question to the panel looking at the future management of these patients, we know the screening for the most common mutation for long QT 1 to 3 is recommended because of its impact on the management of the patients and their relatives, and professor Priori is advocating the utility of also screening for polymorphisms. What does the panel think? I mean this is also relevant for ischemic heart disease where this has been advocated by some but actually not by others, so it is an interesting provocative topic. Perhaps we can ask Helmut because you know the phenotype determines risk in quite a big proportion in INTERHEART, should we be looking for polymorphisms? We are reluctant to use it for the individual patient at present and we still wait for studies where the outcome is changed by using this new diagnostic method, so we wait. The same is true for pharmacogenetics, the RELY genetics have really showed an impact of some common variants on the risk in patients taking dabigatran, so these panels for screening are available, individualised medicine is highly advocated, should that get into the guidelines? Well, I think at the moment for most of the topics that were addressed we don’t have the proper evidence. I think before something goes into the guidelines we really have to have careful evidence to bring it in. Outcome studies which are lacking at the moment as was already raised before, so I think this is very careful take-home message as long as the outcome studies are missing to move it into the guidelines is premature. We have heard that these particular variants affect the absorption and the handling of that particular anticoagulant, so you know it is a difficult choice; not yet ready for prime time in the guidelines, but we have alternatives, so Kurt what should we do? First, I will say if we really can on an individualised basis detect the patients who would not absorb a certain medicament and we would have other opportunities then I would not go for testing, I would go for the other opportunities if they are available, and if they are costly, so that is really an important question, are they much more expensive than the comparators or can they be easily used. There are some patients who are deterred from taking statins because they are afraid of having a myopathy, you can screen and exclude most of these patients from the basis of this screening, I mean do we need outcome data on that or as a patient is it something that is desirable? Or do we wait until they develop the symptoms? That’s another way. What should we do Helmut? People on statins. I think that statins do not have catastrophic side effects, so you could give a trial because the benefit in patients with coronary disease is tremendous and is well established in more than 1,700 randomised patients, so you don’t want to withhold this benefit, so you would like if you have a suggestion if there is in the family or if there is myopathy in the family, then you start with a very low dose and try and see what you get and if the patient tolerates it well, then you continue and maybe even you may increase the dose. But an important message for practice is that very large scale trials have demonstrated a low frequency of myopathy, but when it is used in practice, patients develop all kinds of aches and pains and they attribute this to the drug treatment and many of those may not actually due to the drug treatment. Yes, I am referring particularly to patients that have a familiar myopathy or that have some other myopathic disease; in these two we would be very cautious. Ricardo, are there questions from our wider audience? Yes, we have several questions coming; I have two that are interesting, one from Israel… Only two that are interesting? They are more than two but I have to select some of them. I am teasing. One of them is interesting which is from Israel saying: are health care authorities ready to accept new oral anticoagulants from a financial point of view? Difficult question. Difficult question; are health care authorities prepared to accept the novel agents, what happens in Denmark? Yes in Denmark, the health care authorities are accepting and reimbursing and of course the equation goes not only on the price of the drugs because of course the new drugs are a lot more expensive than warfarin, but actually controlling and testing for the INR values is also expensive, so that is why now both dabigatran and also rivaroxaban, and probably soon apixaban, are being reimbursed in our country. Well even in our health care system, under NICE, they are recommended, they meet the criteria, so it sounds like that is a positive answer. And now Ricardo do you have another question? Yes, two more questions but I will select one of them, which is; what is the role now for left atrial appendage closure in atrial fibrillation? OK, tough one, left atrial. Christophe, what are we going to do about this? I think the guidelines, for the first time, included the left atrial appendage closure, it was not included previously. It is only a small indication, it is in patients who have a definitive contra-indication to vitamin K antagonists or new anticoagulants and who are at high risk of thrombotic events, so it is