Meet The Experts: Catheter Ablation in AF: How to Do It Effectively and Efficiently
Friday, May 16, 2008
Supported by an educational grant from EP Med Systems
Meet The Experts: How can I optimize my EP Lab activity?
Friday, May 11, 2007
Supported by an educational grant from EP Med Systems
CME available
Drug Therapy for AF
Friday, May 11, 2007
Supported by an educational grant from Sanofi Aventis
CME available
Meet The Experts: Catheter Ablation in AF: How To Do It Effectively and Efficiently
Chair: Shih-Ann Chen
Faculty: Boris Schmidt, MD
Luc Jordaens, MD
Written by: Dennis Connaughton
How to Perform Circumferential Pulmonary Vein Isolation
Boris Schmidt, MD, a cardiologist from the Asklepios Klinik St. Georg in Hamburg, Germany, described how to perform circumferential pulmonary vein (PV) isolation using the double Lasso technique he learned from Feifan Ouyang, MD, his colleague at St. Georg, and the inventor of the double Lasso technique.
The primary endpoint of the procedure is to isolate the pulmonary veins on both the septal and lateral sides of the left atrium in patients with paroxysmal atrial fibrillation.
“We perform all our EP studies in deep and algosedation, and although the patient is sleeping, he is breathing spontaneously,” Dr. Schmidt said. “After performing a venous puncture, we perform three transseptal punctures, which are part of the double Lasso technique. The transseptal punctures are performed under fluoroscopic guidance.”
Following the punctures, Dr. Schmidt and his colleagues perform electroanatomical CARTO mapping and then selective PV angiography using strict fluoroscopic angulations. “We use RAO 30 degrees and LAO 40 degrees, so in total we do eight angiographies, or four biplane angiographies,” Dr. Schmidt said.
“What we do next we believe is key to a successful procedure, and that is ostial identification,” he explained. “Using the angiographic pictures, we move our mapping catheter fluoroscopically to the PV ostium, and we mark this point on the CARTO map using 3D technology. In addition to this anatomical information, we also take into account the electrical information of the ostium.”
Using both electrical and anatomic information to identify the PV ostium and working in a circumferential fashion, Dr. Schmidt said, he moves from the roof of the septal and lateral veins and then down the posterior wall to mark the inferior ostium and the anterior wall with 3D tags. He then introduces two Lasso catheters — one in the superior ipsilateral vein and one in the inferior ipsilateral vein — and performs radiofrequency ablation.
“We perform only irrigated-tip catheter ablation in the left atrium. We do not do ablation with solid-tip catheters for atrial fibrillation. We use a standard setting, which means we place the irrigated-tip catheter with 30 watts of power in the posterior wall and the one with 40 watts maximal power in the anterior wall. We use a 17cc flow rate for irrigation and we set the maximal temperature to 45 degrees,” Dr. Schmidt explained.
“Then we start ablating around the 3D tags in the CARTO map and try to establish a circumferential line around both ipsilateral veins so there is just one circle on each side,” he continued. “Usually what we see when we continue to draw a line and ablate during sinus rhythm is that there are some progressive conduction delays from the atrium to the PVs until we achieve a complete PV isolation. When we close the circle, in 95 percent of the cases both ipsilateral PVs are isolated simultaneously.”
When Dr. Schmidt finishes the septal side, he moves to the lateral side. “This is a little bit more tricky because the critical part of the isthmus is in the left atrial appendage, and even with the PV angiographies it is sometimes not easy to identify the anterior border of the PVs. You do not know if you are in the pulmonary vein, on the ridge, or on the appendage side of the ridge,” Dr. Schmidt said.
“There is one short trick I want to share with you: We start marking the ostium at the superior-posterior part of the PV, which is easy to identify in an RAO 30 projection from the angiography, and then we start ablating at that point and through a little bit of the anterior-superior part,” he explained.
“In 99 percent of the cases, you will see a conduction delay with only one application of this technique,” Dr. Schmidt noted. “When you are at the ridge or on the ridge, you will see two signals that are of similar amplitude and when you are on the appendage side of the ridge you will see a huge atrial far-field potential and only a small PV. So this makes it a little easier to avoid ablating inside the PV and to identify the anterior ridge properly.”
