Awareness of the risk of heart disease in women is on the rise. Public cognizance of the fact that cardiovascular disease (CVD)—once thought to be a man’s disease—is the leading cause of death among women in the United States has increased 24% since 1997.1 With this increased awareness comes a rise in public knowledge regarding lifestyle behaviors and drug therapies that help prevent CVD. Just as important and far less publicized are the drug therapies that are not useful and are even potentially harmful in the prevention of CVD. In addition to keeping informed about these medications, pharmacists should educate the public about the risks of these substances and recommend that they not be used for the purposes of CVD prevention.
Epidemiology and Etiology
A report from the American Heart Association (AHA) estimates that, in the U.S, a woman dies of CVD every minute.2 The causes of heart disease are multifaceted, and it is easier to describe ideal cardiovascular health than it is to describe the risks associated with developing CVD. According to the AHA, ideal cardiovascular health involves consistently meeting seven basic criteria, which are listed in TABLE 1.3
A sobering community-based study found that only one out of 1,933 subjects examined was classified as having ideal health (i.e., met all seven criteria).3 As the U.S. struggles to promote strategies to reduce the incidence of CVD, it should be kept in mind that there are a number of medications that should not be recommended or used for prevention. The purpose of this review is to describe the agents that are not effective and may be harmful when used to prevent CVD in women.
Drug Therapy
While a variety of drugs and nutritional agents have been thought to be effective in the prevention of CVD, those discussed in this article come from the 2011 update to the AHA’s guidelines for the prevention of CVD in women.4 These therapies are considered class III interventions (not useful/effective and may be harmful) for the prevention of CVD in women, and they are listed because they were commonly believed to have potential benefit when used for the prevention of CVD. These interventions have been promoted for use despite a lack of definitive evidence from well-designed clinical trials. The available evidence is discussed below.
Hormone Therapy and Selective Estrogen Receptor Modulators (SERMs): Several observational studies suggested that postmenopausal hormone therapy may be beneficial in decreasing the risk of coronary heart disease (CHD) in women.5-7 The majority of evidence from randomized, controlled trials regarding the effects of hormone replacement therapy (HRT) on CHD comes from the Women’s Health Initiative (WHI) studies. Two separate treatments were studied: an estrogen-only therapy in posthysterectomy women and an estrogen-progestin combination in women with an intact uterus.8 The estrogen-alone trial was discontinued early because the estrogen was not found to protect against CHD.8 In addition, the trial that investigated cardiac effects from estrogen and progestin therapy was stopped early because results suggested no benefit, and possibly an increased risk of coronary events, in the treatment group.5
In the estrogen-only trial, a lower risk of CHD was suggested among women who began estrogen treatment at age 50 to 59 years.8 This finding is interesting, considering that most of the observational studies that had beneficial results generally initiated estrogen therapy at menopause.9 Most subjects enrolled in the WHI trials started therapy 10 years after menopause. The WHI trials may not have been able to detect a significant decrease in CHD risk in women aged 50 to 59 years because of the lack of heart attacks, strokes, and other coronary events.8 Further research is warranted in this area.
The same observational studies that led researchers to believe that HRT may help prevent CHD in women prompted the hypothesis that other estrogen receptor agonists may have similar effects. Raloxifene, a SERM, is an estrogen agonist in some tissues and an estrogen antagonist in others. It is associated with beneficial effects on lipoproteins, cholesterol, fibrinogen, and homocysteine.10 The Raloxifene Use for The Heart (RUTH) trial examined the risks and benefits associated with raloxifene use, focusing specifically on cardiovascular and breast cancer effects.10 The study, which compared 60 mg of raloxifene versus placebo, found that raloxifene did not significantly affect the risk of CHD and that it increased the risk of venous thromboembolism and fatal stroke.
Antioxidant Supplements (Vitamin E, Vitamin C, Beta-carotene): Oxidative stress is known to play an important role in the development and progression of atherosclerotic disease.11 In vitro and in vivo studies using the antioxidants vitamin E, vitamin C, and beta-carotene found beneficial effects on CVD.11 However, results from randomized clinical trials have found no benefit, and possible harm, from antioxidant supplementation.12,13
The Women’s Health Study (WHS) assessed the effects of vitamin E supplementation on CVD in women.13 Subjects received a 600-IU dose of vitamin E every other day. The treatment did not affect overall occurrence of cardiovascular events, however.
