PREVENTION OF MYOCARDIAL INFARCTION

Primary Prevention of Myocardial Infarction

General information on primary prevention

• Primary prevention of myocardial infarction should begin in adolescence, based on data from an autopsy study of 760 fifteen - thirty four year old victims of accidents, homicides, and suicides, which found a high prevalence of advanced atherosclerotic coronary artery plaques with qualities indicating vulnerability to rupture in these adolescents and young adults, with the presence of these plaques was associated with traditional risk factors for coronary artery disease (Circulation. 2000. 102. 374-379).

• Data on 42,847 male health professionals in the Health Professionals Follow-Up Study who were free of cardiovascular disease, diabetes, and cancer at baseline showed that adherence to low-risk lifestyle behaviors (not smoking, maintaining BMI < 25, exercise of moderate to vigorous intensity for at least 30 minutes per day, diet in top 40% of Alternate Healthy Eating Index-based score distribution, and 5-30 grams/day of alcohol consumption) had a nearly 90% lower risk of CHD over 20 years of follow-up, compared to men with a high risk profile.

  • Only 4% of men in the cohort were in the low risk category for all 5 lifestyle factors listed above.

  • In the subgroup of subjects already taking prescription medication for hypertension or hypercholesterolemia at baseline, it was determined that 57% of the CHD cases might have been prevented by adhering to a low risk lifestyle in all of the above 5 categories (Circulation. 2006. 114. 160-167; Card Rev. 2006. 24[1]. 13-17).

• Data on 24,444 postmenopausal women in the Swedish Mammography Cohort who were free of cardiovascular disease, diabetes, and cancer at baseline showed that adherence to low-risk diet lifestyle (not smoking, maintaining waist to hip ratio of <0.85, at least 40 minutes per day of walking or bicycling, low-risk diet, and <5 grams/day of alcohol consumption) had a nearly 92% lower risk of CHD over 6.2 years of follow-up, compared to women without any low risk diet and lifestyle factors. This combination of 5 healthy behaviors was present in only 5% of the cohort (Arch Intern Med. 2007. 167. 2122-2127).

• Data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study showed that patients who adhered to healthy dietary principles, never smoked, had a BMI < 30, and had at least 30 minutes per day of physical activity had an 81% lower risk of MI (Arch Intern Med. 2009. 169. 1355-1362).

• Data across four studies involving 55,685 participants show that while the relative risk of coronary events is 91% higher among participants at high genetic risk (top quintile of polygenic scores) than among those with low genetic risk (bottom quintile), a favorable lifestyle in those at highest genetic risk (defined as at least three of four healthy lifestyle factors) was associated with a 46% lower relative risk as compared with those with an unfavorable lifestyle (N Engl M Med. 2016. 375. 2349-2358).

Diet: 

• Overview

  • Historically, the pioneering work of Keys and Aravanis represents the beginning of the scientific study of the relationship between dietary factors and CHD. Their work is summarized in a book (Keys AB and Aravanis C. Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease. Harvard University Press. 1980).

  • A review article concluded "Substantial evidence indicates that diets using nonhydrogenated unsaturated fats as the predominant form of dietary fat, whole grains as the main form of carbohydrates, an abundance of fruits and vegetables, and adequate omega-3 fatty acids can offer significant protection against CHD" (JAMA. 2002. 288. 2569-2578).

  • A systematic review of prospective cohort studies or RCTs investigating dietary intake and CHD risk found that “The evidence supports a valid association of a limited number of dietary factors and dietary patterns with CHD” (Arch Intern Med. 2009. 169. 659-669).

    • Strong evidence supports a protective effect associated with intake of vegetables, nuts, monounsaturated fatty acids, and a Mediterranean diet.

    • Strong evidence supports a harmful effect associated with intake of trans fatty acids and foods with a high glycemic index or load.

    • Moderate evidence supports a protective effect associated with intake of alcohol, beta-carotene, fatty fish, fiber, folate, fruit, vitamins C and E, and whole grains.

    • Insufficient evidence of association for alpha linolenic acid, eggs, meat, milk, polyunsaturated fat, saturated fat, and total fat.

• Mediterranean Diet

  • Seven principle components of Mediterranean diet include (1) plant based foods, (2) locally grown minimally processed food, (3) fish and poultry, (4) infrequent red meat consumption, (5) olive oil as principle source of fat, (6) moderate amounts of red wine with meals, and (7) desserts primarily of fresh fruit.

  • An epidemiologic study which monitored the lifestyle habits of 3000 healthy men and women for one year found that those who followed a strict Mediterranean diet had the lowest level of C-reactive protein (CRP) and other measures of inflammation (JACC. 2004).

  • Pooled analysis of 3 RCTs of combined dietary changes (increased intake of fruits, vegetables, nuts, legumes, fish, and unsaturated fats) showed a 45% reduction in mortality (Circulation. 2005. 112. 924-934).

  • In the PREDIMED trial, a 3-arm, multicenter, RCT of 7447 individuals who were at high risk of cardiovascular disease at baseline, but with no cardiovascular disease at enrollment, the incidence of major cardiovascular events (composite endpoint, defined as MI, stroke, or death from cardiovascular causes) was reduced in those randomized to the Mediterranean diet group supplemented with extra-virgin olive oil, and also reduced in those randomized to the Mediterranean diet group supplemented with mixed nuts, as compared with those randomized to a control diet (advice to reduce dietary fat).The trial was stopped after a median follow up of 4.8 years, based on interim analysis showing benefit, with hazard ratios of 0.70 (0.54 – 0.92) in the group assigned to the Mediterranean diet group supplemented with extra-virgin olive oil, and 0.72 (0.54 – 0.96) in the group assigned to the Mediterranean diet group supplemented with nuts (N Engl J Med. 2013. 368. 1279-1290). In an accompanying editorial, the authors comment that analysis of the dietary intake of each of the 3 groups in this trial suggests that “the most striking differences between the randomized groups resulted from the supplemental foods” (i.e. extra virgin olive oil versus mixed nuts), and thus the results of this trial seem more a testament to the health benefits of mixed nuts and/or extra virgin olive oil, as opposed to the Mediterranean diet per se (N Engl J Med. 2013. 368. 1353-1354).

  • A systematic review and meta-analysis of 40 RCTs (n = 35,548) of 7 dietary programs concluded that in adults with increased cardiovascular risk, structured dietary programs focusing on Mediterranean-style diets reduce all-cause and cardiovascular mortality (BMJ. 2023. 380. e0720030).

• Polymeal (also referred to as Portfolio Diet) – a published study suggests that a polymeal (diet includes regular portions of almonds, dark chocolate, fish, fruits, garlic, vegetables, and wine) could reduce the rate of cardiovascular events by 76% and increase life expectancy by 6.6 years for men and 4.8 years for women, using Framingham Study data (BMJ. 2004. 329. 1447-1450).

• Avocados

  • Prospective cohort data in 68,786 women in the Nurses’ Health Study and 41,701 men om the Health Professionals Follow-up Study shows that at 30 years, those who consumed 2 or more servings per week of avocados had a 16% lower risk of cardiovascular disease (J Am Heart Assoc. 2022. 11. e024014).

• Carbohydrate (and in addition see section just below ‘Sugar-sweetened beverages’)

  • NOTE, historically a two-part review article in the New England Journal of Medicine, written by the Chair of the Nutrition Department at Harvard in and two other professors of Nutrition at Harvard, was influential in regard to the scientific community embracing high dietary fat and cholesterol intake as the primary dietary cause of atherosclerosis, and rejecting high sugar intake as a cause of atherosclerosis (N Engl J Med. 1967. 277. 186-192 and 245-247).

    • The authors did not disclose that the Sugar Research Foundation, which was funded by the sugar industry, paid the authors $6500 to write the review (Gaby AR. Editorial. Townsend Letter. April 2017. 79-80).

    • Critique of this review article shows that observational studies showing a link between sugar intake and atherosclerosis were criticized by the authors as not definitive, but observational studies showing a link between fat and cholesterol intake and atherosclerosis were cited by the authors to support their conclusions(Gaby AR. Editorial. Townsend Letter. April 2017. 79-80).

  • Data on 82,802 women in the Nurses’ Health Study, followed for 20 years, “suggest that diets lower in carbohydrate and higher in protein and fat are not associated with an increased risk of coronary heart disease in women. When vegetable sources of fat and protein are chosen, these diets may moderately reduce the risk of coronary heart disease.” Low carbohydrate for the purposes of this study was defined as <30% of calories; results were similar when the subgroup with a carbohydrate intake of <20% of calories was analyzed separately (N Engl J Med. 2006. 355. 1991-2002).

  • In a 10 year prospective analysis of the Nurses’ Health Study, those women in the highest (fifth) quintile of dietary glycemic load had double the relative risk of coronary heart disease as those women in the lowest (first) quintile of dietary glycemic load (Am J Clin Nutr. 2000. 71. 1455-1461).

  • NEGATIVE trial – OmniCarb trial – this was a 5 week randomized crossover-controlled feeding trial of 163 overweight adults. In this trial, low glycemic index diets were not associated with improvements in insulin sensitivity, lipid levels, or systolic blood pressure, as compared with high glycemic index diets (JAMA. 2014. 312. 2531-2541 and editorial 2508-2509).

• Chocolate

  • A meta-analysis of 16 studies with 344,453 participants reported that most studies found a significant reduction in CVD risk associated with increased chocolate consumption, as determined by food frequency questionnaires or self-report, such that the cardiovascular risk was 0.77 in the group with the highest chocolate consumption, as compared with the group with the lowest chocolate consumption. This study did not distinguish amongst white versus milk versus dark chocolate (Nutrition. 2018. 46. 103-114).

  • Beware though of lead and cadmium contamination - levels are higher on average in dark chocolate bars as compared with milk chocolate bars. Consumer Reports measured the amount of heavy metals in 28 brands of dark chocolate bars, and found high levels of lead and cadmium in 5 brands, high levels of lead or cadmium in an additional 18 brands, and acceptable amounts of lead and cadmium in only 5 of the 28 brands. Some of the brands with high levels were organic brands (Consumer Reports. February 2023. 34-41).

• Fat:

  • Theme – conflicting data. A systematic review and meta-analysis of 32 observational studies (n = 530,525) of fatty acids derived from dietary intake, 17 studies (n = 25,721) of fatty acid biomarkers, and 27 RCTs (n = 103,052) of fatty acid supplementation concludes “current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total fatty acids.” The authors of this review fatty acid biomarkers might provide a more accurate assessment of consumption of various types of fat, as compared with self-report questionnaires, but there is very little published data assessing consistency of findings from dietary self-report questionnaires, as compared with analysis of fatty acid biomarkers (Ann Intern Med. 2014. 160. 398-406).

  • The epidemiologic association between the amount of fat in the diet and MI is actually an association between saturated fat and MI (N Engl J Med. 1997. 337. 1491-1499; N Engl J Med. 1985. 312. 811-818; Am J Epidemiol. 1984. 119. 667-676) and also trans fats in the diet and MI (Lancet. 2001. 357. 746-751; Am J Epidemiol. 1997. 145. 876-887; BMJ. 1996. 313. 84-90), not total fat and MI.

  • Replacing unhealthy fats (trans fats, saturated fats) with unsaturated fat (monounsaturated fats, polyunsaturated fats) is associated with improved cardiovascular outcomes (J Am Coll Nutr. 2001. 20. 5-19).

  • Trans fat intake is associated with an increased risk of coronary heart disease, based on:

    • Data in 85,095 women in the Nurses’ Health Study who completed questionnaires in 1980 and were followed for 8 years (Lancet. 1993. 341. 581-585).

    • Additional epidemiologic data shows that a diet high in trans fats is associated with a doubling of CAD risk (Lancet. 2001. 357. 746-751).

    • A meta-analysis of 4 prospective, long-term studies with 140,000 participants which showed that a 2% increase in caloric intake from trans fats was associated with a 23% increase in the incidence of coronary artery disease (New Engl J Med. 2006. 354. 1601).

  • A one year study of 100 men and women who followed 4 different diets (90 completed the study) found a trend in the 18 subjects on the high fat diet toward worsening of lipid profile values, homocysteine, lipoprotein a, and fibrinogen despite statistically significant weight loss. In this study, the 16 patients on a low fat diet and the 28 patients on a moderate fat, calorie controlled diet showed both statistically significant weight loss and statistically significant improvements in serologic measurement of multiple risk factors. The 28 subjects on the moderate fat program without calorie restriction showed no significant change in weight or measurement of risk factors (Preven Cardiol. 2002. 5. 110-118).

  • In the Women’s Health Initiative Dietary Modification Trial, a RCT in 48,835 postmenopausal women age 50-79, of diverse backgrounds and ethnicities, at 8.1 years of follow up there was NOT a significant reduction in cardiovascular disease (a predefined secondary endpoint) in the “low fat diet” intervention group. The goal in the intervention group was to decrease total fat intake to 20% of calories, to increase fruits and vegetables to 5 servings per day, and to increase grain intake to 6 servings per day. The intervention intensity was moderate – 18 sessions during the first 12 months and 4 times per year thereafter. The intervention group did achieve an 8.2% reduction in total fat intake at year 6 and an increase in fruit and vegetable consumption of 1.1 servings per day and an increase in grain consumption of 0.5 servings per day (JAMA. 2006. 295. 655-666).

    • NOTE that in this trial the increase in carbohydrate consumption did NOT translate into a lower HDL, higher triglycerides, higher insulin, or higher glucose.

    • NOTE that this trial did NOT test the dietary guidelines currently recommended for prevention of cardiovascular disease (i.e. “a plant-based, high-fiber diet rich in vegetables, fruits, WHOLE grains, nuts, beans, low-fat dairy products, fish, and replacement of saturated and trans fats with monounsaturated and polyunsaturated fat and plant sterols”) [Comment section of the article, pg 664, top of column 2].

    • The data on changes in fat consumption in the intervention group were a decrease in saturated fat from 12.7% to 9.5%, a decrease in trans fat from 2.8% to 1.6%, a DECREASE in polyunsaturated fat from 7.8% to 6.1%, and a DECREASE in monounsaturated fat from 14.4% to 10.8% (editorial on the above article pgs 693-695).

• Fiber: 

  • "A higher intake of dietary fiber, particularly water-soluble fiber, reduces the risk of CHD." (Arch Intern Med. 2003. 163. 1897-1904). This conclusion is based on an average of 19 years of follow up of 9776 adults in NHANES I who were free of cardiovascular disease at baseline. Dietary fiber intake is based on a 24 hour dietary recall at the baseline examination.

  • Additional data comes from a systematic analysis of 10 prospective cohort studies which included 91,058 men and 245,186 women. This pooled analysis shows a 27% reduction in risk of a cardiovascular event per 10 gram per day increment in dietary fiber. The reduction in risk is associated with total dietary fiber, soluble fiber, insoluble fiber, fiber from fruit, and cereal fiber. No protective effect was seen with vegetable fiber intake - the authors hypothesize this might be due to the frequent consumption in the U.S. of starchy high-glycemic index vegetables such as potatoes and corn (Arch Intern Med. 2004. 164. 370-376).

  • Data on a total of 11,113 subjects in NHANES 2005-2010 “suggest that dietary fiber intake is independently associated with the predicted lifetime CVD risk, especially in young and middle-age adults” (Am J Cardiol. 2014. 113. 287-291).

  • The FDA allows a health claim for heart disease reduction for viscous fiber (oat beta-glucan and psyllium).

  • Presumed mechanism of action – increases excretion of cholesterol by increasing excretion as opposed to enterohepatic recirculation of bile acids.

• Fish and flax (omega 3 fatty acids): Data on benefit is mixed.

  • The American Heart Association in 2002 deemed the evidence for the role of fatty fish (herring, mackerel, salmon, sardines, trout, tuna) in primary prevention of heart disease strong enough to recommend in a position statement two 3 ounce portions per week of fatty fish or 1 fish oil capsule daily (Circulation. 2002. 106. 2747-2757).

