THE JANUARY 2008 BOSTON SYMPOSIUM

Here is some information from the January 2008 Boston Atrial Fibrillation Symposium selected on the basis of its relevance to patients who are considering how to deal with their AF. For example, you can search for or ask your doctor about developments in new medications that are mentioned. Or you can ask an EP or surgeon you are considering about whether he is using any of the new techniques that are described.

In some cases, I have added material from sources other than the Symposium or added my own comments.

Generally speaking, there were no reports of outcome-tested breakthroughs that you can use right now; however, there are new medications, technology, and techniques in various stages of development. Waiting for these to develop further would be reasonable in cases where the patient’s symptoms are controlled and his time in AF will not make his AF less amenable to treatment.

(For some, using supplements or life-style changes can reduce the AF burden and extend the time before the irreversible physical remodeling takes place, making watchful waiting an especially viable option. Such remodeling will reduce the probability that CA or surgical intervention will be successful. (For information on supplement and lifestyle changes such as trigger avoidance, see the LAF Forum.)

In the more immediate future: Prospective patients should be aware that the increasing use of robotics promises to revolutionize the way CA is performed, increasing both safety and effectiveness. It is, however, a work in progress (see below).

Certain patients can, in consultation with their doctor, seek out a clinical trial, and there are some cases where this would make sense. For example, a patient who cannot take anticoagulants but has a high risk of stroke might choose to take part in Watchman trials (the PROTECT-AF trial --see below).

(By the way, any time an EP or surgeon treats someone with a approach that is new to him, the patient is really in what amounts to a clinical trial. Prospective patients should ask EPs or surgeons they are considering about the number of cases done and the success- and complication rates for their latest approach.)

For the majority of you who will have no reason to look over details of Symposium presentations that require knowledge of AF and its treatment, here are some ?’s for your doctor that are based on the various topics. I consider these to be of much less importance compared to questions regarding success- and complication rates, and on how success is measured (as covered in Choosing treatments...)..

Warfarin and contemporary rat poisons belong to the same class of drugs (coumarins) and both decrease blood coagulation by interfering with vitamin K recycling. Warfarin inhibits vitamin K reductase, which is the enzyme responsible for recycling oxidated vitamin K back into the system. For this reason, drugs in this class are also referred to as "vitamin K antagonists".

Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants by directly inhibiting the enzyme thrombin. Some are in clinical use, while others are undergoing clinical development. Several members of the class are expected to replace heparin (a short-acting anticoagulant) and warfarin in various clinical scenarios

There are at least 5 drugs in various phases of FDA testing. The hope is that one or more of these will reduce stroke risk in AF patients without the some of the drawbacks of warfarin.

1) The need for frequent monitoring to control the unpredictable effects of dosage and of interactions with other drugs or with foods containing vitamin K;

2) A narrow therapeutic window. It is easy to get too much, which can cause bleeding or increase bleeding from falls, etc.; or, too little, which will not reduce stroke risk enough.

Other problems that can be caused by warfarin that are not under research scrutiny include artery calcification and (possibly) osteoporosis. The action of these new medications is different than that of warfarin so these may not be an issue.

Another important goal would be to avoid the potential for liver damage, which was the case with ximelagatran, a promising thrombin inhibitor.

The risk of hemorrhagic stroke will still be significant, as it was in the ximelagatran, where the incidence was the about same as that for warfarin.

The medications furthest along in Phase III trials, which are large-scale, multi-center randomized-group studies, are listed below These are studies on patients with AF, as opposed to patients who have undergone knee- or hip replacement surgery, in whom the drugs have shown promise in preventing thrombi (see below).

The earliest the results of Phase III trials may appear is 2010 (for dabigatran; later for others). So far, there hasn’t been any sign of the liver problems that prevented FDA approval for ximelagatran.

As noted above, these drugs work on a different part of the “coagulation cascade”. For details of this process, see the book Thrombosis and Stroke Prevention by Hans Larsen, available at the LAF website.