A meta-analysis published in 2007 systematically reviewed randomized, controlled trials of antioxidant supplements for primary and secondary prevention in both men and women.14 The doses assessed ranged from 3 mg to 30 mg of beta-carotene, 1,333 IU to 200,000 IU of vitamin A, and 15 IU to 5,000 IU of vitamin E. The meta-analysis concluded that treatment with beta-carotene, vitamin A, and vitamin E may increase mortality and that vitamin C supplementation required further research to ascertain an effect on mortality.
Another meta-analysis suggested a difference between antioxidant consumption through supplements versus consumption of natural antioxidants contained in fruits and vegetables.15 Naturally occurring antioxidants differ from synthetic formulations in both the mixture of stereoisomers and the concentrations of the molecules. This meta-analysis, which examined data from both men and women, also suggested that age may play a role in the negative results from randomized, controlled trials.15 Most of the clinical trials involved older patients (age >50 years) or patients with preexisting heart disease. It is likely that atherosclerotic lesions and plaques were already present in these populations. The authors suggested that further research regarding consumption of naturally occurring antioxidants in younger populations was warranted.
Folic Acid With or Without Vitamin B6 and B12 Supplementation: A high rate of CVD in children with homocystinuria (a rare genetic condition in which plasma homocysteine levels are elevated) prompted the medical community to consider elevated homocysteine a modifiable risk factor for CVD.16 Homocysteine is also known to cause oxidative stress, inflammation, and endothelial damage, as well as promote thrombogenicity.17 The combination of vitamin B12 (cyanocobalamin), vitamin B6 (pyridoxine), and folic acid (vitamin B9) has been shown to lower homocysteine levels 20% to 30%.16
While the homocysteine hypothesis (lowering homocysteine to prevent CVD) is plausible, most large, well-designed studies showed no benefit. The Vitamin Intervention for Stroke Prevention (VISP) trial, the Heart Outcomes Prevention Evaluation (HOPE-2) study, the Cambridge Heart Antioxidant Study (CHAOS-2), the Norwegian Vitamin Trial (NORVIT), the Western Norway B-Vitamin Intervention Trial (WENBIT), and the Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS) all failed to show a CVD prevention benefit from therapy with vitamin B and folic acid.18-23
The doses of folic acid used in the studies ranged from 0.8 mg per day to 40 mg per day. These amounts far exceed the dosage recommended for the prevention of neural tube defects (0.1 mg/day). Folic acid supplements, or dietary intake of 0.1 mg/day, are safe and should be taken by women of childbearing age to prevent neural tube defects.4
Aspirin for Prevention of Myocardial Infarction (MI) in Women Aged <65 Years: It is well documented that aspirin is effective for the secondary prevention of CVD in both men and women.24 However, recommendations regarding aspirin usage for primary prevention in women have recently changed. The use of aspirin for primary prevention was spurred by the Physician’s Health Study (PHS) in 1988.25 The study, which enrolled more than 22,000 healthy men, was stopped early because of a substantially reduced risk of first MI. Subsequently, aspirin was recommended for primary prevention in both women and men at increased risk for CVD.
In 2006, a meta-analysis found that aspirin (dosage range 75-500 mg daily) reduced the risk of a composite of CVDs in both men and women owing to its effect on ischemic stroke in women and MI in men.26 The meta-analysis found no significant effect on MI or cardiovascular mortality in women taking aspirin. A 2005 randomized trial of low-dose aspirin (100 mg every other day) for primary prevention of CVD in women yielded similar results.24 Although there was no overall benefit, a subgroup analysis found that aspirin significantly reduced the risk of major cardiovascular events, ischemic stroke, and MI in women aged 65 years and older.24 This difference in benefit based on age supports the AHA’s recommendation that aspirin not be used for prevention of MI in women under age 65.4
Recently, the use of aspirin for primary prevention of ischemic stroke has also been studied intensively. In 2009, the U.S. Preventive Services Task Force (USPSTF) updated its guidelines for aspirin use in the prevention of CVD.27 The new guidelines recommend that women aged 55 to 79 years use aspirin when the potential benefit of ischemic stroke reduction outweighs the potential harm of increased gastrointestinal bleeding.
