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ISCHAEMIC HEART DISEASE
What is ischaemic heart disease?
Ischaemia is a shortage of oxygen in the blood and fuel to the
heart caused by constriction or blockage (thrombosis) of the blood
vessel feeding it. Ischaemic heart disease (IHD), or coronary heart
disease, has two main forms: angina and myocardial infarction.
Ischaemia is usually due to the build-up of plaque (see
Atherosclerosis) and can affect the brain (see Stroke) or
muscular tissue such as the legs (see Peripheral Vascular Disease),
as well as the heart.
A heart attack, or myocardial infarction (MI), is an emergency
which results when the blood (and hence oxygen) supply to part
of the heart is suddenly reduced or stopped. Because the work
load on the heart is extremely high, heart muscle deprived of
oxygen soon begins to die. Myocardial infarction is most often
caused by a blood clot (see Thrombosis) lodging in one of the
major arteries supplying the heart. A loss of normal heart rhythm
(ventricular fibrillation, (see Cardiac Arrhythmia) with subsequent
circulatory collapse is a significant risk in MI and rapid
hospitalisation is required.
Angina is a consequence of a narrowing rather than a blockage of
an artery and may be due either to atherosclerosis or, less
commonly, arterial spasm. In many people, it is stable over years
and only occurs on exertion or exposure to cold, or after a heavy
meal; in others, however, it progresses and may occur even at rest.
This latter situation is called unstable angina and is serious, as it
may be a warning of an impending heart attack.
Who does IHD affect and what does it cost?
The British Heart Foundation estimates that over 230,000 people
in the UK had a heart attack in 2004 and that just under 2 million
people suffer from angina, with some 345,000 new cases diagnosed
each year. In 2004, IHD is estimated to have caused nearly
106,000 deaths in the UK. It was responsible for over 420,000
hospital admissions in England alone. Death rates from IHD have been falling for more than 20 years, as diagnosis and treatment
have improved.
The British Heart Foundation has estimated that the direct cost to
the NHS of IHD was £3.5 billion in 2003, of which nearly 79
per cent was due to hospital in-patient costs, with the cost of
medications and dispensing them accounting for a further 16 per
cent. To this must be added the indirect costs of lost working days
and non-professional care in the community, making the total cost
to society of IHD an estimated £7.9 billion in that year.
Angina and MI are uncommon below the age of 45, except where
there is a strong family history of heart disease, but after that,
incidence rises with age. The 2003 Health Survey for England
found that 8.2 per cent of men and 4.7 per cent of women in the
age range 65-74 had experienced angina in the preceding 12
months and for those aged 75 or over, the corresponding figures
were 10.3 per cent and 9.4 per cent respectively.
The risk of IHD can be reduced by modifying lifestyle choices
(diet, exercise, smoking), using medication to lower cholesterol
and reduce plaque formation (see Atherosclerosis), maintaining a
normal blood pressure (see Hypertension), and through use of
anti-platelet medicines such as low-dose aspirin. People with
diabetes are especially at risk of heart problems (see Diabetes)
and vigorous efforts to normalise both blood sugar and blood
pressure are necessary.
Present treatments and shortcomings
Treatment of stable angina involves addressing risk factors such as
smoking, hypertension and high blood lipids while managing acute symptoms by giving fast-acting glyceryl trinitrate. Unstable angina
is a medical emergency and will usually necessitate admission to
hospital, as the risk of a myocardial infarction is high.
Longer term preventive treatment of stable angina involves the use
of low-dose aspirin or the anti-platelet agent clopidogrel (Plavix,
sanofi-aventis) and medicines such as a nitrate, a beta-blocker, or
a calcium antagonist, of which there is a large selection available.
Slow-release forms of these preparations are often used, or skin
patches in the case of glyceryl trinitrate. Tolerance may develop
after prolonged use of nitrates and headache is a common
complaint on first starting treatment. Both beta-blockers and calcium
antagonists may aggravate heart failure and some of these medicines
can cause the heart to speed up undesirably.
Surgical treatment may be considered instead of long-term
medication and may be preferable in elderly patients. Angioplasty -
the use of an inflatable device to widen narrowed arteries - and
coronary artery bypass grafting (CABG) are the interventions used.
About 62,000 angioplasties were carried out in the UK in 2004
and just under 29,000 CABG operations were recorded in
2002/03.
There are two major aspects in the management of MI - firstly,
prevention and, secondly, emergency therapy if a heart attack
occurs. Primary prevention consists both of identifying and treating
those at especially high risk of IHD, e.g. because of an inherited
predisposition, and educating and motivating the public to reduce
as far as possible the lifestyle factors linked with the development
of IHD. In practice, prevention tends, unfortunately, to mean
secondary prevention i.e. prevention of another heart attack once
one has already occurred. Thus it represents an attempt to prevent
further worsening of already established heart disease.