  • A meta-analysis of 19 cohort and case-control studies with 228,864 participants (men and women) reported an inverse relationship between fish consumption and heart disease, as well as death rates from heart disease, with fish consumption associated with a 10% reduction in risk of heart disease and 20% reduction in risk of fatal heart disease. Benefit is most pronounced in those consuming two or more portions of fish per week (Am J Cardiol. 2004. 93. 1119-1123). Mechanism of action is uncertain. There is mixed data regarding an anti-arrhythmic effect. There is data showing favorable changes in plaque morphology, with an increased thickness of the fibrous cap (Lancet. 2003. 361. 477-485).

  • A second meta-analysis concluded that each 20 gram increase in fish consumption was associated with a 7% lower risk in CHD mortality (Circulation. 2004. 109. 2705-2711).

  • In the Dutch component of the Seven Countries study, men who consumed 30 grams of fish daily had a 50% lower CHD mortality than men who rarely ate fish, at 20 years of follow-up (N Engl J Med. 1985. 312. 1205-1209).

  • In the Western Electric study, men who consumed at least 35 grams of fish daily had a 40% lower risk of fatal CHD (N Engl J Med. 1997. 336. 1046-1053).

  • In the US Physicians' Health Study, an 11 year study of 20,551 men, weekly fish consumption was associated with a lower risk of sudden cardiac death and total mortality (JAMA. 1998. 279. 23-28). In this study, however, fish intake was NOT related to risk of nonfatal MI (Am J Epidemiol. 1995, 142. 166-175). A prospective nested case-control analysis of men who were followed for up to 17 years in the Physicians' Health Study in which the fatty acid composition of previously collected blood was analyzed showed that baseline blood levels of long chain omega 3 fatty acids (i.e. DHA and EPA) were inversely related to risk of sudden death even after adjustment for potential confounders [p=0.007] (New Engl J Med. 2002. 346. 1113-1118).

  • In the Nurses’ Health Study, with 16 years of follow-up on 84,688 female nurses, higher consumption of fish and omega-3 fatty acids was associated with a lower risk of CHD, particularly CHD deaths. Strengths of this study include repeated measures of fish intake over time and adjustment for potential confounding dietary variables (JAMA. 2002. 287. 1815-1821). Risk of thrombotic stroke was also lower among fish-eating subjects (JAMA. 2001. 285. 304-312). In women with diabetes, total mortality was lower in fish-eating subjects (Circulation. 2003. 107. 1852-1857).

  • A review of the evidence article on the relationship between alpha-linolenic acid (ALA - an intermediate chain-length omega 3 fatty acid) and heart disease concludes that “Evidence from experimental, observational, and clinical studies suggests that consumption of ALA, found in flaxseed oil, canola oil, walnuts, and other plant sources, reduces CHD risk.” The review conclusion section goes on to state “clinical benefits have not been seen consistently in all studies” (Altern Ther Health Med. 2005. 11(3). 24-30).

  • Another review states that, compared to the robust data for fish oil or fish, “The data on ALA have been limited by studies of smaller sample size and limited quality” (Am J Cardiol. 2005. 96. 1521-1529).

  • An exception to all of the above published positive studies is the Health Professionals Follow-up Study, in which no association was found between dietary intake of omega-3 fatty acids and risk of CHD, with only a non significant trend toward lower risk of fatal CHD with higher omega-3 intake (N Engl J Med. 1995. 332. 977-982).

  • For information on mechanism of action, return to Home Page and click on “Nutrition” and scroll to polyunsaturated fats.

  • See also ‘omega 3 supplements’ below in this outline.

• Fruits and vegetables

  • Intake is associated with a protective effect against heart disease (Arch Intern Med. 2001. 134. 1106-1114).

  • A meta-analysis of 95 prospective studies concluded that for each 2.5 gram/day intake in fruits and vegetables (2.5 servings per day), coronary heart disease risk decreased by 8-16%, stroke risk decreased by 13-18% and all-cause mortality decreased by 10-15% (Int J Epidemiol. 2017. 46. 1029-1056).

• Green tea – see ‘tea’ just below

• Nuts: NOTE best stored in refrigerator or freezer in an airtight container, and best consumed raw and unsalted

  • The FDA in approximately 2007 approved a qualified health claim for almonds, hazel nuts, pecans, pistachios, and walnuts, stating that there is supportive data that consumption of 1.5 ounces (45 grams) per day reduces the risk of heart disease (macadamia nuts are excluded from the health claim due to higher content of saturated fat). Excellent review articles appear in Alt Med Alert. 2007. 10. 17-21 and 28-34.

  • A meta-analysis of 29 prospective trials showed that eating at least 20 grams per day of nuts is associated with a lower risk of heart disease (BMC Medicine. 2016. 14. 207).

  • A meta-analysis of 19 prospective studies showed an inverse association between total nut consumption and CVD incidence, CVD mortality, CHD incidence, CHD mortality, stroke mortality and atrial fibrillation (Nutr Rev. 2019. 77. 691-709).

  • Almonds lower LDL cholesterol and also raise HDL cholesterol.

    • The addition of almonds to a Step I (Am J Clin Nutr. 2003. 77. 1379-1384) and also a Step II AHA diet (Circulation. 2002. 106. 1327-1332) produces significant additional cholesterol lowering.

    • When compared to a dairy based diet, an almond based diet produced a 16% reduction in total cholesterol and a 19% reduction in LDL (p<0.001)[ J Am Coll Nutr. 1998. 17. 285-290].

    • A six week crossover RCT comparing whole almonds with almond oil showed equal cholesterol-lowering effects (J Nutr. 2002. 132. 703-707).

  • Hazel nuts lower LDL cholesterol and also raise HDL cholesterol.

    • Benefit seen in a small study in type II diabetics (Proceedings of the Fourth International Symposium on Hazelnut. Acta Hort. 1997. 305-310).

    • Benefit seen in hypercholesterolemic individuals (Eur J Clin Nutr. 2006. Epub ahead of print).

  • Macadamia nuts lower LDL cholesterol and also raise HDL cholesterol.

    • A study in hypercholesterolemic men showed significant benefit on the lipid profile (J Nutr. 2003. 133. 1060-1063).

    • Two controlled feeding studies showed beneficial changes in the lipid profile (Food Australia. 1996. 48. 216-222); Arch Intern Med. 2000. 160. 1154-1158).

  • Pecans lower LDL cholesterol and also raise HDL cholesterol.

    • Benefit seen in individuals with normal baseline cholesterol levels (J Am Diet Assoc. 2000. 100. 312-318).

    • Benefit seen in hypercholesterolemic individuals (J Nutr. 2001. 131. 2275-2279).

  • Pistachios lower LDL cholesterol and triglycerides; raise HDL cholesterol.

    • Benefit seen in individuals with normal baseline cholesterol levels (Nutr Metab Cardiovasc Dis. 2006. 16. 202-209).

    • Benefit seen in hypercholesterolemic individuals (J Am Coll Nutr. 1999. 18. 229-232).

    • Benefit reported in a meta-analysis of 34 trials (Am J Clin Nutr. Jan 1, 2020)

  • Walnuts lower LDL cholesterol and also raise HDL cholesterol.

    • The effects of walnut supplementation on blood lipids and lipoproteins has been evaluated in six studies, including studies of a self-selected diet as well as controlled feeding studies (Alt Med Alert. 2007. 10. 17-21).

    • Individuals study references include (N Engl J Med. 1993. 382. 603-607; Ann Intern Med. 2000. 132. 538-546; Am J Clin Nutr. 2001. 74. 72-79; Eur J Clin Nutr. 2002. 56. 629-637).

    • A walnut-rich diet is associated with a 64% increase in endothelium-dependent vasodilation, and reduced levels of VCAM-1 in a randomized crossover study in 21 hypercholesterolemic men and women (Circulation. 2004. 109. 1609-1614).

    • The addition of walnuts (40 grams) to a high-fat meal improved flow-mediated dilation (J Am Coll Cardiol. 2006. 48. 1666-1671).

    • The Seventh Day Adventist Study in 31,208 participants found that those who reported eating nuts more than 4 times per week had a 50% lower risk of both fatal and nonfatal CHD than those who rarely ate nuts (Arch Intern Med. 1992. 152. 1416-1424).

    • In the Iowa Women’s Health Study, which followed 34,500 postmenopausal women for 5 years, coronary mortality was inversely associated with nut intake, with statistically significant benefit restricted to the small subgroup who consumed nuts one or more times per week (Nutr Metab Cardiovasc Dis. 2001. 11. 372-377).

    • In the Nurses’ Health Study, at 14 years of follow up in 86,016 women aged 34-59 years, there was a 39% lower risk of fatal CHD and a 32% lower risk of nonfatal CHD in women who ate more than 5 ounces of nuts per week (BMJ. 1998. 317. 1341-1345).

    • In the Physicians’ Health Study in 21,454 male participants, at 17 years of follow up the relative risk for sudden cardiac death was 0.53 in those who consumed 2 or more servings of nuts per week, and the relative risk for total CHD death was 0.70 (Arch Intern Med. 2002. 162. 1382-1387).

    • Data in 399,633 European subjects in 10 countries enrolled in the EPIC trial show that consumption of two servings of nuts per week was associated with a 16% reduction in the risk of death from CHD. A serving is 28 grams, or approximately 20 almonds (presentation 2006 European Society of Cardiology).

    • The effects of nut consumption on primary prevention of CHD is being studied in a RCT by the PERIMED Study Investigators.

    • There is emerging information in 2007 that nut consumption beneficially affects markers of inflammation and also LDL particle size.

• Oils

  • Fish oil – see ‘Omega 3’ in the ‘Supplements’ category below

  • Olive oil – the polyphenols are cardioprotective. In a randomized, crossover trial, daily intake of olive oil improved lipid profiles, enhanced antioxidant status, and decreased antioxidant damage to lipids, with benefits linearly related to the polyphenol content of the 3 different types of olive oil used in this trial. Note extra virgin olive oil has the highest polyphenol content (Am J Clin Nutr. 2006. 84. 694-697).

• Plant sterols and stanols

  • FDA permits a health claim for plant stanols (1.6 grams per day) for heart disease risk reduction.

  • Presumed mechanism of action – block absorption of cholesterol.

• Protein

  • Moderately high protein intake is associated with a slightly reduced risk of coronary heart disease (Am J Clin Nutr. 1999. 70. 221-227).

  • In a 20 year follow up of 82,802 women in the Nurses’ Health Study II, only vegetable protein intake was associated with a significantly reduced risk of coronary heart disease, and this reduced risk was apparent only in age-adjusted analyses, not in multivariate analyses (N Engl J Med. 2006. 355. 1991-2002).

• Salt 

  • A Cochrane analysis of 7 RCTs (n=6489) showed that “Interventions to reduce dietary salt do not reduce mortality or cardiovascular morbidity in persons with normotension or hypertension” (Cochrane Database Syst Rev. 2011. CD009217 as cited in ACP Journal Club. 2012. 156. JC1-4).

  • For further information on salt and cardiovascular disease, Return to the Home Page, click on ‘Nutrition’ and scroll way down to the section on ‘Salt.’

• Sugar-sweetened beverages

  • At a mechanistic level, consumption of large amounts of sucrose (table sugar) by humans adversely impact a number of cardiovascular risk factors - intake is associated increases in serum levels of triglycerides, insulin, and uric acid; rises in blood pressure, increases in platelet adhesiveness, and decreases in HDL cholesterol levels (Postgrad Med J. 1969. 45. 602-607; Ann Nutr Metab. 1983. 27. 425-435).

  • Prospective cohort data in 106,178 women participating in the California Teachers Study (and without a diagnosis of CVD or DM at baseline) found that at 20 years of follow up, those who consumed one or more servings per day of sugar-sweetened beverages had a relative risk of 1.19 (95 % CI 1.06 - 1.34) of a diagnosis of CVD, as compared with those who rarely or never consumed sugar-sweetened beverages (J Am Heart Assoc. 2020. 9. e014883).

• Soy 

  • Effective October 1999, the FDA allows for labeling on soy rich foods (defined as having at least 6.25 grams of soy per serving, and assuming 4 servings per day) as "capable of decreasing the risk of heart disease" (Fed Regist. 1999. 64. 57700-57733) based on a meta-analysis of 38 clinical trials showing a 9% decrease in total cholesterol and a 13% decrease in LDL cholesterol in patients taking 25-50 grams of soy per day (N Engl J Med. 1995. 333. 276-282).

  • Presumed mechanism of action – reduced hepatic cholesterol synthesis. NOTE it is unclear to what extent soy isoflavones are responsible for the lipid-lowering effect of soy, as there is not a significant linear correlation between reduction in LDL cholesterol and soy-protein ingestion or isoflavone intake (Am J Clin Nutr. 2007. 85. 1148-1156). The lipid lowering effect of soy may arise from a synergistic action of constituents in soy protein, isoflavones, cotyledon fibers in the cell wall of the plant, phospholipids, saponins, and phytosterols (IMCJ. 2009. 8[4]. 30-40).

• Tree nuts – see ‘Nuts’ just above

Beverages

• Alcohol:

  • Biological plausibility for a causative effect - beneficial effect on HDL, antioxidant effect, anti-inflammatory effect, an antiplatelet effect, and improvement in insulin resistance.

  • Historically, several large epidemiologic studies including the Framingham Heart Study showed an inverse correlation between risk of MI and alcohol in moderation, 1-2 drinks per day for males, 1 drink per day for females, defined as 12 ounces of beer, 5 ounces of wine, or 1 shot of liquor. Relative risk reduction is 35%.

  • Data from a 12 year follow up on the Health Professionals Follow-up Study (51,529 U.S. male dentists, veterinarians, optometrists, osteopaths, and podiatrists 40-75 years of age who returned a mailed questionnaire regarding diet and medical history in 1986; participants return follow up questionnaires every 2 years) shows an inverse correlation between risk of MI and consumption of alcohol on at least 3-4 days per week, among 38,077 participants who were free of cardiovascular disease and cancer at baseline. Neither the type of alcoholic beverage consumed nor the proportion consumed with meals altered the association. Furthermore, it was determined through analysis of the biyearly surveys that men who increased their alcohol consumption during the 12 years of follow up by a moderate amount had a decreased risk of myocardial infarction (N Engl J Med. 2003. 348. 109-118).

  • A cross sectional study using data from the Rotterdam Coronary Calcification Study showed that the risk of extensive coronary calcification was 50% lower in individuals who consumed 1-2 alcoholic beverages per day, compared with nondrinkers (Arch Intern Med. 2004. 164. 2355-2360).

  • Data from the INTERGENE case control study, which included 618 Swedes with CHD and a control group of 3000 healthy subjects concluded alcohol consumption was protective only in 15% of the population with a particular genotype – CETP Taq1B (Alcohol. 2014. 48. 695-700).

  • 2023 - re-analysis of historic data led to the conclusion that even small quantities of alcohol are NOT protective against heart disease

  • Alcohol is not risk free (Ann Intern Med. 2003, 139. 711-714).

    • Alcohol is linked to more than 100,000 deaths each year.

    • Alcohol consumption is associated with an increased risk of atrial fibrillation. Data in 79,019 individuals shows that consumption of risk of atrial fibrillation is increased by 7% in those consuming 7-14 alcoholic beverages per week, 14% in those consuming 15-21 alcoholic beverages per week, and is increased 39% in those consuming >21 alcoholic beverages per week. The same researchers who reported the above associations performed a meta-analysis of 7 prior studies which included 12,554 cases of atrial fibrillation and found the risk was increased by 8% in those consuming 1 alcoholic beverage per day, 17% in those consuming 2 alcoholic beverages per day, 26% in those consuming 3 alcoholic beverages per day, 36% in those consuming 4 alcoholic beverages per day, and 47% in those consuming 5 alcoholic beverages per day (J Am Coll Cardiol. 2014. 64. 281-289).

    • Alcohol consumption in excess of 2 alcoholic beverages per week is associated with an increased risk of breast cancer.

    • Excess alcohol consumption increases the risk of high blood pressure, obesity, stroke, suicide, and accidents.

    • Alcohol is contra-indicated in those with a personal or family history of alcoholism, uncontrolled high blood pressure, high triglyceride levels, heart failure, liver disease, pancreatitis, porphyria, pregnancy, and use of medications that can have adverse interactions with alcohol.

