Homocysteine lowering interventions for peripheral arterial disease and bypass grafts

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1 1 de 5 30/9/ :02 Doença Arterial Periférica e Intervenções para Diminuir a Homocisteína 01/04/2009 Copyright: The Cochrane Library Homocysteine lowering interventions for peripheral arterial disease and bypass grafts Hansrani M, Stansby G This review should be cited as: Hansrani M, Stansby G. Homocysteine lowering interventions for peripheral arterial disease and bypass grafts (Cochrane Review). In: The Cochrane Library, Issue 4, Oxford: Update Software. A substantive amendment to this systematic review was last made on 08 March Cochrane reviews are regularly checked and updated if necessary. Abstract Background Elevated plasma levels of the amino acid homocysteine (hyperhomocysteinaemia) are associated with hardening or blocking of the arteries (atherosclerosis) In addition, there is a poorer prognosis, both in the progression of the disease and outcome after therapy. Treatment to lower homocysteine levels has been shown to be both effective and cheap in healthy volunteers. However, the impact of reducing homocysteine levels on the progression of atherosclerosis and patency of vessels after treatment for atherosclerosis is still unknown and forms the basis for this review. Objective To assess the effects of plasma homocysteine-lowering therapy on the clinical progression of disease in patients with peripheral arterial disease (PAD) and hyperhomocysteinaemia, including, as a subset, those who have undergone surgical or radiological intervention. Search strategy The reviewers (MH,GS) searched the Cochrane Peripheral Vascular Diseases Group trials register (last searched October 2006), the Cochrane Central Register of Controlled Trials in The Cochrane Library, Issue 4, 2006, MEDLINE, EMBASE and reference lists of relevant articles. Selection criteria Randomised trials of the treatment of hyperhomocysteinaemia in patients with peripheral arterial disease, before and after surgical or radiological intervention versus no treatment for hyperhomocysteinaemia. Data collection and analysis Two reviewers (MH,GS) independently assessed trial quality and extracted data. Information on adverse events was collected from the trials. Main results There are currently no randomised trials available for analysis. Reviewers' conclusions Well constructed trials assessing the impact of the treatment of hyperhomocysteinaemia in patients with peripheral arterial disease are urgently required. Synopsis Homocysteine lowering interventions for peripheral arterial disease and bypass grafts Homocysteine is an amino acid, found in proteins. High levels of homocysteine in the blood has been associated with hardening or blocking of arteries (atherosclerosis) and are a risk factor for the progression of peripheral arterial disease. Blood levels of homocysteine can be normalised by taking vitamin B (folic acid, vitamins B12 and B6 or pyridoxine) supplements and betaine. People with peripheral arterial disease have poor blood flow in their legs caused by atherosclerosis. Symptoms include a limited ability to exercise or walk without developing cramping pains in the legs. There is growing evidence that even people without symptoms have a two to three times greater cardiovascular risk than the general population. Although people can be treated surgically (such as a bypass graft) or radiologically (angioplasty) to remove blood clots and improve arterial circulation there is an appreciable risk of failure within 12 months, mainly because the arteries narrow and close up again (restenosis). High levels of homocysteine (hyperhomocysteinaemia) may contribute to restenosis. The review authors made a thorough search of the medical literatures looking for randomised controlled trials using any therapy for the set purpose of lowering plasma homocysteine levels compared with no active treatment. They did not find any completed trials. There is currently a trial underway in the USA, called the Homocysteine and Progression of Atherosclerosis Study (HPAS), where patients are randomised to treatment with 4 mg/day folic acid versus non-active placebo, with a follow up period of five years. Background Estimates of the prevalence of peripheral arterial occlusive disease of the lower extremities (PAD) have ranged from % (Balkau 1994), due to differences in the methods used for assessment. Prevalence is currently believed to be around 20% in adults over 60 years of age in the UK, and increases with increasing age (Meijer 1998; Dormandy 1991; Coni 1992). However, only a third to a fifth of those affected actually present to their general practitioner with symptoms (Criqui 1997; Stoffers 1996). Of these, 90% have angiographic evidence of concomitant coronary artery disease and 40% have carotid artery disease as determined by duplex ultrasound scanning (Tierney 2000), while their mortality from any cardiovascular cause is 2-8 times that of the general population (Bainton 1994; Leng 1996). In patients with critical limb ischaemia mortality may be as high as 70% at five years (Dormandy 1991). There is growing evidence that even people with asymptomatic PAD have a two to three times greater cardiovascular mortality and morbidity than the general population (Leng 1996; Hooi 2001). The demand for therapeutic interventions has been increasing steadily with the advent of new treatments, such as angioplasty (Pell 1994), and an increasingly aging population. Currently 20-30% of angioplasties and bypasses fail within 12 months, requiring further

