Complementary and Alternative Medical Therapy in Cardiovascular Care: Introduction
With publication of the consensus paper on complementary and alternative medicine (CAM) practices in cardiovascular care, the American College of Cardiology (ACC) has pointed cardiologists to a unique dimension of health care concepts, research, and practice.1 As the trend among patients to use CAM therapies has risen exponentially,2 growing professional interest in CAM therapies as adjuncts to the high-tech world of cardiovascular care has been paralleled by concerns about exaggerated claims of efficacy, as well as by quackery and frank toxicity across the largely unregulated pantheon of CAM practices. The combination of relatively unrestricted access to Internet information and widespread cultural interest in self-empowerment and holistic paradigms of health care in the lay public constitute a mandate for cardiologists to become better informed about CAM therapeutics. At the very least such education will support more thoughtful, less defensive dialogue between physicians and patients. At best, cardiologists knowledgeable about CAM therapies will be better positioned to encourage and envision both the many necessary research directions and more integrated clinical strategies necessary for the advance of optimal data-driven practice in modern cardiovascular care.3
Although many CAM therapies have been practiced for thousands of years, the scientific literature is still immature by modern standards in most of these areas. The introduction to the ACC consensus document observes that “Topics chosen for coverage by Expert Consensus Documents are so designed because the evidence base and experience with technology or clinical practice are not considered sufficiently well developed to be evaluated by the formal ACC/AHA [American Heart Association] Practice Guidelines process.”1 Ambiguous nomenclature, lack of practice certification standards, and absence of quantitative profiles of active agents in consumables such as herbal remedies confound evaluation of safety and efficacy in specific heart disease populations. As with other areas of immature literature in medical practices, investigator bias, reporting bias, and publisher bias also confound the interpretation of available data.
Even more essential to the actual integration of modern medical technology and practice with CAM therapies is the challenge to engage whole new paradigms, both of healing and of how research defining optimal healing might be conducted. The modern scientific tendency to articulate biochemical mechanisms and translate them into clinical practice therapeutics tested by clinical protocols is potentially fatally reductionist with regard to holistic systems that view interaction with the body as approximately 20% of the mind–body–spirit process that actually accomplishes the transformation of suffering called healing.4,5 Research in CAM therapies in cardiovascular care must balance standards for clinical trial designs or mechanistic studies with sensitivity to the cultural assumptions of how these therapies actually work.6–9
With the growth of the National Center for Complementary and Alterative Medicine (NCCAM) at the National Institutes of Health, more comprehensive attention and research resources have been directed to sort through some of these issues and to develop the requisite infrastructure. With even the terms alternative, complementary, integrative, and others still in flux, in this chapter the authors have taken selected therapies and references from the general topical framework that NCCAM has developed for CAM therapies10 with a focus, where possible, specifically on cardiovascular applications across NCCAM’s five key treatment areas: biologically based practices, manipulative and body-based practices, energy medicine, mind–body medicine, and whole medical systems.
Biologically Based Practices: Selected Botanicals and Dietary Supplements
Herbal remedies, vitamins and food-substance derivatives, teas, alcohol, nuts, soy, and other specific dietary constituents have a long-standing place in health care as a predominantly culturally based pharmacopoeia. In most cases the initial scientific suggestion of benefit has come from epidemiologic comparisons of different cohorts, with interpretation limited both by different endogenous rates of disease and varied levels of consumption of the substance of interest, which itself can have varied concentrations of active compounds. Early hypothesis-generating studies are typically supported by subsequent case-control studies and, in some cases, larger prospective cohort studies. In cardiovascular applications, surrogate end points in the smaller prospective studies include effects on low-density-lipoprotein cholesterol (LDL-C), platelet function, endothelial function, and immune/inflammatory activity. In some cases larger randomized, controlled trials have been conducted using clinical outcome end points. Studies of herbal medicines have suffered from poorly characterized interventions and often studies of short duration. To improve the reporting of randomized controlled trials using herbal medicine interventions, members of the Consolidated Standards of Reporting Trials (CONSORT) group have developed a checklist to assist investigators in the design and reporting of clinical trials using herbal medicines.11
