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Can Renal Denervation Still Be An Effective Treatment For Resistant Hypertension: Results With The Spyral-HTN Device (Medtronic) In A Sham Controlled RCT Suggest It Can: What About Other Endovascular Treatments
Can Renal Denervation Still Be An Effective Treatment For Resistant Hypertension: Results With The Spyral-HTN Device (Medtronic) In A Sham Controlled RCT Suggest It Can: What About Other Endovascular Treatments
Boston ScientificMedtronicParadise (ultrasound ballon)Peregine (Chemical denervation system)Renal denervation systemSymplicity SpyraltherapeuticVessix (RDS
Transcript

- Good morning everybody, and thank you for inviting me again for the same topic since five years now. Every time I have to rebuild my slides, and you will see why. So, you all know this story, renal denervation was almost destroyed by The Earthquake on January 9, 2014, and that was when Medtronic announced that HTN-3

did not make it to primary endpoint. What has been achieved since the earthquake? Better techniques with old devices, positive trials with old devices, new devices, and some positive trials with new devices. So, what about better technique?

More is better, that's what we learned, total number of ablation is important, circumferential ablation is important. Go distal is important in distal vessel segments, the nerves are closer to the vessel wall. We have the DENER-HTN heart trial with the old system

which was positive, and we have new devices, like the Symplicity Catheter, Spyral Catheter, the Vessix, Paradise, and Peregrine. So, what about new trials with new devices? Spyral HTN-OFF MED, HTN-ON MED, REDUCE HTN, RADIANCE HTN SOLO, RADOSOUND-HTN,

and Peregrine PMS - TARGET BP OFF-MED trial. SPYRAL HTN - OFF MED was a trial with patients without medications, or permitting discontinuing the oral drug therapy at that time, and they had to make certain values of blood pressure office and 24 hours, and you can see the results.

There was a significant effect in all parameters in systolic blood pressure ties to the blood pressure. 24-hour blood pressure and all these differences have been significant in favor of innovative denervation, so renal denervation certainly works. What about in those patients who are on meds,

and this has also been reported now. You see the patients had to have one to three anti-hypertensive medications. Again, they had to fulfill certain criteria regarding their blood pressure, and when you look at the result safety, it's very safe procedure,

no adverse events occurred, and office blood pressure changed from baseline to six months, it was a significant decrease systolic and diastolic blood pressure as well as 24-hour blood pressure, so renal denervation also works in patients

who are on anti-hypertensive medication. Reduce HTN was a trial with the Vessix system, which is not really a new system, but this is a new trial, and they used a balloon-based radiofrequency technique. They did an off-med study, the primary endpoint was reduction in 24-hour ambulatory blood pressure,

at eight weeks, which probably was too early, and the trial was stopped early due to slow enrollment and because it was determined that the trial could not achieve its primary endpoint at eight weeks, but when you look at the long-term results with this trial, there was actually a significant rate

of proportion of Vessix patients with office blood pressure below 140 versus control after six months, and this was significant and there was also over six months, systolic blood pressure continued to decrease in the Vassix group with a lesser decrease in the control group, and these differences

also have been significant to the match major part. RADIANCE HTN-SOLO trial is using the Ultrasound Based Renal Denervation using a balloon technology. You can see that these patients responded. There was a clear benefit in favor of the technique compared to a placebo group, significant difference 0.001.

Radiosound HTN was a trial, a randomized blinded trial comparing the different techniques, like ablation of the center part of the renal artery, distal part of renal artery, and ultrasound, and there was a significant benefit of ultrasound compared to the ablation of the proximal renal artery only.

Peregrine is using alcohol injected into the adventitial space, also significant effect of this technique, so now we have multiple randomized blinded renal denervation trials, OFF and ON meds, which are clearly positive. The decrease of blood pressure is, without any question,

clinically relevant, but it is smaller than expected and hoped. Everybody is asking, "Does it justify an invasive procedure? "So better not to do it?" At the same time, no major adverse events occurred, so why not to do it?

Everybody agrees that more research is needed. There are other device based approaches which are either stopped or covered by other talks in this, so I'm going to skip this. Thank you much for your attention.

- I want to talk to you today about the MobiusHD device. And the question is can we modulate hypertension through the carotid bulb? My only disclosure is that I'm the site principle investigator for the CALM-2 trial at our site at SIU. Well cardiovascular death risk doubles with each

10/20 increase in blood pressure. And we know that hypertension causes or contributes to 60% of cerebrovascular disease, ischemic heart disease, as well as renal disease. And pharma has not really solved this problem for us. First off lifestyle modifications are usually inadequate,

patients often aren't compliant with their drugs. Drugs only work for as long as they're taken. And we know from our own clinical practice only about a third of patients actually have their hypertension adequately controlled. As well, 15 to 20 percent are resistant

to maximal medical therapy in the first place. And say, average effect of any single drug is a reduction only of only about 10/5. So, the question is what if there was a one time treatment with a durable effect? So, we're all familiar with

the carotid sinus baroreceptors. That may be a little bit of a misnomer because they don't actually sense pressure, they're responsive to stretch rather than pressure itself. But that's a surrogate for pressure.

And we know, or have learned that sustained activation only occurs if you have pulsatile stretch. Hence the concept of the MobiusHD device. This is a Nitinol self expanding internal carotid implant that goes into the carotid bulb. And the concept is that it changes the shape

of the carotid sinus in the diastolic phase. So, several different sizes of this. Its sized specifically to exert just enough radial force on the vessel to reshape it in diastolically, but prevent migration in systolically. And reshaping this vessel increases

mathematically the differential strain and therefore stretch. Which is what's measured by the baroreceptors. The device is similar to many of the implants we use. It has delivery system. Here you can see it prior to deployment.

It can be partially deployed and then recaptured and repositioned if necessary to get it in exactly the proper position where you want it. So, the first-in-man trials. So, the first-in-man trials.

