The goal of this monograph is to present current information on the morbidity and mortality of cardiovascular events in women, describe the role of aspirin in the primary prevention of cardiovascular disease in women, and discuss issues relative to its safe and effective use for this purpose.

LEARNING OBJECTIVES

At the conclusion of this lesson, the reader should be able to:

1. Compare cardiovascular morbidity and mortality data for men and women in the United States;
2. Identify common risk factors for cardiovascular disease and discuss how their modification can benefit overall
    health;
3. Identify proposed gender differences in the clinical response to aspirin when used for prevention of
    cardiovascular events;
4. Define the therapeutic role of aspirin in primary and secondary prevention of cardiovascular events;
5. Describe the mechanism of antiplatelet action of aspirin and list guidelines for this use;
6. Identify adverse reactions; drug interactions; and warnings, precautions, and contraindications for antiplatelet
    doses of aspirin;
7. Describe the outcomes of the 2005 Women’s Health Study and state their implications in clinical therapeutics;
8. Delineate the role of healthcare professionals in improving patient adherence to cardiovascular disease
    prevention guidelines; and,
9. Formulate specific information to convey to patients who are taking aspirin for prevention of cardiovascular
    events.

Half of all women in the United States will die of cardiovascular disease (CVD) compared with 4% of women who die from breast cancer. American women are six times more likely to die of heart disease than breast cancer¹; yet in one survey of women, only 8% of them considered cardiovascular disease to be their greatest health threat.² The results of the recently-published landmark Women’s Health Study provide strong evidence to support the health benefits of aspirin for primary prevention in women and may have significant implications for clinical practice, yet aspirin prophylaxis in both primary and secondary prevention is underutilized³ and mismedication with aspirin is common.⁴

This monograph examines the role of aspirin in the primary prevention of cardiovascular events in women. It reviews critical information that supports its use to decrease morbidity and mortality from cardiovascular disease in men and women, and presents current guidelines for therapy. It also provides information for patient counseling on the use of aspirin in prevention of cardiovascular events.

BACKGROUND

Despite tremendous gains in the treatment of CVD over the past couple decades, CVD remains the leading health threat in the United States, Canada, and most developed countries. It has been the major cause of death and disability in the United States every year in which records have been kept except 1918; nearly 2500 Americans die of CVD each day, averaging 1 death every 35 seconds. CVD claims more lives than the next 4 causes of death combined, cancer, chronic lower respiratory diseases, accidents, and diabetes mellitus.⁵ The total direct and indirect cost of all CVD in 2006 is expected to reach $403.1 billion with estimated direct and indirect cost of stroke in 2006 projected to be $57.9 billion. Stroke is a leading cause of functional impairment in the United States,⁶ and currently the leading cause of disability and second leading cause of death worldwide.⁷ The World Health Organization estimates that about 17 million people worldwide die of CVD each year, particularly myocardial infarction (MI) and stroke.⁸ By the year 2020, cardiovascular disease will be the leading cause of death worldwide.⁹

Cardiovascular Disease in Women
Surprising to many women⁵ and some health care professionals¹⁰ in the United States is that coronary heart disease (CHD) resulting from atherosclerosis accounts for the majority of the country’s CVD mortality in women, with excess of 500,000 deaths annually.^5,11 In fact, since 1984, CVD has claimed the lives of more women each year than men⁵ (Figure 1). CVD accounts for greater mortality in women than the aggregate of all forms of cancer (Figure 2),¹² and as stated above, exceeds the next four causes of death in women combined. This translates into approximately one death in women in the United States every minute.¹³ CVD affects not just older women but those in their 40s and 50s as well. Many cardiovascular problems, including atherosclerosis, begin in the teenage years to young adulthood, so prevention must begin at least during that period to have its greatest impact. Heart and stroke statistics for women in 2006 are summarized in Table 1.

Figure 1. Cardiovascular disease mortality trends for males and females in the United States. Death rates are age-adjusted per 100,000 population.⁵

Figure 2. Leading causes of death for white females in the United States.⁵

Table 1. 2006 Heart and Stroke Statistics for Women⁴⁶

• In 2003, 483,800 American females died from CVD; there were 6 million females with CHD and 3.1 million with
  stroke.
• From 1999-2003, age-adjusted death rates from CVD in women decreased about 12% and for CHD they
  dropped about 17%.
• One in 2.6 deaths in women are from CVD.
• 64% of women and 50% of men who died suddenly of CHD in the United States had no previous symptoms of
  this disease.
• In 2003, 96,200 females and 61,600 males died from stroke. Because women live longer than men on average,
  more women die of stroke each year.
• Before age 75, a higher proportion of cardiovascular events due to CHD occur in men than in women, and a
  higher proportion of events due to CHF occur in women than in men.
• In 2003, 373,000 females and 327,000 males suffered a new or recurrent stroke.
• 8% of women and 25% of men will die within one year of having an initial recognized heart attack.
• In the United States in 2004, 20.2 million females and 24.1 million males used tobacco.
• Among Americans age 18 and older, 18.5% of females and 23.4% of males are smokers, putting them at
  increased risk of heart attack and stroke.
• In 2003, 69.6 million males and 66.9 million females were overweight (BMI ≥25). Of these, 27.9 million males
  and 36.1 million females were obese (BMI ≥30).
• In 2003, 35,300 males and 38,700 females died from diabetes.
• 7.1 million females and 7 million males were living with diabetes that had been diagnosed by their physician.
• The average age of a person having a first heart attack is 65.8 years for men and 70.4 years for women. CHD
  rates in women after menopause are 2-3 times those of women the same age who are premenopausal.
_________________
CVD = cardiovascular disease; CHD = coronary heart disease; CHF = congestive heart failure; BMI = body mass index [weight(kg)/height (m²)]

The American Heart Association (AHA) sponsored a recent national study that showed that fewer than 50% of American women know that heart disease is their leading killer.¹⁴ The study included more than 1000 women representing a variety of racial and ethnic backgrounds. More women in this study knew that heart disease was their leading killer than in similar studies conducted in 1997 and 2000; however, there is still a lot of room for improvement.

There are probable explanations as to why there is a wide mortality gap between the genders as noted in Figure 1. Women with symptoms of MI are less likely than men to seek emergency treatment and more likely to die within a year of their event.¹⁵ Women may delay seeking emergency treatment quickly because they are less aware than men of the symptoms and consequently, may be in denial when they experience them. Moreover, women may not experience the classic syndrome of angina characteristic for men¹⁶; for example, they are more likely than men to feel angina at rest and during sleep. Pain may predominate in areas other than the anterior chest, including the lower jaw, both arms, shoulders, back, and epigastrium. Women are more likely to experience fatigue, nausea, vomiting, sweating, dyspnea, presyncope, or palpitations rather than chest pain. They also experience more silent MIs,¹¹ with nearly half of the events remaining unrecognized.¹⁷ Conclusions from the National Healthcare Quality Report, recently published by the Department of Health and Human Services’ Agency for Healthcare Research and Quality,¹⁸ emphasize the opportunities for clinical improvement with regard to cardiac disease. To illustrate, only 69.6% of adult white women, 70.9% of black women, 59% of American Indian/Alaska Native women, and 60.9% of low-income women have had their cholesterol level checked in the past 5 years.

