All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor ----------------------------------------------------------- NOTE: You can make the print bigger with the font button on your browser! (It's usually a big "A") ----------------------------------------------------------- Safety of Antiarrhythmic Agents: The Final Frontier in Treating Atrial Fibrillation? JON'S NOTE : You can gain a lot from this even if you skip the few paragraphs that are technical! INTRODUCTION Few patients qualify for ablation, so first-line treatment for a-fib is drug-based. However, only 20% of patients are satisfactorily treated at 5 years of followup. Bluntly, safe and effective treatments for long-term a-fib are not known. HOW THE HEART "FIRES" Heart muscle cells are activated by the firing of an "action potential," which happens when channels in the cell membrane are selectively "opened" or "closed" to allow an ion to travel into or out of the cell. Generally, the most important exchanges that take place during the action potential are the outflow of sodium (Na) ions and the inflow of potassium (K) ions. The resulting electrical currents (I) are identified as the INa and the IK. The IK electrical current has 2 parts : the rapid rectifier current (IKr) and the delayed, or slow, rectifier current (IKs). HISTORY The first approach to treating arrhythmias used local anesthetic drugs to suppress PVCs (premature ventricular contractions - incomplete, fast heart beats). The first such drug used was quinidine in 1918. A few decades later, several other local anesthetic drugs - procainamide, lidocaine, and disopyramide - were tried. During the 1960s, new anti-arrhythmic drugs focused on lidocaine's actions, producing mexiletine and tocainide, both of which act as strong local anesthetics in the heart. They work by shortening the length of the action potential and by suppressing PVCs. The CAST trial had more than 1700 patients take either encainide, flecainide, or placebo. Relative risk of death with any of the drugs was 2.5 times higher than with placebo. It was learned that the most important property of anti-arrhythmic drugs was their effect on the heart's refractory period : this is the period after being stimulated that a cell has to rest before it will respond to another stimulation. In the 1960s, the inherited syndrome called "long QT interval" was linked to sudden arrhythmic deaths. It was seen that this could happen after treatment with anti-arrhythmic drugs. This is called torsades de pointes, or "twist of points." Work continued on the theory that helping arrhythmia required one of two things: 1) making the elctrical process last longer (prolonging the "action potential") or 2) prolonging the time before a cell could fire again (its "refractory" period). Beta-blockers then came along. Propranolol and sotalol were developed in 1962. It was known that blocking the nervous system's stimulation of the ventricle reduces arrhythmia. Two other drugs - amiodarone and verapamil - were also made in 1962. Singh and Vaughan Williams unexpectedly found that the beta-blocker sotalol had another property : It prolonged the action potential in the ventricle as well as the atrium. Similar effects were seen with long-term amiodarone use. Amiodarone and sotalol are unique because they block both nervous system stimulation of the heart. They also lengthen the refractory period. Verapamil selectively blocked conduction from the heart's second elctrical generator - the AV (atrioventricular node). It slowed ventricular rate in a-fib and ended AV-caused tachycardias. This may be from verapamil's calcium blocking. DRUG CLASSES Anti-arrhythmic drugs are classified according to how they work: Class I : block the sodium channel Class II : block the nervous system's stimulation of the heart (beta-blockers) Class III : block potassium channels Class IV : block calcium channels In 1974, Singh and Hauswirth further classified class I drugs into class Ia and class Ib drugs. Harrison added class 1c for encainide and flecainide. CURRENT DRUG THERAPY In 1992 the SWORD trial was stopped early when it was seen that sotalol use was linked to increased risk of death, especially in CHF patients who had suffered a heart attack. Analysis showed that drugs which prolong the refractory period can cause other dangerous arrhythmias. Current thinking recommends that: Class Ia drugs are for a very small group of patients only. Class Ib drugs have no place in managing a-fib. Class Ic drugs are very effective in patients without ischemia or significant structural heart disease. Class II drugs (beta-blockers) should be used mainly for a-fib in CHF patients. These drugs may also be valuable for preventing recurrence of paroxysmal or resistant a-fib in other patients. Class IV drugs (calcium channel blockers) are mainly high blood pressure drugs. All other uses for this class have shown conflicting and sometimes risky results. This leaves the class III drugs. They have no negative effects on heart pumping strength, and they affect both atriums and the ventricles. Side effects caused by current class III drugs show the need for new anti-arrhythmic drugs. Some newer drugs only block the delayed rectifier potassium current (dofetilide), especially its rapid component (IKr). However, some of these drugs also have effects on other ion channels, such as the sodium channel (ibutilide). They may also partly block the slow part (IKs) of the delayed rectifier potassium current (azimilide). Isolated blockade of IKr has either neutral (DIAMOND trial) or bad effects (SWORD trial) on mortality in survivors of heart attack. THE DRUGS SOTALOL Sotalol is a non-selective beta-blocker that increases the duration of the action potential (electrical "firing") and refractory period (cells resting phase) throughout the heart. Unlike other beta-blockers, sotalol has a slightly positive effect on the heart's pumping strength. It suppresses ventricular ectopy (beats caused by areas of the heart that are not supposed to cause heart beats) better than most beta- blockers. In the ESVEM trial, sotalol prevented more long-term arrhythmia ; was better tolerated ; and sotalol patients