Finally, Dr. Schmidt explained that he prefers to place one of the Lasso catheters back into the septal side to see if the PV isolation there has persisted.
Balloon Cryoablation Therapy for AF
A novel technique for the isolation of pulmonary veins in patients with atrial fibrillation is the use of cryothermal energy applied through a balloon catheter, or balloon cryoablation therapy.
Luc Jordaens, MD, PhD, Head of the Department of Clinical Electrophysiology at the University Hospital Rotterdam, the Netherlands, described the technique he uses to isolate pulmonary veins in patients with atrial fibrillation using an occluding cryoballoon for circumferential ablation. He first described proper patient selection.
“A good candidate for a cryoballoon procedure is a patient with paroxysmal atrial fibrillation or persistent atrial fibrillation,” Dr. Jordaens said. “However, I would not accept a patient with valvular dysfunction. A less important criterion is the size of the patient’s left atrium. Since we began using this new technique, we have limited our acceptance to patients with a left atrial size smaller than 50 mm because larger atria are more difficult to treat. Patients with larger atria are given radiofrequency ablation.”
Once a candidate is accepted for the procedure, Dr. Jordaens places the patient on a waiting list, does a repeat echo exam, and puts the individual on a Holter monitor. Over the three to six months while the patient is on the waiting list, the atrial fibrillation transitions from paroxysmal to persistent.
Patients are given oral anticoagulation for at least one month before the procedure. When patients are admitted to the hospital for the procedure, the anticoagulation is switched to unfractionated heparin and a transesophageal echo exam is done to rule out the presence of thrombi in the left atrium or left atrial appendage. Dr. Jordaens indicated he prefers to perform the procedure with the patient under conscious sedation, but general anesthesia is available if the patient requests it.
Most patients are treated using a double lumen 28 mm cryoballoon catheter. “When we first started performing this procedure, the 28 mm balloon catheter was not always available, so in the series of patients my colleagues and I described in the European Heart Journal [September 2007; 28:2231-7], you will find a mix of patients who received a 23 mm balloon and the 28 mm balloon. The 23 mm balloon is easier to steer in the atrium, but with the 28 mm balloon you can block the pulmonary veins in a more effective way,” Dr. Jordaens explained.
“We use intracardiac echo to guide transseptal puncture of both femoral veins,” he continued. “With echo, you can also check whether the balloon occlusion is perfect if you apply the Doppler over the pulmonary veins. We inject diluted contrast through the balloon and then we have to flush it at the moment it starts to freeze because frozen contrast might damage the lumen of the balloon. We use intracardiac echo in the right atrium to monitor the contrast and any complications.”
After puncturing the femoral veins, Dr. Jordaens advances a circular mapping catheter and positions it in the antrum of each PV to record the presence of PV potentials. After registration, the sheath is exchanged for a 14-F steerable sheath and the mapping catheter is exchanged for the 28 mm, 12-F balloon catheter positioned over an exchange wire to occlude the ostium of each PV. “The balloon goes through a 14-French sheath, and in my opinion, the large sheath size is the most important limitation of this procedure at this moment,” Dr. Jordaens said.
“One of the disadvantages of all balloon approaches is hemoptysis—the coughing of blood related to insertion of a guidewire too distally in the pulmonary vein,” he added. “We have to be very careful to try to avoid this complication. Don’t push the guidewire too far.”
Dr. Jordaens next applies cryoenergy for five minutes twice in each PV, but is cautious not to apply in the same location. The applications per vein are directed toward the major side branches of the PVs. “If the left upper pulmonary vein has two large side branches, we go in one side branch upward and in the other side branch downward or intermediately. If the vein is very large, we just treat these two branches. Then we go to the left-superior, right-superior, and right-inferior pulmonary vein with the steerable sheath,” Dr. Jordaens explained.
Before targeting the right-superior PV, Dr. Jordaens positions a quadripolar catheter in the superior caval vein for continuous phrenic nerve stimulation during the application of cryoenergy. The ablation is instantly terminated at loss of capture. If PV potentials persist, he introduces the cryoballoon again.
