螯合+维生素使糖尿病患者心血管事件减半

达拉斯——美国心脏协会(AHA)年会上公布的TACT研究的最新分析结果显示，乙二胺四乙酸(EDTA)联合大剂量口服复合维生素具有加性获益，支持使用含EDTA的螯合方案在有心肌梗死(MI)史的患者中进行心血管事件的二级预防。与安慰剂+安慰剂相比，螯合+维生素的获益具有统计学显著性，并且获益程度具有临床重要意义，5年内为预防1起主要事件的需治数为12。在600多例糖尿病患者中，螯合+复合维生素的获益进一步增强，该组的需治数仅为5.5。


Gervasio Lamas医生

自1956年起，补充替代医学(CAM)实践中就使用EDTA螯合治疗动脉粥样硬化疾病，但并无任何支持证据。TACT研究的开展目的就是为了检验这一CAM方案。TACT是由西奈山医学中心医学主席Gervasio A. Lamas医生及其同事严谨开展的一项随机、双盲、2×2析因设计研究，在134个北美中心入组1708例既往发生MI的稳定患者。患者接受静脉螯合方案或安慰剂和大剂量口服复合维生素或安慰剂治疗。螯合方案包括30次每周1次的500-cc静脉输注，随后是另外10次间隔2~8周进行1次的输注。复合维生素组患者每天使用6个大的胶囊。

77%的患者完成30次输注，65%完成所有40次输注。3/4以上患者使用维生素至少1年，半数患者使用维生素至少3年。在所有患者中，指南推荐预防药物的使用率较高。主要复合终点是全因死亡、MI、卒中、冠状动脉血运重建、或心绞痛所致住院的5年发生率。既往报告显示，与安慰剂相比，螯合治疗使主要终点发生率显著降低18%(JAMA 2013;309:1241-50)，而大剂量复合维生素治疗使主要终点发生率降低11%，降幅不显著(Ann. Intern. Med., in press)。

在达拉斯AHA会议上，Lamas医生重点报告了421例接受螯合+复合维生素的患者(双重活性治疗组)和437接受安慰剂+安慰剂的患者(双重安慰剂组)的结果。双重活性治疗组和双重安慰剂组的主要复合终点发生率分别为26%和32%，反映的相对风险降幅为26%。因此，在螯合治疗基础上添加复合维生素治疗使风险降幅从18%增至26%。

预设的次要“硬”终点为心血管死亡、复发性MI或卒中的复合终点，在双重活性治疗组和双重安慰剂组中的发生率分别为9%和13%，反映的风险降幅为34%。

在糖尿病亚组患者中观察到的活性治疗结果更显著。单纯螯合治疗组糖尿病亚组患者的主要复合终点5年发生率为25%，而安慰剂组为38%，反映的相对风险降幅为41%。值得注意的是，螯合治疗组糖尿病亚组患者的全因死亡率为10%，而安慰剂组为16%，反映的相对风险降幅为43%；此外，前者的次要复合硬终点发生率为11%，而对照为17%。

螯合+复合维生素双重活性治疗组糖尿病亚组患者的获益甚至更佳，主要复合终点风险与双重安慰剂组对照者相比降低51%。

有关该方案的螯合和复合维生素成分的细节可参见此前发表的论文(Am. Heart J. 2012;163:7-12)。

有与会者询问，这一CAM治疗方案的获益的潜在机制是什么。Lamas医生迅速回应表示，目前尚不清楚，但可通过多种因素加以解释：1）EDTA是优异的金属螯合剂；2）在糖尿病患者中，高级糖基化终点的形成需要借助金属的催化活性才能创建氧物种和交联。

TACT研究由美国国立补充替代医学中心和国立心肺血液研究所支持。Lamas医生声明无相关经济利益冲突。

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By: BRUCE JANCIN, Cardiology News Digital Network

DALLAS – An EDTA-based chelation regimen for secondary prevention of cardiovascular events in patients with a history of myocardial infarction got a boost from a new TACT trial analysis showing additive benefit when chelation was accompanied by high-dose oral multivitamins.

"The benefit of chelation plus vitamins compared to placebo plus placebo is statistically significant and of a magnitude sufficient to be clinically important, with a number needed to treat of 12 to prevent one primary event over 5 years," Dr. Gervasio A. Lamas said in presenting the latest TACT (Trial to Assess Chelation Therapy) results at the American Heart Association scientific sessions.
 