For more information, see http://www.medscape.com/viewarticle/559717. This is a report of Phase III trials on the effects on two anticoagulants on thrombosis occurring after hip or knee replacement. (FYI, “enoxaparin” in the article refers to low molecular weight heparin , such as Lovenox).

?: How long will it be before a good alternative to Coumadin will be available?

The LAA has a number of functions, but Dr Marc Gillanov, a well-known surgeon at the Cleveland Clinic (CCF), stated, “We can do without them,” without explaining why. (See numerous articles by Claudia Stollberger for a dissenting view)

These functions include: cardiac output; serving as a reservoir for atrial- volume or blood pressure overload, atrial natriuretic peptide secretion, and heart rate modulation via stretch receptors.

Surgeons performing Maze surgery regularly either cut off the LAA or close it off. Surgeons approaching the heart from the outside (epicardial approach) can also remove it.

Gillanov stated, however, that, “Complete and permanent excision that is rapid and simple; with no bleeding risk is not yet available”

When the LAA is occluded (blocked off) as opposed to being excised (cut off), it is subject to leak. In patients with Continuous AF, sources of AF may develop in the part that is still functioning.

Excision (removal) may be incomplete (in around 25% of cases), leaving a pocket. It may be, however, that the part furthest from the place where the LAA joins the atrium and is the part that is removed -- and is the part that harbors the bubble-like formations ("trabeculations") that are most likely to harbor clots.

Dr Gillanov is working on a clip that is easy for surgeons to apply, whose urethane cover provides uniform clamping pressure, and whose cloth covering encourages tissue to grow over it.

A promising device called the "Watchman" can be implanted at the entrance to the LAA using catheters is undergoing a 5-year large-scale trial comparing it to Coumadin therapy. The trial is called PROTECT-AF, and it will be finished in 2010. (See:

? : Do you believe that it would be a good idea for me to have my LAA removed or blocked off? What does the research show about this? What is the best way that this can be done? If I am a person that cannot take Coumadin and is at risk for stroke, should I try to get into a Watchman trial? Are there any other options?

The anti-fungal agent ranolazine shows promise in suppressing AF/AFL without affecting the electrical parameters of the ventricles – meaning that there shouldn’t be any danger of producing life-threatening ventricular arrhythmias. (The possibility of doing so is why anyone starting on an AR medication or even increasing the dose of one he is already taking is supposed to spend one or more nights in the hospital.)

Their atrial-specific action could also reduce other side effects which are such a problem with current AR medications. The study reported here was done on cells in vitro; the results are far removed from any clinical application.

Another AR drug, vernakalant (Kynapid) is further along in its trials, but the results don’t seem very impressive to me:

“Cardiome is also investigating vernakalant in oral form for the chronic treatment of atrial fibrillation relapse. Vernakalant (oral) is expected to prevent or slow the recurrence of AF, and is designed to be used as a follow-on therapy to vernakalant IV [used to convert AF to NSR].

In Q3-2006, Cardiome announced top-line results from both the 300mg and 600mg dosing groups for a Phase 2a pilot study of vernakalant (oral). The study was initiated in Q4-2005.

For the 300mg dosing group, 61% (33 of 54) of patients receiving vernakalant (oral) completed the study in normal heart rhythm, as compared to 43% (24 of 56) of all patients receiving placebo. For the 600mg dosing group, 61% (30 of 49) of patients receiving vernakalant (oral) completed the study in normal heart rhythm, as compared to 43% of all patients receiving placebo.”

?: Are there any AR drugs in the pipeline that show promise of controlling my AF without significant side effects?

Here is a recent positive statement from Carl Pappone in an article announcing the introduction of a new catheter to be used in the

The 8mm catheter has been used at San Raffaele University Hospital for the treatment of atrial fibrillation. ‘The 8mm catheter is an important step toward improving the effectiveness and efficiency of atrial fibrillation procedures. The power of the 8mm catheter, combined with the safety of precise and soft contact in critical areas of the heart, simplifies the treatment of complex atrial arrhythmias,’ said Professor Carlo Pappone, MD PhD, FACC, Director of the Arrhythmology Department.