2 2 de 5 30/9/ :02 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 (Hafez 2003; Dormandy ; Pell 1994; Grigg 1988; Wilson 1996; Sayers 1993; Clement 2000). The major cause of failure of these treatments is restenosis (re-narrowing of the artery after treatment) 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 myriad of pharmaceutical agents, changes in technique, endothelial cell seeding of grafts, intravascular irradiation and gene therapy. As yet none of these techniques has had a significant impact on restenosis rates and none of them addresses the high morbidity and mortality in these patients from coronary or cerebrovascular disease (Yla-Herttuala 2000; Thompson 1994; Verin 1995; Hermans 1992). McCully first suggested that there might be an association between homocysteine, a non-essential amino-acid, and atherosclerosis (McCully 1969) when he observed that patients with a rare genetic enzyme deficiency, leading to elevated levels of homocysteine in the blood, developed atherosclerosis prematurely in their second and third decades. Although the initial work looked at levels of homocysteine in the blood >100 µmol/l, milder forms of hyperhomocysteinaemia of µmol/l caused by heterozygous abnormalities in the enzyme cystathionine-b-synthase (CBS), or thermolabile forms of methylene tetrahydrofolate reductase (MTHFR), abnormalities in the methionine synthase complex or dietary deficiencies of the vitamin co-factors folate, B12 and pyroxidine have been shown to be independent graded risk factors for all forms of cardiovascular disease, including deep vein thrombosis (Cattaneo ; McCully 1996; Malinow 1996; Boushey 1995; Refsum 1998; Clarke 1991; Taylor ; den Heijer 1998). Odds ratios are used to compare the risk of a subgroup of the population (e.g. receiving an intervention, or with particular metabolic characteristics) developing a disease against the known risk of developing the disease in the general public which is taken as 1.0. Therefore a ratio of >1.0 implies an increased risk within the subgroup; =1.0 that the intervention/metabolic characteristic has no impact on disease; and <1.0 that the intervention/metabolic characteristic has a protective effect. An odds ratio of 2.0 would therefore imply that the individual is at twice the risk of a normal individual. In an analysis of 27 studies, Boushey (Boushey 1995), calculated an odds ratio of a 5 micromol/l increase in plasma homocysteine for cardiovascular disease at 1.7; for cerebrovascular disease of 1.5; whilst the odds ratio for PAD was 6.8 (though this may reflect the small number of trials looking at PAD in this study). More recently there have been suggestions, based on experimental and clinical data suggesting that hyperhomocysteinaemia may also be a risk factor for myointimal hyperplasia (MIH) the cause of premature restenosis and failure of peripheral bypass grafts and angioplasties (Irvine 1996; Southern 1998; Mireskandari 1998; Iwama 1998; Currie 1996). Homocysteine provides a particularly attractive therapeutic option as blood levels of homocysteine can be easily normalised with the administration of a cheap, patient-acceptable, oral vitamin treatment (Clarke 1998), or betaine (Wilcken 1983; Wilcken 1985; Sakura 1998). In a recent meta-analysis of 12 randomised controlled trials published by the Homocysteine Lowering Trialists' Collaboration (Anonymous 1998), a daily supplement of mg folic acid was shown to reduce blood homocysteine levels by 25%, 0.5 mg of vitamin B12 daily reduced it by a further 7%, whilst the addition of 16.5 mg of vitamin B6 daily had no significant additional effect. It is important to note that these values are for a standardised pre-treatment plasma homocysteine concentration of 12 µmol/l (a value that many units feel falls within the normal range) and that the reduction with vitamin treatment was greater at higher pre-treatment plasma homocysteine levels. Tamoxifen (Anker 1995), oestrogen replacement therapy (van Baal ; van der Mooren 1998), and aminothiol drugs (Wiklund 1996), may also reduce plasma homocysteine levels, but would not be the first choice for treatment. In fact the implementation of a 'cardiovascular lifestyle' is particularly apt, with decreased red meat