The medicinal use of botanicals originated more than 7000 years ago; the written history spans more than 3500 years.12 Prescribed by great ancient physicians such as Hippocrates, Theophrastus, and Pliny, botanicals were catalogued and illustrated, with specific indications noted for each active plant. Intact botanicals were used singly or in combination until the 19th century, when the identification and isolation of individually active compounds was conceived and accomplished. Approximately 25% of pharmaceuticals prescribed today are derived from plant sources. At the same time, there has been a rekindling of consumer interest in the use of natural whole-plant products. A significant result of this public interest and demand for access to herbal products was the passage of the Dietary Supplement Health and Education Act (DSHEA) of 1994. Herbs, vitamins, minerals, and proteins were classified as dietary supplements. Manufacturers are allowed to describe the effects of these supplements on “structure or function” of the body or the “well-being” achieved by consuming the dietary ingredient. To use these claims, manufacturers must have substantiation that the statements are truthful and not misleading, and the product label must bear the statement: “This statement has not been evaluated by the Food and Drug Administration.” Furthermore, neither good manufacturing practices nor labeling certifying concentrations of active ingredients or bioavailability have been required for DSHEA products. As a result, independent examination has revealed great inconsistency between product labeling and actual compound concentration.13 In this setting, safety concerns with potential adulteration of supplements with active prescription compounds, contamination of preparations, and herb–herb and herb–drug interactions are significant.14,15 Research into the safety and efficacy of botanical compounds has been hampered by this lack of standardization.16 Recently the Food and Drug Administration (FDA) has reconsidered these issues, and in July 2007, the FDA announced a final rule establishing regulations to require current good manufacturing practices (CGMPs) for dietary supplements and finished products. The regulations establish the CGMPs needed to ensure quality throughout the manufacturing, packaging, labeling, and storing of dietary supplements. The aim of the final rule is to prevent inclusion of the wrong ingredients, too much or too little of a dietary ingredient, contamination by substances such as natural toxins, bacteria, pesticides, glass, lead, and other heavy metals, as well as improper packaging and labeling.
In December 2006, the Dietary Supplement and Nonprescription Drug Consumer Protection Act (the “AER bill,” Public Law 109-462) was passed by Congress. This bill requires manufacturers of dietary supplements and over-the-counter (OTC) products to submit serious adverse event reports (SAERs) to the FDA. Companies are required to include contact information on their products’ labels to aid consumers in reporting such events. Companies must notify the FDA of SAERs within 15 business days of receiving such reports. Under this Act, a serious adverse event is defined as any adverse event resulting in death, a life-threatening experience, inpatient hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect, as well as any adverse event requiring a medical or surgical intervention to prevent one of the aforementioned conditions, based on reasonable medical judgment.
Physicians may also be proactive and report SAERs directly to the FDA MedWatch Reporting system at .
Garlic has long been touted as a natural product useful for the modulation of immune system activity, in the treatment of hyperlipidemia and hypertension, as well as in the primary and secondary prevention of myocardial infarction. Medicinal use of garlic can be traced back to the ancient Babylonians and Chinese, with long-term usage occurring in Western folk medicine as well.17 Allicin is felt to be the bioactive component responsible for the potential cardiovascular activity of garlic.18 Allicin content is determined by the nature of the garlic preparation, with raw crushed garlic having the highest concentration. Multiple mechanisms of action have been proposed, including decrease in cholesterol and fatty acid synthesis and cholesterol absorption.19 Potent antioxidant properties,20 antiplatelet and fibrinolytic activity with garlic has also been reported.21
Clinical studies of garlic have yielded contradictory results, with significant design flaws notable in trials designed to demonstrate garlic’s effectiveness.22-24 Short-term studies have shown some benefit in the lipid profiles of patients taking garlic, whereas long-term studies of 6 months or more fail to show sustained benefit when garlic is used as a single agent. A recent well-designed randomized controlled trial using highly characterized diet and supplement interventions comparing the effects of raw garlic, powdered garlic supplement, aged garlic supplement, and placebo in 192 moderately hypercholesterolemic adults demonstrated no significant difference in LDL cholesterol between treatment groups.25 A systematic review of 21 garlic studies to evaluate the reporting quality, safety, and efficacy of randomized controlled trials for lipid lowering demonstrated that 53% of the garlic trials reported positive efficacy, with a mean safety score of 63 of 100.26
Studies of garlic’s effectiveness in hypertension have also suffered from poor methodology, and results have revealed small, mostly insignificant decreases in blood pressure.27-29 A subsequent systematic review of 27 small, randomized controlled trials of at least 4 weeks’ duration comparing garlic with placebo, no garlic, or another active agent30 reported mixed effects of various garlic preparations on blood pressure. Two meta-analyses published in 2008 31,32 concluded that compared with placebo, garlic significantly lowered systolic blood pressure in hypertensive individuals but not in normotensive individuals. However, the sample sizes of these two meta-analyses of hypertensive patients were not large. Garlic preparations and doses of 600 to 900 mg/d, providing 3.6 to 5.4 mg of allicin, were common in both meta-analyses. Evidence for the supplemental intake of garlic for both the primary and secondary prevention of heart disease is not sufficient to recommend its use for this indication.
