Introduction
Since the initial scientific statement on Secondary Prevention of Coronary Heart Disease (CHD) in the Elderly was published in 2002 (1), several trends have continued that make an update highly appropriate. First, the “graying” of the US population and those of other industrialized countries has progressed unabated as more adults are surviving into their senior years. The number of Americans aged 75 years and older was estimated at 18.6 million in 2010, representing ~6% of the population (2) and is expect to double by 2050. The population aged ≥85 years is growing the most rapidly, with numbers expected to reach 19.5 million by 2040. In 2008, 67% of the 811,940 cardiovascular (CV) deaths in the US occurred in persons aged 75 years and older (3). In parallel to this increase in the older adult demographic, the number of Americans with CHD has increased to an estimated 16.3 million, over half of whom are over 65 years old (3). Similarly, 7 million have suffered a stroke, the incidence of which approximately doubles with successive age decades after 45–54 years (3). Peripheral artery disease (PAD) affects 8–10 million Americans, the majority of whom are older than 65 years. Between 2015 and 2030, annual U.S. costs related to atherosclerotic cardiovascular disease (ASCVD) are projected to increase from $84.8 billion to $202 billion (3). Moreover, given that ASCVD) often undermines functional capacity and independence and increases reliance on long term care, indirect expenses related to ASCVD are also expected to increase. Thus, the need for effective secondary prevention measures in the older adult population with known ASCVD has never been greater.
Notably, the 2011 AHA/ACCF updated guidelines for secondary prevention of CHD broadened its title to Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease (5). The expanded title acknowledges that benefits of CHD risk reduction extend to atherosclerotic vascular disease throughout the body. Given that CHD as well as peripheral artery disease (PAD), atherosclerotic aortic disease, and ischemic stroke all increase with advancing age (2), the mandate for secondary risk reduction among older adults has also expanded.
Over the decade since the original scientific statement was published, there has been an explosion of randomized controlled trials (RCTs) addressing secondary prevention of ASCVD, especially with regard to treatment of hypertension, hyperlipidemia, diabetes, and antithrombotic therapy. Such trials have included increasing numbers of older adults, though still well below their proportion in the population with ASCVD, and with especially few patients aged ≥80 years. As a consequence, generalizability of the studies’ conclusions to typical older patients is tenuous, and despite the ever-increasing number of published guidelines for management of ASCVD and its risk factors, a large proportion of ostensibly eligible older patients are not receiving evidence-based therapies in clinical practice (6).
Given these relevant trends in ASCVD prevalence and management, the current update is intended to clarify the benefits and risks of secondary prevention interventions in older adults, and to stimulate an increased application of proven secondary prevention therapies to the expanding population of older patients with CHD and the broader spectrum of atherosclerotic vascular diseases. Specific focus will center on utility of secondary prevention in the context of age-related physiologic changes and comorbidities that often complicate the care of patients of advanced age. Although the term “older” in this document refers to individuals aged ≥65 years, the emphasis (where data are available) is on those ≥75 years, in whom these age-associated challenges are most pronounced (1).
Major goals for secondary ASCVD prevention in older as well as younger patients are to prevent or delay the progression of disease that results in major clinical events such as MI, stroke, or critical limb ischemia. By preventing these events, not only is longevity likely to increase, but quality of life (QOL) is likely to improve and yearly health care costs are likely to decrease. Secondary prevention of ASCVD also enhances the potential of seniors to perform activities of daily living and thereby maintain their independence.
Nonetheless, secondary prevention goals in older patients with ASCVD must also incorporate consideration of the greater iatrogenic risks of the therapies themselves in older adults. Comorbidities, polypharmacy, socioeconomic stresses, and cognitive limitations frequently confound secondary prevention considerations. Thus, instruments to better delineate the relative risks and benefits of specific therapies in older patients are needed.