Despite extensive documentation in women of the high risk for morbidity and premature mortality from CVD, disparities by gender are well documented.¹⁹ Women with acute MI may be treated less frequently and less aggressively with thrombolytic and other cardioprotective therapy than men.^12,20 They are less likely than men to receive aspirin within 24 hours of admission (82.6% versus 87.1%), have aspirin prescribed at discharge (84.2% versus 87.2%), or receive beta-blockers at admission (67.34% versus 70.37%).¹⁸ Women also receive fewer coronary angiography and revascularization procedures,²¹ and have greater complication and mortality rates following revascularization.^22,23 Women are also less likely than men to participate in cardiac rehabilitation after an MI.²⁴ Following an MI, women experience a higher death rate during hospitalization than men in a similar age range.²⁵ Historically, decades of study of the treatment of MI have focused on men.¹⁶ Within a year of a first MI, an estimated 25% of men and 38% of women will die.^2,26 The question of whether aspirin confers similar cardioprotective effect in women as has been shown in men therefore takes on heightened meaning. This reinforces the importance of primary prevention of cardiovascular events in women when total morbidity and mortality between the two genders are considered.

Thrombosis, explained subsequently, is the principal cause of acute occlusive vascular events.²⁷ Platelet (ie, thrombocyte) aggregation into occlusive masses comprise the bulk of coronary and cerebral arterial thrombi.^28-30 Attempts directed toward reducing cardiovascular morbidity and mortality in both men and women should therefore be directed toward decreasing the affinity of platelets to adhere to one another and to vascular walls. Aspirin is well documented to possess this therapeutic activity.

ASPIRIN DEVELOPMENT

Therapeutics was changed forevermore with discovery in 1763 that the bark of an English willow tree contained a therapeutically active principal that cured “anguish and intermitting” disorders.³¹ The active principal, salicin, was isolated in 1829 and shown to possess antipyretic activity. Salicin yielded salicylic alcohol on hydrolysis, which could be converted into salicylic acid in vivo and in vitro. Sodium salicylate became a standard remedy for treatment of rheumatoid disorders by 1875. Its success led to synthesis of a stable form of acetylsalicylic acid in 1897, which maintained potent anti-inflammatory activity of the sodium salt but with fewer, less serious side effects.³² Acetylsalicylic acid, under the name of aspirin, was introduced into medicine in 1899³³ and recommended for its analgesic, anti-inflammatory, and antipyretic activities. Anecdotal reports in the 1950s linked aspirin with prolongation of bleeding times, but it would take another two decades before aspirin would be associated positively with reduction of prostaglandin synthesis and inhibition of platelet aggregation, and the thesis that it might reduce the risk of cardiovascular events. Today, aspirin is the “gold standard” to which newer antiplatelet drugs are compared for action in reducing the risk of cardiovascular events. It is certainly the most cost-effective antiplatelet therapy.

Aspirin may, in fact, be the most widely used medication in the world.^34,35 Usage in the United States is projected to be as high as 10,000 to 20,000 tons annually.³⁶ One estimate holds that eighty million aspirin tablets are taken each day in the United States, primarily for their analgesic/anti-inflammatory effects.

THROMBOSIS

Role of Atherosclerosis
Atherosclerosis is the predominant cause of most occlusive CVD. Onsetting in childhood or early adulthood, atherosclerosis progresses over a lifetime in the presence of identifiable risk factors for cardiovascular events such as advancing age, cigarette smoking, hypertension, elevated blood total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, decreased blood high-density lipoprotein cholesterol (HDL-C) level, increased fasting blood glucose level (ie, diabetes mellitus), and a positive familial history of CVD.^37,38 Even during atherosclerosis development, it may be decades before clinical cardiovascular disease is apparent. Therefore, focusing on primary prevention (ie, protecting otherwise healthy persons without known CVD) is important. As noted earlier, platelets, their products, and thrombosis (ie, formation, development, or presence of a thrombus [plug or clot within the vasculature]) are all crucial to development of clinical manifestations of CVD.³⁴ Interrupting the process of thrombosis is therefore of primary importance in preventing cardiovascular events.

Thrombosis is a dynamic condition in which a platelet aggregate and/or fibrin clot occludes an artery.³⁰ An MI may follow when the blood supply to the myocardium is occluded and lead to sudden coronary death. Similarly, a cerebrovascular event (ischemic stroke) results from similar pathology although the precise events and frequency of thrombosis in cerebral ischemic syndromes is less well defined. Additional pathogenic mechanisms may also be involved. In the United States, 85% to 88% of strokes are ischemic in origin (versus hemorrhagic) with the vast majority resulting from occlusion of cerebral arteries with atherosclerotic plaque.^5,39
 

Role of Platelets
The phenomenon of platelet-stimulated thrombus formation in hemostasis requires three critical steps: platelet adhesion, granule release, and platelet aggregation.⁴⁰ The endothelium that lines the vascular walls normally provides a smooth, uninterrupted surface to blood flow that resists thrombus formation. This is accomplished because endothelial cells secrete a prostaglandin named prostacyclin (PGI₂). When the integrity of the vasculature wall is interrupted (eg, injury, atherosclerotic plaque), the subendothelial contents of the vessel wall are exposed to circulating blood elements including platelets. Platelets begin to adhere to one another and to the vessel wall. A variety of agonists can stimulate platelet aggregation leading to thrombosis, including collagen, thrombin, serotonin, epinephrine, and adenosine diphosphate (ADP).²⁸ The binding of these agonists to the platelet surface receptors activates enzymes that catalyze release of the fatty acid arachidonic acid from membrane phospholipids. Some of the released arachidonic acid is converted within the platelet membrane to thromboxane A₂ (TXA₂) and PGI₂. TXA₂ and PGI₂ formation are catalyzed by the enzyme cyclooxygenase.

A finely balanced mechanism mediates the rate and extent of platelet activation toward aggregation.⁴¹ TXA₂ is prothrombotic in that it stimulates platelet aggregation and secretion, and promotes vasoconstriction and vascular smooth muscle proliferation. In contrast, PGI₂ is antithrombotic because it opposes the action of TXA₂ by inhibiting platelet aggregation and causing vasodilation. As the primary hemostatic plug is being formed (ie, primary hemostasis) plasma coagulation proteins are activated to initiate secondary hemostasis (ie, fibrin formation). Fibrin strands add to the platelets to strengthen the primary hemostatic plug.