The anticoagulant properties of garlic can be problematic in the perioperative period and in combination with other anticoagulant compounds and have been reported to interact with the P450 enzyme system. Garlic will also decrease the effectiveness of some HIV drugs.33 Side effects are minor other than occasional nausea with excessive raw intake of garlic and the development of an unpleasant odor.
Hawthorn species are a group of small trees and shrubs found throughout North America, Asia, and Europe. Purported cardiovascular indications include congestive heart failure (CHF), angina, and arrhythmias. Hawthorn’s activity is felt to be related to the presence of a number of key constituents, including flavonoids and oligomeric procyanidins.34
Literature review reveals evidence for hawthorn’s efficacy in the treatment of mild to moderate CHF.35-38 Preparations made from flowers with leaves are sold as a prescription medication in parts of Europe and Asia. Animal and in vitro models reveal positive inotropism with a mechanism of action similar to that of digitalis through a cyclic adenosine monophosphate–independent effect.39,40 There is also evidence of a direct vasodilating effect.41 Some efficacy has been documented in increasing maximal workload capacity and decreasing symptom severity in patients with CHF. One uncontrolled study also reported an increase in ejection fraction measured by angiography from 30% to 41% in patients with stage II to III heart failure.42 A recent systematic review of 14 randomized controlled trials and meta-analysis in 1110 patients with heart failure treated with standard heart failure medications for up to 26 weeks reported that standardized preparations of hawthorn can increase exercise performance and cardiac oxygen consumption and may improve heart failure symptoms such as dyspnea and fatigue.43 In the first mortality driven trial, the SPICE trial, a European multicenter trial randomizing 3601 patients with New York Heart Association (NYHA) class II to III heart failure, a standardized preparation of hawthorn had no significant effect on the primary end point of time until first cardiac event compared with standard treatment therapies. Analysis of secondary outcomes, however, suggested benefit in patients with left ventricular ejection fractions between 25% and 35%. The study preparation was well tolerated, and there were no significant adverse events.44 Post hoc analysis of a smaller but comparably designed clinical trial conducted in the United States suggested that hawthorn did not reduce, but possibly contributed to, early risk of heart failure progression.45
Sales of hawthorn products have increased steadily in the United States for the past 10 years, placing in among the top 40 best-selling botanical products.46 The usual dose of hawthorn for CHF is 300 to 600 mg three times daily of an extract standardized to contain approximately 2% to 3% flavonoids or 18% to 20% procyanidins. Full effects can take up to 6 months to develop. Combination with cardiac glycosides should be monitored closely, and CNS depressants should be avoided. Side effects are rare but include gastrointestinal upset, sedation, dizziness, vertigo, headaches, migraines, and palpitations.47
Ginkgo extracts are derived from the leaf of the ginkgo tree, a botanical with a known history dating back 300 million years. Originally present throughout Europe, the tree died out during the Ice Age, surviving in China and Japan. Ginkgo is the most commonly purchased herbal remedy in the United States, with sales of more than $150 million.48 Widely used for its purported benefits in treating nondementia-related memory problems, Alzheimer disease, and vertigo, ginkgo has also been proposed as a treatment for intermittent claudication and peripheral vascular disease.
