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PERIPHERAL VASCULAR DISEASE
What is peripheral vascular disease?
Peripheral vascular disease (PVD) is also known as peripheral
arterial disease (PAD) and peripheral arterial occlusive disease
(PAOD). It is atherosclerosis of the extremities sufficient to affect
blood flow (see Atherosclerosis). At first, atherosclerosis may just
reduce blood flow in the affected artery by narrowing the internal
space, but in more advanced disease, flow may actually be halted
by formation of a clot through the clumping of tiny blood cells
called platelets and their entrapment in fibres of the insoluble
blood protein fibrin (see Thrombosis). In this case, there may be
growth of smaller blood vessels around the site of blockage that
partially compensates for the blocked blood flow.
Peripheral vascular disease affects the legs eight times more
often than the arms. Its most common symptom, intermittent
claudication, shows as a pain in the leg (usually in the calf
muscles) that develops on walking and subsides on resting. In
another form of peripheral vascular disease, critical limb ischaemia,
a severe pain develops in the lower leg/foot after going to bed that
is relieved, at least initially, by hanging the leg out of bed.
Poor circulation in critical limb ischaemia may lead to wounds
and ulcers that do not heal, leading to gangrene and the need
for amputation.
Pain in peripheral vascular disease has the same cause (inadequate
blood-borne oxygen and nutrient supply to muscle because of
atherosclerosis) as the pain of angina (see Ischaemic Heart
Disease) and patients with peripheral vascular disease typically
have a 2-3 times higher death rate from a heart attack or stroke
than healthy people of the same age, especially if they also have
diabetes. This increased risk of death is not unexpected since, if
atherosclerosis is detectable in the arteries of the legs, it is also
likely to be present in other parts of the body, such as the coronary
artery and in the carotid artery leading to the brain.
Intermittent claudication may be progressive, limiting independent
living. Eventually it may require angioplasty to open or widen the
blocked artery, or vascular surgery to replace a section of blocked
artery, or even amputation. Amputation will be necessary in the
lifetime of only 2-4 per cent of those with intermittent claudication
and in most patients, the disease can be treated medically. Raised
blood triglyceride levels, smoking and diabetes are all important
risk factors for disease progression, stroke and heart attack (See
Ischaemic Heart Disease).
Who does peripheral vascular disease affect?
Peripheral vascular disease is unusual before the age of 50, but its
prevalence rises with increasing age. In a survey of over 1,500
men and women aged 55-74, the overall prevalence of intermittent
claudication was 4.5 per cent. However, the number of people
with symptomless peripheral vascular disease is much greater -
almost two-thirds of people in this age range. It has been estimated that over 100,000 people are diagnosed with peripheral vascular
disease each year in the United Kingdom. PVD was recorded as
the underlying main cause of 2,384 deaths in England and Wales
in 2004, almost 85 per cent of them in people aged 75 and over,
but many PVD-related deaths are likely to have been recorded
under figures for stroke or heart attack.
Present treatments and shortcomings
Non-emergency treatment of peripheral vascular disease has three
aspects: managing the symptoms that degrade quality of life,
addressing risk factors of the underlying atherosclerotic process
and preventing cardiovascular complications. Aggressive treatment
of lifestyle factors (e.g. smoking cessation, weight loss) and
intervention to manage diabetes and reduce blood pressure and
high lipid levels is essential to prevent disease progression (see
Atherosclerosis, Diabetes and Hypertension) but there is evidence
that not all PVD patients currently receive adequate treatment.
Relatively few medicines have been authorised specifically for the
treatment of intermittent claudication. Inositol nicotinate (Hexopal,
Genua) is a medicine that causes blood vessels to dilate or expand
(a vasodilator) that may reduce vascular resistance to blood flow
and cilostazol (Pletal, Otsuka) is both a vasodilator and an agent
that stops platelets sticking together. Pentoxifylline (Trental,
Sanofi-aventis) improves the flow properties of blood, thinning the
blood and increasing red blood cell flexibility. Naftidofuryl oxalate
(Praxilene, Merck Sharp & Dohme) enhances the way muscle uses
glucose and oxygen, making better use of the available blood
supply. The improvements in pain-free walking distance achieved
with these medications is usually modest (40-50 per cent) and
side-effects such as nausea, rashes and drowsiness may be observed. A regime of exercise training should accompany medical
therapy and may sometimes be more effective.
What's in the development pipeline?
Several new anti-platelet agents are in development for peripheral
vascular disease. Nissan Chemical has reported positive results
(increase in walking time) in a Phase 2 study of its NM-702 in the
treatment of intermittent claudication. Another similar compound
is Endovasc's Liprostin. This showed a significant increase in
walking distance in a Phase 2 trial in patients with intermittent
claudication and is now in preparation for Phase 3 studies. Two
other anti-platelet agents under study are DG041 (DeCode
Genetics, Phase 2) and Kowa's K-134 (Phase 1), which has an
inhibitory effect on blood vessel wall thickening.
New thrombolytic agents are also being tried in peripheral
vascular disease. Menarini has amediplase in Phase 3 trial.
In addition, ThromboGenics has microplasmin in Phase 2 study,
and Wyeth has PAI-749 (diaplasinin) in Phase 1 trial.
Among other approaches, sanofi-aventis has a compound
(SL 65.0472) that interacts with serotonin receptors and a
guanylate cyclase activator (HMR 1766, ataciguat), both at Phase 2.
The longer-term future
There have been a number of attempts to use gene therapy in
peripheral vascular disease. These projects typically aim to
promote the growth of new blood vessels to bypass an obstructed
artery. Several companies (sanofi-aventis, Daiichi-Sankyo,
Genzyme) have projects of this type in Phase 2 trials. Lastly,
Cardium Therapeutics has an agent (Genvascor) based on the
enzyme endothelial nitric oxide synthase (eNOS) that, by
increasing local production of artery-relaxing nitric oxide, may
alleviate ischaemic pain in critical limb ischaemia. This project
is still at the pre-clinical stage.
While these gene therapy approaches do not cure the blockage
that causes symptoms, they may provide a relatively simple way of
improving functional status that would bring welcome relief in
patients whose lives are limited by peripheral vascular disease.
FOR FURTHER INFORMATION CONTACT:
CIRCULATION FOUNDATION
Royal College of Surgeons
35-43 Lincoln's Inn Fields
London, WC2 3PE
Phone: 020 7304 4779
Website: www.circulationfoundation.org.uk
THE BRITISH HEART FOUNDATION
14 Fitzhardinge Street
London, W1H 4DH
Phone: 0870 600 6566 (Helpline)
Website: www.bhf.org.uk
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