Vitamins Might Help After Heart Attacks

Benefit is limited to a subgroup of patients

By Jacob Schor, ND, FABNO

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Reference

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 to Assess Chelation Therapy (TACT). Am Heart J. 2018;195:70-77.

Objective

To assess the difference in outcomes in a subset of participants (those not taking statins) who either took a high-dose oral multivitamin (OMV) or a placebo as part of the larger TACT study.

Design

The Trial to Assess Chelation Therapy (TACT) was a clinical trial designed to assess outcomes of ethylenediaminetetraacetic acid (EDTA) chelation and an OMV in participants with a history of a cardiac event. A 2 by 2 multifactorial design was used to assess active use and placebo for chelation and the 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.

Participants

The initial TACT study included 1,708 patients age 50 or older who had experienced a heart attack at least 6 weeks prior to enrollment. The patients were randomized to treatment; 839 patients to chelation and 869 patients to placebo. In the initial study, 73% of the participants were taking statins and 27% (460) of the 1,708 were not. The current publication only included those who were not taking statins while in the study (n=460). Of these, almost half (n=244) of the participants were in the group that received high-dose vitamins while 51% (n=236) received placebo.

The average age of TACT participants was 65. The patients’ heart attacks had occurred an average of 4.6 years before enrollment. Of the participants, 18% were women and 9% were minorities; the rest (73%) were white men.

The original TACT study population (N=1708) had a high rate of diabetes (31%), prior coronary revascularizations (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 is closer to formulas used by integrative and naturopathic physicians. The formula (by XYMOGEN) can be viewed at this link and compared with multivitamins used in other large trials.

Outcome Measures

The primary endpoint of TACT was time to the first occurrence of any component of a composite endpoint: all-cause mortality, myocardial infarction (MI), stroke, coronary revascularization, or hospitalization for angina. The key secondary endpoint, a combination of cardiovascular death, MI, or nonfatal stroke was also calculated. These same endpoints were used in this current study’s analysis.

Key Findings

Primary endpoints occurred in 137 of these nonstatin study participants (30%). Only 23% (51 of 224) of those taking the OMV reached an endpoint event compared to 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).

In regard to the TACT secondary endpoint, the combination of cardiovascular mortality, stroke, or recurrent MI, the vitamin group still did significantly better (HR: 0.46; 95% CI: 0.28-0.75; P=0.002).

Practice Implications

Before examining these new data, we need to refresh our memories about the initial TACT study outcomes. In the initial trial patients received 40 treatments of intravenous EDTA chelation or placebo infusions, and either active OMV or placebo OMV, rendering 4 total arms to the study. The EDTA infusions were associated with a modest reduction in some cardiac events over the 5-year followup. Events occurred in 26% of the chelation group and 30% of the placebo group, which is an 18% reduction in subsequent cardiac events for those who received chelation. But it is not a striking 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 total 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).

The EDTA chelation may have helped a little but the benefit did not overly impress the researchers, especially considering the effort intravenous infusions involved.1

This information may provide ballast to an argument in favor of all MI patients taking a similar high-dose vitamin formula.

This current report is one of a pair that have looked at subgroup populations within the TACT study and report more significant effects.

This new report suggests that multivitamin use in nonstatin users had a clinically significant effect. This information may provide ballast to an argument in favor of all MI patients taking a similar high-dose vitamin formula. We need to keep in mind that this benefit was only seen in a subgroup analysis of patients who did not take statins. The majority of patients we encounter after a heart attack will tend toward high compliance with their physician’s suggestions and be taking a statin drug.

Also note that in participants taking statins there was no benefit from taking the vitamins. In fact, depending on the statistical methods used for analysis, there were modest trends for slightly better and slightly worse outcomes, with an HR of 1.20 (95% CI: 0.80-1.80; P=0.385] by the Anderson and Gill method and an HR of 0.94 (95% CI: 0.73-1.15; P=0.542] by the Wie, Lin, and Weissfeld model. This technicality is noted here as a caution against generalizing the data or extrapolating this information for all patients.

