Adjunctive Therapies to Prevent Atherothrombosis

by James O’Keefe, Jr, MD (Director of Preventive Medicine, Mid-America Heart Institute, Kansas City, MO), Mark S. Freed, MD (Cardiologist, President of Physicians' Press), and Christie Ballantyne, MD (Clinical Director, Section of Atherosclerosis, Baylor College of Medicine)

In addition to control of hypertension, dyslipidemia, diabetes, and lifestyle modification (diet, exercise, smoking cessation), the risk for atherothrombotic events may also be reduced by therapies that target mechanisms such as thrombosis and oxidation.

EVIDENCE-BASED THERAPY

Aspirin
Aspirin has been consistently shown to prevent MI and stroke in patients at risk for atherosclerotic vascular disease. Although aspirin does not prevent atherosclerosis, it does inhibit platelet function and decreases the likelihood that an occlusive thrombus will form at the site of an inflamed and ulcerated atherosclerotic plaque. The optimal aspirin dose is between 81 and 325 mg daily. Doses in excess of 325 mg per day are associated with increased risk of gastrointestinal bleeding in a dose-dependent fashion. Enteric-coated or buffered forms of aspirin are no less likely to cause gastrointestinal bleeding than soluble aspirin. Low-dose aspirin (81-162 mg) should be considered for patients on an ACE inhibitor or with a history of serious bleeding, especially from the gastrointestional tract. All patients with coronary artery disease (CAD) should be on aspirin therapy unless a very strong contraindication exists (e.g., anaphylaxis). Aspirin should also be used in high-risk primary prevention (2 or more risk factors), and in middle-aged or older patients with elevated LDL cholesterol, increased high-sensitivity C-reactive protein, or hypertension. The most recent recommendations for the use of aspirin for the primary prevention of cardiovascular events for the US Preventive Services Task Force have been published in the January 15, 2002 issue of Annals of Internal Medicine (vol. 136, pp. 155-172).

Clopidogrel (Plavix)
Clopidogrel interferes with ADP-mediated platelet activation and is somewhat more effective at platelet inhibition than aspirin. These two agents have additive effects when used in combination. Clopidogrel has been shown to be improve event-free survival in CAD patients compared to aspirin in the CAPRIE secondary prevention study, particularly in patients with peripheral vascular disease. Compared to aspirin alone, combined antiplatelet therapy with clopidogrel plus aspirin improved clinical outcome in patients with unstable angina or non-ST-elevation acute myocardial infarction. The safety profile of clopidogrel is similar to low-dose aspirin, with a rare incidence of thrombotic thrombocytopenic purpura. Clopidogrel is indicated for use in aspirin-intolerant patients, those at very high risk for cardiovascular or cerebrovascular events, and for acute coronary syndromes.

Low-dose Fish Oil (also see, Mediterranean Diet)
In the GISSI Prevention Study, 1 g/d (850 mg of DHA and EPA) of fish oil, a dose too low to affect lipid levels, significantly reduced total mortality by 20%, due in large part to a 45% reduction in sudden cardiac death.

ACE Inhibitors
Angiotensin converting enzyme (ACE) inhibitors block the conversion of angiotensin I to angiotensin II and inhibit the breakdown of bradykinin, resulting in physiologic benefits that confer unique cardioprotective and renoprotective properties to this class of drugs. ACE inhibitors have been shown to improve prognosis in a wide variety of cardiovascular disorders, including hypertension, heart failure, asymptomatic LV dysfunction, MI, post-coronary revascularization procedures, and proteinuric nephropathy. Most recently, compelling data from the HOPE trial demonstrated an important role for ACE inhibitors in the primary and secondary prevention of atherosclerotic vascular disease and in the development of new-onset diabetes mellitus. Ramipril is approved to reduce the risk of MI, stroke, and death from cardiovascular causes in patients 55 years or older at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral arterial disease, or diabetes that is accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria). Ramipril can be used in addition to other needed treatment, including antihypertensive, antiplatelet, and lipid-lowering therapy. The recommended starting dose is 2.5 mg once daily for 1 week, increased to 5 mg once daily for the next 3 weeks, then increased as tolerated to a maintainence dose of 10 mg once a day (which may be given in 2 divided doses for patients who have hypertension or who are post-MI).

ACE inhibitors are generally safe, well-tolerated, and affordable. Patients with atherosclerotic vascular disease, diabetes, or insulin resistance should therefore be considered for ACE inhibitor therapy unless they have an intolerable cough, systolic blood pressure consistently below 100-110 mmHg, or renal failure (creatinine > 2.5 mg/dL). Angiotensin receptor blockers are not equivalent to ACE inhibitors, but nevertheless may be a reasonable alternative for patients who are intolerant to ACE inhibitor therapy.

