Suche
Relation
Issa OM, Roberts R, Mark DB, et al. Effect of high-dose oral multivitamins and minerals in participants not treated with statins in the Randomized Trial for the Evaluation of Chelation Therapy (TACT).Am heart J. 2018;195:70-77.
Objective
To assess the difference in outcomes in a subset of participants (not taking statins) who took either a high-dose oral multivitamin (OMV) or a placebo as part of the larger TACT trial.
Draft
The Trial to Assess Chelation Therapy (TACT) was a clinical trial evaluating the outcomes of ethylenediaminetetraacetic acid (EDTA) chelation and OMV in participants with a history of a cardiac event. A 2-by-2 multifactorial design was used to evaluate active use and placebo for chelation and OMV, consisting of 4 arms: 1) active chelation and active OMV; 2) active chelation and placebo OMV; 3) placebo chelation and active OMV; and 4) placebo chelation and placebo OMV.
Participant
The initial TACT study included 1,708 patients aged 50 years and older who had had a heart attack at least 6 weeks before enrollment. Patients were randomized to treatment; 839 patients with chelation and 869 patients with placebo. In the first study, 73% of participants were taking statins and 27% (460) of the 1,708 were not. The current publication included only those who were not taking statins during the study (n=460). Of these, almost half (n=244) of participants were in the group that received high-dose vitamins, while 51% (n=236) received placebo.
The average age of TACT participants was 65 years. The patients' heart attacks had occurred an average of 4.6 years before admission. Of the participants, 18% were women and 9% were minorities; the remainder (73%) were white men.
The original TACT study population (N=1708) had high rates of diabetes (31%), previous coronary revascularization (83%), and use of medications such as aspirin (84%), beta-blockers (72%), and statins (73%).
Study medication and dosage
The details of the vitamin formula used in the TACT study are closer to formulas used by integrative and naturopathic physicians. The formula (from XYMOGEN) can be viewed at this link and compared to multivitamins used in other large studies.
Target parameters
The primary endpoint of TACT was time to first occurrence of one component of a composite endpoint: all-cause mortality, myocardial infarction (MI), stroke, coronary revascularization, or hospitalization for angina. The key secondary endpoint, a composite of cardiovascular death, myocardial infarction, or nonfatal stroke, was also calculated. The same endpoints were used in the analysis of this current study.
Key insights
Primary endpoints occurred in 137 of these non-statin subjects (30%). Only 23% (51 of 224) of those taking OMV achieved an endpoint event, compared with 36% (86 of 236) of those in the placebo groups. These differences were statistically significant (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.44–0.87;P=0.006).
On the secondary endpoint TACT, the combination of cardiovascular mortality, stroke or recurrent myocardial infarction, the vitamin group still performed significantly better (HR: 0.46; 95% CI: 0.28–0.75;P=0.002).
Practice implications
Before we examine these new data, we need to refresh our memories of the initial results of the TACT study. In the first study, patients received 40 treatments of intravenous EDTA chelation or placebo infusions and either active OMV or placebo OMV, giving a total of 4 arms for the study. EDTA infusions were associated with a modest reduction in some cardiac events over the 5-year follow-up period. Events occurred in 26% of the chelation group and 30% of the placebo group, representing an 18% reduction in subsequent cardiac events in those who received chelation. But it's not a noticeable difference. The primary endpoint occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (HR: 0.82; 95% CI: 0.69-0.99;P=0.035). There was no effect on all-cause mortality with 87 deaths (10%) in the chelation group and 93 deaths (11%) in the placebo group (HR: 0.93; 95% CI: 0.70-1.25;P=0.64).
EDTA chelation may have helped a little, but the benefit hasn't overly impressed researchers, especially considering how strenuous intravenous infusions are.1
This information may provide an argument for all MI patients to take a similar high-dose vitamin formula.
This current report is one of two reports that examined subgroup populations within the TACT trial and reported more significant effects.
This new report suggests that taking multivitamins had a clinically significant effect in non-statin users. This information may provide an argument for all MI patients to take a similar high-dose vitamin formula. We must keep in mind that this benefit was only seen in a subgroup analysis of patients not taking statins. The majority of patients we encounter after a heart attack tend to be highly compliant with their doctor's recommendations and take a statin medication.
Also note that for participants taking statins, there was no benefit from taking the vitamins. In fact, there were modest trends for slightly better and slightly worse outcomes depending on the statistical methods used for the analysis, with an HR of 1.20 (95% CI: 0.80-1.80;P=0.385] using the method of Anderson and Gill and a HR of 0.94 (95% CI: 0.73-1.15;P=0.542]according to the model of Wie, Lin and Weissfeld. This technical feature is mentioned here as a warning not to generalize the data or extrapolate this information for all patients.
This is where things start to get interesting. A second earlier subgroup analysis of the TACT data, published in 2014, examined the outcomes of diabetics in the first study. The authors report surprising results. There was a significant reduction in events among participants with diabetes who received chelation therapy. During the 5-year study, patients with diabetes treated with EDTA had a 25% risk of achieving a primary endpoint versus 38% in the non-EDTA group (HR: 0.59; 95% CI: 0.44-0.79;P<0.001).2
The explanation now put forward to explain the TACT and diabetes results is that metal chelation reduces the metal-catalyzed oxidation reactions that promote the formation of advanced glycation end products (AGEs).3These end products are now considered precursors of diabetic arteriosclerosis. There is evidence of a link between the accumulation of toxic metals and diabetes-related cardiovascular disease (CVD).2Chelation and targeted reduction of advanced glycation end products should now be considered as a strategy to treat this subpopulation of patients.
That's a fascinating idea. The formation of AGEs has recently been described as causing “metabolic memory in diabetics” and is considered a key factor in the formation of atherosclerotic plaques in patients with diabetes.4The AGEs disrupt the integrity of the vessel wall by damaging the endothelial barrier and triggering the formation of foam cells, leading to apoptosis and calcium deposition. End products of advanced glycation also trigger an inflammatory response that leads to plaque formation. All of these processes lead to cardiovascular damage and ultimately rupture and thrombosis.4
Measuring AGEs on the skin surface by simply counting “age spots” is significantly associated with internal measurements of cardiovascular disease and heart function in patients with diabetes.5
To understand whether the results of this current study on non-statin users are relevant, it is important to understand the association between diabetes and AGE cardiovascular disease. We all know the main job of statins: lowering cholesterol. Less known is the ability of statins to ultimately prevent AGEs from causing heart damage.6Therefore, statin users have some protection from harm caused by AGEs. Patients with diabetes are of course much more susceptible to AGEs. Statins offer protection in patients without diabetes. For diabetics not taking statins, the high-dose vitamins and antioxidants provide some, although less measurable, protection simply because AGEs are higher in diabetics.
The simple take-home message from these studies is that the benefits of statins may be due to their ability to reduce AGEs. Diabetics may need all the protection they can get from AGEs, and perhaps this should include chelation therapy. At the very least, we should pay special attention to our diabetics with cardiovascular disease and consider testing them specifically for heavy metal contamination. Finally, patients not taking a statin following a cardiac event should definitely consider a high-dose multivitamin-mineral formula such as that used in the TACT trial.