Ginkgo has been documented to inhibit platelet activation factor, decrease blood viscosity, and decrease vascular resistance.49,50 The mechanisms responsible for ginkgo’s effectiveness in peripheral vascular disease are unknown but can include its ability to scavenge free radicals, promote vasodilatation, and decrease blood viscosity; it also possesses anti-inflammatory and antiplatelet actions. Individual studies have revealed benefit in increasing mean pain-free walking distance.51,52 Two meta-analyses have examined the literature and reported a statistically significant increase in walking distance averaging nearly 25 meters (82 feet).53,54 The clinical significance of this difference is questionable, but it can provide a small benefit in the treatment of peripheral arterial disease.14 A recent randomized controlled trial in 62 adults with peripheral vascular disease confirmed a modest and insignificant increase in maximal treadmill walking time and flow-mediated dilation after 4 months of therapy of 300 mg/d of Ginkgo biloba.55 Provocative, however, are the findings from the Ginkgo Evaluation of Memory Study (GEMS), in which 3069 people age 75 years and older were randomized to placebo or ginkgo and followed-up for 6 years to evaluate the effect of the supplement on dementia. Although no effect was found on dementia, and no differences in heart disease or stroke, the investigators did note a possible benefit in the reduction of peripheral vascular events in a small number of subjects, which warrants further study.56
The usual dose of ginkgo for the treatment of claudication is 40 to 80 mg three times daily of a 50:1 extract standardized to contain 24% ginkgo-flavone glycosides. Caution must be exercised in using ginkgo, as it inhibits platelet aggregation factor and has been reported to increase both spontaneous and trauma-related bleeding, including bleeding during surgery and other procedures.57,58 Ginkgo is considered to be relatively safe. However, caution must also be exercised in combining gingko with heparin, warfarin, clopidogrel, and other compounds that can increase the risk of bleeding. Ginkgo has been reported to decrease the metabolism of trazodone in at least one case report, perhaps by an inhibition of monoamine oxidase.59 Side effects are common and include headaches, dizziness, gastrointestinal complaints, and skin reactions.
The horse chestnut tree is found worldwide. Its seeds contain active compounds known as saponins, which have mild anti-inflammatory properties.60 Aescin, a combination of triterpene saponins, appears to be the pharmacologically active component. Its mechanism of action is considered to be sensitization to Ca2+ ions and a sealing effect on small vessel permeability to water.61 Traditionally, this botanical has been used for hemorrhoids, rheumatism, swellings, varicose veins, and leg ulcers. Research has focused on horse chestnut tree extract in the treatment of chronic venous insufficiency, and multiple studies have reported the superiority of horse chestnut tree extract over placebo, with equal effectiveness to compression stockings as quantified by significant improvement in objective measurements of leg edema and subjective reporting of pain and sensation of heaviness.62-65
The usual dose of horse chestnut tree extract is 300 mg twice daily, standardized to contain 50 mg of aescin per dose, for a total daily dose of 100 mg of aescin. Aescin binds to plasma protein and can affect the binding of other drugs. Side effects are rare, including headache, itching, and dizziness. Concerns regarding risk of renal impairment do not appear to be warranted.66
Policosanol is a combination of aliphatic alcohols derived most commonly from sugar cane wax, although octacosanol, the predominant active ingredient, is also present in wheat germ oil and other vegetable oils.67 Policosanol inhibits cholesterol biosynthesis in a step located between acetate and mevalonate and increases low-density lipoprotein (LDL) receptor–dependent processing. There is no evidence for a direct inhibition of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase.68 Policosanol has been extensively used clinically and researched in Cuba.69 These studies suggest a lipid-lowering effect of approximately 15% for total cholesterol and 20% for LDL cholesterol, which can be increased to 30% with higher doses. Maximal effects are seen after only 6 to 8 weeks of use, and benefits have been demonstrated in studies lasting longer than 1 year. In a head-to-head comparison of 10 mg policosanol with 20 mg fluvastatin in women with elevated cholesterol, the lipid-lowering effects of policosanol were slightly superior to those of fluvastatin, and policosanol alone significantly inhibited the susceptibility of LDL to lipid peroxidation.70 The efficacy of policosanol has been noted in a review suggesting a unique role for this natural compound, given the large number of patients desiring a natural alternative to synthetically derived drugs for cholesterol management.71 However, three recent clinical trials found no evidence of beneficial effects on lipid lowering, casting significant doubt on the efficacy of this therapy.72-74 There are no data on efficacy determined by clinical end points.
