ABSTRACTS

MYTILINI, GREECE. In 1997 Dr. Andrea Frustaci, MD and colleagues at the Catholic University of Rome discovered that some lone afibbers (8 out of 12 patients) had inflamed heart tissue (myocarditis). Since then other researchers have confirmed that afibbers tend to have high levels of C-reactive protein (CRP), a marker of inflammation. Dr. Frustaci also discovered that treatment with the anti-inflammatory prednisone, a glucocorticoid, was effective in eliminating further episodes in afibbers showing signs of inflammation.

Greek researchers have now followed up on Dr. Frustaci's discovery and found that another glucocorticoid, methylprednisolone (Mediol), is effective in preventing further episodes in newly-diagnosed afibbers. Their clinical trial involved 52 men and 52 women who had just undergone cardioversion for their first afib episode. The average age of the patients was 66 years (range of 52-84 years) and none of them had been diagnosed with heart disease. The median CRP concentration among the patients at baseline was 1.14 mg/dL (11.4 mg/L) with a range of 0.1 to 2.58 mg/dL. These values are clearly abnormally high as the normal level is about 0.1-0.2 mg/dL with 0.5 mg/dL indicating inflammation. The patients were all placed on propafenone (Rythmol) therapy at 450 mg/day and were then randomized into a placebo group and an active treatment group. The active treatment consisted of 16 mg/day of methylprednisolone for 4 weeks tapered to 4 mg/day for 4 months.

The patients were followed up through regular examination for an average of 2 years. During the follow-up period 50% of the placebo group members experienced another afib episode as compared to only 9.6% in the active treatment group. Twenty-nine per cent of placebo group members developed permanent AF during follow-up as compared to only 2% in the treatment group. CRP levels were found to be significantly higher in participants who had recurrent episodes or developed permanent AF than in patients who did not. In the placebo group the median CRP for participants who had no further episodes was 0.49 mg/dL as compared to 2.03 mg/dL in those who did. In the treatment group the afibbers with no further episodes had a median CRP level during treatment of 0.16 mg/dL as compared to 0.58 mg/dL in those who did experience another episode. Overall, the methylprednisolone therapy reduced CRP levels in the treatment group by about 80%. The methylprednisolone also significantly reduced the incidence of palpitations.

The researchers conclude that methylprednisolone therapy is effective in reducing the incidence of both recurrent and permanent AF in a group of newly-diagnosed afibbers. The therapy would appear to be most effective at high CRP levels with little effect at levels of 0.6 mg/dL or lower. They also suggest that CRP level is a good indicator of the likelihood of having further episodes or developing permanent AF. A value above 0.62 mg/dL corresponds to a substantially increased risk of experiencing recurrent episodes, while a value greater than 1.56 mg/dL indicates a higher risk of developing permanent AF. The proposed glucocorticoid (methylprednisolone) therapy should thus aim for a CRP level of 0.62 mg/dL or lower.

In an accompanying editorial, researchers from the Cleveland Clinic applaud the new findings, but caution that the treatment may have potential serious complications. They also suggest that further research is required to determine whether the therapy only works for afibbers who have experienced just one episode (minimal remodeling) or would be applicable to afibbers of long standing as well.
Dernellis, J and Panaretou, M. Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation. European Heart Journal, Vol. 25, July 2004, pp. 1100-07
Abdelhadi, RH, et al. New hope for the prevention of recurrent atrial fibrillation. European Heart Journal, Vol. 25, July 2004, pp. 1089-90

Editor's comment: It is certainly promising that methylprednisolone may be an effective treatment for afib. I do have a bit of a problem though with the high CRP levels reported for the trial participants. The average (median) baseline value was 1.14 mg/dL (11.4 mg/L). This is very high considering that a value of 0.1 mg/dL (1 mg/L) is considered normal. My own value is 0.03 mg/dL or 0.3 mg/L, so I would obviously be unlikely to benefit from the treatment. Quite frankly, I have never, in my various surveys, come across anyone with levels as high as those encountered by the Greek researchers. Nevertheless, any afibber with a CRP level above 0.8-1.0 mg/dL may wish to look into the possibility of treatment with methylprednisolone.