    • Alcoholism afflicts more than 8 million adults, and there is a concern that moderate drinking in some genetically predisposed individuals may transform into excessive drinking.

• Coffee:

  • Epidemiologic studies have been inconclusive (numerous references can be found in the introduction section of JAMA. 2006. 295. 1135-1141).

  • Caffeine has been implicated in the development of cardiovascular disease (references can be found in the introduction section of JAMA. 2006. 295. 1135-1141).

  • Chronic coffee consumption has a detrimental effect on aortic stiffness (Am J Clin Nutr. 2005. 81. 1307-1312).

  • Cytochrome P450 1A2, which accounts for approximately 95% of caffeine metabolism, demonstrates wide variability in enzyme activity between individuals (Pharmacogenetics. 1992. 2. 73-77; Clin Pharmacol Ther. 2003. 53. 503-514; Pharmacogenetics. 2002. 12. 473-478).

  • Consumption increases the risk of MI in slow metabolizers (variant CYP1A2 1F allele) but decreases the risk of MI in rapid metabolizers (CYP1A2 1A allele), based on a case control study in Costa Rica between 1994 and 2004, examining 2014 cases with first MI and 2014 controls (JAMA. 2006. 295. 1135-1141). Estimated that 50% of Caucasians have slow variant whereas only 14% of Japanese have the slow variant (Cancer Epidemiol Biomarkers Prev. 1994. 3. 413-421).

  • A prospective study in 127,212 subjects found that coffee consumption was unrelated to CAD risk in never smokers, but associated with a higher CAD risk in ex-smokers and current smokers (Am J Cardiol. 2008. 101. 825-827).

  • Data from 6508 ethnically diverse patients in the Multi-Ethnic Study of Atherosclerosis showed that regular coffee drinkers (defined as 1 cup or more per day) have coronary artery calcium scores and cardiovascular event rates similar to others, suggesting that regular intake is safe (Am J Med. 2017. 130. 188-197).

• Grape juice (purple), based on a 14 day study in 15 patients with coronary artery disease, in which 7.7 ml/kg/day improved flow-mediated vasodilation and reduced susceptibility of LDL to oxidation (Circulation. 1999. 100. 1050-1055).

• Green tea- see ‘Tea’ just below

• Milk:

  • Milk consumption positively correlated with risk of ischemic heart disease in a survey of 21 countries (Proc Nutr Soc. 1980. 39. 77A).

  • Xanthine oxidase is an enzyme which occurs naturally in cow’s milk, and may increase risk of heart disease.

  • Homogenization of cow’s milk (extends shelf life and prevents cream from rising to the top) causes protein molecules such as xanthine oxidase to become surrounded by a protective coating of fat molecules, and it reduces the size of these fat particles to the point whereby they can be absorbed intact from the intestinal tract into the bloodstream.

  • Cardiologist Kurt A. Oster has hypothesized that xanthine oxidase in cow’s milk causes destruction of human arterial walls, predisposing to atherosclerosis. This hypothesis is controversial – the presence of antibodies to cow xanthine oxidase in the blood of humans with atherosclerosis and the presence of cow xanthine oxidase in human atherosclerotic plaque provides some support for this hypothesis. Folic acid inhibits xanthine oxidase in vitro, and a trial in 80 patients suggests that folic acid (40-80 mg/day in the trial) may prevent progression of atherosclerosis (Clin Res. 1976. 24. 521A). A book on this subject is The XO Factor (1983).

  • Note that skim milk is not homogenized and therefore xanthine oxidase in skim milk is probably degraded in the intestine and not absorbed intact into the blood stream.

  • Note that butter and cheese contain little or no biologically active xanthine oxidase, and thus pose little or no risk.

• Pomegranate juice – studies show beneficial effects on blood pressure and blood sugar, but an 18 month RCT in 383 people failed to show a beneficial effect of 240 ml daily of pomegranate juice on carotid intima media thickness (Am J Cardiol. 2009. 104. 936-942).

• Tea:

  • In the Seven Countries Study, a cross cultural study of 16 cohorts, green tea consumption was inversely correlated with mortality from coronary heart disease after 25 years of follow-up (Arch Intern Med. 1995. 155. 381-386; Proc Soc Exp Biol Med. 1999. 220. 198-202).

  • In a meta-analysis of 10 cohort studies and 7 case-control studies, consumption of 3 cups of tea per day associated with an 11% decresase in risk of MI (Am J Epidemiol. 2001. 154. 495-503).

  • In the Rotterdam Study of 4807 subjects, tea consumption was associated with protection against heart disease (Am J Clin Nutr. 2002. 75. 880-886).

  • A prospective cohort study of more than 40,000 Japanese adults found that green tea consumption was inversely associated with cardiovascular mortality, with 5 or more cups per day required for the protective effect (JAMA. 2006. 296. 1255-1265).

  • Data from 6508 ethnically diverse patients in the Multi-Ethnic Study of Atherosclerosis showed that regular tea drinkers (defined as 1 cup or more per day) have less progression of coronary artery calcium scores and lower cardiovascular event rates, as compared to others, suggesting that regular intake is protective (Am J Med. 2017. 130. 188-197).

  • Possible mechanisms of protection include inhibition of development of new plaque (Circulation. 2004. 109. 2448-2453), inhibition of LDL oxidation (J Am Coll Nutr. 2005. 24. 342-346), and inhibition of platelet reactivity (FEBS Lett. 2003. 546. 265-270).

  • Milk may counteract the favorable health effects of tea on vascular function, based on a small study in 16 healthy postmenopausal women (Eur Heart J. 2007. 28. 219-223).

Exercise:

• It has been estimated that the 75% of adult Americans with an inadequate level of activity have a 2-fold higher risk of cardiovascular events (Annu Rev Public Health. 1987. 8 253-287).

• Benefit of exercise in terms of cardiovascular risk reduction is supported by a large amount of evidence, dating back to the 1980s (Berlin JA, Colditz GA. A meta-analysis of physical activity in the prevention of coronary artery disease. Am J Epidemiol. 1990. 132. 612-628).

• Benefit is seen in older adults as well (Batty GD. Physical activity and coronary heart disease in older adults: a systematic review of epidemiological studies. Eur J Public Health. 2002. 12. 171-176).

• Mechanism: in part by lowering BP, in part by lowering cholesterol, and in part by bring about regression of left ventricular hypertrophy (Arch Intern Med. 2002.162. 1333-1339).

• Data would suggest a linear, inverse dose-response relationship such that higher levels of physical activity are associated with further reduction in cardiovascular morbidity and mortality (Med Sci Sports Exerc. 2001. 33. S351-S358; Med Sci Sports Exerc. 2001. 33. S379-S399).

• Cardiorespiratory fitness is a surrogate marker for numerous health outcomes (JAMA. 1996. 276. 205-210; Am J Cardiol. 2001. 88. 651-656), and a RCT in 492 adults randomized to 1 of 4 interventions (30 minutes of walking at 45-55% maximum predicted HR 3-4 sessions per week, 30 minutes of walking at 65-75% maximum predicted HR 3-4 sessions per week, 30 minutes of walking at 45-55% maximum predicted HR 5-7 sessions per week, 30 minutes of walking at 65-75% maximum predicted HR 5-7 sessions per week), found that either hard exertion or high frequency of walking was associated with improvements in cardiorespiratory fitness, and these improvements were sustained for 24 months (Arch Intern Med. 2005. 165. 2362-2369).

• Prospective observational data in 73,743 postmenopausal women enrolled in the Women's Health Initiative Observational Study and followed for a mean of 3.2 years indicate that both walking and vigorous exercise are associated with reductions in cardiovascular events, irrespective of ethnic group, age, or body mass index. In women exercising for 45 minutes - 7 hours each week, the magnitude of the benefit, 3.6 to 7.2 fewer cardiovascular events per 1000 women over the 3.2 years, is similar in magnitude to the benefit in the AFCAPS/TexCAPS trial! (N Engl J Med. 2002. 347. 716-725 and editorial 755-756).

• Data from 44,452 participants in the Health Professionals' Follow-up Study, a prospective cohort study, show that regardless of the total volume of physical activity, higher average exercise intensity is associated with a reduced risk of heart disease (JAMA. 2002. 288. 1994-2000).

• Prospective data from an ethnically diverse cohort of women in the Women's Health Initiative Observational Study found that walking and vigorous exercise were associated with significant reduction in the risk of CV events in a graded manner, and independent of race, ethnic group, BMI, or age, such that those in the highest quintile of energy expenditure had a 53% reduction in the risk of a CV event (N Engl J Med. 2002. 347. 716-725).

• Analysis of data from the Framingham Heart Study cohort of 2236 male and 2873 female respondents from 1948-1951, followed biannually for 46 years, shows that years lived free of cardiovascular disease was increased by 1.1 years in men 50 years or older who have engaged in moderate physical activity, 3.2 years in men 50 years or older who have engaged in high physical activity, 1.3 years in women who have engaged in moderate physical activity, and 3.3 years in women who have engaged in high physical activity (Arch Intern Med. 2005. 165. 2355-2360).

• A systematic review and meta-analysis of 33 physical activity studies which included 883,372 participants reported pooled risk reductions of 35% of cardiovascular disease and 33% for all-cause mortality (Eur J CardiovascPrev Rehabil. 2008. 15. 239-246).

Siesta – a prospective cohort study in 23,681 individuals free of coronary disease at baseline showed that siesta is inversely correlated with coronary mortality, especially among working men (Arch Intern Med. 2007. 167. 296-301).

Tai Chi – in a 1 year RCT of individuals at high risk for heart disease, tai chi significantly boosted exercise capacity, lowered blood pressure, and improved levels of cholesterol, triglycerides, insulin and CRP (J Altern Complement Med. 2008. 14. 813-819).

Tobacco – smoking cessation is associated with a reduced risk of cardiovascular disease.

Weight loss – a meta-analysis of 21 cohort studies (n=302,296) shows that overweight is an independent risk factor for CHD, with the effect of overweight on BP and cholesterol levels accounting for only 45% of the increased risk of CHD (Arch Intern Med. 2007. 167. 1720-1728). This data would suggest that weight loss would reduce the risk of MI.

Supplements

• Antioxidants:  Citations for the studies referred to below found in Am Fam Physician. 2000. 62. 1359-1356, or Postgraduate Medicine. 2001. 109. 109-113.

  • Vitamin E: Prospective observational data from 7 published studies is fairly consistent for a protective effect of Vitamin E in doses of 100-800 IU per day; the magnitude of the benefit is such that 170-250 persons would have to take Vitamin E for 10 years to prevent one MI. Vitamin E in these doses is considered quite safe; the only relative contra-indication is coumadin therapy. HOWEVER, the preponderance of data from randomized, controlled trials fails to show a benefit of Vitamin E for primary prevention, and randomized, controlled trial data is superior to prospective observational data. For more information including citations of all the studies, return to my home page, click on vitamins, and scroll to Vitamin E, or read an excellent summary article in Mayo Clinic Proceedings, 2001, volume 76, pages 1131-1136.

  • Vitamin C: Evidence linking Vitamin C intake to cardiovascular disease is inconsistent, based on data from 8 published studies. NHANES I reported a significantly lower risk of cardiovascular death in persons with high intake of Vitamin C, but a randomized study of more than 29,000 residents in rural China over a 5 year period showed no significant benefits of Vitamin C supplements in reducing cardiovascular mortality, and the CLAS study showed no benefit of Vitamin C supplements in slowing the progression of atherosclerotic plaque in patients with coronary artery disease.

  • Beta carotene: There are 5 published prospective cohort studies, and 3 reveal no evidence of a protective effect, with the other 2 showing a protective effect only among smokers and ex-smokers (but there is data to suggest that smokers who take beta carotene supplements may actually increase their risk of lung cancer, so beta carotene supplements in smokers may not be a good idea). For more information with references, go to my home page, click on vitamins, and scroll to beta carotene.

• Chromium:

  • Benefit is theoretical - may increase HDL cholesterol and lower diabetes risk.

  • Many Americans may be deficient.

  • Present in whole grains, wheat germ, legumes, and peanuts.

• Cocoa flavanols

  • In a 3.6-year RCT of 21,442 US adults who were free of major cardiovascular disease at baseline and were randomly assigned to receive either 2 capsules per day of a cocoa extract (providing 500 mg per day of flavanols), a multivitamin, both treatments, or placebo, the incidence of total cardiovascular events (a composite of myocardial infarction, stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina) was significantly lower by 15% in the cocoa group than in the placebo group. No significant adverse effects were reported (Am J Clin Nutr. 2022. 115. 1490-1500). NOTE one would have to consume a large amount of cocoa powder or dark chocolate to obtain 500 mg per day of flavanols.

• Fish oil – see Omega 3 just below

• Garlic:

  • There is data that aged garlic in vitro increases the resistance of LDL to oxidation (J Nutr. 2006. 136. 765S-768S).

  • In a pilot study, aged garlic slowed the accumulation of coronary artery calcium (J Nutr. 2006. 136. 741S-744S).

  • May lower blood pressure and LDL cholesterol, but data in this regard is equivocal.

• Magnesium

  • Most of the population does not consume the RDA.

  • Low magnesium intake is linearly correlated with elevated CRP levels.

• Niacin:

  • Doses above 1 gram are necessary to lower LDL; lower doses may raise HDL.

  • NEGATIVE RCT (HPS2_THRIVE) in those at high risk of CAD, and already taking prescription statin (N Engl J Med. 2014. 371. 203-212).

  • Toxicity is a significant risk at high doses - gout, diabetes, liver disease.

• Omega 3 fatty acids (also see information at the top of this outline under the category of ‘Diet – Fish’). 

  • The American Heart Association in a 2002 position statement recommended two 3 ounce portions per week of fatty fish or 1 fish oil capsule (Circulation. 2002. 106. 2747-2757).

  • Negative Cochrane Review: An update of a previous Cochrane review in which 48 RCTs and 41 cohort studies examining the effect of fish oil supplementation on (1) overall mortality, (2) cardiovascular disease, and (3) in adults found no significant benefit of omega 3 supplements. The results of the RCTs (enrolling in total over 30,000 patients) and the cohort studies were analyzed separately, but primary and secondary prevention research results were combined for this meta-analysis. In this analysis, long-chain fatty acids (i.e. fish oil) did not produce results different from short-chain fatty acids (BMJ. 2006. 332. 752-760).

  • Negative meta-analysis: A meta-analysis of 20 double-blind RCTs (n = 68,680) of fish or fish oil for primary and secondary prevention showed “Overall, omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke …” None of the 20 trials were categorized as primary prevention trials – 13 were secondary prevention trials, 4 were mixed primary/secondary prevention trials, and 3 trials were in those with an implanted ICD. Nine of the studies had sample sizes > 1000; 2 of the 9 large studies were diet-based and the other 7 were supplement studies (JAMA. 2012. 308. 1024-1033).

  • Negative primary prevention trial: in a RCT of 12,513 men and women with multiple cardiovascular risk factors or atherosclerosis, but not MI, 1 gram of omega 3 fatty acids daily (containing at least 850 mg EPA + DHA) was not associated with improved outcomes at a median follow up of 5 years. The initially specified primary endpoint was cumulative rate of death, nonfatal MI, and nonfatal stroke. At one year, when the event rate was lower than expected, the primary endpoint was revised as time to death from cardiovascular causes or admission to the hospital for cardiovascular causes (N Engl J Med. 2013. 368. 1800-1808).

  • Negative meta-analysis and systematic review: A systematic review and meta-analysis of 27 RCTs (n=105,085) concluded “In patients with, or at high risk for, coronary heart disease, fatty acid supplementation does not prevent coronary events” (Ann Intern Med. 2014. 160. 398-406 as cited in ACP Journal Club. 2014. 161. JC7).