The day after the procedure, Dr. Jordaens performs transthoracic echo to exclude pericardial effusion and a chest x-ray to exclude pneumothorax and other thoracic complications.
“I think this is a very powerful procedure,” he concluded. “We closely monitor the patients in the first three months with daily transmission and we feel that you can predict those who need a redo.”
Meet The Experts: How can I optimize my EP Lab activity?
Chair: Claus Schmitt, MD, PhD
Faculty: Edward Gerstenfeld, MD
Koonlawee Nademanee, MD
Andre Pisapia, MD
Written by: Sharon S. Ballas, MGA
Reviewed by: Roopinder Sandhu, MD
Optimizing EP Lab Activity: Role of Nurses, Techs and Which Equipment, Techniques to Use
“How can I optimize my EP lab activity?” This question was addressed at a Meet-the-Experts lunch, chaired by Claus G. Schmitt, MD, PhD, Karlsruhe, Germany. Talks focused on the changing roles of nurses and technicians, which equipment to use, and new techniques for the future of EP labs.
Role of Nurses and Technicians
First, Edward P. Gerstenfeld, MD, Philadelphia, PA, gave an overview of the changing role of nurses and technicians. He also gave suggestions about how to make their job more enjoyable and fulfilling. The following is a summary.
Changing Role in the EP Lab
In general, as procedures in the EP lab have become more complex, the role of nurses and technicians has become more comprehensive. Even so, their job still begins with the basics—preparing and placing the patient in the correct position for mapping, and monitoring the care of the patient through the entire procedure. Nurses also provide conscious sedation for the patient in many labs.
The next step is setting up and operating the equipment. Nurses and techs have recently taken a bigger role in this area, including troubleshooting system failures.
Performing AF or EP ablations may involve using intracardiac echo (ICE), 3D echo, 3D mapping systems, EP mapping systems, and more. Technicians, nurses, and/or physician assistants are learning how these systems work from various representatives so they can operate them more autonomously.
Running the systems may involve doing the segmentation before the case and segmenting the scan for CartoMerge (Biosense Webster, Inc., Diamond Bar, CA), for instance, as well as running the whole mapping system. Also, with ICE, it may involve measuring all the pulmonary vein flows, ostial diameters, etc., and filling out all the forms, both pre- and post-ablation and throughout the case.
During an ablation procedure, the nurses and/or techs will usually run the generator and monitor the impedance. They generally have a view of the echo as well, so if they see bubbles or steam pops coming off on the generator, for instance, they should report this to the physician. Therefore, providing feedback is another duty.
Many institutions have a detailed database that may list all the patients’ lesions, where they are located, and all the stimulation that is performed. Another role of the nurses and technicians may be to record this information throughout the case. Then a research nurse will enter it into a database, and later the data can be review when doing clinical research.
For a typical AF procedure in Dr. Gerstenfeld’s lab, they usually have two or three nurses, a technician, a fellow, and an attending, along with a rep or physician assistant running the mapping systems. Prep time is usually 45 minutes to an hour, and they generally do 2-3 procedures a day, depending on the complexity.
Making the Job More Enjoyable
Dr. Gerstenfeld gave suggestions for how to make their time in the lab more enjoyable and fulfilling. One way is to interact and work with the fellows in the lab, who have different levels of experience.
Another important way is to get involved in running the systems and to follow what is happening in the case. Asking questions about the equipment and procedures will make working in the lab more interesting and make the entire case flow. Having a monitor at the head and foot of the bed allows nurses and techs to watch what is happening and be involved in feedback.
An additional way to increase knowledge and make the job more fulfilling is to attend conferences. Dr. Gerstenfeld started holding monthly conferences, specifically for the lab staff and associated professionals, on basic EP concepts and different areas of EP drug therapy. That has helped staff morale and causes them to feel more involved. Also helpful are regular meetings with the director of the lab, where one can bring up problems or issues.
Dr. Gerstenfeld emphasized the valuable role well-trained nurses and technicians play in the EP lab, saying that he could not perform the procedures without them, and that the patients’ lives are in their hands.
Which Equipment?