He did add, at a luncheon given by Stereotaxis, that: 1) the catheter design is still evolving; 2) the software needs work, particularly with regard to adjusting to the breathing of the patient; and, 3) the CARTO system, which gives the operator information about catheter location and abnormal conduction pathways, needs an upgrade.

Here is a statement from Bordeaux EP Dr Haissaguerre regarding the potential of the system:

"We are very enthusiastic about the present and future applications for the Stereotaxis system, which represents an engineering tour de force," said Professor Haissaguerre. Today the Stereotaxis system allows stable and precise catheter positioning potentially better than manual manipulation. Our initial experience on atrial fibrillation using the magnetic irrigated catheter is very promising, suggesting notably the potential for a higher safety margin in comparison with conventional manipulation while maintaining at least equivalent efficacy. "

"Our next goal is to achieve complete automation of the many different techniques necessary for catheter ablation of cardiac arrhythmias and particularly atrial fibrillation. We hope our partnership with Stereotaxis will be mutually beneficial in achieving our goals of further understanding and treating the most complex rhythm disturbances leading to better patient care," Professor Haissaguerre concluded.

So, how is the prospective patient to deal with the situation in which various aspects of the technology are developing but which already may have some important advantages under certain circumstances?

First of all, the prospective patient may want to make sure that the Stereotaxis system at the center he is considering is using the latest version of the 8mm/irrigated catheter.

Here are some other thoughts:

1) A robotic system has the potential to make CA safer and to make lesions that are more precisely placed than can be done using manual manipulation. In other words, its effectiveness is less operator-dependent.

>> A reason,therefore, to be comfortable with having a CA from an EP who is not in the top tier -- defined loosely as an EP who has done 100s or 1000s of ablations and has a good track record with your type of AF -- is if he uses the ST system and is far enough along the learning curve.

2) Favoring a robotic system assumes that its outcome represents an improvement over that of whatever manual operator is available.

>> One situation where this might be the case is if the lesion set is likely to require catheter works in tight areas which would be a challenge for even the most experienced and skillful EP -- or in the case where the EP must make an unbroken line or risk the possibility of creating AT.

Again, this is assuming that the robotic system can give adequate feedback to the operator, that it can maintain the right amount of pressure on the surface of the heart as it moves, that the imaging system provides an accurate picture of the location of the catheter, and, that the catheter/energy source combination can deliver an adequate lesion especially in thicker parts of the atrial wall.

>> So, these are all questions that one can ask an EP who uses the ST system.

I suppose that this is asking a lot of the of the prospective patient to delve in to all this. And it is asking a lot of the EP to give answers about a system that is continually improving and whose answers may reflect the place your case would be on his learning curve.

As one presenter at the Stereotaxis dinner put it, "Every case is a learning curve".

And informal estimates of when robotics will be in common use range from two to five years.

A catheter design that can deliver focused energy to a number of places at once, forming an unbroken line, would be most welcome. There is great appeal of a catheter with several electrodes on a flexible rod that can be easily introduced to the LA, that will be the right size for the every patient, and that will conform to and remain in contact with the surface while energy is applied. If the same electrode can be used for mapping and then ablation, shortening procedure time, so much the better. Theoretically, such a device should be easier to learn and to use while shortening procedure time; however having the correct size for every patient and having just the right amount of flexibility (see the following) are challenging problems.

One difficulty encountered with existing ablation catheter tips is that of maintaining of adequate tissue contact. Current electrode architecture does not always conform to the tissue surface, especially when sharp gradients and undulations are present, such as at the ostium of the pulmonary vein in the left atrium and the isthmus of the right atrium between the inferior vena cava and the tricuspid valve. Consequently, continuous linear lesions are difficult to achieve. With a rigid catheter, it can be quite difficult to maintain sufficient contact pressure until an adequate lesion has been formed. This problem is exacerbated on contoured or trabecular (“bubble-like”) surfaces. If the contact between the electrode and the tissue cannot be properly maintained, a quality lesion is unlikely to be formed.

The “brush” configuration should theoretically be able to deal with these challenges. I do not know whether this invention is being tested, but the concept highlights the problem of contact and its importance in creating focal and linear lesions adequate for the conduction block/transmurality, which may be necessary for stopping AF and for preventing its occurrence in the future.

