Prevalence

Heart disease is the leading cause of mortality in the United States for both men and women.¹ While the relative rate of cardiovascular disease (CVD) mortality declined by 31 percent from 2000 to 2010, the burden of disease remains high, with CVD accounting for about one in three deaths in the United States.² In addition to high rates of mortality, many persons live with a CVD diagnosis (16 million) and a large number of individuals are survivors of CVD-related events such as heart attack (7.9 million) or stroke (7 million).³ Each year, an estimated 620,000 Americans have a first heart attack and about 610,000 experience a first stroke.² These high rates of CVD mortality and morbidity represent a significant economic burden to the health care system in the United States. In 2010, for example, the estimated direct and indirect cost of CVD was approximately $315 billion.²

Burden

While CVD impacts much of the population, the distribution of burden and risk factors is not equal among subpopulations. Age, sex, and race/ethnicity are nonmodifiable risk factors that are associated with an increased burden of CVD in the United States. The prevalence of CVD (including heart disease, stroke, and other vascular diseases) increases progressively with age, with a lifetime risk for any CVD of almost two in three for men and greater than one in two for women who are free of disease at age 45 years.⁴ 2010 U.S.-based data showed that individuals age 65 years or older carry the highest prevalence of coronary heart disease (CHD) (19.8%), with those ages 45 to 64 and 18 to 44 years having a prevalence of 7.1 and 1.2 percent, respectively.⁵ Men also bear a higher burden of heart disease than women, with higher incidence at each age strata² and prevalence rates of 7.8 and 4.6 percent, respectively.⁵ While men carry a higher burden of heart disease, women experience higher mortality from certain cardiovascular incidents, such as stroke.² One cause of this difference is that men tend to experience CVD events earlier in life. For myocardial infarction (MI), the mean age of first event is 64.9 years for men and 72.3 years for women.² Perhaps due to their increased age at first MI, women are more likely than men to die within weeks of having an MI.² In addition to age and sex differences, race and ethnicity are also associated with an increased burden of CHD. From 2006 to 2010, American Indians and Alaska Natives had the highest prevalence (11.6%) of heart disease followed by blacks (6.5%), Hispanics (6.1%), whites (5.8%), and Asians or Native Hawaiians/other Pacific Islanders (3.9%).⁵

CVD Risk Factors and Risk Assessment

Risk factors for CVD are well established and include both modifiable and nonmodifiable components. Modifiable risk factors include: high cholesterol, high blood pressure, diabetes, overweight and obesity, smoking, lack of physical activity, and unhealthy diet.^6-8 Nonmodifiable risk factors include: age, sex, and family history.^6,7,9,10

Diabetes is an important risk factor, as prevalence of diabetes is increasing in the U.S. population and patients with diabetes incur a greater risk for heart disease than those without diabetes. In 2010, for example, 8.3 percent of the general population and 26.9 percent of those age 65 years or older had been diagnosed with diabetes mellitus, and these prevalence rates are increasing dramatically.^2,11 This high prevalence of diabetes, especially among older populations, is noteworthy because adults with diabetes are at a two- to four-fold risk for CVD events compared with those without diabetes.^11-13

There are a number of CHD and CVD risk assessment tools available to clinicians and patients.^6,8,14-22 These tools are based on risk prediction equations derived from large prospective cohort studies, randomized trials, and primary care databases. Investigators have cited several sources of heterogeneity among risk assessment tools, including: the definition of CHD or CVD outcomes predicted, risk factors included, and variation in the baseline risk and other characteristics of model derivation cohorts.^23,24 These differences in tools can lead to different risk scores in the same patient.²⁴

Characteristics of these tools are provided in Appendix A. The American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Equation¹⁴ and one of the six Framingham-based models by Anderson²⁵ predict global CVD outcomes and have been externally validated in U.S.-based populations. Models predicting CHD that have been externally validated in U.S.-based populations include those based on Framingham data by Anderson,²⁶ Wilson,⁸ and the Adult Treatment Panel (ATP) III.¹⁵ No stroke prediction model has been externally validated in the United States (Appendix E Table 5).

Mechanism of Action

While aspirin has long been used as a pain reliever, it began to gain traction as an effective antiplatelet drug therapy during the 1980s as clinical trials showed promising results.²⁷ Over the past two decades, researchers gained insights into the mechanism of aspirin and its use as an anticlotting agent to prevent the development of CVD. This research has revealed that atherosclerosis associated with CVD causes narrowing of the arteries and blood vessels through the thickening of the arterial wall, which may lead to reduced blood flow to the tissues and organs of the body.²⁸ Additionally, plaques may form in these narrowed vessels and break or rupture causing blood clots that can block blood flow to the heart or brain resulting in a heart attack or stroke.²⁸ Aspirin therapy helps to reduce these blood clots and, because of this, is often prescribed as a primary or secondary preventive measure for persons at high risk for MI/coronary events or stroke.

