COMMENTARY

Electrophysiology Data From ESC Explained

Neil E. Moat, MBBS, FRCS; Jagmeet P. Singh, MD

Disclosures

October 24, 2014

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Modulation of the Autonomic Nervous System

Neil E. Moat, MBBS: Welcome to the European Society of Cardiology (ESC) meeting in beautiful Barcelona, Spain. I am Neil Moat, a cardiac surgeon from the Royal Brompton in London. I am here today with Dr Jag Singh, an electrophysiologist and director of the cardiac resynchronization therapy program at Massachusetts General Hospital.

There have been several late-breaking trials on electrophysiologic issues at ESC and we are going to cover some of those. An interesting area is in device-mediated, autonomic modulation. Jag, could you tell us what is being talked about in that area?

Jagmeet P. Singh, MD: There has been a lot of excitement about nonpharmacologic modulation of the autonomic system in heart failure, primarily because there is evidence that the sympathovagal balance of the autonomics are totally dysregulated in heart failure. By finding some mechanism to modulate them, you can help reverse the modeling in these patients.

There were two very important studies that we were looking forward to. One was the NECTAR-HF study,[1,2] and the other was ANTHEM-HF study,[3,4] both by different sponsors. I will take you through the results of each study very quickly and then give you a perspective on where they stand.

NECTAR-HF: Neutral Effect on Reverse Modeling

Dr Singh: The NECTAR-HF trial, sponsored by Boston Scientific, looked at a vagal nerve stimulator on the right vagus nerve in patients with heart failure. These patients had ejection fractions < 35% and left ventricular internal diameters > 50 mm.

This was an 18-month-long study; the investigators presented their 6-month results. The endpoints that they were primarily looking at were changes in end-systolic volume and ejection fraction, which is structural remodeling, and they also looked at such secondary endpoints as the 6-minute walk test, quality of life, and so forth.

It was a very elegantly run study. It was a sham-controlled, double-blinded study, with 96 patients who were randomly assigned [2:1] to either the treatment arm or sham procedure. The end result was that they found no difference between the 2 arms. There was no change in any of the reverse modeling parameters.

Some of the secondary endpoints were met. Patients with the vagal nerve stimulator felt better symptomatically. There were improvements in the 6-minute walk test and quality of life. Some of those findings were attributed to the fact that patients believed that they knew they were getting the vagal nerve stimulator, so there could have been an element of bias in terms of symptomatic improvement.

Dr Moat: Both groups, to my understanding, had the device implanted, but one group was not activated. If the device was activated, did the patients have any sensation to indicate to them that the device was active?

Dr Singh: Absolutely. There were visits at which the device dosing was titrated, and when the device is turned on, some patients experience laryngeal irritation or a cough, or they feel some degree of discomfort. Therefore, there is no way of completely blinding a patient as to whether their device is activated or not. It is possible that this influenced the findings.

That was the NECTAR-HF study, which had a neutral result. However, there is an 18-month follow-up, so they will be looking at whether there are any changes over time.

Dr Moat: Is there any plan to have a crossover, so the devices in the control group will be activated? That has been done in other studies.

Dr Singh: Not in the immediate part of the trial that I know of. Neither group had changes in volume, so if you cross them over, you are probably not going to see a whole lot.

Dr Moat: But in terms of the symptomatic effect, at least, it might show something.

ANTHEM-HF: Watch This Space

Dr Singh: ANTHEM-HF, which is a Cyberonics study, looked at 60 patients with an ejection fraction < 40% and New York Heart Association (NYHA) class II-III heart failure. They tested the left vs right vagal nerve stimulator, so both sides were stimulated. The patients were not randomized; it was an open-label patient population. Some patients received the left side and others the right side, and the investigators looked at changes in reverse remodeling, symptomatic improvement, and other secondary endpoints, which are comparable to the NECTAR-HF study.

They found that there was reverse remodeling with both sides. In both left and right stimulation, there was a comparable change in ejection fraction. The change in end-systolic volume did not reach statistical significance, but there was an improvement in ejection fraction in both arms. There was also symptomatic benefit, as well as improvement in the 6-minute walk test.

This study was not sham-controlled or randomized. It was open-label, so there are reservations in the interpretation of the results. It is interesting that there were two different stimulation protocols. There are three types of fibers that go through the vagus nerve (types A, B, and C), and you are trying to stimulate the type B fibers. The stimulation protocols between the two studies were quite different, which might have played a role. It makes us pause and sends us back to the drawing board to try to assess and understand dose-response in this patient population.

We also have to try to get better patient selection, because selecting patients who have some sort of baseline measure of autonomic dysregulation would be more important than taking all-comers with heart failure, and assuming that the patients have autonomic dysregulation.

Those are factors that will come into play. It is very important that we develop some surrogate measures for assessing the effectiveness of the therapy that we are delivering at the time we deliver it, rather than waiting 6 or 18 months only to find that it makes no difference. We need to develop acute procedural surrogates or programming surrogates, so there is a lot of work that still needs to be done.

Dr Moat: It is interesting that the left was the same as the right, because my understanding is that there are significant differences in the fiber content of the right compared with the left.

Dr Singh: That line of thinking was pursued because if they had to integrate a vagal nerve stimulator device, most existing implantable cardioverter-defibrillators are implanted on the left side, so that it would be easier to integrate. That was the hypothesis that they were testing. It was just 30 patients, left vs right, and there is still a lot of work to be done to understand whether it is meaningful.

Dr Moat: "Watch this space," rather than great excitement that it is going to work.

