INTRODUCTION

Poor blood circulation

There are two major types of peripheral vascular disease depending on the type of blood vessel that is most affected. One kind affects the arteries and the other affects the veins.

Arterial disease

Leg pain brought on by exercise and which is relieved by rest, known as intermittent claudication, is a symptom of hardening and narrowing of the arteries to the legs caused by atherosclerosis. The clogging of the artery reduces blood flow to the legs to cause pain and discomfort that limits how far a person can walk, particularly in older people. The discomfort and pain may worsen over time as the disease progresses so that the pain is present all the time. Very few people will go on to have an amputation because of a severe reduction in blood flow and gangrene.

Arteries are the blood vessels that carry the blood from the heart to the rest of the body. If the arteries become clogged up with fatty deposits, blood clots and platelets (a condition called atherosclerosis), circulation of blood to the legs can be decreased. Smoking, diabetes, high blood pressure and high cholesterol can all contribute to arterial disease. Symptoms are treated using drugs to improve blood flow in the legs, such as aspirin, exercise programs and complex vascular surgery.

Leg ulcers are open sores that are slow to heal, particularly in the elderly. Most ulcers are associated with inadequate blood flow in the veins of the legs and pooling of blood in the lower leg, because of damage to the blood vessels or a blood clot. Leg ulcers usually heal with good wound care, dressings and attention to infection.

Leg veins

In chronic venous insufficiency the blood does not flow back to the heart properly and tends to pool in the legs. This leads to swelling of the feet and ankles (oedema), puffiness, leg pain, itching, a feeling of heaviness, cramps and tiredness. The skin can harden and darken and varicose veins develop. Some people are prone to poor circulation; for others it develops after injury or a blood clot. Sitting or lying in one position for a long time may be enough to cause problems. People are encouraged to wear compression stockings or bandages to help blood movement up the legs; the veins can also be treated by surgery. Treatments such as natural flavonoids extracted from plants and similar synthetic products are also used to improve blood flow.

OMEGA-3 FATTY ACIDS FOR INTERMITTENT CLAUDICATION

Intermittent claudication (leg pain brought on by exercise and which is relieved by rest) can occur as a symptom of hardening and narrowing of the arteries to the legs because of atherosclerosis; it is usually a problem with advancing age. The clogging of the artery reduces blood flow to the legs to cause pain and discomfort that limits how far a person can walk. The discomfort and pain generally eases when they stop to rest.  It may, however, worsen over time if the disease progresses so that the pain is present all the time, usually in the feet.

People who have heart and circulation (cardiovascular) problems and peripheral arterial disease often have thick (viscous) blood. Making the blood less sticky is likely to be beneficial. Omega-3 fatty acids in the diet change blood lipids and appear to reduce cardiovascular events. They may also help people with peripheral arterial disease by improving their blood circulation.

What the synthesised research says

Omega-3 fatty acid supplementation (EPA or DHA capsules) did not improve pain-free or maximal walking distance. Nor was the blood pressure difference between the ankle and the arm (ankle brachial pressure index) improved; this is indicative of the severity of leg circulation problems.

Omega-3 fatty acid supplements may still benefit people with intermittent claudication because they reduce blood pressure, blood viscosity and triglyceride levels, after four weeks to four months of taking them. Whether these changes improved how the people felt or how their health was affected is not clear.

Only one trial looked at the incidence of vascular events (strokes and heart attacks) and deaths after two years. There was no difference between being on omega-3 fatty acid supplementation and the control group.

These conclusions are from four trials with a total of 203 participants. Omega-3 fatty acid supplementation was compared with taking other fatty acids (the control group) for from four weeks to two years. The largest study (120 people) used a combination of omega-3 and omega-6 fatty acids.

How it was tested

The researchers made a thorough search of the medical literature for controlled studies randomly assigning people with intermittent claudication to either  omega-3 fatty acids or omega-6 fatty acids (two studies), a monosaturated fatty acid (one study) or a combination of the two (one study).

These four trials were reported between 1984 and 1998, involved a total of 203 participants and were based in the UK, Australia, and the Netherlands. Three of the trials were small, involving between 19 and 32 participants. The largest trial, in the UK, involved 120 participants. Three trials included both men and women; the Australian trial included only men.