  • Negative meta-analysis: A meta-analysis of 18 RCTs (n = approximately 93,000) and 18 prospective cohort studies (n = approximately 732,000) which explicitly and specifically examined CHD risk as a function of EPA + DHA supplementation showed a 6% nonstatistically significant reduction in CHD risk in the RCTs and an 18% statistically significant reduction in CHD risk in the prospective cohort studies, for higher intakes of EPA + DHA. Subgroup analyses of the RCTs showed statistically significant CHD risk reduction among higher-risk populations, including those with elevated triglyceride levels (16% risk reduction in those with triglycerides > 150 mg/dl) and elevated LDL cholesterol (14% risk reduction in those with LDL > 130 mg/dl) [Mayo Clin Proc. 2017. 92. 15-29 and editorial 1-3].

  • Negative trial: In the ASCEND trial of 15,480 diabetics with no evidence of cardiovascular disease, at a mean follow up of 7.4 years, fish oil 1 gram daily (with each 1 gram capsule containing 460 mg of EPA and 380 mg of DHA) did reduce the risk of serious vascular events. Note olive oil 1 gram (a low dose of olive oil) was the placebo in this trial (N Engl J Med. 2018. 379. 1540-1550).

  • Negative Cochrane Review: The most recent update of the Cochrane review included 79 RCTs, 12 to 72 months in duration, 46 trial of primary prevention, 33 trials of secondary prevention and showed no significant reduction of mortality or CV events with fish oil supplementation. 71 trials examined EPA + DHA; 8 trials examined ALA. This review was done prior to the results of the ASCEND trial (just above) were available (Cochrane Database Syst Rev. 2018. 7. CD003177).

  • Negative trial: In the VITAL trial, a RCT of 25,871 older participants (median age 67 years), with a two-by-two factorial design of vitamin D3 2000 IU daily and fish oil 1 gram daily, containing 460 mg EPA + 380 mg DHA, “Supplementation with n-3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo” (N Engl J Med. 2019. 380. 23-32 and editorial 89-91).

    • Additional trial details - median follow up of 5.3 years, olive oil 1 gram (a low dose of olive oil) was the placebo, the primary outcome of “major cardiovascular events” was a composite of MI, CVA, or death from cardiovascular causes, positive secondary endpoint of lower incidence of MI and death from MI in the fish oil treatment group.

    • Additional findings - hazard ratio for death from any cause was 1.02 in the fish oil group and no excess risk of bleeding or other serious adverse events were observed in the fish oil group.

  • Negative trial: In the STRENGTH trial, a RCT of 13,078 patients at 675 academic and community hospitals in 22 countries, those randomized to 4 grams per day of EPA + DHA in carboxylic acid form had the same composite outcome of major adverse cardiovascular events as those randomized to a corn oil placebo. The trial was terminated early secondary to the null outcome. Entry criteria included high cardiovascular risk (70% of participants had DM), statin treatment, hypertriglyceridemia (median level of 240 mg/dl) and low levels of LDL. A greater rate of gastrointestinal adverse events was observed in the omega-3 fatty acid treatment group, and higher rates of atrial fibrillation were observed in the treatment group (2.2% versus 1.3%; P < 0.001). For reasons unclear, blood EPA levels were not linked with outcomes in this trial [JAMA. 2020. 324. 2268-2280 and editorial 2262-2264].

  • Positive trial: In the JELIS trial, an open label RCT of 18,645 Japanese with hypercholesterolemia (TC > 252 mg/dl), those randomized to 1800 mg per day EPA with statins had better outcomes than those assigned to statins alone – there was a 19% reduction in major coronary events (p=0.01) at 4.6 years of follow up. Major coronary event was defined as sudden death from cardiac causes, fatal or nonfatal MI, unstable angina, angioplasty, stenting, or CABG; outcomes were adjudicated independently (Lancet. 2007. 369. 1090-1098; Atherosclerosis. 2008. 200. 135-140). Limitations of this trial included the open label design and that the apparent benefit for the composite endpoint was driven by less objective components such as unstable angina and revascularization. Furthermore, the participants on average consumed plentiful amounts of dietary fish, and in many participants, statin therapy with low intensity rather than high intensity (Editorial. JAMA. 2020. 324. 2262-2264).

  • Positive meta-analysis: A meta-analysis of combined use of EPA and prescription statin medication versus statin medication alone (5 RCTs, n = 27,415) showed that EPA with statin significantly reduced the risk of major adverse cardiac events (MACE) by 18% (P <0.01) and MI by 30% (p < 0.01) but did not reduce the risk of CVA (Am J Cardiol. 2020. 125. 198-204).

• Vitamins B6, B12, and folate - ineffective at reducing risk despite effectiveness at lowering homocysteine (a known risk marker for cardiovascular disease).

  • A retrospective cohort study shows low serum folate is associated with an increased risk of CHD (JAMA. 1996. 275. 1893-1896).

  • A large, prospective cohort study shows higher dietary intake of folate and Vitamin B6 is associated with a lower risk of CHD (JAMA. 1998. 279. 359-364).

  • A meta-analysis shows that folate lowers serum homocysteine levels by 25% and addition of B12 lowers levels by another 7%, but addition of B6 results in no further reduction. There seems to be a plateau effect at a dosage of 1 mg per day of folate (BMJ. 1998. 316. 894-898).

  • For a summary of the data on homocysteine lowering and risk of CHD, go to my home page, click on ‘Cholesterol’ and scroll all the way down to ‘Homocysteine.’

• Vitamin C – see ‘antioxidants’ just above

• Vitamin D:

  • In NHANES 2001-2004, low vitamin D levels found in 74% of 8351 adults with cardiovascular diseases (Am J Cardiol. 2008. 102. 1540-1544).

  • In the Framingham Offspring Study, a prospective observational study in 1739 middle aged whites, the hazard ratio for cardiovascular events was 1.8 for those with a 25 hydroxy vitamin D level < 10 ng/ml (Circulation. 2008. 117. 503-511).

  • A prospective nested case control study in 18,225 men in the Health Professionals Follow-Up Study showed that low levels of 25-OH vitamin D are associated with a higher risk of MI in a graded manner, even after controlling for potential confounding variables (Arch Intern Med. 2008. 168. 1174-1180).

  • A prospective cohort study of 3258 male and female patients scheduled for coronary angiography at a single tertiary care center (angiography indicated based on symptoms or abnormal noninvasive test results) found that those patients in the lowest quartile of 25-OH vitamin D levels had significantly higher cardiovascular and all-cause mortality than those in the highest quartile, at 7.7 years of follow up (Arch Intern Med. 2008. 168. 1340-1349).

  • Additional cross sectional data show that MI incidence increases as distance from the equator increases (QJM. 1996. 89. 579-589), that 25-hydroxy vitamin D levels are lower in heart attack sufferers compared with controls (Int J Epidemiol. 1990. 19. 559-563), and show that heart attacks are 53% more common in winter months than summer months in the U.S. (J Am CollCardiol. 1998. 31. 1226-1233).

  • The only intervention trial is the Women’s Health Initiative - calcium + vitamin D were not associated with a reduction in cardiovascular events; this was not a predetermined endpoint in the study though (Circulation. 2007. 115. 846-854).

• Vitamin E– see ‘antioxidants’ just above

Aspirin: data on benefit is mixed with the most recent data negative

• An article by Dasa O et al. entitled “Aspirin in Primary Prevention: What Changed? A Critical Appraisal of the Current Evidence” (Am J Cardiol. 2021. 141. 38-48) explores the possible mechanisms which have led to the alterations in the published evidence on risk versus benefit for primary prevention. The authors conclude “the current recommendations might be improved by recalibration of the cardiovascular risk threshold above which aspirin should be recommended for primary prevention, including incorporation of newer risk assessment modalities such as calcium scoring. A second enhancement would be developing a bleeding risk calculator to support clinicians’ assessment of risk versus benefit. The use of enteric-coated aspirin vs non-enteric coated aspirin should also be reassessed.” The authors cite some data that enteric coated aspirin may be less effective than regular aspirin, associated with a higher risk of aspirin resistance, and yet not any safer as pertaining to risk of GI bleeding,

• In the 2022 update of the USPSTF Recommendation Statement on “Aspirin Use to Prevent Cardiovascular Disease,“ the Recommendation is as follows: “The decision to initiate low-dose aspirin use for the primary prevention of CVD in adults aged 40 to 59 years who have a 10% or greater 10-year CVD risk should be an individual one. Evidence indicates that the net benefit of aspirin use in this group is small. Persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit. (C recommendation) The USPSTF recommends against initiating low-dose aspirin use for the primary prevention of CVD in adults 60 years or older. (D recommendation) [JAMA. 2022. 327. 1577-1584]. The basis for the 2022 recommendations is an updated review that included 11 randomized trials of low dose aspirin (dose of 100 mg/d or less) for primary prevention (JAMA. 2022. 327. 1585-1597)..

• In the 2019 ACC/AHA (American College of Cardiology/American Heart Association) Guideline on the Primary Prevention of Cardiovascular Disease (posted at www.acc.org) the recommendation for use of aspirin for primary prevention is downgraded to “physician preference.”

• A systematic review and meta-analysis of 13 RCTs, each enrolling at least 1000 participants and each with at least 12 months of follow up, (n = 164,225 participants and 1,050,511 participant years, median age 62 years) found that “The use of aspirin in individuals without cardiovascular disease was associated with a lower risk of cardiovascular events and an increased risk of major bleeding (JAMA. 2019. 321. 277-287).

• In the ASPREE RCT of 19,114 healthy elderly (age 70 years or older, median age of 74 at enrollment) in the US and Australia, aspirin 100 mg daily did not prolong disability free survival (primary composite endpoint of death, dementia, or persistent physical disability) but was associated with a higher rate of major hemorrhage (3.8% vs. 2.8%, HR 1.38, 95 % CI 1.18 - 1.62, P < 0.0001). The trial was terminated at a median of 4.7 years of follow up (N Engl J Med. 2018. 379. 1499-1508). This dose of aspirin also did not reduce the incidence of cardiovascular disease, a secondary endpoint which was defined as a composite of fatal coronary heart disease, nonfatal MI, fatal or nonfatal stroke, or hospitalization for heart failure (N Engl J Med. 2018. 379. 1509-1518). An unexpected result of this trial was slightly higher all-cause mortality in those randomized to aspirin (HR 1.14, 95 % CI 1.01 - 1.29) which was attributed to a higher rate of cancer-related death (HR 1.31, 95 5 CI 1.19 - 1.56) [N Engl J Med. 2018. 379. 1519-1528].

• In the ARRIVE RCT of 12,456 participants without diabetes and with low to moderate baseline risk of cardiovascular disease, during 5 years of follow-up, aspirin 100 mg daily did not confer any vascular benefit, but was associated with a higher risk of bleeding complications. The incidence of the primary composite endpoint of MI, TIA, unstable angina, stroke, or death from cardiovascular disease was 4.3% vs 4.5%, P=0.60) whereas the incidence of GI bleeding events was higher in the aspirin group (HR 2.1, P=0.001) [Gaziano JM et al. Lancet. Epub 8/24/18 as cited in an editorial N Engl J Med. 2018. 379. 1572-1574].

• USPSTF (United States Preventive Services Task Force) 2016 guidelines (Ann Intern Med. 2016. 164. 836-845 and editorial 846-847)

  • "The USPSTF recommends initiating low-dose aspirin for primary prevention of CVD (cardiovascular disease) and CRC (colorectal cancer) in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, and are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low dose aspirin therapy for at least 10 years (B recommendation)." Based on estimates from NHANES survey data, 25% of US men and 4% of US women aged 50-59 meet these criteria. Note the magnitude of benefit is low, and even low-dose aspirin is not risk-free.

  • "The decision to initiate low-dose aspiring use for primary prevention of CVD and CRC in adults 60 to 69 years who have a 10% or greater 10-year CVD risk should be an individualized one (C Recommendation)." Based on estimates from NHANES survey data, 77% of US men and 22% of US women aged 60-69 meet these criteria.

  • "The current evidence is insufficient to assess the balance of benefits and harms of initiating aspirin use for primary prevention of CVD and CRC in adults younger than 50 years. (I statement)."

  • "The current evidence is insufficient to assess the balance of benefits and harms of initiating aspirin use for primary prevention of CVD and CRC in adults aged 70 years or older. (I statement)."

  • Dosage of aspirin - 75 mg daily seems as effective as higher doses. Risk of GI bleeding may increase with age. "A pragmatic approach consistent with the evidence is to prescribe 81 mg per day..."

  • Data

    • 5 new primary prevention trials of about 95,000 persons since the 2009 USPSTF guidelines were published.

    • Commissioned systematic reviews of (1) aspirin for primary prevention of cardiovascular events (Ann Intern Med. 2016. 164. 804-813), (2) aspirin for prevention of cancer (Ann Intern Med. 2016. 164. 814-825), and (3) bleeding risks associated with aspirin use for primary prevention (Ann Intern Med. 2016. 164. 826-835).

• Historically

  • USPSTF 2009 guidelines included sex specific tables by decade of life estimating quantitatively the risk versus benefit of aspirin, and recommended aspirin in men aged 45-79 years and women aged 55-79 years for whom the individual 10 year risk of cardiovascular disease is 10% or greater ( Ann Intern Med. 2009; 150: 396-404). These recommendations were based in large part of data derived from the Antithrombotic Trialists' Collaboration, which included a meta-analysis of individual patient data from 6 primary prevention trials of 95,000 persons (Lancet. 2009. 373. 1849-1860).

  • USPSTF 2002 guidelines - the task force recommended strongly that clinicians discuss aspirin chemoprevention with people at increased risk for coronary disease and suggested that decisions be informed by risk calculators and tables with estimated benefits and harms (Ann Intern Med. 2002;136(2):157-160).

  • USPSTF 1996 guidelines - concluded the balance of harms and benefits was too close to justify a general recommendation

  • USPSTF 1989 guidelines - recommendation to “consider” aspirin prophylaxis for primary cardiovascular prevention in men 40 years or older with coronary risk factors and low bleeding risk. The sole basis for that recommendation was 2 randomized trials in which study participants were exclusively male physicians (Editorial. JAMA. 2022. 327. 1552-1554).

• Historical data

  • Negative trial – Japanese Primary Prevention Project (JPPP) – multicenter, open-label, randomized trial of ECASA 100 mg daily in 14,464 patients over age 60 and with atherosclerosis risk factors. There was no significant reduction in the composite of cardiovascular death, nonfatal stroke, and nonfatal MI (JAMA. 2014. 312. 2510-2520 and editorial 2503-2504).

  • A meta-analysis of 9 RCTs with at least 1000 participants each, reports that over a mean follow up of 6.0 years in over 100,000 participants, aspirin treatment reduced total CVD events by 10% (number needed to treat of 120), primarily due to a reduction in nonfatal MI. There was no significant reduction in CVD death (CI 0.85 – 1.15) or in cancer mortality (CI 0.84-1.03). There was a decreased risk of nonfatal MI (OR 0.80, 95% CI 0.67 – 0.96), but an increased risk of nontrivial bleeding events (number needed to harm of 73). Thus, on average, the harms of aspirin are similar to the risks (Arch Intern Med. 2012. 172. 209-216, and Invited Commentary 217-218).

  • A meta-analysis produced borderline results for a reduction in all-cause mortality, MI, and ischemic stroke (Am J Med. 2011. 124. 621-629).

  • A meta-analysis reported a reduction in the risk of total cardiovascular events [OR 0.87, 95% CI 0.80 – 0.93, p =0.001] (Am J Cardiol. 2011. 107. 1796-1801).

  • A 2009 meta-analysis by the Antithrombotic Trialists’ (ATT) collaboration analyzed individual participant data from 6 primary prevention trials (n=95,000) and found no significant reduction of total mortality or CVD mortality. The relative risk of CVD events was reduced by 12% (absolute risk reduction from 0.57% to 0.51%) [Lancet. 2009. 373. 1849-1860].

  • A meta-analysis of the five primary prevention trials including 55,580 subjects showed that aspirin reduced the risk of a first MI by 32% and the risk of any significant vascular event by 15%, but had no effect on cardiovascular mortality (Arch Intern Med. 2003. 163. 2006-2010).

    • Only two of these trials, the HOT study and the PPP trial included women. Thus, in the five trials analyzed, only 20% of participants were women.