LINZ, AUSTRIA. A group of Austrian and Dutch researchers has compared Quality of Life (QOL) scores in patients before and after pulmonary vein ostial isolation (ostial PVI). Their study group included 89 patients, 75 of who provided complete data for QOL comparison. QOL was measured with the Medical Outcomes Short Form 36 Health Status Questionnaire (SF-36) and the Symptom Checklist (SCL). The researchers compared baseline QOL scores between the PVI group, a group of healthy non-afibbers, and a group of afibbers treated with antiarrhythmic drugs. Not surprisingly, they found that the QOL scores of the members of the two afib groups were "remarkably poor".

Three months after undergoing the PVI procedure, 55% of the patients were completely free of afib and off all drugs, 34% had no further episodes, but had to continue their drugs, while 11% showed no improvement at all. At 6 months following the PVI the QOL scores of the lucky 55% were equivalent to scores for healthy non- afibbers. Those still on drugs or not improved at all still had a "remarkably poor" quality of life.

It is interesting and a little disconcerting that serious adverse events occurred in 9 (12%) of the 75 PVI patients. Significant stenosis was observed in 6 patients of whom 3 had to undergo another procedure to remedy the situation. Other complications involved pericarditis (inflammation of the pericardium), tamponade (blood collecting in the pericardial sac) requiring drainage, and thyrotoxicosis after repeated x-ray dye (contrast medium) injections. This particular complication required removal of the thyroid gland and presumably, lifelong thyroid therapy.
Purerfellner, H, et al. Quality of life restored to normal in patients with atrial fibrillation after pulmonary vein ostial isolation. American Heart Journal, Vol. 148, August 2004, pp. 318-25

MONTREAL, CANADA. Recent research has shown a clear association between the incidence of AF and hypertension (elevated blood pressure). It is estimated that hypertension is associated with the development of AF in about 14% of all cases. It is also estimated that about 20% of the population or about 700 million people worldwide suffer from hypertension. AF is now one of the fastest growing disorders. Hospital admissions in the US for the condition grew from 790,000 to 2,300,000 between 1985 and 1999. Clearly, this is a major and rapidly worsening health problem.

A group of American and Canadian researchers now report that treatment with angiotensin-converting enzyme inhibitors (ACE inhibitors) can significantly reduce the incidence of new AF in hypertensives and can also reduce the severity of existing AF in these patients. Their study matched 5463 patients taking ACE inhibitors with an equal number of patients taking long-acting calcium channel blockers for blood pressure control. About 4% of the group had congestive heart failure, 10% diabetes, and 6-7% had suffered a previous stroke. A small percentage (2.4% and 2.3% respectively) had AF at the beginning of the study.

After 4.5 years of follow-up the researchers determined that the incidence rate of new-onset AF was 1.79% per year in the ACE inhibitor group and 1.89% in the calcium channel blocker group. The incidence of hospital admissions for the patients with a first episode during the study was 0.67% per year in the ACE inhibitor group and 0.85% per year in the calcium channel blocker group. Not surprisingly, the number of patients admitted to hospital among the "veteran" afibbers was significantly higher (10.2% per year) in the ACE inhibitor group and 20.2% per year in the calcium channel blocker group. The researchers conclude that ACE inhibitors are associated with a reduced incidence of AF in patients with hypertension.
L'Allier, PL, et al. Angiotensin-converting enzyme inhibition in hypertensive patients is associated with a reduction in the occurrence of atrial fibrillation. Journal of the American College of Cardiology, Vol. 44, July 7, 2004, pp. 159-64

Editor's comment: The benefits of ACE inhibitors among afibbers with hypertension are certainly noteworthy. It may be worthwhile for hypertensive afibbers now taking long-acting calcium channel blockers to try the ACE inhibition approach.

