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 15-34 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.

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

o   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).

 

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).

·       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).

 

·       Carbohydrate:

  • 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).

·       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).
  • 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).
  • 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).

·        Grains – a meta-analysis of 18 studies (15 cohort studies and 3 case-control studies, n = 400,492) found that higher whole-grain intake has a protective effect against CHD (Am J Cardiol. 2015. 115. 625-629).

·        Green tea – see ‘tea’ just below

·        Nuts: The FDA has 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.

o   Almonds lower LDL cholesterol and also raise HDL cholesterol.

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

§  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].

§  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.

o   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).

o   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).

o   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).

o   Pistachios lower LDL cholesterol and also 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).

o   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).

o   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.’

·       Soy

o   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).

o   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:

  • Several large epidemiologic studies including the Framingham Heart Study show 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%.
  • The most recent data comes from a 12 year follow up on the Health Professionals Follow-up Study, which includes 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.  Analysis of the association of alcohol consumption with the risk of MI among 38,077 participants who were free of cardiovascular disease and cancer at baseline shows an inverse correlation between risk of MI and consumption of alcohol at least 3-4 days per week.  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).
  • Epidemiologic studies show correlation and not necessary causation, but there is biologic plausibility for a causative effect - beneficial effect on HDL, antioxidant effect, anti-inflammatory effect, an antiplatelet effect, and improvement in insulin resistance.
  • It is controversial whether wine provides superior protection compared to other types of alcohol.
  • One of the mechanisms appears to be conversion of omega 6 fatty acids into DGLA, a precursor to anti-inflammatory eicosanoids.
  • Data from the INTERGENE case control study, which included 618 Swedes with CHD and a control group of 3000 healthy subjects concluded that only in 15% of the population with a particular genotype – CETP Taq1B (Alcohol. 2014. 48. 695-700).
  • HOWEVER, alcohol is not risk free (Ann Intern Med. 2003, 139. 711-714).

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

o   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).

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

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

o   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.

o   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).

·       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.

o   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.

o   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).

o   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.

o   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).
  • 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).
  • 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).
  • 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).

 

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.

·       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. Toxicity is a significant risk.

·       Omega 3 supplements (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).
  • However, 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).
  • In the JELIS trial, an open label RCT of 18,645 Japanese with hypercholesterolemia (TC > 252 mg/dl), those randomized to1800 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).
  • In the DOIT trial, a 3 year mostly primary prevention trial in 563 elderly men, there was no significant difference in outcome between those randomized to 2.4 grams per day omega 3 oil, as compared with those randomized to corn oil (Eur J Cardiovasc Prev Rehabil. 2010. 17. 558).
  • 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 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).

·       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 Coll Cardiol. 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

·       USPSTF 2009 guidelines on the use of aspirin for primary prevention of cardiovascular events are published in Ann Intern Med. 2009; 150: 396-404. This includes sex specific tables by decade of life estimating quantitatively the risk versus benefit of aspirin. For an individual, whether male or female, the statistical benefits of aspirin exceed the risks when the individual 10 year risk of cardiovascular disease is 10% or greater.

·       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].

·       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 was14% 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).

·       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).

·       Historically, 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

·       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).

·       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 rorecoxib do not have this effect (N Engl J 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).

 

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 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.

·       As the cost of statins has decreased dramatically (5 statins are available as generic in 2013), recent analyses show statins as cost effective and possibly even cost saving in individuals at lower risk (Circ Cardiovasc Qual Outcomes. 2009. 2. 65-72; Health Aff. 2012. 31. 2276-2285).

  • 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 Engl J 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).

·       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).

·       Elderly (high risk) – beneficial

  • 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).

·       A meta-analysis of 11 trials including 65,229 patients concluded that statin therapy does not significantly reduce all-cause mortality, based on the upper bound of the 95% confidence interval of 1.01 (Arch Intern Med. 2010. 170. 1024-1031). However, a previous meta-analysis of the same studies reported a significant reduction in all-cause mortality (odds ratio of 0.88, 95% CI 0.81-0.96) [Brugts JJ et al. BMJ. 2009. 338. b2376].

·       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:

·       Aspirin:

  • 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).

·       Plavix: 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 Plavix (clopidogrel) 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 Plavix 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 Plavix group (N Engl J Med. 2001. 345. 494-502).

·       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 an  INR 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).

·       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.

·       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.

·       Fibrates: 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 gemfibrozol (Lopid) [N Engl J Med. 1999. 341. 408-418].

·       Niacin – see supplements just below

·       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).

§  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 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.
  • 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).

 

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

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

o   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).

o   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.

o   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 Clin Proceed. 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).

·       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).

  • 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 advise given (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.
  • 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.
  • 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).
  • HOWEVER:
    • An 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).
    • 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).
    •  A review failed to show a reduction in all mortality with fish consumption or fish oil consumption [1000 mg/day] (Circulation. 2005. 112. 924-934). In this review, if the study showing a 15% increase in CAD mortality in association with fish or fish oil consumption (Eur J Clin Nutr. 2003. 57. 193-200) is removed from the analysis, a 20% reduction in mortality is seen.
    • 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 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.
    • 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 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).
    • 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 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 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).

·        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).
  • 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 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 Slo Niacin 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 ug 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).

o   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).

o   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).

·       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 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."  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 (Lancet. 1994. 343. 1454-1459).
  • 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).

·       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).

 

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).

 

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 27% reduction in all cause mortality and a 31% reduction in total cardiac mortality based on a systematic analysis of 8440 patients (Cochrane Database Syst Rev. 2004. 1:CD001800).

·       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).

·       Comprehensive cardiac rehabilitation in the above Cochrane analysis was associated with a 26% reduction in total cardiac mortality, not significantly different from the 31% reduction seen with exercise-only cardiac rehabilitation.

·       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).

·       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.


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