Selena Class

According to a study published in the March 2004 issue of the British Medical Association journal Heart, atrial fibrillation (AF) is a rapidly growing cost to the UK’s National Health Service. As the population ages, the situation is only going to worsen, and at present, there is still no widely acceptable safe and effective drug therapy for the condition. IMS assesses the current market and looks at new products in development for AF.

10% of the elderly afflicted
AF is the most common type of arrhythmia, or irregular heart beat. It occurs when the upper chambers of the heart contract extremely rapidly. This leads the ventricles to pump erratically and inefficiently, causing a variety of symptoms. AF could affect up to 10% of the elderly, and as people are living longer, they are also surviving more with the underlying conditions associated with AF, such as hypertension, coronary heart disease and heart failure.

As well as being distressing to live with, AF is linked to an increased risk of cardiovascular crises, including stroke. Most patients require prophylactic anticoagulant therapy with aspirin, or warfarin (Bristol-Myers Squibb's Coumadin and generics) and its associated monitoring costs. If necessary, patients can be treated with electrical cardioversion, and surgery and pacemakers are other treatment options. For the majority, however, long-term pharmacological therapy is necessary.

According to the Heart researchers, in 1995 the UK had 534,000 AF patients, with a direct NHS cost of £244 million. By 2000, this had risen to £459 million, almost 1% of total NHS expenditure. Hospitalisations and drug prescriptions accounted for 50% and 20% of the cost respectively; nursing home care costs were not included, neither were associated expenses relating to, for example, digoxin toxicity, anticoagulant-induced haemorrhage or stroke rehabilitation. Moreover, the true cost of hospitalisation for AF is difficult to calculate, as it is often a secondary classification behind stroke and heart failure etc.

Anticoagulant monitoring adds to burden
The University of Glasgow-led team estimated that 60% of AF patients are prescribed cardiac glycosides, 50% aspirin, 30% warfarin, and 25% anti-arrhythmics. In 1995, this was equivalent to a £22 million spend on drugs, then another £26.9 million for the extensive anticoagulant level monitoring required with warfarin. Such monitoring was the second largest cost to the NHS for AF, which explains the enthusiasm for the new class of direct thrombin inhibitors, such as AstraZeneca’s Exanta (ximelagatran), designed to do away with the need for constant monitoring and reduce the risk of haemorrhage; Exanta is pending approval for the indication of stroke prevention associated with AF. At present, warfarin is under-used, adding unnecessarily to the overall bill due to strokes that could otherwise have been prevented.

The scientists concluded, “...it is clear that AF related costs are escalating rapidly and that AF is worthy of the attention directed towards heart failure when it became clear the latter was becoming a major public health problem.” This is borne out by studies such as Val-HeFT, through which Novartis showed that its angiotensin II antagonist Diovan (valsartan) could lead to a significant reduction in hospitalisations for heart failure when added to standard therapies. There have been similar findings for the beta-blocker Coreg (carvedilol), from Roche and GSK.

Warfarin usage grows
IMS UK prescribing data for the years 1998 and 2003 suggests that digoxin is still the most widely prescribed medication for patients with AF. The use of warfarin for this indication, however, has more than doubled in the past five years, suggesting that doctors are beginning to take a more aggressive approach to stroke prevention; aspirin is also still widely used. While the use of amiodarone and sotalol, the two leading anti-arrhythmics in the UK by prescription volume (both are available as generics), has increased, their relatively low penetration underlines the problems associated with their use. Antihypertensive agents such as the beta-blocker atenolol (AstraZeneca's Tenormin and generics) and ACE inhibitor ramipril (Aventis' Tritace) are also used in AF.

UK prescriptions for atrial fibrillation



Source: IMS Disease Analyzer

No ideal drug – yet
The major difference between AF and the developments for heart failure is that the drugs shown to help with the latter had all been marketed safely for years as antihypertensives. While there is some evidence that more aggressive treatment of hypertension could at least delay the onset of AF in certain patients, drug development for AF specifically has had limited success. No current AF drug has been associated with a lower overall death rate, and indeed, they may actually increase the mortality rate. Pfizer’s Tikosyn (dofetilide), launched in the USA in 2000, was the first new drug for AF in a decade, but has not been widely used due to its side-effect profile and is generally reserved for serious cases.

There are a number of different classes of agent for arrhythmia. Besides the prevention of thromboembolism, there are two main tactics: controlling the ventricular rate and/or maintaining the sinus rhythm.

Anti-arrhythmic classes

As can be seen from the table above, many of the arrhythmia treatments, particularly from Classes II and IV, are beta-blockers or calcium channel antagonists, also used for hypertension. These are more often used to control the heart rate, as is digoxin. Drugs from Classes I and III are used more frequently to convert to or maintain sinus rhythm (sotalol, Schering AG's Betapace, is a beta-blocker but also has Class III activity). The medical community is still divided over which approach to AF treatment is best, but rate-controlling drugs are often safer.

Sanofi-Synthelabo and Wyeth’s original amiodarone product Cordarone was the top-selling member of the C1B anti-arrhythmic class in the 12 months to September 2003, according to IMS MIDAS data. Like others in the class, however, it has a number of side-effects, and many of the agents can cause ventricular proarrhythmia, a different type of heart rhythm disturbance. Because of such problems, anti-arrhythmia therapy is sometimes commenced in a hospital setting - again increasing costs.

The number two anti-arrhythmic in the period was 3M’s Tambocor (flecainide), followed by Abbott’s Rythmol/Rytmonorm (propafenone). Both Cordarone and Tambocor are seeing a decline in sales following the loss of US exclusivity.

Could dronedarone offer hope?
Sanofi-Synthelabo is now developing a follow-up to amiodarone, dronedarone. The company believes dronedarone could become a blockbuster if it can be shown to have the anti-arrhythmic properties of amiodarone without the older compound's side-effects. In early 2004, dronedarone was in two pivotal Phase III studies in AF and atrial flutter. So far, Sanofi-Synthelabo states that the drug has a similar rate of adverse effects as placebo, and has not been associated with proarrhythmia/Torsade de Pointes.

In January 2003, however, a third trial, known as ANDROMEDA, was discontinued after an interim safety analysis raised concerns about a potential excess risk of death in treated patients; the participants in this trial also had congestive heart failure, and the higher mortality rate could not be explained. This caused some delay to dronedarone's development, and it is now not expected to reach the market until 2005. Sanofi-Synthelabo also has a dronedarone follow-up compound, SSR 149744, which was in Phase I trials in 2003.

Anti-arrhythmics in development

Source: IMS LifeCycle - R&Dfocus

A number of major pharmaceutical firms are now working on new treatments for AF, and some should be on the market by 2005. With a variety of different types of compound in development, the chances have increased that effective, and safe, treatments for this common and debilitating condition are finally on the way.

This article was written by Selena Class, Deputy Executive Editor of IMS Company Profiles. IMS Disease Analyzer provides a longitudinal analysis of patient treatment from 2,000 office-based physicians, with data available for the UK, Austria, France and Germany. For more information, please contact Kate Perry via e-mail or call +44 207 393 5472.

Relevant reports on this topic:

Global and regional sales information:
arrhythmia
C1B
Sanofi-Synthelabo
dronedarone

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