Overview of Coronary Heart Disease in Older Adults
Age-related endothelial dysfunction, inflammation, and vascular stiffness, in combination with increasing prevalence and duration of traditional CV risk factors lead to a progressive rise in the incidence and prevalence of CHD with increasing age in both men and women (3). Autopsy studies indicate that obstructive CHD is present in approximately 50% of older women and 70–80% of older men (1). In addition, older CHD patients tend to have more extensive coronary atherosclerosis with higher prevalence of prior MI, multi-vessel disease, and significant obstruction of the left main coronary artery than younger patients (1). Thus, although people ≥75 years of age account for only 6% of the United States population, 35–40% of incident MIs and up to 60% of deaths attributable to MI occur in this age group (7). Due to their longer life expectancy than men, women aged ≥65 years account for approximately half of all hospitalizations for MI and CHD. CHD is by far the leading cause of CV death in older adults (3), and CHD-related complications, including heart failure and heart rhythm disorders, are a major source of chronic disability, loss of independence, and impaired QOL. Moreover, since atherosclerosis is a systemic process, older patients with CHD often have concomitant PAD and/or cerebrovascular disease that further compromise functional capacity and contribute to diminished QOL (8).
Clinical manifestations
Although chest pain or discomfort is considered the hallmark of symptomatic CHD, the prevalence of chest discomfort as the presenting manifestation of CHD declines significantly with age in both men and women (9). Diminished activity levels may forestall the development of exertional angina until disease severity is far advanced. In addition, exertional dyspnea, which may represent an “angina-equivalent”, could be secondary to deconditioning, pulmonary disease, heart failure, or a host of other conditions rather than CHD. Furthermore, the increasing prevalence of cognitive impairment and dementia with advancing age may make it difficult or impossible to obtain a reliable history, thus contributing to diagnostic uncertainty.
The diagnosis of an acute MI is also confounded by advanced age. In the National Registry of Myocardial Infarction, for example, 77% of patients <65 years of age hospitalized with an acute coronary syndrome (ACS) presented with chest pain, as compared to only 40% of patients ≥85 years of age (10). Conversely, older CHD patients were substantially more likely to present with “atypical” symptoms, including dyspnea (49%), diaphoresis (26%), nausea and vomiting (24%), and syncope (19%). Whereas women have sometimes been reported to experience more atypical symptoms than men, Canto, et al (11) recently demonstrated that such gender differences in presentation narrow markedly with age, essentially disappearing by 75 years. The high prevalence of atypical or non-specific symptoms contributes to the rising proportion of MIs that are clinically silent or unrecognized at older age, from approximately 25% in younger patients to up to 60% in patients over age 85 (10).
Age-related alterations in LV diastolic function (impaired relaxation and increased myocardial stiffness) coupled with increased impedance to LV ejection due to increased arterial stiffness and impaired contractile reserve predispose older patients to develop heart failure in the setting of acute or chronic myocardial ischemia (12). Thus, the proportion of ACS patients presenting with heart failure increases from under 20% in patients <65 years of age to over 40% in patients ≥85 years old (10,13). Cardiogenic shock is also 2- to 4-fold more common in older ACS patients. In turn, the higher prevalence of heart failure and shock portend a less favorable prognosis in older patients after MI, and case-fatality rates following ACS increase exponentially with age (10,14).
Taken together, the above factors often lead to delayed presentation and diagnosis of both acute and chronic CHD in older patients (10, 13). Despite these difficulties, and as discussed in the ensuing sections of this document, existing evidence strongly supports the value of secondary preventive measures in most community dwelling older patients with established CHD. It is therefore incumbent on the clinician to maintain a high index of suspicion for CHD in patients of advanced age, and to implement appropriate diagnostic and therapeutic strategies in accordance with existing guidelines and individual patient circumstances and preferences.
Prognosis
In both clinical trials and observational studies, increasing age is a powerful predictor of both short-term and long-term mortality following acute MI. Median survival following a first MI decreases from 17.0 years and 13.3 years in men and women 55–64 years of age, respectively, to 3.2 years in both men and women ≥75 years of age (3, 10, 13). In the Global Registry for Acute Coronary Events (GRACE), hospital mortality was 6-fold higher in patients ≥85 years of age compared to those <65 years of age, and 30-day mortality was more than 7-fold higher (Figure 1) (10).
Figure 1.
Trial and Community-based assessments of A) In-Hospital and B) 30-Day Mortality relative to age stratifications. ACS mortality increases relative to age. Moreover the progressive increase in death with advancing age is greater in community populations than clinical trials. In addition to greater intrinsic cardiac instability, coexisting conditions such as chronic obstructive pulmonary disease, renal failure and cerebrovascular disease lead to higher morbidity and mortality over time (10) ©2007 American Heart Association, Inc.