Side effects and general cautions

How people felt and the costs involved when taking the supplement were not reported.

Out of two trials looking at side effects with supplementation (in a capsule), one reported that omega-3 supplement was associated with an increased incidence of gastrointestinal upset.

Pain-free walking distance was reported in three out of four trials and maximum walking distance in two. Blood changes were also reported on. Total and LDL cholesterol appeared to be increased with omega-3 fatty acid supplementation, dominated by one trial.

Trials that included participants with acute lower limb ischaemia or who had undergone lower limb vascular surgery within the previous three months were excluded.

Source

Sommerfield T, Hiatt WR. Omega-3 fatty acids for intermittent claudication. The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003833.pub2. DOI: 10.1002/14651858.CD003833.pub2.

VITAMIN E FOR INTERMITTENT CLAUDICATION

Vitamin E is an antioxidant. An important function of vitamin E in the body is preventing fatty acids from being oxidized by free radicals. The cell damage that occurs with a lack of blood flow and oxygen in the tissues is probably caused by these free radicals.

Vitamin E might, therefore, improve tolerance to the ischaemia that occurs during exercise. It may also influence platelet aggregation and red blood cells to improve blood flow. In this way vitamin E may be useful in reducing intermittent claudication.

Eight naturally occurring tocopherol and tocotrienol compounds have vitamin E activity, the most active being alpha-tocopherol. Vitamin E is generally very well tolerated and has had no serious side effects reported. Synthetic vitamin E is inexpensive.

What the synthesised research says

More participants found that their symptoms improved with vitamin E compared with taking a non-active treatment (placebo) in two trials which lasted approximately eight months. The relative risk was 0.6.

Five eligible studies were found with a total of 265 participants, mainly men. Their average age was 57 years. All trials showed positive effects on one of their main measures of outcome. The relevance and comparability of some of the physical measures, such as standing on tiptoes, was not clear, however.

How it was tested

The researchers made a thorough search of the medical literature and found five controlled trials of vitamin E for intermittent claudication (published between 1953 and 1975). Most trials lasted from 12 weeks to 18 months.

No trials were identified that compared vitamin E with treatments other than placebo. Nor were there trials that looked at vitamin E treatment on amputation rate, need for vascular surgery, or deaths.

Side effects and general cautions

No serious side effects were reported in the trials.

The trials were small and generally of poor quality; different physical outcomes were measured. All trials participants were people who were not eligible for surgery and most specified that patients with diabetes were excluded.

Five different doses of vitamin E were used and the exact nature of the 'vitamin E' was not always stated. One study used vegetable oil as the source of vitamin E. 

Source

Kleijnen J, Mackerras D. Vitamin E for intermittent claudication. The Cochrane Database of Systematic Reviews 1998, Issue 1. Art. No.: CD000987. DOI: 10.1002/14651858.CD000987.

GARLIC FOR PERIPHERAL ARTERIAL OCCLUSIVE DISEASE 

Peripheral arterial occlusive disease affects the major arteries of the legs and is caused by fatty deposits blocking the arteries (lower limb atherosclerosis). The most common symptom in early occlusive disease is discomfort in the legs with exercise that is relieved by rest (intermittent claudication). Numerous risk factors have been associated with the development of peripheral arterial disease, including cigarette smoking, raised blood lipids, high blood pressure and diabetes.

The main measures of treatment effect were: ankle pressure, ability to walk on a treadmill, and the level of atherosclerosis at angiography; and a general subjective measure of symptoms.

The medicinal use of garlic can be traced back to Egyptian times. The primary active component of garlic is called allicin. Garlic is an acceptable therapy to many and, apart from the odour, has only minor gastrointestinal (stomach and gut) side effects. Commercially available preparations of garlic have been reported to have beneficial effects on some of the risk factors associated with atherosclerosis, such as blood cholesterol. With fresh garlic, the dosages needed to inhibit platelet aggregation, or lower cholesterol levels are unacceptably high; at least seven cloves of garlic per day. 

What the synthesised research says

Taking garlic for 12 weeks did not improve people’s walking distance without pain. This conclusion was from only one small trial, after twelve weeks of treatment.

There was no difference in change of systolic or diastolic blood pressure, heart rate, or pressure differences between the arm and ankle.