MUNICH, GERMANY. Both pacemakers and implantable cardioverter defibrillators (ICDs) are housed in metal containers and contain batteries and very delicate electronic circuits. It was realized fairly early after the introduction of magnetic resonance imaging (MRI) that scanning patients with an implantable pacemaker was not a good idea since the strong magnetic field used in MRI wreaked havoc with the pacemaker and caused serious malfunction. Thus, having a pacemaker or ICD is generally considered a contraindication to MRI and hospitals have procedures in place to prevent patients with pacemakers from accidentally having an MRI. Newer pacemakers have been modified to, at least partially, overcome the problem so that MRI can be performed under certain circumstances.

The situation is less clear with ICDs. Now German cardiologists report on a case where a patient with an ICD (Guidant Model 1783) was given an MRI brain scan. The procedure was curtailed after a few seconds when the presence of the ICD was realized. The patient suffered no ill effects, but the ICD changed its operational setting, could not be reprogrammed, and needed to be replaced. The cardiologists conclude that even ICDs of a newer generation are susceptible to magnetic interference with the danger of complete loss of programmability.
Fiek, M, et al. Complete loss of ICD programmability after magnetic resonance imaging. PACE, Vol. 27, July 2004, pp. 1002-04

CALGARY, CANADA. AV node ablation and pacemaker implantation is now considered a last resort procedure for afibbers not responding to pharmaceutical drugs. Although the procedure does stabilize the pulse rate, it has four major drawbacks:

• It is irreversible.
• It does nothing to stop the fibrillation of the atria, which in itself can be quite uncomfortable, and necessitates continuing anticoagulation (warfarin) therapy.
• It makes the patient entirely dependent on the pacemaker. If it malfunctions or the batteries run out, the patient dies.
• It does nothing to remedy the fatigue and reduced exercise capacity caused by the fibrillation of the atria.

AV node ablation is performed in much the same way as RF ablation except that it is the area around the node that is ablated.

Researchers at the University of Calgary now report that AV node ablation actually worsens atrial fibrillation and tends to convert paroxysmal AF to the persistent or permanent variety. Their study involved 22 patients who had undergone the procedure and remained on their antiarrhythmic drugs (mainly beta-blockers, calcium channel blockers, digoxin, sotalol or amiodarone) after the procedure. The researchers compared the AF burden (average hours per day spent in afib) for the 10-week period prior to the ablation with the burden in two 2-month post ablation periods separated by 2 months. The average AF burden prior to the ablation was 3 hours/day; this increased to 10.4 hours/day and 11.8 hours/day during the first and second post ablation periods respectively. While only one study participant progressed to persistent AF during the pre-ablation period, 9 participants did so during the post ablation periods.

The researchers simultaneously compared the increase in AF burden over time in a group who remained on antiarrhythmics but did not undergo AV node ablation. In this group AF burden increased from 3.0 hours/day to 3.6 hours/day over the equivalent time period. The researchers conclude that AV node ablation increases AF severity and promotes progression to persistent AF.
Willems, R, et al. Total atrioventricular nodal ablation increases atrial fibrillation burden in patients with paroxysmal atrial fibrillation despite continuation of antiarrhythmic drug therapy. Journal of Cardiovascular Electrophysiology, Vol. 14, December 2003, pp. 1296-1301

The injection of an x-ray dye (contrast medium) is a common practice during ablation therapy. Contrast media are iodine-based and excessive exposure to them can result in kidney failure, especially in patients who already have compromised kidney function. At least one case of hyperthyroidism caused by excessive contrast media exposure has also been reported. This case required removal of the thyroid gland.

Several clinical studies have found that supplementation with the antioxidant N-acetylcysteine during the day prior to and the day of exposure to contrast agents can markedly reduce the risk of kidney damage. The studies used 600 or 1200 mg given twice daily accompanied by adequate hydration. Unless assurance can be given that contrast agents will not be used during the ablation procedure, N- acetylcysteine supplementation for a few days around the time of the procedure would be a prudent preventive measure.