Next, Koonlawee Nademanee, MD, Inglewood, CA, described the equipment he uses in his EP labs. He has two labs dedicated to EP ablation with an identical setup, and another lab for basic EP. He has simple single-plane X-ray equipment capable of doing coronary angiograms in the two labs, and emphasized the importance of having X-ray equipment that can do a variety of procedures, including coronary angiograms. He personally does not believe that bi-plane equipment is needed.
Specific Equipment
For the EP equipment in his labs, they use the EP-WorkMate (EP MedSystems, Inc., West Berlin, NJ) and the CARTO XP EP Navigation System (Biosense Webster, Inc., Diamond Bar, CA). They have the EnSite System and EnSite NavX Navigation and Visualization Technology (Endocardial Solutions, St. Paul, MN) as well, but Dr. Nademanee is more experienced with and partial to CARTO.
For stimulators, his lab uses a built-in that comes with the EP-WorkMate. For ablation equipment, they use the Stockert 70 RF Generator (Biosense Webster, Inc.) because it works well with the CARTO system. In the past, he used the ETP Cardiac Ablation System (Boston Scientific, Natick, MA). Dr. Nademanee believes all the stimulator systems work well.
For hemodynamic monitoring, the Prucka CardioLab EP System (GE Healthcare, Waukesha, WA) is popular, but Dr. Nademanee prefers using the Witt System (Witt Biomedical, Melbourne, FL). He has his own dedicated monitor so if something goes wrong, he can see it right away. When doing the right side, he monitors the left atrial pressure continually.
When ablating the left atrium for AF, Dr. Nademanee uses the ThermoCool Irrigated Tip Catheter and Integrated Ablation System (Biosense Webster, Inc.) exclusively. He believes it is safer than the 8-mm-tip catheter because the stroke rate is lower and he saw a lot of chars with the 8-mm-tip catheter. The only downside is that ThermoCool adds 10-15 minutes to his procedure time, however, compared with the 8-mm-tip catheter.
Dr. Nademanee’s lab also has ICE. He believes this procedure will become increasingly more important because of the new technology coming in the near future, for instance, using 3D imaging with ICE while mapping.
Overall Lab Setup
Overall, an important aspect is making sure the lab is set up with a monitor that is clearly displayed so the entire team can view the operator, recording systems, and X-ray equipment. This is invaluable, especially in complex cases if something goes wrong.
Also, Dr. Nademanee believes it is imperative to have equipment—recording, imaging, and mapping systems—that works well together without causing any noise. The system must be superb in recording signals, especially for complex EP cases. Making the signals noise free usually requires a lot of work, especially when first setting up the lab. Regardless of which equipment is used, it is important to work with the engineer and vendors on this. When using two or more systems, make sure they are compatible.
In closing, Dr. Nademanee emphasized the importance of being well trained and comfortable with whatever equipment is used.
Which Techniques?
Last, Andre Pisapia, MD, Marseille, France, gave insight into new techniques for the future of the EP lab. He described new software for high-density mapping, signal processing, and signal recording.
First, he described new software, Impedance Map (Biosense Webster, Inc.), which integrates technical information with the mapping system. It allows visualization of impedance value in real time, and gives more precise data. For example, in the left atrium, there is an exact ostium of the pulmonary vein. When introducing a catheter in the pulmonary vein and then moving it in the ostium, there is a sudden decrease of impedance. Impedance mapping allows the operator to exactly define the ostium of pulmonary vein. It decreases the risk of stenosis of the pulmonary vein as well.
Second, Dr. Pisapia described a new system developed by Biosense Webster whereby the operator can calculate ultrasound imaging from the CARTO System. When mapping, the operator can build a real-time image of anatomy of the heart. This is currently available in 2D, but will soon become available in 3D echo imaging along with mapping.
Dr. Pisapia described a new tool being developed for ICE. This tool combines the NaviStar ThermoCool Catheter with the CARTO XP Mapping System (developed by Biosense Webster in collaboration with Siemens Medical Solutions, Malvern, PA). It allows the operator to see precise anatomy of different chambers of the atrium in real time.