Dr Singh: I would say, certainly watch this space. There is a study called INOVATE-HF ongoing, which is a much larger study, with approximately 650 patients. It is a hard endpoint study, where they are looking at all-cause mortality and heart failure hospitalization. That study is probably already more than halfway through. That will be a landmark study to tell us whether vagal nerve stimulation works, so everybody is looking forward to those results when they are ready.

BIOPACE: A Mixed Bag and Baggage

Dr Moat: Let's move on to the topic of biventricular pacing, and the trial called BIOPACE.[5]

Dr Singh: BIOPACE was a very interesting study. BIOPACE looked at biventricular pacing for bradycardia-related issues that required a pacemaker. The rationale is that when you pace patients from the right ventricle, you create some degree of electrical and mechanical dyssynchrony, and over time, that can lead to progressive left ventricular dysfunction.

This study has been going on for a long time. They followed the patients for a period of almost 6 years, so a very good study has been conducted.

Patients who required right ventricle pacing could be those with atrioventricular (AV) block, atrial fibrillation with a slow ventricular rate requiring pacing, or patients with sick sinus syndrome who had a prolonged AV interval and needed ventricular pacing. They had a slew of bradycardia indications among patients who were recruited for the study, and approximately 1800 patients were randomized: 900 into the right ventricle pacing arm and 900 into the biventricular pacing arm.

These patients were primarily chosen for bradycardia indications. Ejection fraction was not a selection criterion, so almost all of these patients had a preserved ejection fraction. The mean ejection fraction was about 55% in this patient population.

They followed these patients for a 6-year period and found no significant difference in all-cause mortality and heart failure hospitalization. They looked at hard endpoints. There was a nonsignificant trend for patients to do better with biventricular pacing, and the P value was .08, with reasonable confidence intervals.

It gives us pause, because many patients do well with right ventricular pacing and biventricular pacing does not come without its own baggage. It is a more complicated procedure. It takes more time. It is a more tedious implant, and there are more complications related to either phrenic nerve pacing or dislodgement. Furthermore, the follow-up of these patients is quite different from conventional right ventricle pacing. They need to be programmed and optimized and followed a little more intricately.

Putting it all into perspective, the take-home message from that study is that if you have a bradycardia indication, and you have a preserved ejection fraction, right ventricular pacing is still the way to go. I am interested in the subanalysis when they look at different ejection fractions to see whether there is a subset of patients who do better with biventricular pacing, but those analyses still need to be done.

Dr Moat: Studies like this have a mixed bag of patients. You wonder whether an effect in a subgroup is hidden by the fact there is a mixed bag of people who are not expected to respond.

Dr Singh: That is a very good question. If you were to substratify patients into those with atrial fibrillation and those with normal sinus rhythm, the patients with normal sinus rhythm and complete atrioventricular block with a marginally reduced ejection fraction might benefit, but it is hidden with this large mixed bag of patients. Those subanalyses need to be done, and there might be a subpopulation who can glean benefit from biventricular pacing. It is going to be challenging to move the guidelines with a subanalysis.

MORE-CRT, Fewer Procedural Problems

Dr Moat: The other interesting study looked at quadripolar cardiac resynchronization therapy (CRT) leads, which allow you to have a lot more options for where to pace, and fewer phrenic nerve issues. That seemed to be quite positive in improving the response to biventricular pacing.

Dr Singh: The study you are talking about is the MORE-CRT study.[6] That was also a very well-conducted study. It was a large study that looked at the role of quadripolar leads vs bipolar leads. Those of us who implant resynchronization therapy devices tend to choose a lead that has more electrodes, so it gives you more options.

The study showed that patients who received a quadripolar lead did better from an intraoperative procedural issues standpoint. There were fewer intraoperative procedural issues because they did not have to change and find a new vein. They did not have phrenic nerve issues. There were fewer dislodgements, so overall, the quadripolar leads were superior to the bipolar leads for procedural-related issues.

I agree with you that it gives us more options for pacing, but nobody has elegantly looked at the impact of quadripolar leads on response. Some single-center and retrospective analyses have shown the outcome on mortality and cost effectiveness, but prospectively nobody has been able to show that quadripolar leads enhance reverse remodeling or clinical outcomes in a randomized fashion. Those studies are ongoing, and they will be very telling.

Is Biventricular the Way to Go?

Dr Moat: Moving into a niche area, a field that I am interested in is TAVI (transcatheter aortic valve implantation) or TAVR (transcatheter aortic valve replacement). One of the problems with some of the devices is a high requirement for permanent pacemaker insertion. Our experiences of putting in isolated right ventricular leads is that those patients often don't do very well, but they improve if you upgrade them to a biventricular lead. I am interested in your thoughts as to whether causing acute, complete heart block in patients who have left ventricular hypertrophy (and probably some diastolic dysfunction) makes sense to you.

Dr Singh: That is a very intriguing question. Some work has been done in the past looking at the impact of biventricular pacing on diastolic relaxation and diastolic compliance. A lot of preliminary work has shown that biventricular pacing affects not only systolic function, but also diastolic function.

It makes some sense. If you are changing the activation pattern of the heart, you are also changing the relaxation pattern of the heart by just the change in depolarization wave front. Unfortunately, this is not an accepted indication as of yet, because nobody has done a prospective, randomized trial in that particular subset of patients, but we have seen anecdotal cases in patients who were doing terrible with the right ventricle lead, and the moment they received a biventricular lead or an epicardial lead periprocedurally, they did dramatically well.

Dr Moat: There is a future trial for us. I would like to thank Jag Singh for his insights about the late-breaking electrophysiologic studies that have been reported at the ESC. I hope that you have enjoyed this session.

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