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
| Class |
Examples |
|
Ia |
disopyramide, procainamide,
quinidine |
|
Ic |
flecainide, propafenone |
|
II |
esmolol, propanolol |
|
III |
amiodarone, dofetilide,
ibutilide, sotalol |
|
IV |
diltiazem, verapamil |
|
V |
digoxin |
|
Others |
cibenzoline, magnesium,
pirmenol |
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
| Compound |
Developer(s) |
Mode
of action |
Phase |
|
dronedarone |
Sanofi-Synthelabo |
Class III, oral |
III |
|
RSD 1235 |
Cardiome/Fujisawa |
Na/K channel blocker,
iv |
III |
|
tedisamil |
Solvay |
K channel blocker, iv/oral |
III |
|
AZD 7009 |
AstraZeneca |
Class III, iv |
II |
|
piboserod |
GSK |
5-HT4 antagonist |
II |
|
AVE 0118 |
Aventis |
K channel blocker |
I/II |
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. |