A promising new navigation technique is the Stereotaxis Niobe Magnetic Navigation System (Biosense Webster, Inc.), which controls catheter movement using magnetic fields. This remote, automated technique is considered very safe. For instance, it reduces the risk of perforation with the catheter, and reduces X-ray exposure for the operator. It minimizes the demand of the highly skilled operator to navigate the catheter in various locations of the heart. It is very expensive, however.
Last, Dr. Pisapia discussed cryotherapy, which he does not currently use himself. Cryotherapy uses an ultrasound balloon, which helps isolate the atrium of the pulmonary vein in a short time. This therapy has been shown to be successful in certain areas, and Dr. Pisapia believes this technique may be valuable in the future.
Drug Therapy for AF
Chair: L. Brent Mitchell, MD
Steven Singh, MD
Faculty: Stanley Nattel, MD, FHRS
Richard Page, MD, FHRS
Katherine Murray, MD
Written by: Sharon S. Ballas, MGA
Reviewed by: Roopinder Sandhu, MD
Drug Therapy for Atrial Fibrillation Presents Possibilities
Potential molecular targets, investigational drugs, clinical evaluation, and upstream therapy were discussed at a Heart Rhythm 2007 Core Curriculum session titled “Drug Therapy for AF.”
Potential Molecular Targets
First, Stanley Nattel, MD, Montreal, Quebec, Canada, discussed potential molecular targets. The following is a summary of this presentation.
Ion-Channel Targets
Classically, one of the main approaches in preventing or terminating atrial fibrillation (AF) is to prolong action potential duration of AF circuits. This increases the refractory period and the wavelength, causing many smaller circuits to become larger and fewer circuits.
Two potential mechanisms for prolonging action potential duration are: 1) to increase the inward currents (e.g., sodium and calcium), allowing positive ions to move into the cell, allowing depolarization for a longer period of time, and subsequently, the duration of the action potential would increase and the cell would be refractory for a longer period of time, or 2) to decrease the outward currents, which prolong action potential duration.
The most common drug target for prolonging atrial action potential duration in preventing AF is the rapid delayed rectifier current, which works both in the atrium and the ventricle. As a result of blocking various potassium channels in the ventricle, torsades de pointes can arise.
If one compares the atrial and ventricular action potentials and the complement of ionic currents that each one has, recent work has shown that some currents are present only in the atrium, not the ventricle. These include the ultrarapid delayed rectifier current (IKUR) that flows particularly in the early plateau, and the acetylcholine-dependent potassium current, which is the target of vagal action. Vagal stimulation promotes AF because it stimulates this outward potassium current and shortens the action potential.
Potassium-Channel Blockers with Atrial Selectivity
IKUR is an ultrarapid delayed rectifier that is an atrial-specific current in humans. If one could block this current safely without blocking anything else outside the heart, it should result in atrial selective action potential prolongation. Drug development is currently underway.
Xention developed a highly selective IKUR blocker. The effects on human atrial and ventricular muscle showed a plateau that gets higher and action potential that gets progressively prolonged by this compound in the atrium.
Dr. Nattel and his group conducted experiments in a dog model looking at effects of an IKur blocker (Xen-D0101) on atrial and ventricular refractory periods, and AF duration before and after the drug. There was a dose-related response, with increasing doses having a statistically significant reduction in AF duration, increase in cycle length, and decrease in AF vulnerability.
To further an understanding of atrial tachycardia (AT) remodeling, or AF begets AF, experiments were conducted using goats that were instrumented with an atrial fibrillator electrode and a system to detect sinus rhythm. When sinus rhythm was detected, the goats were put back into AF. Investigators found that the amount of AF that occurred in baseline conditions, and lasted spontaneously, was very short. However, with time, they needed less atrial stimuli to induce AF because the AF lasted spontaneously longer.
An important component of AT remodeling is downregulation of L-type calcium current, which may be a protective mechanism of the cell to prevent calcium overload. But there is also increasing evidence that there may be changes in certain outward currents.
In some species, there is a constitutive component to the acetylcholine-dependent potassium current, IKACh, which is present even in the absence of acetylcholine.