How it was tested

The researchers made a thorough search of the medical literature and found only one trial with sufficient quality to include in the review. The trial was small with only 78 participants randomly assigned to taking either garlic or a non-active treatment (placebo). Both men and women, aged 40 to 75 years, were included although 16 did not keep to the treatment schedule.

The dose of garlic was two coated tablets of 200 mg oral standardised garlic powder twice daily.

Side effects and general cautions

No severe side effects were observed. Nine people taking garlic (28%) and four people taking placebo (12%) complained of a noticeable garlic smell. 

One of the difficulties in showing the effectiveness of garlic is that active ingredients may be lost in processing or the type of preparation (such as fresh, powdered or non-powdered garlic).

The participants in the trial had lower limb atherosclerosis and people with critical limb ischaemia and others without symptoms of the disease may have been included.

Source

Jepson RG, Kleijnen J, Leng GC. Garlic for peripheral arterial occlusive disease. The Cochrane Database of Systematic Reviews 1997, Issue 2. Art. No.: CD000095. DOI: 10.1002/14651858.CD000095. Updated October 2006.

CHELATION THERAPY FOR ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

Cardiovascular disease remains the leading cause of death in developed countries. The main underlying problem is atherosclerosis, a process that is characterised by thickening of the wall of blood vessels and the formation of fatty plaques comprised of platelets, cells, matrix fibres, lipids, and tissue debris in blood vessels. Blood clots can form on the damaged area of the blood vessel wall and fragments break off with serious consequences of heart attacks and stroke. Physical inactivity, diet, smoking and stress can accelerate the clogging of the blood vessels, particularly the arteries. High blood pressure and narrowing and hardening of major and heart (coronary) arteries increase the risk of a heart attack and stroke. People also get pain on exertion (angina).

With high levels of cholesterol, fatty deposits can form in the tendons, skin and blood vessels (arteries), and people are more likely to have heart disease and strokes. Low density lipoprotein (LDL) is sometimes referred to as the ‘bad cholesterol’ because it is associated with increased risk of heart disease. By contrast, high-density lipoprotein (HDL) is referred to as ‘good cholesterol’ because it helps remove cholesterol from the body.

Cardiovascular events include a cardiovascular death; heart attack (myocardial infarction); stroke; angina; heart failure; a peripheral vascular event; and unplanned coronary artery bypass grafting or angioplasty.

What is known

Chelation has been found to be effective in removing toxic metals from the blood. Proponents believe that it can also reduce plaque (fatty deposits and other substances) in arteries and thereby restore blood flow to clogged or blocked arteries. This could potentially prevent symptoms of heart and circulatory disease including chest pain, heart attacks, strokes, and fatigue or pain in the calf muscles that people experience after walking short distances (claudication).

Chelation therapy consists of a series of intravenous infusions into the bloodstream (that is, a solution slowly injected into the blood stream over a period of time). The infusions contained a chemical called EDTA (disodium ethylene diamine tetraacetic acid) in combination with other substances.

What the synthesised research says

No clear benefits were seen for people with peripheral arterial disease (intermittent claudication).

Of the five trials that evaluated people with peripheral arterial disease, four of them, involving a total of 250 participants, did not show any benefit from chelation therapy. Chelation therapy was evaluated by measuring blood pressure at the ankle compared to the arm, computer assisted x-rays, the distance a person could walk, cholesterol levels, and how the person felt. One very small study (10 participants) found some improvement with chelation therapy.

No controlled trials were found looking at any benefits of chelation therapy on heart disease or strokes.

How it was tested

The researchers thoroughly searched the medical literature but could not find any controlled trials of chelation therapy involving people with blocked or clogged arteries that supply the heart or brain.

They did find five trials that evaluated the use of chelation therapy on people with restricted blood flow to the legs (peripheral arterial disease) who experienced cramping, pain, fatigue on and off while walking or exercising (intermittent claudication).

The trials were small, ranging from 30 to 153 people. Participants were randomly assigned to receive 20 infusions of chelation therapy or non-active (placebo) infusions over 5 to 10 weeks. The follow ups and number of infusions varied but in general, there were 10 to 20 infusions and follow ups ranged from 3 to 12 months after treatment.

Side effects and general cautions

One trial reported some possible side effects from chelation therapy including pain and inflammation at the site of the infusion, faintness, gastrointestinal symptoms, protein in urine, and low blood calcium.