POSSIBLE BENEFIT FOR PREVENTION OF ATHEROTHROMBOSIS

Folic Acid
Homocysteine is an amino acid by-product of protein metabolism. An elevated fasting homocysteine levels is an independent risk factor for cardiovascular events and cardiovascular mortality, particularly in patients already diagnosed with CAD. Although the mechanism of action is not clearly understood, homocysteine appears capable of damaging endothelium and promoting a prothrombogenic environment. All adults should be encouraged to take at least 400 mcg of folic acid daily by diet and/or supplementation. Foods that are rich in folate include broccoli, spinach, and other green leafy vegetables, citrus fruits, asparagus, and beans. Because of the lack of outcome trials, currently there are no consensus panel recommendations on criteria for measurement of homocysteine. In our practices, we measure homocysteine in patients with premature or severe atherosclerosis. Folic acid supplementation as well as supplementation with vitamins B₆ and B₁₂ have been shown to decrease homocysteine levels by approximately 15-30%. If elevated homocysteine levels are present, folic acid (800-1600 mcg per day) in conjunction with vitamin B₁₂ (250 mcg per day) and vitamin B ₆ (20-25 mg per day) should be prescribed.

Vitamin E
Vitamin E is an antioxidant vitamin that gets incorporated into lipoprotein particles and prevents the oxidation of LDL, an integral step in atherogenesis. In the CHAOS study, vitamin E decreased the risk of MI in patients with documented coronary disease. However, in the much larger GISSI Prevention and HOPE studies, vitamin E produced no benefit on cardiovascular endpoints. At the present, there is no clear evidence for the benefit of vitamin E on reducing CHD events. Some data suggest the combination of vitamins E and C is more effective at reducing atherosclerotic progression than either vitamin alone, although this issue has not been addressed in a large-scale trial.

Vitamin C
Vitamin C (250-500 mg daily) is another antioxidant that may be used in conjunction with vitamin E, although prospective trial data are pending.

Beta-carotene
No cardiovascular benefit has been shown with beta-carotene in the Linxian Cancer Prevention Trial; the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; and the final report of the Physicians' Health Study.

Estrogen Replacement Therapy
Estrogen has many potentially beneficial effects on the cardiovascular system, including improvements in the lipid profile and endothelial function and antioxidant effects. In observational epidemiologic studies, hormone replacement therapy has been associated with decreased risk for MI and cardiovascular death in women with established CAD or risk factors for CAD. However, no benefit on nonfatal MI or CAD death was demonstrated in HERS, which randomized 2763 women (average age 67 years) with CHD to combination conjugated estrogen (0.625 mg daily) and medroxyprogesterone (2.5 mg daily) vs. placebo (JAMA 1998;280:605). In addition, more cardiovascular events occurred in the first year in women receiving hormone therapy than those receiving placebo, but fewer events occurred in the hormone group in years 4 and 5. Hormone therapy was also associated with an increased risk for thromboembolic events and gallbladder disease. Estrogen also provided no angiographic benefit in the ERA trial, which randomized 309 women with angiographic CAD to estrogen alone, estrogen plus medroxyprogestrone acetate, or placebo. The primary endpoint, per-patient mean minimum lumen diameter of 10 coronary segments at baseline and mean 3.2-year follow-up, was not significantly different among treatment groups (NEJM 2000;343:522).

Definitive evidence to support routine use of hormone replacement therapy in women for the prevention of cardiovascular disease is lacking. The ongoing Women's Health Initiative trial, involving more than 63,000 women, and the Women’s International Study of Long Duration Oestrogen After Menopause (WISDOM) will provide information on the use of estrogen for primary prevention. When estrogen replacement therapy is administered, concomitant use of medroxyprogesterone (Provera) 2.5 mg daily is necessary for women who have not previously undergone hysterectomy. Yearly mammograms and Pap smears are also required. In women with triglyceride levels higher than 300 mg/dL, oral estrogen can cause triglycerides to rise to more than 1,000 mg/dL, increasing the risk of pancreatitis. A fasting lipid profile should be evaluated before beginning postmenopal estrogen replacement, and patients with triglyceride levels >300 mg/dL should be placed on a program of diet, weight loss if necessary, and exercise before initiating estrogen therapy. Topical therapy with a patch can be used in patients with hypertriglyceridemia if indicated without exacerbating the triglyceride elevation. Patch therapy, however, will not raise HDL cholesterol or lower LDL cholesterol.

Selective estrogen receptor modulators (SERMs), such as raloxifene, appear to provide many of the benefits of estrogen without the increased risk for cancer. The potential cardioprotective effects of have recently been examined in the MORE study with raloxifene (Evista), and suggest no early increase in cardiovascular events (as with HRT), and a possible reduction in long-term cardiac events in women at high risk for cardiovascular disease. Recommendations on the use of SERMs for prevention of cardiovascular disease await the results of ongoing trials such as the Raloxifene Use for The Heart (RUTH), which is enrolling 10,000 post-menopal at high risk for or with established coronary disease, and is evaluating cardiovascular events as a predefined outcome.

© 2009 Jones and Bartlett Publishers