It is also possible, but not supported by any evidence I am aware of, that daily N-acetylcysteine supplementation may be beneficial for afibbers taking amiodarone (Cordarone). One of the major side effects of amiodarone is the development of hyperthyroidism associated with the high iodine content of this drug. Although N- acetylcysteine is freely available in health food stores, its long-term use should be cleared with a physician since it may aggravate some conditions, especially diabetes.

Results of LAF Survey VII – Part I

The purpose of our 7th LAF survey is to gather information about and share the various approaches used by fellow afibbers to successfully manage their condition by the use of antiarrhythmic drugs, supplements, dietary changes, or other protocols.

A separate survey was conducted to determine the success rate for those afibbers who had chosen to undergo ablation or the maze procedure. The results of our 8th LAF survey will be discussed in a future issue of The AFIB Report.

It is important to bear in mind when interpreting the results of this survey that only fibbers who have been successful in controlling their condition were invited to participate. There are many, many of us who have tried numerous approaches without success, but hopefully, these survey results will give us ideas for new approaches to try.

Profile of Respondents

A total of 116 respondents completed this survey. The majority (81%) were men. The average (mean) age of the group was 57 years (median: 57, range: 27-79). The mean age at diagnosis was 49 years (median: 51, range: 18-77). The number of years that the respondents had experienced afib varied between 1 and 41 years with a mean of 7 years and a median of 5 years. Only 8 respondents (7%) had been diagnosed with underlying heart disease, while 7 (6.2%) had been diagnosed with mitral valve prolapse. The majority (92%) had received a medical diagnosis of paroxysmal, persistent or permanent AF. The distribution of various types of AF was as follows:

The types of interventions employed by the 116 respondents can be divided into three categories:

• A. Antiarrhythmic drugs as sole remedy (27 respondents)
• B. Alternative methods as sole remedy (41 respondents)
• C. Antiarrhythmic drugs + alternative methods (48 respondents)

A. Antiarrhythmic Drugs Only

Twenty-seven of the 116 survey respondents (23%) had relied solely on the use of antiarrhythmics to manage their afib. The majority of respondents (78%) were men. The average (mean) age of this group was 56 years (median: 59, range: 27-74). The mean age at diagnosis was 51 years (median: 52, range: 26-68). The number of years that the respondents had experienced afib varied between 1 and 13 years with a mean of 5 years and a median of 4 years. Only one respondent had been diagnosed with underlying heart disease, while 3 had been diagnosed with mitral valve prolapse. The majority (89%) had received a medical diagnosis of paroxysmal, persistent or permanent atrial fibrillation. The distribution of the various types of afib was as follows:

Fifteen respondents (56%) had experienced side effects from their drug regimen with the most common being:

• Fatigue or dizziness (4 out of 27 or 15%)
• Exercise intolerance (4 out of 27 or 15%)

Other reported side effects were shortness of breath, reduction in heart rate, skin flushing, and weight gain. One respondent on amiodarone had experienced the beginning of hyperthyroidism, while another reported increased sun sensitivity.

Nine respondents (33%) reported additional benefits from their drug regimen such as mental relief from not having to fear another episode, weight loss, and a reduction in PVCs.

Eleven respondents (40%) no longer needed to avoid their previous episode triggers such as exercise, alcohol, caffeine, MSG, cold drinks, large meals, etc. Five (19%) still needed to avoid their known triggers, 6 (22%) still needed to avoid some triggers, but not as many as before their drug regimen and the remaining 5 (19%) were not sure whether they still had to avoid triggers.

The majority (89%) would recommend their program to other afibbers, but 30% were still contemplating an ablation, while 41% were uncertain whether they would have one or not. Only 29% were quite certain they would not undergo an ablation.

The sources of information used in arriving at the successful drug regimen were as follows:

Please note that percentages do not add up to 100 as many respondents had used more than one information source.