Source

Villarruz MV, Dans A, Tan F. Chelation therapy for atherosclerotic cardiovascular disease. The Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD002785. DOI: 10.1002/14651858.CD002785.

HOMOCYSTEINE LOWERING INTERVENTIONS FOR PERIPHERAL ARTERIAL DISEASE AND BYPASS GRAFTS

Peripheral arterial occlusive disease of the lower limbs increases with age. However, only a third to a fifth of those affected actually go to their general practitioner with symptoms. Of these, most (90%) have evidence of coronary artery disease as well (from an angiogram) and over a third (40%) also have carotid artery disease (seen with ultrasound). They are 2 to 8 times more likely to experience a serious cardiovascular event than the general population.

The demand for therapeutic interventions has been increasing steadily with the advent of new treatments, such as surgical treatment of the wall of the blood vessel under x-ray (angioplasty). Currently 20% to 30% of angioplasties and bypasses fail within 12 months, requiring further interventions. Amputation rates have increased in the last 10 years despite improvements in the medical management of raised blood levels of cholesterol (hypercholesterolaemia), hypertension and diabetes. The major cause of failure of these treatments is re-narrowing of the artery after treatment (restenosis) within the treated vessel or bypass. Any further procedure will be susceptible to the same problem and so current research centres on prevention via a variety of pharmaceutical agents, changes in technique, endothelial cell seeding of grafts, intravascular irradiation and gene therapy.

What is known

Homocysteine is an amino acid produced by the body. People with high blood levels of homocysteine are likely to have hardening and narrowing of the arteries (atherosclerosis) and may also experience worse outcomes from arterial disease. Levels of homocysteine can be lowered by oral vitamin supplements (such as vitamin B12 and folic acid), by quitting smoking, or with dietary changes and regular exercise.

What the synthesised research says

Currently, there is no evidence available to show whether reducing homocysteine levels in the blood can prevent or reduce arterial problems in the legs.

How it was tested

The researchers made a thorough search of the medical literature but could not find any randomised trials of the treatment of high blood levels of homocysteine in people with peripheral arterial disease.
Trials could have involved patients treated surgically (bypass graft, clearing the blood vessel (endarterectomy) and removing blood clots (thrombectomy) or radiologically (angioplasty or thrombectomy).

Source

Hansrani M, Stansby G. Homocysteine lowering interventions for peripheral arterial disease and bypass grafts. The Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD003285. DOI: 10.1002/14651858.CD003285.

There is currently a randomised, blinded, placebo-controlled prospective study underway in USA called the Homocysteine and Progression of Atherosclerosis Study (HPAS). Phase I was a three year natural history study that indicated a relationship between homocysteine levels and progression of disease (HPAS 1999). In Phase II the patients were randomised to treatment with 4 mg/day folic acid versus placebo, with a follow up period of five years.

ZINC SUPPLEMENT FOR LEG ULCERS

Leg ulcers or open sores are more common in women than men and their prevalence increases with age. Most people affected have venous disease is present but other diseases, such as rheumatoid arthritis and diabetes, may also contribute.

Leg ulcers usually heal with good wound care, dressings and attention to infection. Some leg ulcers, however, fail to heal despite good wound care and it may be that poor nutrition reduces the ability of the body to repair itself or encourages ulcers to reoccur.

What is known

Zinc is an essential trace metal. It is necessary for some enzymes and hormones to function and has anti-inflammatory effects. People who have low zinc levels are prone to infections and have slow wound healing. Zinc deficiency is treated with oral zinc sulphate (30 to 150 mg per day). A randomised controlled trial in people with wounds at the base of the spine indicated that oral zinc sulphate (220 mg three times daily) improved healing of the wounds.

What the synthesised research says

There is currently no evidence that oral zinc speeds the healing of either venous or arterial leg ulcers.

Six small trials were eligible for inclusion, with no obvious difference in healing of ulcers between zinc and placebo or no treatment.

These trials were too small to be able to detect even a moderate effect of zinc.

How it was tested

The researchers made a thorough search of the medical literature and found six controlled trials with between 10 and 42 participants randomly assigned to zinc supplement, placebo or no treatment. The oral zinc sulphate dose was 440 to 660 mg daily given for four weeks to a year.