So, these were performed in Europe. The feasibilies if you wish. 30 patients with multidrug resistant hypertension with an average of 4.4 antihypertensive drugs, all had successful insertion of the device. And there were five SAE's in four patients.

Interestingly, two of those SAE's were actually hypotension. Symptomatic hypotension, which may in fact speak to the efficacy of the implant. So, heres some of the data from that if you look at office blood pressures. The mean office blood pressure at the beginning

was 184/109 in these groups. And you can say statistically significant reductions in both systolic and diastolic office blood pressures out at to six months here. What about ambulatory blood pressure? Same thing here you can see significant reductions

at three and six months in ambulatory blood pressure in these patients reduced by an average of 21/12 millimeters of mercury in these populations. But does it have any kind of a long term effect? Well, as you can see the numbers get pretty low, the further out you get on this.

But nonetheless, it does appear to have a sustained, durable effect on reduction of blood pressure and this. And the other interesting thing is the concept of the DDD, which is the daily defined dose. So, not only are the blood pressures being lower,

but the amount of medications that these patients are having to take is also being reduced somewhat as well. So, hence after the feasibility trial on these results, the company has decided to launch what is being named the CALM-2 trial. I'm proud to report that SIU randomized the first patient

in this trial on July fifth 2018. So, the trials still very much in the early phases. The trial will enroll 300 patients at up to 75 European and US centers, with a 1:1 randomization to a sham procedure. The sham patients actually get a sixth French sheath

in the carotid artery. Get their full angiographic evaluation and then they are randomized on the table. And there's a script we go through if they randomize to nothing. And if they randomize to the device

obviously we proceed and implant the device. There's a primary effectiveness endpoint at six months. And that will be assessed by the ambulatory blood pressure and a safety endpoint at three months of the composite cardiac and neuro events. So, in conclusion then, mechanical stimulation

of the carotid sinuses been demonstrated to effectively lower blood pressure. At least in the short term. And the clinical applicability of this we hope to get more information from in this trial. Thank you very much.

- This is what we're going to talk about today. It's a vascular approach to hypertension and AV fistula. This implant was first designed in the early 2000s and directed, actually, at COPD, but then redirected to hypertension. Disclosures. Hypertension, as we age, is largely a result

of the loss of compliance in our arteries. Approximately 85% of uncontrolled hypertension patients are those over 50 with predominantly mechanical hypertension. This is the implant and the procedure. It's simply an AV fistula created

in the external iliac artery with an endovascular procedure done under local. Takes about an hour to do, and it creates a very precise AV fistula that doesn't grow over time, about four millimeters, mediated by the implant.

This is a just sort of appetizer before we get into the data. This is a patient done recently and presented in June of 2018. Patient in Toulouse, France. The difference from renal denervation, of course,

is that it get an immediate effect on the table, a very large drop in blood pressure. And you can see ambulatory blood pressure is roughly 30 points lower systolic, 20 diastolic. And as we'll see that's backed up by long-term data. This is the main body of data that's been generated

to date, a randomized trial in Europe, has six and 12 month data now, and we'll review that. So the Prospective Trial, 83 patients, 44 treatment, 39 control. All of these patients had to be on maximal medical therapy. And the exclusion criteria

were generally cardiovascular morbidities. You can see the groups are very similar. And actually, these results are for the prior renal denervation group. So of note, patients who have had prior renal denervation also respond to this therapy quite well.

Here you can see a very significant drop in both office and ambulatory blood pressure at six months. Here's the broader study. Both six and 12 month data with the right panel being a consistent cohort, just the patients that were not lost to followup.

But you see very consistent results. Again, significant drops, 26 points and 20 points for systolic and diastolic respectively. And if we look at 24-hour ambulatory blood pressure changes at six and 12 months, not quite as much, but still very significant, 13 drop

in both systolic and diastolic. There was a crossover group after six months. Those randomized to no therapy can be crossed over to the therapy, and we see that those respond as well, much smaller group. The primary complication in this procedure

is not congestive heart failure or anything like that, it's iliac vein stenosis. We see this with our other work in arteriovenous fistulas for dialysis. As we know, stent therapy for iliac vein stenosis is very successful in non-thrombotic patients,

and so all of these patients were treated with an iliac vein stent and all resolved without incident or recurrence. Some of these patients in the European study were done from the left and it's always done from the right to avoid the May-Thurner physiology.

Two patients didn't respond. And now the therapy is going into a much larger trial, a 500-patient randomized trial. This is an adaptive study, double blind, sham-controlled, and of course multicenter. These patients have to have, as a primary endpoint,

of 24-hour ambulatory blood pressure and then secondary endpoint of office blood pressure. The inclusion criteria are very rigorous. These patients have to be on maximal drug therapy. They have to be on that same drug therapy and have the same blood pressures on multiple checks

over a three-month period before they're randomized and stay on that same drug therapy, if possible, for six months after randomization. The exclusions are similar to the European study. So in summary we look at this technique of using an AV fistula to reduce blood pressure.

With denervation we don't have a procedural endpoint on the table. Often it's a smaller and less consistent blood pressure effect. What we don't talk about is the fact that autonomic nerves do regenerate,

it's dependent on renal artery anatomy, and there's some risk of renal artery injury, albeit small. But with an AV fistula there's a very immediate and significant effect. It's scalable and reversible with covered stent. It's independent of the renal artery anatomy,

and it's effective in patients with prior renal denervation and durable. Thank you very much.