    • When data was stratified by sex in the HOT study, the decrease in risk in women was not significant (J Hypertens. 2000. 18. 629-642).

    • In the PPP trial, subgroup analysis by sex was not performed (Lancet. 2001. 357. 89-95).

    • The PPP (Lancet. 2001. 357. 89-95), an open label trial of ASA 100 mg/day did show a 44% reduction in cardiovascular mortality with ASA, but it was the only study of the 5 which showed this, and the effect was not apparent in the meta-analysis.

• Stratification of benefit by sex (male versus female) – a sex-specific meta-analysis of 6 RCTs concluded that aspirin reduces the risk of MI but not stroke in men, and reduces the risk of stroke but not MI in women (JAMA. 2006. 295. 306-313).

  • There were 44,144 male participants in these 6 RCTs – in aggregate, there was 14% reduction in cardiovascular events (stroke, MI, cardiovascular death), with a 32% reduction in MI, but with no specific effect on stroke or cardiovascular mortality.

  • There were 51,342 female participants in these 6 RCTs – in aggregate, there was a 12% reduction in cardiovascular events (stroke, MI, cardiovascular death), with a 17% reduction in stroke, but with no specific effect on MI or cardiovascular mortality.

  • NOTE in the Women’s Health Study, in which 39,876 women were randomized to aspirin 100 mg every other day or placebo, and followed for a mean of 10.1 years, aspirin did not affect the primary endpoint (an aggregate measure of nonfatal MI, nonfatal stroke, or CV death) except in the subgroup of women over age 65 (26% reduction, P=0.008). However aspirin did reduce the incidence of all strokes by 17% (P=0.04), the incidence of ischemic strokes by 24% (P=0.009), and the incidence of TIA by 22% (P=0.01) [New Engl J Med. 2005. 352.1293-1304].

  • NOTE in a prospective, nested, case control study of 79,439 women enrolled in the Nurses’ Health Study who had no history of cardiovascular disease, at 24 years of follow up, current aspirin use was associated with a relative risk of cardiovascular mortality of 0.62 (Arch Intern Med. 2007. 167. 562-572). An accompanying editorial explores possible reasons that the positive outcome in this observational study differs from the negative outcome (regarding cardiovascular mortality of the meta-analysis of 5 primary prevention trials cited just above (Arch Intern Med. 2007. 167. 535-536).

• Aspirin for primary prevention in diabetics

  • In the ASCEND trial of 15,480 diabetics aged 40 year or older and with no evidence of cardiovascular disease, at a mean follow up of 7.4 years, aspirin 100 mg daily did reduce the risk of major vascular events (8.5% vs. 9.6%, RR 0.88, 95 % CI 0.79 - 0.97, p=0.01) but also increased the risk of major bleeding events (4.1% vs. 3.2%, RR 1.29, 95 % CI 1.09 - 1.52, p=0.003). there was no effect of aspirin on cancer rates in this trial. An accompanying editorial notes that “serious vascular events” includes small ischemic events detected only by high sensitivity cardiac enzyme testing, and that all-cause mortality was similar in both groups (RR 0.94, 95 % CI 0.85 - 1.04) [N Engl J Med. 2018. 379. 1529-1539 and editorial 1572-1574].

  • In a meta-analysis of 10 RCTs (n = 16,690) of diabetics without cardiovascular disease at baseline, aspirin did not prevent cardiovascular events (or increase bleeding) compared with placebo or no treatment (Kunutsor SK et al. Diabet Med. Epub 2016).

• Risk:

  • The risk of hospitalization for major GI bleeding or cerebral hemorrhage is significant – a population-based cohort study, which used administrative data from 4.1 million citizens in Italy found that during a median follow up of 5.7 years, the incidence rate of hemorrhagic events was 5.58 per thousand person-years for users of low dose aspirin (defined as < 300 mg/day), as compared with 3.60 per thousand person-years for those without aspirin use. Of note, diabetes was associated with an increased risk of major hemorrhage (RR 1.36), independent of aspirin use (JAMA. 2012. 307. 2286-2294).

  • Bleeding risk can be predicted using risk models that were developed using PREDICT, a web-based decision support system integrated with an EMR, and data from a prospective cohort in New Zealand of 385,191 persons; these risk models due require external validation (Ann Intern Med. 2019. 170. 357-368 and editorial 411-413).

  • In post hoc analysis of the ASPREE RCT of 19,114 persons, amongst healthy, community dwelling older adults, low-dose aspirin increased incident anemia at 4.7 years. While the incremental reduction in Hb was only 0.6 g/L over 5 years, there was a 17% increased relative risk of anemia in those taking low-dose aspirin (Ann Intern Med. 2023. 176. 913-921).

• Dose of aspirin for prevention

  • A review article by James Dalen, MD, associate editor of The American Journal of Medicine (Am J Med. 2006. 119. 198-202) concludes:

    • Randomized clinical trials have shown that 81 mg of aspirin is inadequate for primary prevention of MI (and stroke) in men and women.

    • These studies indicate that 162 mg of aspirin (or 325 mg every other day) is adequate to prevent MI in men.

    • The dose of aspirin necessary for primary prevention of MI in women is unknown, but exceeds 100 mg/day.

    • The risk of major bleeding is the same in those taking 81 mg of aspirin and those taking 162 mg of aspirin, but there is an increase in minor bleeding with aspirin 162 mg compared with aspirin 81 mg.

  • However, a systematic review states in the conclusions section of the abstract, “Currently available evidence does not support routine, long-term use of aspirin dosages greater than 75 to 81 mg/d in the setting of cardiovascular disease prevention. Higher dosages, which may be commonly prescribed, do not better prevent events but are associated with increased risks of gastrointestinal bleeding.” (JAMA. 2007. 297. 2018-2024).

    A Commentary by James Dalen MD (Am J Med. 2010. 123. 101-102) reiterates his belief that the dose necessary for primary prevention is 162 mg daily. In the Commentary, he states that each of the 7 RCTs of ASA for primary prevention since 1998 used a dose of ASA of 100 mg or less, and 6 of the 7 studies were negative, with the 7th trial showing a p=0.04 for ASA 75 mg daily for prevention of MI; whereas the Physicians’ Health Study (N Engl J Med. 1989. 321. 129-135) used a dose of ASA of 325 mg every other day, and reported a 44% reduction in MI (p<0.00001).

  • Analysis of individual patient data from 9 primary prevention RCTs (n=102,621) found that “In primary prevention, low-dose aspirin vs. control reduced cardiovascular events in patients weighing < 70 kg but not in those weighing > 70 kg. Higher-dose aspirin was effective at higher body weights.” An accompanying commentary states “We need more research on weight-based dosing of aspirin before changing clinical practice” (Lancet. 2018. 392. 387-399 as cited in ACP Journal Club. 2018. 169. JC57).

• Note that taking NSAIDs with aspirin may eliminate the beneficial antiplatelet effect of low dose aspirin.

  • Test tube data that ibuprofen antagonizes the irreversible platelet inhibition induced by aspirin, whereas concomitant acetaminophen, diclofenac, and rofecoxib do not have this effect (N EnglJ Med. 2001. 345. 1809-1817).

  • A retrospective analysis of 7107 patients who were discharged after first admission for cardiovascular disease and who were prescribed low dose (<325 mg) aspirin showed that patients taking aspirin plus ibuprofen had a statistically significant higher all-cause mortality than those taking aspirin alone (Lancet. 2003. 361. 573-574).

  • A subgroup analysis in the Physician's Health Study, a 5 year RCT of 325 mg aspirin on alternate days among 22,071 apparently healthy US male physicians with prospective observational data on use of NSAIDs, showed that regular use of NSAIDs (at least 60 days per year) was significantly associated with MI, and aspirin appeared to have no protective benefit in this subgroup. Intermittent use of NSAIDs however did not inhibit the clinical benefits of aspirin (Circulation. 2003. 108. 1191-1195).

  • It is hypothesized since NSAIDs inhibit platelets reversibly that taking a NSAID 2 hours after taking aspirin may eliminate the risk of the NSAID offsetting the beneficial effect of aspirin on platelets.

• Note that in a prospective clinical cohort study, low dose aspirin (<160 mg per day) did not increase mortality in patients also taking an ACE inhibitor for CHF, but high dose aspirin (>325 mg per day) did increase mortality rates (Arch Intern Med. 2003. 163. 1574-1579).

Bempedoic acid (Nexleton)

• ATP citrate lyase inhibitor, approved by the FDA in 2020.

• Mechanism of action is upstream of the statins and because this is a prodrug which is metabolized to its active metabolite in the liver but not in the peripheral tissue, there are very few, if any, muscle related side effects (N Engl J Med. 2019. 380. 1022-1032).

• In a specified subgroup analysis of the CLEAR RCT of 13,970 patients, in the group of 4206 (30%) with characteristics associated with a high risk of adverse cardiovascular outcomes, but without a prior event, bempedoic acid was effective in prevention of adverse cardiovascular outcomes in this primary prevention population (JAMA.  2023.  330. 131-140).

Bile acid sequestrants

• Bind to bile acids in the small intestine, which interrupts the enterohepatic circulation of bile acids and increases the conversion of cholesterol to bile acids in the liver.

• Benefit shown in the LRC-CPPT, with a statistical reduction in CHD death and nonfatal MI in the group receiving cholestyramine 24 grams/day (JAMA. 1984. 251. 351-364).

• Interfere with absorption of other medications, so must be taken at a different time of the day from other medications.

Fibrates - PPAR (peroxisome proliferator-activated receptor) alpha-agonists

• Statistically significant reduction in major coronary events shown in the Helsinki Heart Study, a primary prevention trial with gemfibrozil (N Engl J Med. 1987. 317. 1237-1245).

• Significant reduction in major coronary events in the Fenofibrate Intervention and Event Lowering in Diabetes trial, using fenofibrate (Tricor®) 200 mg daily (Lancet. 2005. 366. 1849-1861).

Statins:

• Numerous major primary prevention trials demonstrate that lowering LDL cholesterol levels (and in JUPITER, lowering hs-CRP levels) with statins reduces CHD events. A Cochrane review of statins for primary prevention identified 18 RCTs (n=56,934, mean age 57, age range 40-75) and found that “statins reduce mortality and major vascular events and increase the risk for diabetes without increasing other adverse events.” Specifically, the Cochrane review concluded there was no increased risk of cancer, myalgia, rhabdomyolysis, liver enzyme elevation, renal dysfunction, or arthritis associated with statins. Discontinuation rate was 12% in the active treatment group, and 12% in the placebo group. Relative risk reduction with statins in primary prevention trials (14% for all-cause mortality, 22% for fatal and nonfatal cardiovascular disease, 27% for coronary heart disease, 22% for stroke, and 38% for coronary revascularization) is similar to RRR in secondary trials, but NNT for 5 years in primary prevention trials to avoid one death is 138 (compared to NNT in secondary prevention trials of 30). Caution regarding findings, as all but one of the trials were partly or fully funded by pharmaceutical companies (Cochrane Database Syst Rev. 2013. CD004816, as cited in ACP Journal Club. 2013. 159. JC2, and as cited in a JAMA Clinical Evidence Synopsis and accompanying editorial. JAMA. 2013. 310. 2451-2452 and 2405-2406).

  • The AFCAPS/TexCAPS study was a RCT of 5608 men and 997 women at average risk, with an average LDL of 150. Those on lovastatin 20-40 mg daily had a 37% lower relative risk of heart attacks. However total mortality was the same in both groups (JAMA. 1998. 279. 1615-1622).

  • The Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA), a trial of 19,342 hypertensive patients (aged 40-79 years with at least three other cardiovascular risk factors), 10,305 with non-fasting total cholesterol concentrations 6.5 mmol/L or less were randomized to receive either atorvastatin 10 mg or placebo. Treatment was stopped after a median follow-up of 3.3 years. By that time, 100 primary events (non-fatal myocardial infarction and fatal CHD) had occurred in the atorvastatin group compared with 154 events in the placebo group – thus there was a 36% lower risk of events in the treatment group (p=0.0005). Note though that the absolute risk reduction was only 1%, with a 3% event rate in the placebo group and a 2% event rate in the treatment group. Thus the NNT for 3.3 years is 100 people to prevent one heart attack (Lancet. 2003. 361. 1149-1158).

  • The CARDS study was a multicenter RCT of 2838 diabetics without CVD, which showed a 37% reduction in major cardiovascular events with atorvastatin (Lancet. 2004. 364. 685-696).

  • The WOSCOPS study was a RCT of 6595 men aged 45-64 at high risk, with average LDL cholesterol before treatment of 192. Those on pravastatin 40 mg daily had a 31% reduction in relative risk of heart attacks. At 5 years of follow up, the combined outcome of death from definite coronary artery disease or definite nonfatal MI was reduced from 7.9% to 5.5% (p<0.001). There was no adverse effect on non-cardiovascular death (New Engl J Med. 1995. 333. 1301-1307). The population enrolled in this study was re-examined 5 years after the trial ended (corresponding to 10 year follow up from initial trial enrollment). 38.7% of the original statin group and 35.2% of the original placebo group were being treated with a statin. The combined outcome of death from definite coronary artery disease or definite nonfatal MI was 8.6% in the original pravastatin group and 10.3% in the original placebo group (p=0.02) [N EnglJ Med. 2007. 357. 1477-1486 and editorial 1543-1545].

  • The JUPITER trial, in which 17,802 men and women with LDL < 130 mg/dl and hs-CRP > 2, treated with each rosuvastatin 20 mg/day or placebo, those in the treatment group showed a 50% reduction in LDL, a 37% reduction in hs-CRP, and a 54% reduction in MI, 51% reduction in ischemic stroke, 46% reduction in the need for CABG or angioplasty, 43% reduction in VTE, and a 20% reduction in all-cause mortality [p=0.02](New Engl J Med. 2008. 359. 2195-2207).

  • A meta-analysis of 8 RCTs (N = 65,383) reported that in adults aged 50 to 75 without CVD, treating 100 persons with statins for 2.5 years prevents one MACE (JAMA Intern Med. 2021. 181. 179-185; as cited in ACP Journal Club. 2021. 174. JC39).

• HOWEVER there are also negative studies of primary prevention (Commentary. Am J Med. 2016. 129. 235-237)

  • 3 RCTs of statin therapy in CKD failed to show significant benefit (even though other studies in CKD did show benefit) - negative studies are German Diabetes and Dialysis Study (4D study), AURORA study, and SHARP study.

  • In the PROSPER study of seniors aged 70-82, those without prior vascular disease showed no significant reduction in cardiovascular events or mortality with pravastatin.

  • 3 RCTS in diabetics failed to show significant mortality benefit (ASPEN, 4D, and CARDS). Furthermore, only CARDS showed a significant reduction in cardiovascular events.

• The American Heart Association and American College of Cardiology in 2013 published “2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults” (Stone NJ et al. Circulation. Epub 11/12/2013.) recommends moderate-intensity or high intensity statin therapy for the primary prevention of atherosclerotic cardiovascular disease in individuals with 7.5% or greater 10 year atherosclerotic cardiovascular disease risk, and consideration of moderate-intensity statin treatment for individuals with a 5% to 7.5% 10 year risk. Note though that statins have not been shown to reduce risk in trials performed in populations with heart failure or those receiving maintenance hemodialysis.

• USPSTF guidelines published in 2016, based on 19 RCTs, and recommended statin prescription in individuals with a 10% or greater 10-year risk of CVD (JAMA. 2016. 316. 1997-2007).

• USPSTF updated guidelines in 2022 (guidelines based on only one additional RCT since 2016) recommend the following (JAMA. 2022. 328. 746-753).

  • Statin treatment for adults ages 40-75 who have 1 or more CVD risk factor and an estimated 10-year CVD risk of 10% or greater (B recommendation).

  • Statin treatment for adults ages 40-75 with a 10-year CVD risk of 7.5% - 9.9% (C recommendation).

  • Insufficient evidence to assess balance of benefits and harms of initiating statins for primary prevention in adults 76 years or older (I statement).