Four of the included trials involved hospital outpatients, one inpatients and in the other it was not clear. Five of the trials included people with venous ulcers, in England and Sweden. The sixth included people with arterial ulcers, in Sweden.

Side effects and general cautions

Side effects with zinc did not appear to be a major problem. Two trials reported constipation, dizziness, itching or rash with both zinc and placebo. Nausea caused a total of three people to withdraw from the trial.

Large and small ulcers heal at different rates with large ulcers taking longer to heal. If treatment groups were imbalanced at baseline (ulcers were larger in one of the groups) then this is likely to affect the findings.

A person may be deficient in zinc, which would be expected to influence healing.

Results were reported as the number of ulcers healed at the end of the study and, in some cases, by the average rate of healing. No study reported the time to complete healing of ulcers.

Studies in people with isolated foot ulcers were excluded.

Source

Wilkinson EAJ, Hawke C. Oral zinc for arterial and venous leg ulcers. The Cochrane Database of Systematic Reviews 1998, Issue 4. Art. No.: CD001273. DOI: 10.1002/14651858.CD001273.

ELECTROMAGNETIC THERAPY FOR TREATING VENOUS ULCERS

Venous leg ulcers can be a problem in older people. Most ulcers are associated with inadequate blood flow in the veins of the legs, because of damage to the blood vessel walls or a blood clot, and pooling of blood in the lower legs. Treatment involves dressing the ulcer, putting a compression bandage on the leg and keeping the leg raised to improve blood circulation and help the ulcer to heal.

What is known

Electrical stimulation (or pulsed electromagnetic therapy or PEMF) of the involved tissue has been used as a part of treatment of leg ulcers and chronic wounds for decades. Electromagnetic therapy uses an electric current to create magnetic field effects, often termed pulsed electromagnetic field therapy (PEMF).

What the synthesised research says

There is little evidence to support the use of electrotherapy to improve the healing of leg ulcers caused by poor venous blood flow.

How it was tested

The researchers made a thorough search of the medical literature and found three randomised studies comparing real electromagnetic therapy with sham stimulation with or without compression bandaging or standard treatment.

The studies had small numbers of participants. The method of diagnosis of venous ulceration differed between the studies, and the different groups in one study, so the actual type and size of ulcer may differ. Some people left the studies before they were finished and the healing rates in the control groups of all the studies were poorer than normally expected with standard treatment. There were differences in the electromagnetic therapy received; it was applied using different electrical currents for to four hours a day. The duration of the trials varied between thirty days to three months. The studies were small with each involving only 19 to 44 people with venous leg ulcers who lived in the community.

Side effects and general cautions

There is no reliable evidence of an effect of electromagnetic therapy on venous leg ulcer healing as only three very small trials have been undertaken. These three completed studies were too small to detect even a clinically important effect.

This review was first published in The Cochrane Library, Issue 1, 2001 with three included studies. For the first update, new searches were carried out in October 2005. No new studies were identified. The reviewers’ conclusions remain unchanged.

Source

Ravaghi H, Flemming K, Cullum N, Olyaee Manesh A. Electromagnetic therapy for treating venous leg ulcers. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD002933. DOI: 10.1002/14651858.CD002933.pub3.

THERAPEUTIC ULTRASOUND FOR VENOUS LEG ULCERS

Venous leg ulcers (open sores) can be caused by a blockage or breakdown in the veins of the legs. Prevalence of active leg ulceration increases with age, and is higher among women. Leg ulceration is typically a chronic recurring condition, with 45% of patients in a Scottish study reporting episodes of ulceration for more than 10 years. There is a considerable cost both to the patient and to the health service. Most leg ulcers are associated with venous disease. Venous insufficiency has been shown to be associated with increased fluid pressure in the veins of the leg, and the use of externally applied compression, using bandages or hosiery (stockings), to reverse this, is largely successful in healing venous leg ulcers.

A significant proportion of people need additional treatments as their ulcers do not heal with compression therapy.

