Chelation therapy for atherosclerotic cardiovascular disease.

BACKGROUND: Chelation therapy is promoted and practiced around the world as a form of alternative medicine in the treatment of atherosclerotic cardiovascular disease. It has been suggested as a safe, relatively inexpensive, non-surgical method of restoring blood flow in atherosclerotic vessels. However, there is currently limited high-quality, adequately-powered research informing evidence-based medicine on the topic, specifically regarding clinical outcomes. Due to this limited evidence, the benefit of chelation therapy remains controversial at present. This is an update of a review first published in 2002. OBJECTIVES: To assess the effects of ethylene diamine tetra-acetic acid (EDTA) chelation therapy versus placebo or no treatment on clinical outcomes among people with atherosclerotic cardiovascular disease. SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register to 6 August 2019. We searched the bibliographies of the studies retrieved by the literature searches for further trials. SELECTION CRITERIA: We included studies if they were randomised controlled trials of EDTA chelation therapy versus placebo or no treatment in participants with atherosclerotic cardiovascular disease. The main outcome measures we considered include all-cause or cause-specific mortality, non-fatal cardiovascular events, direct or indirect measurement of disease severity, and subjective measures of improvement or adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality using standard Cochrane procedures. A third author considered any unresolved issues, and we discussed any discrepancies until a consensus was reached. We contacted study authors for additional information. MAIN RESULTS: We included five studies with a total of 1993 randomised participants. Three studies enrolled participants with peripheral vascular disease and two studies included participants with coronary artery disease, one of which specifically recruited people who had had a myocardial infarction. The number of participants in each study varied widely (from 10 to 1708 participants), but all studies compared EDTA chelation to a placebo. Risk of bias for the included studies was generally moderate to low, but one study had high risk of bias because the study investigators broke their randomisation code halfway through the study and rolled the placebo participants over to active treatment. Certainty of the evidence, as assessed by GRADE, was generally low to very low, which was mostly due to a paucity of data in each outcome's meta-analysis. This limited our ability to draw any strong conclusions. We also had concerns about one study's risk of bias regarding blinding and outcome assessment that may have biased the results. Two studies with coronary artery disease participants reported no evidence of a difference in all-cause mortality between chelation therapy and placebo (risk ratio (RR) 0.97, 95% CI 0.73 to 1.28; 1792 participants; low-certainty). One study with coronary artery disease participants reported no evidence of a difference in coronary heart disease deaths between chelation therapy and placebo (RR 1.02, 95% CI 0.70 to 1.48; 1708 participants; very low-certainty). Two studies with coronary artery disease participants reported no evidence of a difference in myocardial infarction (RR 0.81, 95% CI 0.57 to 1.14; 1792 participants; moderate-certainty), angina (RR 0.95, 95% CI 0.55 to 1.67; 1792 participants; very low-certainty), and coronary revascularisation (RR 0.46, 95% CI 0.07 to 3.25; 1792 participants). Two studies (one with coronary artery disease participants and one with peripheral vascular disease participants) reported no evidence of a difference in stroke (RR 0.88, 95% CI 0.40 to 1.92; 1867 participants; low-certainty). Ankle-brachial pressure index (ABPI; also known as ankle brachial index) was measured in three studies, all including participants with peripheral vascular disease; two studies found no evidence of a difference in the treatment groups after three months after treatment (mean difference (MD) 0.02, 95% CI -0.03 to 0.06; 181 participants; low-certainty). A third study reported an improvement in ABPI in the EDTA chelation group, but this study was at high risk of bias. Meta-analysis of maximum and pain-free walking distances three months after treatment included participants with peripheral vascular disease and showed no evidence of a difference between the treatment groups (MD -31.46, 95% CI -87.63 to 24.71; 165 participants; 2 studies; low-certainty). Quality of life outcomes were reported by two studies that included participants with coronary artery disease, but we were unable to pool the data due to different methods of reporting and varied criteria. However, there did not appear to be any major differences between the treatment groups. None of the included studies reported on vascular deaths. Overall, there was no evidence of major or minor adverse events associated with EDTA chelation treatment. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to determine the effectiveness or ineffectiveness of chelation therapy in improving clinical outcomes of people with atherosclerotic cardiovascular disease. More high-quality, randomised controlled trials are needed that assess the effects of chelation therapy on longevity and quality of life among people with atherosclerotic cardiovascular disease.

Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the Folic Acid for Vascular Outcome Reduction in Transplantation trial.

BACKGROUND: Kidney transplant recipients, like other patients with chronic kidney disease, experience excess risk of cardiovascular disease and elevated total homocysteine concentrations. Observational studies of patients with chronic kidney disease suggest increased homocysteine is a risk factor for cardiovascular disease. The impact of lowering total homocysteine levels in kidney transplant recipients is unknown. METHODS AND RESULTS: In a double-blind controlled trial, we randomized 4110 stable kidney transplant recipients to a multivitamin that included either a high dose (n=2056) or low dose (n=2054) of folic acid, vitamin B6, and vitamin B12 to determine whether decreasing total homocysteine concentrations reduced the rate of the primary composite arteriosclerotic cardiovascular disease outcome (myocardial infarction, stroke, cardiovascular disease death, resuscitated sudden death, coronary artery or renal artery revascularization, lower-extremity arterial disease, carotid endarterectomy or angioplasty, or abdominal aortic aneurysm repair). Mean follow-up was 4.0 years. Treatment with the high-dose multivitamin reduced homocysteine but did not reduce the rates of the primary outcome (n=547 total events; hazards ratio [95 confidence interval]=0.99 [0.84 to 1.17]), secondary outcomes of all-cause mortality (n=431 deaths; 1.04 [0.86 to 1.26]), or dialysis-dependent kidney failure (n=343 events; 1.15 [0.93 to 1.43]) compared to the low-dose multivitamin. CONCLUSIONS: Treatment with a high-dose folic acid, B6, and B12 multivitamin in kidney transplant recipients did not reduce a composite cardiovascular disease outcome, all-cause mortality, or dialysis-dependent kidney failure despite significant reduction in homocysteine level.

Predictores de mortalidad por cardiopatía isquémica en un hospital de Asturias / Predictors of mortality by ischemia cardiophaty at a hospital in Asturias

Objetivos: La mortalidad por cardiopatía isquémica es una de las principales causas de muerte en nuestro país, a pesar de su descenso. Quisimos identificar los factores pronósticos de mortalidad en los pacientes ingresados por isquemia miocárdica en un hospital de Asturias. Métodos: Estudio retrospectivo de 484 pacientes con cardiopatía isquémica que fueron admitidos en el Hospital Álvarez Buylla del 1/1/1999 al 31/12/2001. Fueron analizados: sexo, edad, vivir solo, factores de riesgo cardiovascular, pruebas complementarias y mortalidad. Se realizó tanto análisis univariante como multivariante. Resultados: De los pacientes del estudio, la mortalidad fue el 10,5% (51). Los fallecidos presentaban con mayor frecuencia que los supervivientes las siguientes variables: edad > 60 años, ACV, diabetes e hiperglucemia, insuficiencia renal crónica, creatinina alta (> 1,2 mg/dl), ácido úrico (> 7,2 mg/dl) y fibrinógeno (> 600 mg/dl). Fue más frecuente ser fumador entre los supervivientes que en los fallecidos. En el análisis multivariante las variables predictoras de mortalidad fueron vivir solo y la tensión arterial sistólica. Conclusiones: La mortalidad fue mayor en los ancianos, diabéticos, pacientes con IRC, ACV, hiperglucemia y elevación de creatinina, ácido úrico y fibrinógeno. Y en la regresión logística los factores independientes de mortalidad fueron: vivir solo y la tensión arterial sistólica (AU)

Aim: The mortality by ischemic cardiophaty is one of the mean causes of mortality in our country in spite of its decrease. We want to identify the prognostic factors of mortality of myocardial ischemia in patients admitted at a hospital in Asturias. Methods: A retrospective study of 484 patients with ischemic cardiophaty who were admitted to the Hospital Álvarez Buylla from 1/1/1999 to 31/12/2001. They were analyzed regarding: sex, age, to live along, cardiovascular risk factors, complementary tests and mortality. They were studied and analyzed by univariate and multivariate techniques. Results: Of the study patients, mortality was 10, 5% (51). The dead patients had a greater proportion of the following parameters as compared with survivors: age > 60 years, stroke, diabetes and hyperglycaemia, chronic renal failure, high creatinina (>1.2 mg/dl), uric acid (> 7.2 mg/dl) and fibrinogen (> 600 mg/dl). To smoke were more frequent in the survivors than in the dead. In the multivariate analysis the predictors of mortality were: to live along and systolic blood pressure. Conclusions: The mortality was higher in elderly, diabetics, stroke, chronic renal failure, hyperglycaemia, high creatinina, uric acid and fibrinogen. In logistic regression independent factors for death were: to live along and systolic blood pressure (AU)

Oxidative stress, alpha-tocopherol therapy, and atherosclerosis.