The typical starting dose of policosanol is 5 mg/d, which can be increased to a maximal dose of 20 mg/d. Side effects are infrequent, with weight loss, polyuria, and headache most commonly reported. There is concern that policosanol can potentiate anticoagulant activity; it should therefore be used with caution in combination with any agents known to increase the risk of bleeding. There is also a report of an increased effect of L-dopa when used in combination with policosanol, leading to dyskinesias.75
Guggul is a substance derived from the mukul myrrh tree in India. It has played a role in traditional Indian medicine (Ayurveda) for several thousand years. It is used in the treatment of arthritis, and for digestive, skin, and menstrual problems. Today, guggul is used as a lipid-lowering agent that is believed to work by blocking the farnesoid X receptor in liver cells and, as a consequence, altering cholesterol metabolism.76 Studies of guggul have demonstrated a significant reduction in total cholesterol and LDL-C of 15% to 23% and triglyceride reduction of 20%.77,78 The usual dose is 100 mg of guggulsterone per day. Side effects are usually limited to mild gastrointestinal symptoms. A hypersensitivity rash was reported in a small number of healthy subjects enrolled in a randomized control trial for hypercholesterolemia.79 There is some evidence that when guggul is used concomitantly with diltiazem or propranolol, there can be a reduction in the bioavailability of those drugs and therefore decreased clinical efficacy.80 Currently, no clinical studies have been conducted to evaluate the safety of long-term use of guggul or guggulsterone.
Red rice yeast is a product that is derived from a yeast that grows on rice. Red rice yeast has been a food staple and folk remedy for thousands of years in the Asia. It was noted in the 1970s that a product of the yeast, monacolin K (lovastatin), was an inhibitor of HMG-CoA reductase.81 The concentration of lovastatin varies in red rice yeast but averages near 0.4% by weight.
In an early multicenter study of 187 subjects, red rice yeast lowered total cholesterol by 16.4%, LDL-C by 21.0%, triglycerides by 24.5%, and the ratio of total-to-high-density lipoprotein (HDL) cholesterol by 17.7%; it increased high-density-lipoprotein cholesterol (HDL-C) by 14.6%.82 The China Coronary Secondary Prevention Study randomized 4870 patients with a prior history of myocardial infarction to either a commercial red yeast rice product 600 mg twice daily or placebo for a mean duration of 4.5 years. The primary end points of nonfatal myocardial infarction and fatal coronary events, cardiovascular mortality, and total mortality were significantly reduced in the treatment group. The need for coronary revascularization was similarly reduced. Total cholesterol was reduced by 13% and LDL-C was reduced by 20%, with a noted 4.2% rise in HDL-C. No treatment-related serious adverse events or deaths were reported during the study period.83 Although the reported side effects of red rice yeast are few—including mainly gastrointestinal upset, headaches, and dizziness—red rice yeast must theoretically be considered a typical HMG-CoA reductase inhibitor, and caution is advised with regard to potential side effects, including rhabdomyolysis. However, red yeast rice has been successfully used in statin-intolerant patients with dyslipidemia and may provide a alternative treatment for some difficult-to-treat patients.84 Similarly, drug interactions should be considered to be identical to those with lovastatin, requiring caution when red yeast rice is combined with niacin, macrolides, cyclosporine, ketoconazole, and many other agents. Products range in their recommended dosage from 2.5 to 10 mg of lovastatin equivalent per day. However, red yeast rice is no longer marketed with standardized lovastatin levels in the United States, owing to legal issues, and it is now sold without lovastatin levels declared.
A number of dietary components have been postulated to have beneficial effects on cardiovascular disease and have been used therapeutically. These include omega-3 fatty acids, antioxidant vitamins, B vitamins, plant sterols, soluble fiber, soy, and teas.85,86
Omega-3 polyunsaturated fatty acids (FAs) can be derived from either plant or marine sources. The principal plant-based omega-3 FA, alpha linolenic acid (ALA), is found in soy and its derivative tofu, as well as in canola oil, flax seeds, and nuts. Omega-3 FAs derived from the tissues of marine animals (fish oil) include docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Typical dietary sources include mackerel, salmon, herring, sardines, anchovies, and albacore tuna. Early suggestions that fish oil consumption might provide protective health benefits came from epidemiologic comparisons of Greenland Eskimos, Alaskan Inuits, and Japanese islanders with high fish consumption with other cohorts.87 Three follow-up epidemiologic studies in the 1980s found that persons who ate fish every week had a lower mortality from coronary artery disease (CAD).88,89
Several mechanisms of benefit have been proposed for omega-3 FAs. The reductions in sudden cardiac death observed in several studies suggest a direct antiarrhythmic effect. High-dose omega-3 FAs produce a significant reduction in serum triglyceride concentrations and a small drop in blood pressure.87,90,91 They also decrease platelet aggregation.87 Other suggested mechanisms include an anti-inflammatory effect and enhanced production of nitric oxide. In addition, there are many reports of fish oil ingestion favorably affecting a variety of other intermediate targets believed to be relevant to cardiovascular disease.92,93 More than 40 cohort studies have now examined the effects of fish consumption on CAD outcomes.89,92-94 The best of these suggest a protective effect, with a stronger effect on death (four studies, relative risk [RR] 0.65) than on cardiovascular events (seven studies, RR 0.91).