• Statins for primary prevention in subgroups

  • Congestive heart failure (CHF) – lack of benefit on cardiovascular outcomes in large clinical trials, namely rosuvastatin in CORONA (N Engl J Med. 2007. 357. 2248-2261) and rosuvastatin in GISSI-HF (Lancet. 2008. 372. 1231-1239).

  • Chronic kidney disease

    • For those not requiring dialysis, a Cochrane review shows reductions in cardiovascular events, cardiac death and all cause death (Cochrane Database Syst Rev. 2009. CD007784).

    • For those requiring dialysis, major clinical trials report no protective effect (Cochrane Database Syst Rev. 2009. CD004289).

  • Diabetes – 9 clinical trials (n=16,032) show an 8%-50% reduction in 10 year risk of major cardiovascular events (Diabetes Care. 2009. 32 Suppl 1. S13-S61).

  • HIV - in adults with HIV, receiving ART, and with low to moderate cardiovascular risk, daily pitavastatin reduced MACE over a median of 5.1 years. Pitavastatin does not interact with ART (N Engl J Med. 2023. 389. 687-699).

  • Seniors – some data on benefit; NOTE very limited data for those > age 75

    • PATE study of >600 patients, mean age 63, comparing low dose and high dose pravastatin (J Atheroscler Thromb. 2001. 8. 33-44).

    • SAGE study of 893 patients aged 65-85, comparing high dose atorvastatin and high dose pravastatin (Circulation. 2007. 115. 700-707)

    • A cohort of 20,132 high risk male veterans at least 60 years of age (Prev Cardiol. 2009. 12. 80-87)

    • PROSPER study (see ‘Secondary Prevention’ below in this outline).

  • Women – although under-represented in clinical trials, risk reduction in men and women seems similar (Curr Pharm Des. 2009. 15. 1054-1062; Circulation. 2010. 121. 1069-1077).

• Cost-effectiveness of statins: A Markov model indicates that adding a statin to aspirin costs $56,200 per QALY in men with a 7.5% 10 year risk of CAD, but only $42,500 in men with a 10% 10 year risk of CAD (Ann Intern Med. 2006. 144. 326-336).

Secondary Prevention of Myocardial Infarction

Medications:

• ACE inhibitors:

  • A systematic review of 6 major ACE inhibitor trials (HOPE, SOLVD prevention, SOLVD treatment, AIRE, TRACE, and SAVE) shows a 22% reduction in major clinical outcomes.  The magnitude of benefit is much greater for those with ejection fraction <40%.  Based on this data from the 6 RCT's with 22,060 patients, aspirin does not significantly attenuate the beneficial effect of ACE inhibitors.  Only the SOLVD study suggested a small attenuation of benefit (Lancet. 2002. 360. 1037-1043).

• Angiotensin receptor blockers:

  • The data as of 2004 is mixed.

• Aspirin: NOTE in 2023 standard of care is shifting from Aspirin for secondary prevention to P2Y12 inhibitors for secondary prevention (see section below)

  • A 2009 meta-analysis by the Antithrombotic Trialists’ (ATT) collaboration analyzed individual participant data from 16 secondary prevention trials (n=17,000) and found that aspirin reduced the relative risk of total mortality and CVD mortality by 10%, and reduced the relative risk of CVD events by 20% (absolute risk reduction from 8.2% to 6.7%), with similar reduction in coronary events and ischemic stroke (Lancet. 2009. 373. 1849-1860).

  • Historically, a meta-analysis of 25 trials demonstrated that aspirin reduced vascular mortality by 15% and CVD events by 30% (BMJ. 1988. 296. 320-331). A follow up meta-analysis of approximately 70,000 patients with CVD found that aspirin 75-325 mg daily reduced CVD events by 33% (BMJ. 1994. 308. 81-106). A third meta-analysis confirmed these findings (BMJ. 2002. 324. 71-86).

  • Risk versus benefit – treating 10,000 patients for secondary prevention will prevent 250 major vascular events (NNT = 40), but will cause approximately 40 major extracranial bleeding events (number needed to harm = 240).

  • Dosage

    • Data suggests that 160 mg daily is the optimal dose of aspirin for secondary prevention.

    • A report suggests that aspirin at a daily dose of less than 100 mg daily is associated with a higher incidence of aspirin resistance in patients with coronary artery disease (Am J Med. 2005. 118. 723-727).

• Beta-Blockers:

  • Reduce mortality 22%, sudden death 33%, reinfarction 20% based on a meta-analysis (JAMA. 1988. 260. 2088-2093). Benefits for at least 1 year. Greatest benefit in those with reduced ejection fraction and ventricular arrhythmias.

  • Most trials which showed a benefit included patients with large myocardial infarctions and were conducted in an era before the availability of treatment with percutaneous coronary intervention, antithrombotic agents, high intensity statins, and renin-angiotensin-aldosterone system antagonists, so the clinical significance of these studies post the year 2000 is uncertain (N Engl J Med. 2024. 390. 1372-1381).

  • Lack of statistically significant benefit in a parallel-group open-label trial at 45 centers, and including 5020 patients who underwent early coronary angiography and had preserved ejection fraction (N Engl J Med. 2024. 390. 1372-1381).

• Bempedoic acid (Nexleton)

  • ATP citrate lyase inhibitor, approved by the FDA in 2020.

  • Mechanism of action is upstream of the statins and because this is a prodrug which is metabolized to its active metabolite in the liver but not in the peripheral tissue, there are very few, if any, muscle related side effects (N Engl J Med. 2019. 380. 1022-1032).

  • In the CLEAR RCT of 13,970 patients who had or were at high risk for atherosclerotic vascular disease, and unable to tolerate more than a very low-dose of statin, those randomized to 180 mg of bempedoic acid had a 21% lowering of LDL cholesterol, and a 13% lower risk of a composite endpoint of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or coronary revascularization, at a median of 3.4 years of follow-up (N Engl J Med. 2023. 388. 1353-1364 and editorial 1425-1426).

• Colchicine:

  • A meta-analysis of 5 RCTs with follow up of > 6 months (N = 11,790) found that colchicine reduced the risk of MI, CVA, and coronary revascularization but did not alter cardiovascular mortality. The dose of colchicine in 4 of the 5 trials was 0.5 my daily, and the dose in one trial (N = 100) was 0.5 mg twice a day (Am J Cardiol. 2021. 140. 33-38).

• Ezetimibe (Zetia):

  • Intestinal cholesterol absorption inhibitor, approved by the FDA in 2002.

  • Can be safely combined with statins. 

  • Inhibits absorption of not just dietary cholesterol but also the cholesterol released into the bowel as part of bile acids.

  • In the IMPROVE-IT trial of 18,144 adults hospitalized within the past 10 days for acute coronary syndrome, Zetia 10 mg daily, when added to Zocor 40 mg daily was associated with improved cardiovascular outcomes, as compared with Zocor monotherapy (N Engl J Med. 2015. 372. 2387-2397).

• Fibrates - PPAR (peroxisome proliferator-activated receptor) alpha-agonists

  • In the VA-HIT trial, a 5 year RCT in 2531 men with CAD, there was a statistically significant 22% reduction in the risk of nonfatal MI or coronary heart disease death in the men treated with gemfibrozil (Lopid) [N Engl J Med. 1999. 341. 408-418].

• Fully humanized monoclonal antibodies (evolocumab, alirocumab, and bococizumab)

  • Disrupt the interaction between PCSK9 and the LDL receptor – by inactivating PCSK9, these drugs decrease LDL receptor degradation, and increase recirculation of the receptor to the surface of the hepatocyte, thus lowering LDL levels in the bloodstream.

  • In the FOURIER trial, a 48 week RCT of evolocumab either 140 mg sub q every 2 weeks or 420 mg sub q monthly, in 27,564 patients with atherosclerotic cardiovascular disease, on statins, and with a median LDL cholesterol of 92 mg/dl, LDL levels were lowered to 30 mg/dl in the treatment group and there were reduced cardiovascular events in the treatment group at a median follow up of 2.2 years (N Engl J Med. 2017. 376. 1713-1722 and editorial 1790-1791).

  • In the ODYSSEY OUTCOMES trial, a RCT of 18,924 patients with acute coronary syndrome within 1 -12 months prior to trial and taking high-intensity statin treatment at trial entry, those randomized to receive alirocumab 75 mg sub q every 2 weeks had a lower composite primary endpoint of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization (9.5% vs. 11.1%, HR 0.85) at a median follow up of 2.8 years. The investigators calculated that 49 patients would need to be treated for 4 years to prevent the occurrence of one of the primary endpoints. Goal LDL in this trial was 25 -50 mg/dl; 750 patients were switched from treatment to placebo because they had two consecutive measurements of LDL cholesterol < 15 mg/dl on a reduced dose (75 mg) of alirocumab. Note that there was not a significant reduction in the secondary endpoints of death from coronary heart disease or death from cardiovascular causes (N Engl J Med. 2018. 379. 2097-2107 and editorial 2161-2162).

• Niacin - clinical data is mixed pertaining to primary and secondary prevention of MI (reduced risk of death/events). For detail, see the section of this web page on ‘Supplements,’ just below.

• P2Y12 inhibitors

  • This is a category of antiplatelet drugs which includes clopidogrel, ticlopidine, ticagrelor, prasugrel, and cangrelor.

  • In the CAPRIE trial, a RCT of 19,185 patients with a history of MI, stroke of symptomatic PVD, there was an 8.7% reduced risk of CVD events in the clopidogrel (Plavix) 75 mg/day group after 3 years, compared to the group which received aspirin 325 mg per day (Lancet. 1996. 348. 1329-1339).  In the CURE trial, a 12-month RCT comparing aspirin 75-325 mg per day versus aspirin plus clopidogrel 300 mg load and then 75 mg per day in 12, 562 patients randomized at the time of diagnosis of an acute coronary syndrome, there was a 20% reduction in CVD events in the aspirin plus clopidogrel group (N Engl J Med. 2001. 345. 494-502).

  • An individual patient data meta-analysis of 7 RCTs (n = 24,325) shows that single antiplatelet therapy with a P2Y12 inhibitor is more effective than aspirin for secondary prevention of cardiovascular disease (J Am Coll Cardiol. 2023. 82. 89-105).

• PCSK9 inhibitors - must be injected subcutaneously, not available as a pill

  • In a network meta-analysis of 17 RCTs (n = 13,083), PCSK9 inhibitors reduced LDL cholesterol by 57% compared with placebo, by 36% compared with ezetimibe (Zetia), and reduced all-cause mortality by 57% from 0.5% to 0.2%, but did not significantly reduce cardiovascular events or major adverse CV events. Neurocognitive adverse events were increased by 133% from 0.3% to 0.7% (Eur Heart J. 2016. 37. 536-545).

  • A meta-analysis of 24 RCTs (n = 10,159) show that PCSK9 inhibitors are associated with a 47% reduction in LDL cholesterol, and 26% reduction in Lipoprotein (a), compared with placebo or ezetimibe (Zetia) control groups (Ann Intern Med. 2015. 163. 40-51 and editorial 64-65).

• Statins (HMG CoA reductase inhibitors)

  • Benefits reported in several large clinical trials, which included >38,000 subjects. On average, statin use is associated with a reduction in vascular events of 23% to 34% and a reduction in mortality of 17% to 42%.

    • Scandinavian Simvastatin Survival Study (4S) of 4444 patients with a history of MI or active angina, which showed a 30% relative reduction in all-cause mortality, a 42% reduction in risk for coronary death, and a 34% reduction in major cardiovascular events at a median of 5.4 years of follow up (Lancet. 1994. 344. 1383-1389).

    • Cholesterol and Recurrent Events (CARE) [N Engl J Med. 1996. 335. 1001-1009]

    • Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) [New Engl J Med. 1998. 339. 1349-1357]

    • Heart Protection Study (HPS) of simvastatin in 20,536 high risk individuals in the UK (coronary disease, occlusive arterial disease, or diabetes), which showed an 18% reduction in coronary death and a 25% reduction in major cardiovascular events, with improved outcomes independent of baseline LDL, type or duration of diabetes, preexisting disease, or blood glucose control (Lancet. 2002. 360. 7-22).

  • A meta-analysis of 14 trials including 90,056 patients (5 trials were primary prevention and 9 trials were secondary prevention) showed that statins reduce 5 year overall mortality and specifically decrease cardiovascular morbidity and mortality. Patients at highest baseline risk derive the greatest benefit. Reductions in coronary events are greater with longer duration of use. Most of these trials used targeted doses of statins rather than titrating the dose to a pre-specified LDL level; it is uncertain how much of the benefit of the statins is derived from their lipid lowering effects versus pleotropic effects (Lancet. 2005. 366. 1267-1278, as reviewed in Am Fam Physician. 2006. 73. 690-693).

  • Pleotropic effects of statins: Return to Home Page and go ‘Cholesterol’ outline.

  • Statins for secondary prevention in seniors

    • Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) was conducted in 5804 high risk seniors (history of MI or multiple risk factors for CVD) aged 70-82, and showed a 15% reduction in risk of major cardiovascular events with pravastatin 40 mg/day. NOTE there was a 25% increase in new cancer diagnoses in patients randomized to pravastatin (Lancet. 2002. 360. 1623-1630).

    • A systematic review and meta-analysis of 29 RCTs (21, 492 of the 244, 090 participants in these 29 studies were > 75 years old) concluded that statin (and non-statin) lowering therapies reduced the risk of cardiovascular events in those > 75 years old, with no increased risk of cancer, hemorrhagic stroke, diabetes, or neurocognitive dysfunction. 77% of the included trials were secondary prevention trials (Lancet. 2020. 396. 1637-1643 as cited in ACP Journal Club. 2021. 174. LC38).

  • The guideline to lower LDL to 60-80 mg/dL in patients with coronary artery disease is based on data derived from trails in patients with acute coronary syndromes (ACS).

    • A 4.8 year RCT in 8888 adults who received either Lipitor 80 mg/day or Zocor 20 mg/day (titrated to 40 mg/day if total cholesterol was greater than 190 after 24 weeks) found using an intent to treat analysis that there was no difference in major coronary events between the Lipitor group with a mean LDL of 81 mg/dL and the Zocor group with a mean LDL of 104 mg/dL (JAMA. 2005. 294. 2437-2445).

    • A 2006 POEM article concludes that “Aiming for an LDL level of approximately 100 mg per dL seems optimal for most patients with stable disease” (Am Fam Physician. 2006. 73. 890-893).

    • A 2006 narrative review states at the end of the abstract “…current clinical evidence does not demonstrate that titrating lipid therapy to achieve proposed low LDL cholesterol levels is beneficial or safe.” Low is defined at the beginning of the abstract as <70 mg/dl (Ann Intern Med. 2006. 145. 520-530).

• Warfarin (Coumadin):

  • Historically, in WARIS I, which compared coumadin in a dose to achieve an INR of 2.8-4.8 and placebo, the incidence of major hemorrhage was twice as high in the coumadin group as the placebo group, but the mortality rate was reduced by 24% and the reinfarction rate by 34% (N Engl J Med. 1990. 323. 147-152).

  • Historically, a meta-analysis of 31 trials which compared aspirin plus coumadin with aspirin alone or placebo failed to show a statistically significant difference in MI incidence between the coumadin plus aspirin group and the aspirin alone group. There was however a trend toward a reduction in MI incidence, 4.2% in the aspirin plus coumadin group compared with 7.5% in the aspirin alone group (P=0.32). In retrospect, this trend may not have reached statistical significance because of the relatively small numbers of patients included (JAMA. 1999. 282. 2058-2067).

  • WARIS II is a randomized, multicenter, open label trial in 3630 patients, in which 1216 patients received coumadin to achieve anINR 2.8-4.2, 1206 received aspirin 160 mg daily, and 1208 received aspirin 75 mg combined with coumadin to achieve an INR of 2-2.5. Mean duration of observation was 4 years. The primary outcome was a composite of death, nonfatal reinfarction, or thromboembolic stroke. Primary outcome occurred in 20% of the aspirin group, 16.7% of the coumadin group (p = 0.03), and 15% of the aspirin plus coumadin group (p = 0.001). This represents an overall relative risk reduction of 19% in the coumadin group and 29% in the combined group. Episodes of major, nonfatal bleeding were observed in 0.62% of patients per treatment year in both groups receiving coumadin, and 0.17% of patients receiving aspirin. Conclude that warfarin alone or in combination with aspirin is superior to aspirin alone, but is associated with a higher risk of bleeding (N Engl J Med. 2002. 347. 969-974).