What is known

Low levels of ultrasound (not enough to generate heat) or laser are sometimes tried to relieve leg ulcers. It is not clear how ultrasound might affect healing, and ultrasound waves may have a positive or negative impact on the blood flow around the ulcer.
The cellular effects of ultrasound can be divided into warming (thermal) and non-thermal when lower intensities are used therapeutically. Some of non-thermal effects may be beneficial whilst others could be harmful by interfering with blood flow. Careful choice of exposure time, intensity, and continuous movement of the ultrasound applicator should minimize these effects. Therapeutic ultrasound has been evaluated in a number of different regimens: varying pulse duration, power output, and frequency.

What the synthesised research says

The available evidence suggests a possible benefit of ultrasound therapy in the healing of venous leg ulcers.

The researchers made a thorough search of the medical literature and found seven eligible trials with a total number of participants of 274. Four trials compared ultrasound therapy with sham ultrasound and three trials compared ultrasound therapy with usual treatment.

Ultrasound was given with standard treatment once to three times weekly for four to twelve weeks. Of the 4 included studies, 2 trialists measured the time it took for wounds to heal and 2 measured the percentage decrease in ulcer size.

None of the trials found a clear difference in healing rates between any of the therapies, although the direction of treatment effect was consistently in favour of ultrasound.

Side effects and general cautions

Overall the quality of the trials was poor. Most had only small numbers of participants, between 12 and 44, with the exception of one trial with 108 participants.

Source

Flemming K, Cullum N. Therapeutic ultrasound for venous leg ulcers. The Cochrane Database of Systematic Reviews 2000, Issue 4. Art. No.: CD001180. DOI: 10.1002/14651858.CD001180.

HORSE CHESTNUT SEED EXTRACT FOR CHRONIC VENOUS INSUFFICIENCY

Compression stockings are the recommended treatment, but can be uncomfortable or people refuse to wear them. They are also expensive. This makes taking medications by mouth an attractive option. Rutosides are reported to reduce leg swelling and have beneficial short-term effects.

What is known

Horse chestnut (Aesculus hippocastanum L.) has traditionally been used as a herbal remedy for treating chronic venous insufficiency. The seed extract contains an active compound that has soap-like properties (escin, a saponin), which may reduce inflammation.

What the synthesised research says

Oral horse chestnut seed extract improved symptoms of leg pain, swelling and itching in people with chronic venous insufficiency.

People taking horse chestnut seed extract had reduced leg pain compared with those who had taken the placebo in six trials (543 participants) and compared with sytarting levels of pain (baseline) in one trial. Similarly with leg swelling, which was reduced in four trials (461 participants) compared with placebo and one from baseline; and leg volume (six trials, 502 participants). Itchiness also improved, in four trials (407 participants) compared with placebo and two trials from baseline.

Taking horse chestnut extract was as effective as wearing compression stockings for reducing swelling in the only trial (194 participants) that looked at this. Single trials found horse chestnut extract to be comparable to compression stockings, rutosides and pycnogenol on leg pain and symptom scores. It may have been less effective than pycnogenol for reducing swelling.

How it was tested

Seventeen trials met the inclusion criteria. Ten compared oral horse chestnut seed extract with non-active treatment (placebo); four against medication with rutosides (O-ß-hydroxyethyl rutosides); two with using compression stockings and placebo; and one trial against medication with pycnogenol. Horse chestnut seed extract was given in capsules and the extract was standardised to escin as the main active constituent (100 to 150 mg escin daily).

In three studies using 100 mg escin daily, leg volume was reduced after two weeks of treatment and one study reported that this benefit was still there six weeks later.

Side effects and general cautions

Adverse events were mild and infrequent in the fourteen studies that reported on them. Four studies reported no treatment-related adverse events whereas six studies reported gastrointestinal complaints, dizziness, nausea, headache and itchiness with horse chestnut seed extract. Four other studies reported good tolerability to horse chestnut seed extract.

Post-marketing surveillance studies report itching, nausea, gastrointestinal complaints, headache and dizziness in 43 of 6183 patients (0.7%) treated with horse chestnut seed extract.

Trials assessing horse chestnut seed extract as one of several active components in a combination preparation, or as a part of a combination treatment, were not included in the synthesis of evidence (review).

Source

MH Pittler, E Ernst. Horse chestnut seed extract for chronic venous insufficiency. The Cochrane Database of Systematic Reviews 2006, Issue1. Art. No.: CD003230.pub3. DOI: 10.1002/14651858.CD003230.pub3.