- Thank you. Disclosure related to this talk. So the evidence on beta blocker use has been very controversial, and with the first randomized trial being discredited, this is one of the earliest trial that showed, actually, a benefit,

and this one was not discredited, and showed significant reduction in mortality in patient undergoing non-cardiovascular surgery, and this was persistent up to one and two years. This particular study that was published in Lancet

shows just the opposite, with larger number of patient to post trial, showing no benefit of beta blockers. In these two next slides I'm going to show you both of them were randomized trials, comparing metoprolol to a, basically a sham,

or placebo, and showed in vascular patient, no benefit. However, the problem with both of these randomized trial that they included apple and oranges in vascular surgery, so they included aneurism and peripheral vascular disease, axbifem, and even amputation. Very different procedures.

Despite this controversial evidence, both the European Society of Cardiology and American Heart Surgery revised their guideline and recommended to continue use of chronic beta blockers, but not to initiate beta blocker before surgery. And the problem that I have with a lot of this data is

that they did not really look at the specific type of beta blocker, the route of administration or dose, and also what I've showed you, the inclusion of apple and oranges, or even in the first 2 large randomized trial, not just vascular patient, they included colorectal patient,

plastic surgery and orthopedic. So what I wanted to do is to look at real world data and we used the Premier Health Data with a cut from the data from 2009 to 2015. And we included non-rupture aneurysms

in looking at all adverse events and mortality. And we did the usual statistical analysis. But you can see here, we had 6,500 patients, 1,000 of them were not on beta blocker, and the remainder receive a different kind of beta blockers. In table one, you see that the group that receive

beta blocker as expected were a little bit sicker, with the more urgent, non-rupture presentation, more statin use, and they had more coronary artery disease, as well as kidney disease. And the conclusion with the results was

that there was a lot more complication, actually, in the beta blocker user, but the mortality was significantly less, about 4 versus 8%, and there was significant rescue phenomenon, i.e., people who develop major adverse event,

but they survived the adverse event, was a lot higher in a group that received a beta blockers. And some of the predictor of mortality, the usual suspect being older, have more significant coronary artery disease, and other cardiovascular morbidity,

as well the urgency of the presentation, but the interesting thing that I'm showing you here, that when we tried to see if the coronary artery disease has an effect, and there was clearly an effect modification. Meaning, if you have coronary artery disease,

the benefit was a lot higher, as you can see, 80% reduction in mortality, versus 60%. And then when we further stratified this, having or not having adverse event, we saw the same thing in the group that have adverse event. The more benefit in coronary artery disease patient,

but the interesting finding, if you did not have coronary artery disease, and did not develop a complication, there is really no benefit for beta blocker. That is the only group that did not benefit. But the group that had no adverse event and

coronary artery disease, had the most benefit, 93% reduction in mortality. Another unique finding that I don't think any other the study looked at, we looked at different kind of beta blockers, and we found that if you give IV beta blockers,

you actually have higher mortality if you don't have beta blocker at all. And we found that metoprolol is the most beneficial, comparing to other kind. Another thing that we did, we showed that there is a dose response.

So if you go from no dose to intermediate, to low dose to intermediate, you see the mortality dramatically dropping, specifically from 5 to 2% within the dose, so the dose has an effect, and if you go supertherapeutic dose,

you actually have no benefit. Limitation, of course, the usual retrospective study. And the conclusion is that in hospital mortality was reduced by 55%, there was failure to rescue, with 60% lower in the group that received beta blockers. There was a dose response,

and metoprolol is the most beneficial. And based on that, I think recommendations should be revised, specifically for triple A. Thank you.

- Thank you very much, I appreciate the invitation to this great meeting. So I'm going to talk a little more broadly about beta blockade, then Dr. Mollis, and let's review again some of the randomized control trial data. So, just like the first slide with prior speaker, this really kind of turned me on to beta blockade.

It did show a benefit to Atenolol over placebo, fairly far out with regards to when its effect really was manifest, but it started to change practice, and then really, the decrease one trial was a game changer based on, it was high risk vascular surgical patients all had a positive stress test, moderate dose of Bisoprolol,

and they found a significant reduction in death and MI out to 30 days, but as many of you are aware, many of these are discredited. They didn't really look back at decrease one to see if that was fraudulent of fictitious, but many of their further trials have since been discredited.

So then, the POISE Trial came, and again, this was previously mentioned, and it does include vascular, non-vascular patients, but 8300 patients, Troprolol, pretty high dose right around the time of surgery versus placebo, and you can see that the non-fatal MI was significantly reduced, as well as a composite endpoint,

but stroke and bradycardia were significantly increased, and in fact, if you look at this out to one year, you can see that it was a 16% increase in all cause mortality, no difference in CV mortality, and then again, non-CV mortality was increased 22% and caused 54 excess deaths

compared to placebo, so that's real. Put it another way, 1,000 patients treated with a beta blocker would benefit from reducing 12 MIs and six revascularization, but increase harm significantly with 13 deaths and six strokes. Some of these trials, again, were otherwise mentioned,

and this is in vascular surgical patients, howbeit, not just AAA patients, but about 50 in each group, relatively small, and with 30 day assessment, it again was 50 to 100 milligrams Metoprolol the day before or on the day of surgery, mortality was not significantly different at the time of their discharge.

Another, slightly larger trial in patients with diabetes and beta blockade, 100 milligrams of Metoprolol, at least two hours prior to the OR, and they did two tests dosing to make sure the patients tolerated this out to day eight, and then they did a control for those who had bradycardia

or hypotension weren't included, so about 460 patients in this trial, and again, early 30 day outcome, not significantly different, and out to 700 days, again, the composite of death and cardiovascular morbidities. Last trial in terms of this review, same dosing regimine, basically, with Metoprolol here, about 250 patients

in each group, and again, no significant difference at six months, but significantly increased intraoperative hypotension requiring treatment in intraoperative bradycardia. So, putting these together with meta-analyses, looking at the effect of beta blockade

and perioperative death, actually a significant increase based on this meta-analysis, and particularly more striking was the 73% increase in overall nonfatal strokes with beta blockade. Again, the thing it did reduce was nonfatal MIs out to 30 days, even if you did