Prevention of blood clot formation and plaque deposition inside
blood vessels (see Atherosclerosis, Thrombosis and Stroke) is a vital
approach to reducing heart attacks and angina. Large studies
performed in the mid-1990s showed that cholesterol-lowering
statins effectively reduce rates of death, stroke and coronary events
when used for secondary prevention. At least part of this effect is
as a result of their ability to stabilise existing plaques, as well as
lower cholesterol to prevent the formation of new plaque. Treating
high blood pressure can significantly decrease stroke,
MI and cardiovascular death rates, and some anti-hypertensive
medicines such as the ACE-inhibitor ramipril (Tritace,
sanofi-aventis) can also inhibit or reverse left ventricular
hypertrophy (LVH, a thickening of the heart muscle in response to
raised blood pressure that may lead to heart failure) in patients
with IHD. A similar effectiveness against LVH has also been found
with the diuretic indapamide (Natrilix, Servier) and angiotensin 2
receptor blockers (ARBs) such as candesartan (Amias, Takeda).
Thus, medical treatment for secondary prevention after MI might
well involve taking a statin, an ACE inhibitor (or an ARB or
diuretic) and low-dose aspirin.
Emergency treatment of a heart attack, or unstable angina,
involves measures in the first few hours to dissolve the blood clot
that is causing ischaemia, re-establishing blood flow to the heart,
to prevent or reverse arrhythmias, and subsequently to prevent
formation of new clots. (see Thrombosis).
What's in the development pipeline?
New modes of action are being explored in the search for
improved medications for angina. Servier's ivabradine
(Procorolan), for use in chronic stable angina, reduces the
symptoms of angina by acting to reduce heart rate, thereby
reducing oxygen consumption and lessening ischaemia. Astellas
has a compound (YM758) with a similar action currently in Phase 2
trial in stable angina. CV Therapeutics has ranolazine, which acts
on sodium channels and is at Phase 3 in chronic angina. Cardium
Therapeutics is developing a gene therapy approach in an attempt
to stimulate the growth of new blood vessels around areas of
blockage in chronic angina, improving blood flow to the heart,
which is in Phase 3 trial.
Other agents in trial for angina and acute coronary syndrome
include prasugrel (Lilly), AZD 6140 (AstraZeneca), fondaparinux
(Arixtra, GSK) and enoxaparin (Clexane, sanofi-aventis), all at
Phase 3.
Other new approaches are also being explored:
- deCODE genetics is preparing a Phase 3 study of DG031
to prevent plaque rupture and subsequent infarction in
unstable angina.
- Sanofi-aventis has ataciguat in Phase 2 trial for chronic
angina that may work by relaxing blood vessels and
improving blood flow to the heart. The company is also
studying SR 123781 and otamixaban in Phase 2 trials for
acute coronary syndrome.
- Bayer has BAY 68-4986 in Phase 1 trial to reduce angina.
Re-establishment of blood flow in ischaemia can lead to an
inflammatory reaction called reperfusion injury. Activation of the complement system (part of the body's defence against infection)
has been shown to be involved, and Procter & Gamble is studying
pexelizumab in Phase 3 trial in myocardial infarction to see if this
can reduce death and strokes.
Increasingly, angioplasty includes placing a stent (a small wire
tube) inside the affected artery to keep it open. In about 20 per
cent of cases, this stent later becomes blocked. Abbott has a stent
(ZoMaxx) in Phase 3 trial that continually releases a substance to
prevent this blockage.
Medical treatments for prevention of MI and other cardiovascular
events have now reached the point where advances are mainly
being made through the optimal use of existing medications, rather
than from the development of new compounds. To determine the
best way to use medicines such as ACE inhibitors, ARBs and others
requires very large and prolonged clinical studies, and several
studies of this kind are taking place.
One of the largest comparative studies showed that a calcium
channel blocker was superior to a beta-blocker in terms of
preventing stroke and cardiovascular deaths, as well as being less
likely to be associated with the development of type 2 diabetes.
Findings of this kind have been taken into consideration in the
recent revision in treatment guidelines. An even larger trial is
comparing the ARB telmisartan (Micardis, Boehringer Ingelheim)
with the ACE-inhibitor ramipril (Tritace, sanofi-aventis) and a
combination of the two in patients with coronary artery disease
or stroke or peripheral vascular disease. When this and other large
studies are complete, clinicians will be in a much better position
to decide on the best secondary prevention regimen for each
individual.
FOR FURTHER INFORMATION CONTACT:
British Heart Foundation
14 Fitzhardinge Street
London, W1H 4DH
Phone: 0870 600 6566 (Helpline)
Website: www.bhf.org.uk
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