Not too surprisingly, the majority of afibbers relying solely on drugs to control their condition had obtained their information from a cardiologist or electrophysiologist.

Effectiveness of Drug Protocols

Flecainide (Tambocor) was, by far, the most widely prescribed drug among the 27 respondents. It was used either alone or in combination with beta- or calcium channel blockers by 13 afibbers or 48% of the group. Sotalol was used by 5 afibbers or 19%, while amiodarone and propafenone were each used by 2 respondents. The remaining 5 respondents used beta-blockers (2), calcium channel blocker (diltiazem), disopyramide or digoxin.

It is of interest that, out of these 7 drugs, only flecainide and propafenone are actually labelled (approved) for use in the treatment of paroxysmal atrial fibrillation.

A total of 19 afibbers in the group had submitted sufficient data for detailed analysis and fulfilled the criteria of having spent at least 50% less time in afib (number of episodes x average duration) in the 3 months after their program became effective as compared to the 3 months prior to embarking on their program.

The 19 afibbers had been on their program for an average of 18 months (4-156 months) and the time before it became effective varied from 1 day to 3 months. Afib severity parameters for a 3-month period before and for a 3-month period after the program became effective are listed below.

The percentage reduction in time spent in afib over a 3-month period varied from 60-100% with 8 (42%) of respondents reporting no episodes at all since their program became effective. The average (mean) reduction in time spent in afib among all the 19 afibbers was 94% (median 99%).

The reduction in episode frequency and duration reported by the 19 afibbers is impressive; however, it must be kept in mind that this is a very small sample indeed. There is certainly no guarantee that similar results would be obtained by the general afib population.

Eleven or 58% of the group of 19 were using flecainide either alone or in combination with a beta-blocker or calcium channel blocker; 3 were using sotalol, 2 propafenone, and 1 each amiodarone, Toprol XL (metoprolol) or diltiazem.

Flecainide (Tambocor) was used as sole remedy by 3 afibbers with the mixed variety and by 2 with vagal afib. It was used in combination with a beta-blocker (atenolol, metoprolol or bisoprolol) by 3 mixed and 2 vagal, and in combination with diltiazem by 1 mixed afibber. The dosage when used as a sole remedy ranged from 3x50 mg/day to 2x100 mg/day and the dosage when used in combination ranged from 1x50 mg/day to 2x100 mg/day. The most common concomitant dosage of metoprolol and atenolol was 25 mg/day with that for bisoprolol and diltiazem being 5 mg/day and 240 mg/day respectively.

Only 1 out of 5 (20%) reported negative side effects when using flecainide alone, while 5 out of 6 (83%) reported adverse effects when using combinations. This could indicate that it is primarily the beta- or calcium channel blocker that is responsible for the side effects.

The average (median) percent reduction in time spent in afib for the 11 flecainide users was 99% and 5 of them had experienced no episodes at all since beginning their therapy. It is encouraging to note that 5 out of 11 (45%) flecainide users no longer needed to avoid the common afib triggers. Also of note is the finding that 2 persistent afibbers had benefited substantially from using flecainide with one having experienced no episodes at all since beginning therapy and one now experiencing episodes lasting only about 5 hours.

From this very small sample it would appear that flecainide, when it works, works very well indeed. Because peak plasma levels of the drug are reached about 3 hours after ingestion, it is best to take flecainide in divided doses throughout the day. A dosage of 50 mg taken every 8 hours would likely be a good starting regimen. A further refinement may be to make sure that one of the daily doses is taken about 3 hours before the most vulnerable period. So if bedtime (10-11 pm) is the "danger zone" then a dose should be taken around 7-8 pm. The absorption of flecainide is not affected by food or antacids.

Sotalol (Betapace) was used as the sole remedy by 1 mixed and 1 adrenergic afibber (daily dose of 2x80 mg). One vagal afibber reported good results with a combination of sotalol and irbesartan (Avapro). Irbesartan is an angiotensin II receptor blocker and has, on its own, been found to help maintain sinus rhythm for extended periods when combined with amiodarone. German researchers have found that lone afibbers have more angiotensin II receptors in the left atrium than do non-afibbers, so blocking these receptors could be important.