discount the decreased trials. A database review was presented by Dr. Mallis, and this was a VA cohort study, slightly different one, 37,000 patients in the VA system propensity matched and had received beta blockade within one day of surgery and thereafter, and I'm pointing out that

the vascular surgical patients, whether they were low risk or high risk, all achieved no benefit from this. So again, it may be just as much an issue of two large a dose as too short of time for it to, the medication to be administered,

and if you don't totally disbelieve the decrease one trial, they found that when the heart rate was titrated less than 65 compared to over 65, the benefit was really striking there. So, what do the guidelines say about this? Well, the AHA and 2014 perioperative beta blockade

started with one day or less before non-cardiac surgery prevents non-fatal MI, but increases the risk of stroke, death, hypotension, and bradycardia. So, what do I recommend? Well, I think that you need to keep your patients on beta blockers, if they're on them for

any indication already, such as heart failure. If they're at high risk for perioperative MI, such as those with positive stress tests that aren't a candidate for revascularization, start low dose Metoprolol, and/or Atenolol, and at least 15 to 30 days in advance,

try to titrate that heart rate, avoid the dose on the morning of surgery, and really do need a randomized control trial of titrated low dose beta blockade in high risk patients, thank you.

- Alright, good morning, I'd like to thank Dr. Veith for having me here. Before I begin, I would just like to ask for a recount in the spirit of the times. So I'm going to try and bring us back on time and talk about the optimal medical therapy

for critical limb ischemia. These are my disclosures, non-relevant to this topic. So PAD patients, the mortality is high, as you all know. And in critical limb ischemia, the numbers are even worse as you can see here. The older the patients,

the more risk factors they have, the worse the mortality. And it is quite dismal over years. So treatment should definitely follow causes of mortality. So why do these patients die? So actually most of the reasons for these patients to die are actually nonvascular, as you can see here.

And it's obviously beyond the scope of this talk to explain what to do with these conditions, and obviously they're variable. But for cardiac and vascular causes of death, the treatment is medical and obviously not opening up the flow channel to be to the foot.

So just to answer the topic of the talk, my interim first conclusion is that even today, intervention is insufficient for CLI patients. And obviously medical therapy is key. But the goals of therapy should not only focus on the mortality,

but also obviously on morbidity. So my second interim conclusion is that for morbidity and complications, even in 2028, you know even in 10 years, medical therapy will not be sufficient to replace intervention.

And because I have very little time, instead of going into the data about each and every potential medical therapy that could be offered to these patients, I'd like to give sort of a focused bottom line and a few chosen medical therapies

that are relevant to this population. Anti-platelet therapies in peripheral artery disease, and obviously in CLI also, reduce mortality in a significant manner. And obviously patients with CLI should and will be, I think, still on an anti-platelet agent in the future.

Adverse events including mortality and vascular amputations are very much increased when patients have a major adverse limb event. And so for that reason, affecting these limb events is crucial. And identifying anti-platelet agents

that are safe but also reduce adverse limb events is key. So Vorapaxar did reduce acute limb ischemia. However, the price of excess bleeding, and for that reason is not being used routinely in these patients. However, I hope that in the future

we will have other options that targets not only mortality but also acute limb events. Ticagralor reduced both MACE and MALE, so both adverse cardiovascular events and also limb events. And so this is the cardiovascular events and this is the limb events.

And so it was very impressive in patients with PAD. What about a completely different mechanism? So plaque rupture may induce atherothrombosis, so there could be atherosclerosis as a result of plaque rupture with a thrombotic component, locally resulting in critical limb ischemia.

And indeed in this pathological study of 75 patients with CLI, post-amputation thrombosis in the lumen was seen in many of these patients. So is there a role for anticoagulation? Well you've heard of the COMPASS trial

in the previous session from two speakers, and indeed low-dose Rivaroxaban resulted in fewer events. And although there were more bleeds, there was net benefit for this therapy, which was recently approved by the FDA. Statins, as you've heard from most previous speakers,

reduce major adverse cardiovascular events, but also reduce adverse limb outcomes, specifically high-intensity statins. And what about PCSK9 inhibitors? Well the reason I put them here and not at the sort of cardiovascular events

is just because their use is still very limited. But still they were very impressive, specifically in the PAD sub-analysis of Fourier. And what you can see here, that there's a very low number needed to treat in order to reduce adverse cardiovascular events

with these medications, even if many of them were on high-intensity statins. So my third interim conclusion is that in my opinion, by 2028 every CLI patient will be on an anti-platelet agent, on a statin and perhaps another anti-lipid medication. And likely on an anticoagulant of some sort.

However, in 2028 I still think that CLI will remain a team sport. Medical therapy and intervention I think will still go hand in hand, and I don't think one will replace the other. Thank you very much.

- [Lecturer] Here we go. These are my disclosures. In 2013 the ACC and AHA wrote updated lipid management guidelines, which for the first time included specific recommendations for patients with peripheral arterial disease.

They also shifted the focus away from specific LDL targets, but instead they targeted statin intensity. This is the overview of the guidelines,

but in terms of the specific recommendations for PAD patients it's a fairly focused section. After excluding recommendations about dialysis patients because of a lack of data,

they basically broke it down that anyone with PAD who's less than 75 should be on a high intensity statin. Anyone above 75 should be on a moderate intensity statin.

What are the high intensity statins? These are the ones that you need to remember. It's Atorvastatin 40 or 80, or Rosuvastatin 20 or 40. This table is available in their paper

and in ours. We wanted to look at the impact of statins, and in particular the statin dosing. According to these guidelines, our patients undergoing revascularization

either endovascular or open surgery, for CLTI at our institution from 2005 through 2014 we used propensity scoring to account for baseline differences in patients. We had 11 hundred limbs

and 930 patients after excluding the dialysis cohort. Our follow up was 380 days. Our primary outcome was overall survival, but we also looked at major

adverse limb events, which has noted our amputation and major re-interventions. Our statin use over time did increase as of 2014. 90% of our patients

were discharged on a statin, but in terms of whether they were on the guideline appropriate dose, that was pretty dismal albeit the guidelines didn't come out until the end of this period.