Under controlled conditions in dogs, Dr. Nattel’s group found a specific acetylcholine-dependent potassium current called Tertiapin-Q (TQ). The TQ-sensitive currents from a dog atrial myocyte were fairly large, and even larger after mimicking a tachycardia produced by AF. Interestingly, with TQ, the currents were strongly suppressed, but still larger than the TQ-insensitive currents in baseline. Looking at the TQ-sensitive component, AT largely increased this current.
They also found evidence for a role for TQ in the action potential and arrhythmia changes caused by AT remodeling, whereby the action potential was much longer when given TQ. Further studies showed that TQ is important in shortening the action potential with AT, as well as in maintaining AF caused in a setting of AT remodeling. Dr. Nattel’s group was able in the tachycardia-remodeled preparations to induce longer-lasting and sometimes sustained atrial tachyarrhythmia in vitro and then to use TQ to see what happened. In each case, it induced termination of the tachycardia.
These data suggest that the constitutive acetylcholine-dependent potassium channel is important in AT remodeling and could be an interesting target for AF.
A Japanese company developed an IKACh selective blocker. Investigators looked at its effect on AF in two canine models. In both, they saw a dose-related termination of AF by the compound. Further studies evaluating the collateral effects on extra-atrial and extra-cardiac tissues are needed.
Gap-Junction Enhancers
Gap-junction enhancer compounds explore the role of cell coupling in cardiac conduction. Cardiac myocytes have to be connected together to produce electrical continuity. Gap junctions connect them, and the connections are actually produced by proteins called connexins, which form structures called connexons. When a loss of connexins impairs conduction, a progressive reduction in action potential amplitude occurs because the source current is not large enough to activate fully distal cells.
Changes in connexins have been shown in AT remodeling, as well as in congestive heart failure (CHF) and ischemia, which both cause AF. So, impaired connexin function could be important in AF. Therefore, drugs that improve connexin function and tissue coupling are potential targets for treating AF.
Dr. Nattel’s group recently looked at the effects of AF in both AT and heart failure remodeled atria using a compound called rotigaptide. This approach did not seem to be effective. However, when they looked at rotigaptide in a model of ischemic AF ischemia, it prevented ischemic AF. So, connexin enhancement is effective in certain types of AF, but the efficacy depends on the underlying mechanism, with ischemic AF showing particular responsiveness and other models not showing much responsiveness.
Heat-Shock Protein Enhancers
Dr. Nettel’s group looked at the potential role of heat-shock proteins and developed several experiments. First, they used in vitro heat-shock protein inducers and developed an isolated dog atrial myocyte model of AF. After 24 hours of rapid atrial pacing, a shortening in atrial action potential duration was shown. A typical response was shown for AT remodeling. In the tachypaced cells, the rate adaptation was lost and the action potential was shortened. This is similar to the physiological phenomenon.
The compound GGA stimulates heat-shock protein production and is relatively nontoxic. Dr. Nettel and colleagues studied the effects of GGA in several canine models. GGA therapy substantially increased heat-shock protein expression in these experiments.
These data suggest that heat-shock protein induction is an interesting potential approach to AF therapy.
Conclusion
Dr. Nattel concluded that: 1) novel atrial- and/or AF-selective potassium-channel blockers present interesting theoretical advantages in AF therapy, 2) connexin-function enhancing drugs present new therapeutic possibilities but seem to be effective only in certain types of AF, and 3) arrhythmogenic remodeling prevention may be possible with a variety of novel classes of agents.
Investigational Drugs
Dr. Nettel also gave an overview of the investigational new drug field. He commented that a number of compounds are in development. Those closest to being introduced are probably going to be the least miraculous, and the ones that promise to be the most miraculous are the farthest from being introduced and may turn out to be useless.
One drug that seems close to getting to market is dronedarone, which is chemically related to amiodarone. It has the advantage of lacking the iodine moiety and therefore avoids thyroid complications (unlike amiodarone), and may also be safer for pulmonary complications. Clinical development data show that it may not be as effective as amiodarone, however, and has some risk of toxicity.