The two afibbers who used sotalol on its own both reported significant side effects (skin flushing and exercise intolerance), but had seen a 100% improvement in their condition. They had been taking sotalol for 3 and 5 years respectively and during that period had only experienced one episode between them. Two of the 3 sotalol users still needed to avoid the usual triggers to some degree and one was not sure whether avoidance was still required.

From this extremely small sample it would seem that sotalol can be of considerable benefit in selected individuals. Unfortunately, there is some evidence that there may not be too many of these individuals among lone afibbers. An earlier LAF survey found that not a single one of 38 respondents had found sotalol to be beneficial and 76% had experienced significant side effects.

Propafenone (Rythmol) was used as the sole remedy by 1 vagal afibber and in combination with verapamil (120 mg/day) by a mixed afibber. The daily dosage of propafenone was 3x150 mg/day in both cases. Neither of the 2 respondents had experienced any episodes since starting therapy (8 and 33 months respectively), nor felt any side effects, and they no longer had to avoid the usual triggers. The earlier LAF survey found that 7 out of 19 respondents had found propafenone to be beneficial and 47% had experienced significant side effects.

Peak plasma levels of propafenone are reached 1-2 hours after ingestion and the elimination half-life of the drug varies between 4 and 10 hours. Thus taking this drug in divided doses is even more important than in the case of flecainide. A dosage of 150 mg taken every 8 hours is the standard starting regimen, but I suspect some afibbers may need 4x150 mg/day to see a beneficial effect. Again, it may be possible to optimize the regimen by ensuring that a dose is taken a couple of hours prior to the most vulnerable period. Propafenone is better absorbed if taken with food.

Amiodarone (Cordarone) was used in combination with 5 mg bisoprolol by 1 mixed afibber. The daily dose was 200 mg. This respondent reported a 99% improvement (from 24 6-hour episodes in the 3-month period preceding therapy to 2 4-hour episodes in the 18 months of therapy). However, a thyroid problem was developing. Amiodarone is absorbed very slowly and eliminated even more slowly. It can take 8 months or more to reduce plasma levels by 50%. Amiodarone is absorbed quicker and more fully if taken with food.

Toprol XL (slow-release metoprolol) had benefited 1 adrenergic afibber by reducing the number of episodes from 3 to 1 in the 3-month period before and after therapy initiation. Occasional dizziness was reported as a side effect and some triggers still had to be avoided. Obviously, a sample of one predicts nothing about the effectiveness of metoprolol. The earlier survey found that 2 out of 5 adrenergic and 4 out of 5 mixed afibbers had obtained benefits from using this beta-blocker, but 71% reported side effects such as fatigue, slow heart rate and low blood pressure.

Diltiazem (Cardizem) in one daily dose of 240 mg was used by 1 vagal afibber to obtain a reduction in afib frequency from 2 episodes per 3 months to 2 episodes per year. No side effects were reported and the usual trigger factors did not need to be avoided. Again, a sample of one is not enough on which to draw a valid conclusion. The earlier survey found that none out of 8 paroxysmal afibbers had found diltiazem useful in preventing episodes.

Profiles of the 8 afibbers who had completely eliminated their episodes solely through the use of antiarrhythmics are presented below.

It is clear that a well-designed drug protocol can, on its own, be highly effective in reducing afib severity in a select group of afibbers. Flecainide (Tambocor) would appear to be the most successful antiarrhythmic and may be effective in a dose as low as 50 mg/day if combined with a small amount of beta-blocker. Although flecainide has the potential for very serious adverse effects, a trial may be worthwhile in afibbers with sound hearts, especially those having the mixed or vagal variety of AF.

A summary of the findings from the group of 41 afibbers who are using alternative means to manage their afib will be presented in the October issue.