Another common pathway in platelet aggregation is activation of glycoprotein (Gp) IIb/IIIa receptors that form on activated platelets and serve as the binding site for fibrinogen.^42,43 These receptors are expressed only on activated platelets. The arginine-glycine-aspartic acid complex mediates the cross-linking between fibrinogen and the activated GpIIb/IIIa complex. The resultant platelet aggregates are anchored firmly by fibrin.³⁰ Additional platelets are attracted, and ultimately a thrombus is formed.²⁸

Cyclooxygenase
Cyclooxygenase (prostaglandin endoperoxide synthase; COX) catalyzes a number of key physiological functions including TXA₂ and PGI₂ synthesis from arachidonic acid (Figure 3). Two isoforms of COX, dubbed COX-1 and COX-2 have been identified to date and serve different functions. COX-1 is present in most cells throughout the body and is synthesized constitutively (continuously). COX-1 stimulates synthesis of the prostaglandins that regulate platelet aggregation and vascular homeostasis. It also maintains cellular integrity of the gastrointestinal mucosa and renal system. COX-1 may therefore be considered to be a “housekeeping” enzyme. In contrast, COX-2 is less abundant in many tissues. It is expressed (induced) rapidly and far more selectively than COX-1 in response to local inflammatory stimuli and released in tissues as a result of damage where it initiates the characteristic response of inflammation and pain.⁴¹ The two isoforms differ by a single amino acid at position 509 of cyclooxygenase (COX-1, valine; COX-2, isoleucine).

Figure 3. Effects of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) on thromboxane (TXA₂) and prostacyclin (PGI₂). Aspirin is an irreversible inhibitor of cyclooxygenase (COX-1); non-aspirin NSAIDs are reversible inhibitors of the enzyme.²⁶

ASPIRIN IS A POTENT ANTIPLATELET AGENT

The cardioprotective benefit from aspirin is believed to be due to its potent antiplatelet (ie, antithrombotic) activity by inhibiting prostaglandin synthesis in platelet membranes to prevent platelet plug formation in atherosclerotic vessels.^44,45 Additional sites and possible mechanisms for aspirin’s role in reducing cardiovascular events include an antioxidant action, and effects on neutrophils, fibrinolysis, thrombin generation, and atherogenesis in higher doses.^46-50 Since inflammation may also play an important role in atherosclerosis,⁵¹ and aspirin modifies inflammation,⁵² its anti-inflammatory action may help modify thrombosis.

Aspirin irreversibly inhibits platelet-dependent COX by selectively transferring its acetyl group for covalent binding with the hydroxyl group of a serine residue (Ser529) that is near, but not inside, the COX active site.^30,35,44 This blocks access of arachidonic acid into the catalytic site to inhibit COX action. Aspirin is absorbed rapidly across the gastric mucosa. Irreversible inhibition of platelet function is evident within 15 minutes after taking a 325 mg dose of aspirin,⁵³ and full antiplatelet effect is achieved within 30 minutes of ingestion. This action may be explained by considering that the platelets are probably acetylated presystemically, within the portal circulation, before aspirin is deacetylated to salicylic acid in the liver.³⁶ Approximately 10% of circulating platelets are replaced each day because of their lifespan of approximately 7 to 10 days,^30,36 with half of platelet function returning to normal 5 to 6 days after an aspirin dose.⁵⁴ Platelets retain antithrombotic activity throughout their lifespan.^30,36

Its action on platelets is irreversible⁴³; since platelets are anucleate, they lack the ability to synthesize new enzyme (protein) de novo and thus regenerate COX. For platelet aggregation to be impeded, platelet production of TXA₂ must be inhibited to greater than 95% extent.⁵⁵ This explains, in part, how a drug with a 20 minute half-life can confer complete antiplatelet activity when taken in once-daily doses. In contrast to aspirin, nonacetylated derivatives of salicylic acid such as salsalate and sodium salicylate, and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) have a reversible effect on COX; acetaminophen is without antiplatelet activity. Data from randomized, controlled clinical trials have clearly demonstrated that because of this action, aspirin reduces both primary⁵⁶ and secondary⁵⁷ risk of serious cardiovascular events. Aspirin, therefore, is an exception to any “class effect” of increased risk for serious adverse cardiovascular events that may exist with some traditional NSAIDs.

Levels of endothelial PGI₂ decrease after usual doses of aspirin, so reducing endothelial PGI₂ could theoretically interfere with aspirin’s cardioprotective effect mediated via the platelets. Fortunately, endothelial cells contain a nucleus and can produce additional COX, increasing PGI₂ production while maintaining vessel wall PGI₂-dependent nonadhesiveness. Therefore, a balance is achieved favoring platelet TXA₂ inhibition.^54,58 This dynamic interaction differs at various aspirin concentrations and is the reason for differing doses and dosing schedules encountered in cardiovascular trials.

ASPIRIN EFFECTS IN WOMEN

Secondary Prevention
Aspirin reduces subsequent cardiovascular events and mortality in women who have a history of cardiovascular disease. The Antiplatelet Trialists’ (APT) collaboration was a meta-analysis of the results of 145 randomized trials of antiplatelet therapy in approximately 54,000 patients with prior occlusive cardiovascular disease.⁵⁶ The APT established a clear benefit of aspirin in secondary prevention of MI, stroke, and vascular death in a wide range of patients including those with histories of prior MI, stroke, transient ischemic attacks (TIAs), stable and unstable angina, atrial fibrillation, valvular disease, peripheral vascular disease, revascularization surgery, and angioplasty. Aspirin reduced the risk of subsequent events (nonfatal MI, nonfatal stroke, and vascular death) by about 25% in middle-aged and older men and women, hypertensive and normotensive patients, as well as diabetic and nondiabetic patients. Women seemed to derive about as much benefit as men.

The second International Study of Infarct Survival (ISIS-2) demonstrated that aspirin provided clear and conclusive benefit in protecting against acute MI.⁵⁹ The study enrolled 17,187 individuals (women 35%) who had symptoms of impending MI. Within 24 hours (median 5 hours) of onset of symptoms, those who received aspirin at 162 mg/day, had a lowered risk for vascular death by 23%.

The Antithrombotic Trialists (ATT) collaboration was a meta-analysis of randomized trials of antiplatelet therapy.⁶⁰ Included were 287 studies involving 135,000 patients on antiplatelet therapy versus placebo, plus another 77,000 patients in comparisons of different antiplatelet therapies. Nonfatal MI and stroke, or vascular death were reduced by one-third. Nonfatal stroke was reduced by one-quarter, and vascular mortality by one-sixth. The study revealed that absolute reductions in the risk of experiencing a serious vascular event were 36 per 1000 in patients with previous MI who were treated for 2 years; 38 per 1000 patients with previous MI who were treated for 1 month; 36 per 1000 patients with a history of stroke or TIAs who were treated for 2 years; 9 per 1000 patients with acute stroke who were treated for 3 weeks; and 22 per 1000 patients with other high-risk conditions who were treated for 2 years. In all high-risk categories, the benefit of therapy outweighed the risk of major bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75 to 150 mg daily being at least as effective as higher daily doses. Doses less than 75 mg daily were less likely to confer protection.