A systematic review of randomized trials of omega-3 FAs published from 1966 to 2003 involving more than 33,000 patients found a small, nonsignificant reduction in all-cause mortality with a strategy of high omega-3 intake relative to low omega-3 intake (RR 0.87, 95% confidence interval [CI], 0.73-1.03).94 For cardiovascular events, the RR for high omega-3 was 0.95. Among these trials, the ones with the largest estimated benefit for high omega-3 intake were almost always the smallest trials. The largest of these is the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione study, which randomized 11,324 post-myocardial infarction (MI) patients to 1 g/d or usual therapy.95 The primary analysis showed a 20% reduction in all-cause mortality (P = .01) and a 45% reduction in sudden death (P < .01).95
The Diet and Angina Randomized Trial (DART) 2 estimated borderline excess mortality from high omega-3 intake (adjusted hazard ratio [HR] = 1.26; P = .047).96 This study randomized 3114 men younger than age 70 years to a factorial design involving advice to eat two portions of oily fish each week (or take 3 g of fish oil capsules daily) versus sensible eating advice. The plasma levels of omega-3 FAs increased significantly in a small subset of the fish advice arm relative to the control arm, but data on adherence to the dietary advice in this trial is inconclusive. The apparent excess mortality seen in this trial appeared to be driven by results in the subjects given fish oil capsules.
The Japan EPA Lipid Intervention Study (JELIS) randomized 18,654 hypercholesterolemic patients to 1800 mg of EPA per day plus statin therapy versus statin therapy alone.97 After a mean follow-up of 4.6 years, the EPA group had a 19% reduction in composite cardiac events (P = .01). The two treatment arms had an equivalent reduction in LDL-C of 25%. The magnitude of the treatment effect was similar in the primary prevention and secondary prevention subgroups. Among the individual types of cardiac events, there was no evidence of an effect on sudden cardiac death, but there were trends of benefit for MI, unstable angina, and coronary revascularization. Neither stroke nor all-cause mortality showed a treatment effect. One notable aspect of this trial is the fact that it was carried out in a population that typically has a high dietary intake of fish.
The GISSI-HF trial randomized 7046 NYHA class II to IV heart failure patients (10% with ejection fraction >40%) to 1 g/d of n-3 polyunsaturated fatty acids (PUFA) or placebo.98 With median 3.9 years of follow-up, a significant risk reduction in those assigned to the n-3 PUFA group was seen for all-cause mortality (HR = 0.91; P = .041), cardiovascular deaths (HR = 0.90; P = .045), hospital admissions for any reason (HR = 0.94; P = .049), and hospital admissions for cardiovascular reasons (HR = 0.93; P = .026).
Three smaller clinical trials have tested fish oil supplements in patients with implanted cardioverter-defibrillators (ICDs).99,100 In pooled analysis of 1148 patient, no evidence was seen for a protective effect for fish oil (RR = 0.90). The subgroup of patients with CAD showed a trend toward benefit.
In a study of 102 ICD patients with NYHA class II or III heart failure, elevated levels of red blood cell omega-3 FA levels correlated with an increased risk of ventricular arrhythmia requiring antitachycardic therapy.101
Currently, there are strong recommendations for the general public to consume two servings of fish (especially fatty fish) per week as part of a heart-healthy diet.102 In Europe, use of fish oil for secondary prevention after myocardial infarction is almost considered routine. Nonetheless, there is still much uncertainty regarding the value of dietary sources of omega-3 FAs compared with supplemental omega-3 FAs, appropriate target populations, and proper dosage. Early concerns about the concomitant use of omega-3 FAs with antiplatelet or antithrombotic medications causing significant bleeding have not been supported by the evidence.103 Contaminants in dietary sources of fish (particularly farm-raised fish) remain an important concern regarding recommending population-level increases in fish consumption for health reasons. The effect that such recommendations will have on increasing the rate of depletion of the world’s fish stores from industrial overfishing is also a significant concern.104
Despite a large body of epidemiologic evidence suggesting a favorable association between a diet high in antioxidants and reduced risk of coronary heart disease (CHD), the clinical trial evidence has failed to confirm the expected benefits. Most of the observational studies examined the consumption of foods and estimated the likely vitamin content, whereas a few studies have examined the supplemental consumption of vitamins.