a IIb indication, it is not a very important indication, but I think it is the beginning for this therapy and we do need more clinical trials which are designed to carefully evaluate the benefits and the risks also of this invasive technology for the patients, first refractory to anticoagulation. Refractory or cannot take the anticoagulation but at risk of embolism. We need to move forward and we know that there have been a series of clinical trial updates and further information from the studies presented in Munich, the REVERSE study in relation to CRT and the outcomes at 5 years, SHIFT with hospitalisation for heart failure and the ALDO-DHF regarding aldosterone receptor antagonists with diastolic heart failure, and they have been lessons from these trials but importantly some key updates from the guidelines, so let us hear about those now. The three major new recommendations for treatment in the 2012 guidelines, I believe, are a broadened indication for mineralocorticoid receptor antagonists. The second new pharmacological indication is for a drug called ivabradine, that is a completely new type of treatment for heart failure, and we believe that it is indicated in patients who, despite full conventional therapy, continue to have symptoms and continue to have a heart rate of 70 beats per minutes or greater. The third important therapeutic development that could affect many patients with heart failure is a broadened indication for cardiac resynchronisation therapy. So Christophe, we have heard about this broadened indication for cardiac resynchronisation therapy, how does this translate? What are the key things that are in the guidelines? I think that for the first time in the European guidelines, CRTs are indicated not only on the QRS duration but also based on the type of conduction disorders and in patients with QRS of more than 120 milliseconds and the presence of left bundle bunch block, class 3 and 4 or 2, they have a class I indication. But for patients with wider QRS of more than 150 milliseconds but without left bundle bunch block, that means patients with right bundle bunch block or intra-ventricular conduction disturbances, these CRTs are indicated with a IIA indication. So for the first time the presence of a left bundle bunch block is a strong factor to include patients for CRT. Okay, now let’s come to the issue of heart failure with preserved systolic function, still no trials affecting outcome? I would say that it is the poor parent of the treatment for heart failure because we have many patients, about 50% of the patients, who have heart failure with preserved systolic function but so far we don’t have any evidence of the efficacy of our treatment, but we have 2 promising results, one with antialdosterone and the other one with a new drug, angiotensin receptor neprilysin antagonist, which did show that these two drugs, in patients with preserved ejection fraction, reduce proBNP So it is not a hard endpoint but I see it as a very promising study and we are waiting for other studies in this field. We have also heard about some new evaluation techniques and imaging techniques in patients with preserved systolic function, do you see a role for these, Jeroen? Well, it was specifically highlighted in these heart failure guidelines that the sophisticated echocardiography is now starting to play a role, the tissue Doppler is well recognised as being important, so I think that indeed the more sophisticated technologies are moving into this field, not only for the particular topic of diastolic function assessment but also for the more sophisticated evaluation of heart failure patients in general, you see also the MRIs becoming more and more accepted and integrated, so I think sophisticated imaging is coming. So we can identify the patients better, we just need to know how to treat them. Exactly, because the identification is one step but as long as no successful therapies are available, this is what we need actually. We are going to move on to the next topic, Barbara. Yes, patients with stable coronary artery disease have been frustrating the interventional cardiologists for a while, and maybe the results of FAME II at the ESC meeting will change that, and we will discuss this in a minute, we are also discussing new development in the use of non-invasive techniques such as CT for the evaluation of both coronary anatomy and perfusion. 1,220 patients with stable CAD scheduled for 1, 2 or 3 vessel DES PCI were enrolled in FAME II. Fractional flow reserve was measured in all target lesions, if FFR stenosis was significant; the patient was randomised to PCI plus medical therapy or medical therapy alone. If FFR was not significant; the patient was assigned to a parallel medical therapy alone registry. The patient followed under medical therapy without ischaemic lesions, they are doing very, very well, approximately 3% of primary endpoint events. If we focus on the patients with an ischaemic lesion, in patients randomised to receive medical therapy alone, we see a statistically significant increase of their endpoint events and this difference increases over time while those patients randomised to receive PCI plus medical therapy, their event rate is