RSD1235 is an interesting compound that acts on a variety of ion channels, and acts mainly by blocking sodium channels. It is being developed for terminating vagal AF as an IV compound. Oral drug preparation may be limited secondary to potential toxicities.
Although sodium channel blockade has been written off as a mechanism for AF therapy based on the CAST trial results, it is at least theoretically possible to have drugs that are atrially selective for AF. So that as an approach may turn out to be interesting. Sodium blockers can be effective, but the question is whether they can be safe.
The AVE 0118 compound created a lot of interest because it acted on IKUR and other currents, but it was not found to be very effective. Perhaps the dose selection for the AVE compound was too low, however.
Ranolazine was developed initially as an antianginal compound, which was thought to work via fatty acid metabolism. Subsequently, that mechanism of action has questioned. It may be useful for AF, and data suggest it may be as safe as selective atrial sodium channel blocking drugs.
Several other compounds are in the preclinical phase or phase one trials and it is too early to determine their effectiveness.
Azimilide is no longer being looked at for treating AF.
Clinical Evaluation of Drug Therapy
Richard L. Page, MD, Seattle, WA, shared his earlier experience with antiarrhythmic drugs in clinical trials. The following is a summary of his talk.
Goal of Drug Therapy
The goal of chronic antiarrhythmic drug therapy for AF is to:
· Reduce or eliminate AF. When a patient is already in AF or is converted, is there a difference? The FDA is interested in the answer to this question.
· Reduce or eliminate AF symptoms. Is that enough? What about AF burden?
· Reduce stroke or the need for warfarin.
· Have a lack of proarrhythmia and no effect on mortality.
First, the concept that any drug other than warfarin will reduce the risk of stroke has not been established. Antiarrhythmic medications have not been shown to reduce the risk of stroke.
A few decades ago, the goal of antiarrhythmic therapy for AF was to reduce the detection time of symptomatic recurrences of AF.
Current Drug Models Under Investigation
Azimilide: Although azimilide will not be pursued as an AF drug, it is a good model for investigation. It is a class III drug with IKr blocking characteristics and has IKs blockade. It did not necessarily reduce risk of torsades de pointes, however.
In one study, azimilide showed a dose response curve that suggested real efficacy. When looking at the median time to symptomatic recurrence for symptomatic patients, it appeared to be useful when going out to 125 days or so. The FDA has used this type of trial to demonstrate efficacy for other drugs such as propafenone.
Sotalol: Sotalol is another drug that has been worked up for AF. One large trial of efficacy, safety, and dose response was conducted with patients currently in normal sinus rhythm (NSR). A nice dose response curve was generated for sotalol.
In pivotal sotalol trials for AF, there was demonstrated benefit in patients who were in NSR at time of entry. The FDA panel did not see convincing evidence that the drug worked for patients who were already in AF. As a result, the indicated label use for sotalol in AF and atrial flutter is for the maintenance of sinus rhythm. There was no indication for rhythm conversion.
Dofetilide: In contrast, the SAFIRE-D study looked at various doses of dofetilide in patients with AF/atrial flutter. SAFIRE-D demonstrated significant conversion to and maintenance of sinus rhythm.
Dofetilide is indicated for maintenance of patients who were already in sinus rhythm. Of important note is the life-threatening ventricular arrhythmias that can be caused by dofetilide and therefore should be reserved for patients in whom AF/atrial flutter is highly symptomatic. It was also noted that, in general, antiarrhythmic therapy for AF/atrial flutter aims to prolong the time in NSR, but recurrence is expected in some patients.
Dofetilide also has an indication for the conversion of AF/atrial flutter to NSR. There are limited data on the effective use in patients with paroxysmal AF.
Importance of Safety
The preceding studies showed that the goal of sinus rhythm could be achieved or maintained. But is maintenance of sinus rhythm enough? After the initial quinidine mortality meta-analysis and the CAST trial, there has been increased attention to drug safety in AF. The goal is to have sinus conversion, but without dangerous ventricular arrhythmias. In the development of new antiarrhythmic medications, demonstration of safety is imperative.
The safety profile is currently available for some of the new drugs. In both high-risk and at-risk patients, in a post-infarct period, azimilide was associated with no change in mortality. Additional trials providing safety data are the DIAMOND CHF and DIAMOND MI trials, both using dofetilide.