In addition to higher mortality, older patients are at increased risk for hemorrhagic complications, stroke, re-infarction, and readmission following an incident coronary event (3, 10, 13). Among patients ≥65 years of age with a first MI, 21% of white men and women, 33% of black men and 26% of black women will experience a recurrent MI or fatal CHD event within 5 years (3). Over this 5 year time frame, heart failure will develop in 19% of white men, 31% of black men, 23% of white women and 24% of black women ≥65 years old; a stroke will occur in 5%, 9%, 8%, and 10% of these respective groups (3). The exceptionally high rate of adverse outcomes in older patients with CHD provides further support for the role of secondary prevention in this population.
Several pharmacological agents have shown efficacy in reducing the high residual morbidity and mortality in older adults with known CHD. The 2011 AHA/ACC Secondary Prevention Update recommends that all patients without contraindications should receive a beta blocker after an MI or ACS (5). In older patients with cardiac conduction disorders, claudication, or obstructive lung disease, beta blockers should be started at low doses and uptitrated slowly. Angiotensin converting enzyme (ACE) inhibitors should be used in all CHD patients with LV ejection fraction <40% unless contraindicated; in patients intolerant of ACE inhibitors, an angiotensin receptor blocker should be substituted (5). Antiplatelet drugs, including aspirin 75–162 mg daily is recommended in all CHD patients unless contraindicated. In patients receiving anticoagulation for atrial fibrillation, prosthetic heart valve, LV thrombus, or venous thromboembolic disease, aspirin dose should be 75–81 mg. Clopidogrel 75 mg daily is recommended for patients with aspirin intolerance or allergy. For patients receiving a bare metal or drug eluting stent, clopidogrel or another P2Y12 receptor antagonist should be given for at least 12 months (5). Lowering of LDL-cholesterol with statins has shown benefit in patients up to the early 80’s, as will be discussed subsequently.
Despite the class 1 indications for these pharmacologic therapies for patients with established CHD, they are underutilized, especially in older adults. Such underutilization extends to nonpharmacological therapies as well, most notably cardiac rehabilitation. Underutilization of specific proven secondary prevention therapies will be covered in greater detail later in this document.
Cerebrovascular disease and stroke in older adults
An estimated 7 million adults have suffered a stroke, the prevalence of which increases from 2% in persons 40–59 years to nearly 15% in those >80 years (3). Of the 610,000 first and 185,000 recurrent strokes that occur annually, 87% are ischemic in origin, usually due to disruption of advanced atherosclerotic plaque (3). The mean age of those dying from a stroke is 79.6 years, and about 60% are women (3). The 1-month case-fatality rate from ischemic stroke in Medicare beneficiaries is 8%. However, residual disability rates are much higher. In ischemic stroke survivors >65 years old from the Framingham Heart Study (FHS), 50% had residual hemiparesis, 30% could not walk without assistance and 26% were institutionalized (15). Thus the medical and societal costs of stroke in older adults are very high.
In addition to age per se, the classic atherosclerotic risk factors for CHD – hypertension, dyslipidemia, diabetes, and smoking—also increase the risk of ischemic stroke. Control of hypertension and hyperlipidemia have shown strong and consistent reduction in new and recurrent stroke risk in numerous clinical trials of older adults although data in persons >80 years is limited. Smoking cessation has similar benefits in reducing stroke risk; within 5 years of smoking cessation, risk of stroke declines to that of persons who never smoked (16). Antiplatelet drugs reduce the risk of recurrent stroke as well as nonfatal MI and vascular death in stroke survivors. In patients with >50% stenosis of the internal carotid artery, carotid endarterectomy (CEA) or stenting reduces stroke risk; greatest benefits accrue in patients with a 70%–99% stenosis. In the CREST trial there was no overall difference between CEA and stenting on CV events, but CEA was superior to stenting in reducing stroke risk in patients >70 years old (17).