almost super-imposable to that observed in the registry patients. The CORE 320 study evaluated the potential for the non-invasive detection of flow limiting stenosis by comparing 320 row detector CT angiography followed by CT perfusion to classical invasive angiography followed by SPECT in 381 patients referred for coronary catheterisation. The main impact of the study will be in defining, non-invasively, who should go for revascularisation, because we have showed that the combination of the CTA-CTP, CT angiography, CT perfusion, could predict as well as the combination of invasive angiography and SPECT, who went through revascularisation at 30 days. FAME, the main problem was; can we refine the management of patients with stable coronary artery disease by intervening on FFR positive vessels. In that respect, you know what does FAME have to deliver? Do we know something more about the outcome of this patient or shall we perhaps accept that revascularisation is a good outcome? I think what we show with this trial is just a confirmation of what we already know, that patients, who have significant stenosis, and this can be clearly shown by FFR measurement, benefit from an intervention in terms that recurrent interventions are lower in these patients. We have no clear evidence that this would lead to a reduction of hard clinical endpoints, but patients have less complaints and for me this study just confirms what we already have seen so far. Is this going to change our practice? We are already using FFR in many of our patients in the cath lab that have borderline lesions and in particular multi-vessel disease, and I think, like Kurt, that this study confirms that this it is a good strategy. I would say also that these are stable patients, we could not really expect to save lives in this group of patients, you could maybe criticise the end point of revascularisation, it might somehow be subjective as the study is unblinded, but on the other hand, I do not actually see a better way of performing this study and I think it is a fine study. So this really brings the question to you, Jeroen, after what we know from the FAME II and these results, should we send all patients with stable coronary artery disease to the cath lab or is there something else we should do before that? Yes, so that is a very important issue of course. I think the general consensus is that we need to work from pre-test probability of coronary artery disease and that’s really what we should think of. Now, you can then differentiate into different scenarios, scenario one is that a patient comes with a very low pre-test probability, these patients probably do not need anything, they do not need any invasive or non-invasive testing. Then you have the patients with a very high pre-test probability, very clear symptoms, very clear settings, those patients are probably going to be referred directly to the cath lab and in those patients, you could argue to do the FFR first and then do the further treatments, but for sure these patients are referred for invasive evaluation directly. The biggest group of patients will be the ones in the middle, the so called “intermediate pre-test probability” and I think the future is going to look like that patients will be divided into the lower end of this pre-test probability intermediate group, and these will be evaluated mainly non-invasively for the detection or the rule out of atherosclerosis, the clinician is indicating that there will probably not be ischemia but he wants to know if there is atherosclerosis or not, and based on that he will do an anatomic test and that will probably be a CT angiogram looking at the atherosclerosis. Then you have the other end, which is the higher group of pre-test probability intermediate group, and those patients probably you are interested in knowing if there is ischemia or not, in that group of patients, we will use a stress test, or an imaging test with echo, MRI or maybe even with CT in the future, by looking at CT FFR or CT perfusion as has been demonstrated in this CORE 320 study. It seems to me that there is still a lot of room for clinical judgement. Absolutely, and the difficulty is really what patient fits what criteria, that is the most difficult thing that we have to challenge, but I think if you accept the concept of pre-test evaluation of patients you can probably stratify them easily into groups where you want to do a test or a direct referral or nothing at all. OK, so these broad groups are really very helpful, but even taking those with a high pre-test probability, clear symptoms of angina, you know, provoked by stress testing, and they have got demonstrated ischemia, you take them to the lab and they have got a 95% single vessel stenosis; in your labs that frequently use FFR, would you do FFR on that patient, Steen? Not in this patient, Keith, there we would do a PCI or in some cases maybe even surgery if it is the left main. In obvious cases, we would not do FFR, but it is very useful when there is a borderline lesion, also sometimes when there are several lesions in different vessels, then I find FFR very useful. OK, and as we know, just going back to the original FAME I, that was very helpful in