  • Historically, in WARIS I, which compared coumadin in a dose to achieve an INR of 2.8-4.8 and placebo, the incidence of major hemorrhage was twice as high in the coumadin group as the placebo group, but the mortality rate was reduced by 24% and the reinfarction rate by 34% (N Engl J Med. 1990. 323. 147-152).

  • However, the CARS study which compared aspirin with coumadin in a dose to achieve an a median INR of 1.3 (Lancet. 1997. 350. 389-396) and the CHAMP study which compared aspirin with coumadin in a dose to achieve a median INR of 1.8 (Circulation. 2002. 105. 557-563) found no reduction in mortality or reinfarction or stroke rate in the warfarin groups compared to the aspirin group.

  • Conclude from these and the recently published ASPECT-2 study and the APRICOT-2 trial that if a target INR of 3 (range 2.5-3.5) is chosen for coumadin alone or a target INR of 2.5 (range 2.0-3.0) is chosen for aspirin plus coumadin, that "the available data, based on nearly 20,000 patients participating in randomized clinical trials, are strong and show that oral anticoagulants, when given in adequate doses, reduce rates of reinfarction and thromboembolic stroke but at the cost of increased rates of hemorrhagic events" (N Engl J Med. 2002. 347. 1019-1022).

Supplements

• Fish oil – see omega 3 just below

• L-arginine

  • Postulated to be beneficial based on the fact that it is a substrate for nitric oxide synthase.

  • Lack of benefit documented in the VINTAGE MI trial, a 6 month RCT in 153 patients following a first ST-segment elevation MI, at a dose of 3 grams tid. No improvement in vascular stiffness or ejection fraction (JAMA. 2006. 295. 58-64).

  • L-arginine has a very short half life; it is plausible that a slow release formulation such as Perfusia SR (Thorne) may have benefit.

• L-carnitine 

  • In one study, improved one year survival after MI at a dose of 4 grams daily (Drugs Exp Clin Res. 1992. 18. 355-365).

  • In another study in 31 males with angina, L-propionyl-carnitine 15 mg/kg iv reduced ischemia-induced myocardial dysfunction (Am J Cardiol. 1994. 74. 125-130).

  • Review article: Ferrari R et al. Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review. Ann NY Acad Sci. 2004. 1033. 79-91.

  • BENEFIT noted in a systematic review of 13 controlled trials (n=3629), when administered to those with an acute MI (heart attack). The median trial size was 96 and the median follow up was 2 weeks. Dosage used in the individual trials is not specified in the review. Findings of the review: “Compared with placebo or control, L-carnitine is associated with a 27% reduction in all cause mortality, 65% reduction in ventricular arrhythmias, and a 40% reduction in angina symptoms in patients experiencing an acute myocardial infarction” (Mayo ClinProceed. 2013. 88. 544-551).

• L-taurine – benefit is theoretical.

• Magnesium - most of population does not consume RDA; low magnesium intake is linearly correlated with elevated CRP levels.

• Niacin: 

  • In the Coronary Drug Project, a prospective study in 8341 men with a prior MI, niacin at 1-2 grams per day reduced the 5-year incidence of nonfatal reinfarction by 27% (JAMA. 1975. 231. 260-281). After a mean follow up of 15 years, reduced all cause mortality by 11% compared to placebo (p<0.001) [J Am Coll Cardiol. 1986. 8. 1245-1255].

  • A review of Coronary Drug Project and 5 additional small clinical trials with cardiovascular endpoints concluded that niacin was beneficial in all trials except for one trial in patients with near-normal LDL (mean 138 mg/dl) at entry (Guyton JR. Am J Cardiol. 1998. 82. 18U).

  • In the HATS trial, the group which received OTC niacin with the prescription statin Zocor showed a 60% reduced risk of cardiovascular events, compared to the placebo group (N Engl J Med. 2001. 345. 1583-1592).

  • High doses (2 grams per day) in conjunction with prescription statin medication was associated with improvements in lipid profiles and MRI-measured atherosclerotic plaques, based on a one year RCT in 71 individuals with HDL < 40 and with atherosclerosis at baseline (J Am Coll Cardiol. 2009. 54. 1787-1794).

  • A meta-analysis of 11 RCTs (n=6616) with hyperlipidemia found that niacin alone or in combination with a statin reduced the carotid intima thickness and decreased the incidence of coronary events and stroke (Atherosclerosis. 2010. 201. 353). HOWEVER, the correlation between improvement in this surrogate measure and better clinical outcomes is uncertain analysis (N Engl J Med. 2011. 365. 213-221).

  • Negative trial: In the AIM-HIGH trial in 3414 patients (855 men), with cardiovascular disease, low HDL, and high triglycerides, randomized to Niaspan 1500-2000 mg/day or placebo with Zocor 40-80 mg/day, and if needed Zetia 10 mg/day, with a goal of lowering LDL to 40-80, there was no added clinical benefit from niacin during the 36 month follow-up period, despite a 25% increase in HDL, 12% decrease in LDL, and 29% decrease in triglycerides. In this trial, the composite primary endpoint was death from CHD, nonfatal MI, ischemic stroke, or hospitalization for ACS or symptom-driven coronary or cerebral revascularization. In the placebo group, median LD was < 70 at the end of the trial. There was a borderline significant increase in the risk of ischemic stroke in the niacin group, based on post hoc analysis (N Engl J Med. 2011. 365. 2255-2267 and editorial 2318-2320).

  • Safety of high dose niacin - adverse effects are as follows

    • Diabetes - niacin therapy 1-4 grams per day associated with a 34% increase in incidence of diabetes at a mean follow-up of 3.6 years, based on a meta-analysis of 11 RCTs (n=26,340 nondiabetic participants) [Heart. 2016. 102. 198-203].

    • Gout

    • Liver toxicity - lecithin 1200 mg twice a day with niacin may decrease the risk of elevated liver function tests.

• Omega-3 fatty acids: 

  • Note an anti-arrhythmic effect of omega-3 fatty acids which has been documented in animal studies.

  • Review article (Jacobson TA. Am J Cardiol. 2006. 98. 61i-70i).

  • The American Heart Association in 2002 recommended daily consumption of omega 3 fatty acids, either by consuming 3 ounces of fatty fish such as herring, trout, salmon, or herring, or 1 gram per day of supplemental EPA + DHA (Circulation. 2002. 106. 2747-2757).  Note that OTC 1 gram fish oil capsules typically contain 180 mg of EPA and 120 mg of DHA, so 3 of these should be taken daily, as per the 11/02 AHA Guidelines.

  • Clinical studies

    • In the Diet and Reinfarction Trial (DART 1), which included 2033 male survivors of myocardial infarction randomly assigned to 3 dietary interventions, those who received advise to eat more fish had a significantly lower (29%) total mortality at two years of follow-up, with only a non significant trend toward fewer heart disease events. The other two dietary interventions were advise on increasing the ratio of polyunsaturated fat to saturated fat and increasing consumption of cereal fiber – the study design was unavoidably open label with regard to the advisegiven (Lancet. 1989. 2. 757-761).

    • In the GISSI-Prevenzione trial, an open-label RCT, 11,324 survivors of recent MI patients were randomly assigned to 1 g per day of an omega-3 supplement (containing 850 mg EPA + DHA), 300 mg per day of vitamin E, or both. At 3.5 years of follow-up, those who received omega-3 supplementation alone showed a 15% reduction in the composite primary endpoint of death, nonfatal MI, or nonfatal stroke (p<0.02). In addition, there was a 20% reduction in death from any cause (p<0.01) and a 45% reduction in rate of sudden death (p<0.001). The study was open-label and had a high (>25%) dropout rate (Lancet. 1999. 354. 447-455).

    • A meta-analysis of randomized, controlled secondary prevention trials concluded that dietary (at least 2 servings of fatty fish per week) or supplemental (1 gram per day) omega-3 fatty acid intake reduces fatal myocardial infarction, sudden death, and overall mortality by 20-30% (Am J Med. 2002. 112. 298-304).

    • An excellent review can be found in Arch Intern Med. 2001, vol 161, pages 2185-2192.

    • A 2005 review concludes “the evidence suggests a role for fish oil…in secondary prevention” (Am J Cardiol. 2005. 96. 1521-1529).

    • A systematic review of 14 RCTs reported a RR of all-cause mortality of 0.77 in patients with pre-existing CHD in association with omega 3 supplementation, but this review excluded a RCT of 3114 male patients with angina (Arch Intern Med. 2005. 165. 725-730).

    • A systematic review of trials (N=39,044) found that fish oil supplementation significantly reduced the risk of cardiovascular deaths, sudden cardiac death, all-cause mortality, and nonfatal cardiovascular events in those with heart disease (Clin Cardiol. 2009. 32. 365-372).

    • Supplementation is associated with improved CABG graft patency, based on a 1 year RCT of 610 patients undergoing CABG - those who received 4 grams per day of fish oil concentrate showed a lower rate of vein graft occlusion per distal anastamosis (27% versus 33% in controls, p=0.034). Furthermore, there was a significant trend to fewer patients with vein graft occlusions with increasing relative change in serum phospholipid n-3 fatty acids during the study period (p for linear trend = 0.0037). All patients in this trial received antithrombotic treatment, either aspirin or warfarin. (Am J Cardiol. 1996. 77. 31-36).

    • Supplementation reduces aspirin resistance in those with stable coronary artery disease on low dose aspirin, based on data generated in a trial of 485 patients with stable coronary artery disease taking 75-162 mg/day of aspirin for at least a week and with platelet testing showing aspirin resistance (present in 30 patients, 6.2% of the 485 patients). Those with aspirin resistance were randomized to receive aspirin 325 mg daily or to continue on low dose aspirin with the addition of 2 fish oil capsules twice a day (each fish oil capsule contained 360 mg EPA and 240 mg DHA). After 30 days, 80 % of the patients supplemented with fish oil were no longer aspirin resistant, similar to the 73% treated with aspirin 325 mg daily who were no longer aspirin resistant (J Am Coll Cardiol. 2010. 55. 114-121).

    • EPA 1800 mg/day, initiated within 24 hours of percutaneous intervention for acute coronary syndrome was associated with a 54% lower incidence of cardiovascular events (9.2% vs. 20.2%, p=0.02) and an 81% lower cardiovascular-disease related mortality (0.8% vs. 4.2%, p=0.04) in a 1-year RCT of 241 patients. Both groups received 2 mg/day pitavastatin within 24 hours of the intervention (Int J Cardiol. 2017. 228. 173-179).

    • In the REDUCE-IT trial, a RCT of 8179 patients with diabetes (59.7%, and half of those with diabetes in this trial also had CAD) or established cardiovascular disease (70.7%) and a fasting triglyceride level of 135-499 mg/dl despite statin therapy (but with LDL of 41 - 100 mg/dl), at a median follow up of 4.9 years, “the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 4 grams of icosapent ethyl daily than among those who received placebo.” Icosapent ethyl is a highly purified and stable EPA ethyl ester. Higher blood EPA levels correlated with better outcomes (N Engl J Med. 2019. 380. 11-22 and editorial 91-93). NOTE that mineral oil was the placebo and the positive results might be a function of a negative impact of the placebo. The trial was funded by the manufacturer of the prescription medication reported as beneficial in this trial (Gaby AR. Editorial. Townsend Letter. May 2019. 87-88). Of note, in this trial there was a higher incidence of atrial fibrillation and a trend toward a higher incidence of serious adverse bleeding events (Editorial. JAMA. 2020. 324. 2262-2264).

    • A meta-analysis of 8 studies using various imaging techniques to evaluate coronary plaque found that a combination of omega-3 fatty acids with statins was superior to statins alone “in stabilizing and promoting coronary plaque regression and may help to further reduce the occurrence of cardiovascular events (Am J Cardiol. 2021. 151. 15-24).

    • HOWEVER:

      • A Cochrane review of 48 RCTs and 41 cohort analyses concludes that there is no clear evidence of a reduced risk of cardiovascular events in persons with or at high risk of cardiovascular disease (Cochrane Database Syst Rev. 2004. CD003177).

      • In AHRQ evidence report in 2004 concluded that although some studies did show benefit with omega 3 supplementation, there was an imbalance in the design of the studies, and data on women and specific effects of different CHD outcomes are uncertain (Balk E et al. 2004. 1-6).

      • An update of a previous Cochrane review in which 48 RCTs and 41 cohort studies examining the effect of fish oil supplementation on overall mortality and cardiovascular disease in adults found no significant benefit of omega 3 supplements. The results of the RCTs (enrolling in total over 30,000 patients) and the cohort studies were analyzed separately, but primary and secondary prevention research results were combined for this meta-analysis. In this analysis, long-chain fatty acids (i.e. fish oil) did not produce results different from short-chain fatty acids (BMJ. 2006. 332. 752-760).

      • Negative RCT (SU.FOL.OM3) in 2501 patients with a history of ischemic heart disease or stroke randomized to 600 mg/day of omega 3 versus placebo – at a median of 4.7 years of follow up, no significant differences in major vascular events (BMJ. 2010. 341. c6273).

      • Negative RCT (OMEGA) in 3818 patients after an acute MI randomized to 1 gram per day of omega 3 versus olive oil – at one year of follow up, no difference between the groups in rates of sudden death, total mortality, or major cerebrovascular and cardiovascular events (Circulation. 2010. 122. 2152).

      • Negative multicenter RCT (Alpha Omega trial) of 4837 patients aged 60-80 (78% men) status post myocardial infarction and receiving state of the art antihypertensive, antithrombotic, and lipid modifying therapy were randomized to one of four arms for 40 months – (1) a margarine supplemented with a combination of EPA + DHA, with a targeted intake of 400 mg/day EPA + DHA, and an actual intake of 376 mg/day EPA + DHA, (2) a margarine supplemented with ALA, with a targeted intake of 2 g/day of ALA, and an actual intake of 1.9 g/day ALA, (3) a margarine supplemented with EPA + DHA and ALA, and (4) a placebo margarine. The rate of major cardiovascular events (and the rate of adverse events) was similar in all four treatment arms (N Engl J Med. 2010. 363. 2015-2026). Possible explanations for the null results include the small supplementation dose (targeted intake of 400 mg EPA +DHA), ALA administered in 2 of the 4 groups might have obscured a positive effect of EPA + DHA, underpowered study.

      • A meta-analysis of 20 double-blind RCTs (n=68,680) of fish or fish oil for primary and secondary prevention showed “Overall, omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke …” None of the 20 trials were categorized as primary prevention trials – 13 were secondary prevention trials, 4 were mixed primary/secondary prevention trials, and 3 trials were in those with an implanted ICD. Nine of the studies had sample sizes > 1000; 2 of the 9 large studies were diet-based and the other 7 were supplement studies (JAMA. 2012. 308. 1024-1033).

      • A meta-analysis of 14 double-blind RCTs (n=20,485) of patients with a history of CVD showed that fish oil did NOT reduce the risk of overall cardiovascular events (RR 0.99), all-cause mortality, sudden cardiac death, MI, CHF, or TIA/stroke. Furthermore, no protective effect of fish oil was observed in various subgroup analyses (Arch Intern Med. 2012. 172. 686-694). An invited commentary notes that most of the individual studies included in this meta-analysis were small, short terms studies and not designed to evaluate CVD end points. Another possible explanation for negative trials is that conventional treatment has improved ( prevalence of statin use was 29% in GISSI-Prevenzione, 23% in GISSI-HF, 85% in Alpha Omega, 94% in OMEGA, and 87% in SU.FOL.OM3), and thus very large sample would be required to see a positive effect (Arch Intern Med. 2012. 172. 694-696).

      • A systematic review and meta-analysis of 27 RCTs (n=105,085) concluded “In patients with, or at high risk for, coronary heart disease, fatty acid supplementation does not prevent coronary events” (Ann Intern Med. 2014. 160. 398-406 as cited in ACP Journal Club. 2014. 161. JC7).

