Atrial fibrillation (AF), the most common type of arrhythmia, is a rapid uncoordinated generation of electrical impulses by the atrial chambers of the heart. Its prevalence increases with age from less than 1% in people aged <60 years to 10% in individuals aged >80 years. AF is a powerful independent risk factor for stroke and mortality, conferring a five-fold and 1.5- to 1.9-fold increase in risk, respectively.
With AF, the ventricles are activated irregularly and commonly very rapidly. At times, the ventricles are activated so rapidly that they cannot fill with blood well enough prior to their contraction and the patient's blood pressure will drop. Symptoms of AF can be divided into two categories: those associated with arrhythmia such as heart palpitations, fainting, tiredness and dyspnoea; and symptoms relating to an underlying heart condition or a stroke. However, patients can be asymptomatic.
The most serious side effect of AF is stroke. Half of all strokes associated with AF are major and disabling. Depending on the presence of additional risk factors, the rate of stroke from AF can exceed 8% per year. Anticoagulant or antiplatelet medications, such as warfarin, reduce the risk of blood clots and stroke. However, they do not eliminate the risk. Warfarin is highly effective but is often under-used or inappropriately used for stroke prevention because of its narrow therapeutic window, potential for bleeding complications, and significant drug and food interactions. Furthermore, the unpredictable response to warfarin necessitates close monitoring and frequent dose adjustments. Doctors are keen to find better ways to identify patients at high risk of stroke and prescribe anticoagulation treatments in these cases only, as other patients may be effectively treated with aspirin instead.
Experts are waiting for fixed-dose oral anticoagulants, with predictable effects, no need for coagulation monitoring and a low risk of bleeding, to prevent stroke in high-risk patients. A possible contender, AstraZeneca's direct thrombin inhibitor Exanta (ximelagatran), was withdrawn from development earlier this year owing to a report of severe liver injury in a patient in the EXTEND study. The company has decided to focus its attention on a follow-up compound, AZD0837, a thrombin inhibitor in phase II clinical studies.
The next anticoagulant agent approved could be from the Factor Xa inhibitor class, such as Bayer's Bay 59-7939 and Lilly's LY517717, both in phase II. Also in the running is GlaxoSmithKline's indirect thrombin inhibitor, odiparcil, also in phase II. Other products in trials for the prevention of venous thromboembolic events (VTE) include Merck's factor Xa inhibitor, EMD-503982, and LG Life Sciences's thrombin inhibitor, LB-30870, both in phase I.
Earlier this year, Boehringer Ingelheim started a large clinical trial programme in thromboembolic disease with its ximelagatran-like compound, the oral direct thrombin inhibitor, dabigatran etexilate (Rendix). The company has begun a series of seven phase III trials of dabigatran under the umbrella name Re-Volution. These will include more than 27,000 patients worldwide in a range of target indications, the largest study being the Re-Ly trial looking at its use in stroke prevention in AF patients. The Re-Ly trial will enrol 15,000 patients worldwide and compare dabigatran with warfarin in AF patients with a treatment period of up to three years. The first results are expected at the end of 2009.
Many people live for years with AF without problems. However, the irregular blood flow makes the blood susceptible to clotting. If the clot is pumped out of the heart, it can travel to the brain, resulting in a stroke. AF can also decrease the heart's pumping ability by as much as 20-25%. AF combined with a fast heart rate over a long period of time can result in heart failure (HF). The evaluation of patients who develop AF includes a medical history and physical examination, an electrocardiogram (ECG), and an echocardiogram (cardiac echo). Monitoring devices such as a Holter monitor, portable event monitor or a transtelephonic monitor can also be used.
Many options are available to treat AF, including medication, lifestyle changes, procedures and surgery. The choice of treatment is based on the type of arrhythmia and symptoms. Traditionally, the aim of AF treatment was, in order of importance, to regain normal heart rhythm; treat any underlying heart condition; and prevent stroke.
However, the focus is now shifting to reverse the order of these goals, making stroke prevention the most important aim of AF treatment.
When medications do not work to correct or control AF, or when medications are not tolerated, a procedure may be necessary, such as:
- Electrical cardioversion - where an electric current is used to reset the heart's rhythm back to its regular pattern. The low-voltage electric current enters the body through metal paddles or patches applied to the chest wall.
- Catheter-based or surgical pulmonary vein isolation - almost all atrial fibrillation signals come from the four pulmonary veins. In these procedures, energy sources such as radiofrequency (RF), cryothermy, microwaves or lasers are used in the pulmonary veins to produce lesions and ultimately scar tissue to block the abnormal electrical impulses.
- Ablation of the AV node - catheters are inserted through the veins (usually in the groin) and guided to the heart. RF energy is delivered to sever or injure the AV node. The end result is a permanent, very slow heart rate. Therefore, the patient needs a permanent pacemaker to maintain an adequate, sufficient heart rate.
- Device therapy - an implantable atrial defibrillator can be used to treat AF symptoms. When AF symp-toms occur, the patient can turn on the device or the device can be set to operate automatically.
Prevention of AF would be the ultimate goal. Patients who present with AF are often hypertensive and around 8% of these develop AF in a seven-year timeframe. It is important for doctors to study their hypertensive population to see who could develop AF and thereby try to prevent the remodelling of the atria caused by hypertension that results in AF.
It is important for doctors to remember that while a hypertensive patient may be presenting with their first episode of AF, the heart is already damaged and it is almost too late for treatment. Doctors need to seek ways of screening hypertensive patients for AF.