identifying that there were lesions that would have been done by visual interpretation that were not done by formal FFR testing, would you agree with that, Kurt? Absolutely. OK, Ricardo, what about questions from the audience? Yes, we are receiving some questions and some of them are related, at least two, one from South Africa and Spain regarding the same topic, which is the relation between FAME II and the COURAGE trial, they are asking if they contradict each other, if they complement each other and there are people even asking “who is the winner?” OK, so FAME II and COURAGE, very different designs, do you want to put that in a nutshell, Steen or Kurt? Well I think this is very difficult, as you say, it is totally different and I think we should remember that the FFR is a tool that we have in the cath lab and it’s actually patients that already have undergone an angiography, so it is a different situation from the COURAGE trial. Eventually, this question could be answered in the future because there is a huge trial that has just started, it is Ischemia trial and here also FFR is involved in the diagnosis, so I think, in the near future maybe in two or three years from now, we exactly will be able to answer the question. So, at the moment, they are slightly different questions but keep watching this space for Ischemia in the future. OK, so I think we had best move forward, our next topic concerns intra-aortic balloon counter-pulsation, and that is been widely used in acute myocardial infarction especially complicated by cardiogenic shock, and this was a class I recommendation in international guidelines, despite the fact there was not very much evidence. So, the results of the IABP Shock II trial presented in Munich will clearly change some of that practice, and we are going to hear about that, and also the updated guidelines on ST elevation infarction from Gabriel STEG, if we could roll the video. For the interventional community we can summarize by saying coordinate networks of care with accepted written protocols of all the stakeholders and demanding delays to strive for, with a target of 60 minutes to primary PCI in a PCI capable hospitals and the interventionists will be reassured to see that we have incorporated in the new guidelines, drug-eluting stents, the radial approach, and all of the novel medications for anti-platelet agents and anticoagulants that are emerging. For primary care physicians, cardiologists in the outpatient settings, I will emphasise the long term secondary prevention in which the new guidelines have incorporated the evidence for dual anti-platelet therapy for a year, but accepting that it may need to be abbreviated for one month for bare metal stents, 6 months for drug-eluting stents. And we have emphasised the importance of rehabilitations, smoking cessation, aggressive lipid management with statins starting at day 1 and aiming to achieve a target LDL of less than 70mg per decilitre. IABP-Shock II is a multi-centre German study in which patients with acute myocardial infarction complicated by cardiogenic shock were randomised to either intra-aortic balloon counter-pulsation or control. With 600 patients it is the largest randomised clinical trial which has been performed so far in cardiogenic shock. The primary study endpoint, we failed to show, this was our assumption, that the intra-aortic balloon pump can reduce the mortality, so, the mortality was 39.7% in the intra-aortic balloon pump group and 41.3% in the control group. The most important thing is that revascularisation has to be offered to our patients as quick as possible, you know that primary percutaneous intervention should be the method of choice and we are only able to offer this in the given timelines if we organise very well our function, I think, network This is extremely important and for the first time has also IA recommendation in the new STEMI guidelines. So, networks of care and your group and others have got a lot of experience in establishing these networks, but not easy. It is relatively difficult to organise such networks but in the end it works and the most important thing is to that you are really able to reduce in-hospital and long term mortality within one year if a network is starting. So these are very good data from many different centres, the problem with the networks is that a 60 minute time spent between first medical contact diagnosis and intervention is very difficult to reach. This is even not possible in networks where the transfer times are relatively short but this is a goal we really should go for especially in fresh infarctions. But as soon as we see that the patient could be treated within 2 hours in the cath lab, the patient should be referred for primary PCI. Only if this is not possible we should think on other re-perfusion methods, but it is important to be as quick as possible, not to be happy with 2 hours, we should really go for the 60 minutes that are recommended now. And you and others have emphasised the importance of an integrated approach that does not involve a patient having a double stop, which obviously is a big delay. It is extremely important, as soon as a patient is on the run to the cath lab you should avoid