Primary Prevention
The benefit of aspirin for patients with previous symptomatic atherothrombosis in the secondary prevention of recurrent cardiovascular events is well established. However, its effect in primary prevention in people who have no symptoms, principally women, is less clear since the majority of early trials focused on men.⁶⁰ There is, however, convincing evidence to affirm the contention that women are also benefited.

Evidence of the safety and effectiveness of long-term aspirin use (75-500 mg daily or every other day) is based on a systematic review of five randomized, controlled trials involving more than 50,000 individuals with no previous symptomatic cardiovascular disease. Three trials involved men only. More than 10,000 women were included in two trials. A substantial number of individuals were aged 70 to 80 years in four of the trials.

The US Physicians’ Health Study (PHS) was the first and largest investigation.⁶¹ The study involved 22,071 male physicians age 40 to 84 years who were randomly assigned alternate-day doses of aspirin (325 mg) or placebo. The trial was terminated early, after 5 years of treatment and follow-up, because men assigned to the aspirin group were showing a statistically extreme 44% reduction in their risk (fatal or nonfatal) of first MI compared with placebo. Most of the risk reduction represented nonfatal MI, since more than 9 times more nonfatal than fatal MIs occurred.

The smaller British Male Doctors’ Trial (BDT) was a single-blinded study enrolling 5139 physicians 50 to 70 years of age.⁶² Two-thirds of the subjects received aspirin, 500 mg/day; the other men were told to avoid aspirin and aspirin-containing compounds. After 6 years, the trial showed no significant benefit for aspirin in the rates of mortality or nonfatal MI or stroke. Disabling strokes occurred more commonly in men taking aspirin, but the overall risk of stroke was not significantly greater in persons taking aspirin. The rate of TIAs was significantly decreased. Compliance with aspirin dosage was poor.

The Thrombosis Prevention Trial (TPT) enrolled 5085 men ages 45 to 69 years who were at high risk for ischemic heart disease.⁶³ End points were nonfatal and fatal MI and coronary-related death. Aspirin (75 mg/day) reduced ischemic heart disease events by 20% due primarily to a 32% reduction in nonfatal events.

The Hypertension Optimal Treatment (HOT) Trial was designed to target the optimum blood pressure that would reduce cardiovascular events in hypertensive patients.⁶⁴ Patients were evaluated based on their level of blood pressure reduction, rather than efficacy of any particular antihypertensive agent; thus, the study was not placebo controlled. Recruited were 18,790 men and women (women 47%) age 50 to 80 years who were treated with various antihypertensive drugs as well as aspirin. As expected, lowering of blood pressure in patients with hypertension correlated positively with reduced risk for cardiovascular events. Addition of aspirin, 75 mg/day, lowered the risk of MI by 36% and major cardiovascular events by 15%. The risk of major bleeding episodes and stroke was unchanged by aspirin. Nonfatal hemorrhage (gastrointestinal or nasal) occurred twice as often in patients taking aspirin compared to those not taking aspirin.

The Primary Prevention Project (PPP) enrolled 4495 patients (women 57%) age 50 to 80 years and older who had a history of one or more major risk factors for coronary heart disease.⁶⁵ Persons who received aspirin, 100 mg/day, had a significant 23% reduction in the risk of all cardiovascular events and 44% reduction in the risk of cardiovascular death. Cardiovascular events were defined as angina pectoris, TIAs, fatal and nonfatal stroke, MI, peripheral vascular disease, and revascularizations.

A meta-analysis of the five studies listed above showed that among all 55,580 participants (women 21%), aspirin was credited with a statistically significant 32% reduction in the risk of non-fatal MI and a small, nonsignificant reduction in ischemic stroke.⁶⁶ Subgroup analyses of the 8883 women from HOT and 2583 from PPP (total 11,466) showed a possible but nonsignificant 19% reduction in risk of a first MI (HOT), and equal overall benefit of 31% reduction in risk of a first MI for men and women (PPP). The overall estimate of reduction in risk of a first MI for women who use aspirin was about 22%. Aspirin was associated with a nonsignificant 40% risk increase in the odds of hemorrhagic stroke, which was consistent with the increased risk of hemorrhagic stroke observed in secondary prevention trials with use of aspirin.⁶⁰ In absolute terms, this translated to an increased risk of one hemorrhagic stroke per 10,000 patients treated with aspirin per year. Aspirin was also associated with a 70% increase in the odds of gastrointestinal hemorrhage, which translated to an excess of 0.7 gastrointestinal hemorrhages per 1000 patients treated with aspirin per year.⁶⁷

Although women were included in only two of the five studies and accounted for only 20% of the people studied, the cardioprotective action of aspirin prompted recommendations for aspirin use in primary prevention in both men and women from the US Preventive Services Task Force (USPSTF)^68-70 and the American Heart Association, discussed subsequently.³⁷

These data from the five randomized controlled trials are augmented by the Nurses’ Health Study. The trial was a prospective observational cohort investigation of apparently healthy middle-aged women taking differing weekly amounts of aspirin.⁷¹ The study population included 87,678 nurses aged 34 to 65 years from eleven states who were free of diagnosed CHD, stroke, and cancer at the beginning of the investigation. The women completed questionnaires at 2-year intervals for 6 years (three surveys total), which sought information relating to their risk factors, aspirin products, indication for aspirin use, average aspirin consumption per week, and physician visits. Study endpoints were first occurrence of MI, stroke, all important vascular events, and cardiovascular death. Women who took one to six aspirin tablets each week experienced a 25% lowered risk of MI (p=.005), as compared with women who took no aspirin. There was no difference in the risk for stroke and only a slight, but insignificant, decrease in risk for cardiovascular death. Unfortunately, there was no attempt to confirm daily or weekly aspirin doses; unless otherwise specified, they were all assumed to be 325 mg/dose. The trial design limited the study’s validity, but it did offer valuable insight into aspirin’s safety and efficacy for purpose of hypothesis generation.

TREATMENT GUIDELINES AND PRACTICE OUTCOMES

US Preventive Services Task Force
The US Preventive Services Task Force (USPSTF) represents an independent panel of health experts who review published research data and from it makes recommendations relative to preventive health care. The Task Force receives federal funding but is independent of federal intervention. Most members have been primary care physicians whose professional expertise is in the evaluation of published data.⁷²

The USPSTF concluded that there is good evidence that aspirin reduces the incidence of CHD in men and women who are at increased risk. It stated that there was fair evidence that aspirin increases the risk of hemorrhagic stroke.^68,70 The group strongly recommended that physicians discuss aspirin therapy with patients who are at high risk for CHD and cardiovascular events, focusing on the benefits and risks. Persons at risk for CHD who are likely to benefit from aspirin therapy are men older than 40 years, postmenopausal women, and younger patients who have diabetes or hypertension, or who smoke. Higher-risk patients are characterized further as those with a 3% or greater chance of developing cardiovascular complications within the next 5 years. Persons at lower risk of cardiovascular disease may also benefit from aspirin therapy, but the risks of adverse effects may outweigh the benefits.