      • The most recent update of the Cochrane review included 79 RCTs, 12 to 72 months in duration, 46 trial of primary prevention, 33 trials of secondary prevention showed no significant reduction of mortality or CV events with fish oil supplementation. 71 trials examined EPA + DHA; 8 trials examined ALA (Cochrane Database Syst Rev. 2018. 7. CD003177).

• Red yeast rice

  • Xuezhikang (XZK), a partially purified extract of red yeast rice, shown at a dose of 600 mg per day to significantly reduce LDL cholesterol (45%) and to reduce the risk of a recurrent event and death (33%) in a 4.5 year RCT in 4870 Chinese patients. Each 300 mg capsule of XZK contained 2.5 – 3.2 mg of lovastatin, along with other components of the red yeast rice (Am J Cardiol. 2008. 101. 1689-1693).

• Vitamins B6, B12, and folate

  • Ineffective at reducing risk despite effectiveness at lowering homocysteine (a known risk marker for cardiovascular disease)

  • A meta-analysis of 12 RCTs (16,958 participants, all with preexisting vascular disease) does not show a reduced risk of CHD with folate supplementation (JAMA. 2006. 296. 2720-2726).6For a summary of the data on homocysteine lowering and risk of CHD, go to my home page, click on ‘Cholesterol’ and scroll all the way down to ‘Homocysteine.’

• Vitamin E: Several clinical trials have addressed this.

  • Data from the first two trials (ATBC and CHAOS) appeared promising, at least in terms of reduction in of nonfatal MI, but the data from three larger subsequent trials (HOPE, GISSI-Prevenzione, and PPP) showed no effect on the incidence of fatal or nonfatal MI.

  • For more information including citations of all the studies, return to my home page, click on vitamins, and scroll to Vitamin E.

  • Vitamin E was shown in a subgroup analysis of the CLAS trial to slow the progression of atherosclerotic plaque in patients with coronary artery disease, but this trial did not use MI or death as endpoints (JAMA. 1995. 273. 1849-1854).

  • MIGHT ACTUALLY BE HARMFUL, based on a three year RCT in which 160 patients were assigned to one of four regimens: (1) placebo, (2) simvastatin (Zocor) plus niacin (OTC SloNiacin or Niacor) with specific parameters for dosage titration based on LDL and HDL cholesterol levels, (3) antioxidants twice daily (total dose daily of 800 IU of d-alpha-tocopherol, 1000 mg of vitamin C 25 mg of natural beta carotene, and 100 mcg of selenium, or (4) simvastatin plus niacin plus antioxidants. This study showed that antioxidant vitamins when taken with niacin and prescription Zocor attenuated benefits in terms of HDL2 cholesterol level, clinical events, and coronary atherosclerosis by quantitative angiography (N Engl J Med. 2001. 345. 1583-1592).

  • Another study which suggested a harmful effect, the WAVE trial, enrolled 423 postmenopausal women in a 2 x 2 design in which women received either Prempro, Vitamin E 400 IU daily with Vitamin C 500 mg twice a day, or placebo. The main outcome measure was a change in lumen diameter by angiography, and there was a trend toward worse outcomes in those in the both the antioxidant vitamin group as well as the Prempro group (JAMA. 2002. 288. 2432-2440).

Chelation:

• Intravenous disodium EDTA – in the TACT trial of 1708 stable patients (at 134 clinical sites) with a history of MI (median of 4.6 years prior to enrollment), intravenous chelation modestly reduced the risk of adverse cardiovascular outcomes, during a mean follow up of 55 months. The primary endpoint, a composite of total mortality, recurrent MI, stroke, coronary revascularization, or angina occurred in 18% fewer patients in the chelation therapy group than the placebo group (p=0.035). This was a 2 x 2 trial design, with an oral and intravenous vitamin regimen, along with intravenous chelation and placebo. The infusions were administered weekly for 30 weeks, and then 2-8 weeks apart for the final 10 infusions. Median age of patients at the time of enrollment was 65, and median BMI was 30. Creatinine > 2 mg/dl was an exclusion criteria. No safety issues identified, and > 55,000 infusions administered in conjunction with this trial (JAMA. 2013. 309. 1241-1250).

  • Limitations of this trial include missing data, potential investigator or patient unmasking, use of subjective endpoints, and intentional unblinding of the NHLBI and NCCAM sponsors (Editorial. JAMA. 2013. 309. 1293-1294).

  • Dr Alan Gaby, in an editorial (Townsend Letter. Aug/Sept 2013. Pages 122-124) notes that the beneficial effect of chelation was greater at conventional cardiology sites than at CAM sites, and this argues against the hypothesis that bias among CAM practitioners skewed the results of this RCT. Dr. Gaby also notes that the vast majority of ‘placebo’ patients were receiving state of the art conventional medical therapy (84% taking aspirin, >80% taking beta blockers, 73% taking statins, many taking ACE or ARB), and thus an 18% further improvement in the treatment group is clinically significant. Finally, Dr. Gaby notes that subgroup analysis suggests that diabetics (a pre-specified subgroup) derive relatively greater benefit from chelation therapy than non-diabetics (40% reduction in events in diabetics).

Diet:

• Atkins Diet: A one year study of 26 individuals found that the 16 who modified their dietary intake as instructed had reduction in each of the independent risk factors studied and regression in the extent and severity of coronary artery disease, whereas the 10 individuals who elected instead to follow a high protein diet showed worsening of some of the independent risk factors and progression in the extent and severity of coronary artery disease (Angiology. 2000. 51. 817-826).

• Fish - in the Diet and Reinfarction Trial (DART), which included 2033 men allocated to 3 dietary interventions, those who received advice to eat more fish had a significantly lower (29%) total mortality at two years of follow-up, with only a non-significant trend toward fewer heart disease events (Lancet. 1989. 2. 757-761).

• Grape juice (purple), based on a 14 day study in 15 patients with coronary artery disease, in which 7.7 ml/kg/day improved flow-mediated vasodilation and reduced susceptibility of LDL to oxidation (Circulation. 1999. 100. 1050-1055).

• Low fat diet - see ‘Ornish’ just below

• Mediterranean-style diet

  • Seven principle components of Mediterranean diet include (1) plant based foods, (2) locally grown minimally processed food, (3) fish and poultry, (4) infrequent red meat consumption, (5) olive oil as principle source of fat, (6) moderate amounts of red wine with meals, and (7) desserts primarily of fresh fruit.

  • In the Lyon Diet Heart Study, a prospective, randomized, single-blinded study which included 605 participants post first MI, the experimental group consumed a Mediterranean diet which provided 30% of calories from fat but only 8% from saturated fat, 9-11 servings of grains per day, and 5-9 servings of fruits and vegetables per day. Dairy products and red meat were consumed sparingly, but the experimental diet included an omega-3 fatty acid supplemented margarine. The control group consumed a "prudent western-type diet” (a low-fat American Heart Association diet. In the experimental group, plasma levels of vitamin E and vitamin C were increased. After a mean follow up of 27 months, there were 16 cardiac deaths in the control group and 3 in the experimental group; 17 non-fatal MI's in the control group and 5 in the experimental group. The number needed to treat (NNT) with a Mediterranean diet to prevent one cardiovascular event was 12 (Lancet. 1994. 343. 1454-1459). At 46 months of follow up, there were 44 events versus 14 events, p<0.0001. Note the benefit of the Mediterranean diet seemed in this study to be independent of cholesterol-lowering, as there were not significant changes in cholesterol or LDL cholesterol levels (Circulation. 1999. 99. 779-785).

  • In this same study, after a mean of 46 months of follow-up, the composite endpoint of cardiac death plus nonfatal MI was reduced significantly, with 14 events in the experimental group versus 44 events in the control group (p = 0.001). Adherence to this diet was good in this study (Circulation. 1999. 99. 779-785).

  • A 3 month study in stable patients who experienced coronary events within the previous 2 years, and taking appropriate prescription medications for secondary prevention, looking at markers of oxidative stress, inflammation, and endothelial function showed that “medicated secondary prevention patients show evident although small responses to the MD and TLCD (low fat), with improved markers of redox homeostasis and metabolic effects potentially related to atheroprotection (Am J Cardiol. 2011. 108. 1523-1529).

  • A prospective cohort study in 31,546 high risk individuals in 40 countries showed that those who followed a healthy diet (whole grains, fruits, veggies, fish and nuts; minimizing meat, eggs and low glycemic index carbohydrates) had a 35% reduction in cardiac death rate of 5 years of follow up (Circulation. 2012. 126. 2705-2712).

  • Mediterranean diet is more effective than a low fat diet - in the CORDIOPREV RCT of 1002 patients who had established CHD, at a median of 7 years of follow up, major CV events were lower in the group which followed the Mediterranean diet (28 events versus 38 events, relative risk reduction 23%, NNT of 20) [Lancet. 2022. 399. 1876-1885 as reviewed in ACP Journal Club. 2022. 175. JC100].

• Ornish's Lifestyle Heart Trial (Therapeutic Lifestyle Changes Diet)

  • Vegetarian diet, 10% fat, <5 mg/day cholesterol, stress management techniques 1 hr/day, smoking cessation, exercise 3 hr/week, twice a week discussion groups.

  • The results at 1 year show a reduction in frequency, severity, and duration of angina and regression of arteriosclerosis by quantitative angiography (Lancet. 1990. 336. 129-133).

  • Five year follow up shows persistent beneficial effects from these lifestyle changes, with continued regression of coronary artery disease as well as reduction in cardiac event rates (JAMA. 1998. 280. 2001-2007).

  • Consider reading Dr. Dean Ornish's Program for Prevention of Heart Disease (1992) for guidance regarding this stringent diet.

  • A 3 month study in stable patients who experienced coronary events within the previous 2 years, and taking appropriate prescription medications for secondary prevention, looking at markers of oxidative stress, inflammation, and endothelial function showed that “medicated secondary prevention patients show evident although small responses to the MD and TLCD (low fat), with improved markers of redox homeostasis and metabolic effects potentially related to atheroprotection (Am J Cardiol. 2011. 108. 1523-1529).

• Pomegranate juice

  • A 3 month RCT in 45 patients found that consumption of 240 ml/day (8 ounces/day) was associated with a reduction from baseline in stress-induced ischemia by nuclear stress test. The control group which consumed a placebo beverage of equal caloric content showed an increase from baseline in stress-induced ischemia. On average, the improvement in myocardial perfusion was 17% in the pomegranate group, and the worsening in myocardial perfusion was 18% in the control group. On average, angina episodes decreased by 50% in the pomegranate group and increased by 38% in the control group. There were no significant changes in BP, BS, HbA1c or weight in either group (Am J Cardiol. 2005. 96. 810-814). BEWARE pomegranate juice can inhibit CYP 3A4, and thus there is the possibility of increasing statin serum levels, and the possibility of inducing rhabdomyolysis.

Exercise

• A one year randomized, controlled trial in 62 patients with angiographically proven CAD showed regression of CAD in those who exercised the most and progression in those who exercised the least (J Am Coll Cardiol. 1993. 22. 468-477).

• A one year randomized trial of 101 men with single vessel CAD by angiogram and stable angina in which one group was instructed to exercise for 20 minutes each day on a bicycle ergometer and the other group had stent angioplasty followed by aspirin 100 mg per day and clopidogrel 75 mg per day for the first 4 weeks post-procedure found that the men in the exercise group had a higher event free survival (88% versus 70%; p=0.023) at a significantly lower expense ($3708 versus $6086; p=0.001) [Circulation. 2004. 109. 1371-1378].

• A 5 year prospective observational study of 773 men with known CAD found a 58% reduction in all cause mortality in those who engaged in self-reported light activity, and a 53% reduction in all cause mortality in those who engaged in self-reported moderate activity, compared to self reported sedentary men (Circulation. 2000. 102. 1358-1363).

• In the ARTEMIS study, in a cohort of 1746 patients with stable, angiographically documented CAD, patients who remained inactive (leisure-time physical activity) had a 4.9-fold increased risk for cardiac death at two years, as compared with those who remained at least irregularly active. Those who became inactive during the two years of monitoring had a 2.4-fold increased risk for cardiac death (Am J Cardiol. 2018. 121. 143-148).

Meditation: 

• A RCT in 103 patients with stable CHD found that a 16 week TM program produced meaningful improvements in blood pressure, insulin resistance, and cardiac autonomic tone (Arch Intern Med. 2006. 166. 1218-1224).

• In a RCT of 201 black men and women with coronary heart disease comparing TM vs health education, after 5.4 years, there was a 48% lower risk of a primary end point (all cause mortality, MI, stroke) in the TM group and a 24% lower risk for secondary end points (CVD mortality, hospitalizations, and revascularizations)[Circ Cardiovasc Qual Outcomes. 2012. 5(6). 750-758].

Yoga

• A pilot study presented at the 2004 annual scientific sessions of the American Heart Association found that six weeks of training in yoga and meditation markedly improved endothelial function.

Cardiac rehabilitation

• Exercise-only cardiac rehabilitation is associated with a 26% reduction in all cause mortality, based on a meta-analysis (J Am Coll Cardiol. 2016. 67. 1-12).

• Exercise-only cardiac rehabilitation is associated with a 27% reduction in all cause mortality and a 31% reduction in total cardiac mortality based on a systematic analysis of 8440 patients. Comprehensive cardiac rehabilitation was associated with a 26% reduction in total cardiac mortality, not significantly different from the 31% reduction seen with exercise-only cardiac rehabilitation (Cochrane Database Syst Rev. 2004. 1:CD001800 - updated analysis published in 2011).

• Similar benefits from exercise-only cardiac rehabilitation were reported in a systematic review and meta-analysis of 48 RCTs with 8940 participants, mean age 55 years old (Am J Med. 2004. 116. 682-692).

• A meta-analysis of 12 RCTs showed a 25% risk reduction in mortality with an exercise-based rehabilitation program (Circulation. 2005. 112. 924-934).

• Additional studies show that cardiac rehabilitation is associated with improved survival, improved exercise capacity, lower hospital readmission rates, and improved quality of life, including social functioning and psychological well being (J Am Coll Cardiol. 2009. 54. 25-33; Circulation. 2010. 121. 63-70; Circulation. 2011. 123. 2344-2352; Am Heart J. 2011. 162. 571-584; Diabetologia, 2015. 58. 691-698).

• Historically, the benefits of cardiac rehabilitation were reported in two meta-analyses of 21 RCT's conducted in the 1970's and 1980's, which found 25% reduction in both CV mortality and total mortality in conjunction with cardiac rehabilitation (JAMA. 1988. 260. 945-950; Circulation. 1989. 80. 234-244).

• There is data to indicate that cardiac rehabilitation is cost saving from a cost-benefit analysis (N Engl J Med. 2001. 345. 892-902).

• A case control study of 6284 patients referred to cardiac rehabilitation in Ontario, Canada found that "Participation in cardiac rehabilitation is associated with lower long-term health service utilization expenditures within a publicly funded health care system" (Mayo Clin Proc. 2017. 92. 500-511).

• HOWEVER, in the RAMIT trial, a multicenter RCT of 1813 patients hospitalized with a primary diagnosis of acute MI, (conducted in 14 hospitals in England and Wales), those patients randomized to multifactorial rehab programs for > 10 hours did not differ from the usual care group with regard to total mortality or any of the 8 measured health-related quality of life domains. The cardiac rehab sessions occurred weekly or biweekly, and averaged 20 hours over 6-8 weeks. This negative result raises the possibility that contemporary revascularization procedures and cardioprotective medications may attenuate the previously reported beneficial effects of cardiac rehab (Heart. 2012. 98. 637-644).

Tertiary Prevention in Myocardial Infarction

• Deep breathing and other relaxation techniques likely reduce the risk of arrhythmias in acute MI by increasing parasympathetic tone.

References: 

• Becker RC. Antithrombotic therapy after myocardial infarction. N Engl J Med. 2002. 347. 1019-1022.

• Gluckman TJ et al. A practical and evidence-based approach to cardiovascular disease risk reduction. Arch Intern Med. 2004. 164. 1490-1500.

Page Updated April 20, 2024