Vitamin E refers to a group of molecules that includes four tocopherols and four tocotrienols. Alpha tocopherol is the most prevalent and most potent lipid-soluble antioxidant in plasma. Several large epidemiologic studies involving more than 170,000 subjects have assessed the association between dietary and supplement-based vitamin E and CHD outcomes.105-107 Three of these found supplement-based vitamin E to be associated with a significant reduction in hard cardiac events, especially in doses >100 international units (IU) for >2 years.
In secondary prevention trials, the Cambridge Heart Antioxidant Study (CHAOS) demonstrated that 400 to 800 IU of vitamin E reduced the combined end point of death or nonfatal MI by 47%.108 The Heart Outcomes Prevention Evaluation (HOPE) trial, which tested 400 IU of vitamin E in a high-risk secondary prevention population, found no therapeutic benefit on a variety of outcome measures, including disease progression as assessed by carotid ultrasound.109 The GISSI-Prevenzione trial, which tested 300 mg/d of vitamin E in almost 11,324 patients, also failed to detect a benefit.110 The HOPE—The Ongoing Outcomes (TOO) trial reported on almost 4000 patients from the original HOPE study with long-term follow-up. As with the original HOPE analysis, there was no evidence of a benefit of vitamin E on cardiovascular outcomes, and there was actually a modest increase in heart failure with active treatment.111
In primary prevention trials, the collaborative group of the Primary Prevention Project (PPP) found no evidence for a therapeutic benefit for 300 IU of vitamin E in 4495 subjects with one or more major cardiovascular risk factors.112 The Women’s Heath Study of 39,876 apparently healthy women age 45 years and older found that vitamin E (600 IU on alternate days) reduced cardiovascular death (RR = 0.76; P = .03) but had no effect on total cardiovascular events, MI, or stroke.113 In the Physicians’ Health Study II randomized trial, no benefit was found for 400 IU/alternate day in 14,641 male physicians with cardiovascular disease over an 8-year follow-up.114 At present, therefore, the preponderance of the evidence does not support a role for vitamin E supplements in either primary or secondary prevention of CHD.
Vitamin C (ascorbic acid) is a strong water-soluble antioxidant. In the Nurses’ Health Study, 85,118 female nurses completed a detailed dietary questionnaire in 1980 and were followed-up for 16 years. Estimated vitamin C intake using the questionnaire data was modestly related to incident heart disease events with an adjusted RR of 0.72 (P < .05).115 Several randomized trials have tested vitamin C supplements in varying doses for CHD prevention. In the Heart Protection Study, 20,536 patients with CAD or diabetes were randomized to antioxidant vitamins (600 mg of vitamin E, 250 mg of vitamin C, and 20 mg of beta-carotene) versus placebo.116 Although the vitamin regimen was found to be safe, there was no evidence for a therapeutic effect after 5 years of treatment. In the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study, hypercholesterolemic patients were randomized to twice-daily supplements of 136 IU of vitamin E, 250 mg of slow-release vitamin C, both, or placebo only.117 At 6 years among the 440 subjects completing the study, vitamin supplementation slowed carotid atherosclerosis (judged by common carotid intimal-medial thickness) by 25%. In the Physicians’ Health Study II, 500 mg/d of vitamin C provided no significant risk reduction for major cardiovascular events, MI, stroke, or cardiovascular mortality.114
Coenzyme Q10 (CoQ10) is a fat-soluble vitamin-like compound that is involved in mitochondrial adenosine triphosphate generation, serves to protect low-density lipoprotein particles from oxidation, and aids cell membrane stabilization. Some data suggest that this micronutrient is deficient in patients with heart failure.118 For this reason, several small studies have been conducted to assess its impact in heart failure patients, with improvement seen in a number of markers, including ejection fraction, cardiac output, and pulmonary artery pressures.118-120 The ongoing Q Symbio randomized clinical trial is examining 300 mg/d of CoQ10 versus placebo in 550 NYHA class III or IV chronic heart failure patients to assess its impact on cardiovascular morbidity and mortality.121
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