When we looked at it based on age, you can see that in patients under 75, they're suppose to be on high intensity here in red and we're not very good at that although we were increasing over time.

Most were on moderate dose. In the patients over 75 who were suppose to be on moderate intensity we see that that's actually decreasing and largely being replaced

by high intensity statins. In terms of what's the benefit of statin versus no statin, there is a significant reduction in mortality and this is long term survival

in patients discharged on a statin compared to no statin. For limb events, there was a benefit in the sub group of patients over age 75 only.

When we looked to see if there was additional benefit to being on the guideline directed dose, we did find a significant benefit in overall survival

and in limb events in being on the appropriate intensity statin. Since there was a suggestion that in the older age group they should perhaps be on the moderate rather

than the high intensity statin, we looked specifically at this subject group and we actually did not find a significant difference between moderate or high intensity

dosing in that group. We also noted that adherence is poor so we wanted to look at what happened one year, how many patients stopped their statins or dropped the dose

and then how does that impact survival after a year. What we found is that it wasn't so much the guideline directed dose so much as just being on either a high

or a moderate intensity statin was associated with significantly improved survival compared to no statin or low dose statin after one year. We also found that 12%

of our patients stopped taking their statin or decreased the dose. The best survival was in those who remained on their statins and a close second was those who started statin

or increased their dose, but the patients who stopped taking their statin or dropped the dose had no survival benefit compared to patients who were never on a statin.

Statins are associated with an improved survival and a decreased limb events after revascularization for CLTI and the correct dose based on the 2013 ACC guidelines

does provide incremental benefit. 2/3 of our patients are not on the recommended doses. Moderate and high intensity statin after a year is associated with improved long term survival

and discontinuation or decreasing the dose is common and results in a loss of this benefit. It's not enough to just discharge patients on a statin,

we have to make sure that it's the right dose and we have to make sure that they stay on that during follow up. Thank you very much.

- Okay, it's great to be back. Thank you. So, moving on. So we know that inflammation is very important in the pathogenesis of cardiovascular disease. In this figure on the left, do you see how macrophages, mast cells, T-cells, all contribute to endothelial cell activation, eventually contributing to thrombus formation.

There is a large literature out there that when you measure biomarkers of inflammation in. In this figure on the right, when you measure levels of high sensitivity C-reactive protein, the higher the level whether you're on placebo, whether you're on aspirin, the higher your risk of cardiovascular events.

So, I think most people now believe strongly that you can discriminate cardiovascular risk by levels of inflammation in your blood. As low level, average, or high, depending on your level of high sensitivity CRP. Further to this, is this idea that when you look

at some of the statin therapy trials, like on the left, prove it, or even the ezetimibe trial on the right. When you lower both inflammation and LDL cholesterol, in the red bar, patients do better. If you don't lower LDL cholesterol or inflammation,

as seen in the blue bar, patients did really bad. If you lower one, regardless of which one it was, patients had this intermediate phenotype. So the lower your inflammation, the lower your cholesterol, patients do better. There is this idea that we have

this residual risk paradigm. Right? If you have an elevated cholesterol, as seen on the right side of this figure, then you have this residual cholesterol risk. Sorry, on the left side. If you have low cholesterol but you still have high levels of inflammation, you're believed to have

this residual inflammatory risk. So with this idea, the Cantos trial was performed. This was looking at canakinumab, which is an interleukin-1 beta receptor antagonist for the prevention of cardiovascular disease. Now, what's really interesting, is this figure on the left.

You see on the top, when you're looking at high sensitivity CRP, there was a dramatic reduction in CRP levels with this therapy. No difference in LDL cholesterol. No difference in HDL cholesterol, and no difference in triglycerides.

So finally we were going to be able to answer the inflammatory hypothesis. When you look at major adverse cardiac events, when you combine two of the doses of canakinumab, there was a significant 15% reduction in the incidence of cardiovascular events.

Now, the authors really nicely went back and saw, "What about the people who had "the greatest inflammatory reduction?" so those with the lowest levels of CRP, that's the red group right here. Showing that in that group that had

the lowest levels of inflammation, once again, had the lowest risk of cardiovascular events. So this was very exciting. But, there was some very significant adverse events. Adverse and actually pro. So in the green, you actually see that fatal cancer

was actually lower in the group that received canakinumab. But there was significant leukopenia, there was was significant thrombocytopenia in the group. So, this was sort of a mixed picture. I think because of this, and because of the less than compelling primary outcome,

the FDA as of a few weeks ago, did not approve this drug, for the reduction of cardiovascular events. So, I think it raises this hypothesis, but clearly it did not definitively stated, and we're not going to be giving it to patients

also because of this significant cost. So, what about other inflammatory drugs? As of three days ago, the New England Journal published this cert trial as an NIH funded trial. Looking at low dose methotrexate for the same purpose. Done by the same group of investigators.

As you can see, the hazard ratio was 0.96. There was no significant reduction in the endpoint of cardiovascular events. So, inflammation and cardiovascular disease. Is the inflammation hypothesis viable? I personally think the answer is yes,

but I believe that we need future trials that focus on specific pathways that will not have untoward side effects, that will be able to sort of target specifically what the issue is. I think future trials are being considered as we speak.

I think it's a very exciting time, but I think for once we can say that when you target inflammation, at least using the IL-1 receptor antagonist, you can lower the risk of cardiovascular events. Thank you very much.

