Peripheral vascular disease restricts or stops blood flow to the legs. People with PVD cannot walk far without pain. New medicines to treat it are being studied. The research should bring welcome relief to patients whose lives are limited with PVD.
Peripheral vascular disease (PVD), also known as peripheral arterial occlusive disease (PAOD), is atherosclerosis of the lower extremities that restricts or obstructs blood flow to the legs and feet. Its characteristic symptom, intermittent claudication (IC), is a pain in the leg (usually in the calf muscles) that develops on walking and subsides on resting.
In another form of PVD, 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 PVD has the same cause (inadequate blood-borne oxygen and nutrient supply to muscles because of atherosclerosis) as the pain of angina pectoris in people with cardiovascular disease. Patients with IC typically have a 2-3 times higher mortality due to heart attack or stroke than healthy people of the same age.
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 arteries and in the carotid arteries leading to the brain.
IC may be progressive, limiting independent living and eventually leading to critically restricted blood flow in the limb that demands emergency treatment, such as thrombolytic treatment or angioplasty to open or widen the blocked artery, vascular surgery to replace a section of blocked artery, or even amputation.
Raised blood triglyceride levels, smoking and diabetes are all important risk factors for disease progression. Diabetic patients having angiograms for PVD are five times more likely to have an amputation than non-diabetic patients and in another study, smokers had an amputation rate eleven times that of non-smokers.
Nevertheless, an amputation will be necessary in the lifetime of only two to four per cent of those with IC and in the majority of patients, the disease runs a relatively benign course that can be treated medically.
PVD is unusual below the age of 50, but prevalence rises with increasing age. In a survey of men and women aged 55-74 in the UK, the overall prevalence of IC was 4.5 per cent. However, the number of people with symptomless PVD is much greater: almost two-thirds of people in this age range. It has been estimated that over one million people in the European Union are diagnosed with PVD each year.
Non-emergency treatment for PVD has two aspects: managing the symptoms that degrade quality of life (IC) and addressing the risk factors of the underlying atherosclerotic process. Aggressive treatment of lifestyle factors (e.g. smoking cessation, weight loss) and intervention to manage concomitant diabetes and reduce hypertension and elevated lipids is essential to prevent disease progression.
Relatively few medications have been authorised specifically for symptomatic treatment of IC. Vasodilating medicines, i.e. molecules that cause blood vessels to dilate or expand, are given to reduce peripheral vascular resistance to blood flow.
The commonly used vasodilators improve the flow properties of blood, lower blood viscosity and increase red blood cell flexibility. Some of the medicines available have a dual action: they are both a vasodilator and an agent that stops platelets sticking together.
Another compound enhances the utilisation by muscles of 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), but can be crucial at home, where walking distances can be covered without pain. In physically active patients, a regime of exercise training should accompany medicines therapy and may sometimes be more effective.
The development of new medications for IC has suffered setbacks in the past, with new compounds showing only limited improvement in pain-free walking distance (the main indicator of efficacy).
However, there is a new 5HT₂ᴀ receptor antagonist currently in Phase 3 trial in the EU. 5HT₂ᴀ receptors are involved in platelet aggregation and the relaxation of smooth muscle, so this anti-platelet therapy may both reduce eventual formation of blood clots and relax arteries, improving blood flow.
Research is also progressing with another anti-platelet compound in Phase 3 trials. Two plaque-formation inhibitors are also under study in PVD, a lipid-lowering agent and a new ACAT inhibitor, both in Phase 3.
The diffusion of oxygen from blood to muscle could be a component of the overall decreased delivery or deficit of oxygen to skeletal muscle resulting in symptoms in PVD patients. Scientists are studying a compound that aims to enhance the diffusion of oxygen through the plasma to alleviate the symptoms caused by the low levels of oxygen in the tissues. This project is still in clinical Phase 1.
New thrombolytic agents are also being tried in PVD. Their mechanism of action is characterised by the conversion of naturally occurring plasminogen into plasmin which is able to dissolve existing clots in the vessels of patients with PVD.
As the majority of patients with significant atherosclerotic obstruction of the lower extremities typically do not seek clinical care until the disease reaches a critical dimension, there is a need to study the progression of PVD in individuals in the early stages of the disease.
Most probably, multi-factorial interventions need to be evaluated, including lipid-lowering agents, anti-platelet therapy, anti-hypertensive therapy, exercise, and control of blood glucose to determine how to attain the maximum benefit for these patients.
Also, new techniques for functional imaging that provide quantitative and objective measures of impairment are critical to future vascular studies. Imaging could also be used to assess the impact of systemic changes induced by treatment with medicines or other therapeutic approaches.
PVD is an area that may see the application of gene therapy, with several separate initiatives already underway to use this technique to promote angiogenesis, the growth of new blood vessels that may bypass an obstructed artery. Phase 1 and 2 studies are underway to test whether these therapeutic approaches hold promise.
Such medicines would act locally in muscle cells to produce an angiogenesis-promoting protein that is not secreted into the bloodstream. In Europe, the first clinical studies have started with a vector that inserts the gene for fibroblast growth factor 4 (FGF-4), an angiogenic protein.
Researchers are also studying the effects of an agent 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 a pre-clinical stage.
Further, researchers are testing the use of granulocyte colony-stimulating factor (G-CSF) in PVD. The investigators hypothesise that mobilisation of angiogenic cells into the blood by G-CSF may stimulate the formation of new blood vessels, resulting in a sustained improvement in blood flow in patients with severe PVD. This study is at clinical Phase 1.
Another approach is to develop placental growth factor (PIGF) as a possible treatment for ischaemic disease, based on preclinical results that it has a targeted effect at the site of ischaemia. Further, scientists are investigating a hepatic growth factor (HGF) genetic medicine which induces blood vessel regeneration.
While this gene therapy approach does not cure the blockage that causes symptoms, it may provide a relatively simple way of improving functional status (pain-free walking) that would bring a welcome relief for patients whose lives are limited by peripheral vascular disease.