Aspirin belongs to the family of nonsteroidal anti-inflammatory drugs (NSAIDs) and has been determined to be an irreversible cyclo-oxygenase (COX)-1 and -2 enzyme inhibitor, although unlike other NSAIDs, it affects more of the COX-1 variant than COX-2.²⁹ When used in low doses (≤100 mg/day), aspirin works by preferentially inhibiting COX-1 activity, which results in a decreased production of thromboxane A2.³⁰ Thromboxane promotes platelet clotting and vasoconstriction, which explains aspirin's anticlotting effects.²⁹ With low doses of aspirin, throughout this process, COX-2 activity remains intact, which allows prostaglandin I2 (a vasodilator and platelet inhibitor) to continue to be produced. COX-2 typically helps to produce prostanoids, the majority of which are proinflammatory and are an important part of the inflammatory response system.³¹ This resulting decrease in thromboxane A2 and continued production of prostaglandin I2 explains aspirin's potential ability to diminish arterial thrombosis and prevent MI/coronary events and stroke.²⁹ The COX-1 enzyme is also responsible for producing a variety of prostaglandins, some of which are actively involved in protecting the gastrointestinal (GI) mucosa.³² By inhibiting this enzyme, aspirin use can leave the patient vulnerable to GI bleeding, which is a major harm to consider when weighing the benefits of regular aspirin therapy.²⁹ At higher doses (≥300 mg/day), aspirin begins to inhibit COX-2 activity, taking on greater anti-inflammatory effects, but also increases the inhibition of prostaglandins produced by COX-1, further increasing the risk of GI bleeding in the patient.^29-31

Current Clinical Practice in the United States

Research has demonstrated that aspirin therapy can effectively reduce the recurrence of serious vascular events in patients with a history of a previous MI, stroke, or transient ischemic attack (TIA) by approximately 20 percent.³³ Because of this consistently reported benefit, which has been found to significantly outweigh the risk of major bleeding, aspirin therapy for secondary prevention has gained widespread clinical acceptance.^33,34 The potential benefit of aspirin in primary prevention, however, is smaller because of the lower absolute risk in this population.³³ Therefore, many recommendations have focused on identifying primary prevention patients at sufficiently high CVD risk to outweigh bleeding harms. As illustrated in Appendix E Table 1, U.S.-based recommendations published more than 3 years ago by the U.S. Preventive Services Task Force (USPSTF),³⁵ AHA,³⁶ and American Diabetes Association³⁷ recommend aspirin for patients meeting various CVD/CHD risk thresholds. In contrast, European recommendations published more recently^38-41 do not recommend the use of aspirin in primary prevention, with the exception of a weak consideration from the United Kingdom's National Institute for Health and Care Excellence for use in patients with hypertension age 50 years or older with a greater than 20 percent 10-year CVD risk or reduced renal function.

The Centers for Disease Control and Prevention released data from 2007–2008 that demonstrates that physicians prescribed aspirin and other antiplatelet medications at relatively few visits in the population recommended by the USPSTF: 16.2 percent in men and 21.7 percent in women.³ Possible reasons for low uptake of the recommendation could include lack of knowledge about guidelines, competing demands during the clinical encounter, or the expectation that patients will not adhere to advice.

Previous USPSTF Recommendations

In 2002, the USPSTF found good evidence from five randomized, controlled trials (RCTs) that aspirin decreases the incidence of CHD in adults at increased risk for heart disease.⁴² It also found good evidence that aspirin increases the incidence of GI bleeding and fair evidence that aspirin increases the incidence of hemorrhagic stroke. The USPSTF concluded that the balance of benefits and harms is most favorable in patients at high risk for CHD (those with a 5-year risk ≥3%) but is also influenced by patient preferences. As a result, the USPSTF strongly recommended that clinicians discuss aspirin with adults who are at increased risk for CHD.⁴²

In contrast to the 2002 recommendations, in 2009, the USPSTF concluded that there was evidence to support variations in aspirin use by age and sex.³⁵ Based on data from six RCTs, the USPSTF concluded there was good evidence that aspirin decreases the risk of MI/coronary events in men and ischemic strokes in women. It also concluded there was good evidence that aspirin increases the risk of GI bleeding and fair evidence that aspirin increases the incidence of hemorrhagic stroke. The USPSTF determined that overall reduction in CVD events with aspirin use is dependent on both baseline CVD risk (specifically, CHD risk in men and stroke risk in women) and risk for GI bleeding.³⁵ The USPSTF found insufficient evidence to assess the balance of risks and benefits in men and women age 80 years or older. There was modest certainty that the benefits of reducing MI/coronary events or ischemic stroke do not outweigh harms in men age 44 years or younger and women age 54 years or younger. As a result, the USPSTF recommended aspirin use for men ages 45 to 79 years for prevention of MI and for women ages 55 to 79 years for prevention of ischemic stroke when the potential benefit outweighs the risk of an increase in GI hemorrhage. The USPSTF recommended against treatment in men and women age 80 years or older and did not issue a recommendation for men age 44 years or younger or women age 54 years or younger.³⁵

Since the previous review, results are now available from three new trials conducted in populations selected for diabetes, asymptomatic peripheral artery disease, or both.^43-45