- Thank you for the opportunity to speak today. I have no disclosures. We've heard a lot about this, this morning, but, I'll just reiterate, for those of you who may or may not be familiar, The Fourier trial was a randomized trial of Evolocumab versus placebo in nearly 30,000 patients with atherosclerotic disease, and that the primary end point

was a composite of cardiovascular death, MI, stroke and hospital admission as well as some secondary end points as well. So what about these inhibitors in Peripheral Arterial Disease? Well, a sub analysis investigated the efficacy and safety of

Evolocumab in patients with PAD. And patients were defined as having PAD at baseline, if they had either intermittent claudication and an ankle brachial index of <0.85 or if they had a prior peripheral vascular procedure. So of the total cohort, 3,600 and some patients where 13%

had PAD based upon this definition, Evolocumab significantly reduced the primary end point consistently in patients with PAD with a hazard ratio of 0.79. What about Cardiovascular efficacy in the PAD population? Evolocumab significantly reduced both the primary end point

and the composite end point of cardiovascular death, MI or stroke very significantly and you can see in looking at this slides that the relative risk reduction was of higher magnitude in the patients with PAD than without PAD. Major advers limb events were significantly reduced in the overall population

as well as the patients with PAD and the results with regards to major amputation, I think are quiet compelling here. Again if you look at major advers limb event reduction you can see here in all patients and in patients with PAD there was a market reduction in events.

And then if we finally look at a composite outcome of MACE, and Male in patients with PAD, overall Evolocumab again reduced this composite outcome by nearly 21%, and if you look at the slide again, you can see that the magnitude of reduction, was of higher magnitude in the PAD group.

What about the safety? There were no differences in the incidents of adverse or serious events with the medication in patients with PAD. And importantly there was a consistent relationship between lower achieved LDL levels and lower risk of limb events that extended down to

very low levels of LDL cholesterol. So in summary Evolocumab significantly reduced the primary end point with patients with PAD because of their overall higher risk, patients with PAD actually had a larger absolute risk reduction for many of this end points than many patients without PAD and Evolocumab

significantly reduced major adverse limb events in all patients and in patients with PAD. What about Coronary disease as doctor Veith asked me to address? With in the of patients with prior MI, it was hypothesized that may be we could identify some that would

benefit more from this medication. So, 22,000 patients had a prior MI, and they were classified in several areas, one of them being, that based on the time of their most recent MI, 8,400 patients or 38 percent were with in two years of their most recent MI,

and this recent MI as well as other factors were independent predictors of a future cardiovascular outcome. So, if you see her in the placebo arm compared with patients with a remote MI , those with a recent MI were significantly higher risk in the placebo arm for the primary end point.

The relative risk reductions for the primary end point was greater in these high sub groups including recent MI, than for those with remote MI, and you can see this here in this slide as well. And patients with a recent MI and with remote MI and the magnitude of the reduction being much greater in the higher risk group.

So in conclusion recent MI, was felt to be a high risk condition and that these patients significantly benefit from cholesterol lowering with Evolocumab. So it's being reiterated here this morning, how low should we go, the targets are constantly changing and again changed just as recently as last week, and there

are a lot of good arguments for extensive lowering of LDL cholesterol, it's important to realize that because of the anticipated extreme reductions in LDL cholesterol regulatory agency require enhanced monitoring of adverse events. Particularly neuro-cognitive events, and in a sub study of FOURIER, there were no group differences in many of these

parameters between the placebo and medicated groups. in FOURIER the reduction in the primary and secondary composite end points was in fact linearly relate to the achieved LDL cholesterol. And in a post hoc analysis five percent of these patients achieved extraordinarely low levels.

In this group importantly, there were no associations between this achieved levels and predetermined safety event. So I tried very hard to find a slide that said when they go high we go low but unfortunately no one wanted to make that so I'll just say go low or go home.

- Thanks again for the invitation to talk about, I think a lot of excitement on these new medications, and you've heard a lot from our prior speakers. So, first focusing on antiplatelet, antithrombotic therapy, this very simple cartoon. Certainly, we've known about aspirin forever. Xa inhibitors, thrombin inhibitors,

the PAR inhibitors now are coming about to to prevent this atherothrombosis. And this, I think pretty well done analysis, looking at peripheral arterial disease patients, looked at which agents perhaps are the most efficacious. And what was shown here is ticagrelor and aspirin

or clopidogrel. Put another way that looks at both safety and efficacy, really, clopidogrel and ticagrelor and aspirin stand out more than aspirin alone. So you've already heard about the COMPASS Trial in a fair bit of detail, but again,

this was rivaroxaban plus aspirin versus aspirin alone. And this substudy in patients with a PAD specifically looked at MALE, AMP, et cetera. 6300 patients, and you can see a significant reduction with, again, rivaroxaban plus aspirin versus aspirin alone. 43% reduction MALE, 67% reduction to amputation,

decreased vascular interventions, but at the cost of increased bleeding. Vorapaxar is a PAR inhibitor. It's gotten a little less use because of the bleeding events, but of interest in patients, a substudy of patients with PAD, 3700 patients,

again, there was no difference in the composite CV outcome, but acute limb ischemia was significantly reduced, incident acute limb ischemia, and the need for revascularization. So there's a lot of these agents, and Dr. Hiatt, I think in this nice review in JAMA Insights,

helped clarify this with this table. So if you have asymptomatic patients with PAD, probably antithrombotic therapy aspirin may not be of benefit, but for patients with PAD-associated limb symptoms, probably clopidogrel or ticagrelor monotherapy

is most efficacious to prevent long-term cardiovascular events. Still, with patients with revascularization, a bypass aspirin should be maintained. For patients with polyvascular disease, PAD plus manifest CAD, again,

antithrombotic therapy for stable cardiovascular disease, either adapt or clopidogrel alone. For patients who are at risk of cardiac and ischemic limb events, either ticagrelor plus aspirin is probably better than Plavix, or low-dose rivaroxaban.