emergency rooms or other hospitals, you should go directly to the cath lab of a PCI capable hospital, this is the most important. So that is an important practice management point. And now, one of the other things that Gabriel STEG, talking about the guidelines, highlighted was, you know, it is not all over after the acute phase, there is all the secondary prevention, and we are not very good at that, Helmut? Yes, this is true, many people, many patients feel cured after they have seen that the stenosis is abolished and this is a great mistake, so the persistence of secondary prevention is very low, the EuroAspire studies I, II and III have shown that the control of risk factors is less than desirable and goes down after 6 months, also the use of medications is going down after 6 months like only 50% have the initial dose of the statin and also the plated inhibiting agents are decreased, so this is a big problem. Cardiac rehabilitation is a class I recommendation, it was good to hear from this interventionist that he has very strict targets for LDL and this is also a new development in the prevention guidelines that the LDL target for all patients with coronary disease is below 70 mg per decilitre or 1.8 mmol per litre. So that has got to be pursued aggressively. Yes, this has to be pursued aggressively and this will be a major change in the lipid management. And smoking cessation... Smoking cessation, of course, is one of the most important messages and one of the most important things that you can do to improve your prognosis, so smoking beats everything in terms of harm to the patient. OK, so a very important message there... Now, we do want to mention that there were a series of presentations on the topic of TAVI in this congress, and there was information on the long term outcomes, information on the ways of imaging and evaluating a patient with TAVI, so who would like to start, what have the registries told us about TAVI? One of the biggest registries that has been presented was the GARY registry from Germany and here several thousands of patients are within each group, either patients referred for surgery or surgery plus CABG, or TAVI transfemoral, or TAVI transapical, and the interest finding, but this is only in hospital mortality at the moment, is that in hospital mortality is similar between these groups, although patients who receive TAVI are the sicker patients, they are older, they have more risk factors, it is quite interesting to see this, and also their periprocedural complications are comparable. But this is a registry now and what we really would need is first, long term outcomes with this new strategy, and what we also need is prospective randomised trials and I think we can be really positive about this method but we have to look at studies that are ongoing. So we really need robust long term outcome data to change that practice and you know, people have raised concerns about lower indication individuals who might be suitable for surgery going to TAVI, what about the guidelines have emphasised the heart team, and so, Steen, what should we do about this? I think it is very important that we discuss the cases with our surgeons and certainly in our hospital this is the case and we say the general rule in our country is still that if the patient can get surgery, this is the preferred option, and this is also what the guidelines tell us. And we should not forget that the current recommendation for TAVI is a IB recommendation in patients not suitable for surgery and with a life expectation of more than one year, this is still the indication. OK, it is very important to focus on that. Right, any questions from the audience on those topics at the moment? We have questions, we are receiving a lot of them, regarding especially the Shock trials, sorry for going back, but people ask for a clear message and also there is another question from Germany which is, if it is probable that we had, because they see benefits in individual patients, if there is a probability of having a selection bias in this trial? OK, so, intra-aortic balloon counter-pulsation, the Shock trial, I am going to ask everybody, would this potentially change your practice, Christophe? Personally yes, and I agree with Steen, because this study for me was well conducted, I did not see any bias in the selection of the patients and I think, as you mentioned previously, we want to do something and put a balloon, but today we have the evidence that to insert a balloon in a patient, there is no change in the prognosis of this patient, I think it is a clear message and perhaps we have to think of other technologies such as ECMO or something like that, more rapidly in selected patient. Anybody disagree with that? I think this is specifically the point that we were getting at, if trials have been conducted in the right manner and we have the evidence, this will be sooner or later implemented in guidelines because this is the criteria, we need the trials, we need the outcomes, the outcomes show this and then it goes in. So I think we are running a little short of time, we should move on to the last topic. The last but not the least, the last topic is about prevention and what we are going