Atherosclerosis is the leading cause of morbidity and mortality in the United States. Evidence suggests that antioxidants, especially alpha-tocopherol (AT), have potential benefits with respect to cardiovascular disease. AT has been shown to decrease lipid peroxidation, to inhibit platelet adhesion, aggregation, and smooth muscle cell proliferation, to exert anti-inflammatory effects on monocytes, and to improve endothelial function. Low levels of AT are related to a higher incidence of cardiovascular disease and increased intakes appear to afford protection against cardiovascular disease. Although clinical trials with AT supplementation to date have been conflicting, the majority of evidence supports a benefit for AT supplementation in patients with pre-existing cardiovascular disease. Clearly, more clinical trials are required in individuals with increased oxidative stress before a definitive recommendation can be made with respect to AT supplementation in atherosclerosis.

The antiatherosclerotic effect of Allium sativum.

In a randomized, double-blind, placebo-controlled clinical trial, the plaque volumes in both carotid and femoral arteries of 152 probationers were determined by B-mode ultrasound. Continuous intake of high-dose garlic powder dragees reduced significantly the increase in arteriosclerotic plaque volume by 5-18% or even effected a slight regression within the observational period of 48 months. Also the age-dependent representation of the plaque volume shows an increase between 50 and 80 years that is diminished under garlic treatment by 6-13% related to 4 years. It seems even more important that with garlic application the plaque volume in the whole collective remained practically constant within the age-span of 50-80 years. These results substantiated that not only a preventive but possibly also a curative role in arteriosclerosis therapy (plaque regression) may be ascribed to garlic remedies.

Randomized controlled trial of gamma-linolenic acid and eicosapentaenoic acid in peripheral arterial disease.

BACKGROUND AND AIMS: epidemiological studies suggest polyunsaturated fatty acids protect against the development of atherosclerosis. The aim of this study was to perform a randomized controlled trial of gamma-linolenic and eicosapentaenoic acids in patients with lower limb atherosclerosis. Main outcome measures were: cholesterol and lipoprotein concentrations; haemostatic and rheological variables; the ankle brachial pressure index; walking distance; and cardiovascular events and death. METHODS: 120 men and women with stable intermittent claudication were randomized to 2 years treatment with either a combination of gamma-linolenic and eicosapentaenoic acids, or placebo. RESULTS: 39 (65.0 cent) of those taking fatty acids and 36 (60.0 cent) of those taking placebo completed the trial. Lipid concentrations did not differ significantly during the trial. In those taking fatty acids, haematocrit was significantly higher than in the placebo group after 6 months (46.1 cent compared with 44.6 cent, P 0.05). CONCLUSIONS: a combination of polyunsaturated fatty acids produced a statistically significant reduction in systolic blood pressure, but no other significant benefits on risk factors. The trend towards fewer coronary events in those taking fatty acids warrants further investigation.

Atherosclerosis in Alaska Natives and non-natives.

Low mortality from coronary heart disease (CHD) among Eskimos has been attributed to less atherosclerosis in the coronary arteries because of a high dietary intake of omega-3 fatty acids. Other investigators attribute this low mortality to the fact that Eskimos have a high mortality from other causes before middle age, when CHD is common. However, most studies have been epidemiological, either by death-certificate review or risk-factor evaluation. We evaluated the extent of atherosclerotic lesions in the coronary arteries and aortas from Alaska Natives. Standardised comparisons between samples from 103 Native and 101 non-native residents show that the extent of raised lesions increases with age in both groups, but the prevalence of raised lesions in native specimens was consistently lower than in those from non-natives. This difference was statistically significant. The data suggest that the differences in CHD mortality between Alaska Natives and non-natives are, at least in part, the result of less atherosclerosis in natives.

Bee-sting diseases: Who is at risk? What is the treatment?