Pharmacist Involvement
Although AHA guidelines state that aspirin should not be used to prevent MI in women younger than 65 years, a recent study found that more than 80% of women in this age group think that aspirin will prevent heart disease.28 Since it is the responsibility of pharmacists to ensure safe medication usage and to recommend nonprescription medications for their patients, this is an excellent opportunity for intervention.
All of the other medications discussed above were previously thought to decrease cardiovascular risk. The inconsistencies in information available to the public may lead to poor choices in self-prescribed therapies. It is important to counsel patients and ask about nonprescription therapies that are being used so that interventions can be made when women are taking high doses of vitamin E, vitamin C, beta-carotene, folic acid, or B vitamins to prevent CVD. It is also important to counsel women about the risks and benefits of HRT and to ascertain that HRT is not being prescribed for CVD prevention.
Conclusion
Given the prevalence of CVD and the difficulty of attaining ideal cardiovascular health, the pharmacist is perfectly positioned to prevent harm to patients by becoming familiar with the medications that should be avoided in the prevention of CVD in women. Based on current research, cardiovascular-prevention efficacy cannot always be extrapolated from success based on observational data. It is through well-designed clinical studies with populations randomized to treatment that evidence will emerge and recommendations can be drawn. As more women participate in cardiovascular research studies and more gender-specific analyses are conducted, more definitive recommendations can be made.
Current evidence suggests that HRT with estrogens, progestins, and SERMs, antioxidant supplements (vitamin E, vitamin C, and beta-carotene), and folic acid with or without B-vitamin supplementation should not be used for CVD prevention in women. Additionally, aspirin should not be used for MI prevention in women younger than 65 years.
REFERENCES
1. Mosca L, Mochari-Greenberger H, Dolor RJ, et al. Twelve-year follow-up of American women’s awareness of cardiovascular disease risk and barriers to heart health. Circ Cardiovasc Qual Outcomes. 2010;3:120-127.
2. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation. 2011;123:e18-e209.
3. Bambs C, Kip KE, Dinga A, et al. Low prevalence of “ideal cardiovascular health” in a community-based population: the heart strategies concentrating on risk evaluation (Heart SCORE) study. Circulation. 2011;123:850-857.
4. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. Circulation. 2011;123:1243-1262.
5. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-534.
6. Grodstein F, Stampfer M. The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog Cardiovasc Dis. 1995;38:199-210.
7. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016-1037.
8. Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med. 2006;166:357-365.
9. Taylor HS, Manson JE. Update in hormone therapy use in menopause. J Clin Endocrinol Metab. 2011;96:255-264.
10. Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125-137.
11. Farbstein D, Kozak-Blickstein A, Levy AP. Antioxidant vitamins and their use in preventing cardiovascular disease. Molecules. 2010;15:8098-8110.
12. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293:1338-1347.
13. Lee IM, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA. 2005;294:56-65.
14. Bjelakovic G, Nikolova D, Gluud LL, et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007;297:842-857.
15. Ye Z, Song H. Antioxidant vitamins intake and the risk of coronary heart disease: meta-analysis of cohort studies. Eur J Cardiovasc Prev Rehabil. 2008;15:26-34.
16. Clarke R, Halsey J, Lewington S, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med. 2010;170:1622-1631.
17. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1567-1577.
18. Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004;291:565-575.
19. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1567-1577.
20. Baker F, Picton D, Blackwood S, et al. Blinded comparison of folic acid and placebo in patients with ischaemic heart disease: an outcome trial [abstract]. Circulation. 2002;106(suppl 2):741.
21. Bønaa KH, Njølstad I, Ueland PM, et al. NORVIT Trial investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006;354:1578-1588.
22. Ebbing M, Bleie Ø, Ueland PM, et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA. 2008;300:795-804.
23. Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008;299:2027-2036.
24. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352:1293-1304.
25. Eidelman RS, Hebert PR, Weisman SM, Hennekens CH. An update on aspirin in the primary prevention of cardiovascular disease. Arch Intern Med. 2003;163:2006-2010.
26. Berger JS, Roncaglioni MC, Avanzini F, et al. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA. 2006;295:306-313.
27. U.S. Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Arch Intern Med. 2009;150:396-404.
28. Christian AH, Rosamond W, White AR, Mosca L. Nine-year trends and ethnic disparities in women’s awareness of heart disease and stroke: an American Heart Association national study. J Womens Health (Larchmt). 2007;16:68-81.
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