to discuss, first is the Japanese earthquake. On March 11, 2011, an earthquake and tsunami hit the North East coast of Japan causing 16,000 deaths but unfortunately it was not the end, there was then an aftermath with an increased risk in coronary and ischemic strokes and we will discuss that and the reasons behind it, after which in a nutshell we will hear about the new guidelines on prevention from Dr PERK. In the Great East Japan Earthquake Disaster and Cardiovascular Diseases study, all ambulance transport records in the Miyagi prefecture were examined 4 weeks before and 16 weeks after the earthquake. We found that there were three different time causes of the increase in the disease; first, the occurrence of heart failure and pneumonia significantly increased and sustained and only gradually returned to the previous level, the second pattern was found for strokes and CPA, cardiac pulmonary arrests, rapidly increased and rapidly decreased and very interestingly, a second peak, in response to the largest aftershock. The third pattern was found for acute coronary syndrome, again rapidly increased and rapidly decreased and in the third month, the occurrence was significantly lower compared to the previous three years which means that occurrence of acute coronary syndrome could be accelerated in this disaster situation. We introduce four levels of cardiovascular risk. The very high and high-risk groups are important because we have seen in many studies now that these patients throughout Europe do not really get the real preventive care that they deserve. In our guidelines, we put special emphasis on lifestyle and behavioural factors. Lifestyle is at least as important or even maybe more important than drugs. Much of the prevention is on the political effort, here, we ask our colleagues, speak up, contact politicians, work with decision makers so that they create a society where we do not have to suffer from an unnecessary disease. So there is, as you know, an increase in the incidence of ischemic stroke, heart failure, pneumonia, all happening after the earthquake. The reasons can be many, why this happening and as has been shown for other tragic events previously, do you want to comment on what might be the reasons behind them? Do we underestimate stress as a risk factor factor or are we looking for other things such as availability of medications, cold, infections and other things? Well, of course this is a very complex situation where the availability of medications is also decreased but the unique situation here is that we have two shocks and two episodes of stress shortly one after another. So the acute coronary events went up with the first shock but not with the second, but stroke events, for instance, went up with the first shock and also again with the second shock probably related to the increase in blood pressure that is associated with the shock, whereas with the acute coronary syndrome probably unstable plaques were ruptured and they were all used up and for the second shock, there were no unstable plaques left, that is one possible explanation. Similar with cardio pulmonary arrest, which of course, also related to catecholamines, probably is more related to rhythm disturbances which may be induced by high levels of catecholamines, plus increased blood pressure. So, pneumonia, of course in this setting, it was a cold time of the year, people were without housing, without electricity, without heating and many of them were wet for quite a time, so pneumonia is likely to occur in these circumstances. It seems to be a nightmare situation for coronary artery disease and other situations where you have inflammation, drug withdrawal, stress, high blood pressure, any messages that we can take for our prevention? Well, stress is important, that we can see, although such extreme forms of stress in daily life very rarely occur in Europe. I think with the 9/11 events in the United States, we had a similar episode, just one episode, and also persons watching on TV in Florida had a higher incidence of ventricular tachycardia with their ICD where it was monitored, so the emotional involvement and the anxiety associated with these situations that creates rhythm disturbances, this is well established. What I would really be interested in these data, I don’t know whether this has been investigated is, what the percentage of Tako Tsubo syndromes is in these patients, usually it is less than 10% in our population if an infarction comes in, but it would be very interesting to see whether this percentage is much higher, and I hope that we will get data in respect to this. Yes, because this is extreme stress and I would expect it to be. The other thing is that doctor Perk was very militant in his defence of prevention, we should lobby with our government, we should change policy, and one of the things, amongst the many good news in the congress, was bad news about smoking, smoking in young women in France being associated in parallel with an increase, a doubling, of the incidence of myocardial infarction in women below the age of 55, so this is a big problem in public health, how are you going to tackle precisely young women and stop them from starting smoking? Yes, even