?: What new techniques are you using that will affect the safety and effectiveness of the procedure that you recommend for me? How long have you been using these improvements? What effects would they have on the work you are planning for me?

CA and Surgical Techniques: The Edgerton trigone lesion; The hybrid endo- epicardial ablation approach; Stepwise CA approaches

The Edgerton trigone lesion

Making a lesion from the Left Inferior PV to a location on the mitral valve annulus – the MV isthmus lesion -- is considered likely to be required when treating CAF. Unfortunately, this lesion is difficult to do during both CA and epicardial surgery (such as the Wolf Minimaze). Doing so is quite feasible during open-heart Maze surgery: however, this operation is quite invasive and typically requires some time on the heart-lung pump.

In the case of CA, the EP must make a complete line using dots, a difficult task. Failure to do make the line complete is common, and the break is likely to result in atypical AFL, which can be difficult to treat.

(A reason for problems creating conduction block with this line may be that where the line passes over the coronary sinus, the blood flowing through this large vessel may soak up RF energy (a “heat sink”) and prevent block or transmurality. If this is so, perhaps a way to temporarily prevent the blood from occupying that part of the CS can be developed?)

If you have CAF, the best chances for success will result from (endocardial) Maze surgery, such as the Cox Maze IV, or from CA where the EP has the skill to perform the necessary lines successfully. The Wolf Minimaze has not been the best choice for CAF, but an innovation currently being tested by Dr James Edgerton may change this :

The epicardial surgeon is faced with the fact that making the MV isthmus lesion would damage the circumflex coronary artery because the RF current must pass through it. Dr Sonny Jackman, an EP from Oklahoma, who incidentally pioneered work on the role of GPs (ganglionated plexi) in AF, suggested to Dr Edgerton, that this line might intersect with the MV annulus anywhere and still be effective. In other words, why not make a line along a route that would avoid the circumflex artery but still intersect the MV ring? Dr Edgerton is currently testing this possibility. If it (the so-called "PV-trigone lesion") were effective this could significantly increase the success rate for the epicardial surgical approach to treating CAF.

?: Do you know of any surgeon who is using an epicardial approach making the Edgerton PV- trigone lesion from the PV to anywhere on the mitral valve annulus?

This approach, in which catheters are introduced through the pericardium to the outside of the heart (epicardial approach) is seen as an adjunct to CA in selected patients.

The inclusion criteria for the percutaneous epicardial catheter ablation (PECA) of AF were: a high risk for PV stenosis, difficulty in achieving complete block with the LA linear ablation endocardially for the ablation of arrhythmogenic epicardial structures -- such as the ligament of Marshall, ganglionated plexi and PVs that are resistant to attempts at endocardial isolation.

The reason for this last may be that PV electrical potentials may be found on the outside musculature of the PVs that are insulated from the endocardial energy application by pads of fat.

The first stage consists of the Wolf "minimaze" procedure . If the patient does not seem to be sufficiently helped after about one month, Stage II, a CA is done. According to a recent webcast (April 2008, on OR Live), the EP will make the line from the Left Inferior PV to the mitral valve annulus ( or ring) that is often necessary in cases of CAF. My understanding is that this is a difficult line to make without a break.

Dr Lee reports a 90%+ success rate for 100+ patients about six months out for PAF. The rate for CAF is much lower: 50-70%. Perhaps this was because the EP stage was less successful and the PV-mitral annulus line was not successfully done. This line requires an especially skilled EP -- and perhaps a bit of luck.

The details of this procedure will be forthcoming at the May 2008 AATS convention.

More EPs are using a stepwise approach to CA in which they ablate or isolate several areas in order of their predicted contribution to AF. The goal is do only those steps needed to terminate the AF (or AFL, if the AF converts to that form), thereby reducing the amount of tissue rendered non-functional.

Carl Pappone is a well-known EP from Italy who has long been a proponent of the circumferential isolation of the PVs as a way of treating both Paroxysmal and Continuous AF (http://content.nejm.org/cgi/content/short/354/9/934).