Here’s where it starts to get interesting. A second earlier subgroup analysis of the TACT data, published in 2014, examined the outcomes of diabetic patients in the initial trial. The authors reported surprising results. There was a marked reduction in events in the participants with diabetes who received chelation therapy. Over the 5-year study, patients with diabetes who were treated with EDTA had a 25% risk of reaching a primary endpoint vs 38% for 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 formation of advanced glycation end products (AGEs).3 These end products are now thought to be the precursors of diabetic atherosclerosis. There is evidence that links toxic metal accumulation and diabetes-related cardiovascular disease (CVD).2 Chelation and targeted reduction of advanced glycation end products should now be considered a strategy for treating this subpopulation of patients.

This is a fascinating idea. Formation of AGEs was recently described as causing “metabolic memory in diabetic patients” and is considered a key factor in the formation of atherosclerotic plaques in patients with diabetes.4 The AGEs disrupt the integrity of the vascular wall by damaging the endothelial barrier, triggering foam cell formation that leads to apoptosis and calcium deposition. Advanced glycation end products also initiate an inflammatory response leading to plaque formation. All of these processes lead to cardiovascular damage and eventual rupture and thrombosis.4

Measuring AGEs on the skin surface through 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 nonstatin users is relevant you must understand the AGEs link between diabetes and CVD. We are all familiar with the primary role of statins: cholesterol reduction. Less well-known is statins’ ability to ultimately block AGEs from causing heart damage.6 Thus, statin users have some level of protection against damage from AGEs. Patients with diabetes of course are far more vulnerable to AGEs. In patients without diabetes the statins offer protection. For diabetic patients who are not taking statins, the high-dose vitamins and antioxidants provide some, albeit to a lesser degree, measurable protection simply because the AGEs are higher in those with diabetes.

The simple take-home message from these studies is that statins’ benefits may be attributable to their ability to reduce AGEs. Diabetic patients may need all the protection they can get from AGEs, and possibly this should include chelation therapy. At the least we should pay particular attention to our diabetic patients who have CVD and consider testing them specifically for heavy metal burden. Lastly, patients who are not taking a statin after a cardiac event should certainly consider a high-dose multivitamin mineral formula such as the one used in the TACT trial.

About the Author

Jacob Schor ND, FABNO, is a graduate of National College of Naturopathic Medicine, Portland, Oregon, and now practices in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and is on the board of directors of the Oncology Association of Naturopathic Physicians. He is recognized as a fellow by the American Board of Naturopathic Oncology. He serves on the editorial board for the International Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR), and Integrative Medicine: A Clinician's Journal. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, the Townsend Letter, and Natural Medicine Journal, where he is the Abstracts & Commentary editor.

References

  1. Lamas GA, Goertz C, Boineau R, et al; TACT Investigators. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013;309(12):1241-1250.
  2. Escolar E, Lamas GA, Mark DB, et al. The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). Circ Cardiovasc Qual Outcomes. 2014;7(1):15-24.
  3. Diaz D, Fonseca V, Aude YW, Lamas GA. Chelation therapy to prevent diabetes-associated cardiovascular events. Curr Opin Endocrinol Diabetes Obes. 2018;25(4):258-266.
  4. Wang ZQ, Jing LL, Yan JC, et al. Role of AGEs in the progression and regression of atherosclerotic plaques [published online ahead of print July 10, 2018]. Glycoconj J.
  5. Ninomiya H, Katakami N, Sato I, et al. Association between subclinical atherosclerosis markers and the level of accumulated advanced glycation end-products in the skin of patients with diabetes [published online ahead of print June 30, 2018]. J Atheroscler Thromb.
  6. Chen M, Li H, Wang G, Shen X, Zhao S, Su W. Atorvastatin prevents advanced glycation end products (AGEs)-induced cardiac fibrosis via activating peroxisome proliferator-activated receptor gamma (PPAR-γ). Metabolism. 2016;65(4):441-453.