France has been a role model for prevention in Europe and has been very successful in implementing smoking bans. So, a smoking ban is probably very important, but it is more for the non-smokers' protection, so we have to implement other things that could reduce the smoking, like plain packaging which has been now established against fierce resistance of the tobacco industries in Australia, for instance, or the pictures that show the dismal consequences of smoking which have been used in Canada, very successful, of course it is not a randomised trial, but the rate of smoking has gone down dramatically after these pictures were introduced and I think this is one way we could pursue also in Europe and people are working on that, but again there is much resistance from the tobacco industries. Young people are not afraid of dying; we have to find something else to convince them not to start smoking. So, we have been hearing about this disastrous surge of catecholamines, of anxiety, of all the factors with the earthquake, Christophe, if you were the expert being called up saying that there is a tsunami on the way, should people be taking beta-blockers? Personally, I will take beta-blockers, yes, I will. I will do it because we know that catecholamines are a risk factor for ventricular arrhythmia and I think that in this setting of event, we usually have a dramatic increase of catecholamines and I think that beta-blockers could be prevention but I think we will never have the answer without a trial of course. So, a phenomenal tragedy in Japan but, you know, but we are learning things from that, this is really important. But I think you have to be sure to make a pre-test before that you are not low when you want to run with beta-blockers because sometime some people are very low when they try to run with beta-blockers, so you have to make a pre-test before to be sure. Right, so we are about to wrap up this programme and before we do, what I want to do is ask each of our panel for a take-home message for what should they do in practice and maybe we could start with you, Jeroen, what should be your take-home message? I think what we have seen at this congress, that the guidelines are developing really fast and implementing the new evidence and at the same time, keeping a balance with what is there from the information, given it is sometime too mature. Another thing that I personally think is quite interesting and the take-home message could be that the handling of coronary artery disease, particularly the invasive versus non-invasive assessment, I think that assessing ischemia, the evidence is really accumulating, that is becoming more and more important in the management of coronary artery disease. OK, thank you very much, Helmut? There are two things I would like to emphasise, again, we have seen that an increase in smoking increases the risk of myocardial infarction particularly in young women, the average age of the myocardial infarction population has decreased in France in this registry. Second, in secondary prevention, all patients with coronary disease have the target LDL of less than 70 and this is new, this was an optional target at present, but the evidence is accumulating that this gives additional benefits compared to the less than 100 target. We have not tackled the problem of type-two diabetes and obesity which is quite challenging. Well, type-two diabetes with risk factors and organ damage is also categorised in the very high-risk group and needs very aggressive treatment. So Kurt, your take home message? Well the message not only for acute coronary syndromes, I think is that you should read and implement guidelines in order to treat your patients in an optimal way. We might achieve more by doing that in comparing some treatments, Steen? Very simple, as I already said, we should put less intra-aortic balloon pumps into our patients with STEMI and cardiogenic shocks. Two short take home-messages, the first is about atrial fibrillation and the risk of embolic event with the recommended use of new anticoagulants over warfarin and also the second message is for CRT, we have important data about the long survey from the REVERSE trial with mortality at 5 years which was only 12% so with a good efficacy to reduce mortality in this population and the message is that people should be referred not too late for CRT but when they are in class II. Very good, so we are going to be closing out this programme, Barbara if we can ask you to close the programme? All is left is to thank you very much for your participation in this programme and for the hard work you have done, and to thank the ESC staff for organising this event and our sponsors, Servier and AstraZeneca, for their unrestricted grant, and you, the audience for really making the event more lively and interesting, so now, we leave the last words to the new ESC president who is professor Panos Vardas, bye, bye from us. On behalf of the ESC board, I would like to thank you for participating in the second edition of the best of ESC. I hope you found this programme important for your practice and we are working onward to welcome you in Amsterdam on the 31st of August next year. See you in Amsterdam.