The USPSTF recommendations predict that aspirin would prevent six to 20 MIs in every 1000 patients with a 5% risk of coronary heart disease over 5 years. For every 1000 patients with a 1% risk of coronary heart disease, aspirin would prevent one to four MIs. These benefits were weighed against the risk of two to four major gastrointestinal hemorrhages and zero to two hemorrhagic strokes in both the 1% and 5% CHD risk groups. The risk for gastrointestinal bleeding with aspirin remains constant; however, the benefits for aspirin therapy begin to outweigh its risks in persons in the 3% CHD risk group. The USPSTF recommendations for aspirin suggested a drug-induced reduction of 28% in the risk of MI, a small increased risk of hemorrhagic stroke and major gastrointestinal bleeding, and nonsignificant trend toward reduction of all-cause mortality.

American Heart Association
The first American Heart Association Guide to the Primary Prevention of Cardiovascular Diseases was published in 1997 as an aid to health care professionals and their patients.⁷³ It was intended to complement the AHA/ACC (American College of Cardiology) Guidelines for Preventing Heart Attack and Death in Patients with Atherosclerotic Cardiovascular Disease, and to provide health care professionals with a comprehensive approach to patient care across a broad spectrum of risks. The current AHA Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women was released in 2004 to assist health care professionals in providing exemplary preventive care based on women’s probable risk of future CHD.¹³ The Guidelines recommend use of low dose aspirin therapy in women whose 10-year risk of a first coronary event exceeds 20%, and consideration for aspirin use in women whose 10-year risk is 10% to 20%. The Guidelines acknowledge a number of advances in the science of primary prevention since 1997.³⁷ Research continues to refine the recommendations on detection and management of established risk factors. The current Guidelines for aspirin use agree with the USPSTF report in that the antiplatelet drug should be used in primary prevention in women at moderate to high risk of a first episode of coronary disease or stroke. The Guidelines are presented in Appendix I.

Of note is that the ability to identify CVD in its earliest stages has improved over the past decade, resulting in blurring of the difference between primary and secondary prevention. Instead of considering CVD as an all-or-none condition, there is strong reason to consider it as a continuum of CVD risk.¹³ Table 2 illustrates a spectrum of CVD risks, with various groups defined by their absolute probability of experiencing a coronary event in 10 years according to the Framingham Risk Score for women (Figure 4). Clinical scenarios that stratify women into areas of high, intermediate, and lower risk are also shown in Table 2. These positions are consistent with recommendations by the Sixth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy,⁷⁴ the American Diabetes Association,⁷⁵ and the American Society of Hospital Pharmacists.⁷⁶

Figure 4. Framingham point score estimate of 10-year coronary heart disease risk for women in the United States. Find the total point score in Boxes A through E, then estimate the 10-year risk from Box F. A risk >20% is high; a risk of 10% to 20% is intermediate; and a risk <10% is low.¹³

CHD = coronary heart disease; CVD = cardiovascular disease.
^*Cerebrovascular disease may not confer high risk for CHD if the affected vasculature is above the carotids.
 Carotid artery disease (symptomatic or asymptomatic with >50% stenosis) confers high risk.
^†As chronic kidney disease deteriorates and progresses to end-stage kidney disease, the risk of CVD
 increases substantially.
^‡Some patients with subclinical CVD will have >20% 10-year CHD risk and should be elevated to the  high-risk category.
^§Patients with multiple risk factors can fall into any of the 3 categories by Framingham scoring.
^¶Most women with a single, severe risk factor will have a 10-year risk <10%.

Evidence that suggests CVD can be prevented in both women and men by eliminating the risks is overwhelming. Strategies to implement the AHA Guidelines and prioritize risk-reducing therapies in clinical practice are outlined in Table 3.

Table 3. Priorities for prevention in practice according to risk group¹³

High-risk women (>20% risk)
Class I recommendations:
 • Smoking cessation
 • Physical activity/cardiac rehabilitation
 • Diet therapy
 • Weight maintenance/reduction
 • Blood pressure control
 • Lipid control/statin therapy
 • Aspirin therapy
 • Beta-blocker therapy
 • ACE inhibitor therapy (ARBs if contraindicated)
 • Glycemic control in diabetics

Class IIa recommendation:
 • Evaluate/treat for depression

Class IIb recommendations:
 • Omega 3 fatty-acid supplementation
 • Folic acid supplementation

Intermediate-risk women (10% to 20% risk)
Class I recommendations:
 • Smoking cessation
 • Physical activity
 • Heart-healthy diet
 • Weight maintenance reduction
 • Blood pressure control
 • Lipid control

Class IIa recommendation:
 • Aspirin therapy

Lower-risk women (<10% risk)
Class I recommendations:
 • Smoking cessation
 • Physical activity
 • Heart-healthy diet
 • Weight maintenance/reduction
 • Treat individual CVD risk factors as indicated

Stroke prevention among women with atrial fibrillation
Class I recommendations:
 High-intermediate risk of stroke
  • Warfarin therapy

 Low risk of stroke (<1%/y) or contraindication to warfarin
  • Aspirin
_____________________________
Class I = Intervention is useful and effective; Class IIa = Weight of evidence/opinion is in favor of usefulness/efficacy; Class IIb = Usefulness/efficacy is less well established by evidence/opinion.
ACE = Angiotensin-converting enzyme; ARB = Angiotensin receptor blocker

Physician Awareness of and Adherence to Guidelines
Numerous factors including physician awareness and agreement, and patient- and system-related issues influence successful adoption of practice guidelines.⁷⁷ To assess their knowledge of the AHA Guidelines, an online national survey was administered to 500 physicians (300 primary care physicians [PCPs], 100 obstetricians/gynecologists [OBGyns], and 100 cardiologists [CARDs].¹⁰ The survey included questions to determine their awareness of and barriers to CVD prevention guidelines. Physicians were asked to identify preventive therapies that they routinely recommended for patients at high, intermediate, and lower risk of CHD. They were then presented experimental case studies to test their knowledge of published practice guidelines. The patient cases included information about age, sex, ethnicity/race, smoking status, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, blood pressure, treatment for hypertension, body mass index, family history of CHD, and personal history of CHD or diabetes mellitus. Once the physicians assigned a level of risk to each case, they were asked to recommend preventive treatment.