Again, you heard about the COMPASS Trial. And probably vorapaxar, less likely to recommend that. From Dr. Rockman, you just heard a nice overview in terms of LDL, but again, the greater the reduction, the greater the decrease in events. This meta-regression just shows

that it does matter where you start. So if you start at a pretty high LDL level, and you get one of these agents, you have a greater relative risk reduction as comparative if you're already starting fairly low. Again, from this same summary,

for patients that were already at a low level LDL, you still gained a benefit from the addition of the PCSK9 inhibitors without any increase adverse events. So, just again, you heard about this from the last speaker, but this, again, focusing on patients with PAD. Here, overall it was 27,000 patients in this large trial,

follow up, 2.2 years, and again, as was highlighted previously, those with PAD gained a greater benefit than those without PAD. And again, major adverse limb events significantly reduced, 37% over time.

How about ezetimibe that blocks cholesterol at the GI tract level. Safe drug, this was a randomized controlled trial of ezetimibe versus simvastatin, plus simvastatin. 18,000 patients, these weren't PAD-specific. Acute coronary syndrome was the inclusion.

And here, they really decrease the LDL from 70 to 54, with about a 7% decrease overall cardiovascular morbidity and mortality. Raising HDL, you heard from one of the very early speakers, this is off the market now, really not worthwhile to do. And Dr. Berger noted that this agent just was presented

the American Heart Association, I think it's very interesting, patients with hypertriglyceridemia in this derivative of Omega 3, iscosapent ethyl, five year out follow-up, and everything they looked at was significantly reduced,

which I think is quite exciting. So what should we do about our high-risk PAD patients? Aspirin, but really probably lean more toward Plavix should be the first line therapy for symptomatic PAD patients. Consider rivaroxaban in those with coronary artery disease

would be my first line, and again, reducing both cholesterol and inflammation with statins should be standard. If you can't get that LDL less than around 70, maybe add ezetimibe, that seems to be safe and efficacious. PCSK9 inhibitors in refractory patients,

particularly those that are still above 200, there seems to be no lower limit of LDL, and again, keep your eye on this new triglyceride-lowering drug. Thank you!

- So these are my disclosures. And let's start first of all for the merit to have them, what are the potential benefits? So we'd like to get rid for permanent rigid metallic cage. We'd like to restore vasomotion, angulation, eliminate instant restenosis of metallic stents which is hard to treat.

We also have to keep the ability of late luminal enlargement, preserve the target for CABG and freedom from long-term polymer exposure, inflammation, and it is very appeal to patients and physicians not to have a permanent implant.

But with all these we have seen what is the desire. The desired is to have this absorbed treated artery looks like, very nice healing. Large lumen compared to metallic DES. Does it really happens? And the question was driven initially from data from Europe,

that look on large registries that the results of 30 days and six months with Bioresorbable Scaffolds was acceptable except for one thing, which definite, probable stent thrombosis. 1.5% and 2.1% in the coronary, it is not acceptable. This was also driven or repeated in a similar magnitude

in ABSORB II and ABSORB III which were randomized trials comparing Xience, which was the drug eluting with metallic stents to BVS or Absorb, which showed again over time higher thrombosis rate for both of those randomized trials and this was despite the patients were on DAPT.

As a matter of fact, the recommendations were extended for the Absorb now to three years, for the duration of the absorption time. So the question was whether these were two early studies without implying good technique. And then what is the good technique?

You doing pre-dilatation, you're doing post-dilatation, you're doing imaging. And that was actually implemented later on. So if we look at the latest data that was presented with the Absorb, which was ABSORB IV studies,

now the stent thrombosis are better. They're only 0.7% at one year compared to 0.3% with Xience. It still looks a little bit higher numerically, but these are within the range of what you can expect from drug eluting stent. The other thing that this study showed,

if you look on ABSORB III-like studies, your results are going to be relatively much better that what you have seen with ABSORB III. But nevertheless, this first generation stent, if you can look at the totality of the data was still higher events compared to metallic stent.

Now why did we prolong the DAPT from three years? Because we do know that the three years we still have PLLA that is still there and it could dismantle and cause scaffold thrombosis. Now Abbott pulled out the technology from the market for commercial reasons.

I think the main reason was the fear from thrombosis and patients and physician didn't want to use it. And the ESC guidance just changed their recommendations to Class IIIC, which means you should not use it unless you doing it in clinical trials. So this is really was hampering on the whole field.

And the question, can we resuscitate from this situation. First of all, we need to know how to improve it. We have to improve the technique, PSP, imaging, prolonged DAPT, and also we have to improve the technology with thinner struts, improved mechanical properties.

Are these coming along? Definitely yes. We have a array of second generation BRS with 80 micron, 99 micron, 100 micron compared to 228, 170, 150 in the first generation. So we are going to see secondary generation scaffolds

that perhaps will solve all those issues which we have seen with the thrombosis. And indeed, if it's not going to come from the U.S., probably not very soon, it's coming from China. And look at the number of programs right now. Five programs completed First In Man,

two of them in randomized clinical trials, two already completed registries. So the data from China which is randomized, will come and we'll see how that goes. This is a project that I've been working on, Magnesium just to show you,

that if you compare Magnesium to ABSORB you see no thrombosis on the porcine model shunt. And this is even better than metallic DES stent. So I think we can able to solve the thrombosis rate. If we do that, then I think we see those technology coming back again.

What about the periphery? There's was one study at ESPRIT, very small one, with actually promising result. And again, it's up to the companies to see if they're going to encroach to the SFA program. So my final thoughts are that the unmet need

for Bioresorbable scaffolds remain despite improvement of second generation DES. The first generation BRS are inferior to the best in class DES and should not suitable for routine use. We always will have to show randomized trials

that at least we have known inferiority of Bioresorbable technique to metallic DES and then with second generation BRS we have the hope to make scaffolds great again. Thank you very much.