had reduced risk of death than those taking class I drugs. Sotalol was 1 of 2 drugs compared to ICDs in the AVID trial. This study showed that - unlike amiodarone - sotalol does may lower the defibrillation threshold. So sotalol is a preferred drug for use in patients with ICDs. Sotalol is also active against atrial arrhythmias. It is probably less effective for this than amiodarone but it is at least as good as propafenone or quinidine in preventing a-fib recurrence. It is better tolerated than quinidine and gives excellent heart rate control. Sotalol's side effects include fatigue, shortness of breath, and risk for torsades de pointes (overall risk of 2% to 4% with higher risk in women). Unlike amiodarone, it has no drug-drug interactions. Starting dose is 80 mg twice a day with gradual rise to 240 to 360 mg per day as needed. Dose must be reduced in patients with kidney failure. AMIODARONE The current standard is amiodarone, a fairly effective class III drug. Amiodarone blocks the sodium channel (class I action), reduces nervous system stimulation (class II action), blocks potassium channels (class III action) and calcium channels (class IV actions). Amiodarone lengthens the action potential and increases the refractory period in all heart tissues. Short-term effects may be different from long-term effects. Amiodarone is effective for restoring and maintaining normal rhythm in a-fib, and for preventing ventricular tachycardia and fibrillation. At the SA (sinoatrial node - a generator of electrical signals in the heart), it slows the heart rate. At the AV (atrioventricvular node - the second normal generator of electrical signals in the heart), it slows conduction. Amiodarone maintains normal rhythm in about 60% of a-fib patients. Amiodarone is the first choice for controlling a-fib in CHF patients. It does not reduce the heart's pumping strength. In more than 30% of patients who have open-heart surgery, atrial flutter or a-fib develops. Given orally for a week before surgery, amiodarone reduces chances of this happening. It increases the QT interval to more than 500 msec, but this rarely causes torsades de pointes. According to Hohnloser, risk of amiodarone triggering arrhythmia is 2%. Although it does not increase mortality, amiodarone has SIGNIFICANT NEGATIVE SIDE EFFECTS. It may cause problems with the cornea of the eye, can change thyroid function, and can damage skin and lungs. As many as 20% of patients experience some kind of lung fibrosis. It causes sensitivity to light in almost all patients. The major ill effects are lung damage and serious liver damage. Thyroid function must be checked regularly because the drug can cause both too-active and not-active-enough thyroid function. This is related to the iodine in the drug. IBUTILIDE Ibutilide is available for stopping (rather than preventing) a-fib and flutter. Ibutilide activates a slow inward sodium current (INa-s). It also blocks the rapidly activating part of the delayed rectifier potassium current (IKr). In trials, ibutilide shows better conversion rates for a-fib and flutter than sotalol or procainamide. Ibutilide should be avoided in patients with very low ejection fractions because of risk for tachycardia. Ibutilide is used as a short-acting IV infusion. Use is restricted by the risk for long-QT syndrome. The risk for torsades de pointes is relatively high at 8%. Patients must be carefully monitored during drug infusion. DOFETILIDE Dofetilide is a potent, selective potassium channel blocker. It is specific for the rapidly activating, delayed rectifier potassium current (IKr). More than 1100 heart failure patients took either dofetilide or placebo to study whether it could prevent a-fib. All patients were in normal rhythm when starting the drug. Forty placebo patients got a-fib, compared to 12 dofetilide patients. DIAMOND also studied dofetilide for maintaining normal rhythm after cardioversion. The drug is especially effective in patients with structural heart disease. Normal rhythm was maintained at greater than 80% at one year compared to 40% for placebo patients. In DIAMOND - in patients who had suffered a heart attack - results were neutral BUT patients taking both dofetilide and a beta-blocker had lower risk of death. Starting the drug in the hospital lowered risk of torsades de pointes (3 deaths, all within the first 2 days). Dofetilide is eliminated mainly by the kidneys and it CAN interact with other drugs, especially cimetidine. Care must be used in patients with kidney failure. AZIMILIDE Azimilide's effectiveness is similar to amiodarone, but it causes fewer non-heart-related side effects. Azimilide does cause a low risk of torsades de pointes, and a possible drop in white blood cell count - all within the first 45 days of therapy. However, no deaths have been seen with either effect. This is a unique class III drug. Because it lacks one chemical "group" (the methanesulphonamide group), it is not chemically related to other class III drugs. Azimilide blocks both the rapid (IKr) and slow (IKs) parts of the the delayed rectifier potassium current. Because of this, the drug has an effect regardless of slow or fast heart rate. For this reason, it may be more effective than other class III drugs. Azimilide was studied in the ASAP a-fib trial with over 1000 patients. In tachycardia patients a 100 mg dose was effective. In patients with a-fib or flutter, once-daily azimilide (100 and 125 mg doses) prolongs time to first a-fib recurrence. Average time to recurrence in the third ASAP study (125 mg) was 130 days versus 17 days for placebo. A fourth ASAP study showed the drug's effectiveness at preventing recurrent a-fib in patients with structural heart disease, but not in patients without structural heart disease. Azimilide is generally well tolerated. The most common side effect is headache. Overall risk of torsades de pointes is 1%. Azimilide is also being studied for preventing sudden cardiac death. The ALIVE trial is a one-year double-blind, placebo-controlled study that will enroll 3500 at-risk patients. The goal is to learn whether azimilide improves survival in patients at risk for sudden cardiac death.