Silent AF
Another issue when considering antiarrhythmic therapy is asymptomatic or silent AF. Is it really a problem? In the past, studies of antiarrhythmic strategies in AF focused on symptomatic recurrence. If the patient appears to be in sinus rhythm, and was asymptomatic, why worry about silent AF? Silent AF is especially important, however, because it poses a risk for stroke.
Data from the SPAF studies looked at intermittent and sustained AF in a large cohort of patients given aspirin. The annualized rate of ischemic stroke was similar for those with intermittent (3.2%) and sustained AF (3.3%). So, those with intermittent AF had stroke rates similar to patients with sustained AF and similar stroke risk factors. Many elderly patients with recurrent intermittent AF have substantial rates of stroke and likely benefit from anticoagulation.
Studies Using Transtelephonic Monitors
Dr. Page was involved in several studies looking at patients with paroxysmal AF and paroxysmal supraventricular tachycardia to see whether they had asymptomatic AF. They demonstrated that the symptomatic events were actually 8.3% as frequent as the asymptomatic events, based on Holter and simultaneous transtelephonic monitors.
The azimilide trials looked at the occurrence of AF based on transtelephonic monitors recorded every 2 weeks for 30 seconds. Investigators found that in AF patients who were on placebo, 18% showed silent AF before they ever had a symptomatic event. The number was reduced to 13% in the azimilide patients. This may suggest that antiarrhythmic drugs can reduce silent AF as well as symptomatic recurrence.
A further study based on implanted antitachycardia devices showed that the likelihood of demonstrating recurrent AF was much higher followed over time with a device compared with ECGs recorded during symptoms, once again demonstrating that asymptomatic AF is a real phenomenon. These events were sustained by all characteristics, potentially likely to cause thrombosis in the atrium, but were completely silent.
Some interesting data regarding silent AF came out of the recent SOPAT (suppression of paroxysmal atrial tachyarrhythmias) trial. Patients with symptomatic AF were given quinidine + verapamil versus sotalol or placebo. They received transtelephonic ECG monitoring daily or with symptoms. The higher dose of quinidine + verapamil reduced symptomatic recurrence of AF. But when exploring further, this reduction in symptomatic AF had to do with increased episodes of asymptomatic AF.
Conclusion
In closing, Dr. Page said that the goal of drug therapy for AF is to reduce symptomatic recurrence, but said it is not enough. Demonstration of safety is imperative, and reduction of asymptomatic AF, or AF burden, needs to be considered. The FDA may be looking more at quality of life in the future. Finally, newer monitors will allow better evaluation of drug effects on overall recurrence of AF. Keeping track of the amount of AF patients are having, whether it is symptomatic or asymptomatic, is important.
Upstream Therapy for AF
Last, Katherine Murray, MD, Nashville, TN, spoke about upstream therapy for AF. The following is a summary of her lecture.
Mechanisms in AF
In the effort to look at different ways to approach AF, many studies have improved our understanding of the mechanisms that lead to the generation and progression of AF.
A number of situations make the atrium fibrillation prone. Chief among these is intercellular fibrosis. This can occur in structural heart disease/CHF, inflammation/oxidative stress, and atrial refractoriness. Also, the triggers in terms of reentry and ectopic fosa are now better understood. Importantly, cardiac remodeling can modulate both of these processes.
Atrial Remodeling
Many strategies and data for upstream therapy originated in the following AF models.
The AF begets AF model shows that the repetitive induction of AF causes remodeling in the atrium to increase AF susceptibility. This occurs because atrial refractoriness shortens due to a shortening of action potentials in the atrium. A principle component is downregulation of L-type calcium current, but upregulation of inward rectifiers play a role as well.
Atrial remodeling in experimental AF showed a loss of efficacy for IKr blockers. Data on d-sotalol showed that in the remodeled goat, the effects of refractoriness were far less potent and were quite diminished over time. So, this remodeling process may play a role in drug efficacy.
Another common model is rapid ventricular pacing of CHF. It showed increased evidence of fibrosis and AF susceptibility. There does