Physicians did not rate themselves as very effective in their ability to recommend preventive treatment for CVD and manage patient risk factors (Table 4). Recommendations for aspirin therapy varied by patient risk level, with those at high risk more likely to receive a recommendation (90% PCPs, 84% OBGyns, 86% CARDS). About one-third of physicians recommended aspirin therapy for low-risk patients. The most frequently recommended dose was 81 mg; however, one-third of PCPs and CARDs recommended 325 mg for high-risk patients, despite guidelines suggesting a dose range of 75 to 162 mg daily.¹³ Notwithstanding the fact that more women die of CVD each year than men, less than one in five physicians from any of the specialties (8% PCPs, 13% OBGyns, and 17% CARDs) strongly agreed or agreed with the statement. A prominent finding from the study was that women were more likely than men to be assigned a lower-risk category despite a similar calculated risk. This outcome agreed with previously published reports that showed gender did influence how physicians managed cardiovascular events.

PCP = primary care physicians; OBGyn = obstetricians/gynecologists; CARD = cardiologists

The outcome of the national survey underscored the need for educational programs about heart disease and health for women among health care professionals. Many physicians in the survey reported that they were willing to seek additional training to guide them in providing better preventive health treatment for CVD in women.

WOMEN’S HEALTH STUDY

The Women’s Health Study (WHS) was a recently completed randomized, double-blind, placebo-controlled clinical trial, the largest and longest to date, of low-dose aspirin in the primary prevention of CVD in women only.⁷⁸ The scientifically rigorous trial, funded by the National Heart, Lung, and Blood Institute, was designed to address the balance between the lowest dose of aspirin that would protect against cardiovascular events and its risk of gastrointestinal adverse effects. Participants were apparently healthy and health-conscious female health care professionals, 85% of whom had a 10-year Framingham risk score for CVD of less than 5%, and 75% had zero or one coronary disease risk factor. The women were 45 years of age or older, postmenopausal or with no intention of becoming pregnant, and were free of self-reported CHD, cerebrovascular disease, cancer (other than nonmelanoma skin cancer), or other major chronic illness at study entry (1992-95). Participants had to have no history of side effects to the study medication; were not taking aspirin, other NSAIDs, or individual supplements of vitamin A, E, or beta-carotene more than once a week; were not taking anticoagulants or corticosteroids; and were not a participant in the Nurses’ Health Study. Women were randomized to receive 100 mg of aspirin on alternate days or placebo and then were monitored for a mean of 10 years for a first major cardiovascular event (ie, nonfatal MI, nonfatal stroke, or death from cardiovascular causes).

Aspirin use in this setting was associated with a significant 17% reduction in risk of first stroke in women aged 45 years and older. It was also associated with a significant 26% overall reduction in the risk of first major cardiovascular events in women aged 65 years and older. Most stroke benefit was derived from nonfatal stroke. A similar decrease (22%) in TIAs was noted in aspirin-treated women.

The WHS supported aspirin’s favorable safety profile. There was a slight, nonsignificant increase in the risk of hemorrhagic strokes and increase in the number of episodes of overall gastrointestinal bleeding. There was no significant difference between aspirin and placebo in the risk of stomach upset or fatal gastrointestinal bleeding. These were important clinical findings.

Like most previous primary prevention trials, the WHS was well conducted. Aspirin and control groups were well balanced with respect to initial characteristics. Follow-up for outcomes was excellent. The WHS results clearly advanced knowledge of aspirin activity in women. However, they did not prove that aspirin affects women and men differently. At a given level of cardiovascular risk, women are more likely to experience strokes than MI. Men have the opposite pattern. Nonetheless, there is as yet little biological evidence to support differences in aspirin effectiveness based on gender. The WHS used a lower dose (100 mg every other day) than currently recommended. However, 100 mg every other day has been shown to be as effective as 81 mg/day at inhibiting TXA₂.⁷⁹

To better understand the impact of sex on the response to aspirin, Berger and coworkers recently initiated a gender-specific meta-analysis of 6 randomized controlled trials of aspirin in primary prevention of cardiovascular events.⁸⁰ Three trials (HOT, PPP, WHS) included a total of 51,342 women. The analysis demonstrated that in women, aspirin was associated with a significant 12% reduction in total cardiovascular events and a 17% reduction in stroke, reflecting a reduction in ischemic stroke. There was no significant effect of aspirin therapy on MI or cardiovascular mortality. The majority of women in this analysis were participants in the WHS, so these observations primarily represent the findings of the WHS.

OTHER ISSUES

Safety
The principal adverse effect of concern is gastrointestinal bleeding, which is more common at higher doses and is dose-related. There does not appear to be an obvious dose-response relationship across the commonly used range of antiplatelet doses of 75 to 325 mg/day.^28,81 Adverse effects at these doses include stomach pain, nausea, heartburn, and constipation, and are usually mild. Compared to any other proven therapy for acute MI, aspirin has the best benefit-to-risk ratio. Its benefit in cardioprotection is substantial, with risks of hemorrhage and hypersensitivity reactions minimal.

The risk for adverse reaction on the gastrointestinal tract is not significantly different with various aspirin formulations.^{42,67,68,82,83} Counterintuitive results were shown in a multicenter, case-control study that compared the relative risks for gastric and duodenal bleeding with 3 different formulations of aspirin (plain, coated, and buffered tablets) at doses of 325 mg or less/day.⁸¹ Contrary to popular belief, the relative risk for gastrointestinal bleeding with buffered and coated aspirin formulations were not significantly different from that with plain aspirin tablets (Table 5). Risk factors other than dosage for hemorrhagic complications of aspirin include increasing age, any bleeding diathesis, uncontrolled hypertension, and concomitant use of other NSAIDs or anticoagulants.⁶⁷

CI = confidence interval

The risk of developing a gastric ulcer is unlikely with doses less than 15 tablets (325 mg)/week.⁸⁴ Moreover, it has been noted that duodenal or gastric peptic ulcers heal while patients continue on prophylactic therapy.⁸⁵ Studies have confirmed that co-therapy with a proton pump inhibitor or misoprostol decreases the risk for gastrointestinal injury and complications.²⁶

Individuals may experience occasional respiratory and/or cutaneous symptoms characteristic of aspirin hypersensitivity reactions. These may appear within minutes to several hours of a dose. Their occurrence is uncommon.

The occurrence of adverse effects to doses of 1000 mg/day was assessed in a postinfarction study of 4500 patients.⁸⁶ The percentage incidence of unwanted responses to aspirin or placebo, respectively, were: stomach pain (14.5%, 4.8%), heartburn (11.9%, 4.8%), nausea and/or vomiting (7.6%, 2.1%), and hospitalization for gastrointestinal disorders (4.9%, 3.5%). Minimal increases in systolic blood pressure of 1.5 to 2.1 mm Hg, and diastolic pressure of 0.5 to 0.6 mm Hg, were noted with aspirin treatment. Blood urea nitrogen levels increased less than 10 mg/dL.