intake, increased fruit and fibre, low coffee consumption, smoking cessation and regular exercise (Refsum 1998). In vitro studies examining the pathological processes involved in atherosclerosis and restenosis have demonstrated empirical reductions in endothelial cell damage, vascular smooth muscle cell proliferation and inhibition of vasodilatation when any of the above named vitamins were added (Carmody ; Chao ; Constans ; Franken 1994; Malinow 1998; Woo ). At present it is not known whether lowering homocysteine affects the clinical outcome of the disease or reduces the rate of restenosis in patients. There is still wide variation on the value used as the cut-off for determining a pathological elevation in homocysteine, with many studies simply using any value above the 95th percentile for their control group. This has to led to the suggested cut-off point varying from 9-15 µmol/l in various studies (Hackam 2000; Ambrosi 1998). Also, there are currently no defined guidelines regarding recommended doses of these vitamins, or the level of homocysteine at which treatment should be initiated (Refsum 1998; Sakura 1998; Brattstrom 1996; Hackam 2000). Large-scale, long-term randomised controlled trials of such regimens in people at high risk are needed to answer this question and are currently underway. We feel that the vascular surgery community would benefit from a review and meta-analysis of current evidence regarding the role of homocysteine, and the value of treatment, in this large group of patients. No such systematic review focused on PAD currently exists. Discussion There are several studies and trials available which have confirmed the reduction of plasma homocysteine levels using folic acid, vitamin B12, vitamin B6 or betaine alone or in combination, in healthy volunteers or in patients presenting with venous thrombosis. The Homocysteine Lowering Trialists' Collaboration (Clarke 1998), in a meta-analysis of 12 randomised trials of folic acid-based supplements demonstrated that, after standardisation for homocysteine and blood folate concentrations, folic acid treatment reduced plasma homocysteine levels by 25% (95% CI 23-28%). The effects were similar in the range of folic acid mg/day. The higher the pre-treatment plasma homocysteine level and the lower the pre-treatment blood folate level, the greater the reduction in plasma homocysteine levels. Vitamin B12 (mean 0.5 mg/day) produced an additional 7% (3-10%) reduction, whilst vitamin B6 (mean 16.5 mg/day) did not produce any further significant reduction in plasma homocysteine concentrations. However, all of these trials were based on healthy volunteers or patients presenting with venous thrombosis and therefore did not meet the inclusion criteria of this review. De Jong (De Jong ), followed 232 patients with PAD, of whom 70% had normal homocysteine levels and 30% had hyperhomocysteinaemia which they treated with vitamin supplements (folic acid 5 mg/day + vitamin B6 250 mg/day). De Jong demonstrated that vitamin treatment significantly reduced plasma homocysteine concentrations (17.8 µmol/l µmol/l to 8.2 µmol/l µmol/l) and further suggested that the incidence of a new cardiovascular event was reduced in the hyperhomocysteinaemic group to that of the group with normal homocysteine levels after vitamin treatment. Vermeulen (Vermeulen 2000), demonstrated that vitamin treatment with folic acid 5 mg/day + vitamin B6 250 mg/day for two years in 78 healthy siblings of patients with early onset atherothrombotic disease, reduced fasting homocysteine concentration (from 14.7 µmol/l to 7.4 µmol/l vs 14.7 µmol/l to 12.0 µmol/l) and was associated with a decreased rate of abnormal exercise electrocardiography tests. However, there was no apparent effect of vitamin treatment on ABPIs or on carotid or femoral patency. Another study of asymptomatic adults with hyperhomocysteinaemia treated with folic acid 10 mg/day for eight weeks, demonstrated a significant improvement in endothelium dependant dilatation of the brachial artery (8.2% + 1.6% vs 6.0% + 1.3%, p<0.001) (Woo ). These studies suggest that vitamin treatment may improve peripheral arterial outcomes, however, without evidence from well conducted large randomised trials these results must be viewed with caution. In the excluded randomised trial (Garg ), the purpose of niacin treatment was to lower plasma lipids. With increasing evidence of the role of hyperhomocysteinaemia in PAD, the trialists extended their investigation to use a subset of patients and analyse the effect of the vitamin on plasma homocysteine concentrations. It is not a drug commonly used for the treatment of hyperhomocysteinaemia and therefore the result that niacin in fact increases plasma homocysteine levels is not extraordinary. This is a small study (52 patients), but based on these results, clinicians should be aware that in lowering lipids using niacin, they could potentially be increasing the effects of another risk factor. The authors of the trial have recommended the initiation of a further study looking at the combination of niacin and homocysteine-lowering treatment in patients with PAD. We are currently awaiting results. Treatment of the effects of PAD and subsequent treatment for the failure of such interventions involves a large section of our community and produces a huge burden on the NHS. Any measures to inhibit progression of the disease and delay the need for