Many of the large number of people who are stung each year by bees experience frightening systemic reactions, but the vast majority of such reactions are not life-threatening. There is no evidence that the very few who die as a result of a bee sting come from the pool of those who once before sustained a systemic reaction. On the contrary, no reaction at all may be a more ominous predictor of a lethal outcome on a subsequent sting. Death comes about through multiple mechanisms, and not through anaphylaxis alone. Like most cases of sudden death, underlying coronary atherosclerosis appears to be the principal mechanism. External factors that affect mortality include environmental temperature and site of sting. In general, however, because the numbers of deaths are so small, death comes unpredictably, and those at risk have not been identified. Immunotherapy, whether with venom or whole-body extract, has not been proven to prevent death from a bee sting.

Renin as a risk factor for atherogenesis. Effects of hypercholesterolemia and two-kidney--one-clip hypertension in the rabbit.

Four groups of New Zealand rabbits were used to study the effect of plasma renin activity (PRA) on atherogenesis. Control groups were fed normal rabbit chow (Group I) or chow supplemented with 0.25% cholesterol and 0.75% corn oil (Group II). The two-kidney--one-clip (2K-1C) hypertensive model was produced in 2 additional groups; Group III (normal diet) and Group IV (atherogenic diet). The latter 2 groups were subgrouped according to PRA levels. Each group was examined over a 7-month period. Group II became hyperlipidemic and developed extensive lipoidal vascular lesions. Mean arterial pressure remained normal throughout the experimental period; PRA fell below normal. Group III and Group IV rabbits developed sustained hypertension irrespective of circulating PRA. The atheromas of Group III were predominantly microscopic and fibromuscular; the extent of aortic and coronary artery involvement was independent of renin response. The most extensive and complicated atheromas were seen in the 2K-1C rabbits consuming the atherogenic diet (Group IV). The lesions were mostly lipoidal, although some were fibromuscular. These results demonstrated that cardiovascular lesions and atherogenesis were exacerbated in the 2K-1C rabbits on a high cholesterol diet; however, PRA was excluded as the cause.

[Interest of the local regional anesthesia in lumbar sympathectomy (author's transl)]. / Intért de l'anesthésie loco-régionale dans la sympathectomie lombaire

Authors report 163 cases of lumbar sympathectomy they did under local anesthesia from 1968 to 1975. All were older--and poor risk patients. Approach was always lumbar with resection of distal part of the 12th rib. If good care is taken to do anesthesia infiltration of the five lower intercostal nerves and of the 1st and 2nd posterior lumbar nerves, anesthesia is quite good, and surgery easy and painless. The main advantages are:--easy excision of the first lumbar sympathetic node through this lumbar approach;--low lethality as far as authors consider almost no contra-indications;--very fast recovery of bowel movements;--immediate oral feeding which is important for diabetic patients;--no tracheal, bronchial or lung postoperative infestation or trouble. Patients have never had any trouble (convulsions) from lignocaine since gardenal is given in pre-anesthesia.

Prognostic and therapeutic considerations in pure hypertension vs hypertension and superimposed arteriosclerosis.

In summary, a prognostic and therapeutic evaluation of 227 patients first seen from 1967 to the end of 1969 with a follow-up of 4-7 years was made. The results are indeed depressing. In spite of close follow-up and systematic treatment with modern antihypertensive agents, the mortality of patients having hypertension with superimposed arteriosclerosis was 27% (15 to 56) for males as contrasted to 3% (2 of 75) for females. Since the last casual blood pressure in both living and deceased patients of the mixed group were similar, the level of blood pressure following treatment could not be incriminated for the deceased patients. An exaggerated systolic and pulse pressure cold pressor response emerged as an important indicator of presence of arteriosclerosis alone. When hypertension and arteriosclerosis coexisted there was also exaggeration in diastolic cold pressor response. A further exaggeration in systolic and diastolic cold pressor response was seen in the decreased as compared to living male patients, a finding which appears to have grave prognostic significance for coronary heart disease and stroke. Thus a marked exaggeration in both systolic and diastolic cold pressor response in males might prove to be the single most important predictor of premature death from atherosclerotic vascular disease. A further analysis of the deceased male patients having hypertension and superimposed arteriosclerosis, indicates that treatment of hypertension may prevent oeath from stroke but not form coronary heart disease. Two-thirds of the deaths occur suddenly and only one-third of the deceased patients reached the hospital befor dying. In view of these distressing findings a plea for early detection and treatment of hypertension, prior to the development of superimposed arteriosclerotic changes, particularly in males, is made.