- [Male Audience Member] I'd like to ask a question just to most of the panel. So, where would you put your efforts now in 2018? Should it be on compliance with current guidelines? Or should it be on these novel medications with the associated price, and the novelty of these medications?

- So, I can start, but I mean there are a lot of people on this panel who can answer that. So, I think it's amazing that we have so many potential therapies that are add-ons that really show a reduction in both cardiac

as well as limb events. I think it's a really impressive time. Despite that, I think the data, the national data of Howard Dewing with the established therapies, simple therapies, like antiplatelet therapy with Aspirin, or Clopidogrel,

or just putting patients on statins, or getting them off their 10 or 20mg of Simvastatin, or Pravastatin. I mean, to me, I think we should really spend a lot of our time just getting people on established therapies.

Once you have that done then I think we should be thinking about can we move the needle even further. But I think we have a long way to go just to get people on established therapies that could help lower their risk

of both heart and limb events. - If I may just add to that, and take a little bit different spin. We had two great sessions in this morning about all the statins, the Rivaroxaban and all the other great drugs

that's coming, omega-3. But really no one talked about prevention, and I think we really have to start with primary prevention. So to your question I would say, we have to make more emphasis on primary prevention, cessation of smoking, diet, exercise.

Then after, we're going to go after the drugs. And with the drugs there is always the issue, even if we think it's very believable that they work, there is always the side effects. And no one of the patients like to have the side effects. Even if you tell them the biggest story

that this is effective. So I think one of the issues, that it's hard to sell those drugs to a patient, as soon as start to have a bleed. For Rivaroxaban, they don't want to take it anymore, if they have muscle issues,

they don't want to take statins anymore. So I think with prevention at least you don't have side effects. So you should really really push the flag on that. - Except for knee pain with the running. - So, yeah, that's a very interesting point Ron,

but I think it almost challenges the paradigm of healthcare delivery, right? We just don't have a way, our system doesn't do healthcare maintenance and stuff, so, does anyone have thoughts about how we should

go from treating sick people to maintaining peoples health. Which is prevention. It's almost like going to the, I guess the medical gym, but you need to go to the medical gym once a week. - There is a way to do that,

which works in the American system very well. It's called reimbursement. So if you're going to give reimbursement to physicians, and to patients and motivate them, you're going to save a lot of money but you'd need to give them the incentive.

And I know it's very cheap to say money talks, but reimbursement talks in the US, and I think that has never been implemented. - Well I'll just give you one little anecdote, but I think this is a possibility. One of my good high school friends has started a business

of workplace health clinics, but I think integrating healthcare onsite in the workplace, certainly his business is going crazy. But to reduce insurance costs, and like you say Ron, incentivize employees that you have to do this to maintain your insurance.

Any other, go ahead. - You know, I think that primary prevention is very important, and I think that so called lifestyle changes are critically important, and that would be the optimal way to do it,

and certainly reimbursement is a great motivator. But I don't think that means we can withhold thermedical therapy from those patients who are not going to comply with those things, and that becomes a challenge as well. - We have someone at the microphone,

go ahead and introduce yourself. - [Raymond] Raymond Shields, Mayo clinic. We appreciate all the comments from the panel, and I enjoyed your session. I think one of the things that we have to keep in mind is that we as physicians,

healthcare providers, we also tend to get caught up in the fervor of procedures that may show a little bit of benefit to help in treating hypertension, or hyperlipidemia, or what have you, and so, thereby we have to be careful about that temptation

to use a procedure, whether it's renal artery denervation, or what have you, we see what happened with that, as far as the disaster as far as the results with that, and our having to rethink technology. So technology has,

provides a lot of opportunity, perhaps enthusiasm, so we have to think about these things as far as prevention being very very important. Not as exciting. It requires tremendous amount of commitment over days, weeks, months, years, and so

that's a real challenge, and thank you for your comments. - So I'll give you one example. At NYU we have a center for the prevention of cardiovascular disease, and it is a bonafide center, it's really well established,

and I think we really made some great strides, to the point where patients will get admitted into the medical center for a variety of different reasons, and we've implemented a way where a prevention focused physician will go see them. We'll not bill, we'll just go see them,

and we'll deal with a lot of these other issues so that when they're there, when you sort of have their attention, you can sort of deal with a lot of these things. Which I think is a tremendous step forward. - If I can add to that,

and these are our patients of course. So we work together, and these are the vascular surgery patients that are getting admitted with these key diagnoses that are then getting these preventive cardiology consultations, if you want,

in the hospital, and it's amazing, and it's wonderful. We don't always know if when the patient leaves, whether they're stick with that, or whether their primary care physician, and the community perhaps, has the same feelings about those things,

and I think that's a challenge as well. - It is, it's very clear that, I was involved in a wound care center during my tenure at Georgetown, it really was a team approach wherein podiatrists, plastic surgeons, but it's very clear to me

from our session today that we need a team approach for all of our patients, and it's a reorganization of how we deliver vascular healthcare. If any of the panel members have comments from their own institutions

about how well that team approaches, achieves certain, sounds like it's going well at NYU, Edo what's it. - I would like to say that in the treatment of vascular patients, I think a team approach, especially to critical limb ischemia patients,

but also preventive cardiology for patients who are able to comply with that is definitely taking off, and in our center as well is something that is definitely something that we do. - We do as well, and I'd just like to mention that

I do think in terms of increasing compliance with these evidence based standard therapies, participating in a registry, getting that feedback, and then looking at how you compare does make a difference. I think that's been shown in the VQI, and in the state of Michigan

we have Blue Cross Blue Shield underwritten one, where our discharge rates of statins are well above 90%. - And so you said, is that reimbursed in Blue Cross? - No it's just sponsored that Blue Cross Blue Shield pays for basically a nurse abstractor onsite to collect the data very much in the same way

VQI variables and outcomes are done. - Right, very good.

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