If I heard him correctly, he called this approach, the “destruction of the left atrium” (?!) – tongue-in-cheek or at least grain-of-salt, I assume?

“Each region is targeted in sequence and the impact of ablation upon the global fibrillatory process assessed by measurement of AF cycle length (AFCL) at a site remote from the ablation target. In addition to pulmonary vein electrical disconnection and demonstrable complete conduction block across the roof and mitral isthmus lines (when performed), ablation is performed at those sites displaying continuous electrical and complex fractionated activity, with the endpoint of local organization, as well as at sites displaying electrograms consistent with focal sources driving AF”

?: Do you use some kind of stepwise approach to deal with my type of AF? How long have you been doing the latest version of this approach? What has your success- and complication rate been using this approach?

?: (Surgery only) What energy source or sources will you be using for my surgery? What are the advantages and disadvantages of this choice?

The FDA is interested in so-called “upstream therapies” -- meaning preventive measures -- for AF, including: ACE/ARB inhibitors, statins , omega 3 fish oils and other anti-inflammatories.

The idea that reporting of success should be standardized has been discussed before (http://www.hrsonline.org/News/Media/press-releases/CSAblation.cfm). It was suggested that a single EKG snapshot during follow-up will underestimate the incidence of AF by about 20%. On the other hand, defining failure as an episode of AF/AFL lasting more than 30 seconds (as is done in the HRS Guidelines) is overlooking the substantial improvement in quality of life and the benefit to the heart that can result from more modest improvement.

When should a particular CA procedure be stopped? Insisting on non-inducibility by pacing or isoproteranol leads to falsely labeling cases as failures. Conversion to AF is a better indicator of success, but there are still a substantial number of patients who must be converted at the end of the CA but who continue and remain in NSR. There was disagreement in this area… There is also the idea that CA must be stopped at some point to spare further damage to heart tissue.

There was a great deal of interest in imaging techniques, with the vast majority of the EPs present (84%) saying that they use pre-CA imagery (MRI’s or CT scans), and 74% using image integration during the procedure (in which the catheter position is indicated by superimposing catheter position on a previously obtained or real-time 3D image). A popular combination seems to be 3D CARTO imaging alongside ICE. The latter may be a more reliable indicator of catheter position, while CARTO provides more information.

Using such imaging techniques to their full advantage can reduce CA time and safety, especially since there can be considerable variation in the number and configuration of the PVs (see articles by Moussa Mansour and http://www.touchbriefings.com/pdf/1755/ACF1BC.pdf ).

The esophagus can move during CA. Real-time imaging can detect this movement and possibly prevent problems that might occur when working on the LA posterior wall. General anesthesia may prevent the esophagus from moving from its position when initially mapped, which would be a positive effect if no real-time images were available. On the other hand, the esophagus ordinarily recoils to protect itself from high temperature passing through any adjacent part of LA. Would general anesthesia also prevent the recoil of the esophagus from any heat that might come at it through the wall?

Studies show that ulceration of the esophagus following CA is very common, but that it heals in 2-4 weeks. It might progress to esophagitis with a very small possibility of fistula. Taking PPI’s (proton pump inhibitors) such as Prevacid is recommended as a cheap safety measure.

There was a whole section devoted to the so-called mitral isthmus line or lesion (from the Left Inferior PV to the mitral valve annulus or ring).

…difficult for EPs to do, because the line must be made using a series of transmural dots;

…impossible for surgeons applying RF energy from the outside of the heart (in the epicardial approach, such as the Wolf minimize), because the energy would have to go through the circumflex artery, causing damage, although a HIFU device should be able to make this lesion safely from outside the heart;

… but (relatively) easy for Maze surgeons making their lesions on the inside of the heart.

Making this lesion effectively has long been considered as necessary for treatment of Continuous AF.

One reason that making this lesion transmural throughout its length may be that the blood coursing through vessels – particularly the large vessels underneath certain parts of its route act as a “heat sink”, draining away the “burn” energy being applied at that part of the line.

Perhaps there is a way to block the blood flow at these points to prevent this from happening?