Aspirin therapy should cease 1 week prior to surgery unless surgery is mandated earlier. Persons on long-term anticoagulant therapy, and those with vitamin K deficiency, hemophilia, hypoprothrombinemia, or severe hepatic damage should be monitored closely while taking aspirin because of the increased potential for hemorrhage.³⁶ Aspirin should not be administered with alcohol due to increased potential for gastric ulceration. Aspirin must be administered cautiously, if at all, to patients with active or recent hemorrhage, including bleeding due to hemorrhagic stroke or peptic ulcer disease. It should be stressed that contraindications to aspirin are relative rather than absolute.

Drug Interactions
A number of drugs have been shown to interact with aspirin. They are listed, along with the reported outcome of interaction, in Table 6.

Resistance
A clinical syndrome identified as aspirin resistance (nonresponse; variable response) has been described.^42,87-89 It appears in some patients as persistent formation of TXA₂ despite adequate therapeutic doses of aspirin. Continued formation of TXA₂ is associated with increased risk of MI and cardiovascular death.

The suggestion that some patients may be resistant to aspirin’s antiplatelet action was first reported in 1978 when it was observed that 30% of patients with coronary artery disease responded less than expected to a single 650 mg dose of aspirin.⁹⁰ Subsequent reports noted diminished protection from platelet aggregation in 5% to 10% of patients. These patients tend to be women and nonsmokers.^38,91 It was later noted that platelet aggregation was not inhibited in 14 of 143 patients on daily aspirin, but this was overcome in all but two patients when an additional 75 or 100 mg aspirin was taken.⁹² This variability in the antiplatelet effect of aspirin seems to be present both in patients with coronary artery disease and young, healthy volunteers.⁸⁷

The significance of aspirin resistance remains unknown, largely because of the wide variety of methods used to define it, variations in methodology used to detect it, and limited study data. For example, aspirin resistance has been defined based on laboratory findings and/or clinical response. In some investigations, patients with thrombotic events during aspirin therapy have been defined as resistant, while other patients have been termed aspirin nonresponders. Some studies have reported that resistance was based on aspirin’s failure to prolong bleeding times, while others have defined resistance as failure to produce appropriate responses to platelet inhibition tests.

The mechanism by which some patients’ platelets fail to respond maximally to aspirin remains elusive. Table 7 summarizes possible mechanisms for resistance that have been suggested. More obvious reasons for less-than-adequate response include an incorrect diagnosis, inadequate dosing, and/or poor compliance with therapy.^42,89,93,94

Table 7. Proposed mechanisms for aspirin resistance^87,116

Extrinsic Mechanisms
• Accentuation of platelet thrombosis by exogenous substances (eg, cigarette smoke)
• Drugs, such as some NSAIDs, that may interact with aspirin’s acetylation of COX-1
• Increased platelet turnover to overcome once-daily aspirin dosing
• Inadequate aspirin doses

Intrinsic Mechanisms
• Inducible COX-2 enzyme that is not adequately inhibited by low-dose aspirin, thereby allowing for platelet TXA₂ production despite inhibition of COX-1
• Polymorphisms in the COX-1 gene that alter the structure of the active site and prevent acetylation by aspirin
• Regenerated, uninhibited COX-1 in nucleated cells such as macrophages and vascular endothelial cells producing prostaglandin H₂ that is shunted into platelets, thereby bypassing platelet COX-1
• Polymorphisms in the glycoprotein 11b/111a receptor complex that confer varying degrees of platelet responsiveness to aspirin

Current Usage
Despite the evidence that chronic, daily aspirin therapy reduces the risk of certain cardiovascular events, and considering that it is available without prescription, at relatively low cost, and is associated with a low risk of intolerance, its use as an antiplatelet agent continues to be disappointingly low.⁹⁵ One possible explanation for its underutilization is physicians’ concern about its potential for causing serious adverse effects on the gastrointestinal tract. As noted earlier, the incidence of adverse effects to antiplatelet doses is small.

Aspirin is believed to be currently used in secondary prevention by 70% to 80% of eligible patients, during acute MI by 50% to 70% of eligible patients, and in primary prevention by fewer than 50% of eligible patients.²⁷ Considering its reported cardioprotective action, it has been estimated that more intensive use of aspirin would prevent approximately 10,000 MIs in secondary prevention and approximately 100,000 in primary prevention in the United States each year.³⁴ In fact, it has been suggested that if aspirin were only 50% as effective, ten times more expensive, and required a prescription for use, it would be more widely used.³⁴

ADVISING PATIENTS ON ANTIPLATELET DOSES OF ASPIRIN

Women need to be informed about potentially lifesaving preventive therapies and urged to take action to lower their risk of CVD. They use less aspirin for prophylaxis of cardiovascular events than men. There is no clear explanation for this finding. Extensive research clearly does not suggest a less beneficial effect of aspirin in women,^56,96 a greater incidence of contraindications to aspirin use in women,⁹⁷ or differential rates of adherence to medication regimens by women.²⁰ On the basis of extensive scientific and clinical evidence, it appears the risk of no action exceeds the risk of applying knowledge to prevent CVD. This is where health care professionals can truly serve their clientele. Women will listen to advice from health care professionals and, if they hear it again and again, from all of them, they may place higher priority on taking the advice seriously! In its final rule regarding aspirin labeling, FDA stated it is not possible, in OTC product labeling, to provide adequate directions and warnings to enable consumers to make a reasonable self-assessment of risk factors.⁶⁹ The Agency urged that safe and effective use of aspirin for cardioprotection required professional supervision. Supervision by physicians to ensure the safe use of aspirin is ideal⁴; however, patient education from all health care professionals is necessary.

Its wide availability without need for a prescription may be a major reason why people may fail to take aspirin’s ability to effectively reduce morbidity and mortality from cardiovascular events more seriously. This misunderstanding can lead to poor compliance in dosing with ultimate reduction in extent of cardioprotective activity.⁹⁸ Patients frequently stop their medication within 1 year of its recommendation.⁹⁹ Tarjan and colleagues found that 11% of a group of coronary care patients were nonadherent with their aspirin dosing instructions.¹⁰⁰

As an antiplatelet therapy, aspirin should ideally be used along with an overall program of measures to eliminate the risk factors for CVD. Lifestyle modification includes healthy eating, cessation of smoking, regular exercise, and control of blood pressure.¹⁰¹ As described earlier, up to 90% of all CVD in the United States may be attributed to these, and other, modifiable risk factors. Results of long-term prospective studies consistently confirm that persons with low levels of cardiovascular risk factors enjoy lifelong low levels of CVD and stroke.^102,103 One outcome of the Nurses Health Study, for example, was the suggestion that in women, maintaining a healthy diet, exercise regimen, and desirable body weight, not smoking, and consuming a moderate amount of alcohol could account for an 84% reduction in risk of CVD.^71,104 Nonetheless, only 3% of the women (recall that all of them were health care professionals!) studied were in that category. Clearly, the vast majority of causes of CVD are known and modifiable.³⁷ No single risk factor should be considered in isolation. Risk stratification should incorporate known information about interaction between multiple risk-factors, rather than simply counting the number or risk factors.⁶⁷ While each factor independently modifies the risk of CVD, they may work additively and/or synergistically to multiply an individual’s risk.²⁶ Intervention leads to a decline in the incidence of CVD. Table 8 shows that, depending on the specific intervention used, significant reductions in total mortality can be achieved.