3 3 de 5 30/9/ :02 intervention, and to decrease further the requirement for re-intervention could potentially have a considerable impact on modern hospital practice. Hyperhomocysteinaemia has been shown to be an independent risk factor for the progression of PAD. Measurement of plasma levels of homocysteine is now widely available, and studies in healthy patients have demonstrated that treatment with B vitamins in particular, can effectively and safely reduce plasma homocysteine to normal levels. However, the effect of such treatment in patients with PAD and those undergoing surgical or radiological intervention is currently unknown. Large trials of folic acid, vitamin B12, vitamin B6 and betaine alone or in combination in patients with PAD are urgently required. Reviewers' conclusions Implications for practice There are currently no available trials on the treatment of hyperhomocysteinaemia in patients with peripheral arterial disease. Implications for research There is a profound lack of data available for analysis looking at the effect of treating elevated plasma homocysteine levels on progression and outcomes for patients with peripheral arterial disease. Plasma homocysteine is easy to assay and, more importantly, easy and cheap to treat. Therefore the potential impact of such treatment on this large population is huge, both for the patient and financially for the NHS. Such research is urgently required. Tables Characteristics of excluded studies Study Reason for exclusion Constans Non randomised study of 18 patients with cardiovascular disease and hyperhomocysteinaemia (9 with PAD), treated with folic acid 5mg/day + vitamin B6 250mg/day for 3 months. Outcomes were changes in thcy, vwf and soluble thrombomodulin. De Jong Non randomised study of 70 patients with hyperhomocysteinaemia treated with folic acid 5mg/day + vitamin B6 250mg/day. Outcomes were changes in thcy and new cardiovascular events. Garg Randomised study of 52 patients with peripheral arterial disease treated with niacin to lower cholesterol. Plasma homocysteine levels were also measured. Characteristics of ongoing studies Study Trial name or title Participants Interventions Outcomes Starting date Contact information Notes Taylor References Homocysteine and Progression of Atherosclerosis Study Patients with symptomatic PAD (claudication, CLI) or cerebrovascular disease (TIA, CVA) with at least one unoperated vessel. Folic acid 4 mg/day versus placebo. ABPI, degree of carotid stenosis, death, clinical progression of cardiovascular disease. Phase I 1995 Phase II 1998 * indicates the major publication for the study References to studies excluded from this review Constans Constans J, Blann AD, Resplandy F, Parrot F, Renard M, Seigneur M. Three months supplementation of hyperhomocysteinaemic patients with folic acid and vitamin B6 improves biological markers of endothelial dysfunction. British Journal of Haematology ;107: De Jong Jong SC, Stehouwer CD, Berg M, Geurts TW, Bouter LM, Rauwerda JA. Normohomocysteinaemia and vitamin-treated hyperhomocysteinaemia are associated with similar risks of cardiovascular events in patients with premature peripheral arterial occlusive disease. A prospective cohort study. Journal of Internal Medicine ;246: Garg Garg R, Malinow R, Pettinger M, Upson B, Hunninghake D. Niacin treatment increases plasma homocyst(e)ine levels. American Heart Journal ;138: Ongoing studies Taylor Taylor LM, Moneta GL, Sexton GJ, Schuff RA, Porter JM. Prospective blinded study of the relationship between plasma homocysteine and progression of symptomatic peripheral arterial disease. Journal of Vascular Surgery ;29:8-19; discussion Additional references Ambrosi 1998 Ambrosi P, Garcon D, Riberi A, Habib G, Barlatier A, Kreitmann B. Association of mild hyperhomocysteinemia with cardiac graft vascular disease. Atherosclerosis 1998;138: Anker 1995 Anker G, Lonning PE, Ueland PM, Refsum H, Lien EA. Plasma levels of the atherogenic amino acid homocysteine in post-menopausal women with breast cancer treated with tamoxifen. International Journal of Cancer 1995;60: Anonymous 1998 Anonymous. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. British Medical Journal 1998;316: Bainton 1994 Bainton D, Sweetnam P, Baker I, Elwood P. Peripheral vascular disease: consequence for survival and association with risk factors in the

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