Moreover, the benefit of chelation plus multivitamins was magnified in the more than 600 TACT participants with diabetes. The number needed to treat in that group was an impressively low 5.5, added Dr. Lamas, chairman of medicine at Mount Sinai Medical Center, Miami Beach, and chief of the Columbia University division of cardiology at Mount Sinai Medical Center.

Since 1956, EDTA (ethylenediaminetetraacetic acid) chelation has been utilized in complementary and alternative medical (CAM) practice to treat atherosclerotic disease, despite an absence of any supporting evidence. The TACT trial, sponsored by the National Institutes of Health, was conducted in order to put the CAM regimen to the test.

TACT was a rigorously conducted, randomized, double-blind, two-by-two factorial design trial in which 1,708 stable patients with a previous MI at 134 North American sites were placed on the intravenous chelation regimen or placebo and high-dose oral multivitamins or placebo. It was an arduous regimen designed to replicate what’s being used in CAM practice. The chelation regimen consisted of 30 weekly 500-cc intravenous infusions followed by another 10 infusions at 2- to 8-week intervals. Patients randomized to the multivitamin arm took 6 capsules per day.

"The capsules are large. They’re a bear to take," according to the cardiologist.

Nevertheless, 77% of patients completed 30 infusions and 65% completed all 40. And more than three-quarters of patients took the vitamins for at least a year, and half of participants did so for at least 3 years. All participants had high rates of guideline-recommended preventive medications usage.

The primary composite endpoint was the 5-year rate of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for angina. As previously reported, chelation therapy resulted in a statistically significant 18% reduction in the primary endpoint relative to placebo (JAMA 2013;309:1241-50), while high-dose multivitamin therapy led to a nonsignificant 11% reduction (Ann. Intern. Med., in press).

At the Dallas AHA meeting, Dr. Lamas focused on the results in the 421 subjects randomized to both chelation and multivitamins as compared to the 437 patients on double placebo. The primary composite endpoint occurred in 26% of patients on double active therapy and 32% on double placebo, representing a 26% reduction in relative risk. Thus, the addition of multivitamin therapy increased the magnitude of risk reduction in patients on chelation therapy from 18% to 26%.

The prespecified secondary ‘hard’ endpoint, a composite of cardiovascular death, recurrent MI, or stroke, occurred in 9% of participants on chelation plus multivitamins versus 13% of those on dual placebo, for a 34% reduction in risk.

The results of active therapy were even more impressive in patients with diabetes. They had a 41% reduction in risk of the primary composite endpoint with chelation alone compared with placebo, with a 5-year incidence of 25%, compared with 38% in controls. Notably, diabetic patients’ all-cause mortality with chelation therapy was 10%, compared with 16% with placebo, a 43% reduction in relative risk, while their rate of the secondary composite hard endpoint was 11%, versus 17% in controls.

The diabetic subgroup assigned to dual active therapy with both chelation and multivitamins fared even better, with a 51% decrease in the primary composite endpoint compared with controls on double placebo.

"A lot more work needs to be done on this before we can bring it to the bedside, but this is certainly suggestive data," Dr. Lamas said in summary.

Specific details on the chelation and multivitamin components of the regimen are available in an earlier publication (Am. Heart J. 2012;163:7-12).

Asked about the proposed mechanism of benefit of this CAM therapy, the cardiologist was quick to reply, "The simple answer is we do not really know what is happening."

Plausible hypotheses abound, though. One of the leading ones has to do with the fact that EDTA is a superb metal chelator.

"Heavy metals are associated very well in epidemiologic data with cardiovascular events; in particular, lead, cadmium, arsenic, sometimes mercury, and others that have less evidence, like tungsten and antimony. They’re all in our environment. Any of us who are of an age to have been exposed to leaded gasoline have lead in our bones. If we get an infusion of EDTA, we’ll have lead in our urine. It’s just the way it is. And as you get older and become osteoporotic, that lead starts getting released," Dr. Lamas explained.

In addition, in diabetic patients the formation of advanced glycation endpoints requires catalytic activity by metals in order to create oxygen species and cross linkage, he continued.

The TACT trial was sponsored by the National Center for Complementary and Alternative Medicine and the National Heart, Lung, and Blood Institute. Dr. Lamas reported having no relevant financial interests.