Individuals who may benefit from daily aspirin dosing should first be evaluated by a physician. Aspirin therapy for the primary prevention of cardiovascular events should be based on an assessment of the patient’s risk of an impending vascular event without aspirin, absolute risk of a gastrointestinal or intracranial hemorrhage with aspirin, and the patient’s preference. Decisions concerning continuance of aspirin therapy should be reviewed at least every 5 years, or when new vascular risk factors are detected.

Health care professionals should inform individuals who have not been evaluated medically and who ask about potential health benefits, that self-therapy with aspirin is not in their best interest. Reasons for this stance are twofold: (1) there is a risk, albeit slight, for adverse reactions; and (2) there is a chance that these individuals may not have received a thorough medical examination for some time in the past and a reminder at this point may be sufficient to encourage them to move forward on this. One exception to the general rule advising against self-medication is, since the extent of heart muscle damage is directly related to the time interval between onset of symptoms of MI and initiation of drug therapy, an uncoated aspirin tablet 325 mg should be taken at once if an MI is suspected.

In clinical practice, the decision to use aspirin for primary prevention should be based on the risk/benefit ratio at the patient level. Before advising aspirin, clinicians should assess the patient’s 10-year cardiovascular risk and compare it with the likelihood of adverse effects. Multivariate risk factor algorithms provide a more accurate estimation of cardiovascular risk than simply counting the number of risk factors.¹⁰⁵ Many risk factor algorithms based on the Framingham database are available on the Internet and are easy to use. These algorithms are often underused¹⁰⁶ and thus aspirin therapy may not be targeted to patients at high risk for cardiovascular events.¹⁰⁷

One helpful tool for patients and health care professionals to quickly calculate an individual’s risk of future coronary events is shown in Figure 5.¹⁰⁸ The strategy for defining risk is based on figures from the Framingham database and is valid for patients ages 30 to 75 years living in the United States who have no previous history of cardiovascular disease. If the risk of MI over the next 5 years is greater than or equal to 3%, the benefits of aspirin are likely to outweigh the risk of adverse effects. The decision whether or not to take aspirin will depend on the individual’s personal feelings concerning avoiding a cardiovascular event while risking the chance for complications of bleeding in the gastrointestinal tract or brain.¹⁰⁸

Figure 5. Coronary heart disease risk assessment. Estimate is valid for patients ages 30 to 75 years without a previous history of cardiovascular disease living in the United States.¹⁰⁸

The need for patient counseling and education is realized when patterns of aspirin utilization and mismedication are considered. With regard to underutilization, survey after survey confirm that it is underutilized. With respect to mismedication, 21% of patients in one study who were prescribed aspirin were actually taking acetaminophen (11%) or non-aspirin NSAIDs (10%) instead of aspirin.⁴ The survey authors concluded that as many as 1.3 million people 40 years of age and older may erroneously be taking only acetaminophen or non-aspirin NSAIDs for cardiovascular protection, and another 1.4 million may be taking these agents along with aspirin. A list of helpful Internet websites to aid in counseling women on aspirin use in prevention of cardiovascular events is given in Table 9.

Table 9. Helpful Internet Websites*

Specific sites
Cigarette smoking
 • www.surgeongeneral.gov/tobacco/treating_tobacco_use.pdf
Diet
 • www.cfsan.fda.gov/~frf/sea-mehg.html
Weight management
 • www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm
Lipids
 • http://circ.ahajournals.org/cgi/reprint/106/25/3143.pdf
Blood pressure
 • http://hyper.ahajournals.org/cgi/content/full/42/6/1206
 • http://www.nhlbi.nih.gov/health/public/heart/hbp/dsh/index.htm
Diabetes
 • http://www.diabetes.org/home.jsp
 • http://circ.ahajournals.org/cgi/content/full/105/18/2231
Atrial fibrillation/stroke prevention
 • http://www.nhlbi.nih.gov/about/framingham/stroke.htm
 • http://www.americanheart.org/downloadable/heart/222_ja20017993p_1.pdf
Absolute CHD risk calculation
 • http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm

Other sites
 • http://www.hearthealthywomen.org
 • http://www.womenheart.org
 • http://www.smallstep.gov
 • http://www.bayeraspirin.com
 • http://www.4women.org
 • http://www.womenshealth.gov
 • http://www.med-decisions.com/cvtool
 • http://strokecenter.org
_____________
*Listed is a small sample of helpful sites of interest to health care professionals and patients.

OVERVIEW AND CONCLUSIONS

Aspirin is one of the simplest, yet most effective, pharmacologic therapies proven to reduce the risk of certain cardiovascular events. The increasing burden of CVD in the United States and around the world emphasizes the importance for more widespread use of aspirin in the primary prevention of cardiovascular events. Aspirin should be seriously considered for primary prevention in healthy men and women who meet specific guidelines discussed within this monograph. Its use in primary prevention should not be undertaken as an alternative to lifestyle modification, but as an adjunct to it. Aspirin is recommended by the AHA and USPSTF, and other groups, in the absence of specific contraindications, for primary prevention of cardiovascular events in persons of both genders.

There is substantial evidence to support the effectiveness and safety of aspirin in this regard. The WHS and subsequent meta-analysis of more than 51,000 women indicated that low-dose aspirin therapy is associated with a significant reduction in cardiovascular events. The results are particularly noteworthy in reduction of stroke in women. The final decision to recommend aspirin for primary prevention requires a thorough assessment of the patient’s risk for experiencing an event without aspirin, the risk of a gastrointestinal or intracranial hemorrhage with aspirin, and the preferences of the patient. A positive patient response is needed to assure compliance with dosing instructions since, according to current information, commitment to daily therapy must extend over a lifetime.

Because it is easy to give, inexpensive, and has relatively few adverse effects at recommended antiplatelet doses, aspirin is unlikely to be replaced in the near future as a first-line antiplatelet agent. At the same time, newer agents that act by different mechanisms will continue to be developed. These agents will probably be used to supplement, rather than replace, aspirin.

As noted, aspirin still remains underutilized in the treatment and prevention of cardiovascular events. Thus, interventions to increase awareness and adoption of CVD prevention guidelines among health care professionals need to be intensified. Educational eff