Peripheral Artery Disease in Older Adults
Atherosclerotic peripheral artery disease (PAD) affects an estimated 8–10 million Americans, with a marked increased prevalence with age (18, 19). In the Rotterdam study, PAD was present in 10% of subjects 55–59 years old, increasing to nearly 60% in those ≥85 years (19). Among older persons with PAD, 30–50% are asymptomatic, and only 5–19% have classic claudication (18,19). The high proportion of asymptomatic older PAD patients parallels that for asymptomatic CHD and probably relates in part to the low physical activity levels in this population. Furthermore, given the diffuse nature of ASCVD and that risk factors for PAD closely parallel those for coronary and cerebrovascular disease, many older adults with PAD have coexistent disease in these vascular beds. For example, among 1802 persons 60–90 years residing in a chronic care facility, 79% of patients with PAD also had clinical CHD and/or a prior stroke (8). Smoking and diabetes are particularly potent risk factors for PAD in older as in younger adults.
The ankle-brachial index (ABI) is the best screening test for PAD due to its simplicity, wide availability low risk and low cost. An ABI <0.9 suggests PAD with a sensitivity of 79–95% and specificity ≥95% (18). However, an ABI > 1.3 is more common in older than younger PAD patients due to calcified, non-compressible arteries. Greater reduction in ABI is associated with both a higher prevalence of claudication symptoms and risk for critical limb ischemia. Among 6,880 older patients in primary care setting, low ABI was a strong and graded independent predictor of mortality and was the best predictor of death, stroke, or MI (20). Given the high prevalence of asymptomatic PAD in older adults, those with claudication or atypical leg symptoms, as well as those with known CHD or prior stroke should undergo ABI testing.
Goals of PAD treatment include relief of symptoms and improvement of function in symptomatic older adults and reduction of the high risk for atherothrombotic events. Supervised walking programs are particularly effective in reducing ischemic leg symptoms and increasing walking distance (21). Smoking cessation may also reduce claudication as well as future CV events. Aggressive treatment of dyslipidemia and hypertension, and antiplatelet drugs have all been shown to improve the prognosis of older PAD patients (18). Limb revascularization is usually reserved for patients with refractory symptoms or critical limb ischemia.
Atherosclerotic Risk Factors in Older Patients with ASCVD
Atherosclerotic risk factors are highly prevalent among older men and women with ASCVD. In a recent analysis of the Get with the Guidelines and National Cardiovascular Disease Registry (NCDR) databases (10), 76% of women and 68% of men (average age 74 years [range 61–83 years]) presenting with a non-ST elevation MI had hypertension, 36% and 32% of women and men, respectively, had diabetes, 20% and 30% were current or recent smokers, and 49% and 53% had dyslipidemia. Obesity and physical inactivity among older adults were also common. Moreover, risk factors often occurred in clusters and in association with substantial comorbidity burden. As discussed above, atherosclerotic risk factors are also highly prevalent in seniors with an ischemic stroke and PAD. The remainder of this document will discuss the management of these risk factors and other secondary prevention strategies in older adults with ASCVD.
Obesity in Older Persons
The absolute number and proportion of older persons with obesity has increased dramatically over the past 2 decades. Recent estimates from NHANES suggest that 35% of non-institutionalized women and 40% of men 65–74 years old adults are obese, as defined by a body mass index (BMI) ≥30 kg/m2— indicating about 40 or more extra pounds; comparable numbers in those ≥75 years are 27% of women and 26% of men (3). These percentages have increased 30–40% in older women and 67–100% on older men between 1988–1994 and 2007–2008 surveys. Approximately another 33% are overweight (BMI 25–30 kg/m2—or 10–30 extra lbs) (3). Thus, nearly 2/3 of seniors are overweight or obese, closely paralleling these rates in the general population.
There are several contributors to high rates of obesity among older persons. Metabolic rate declines with age, such that older persons require fewer calories to support their energy needs than they did when they were younger. Changing life-long dietary habits are difficult. Combined with age-related declines in daily physical activity, these habits can lead to even more rapid weight gain in later decades of life. Persons who have struggled with overweight/obesity their entire life often find it more difficult to lose weight when they are older due to their lower metabolic rate and to physical limitations that restrict their ability to exercise.
Even though both obesity and ASCVD are highly prevalent among seniors, there are considerably fewer data specifically in the older population regarding the relationship between obesity and ASCVD than in younger-middle aged patients. Obesity increases the risk for multiple atherosclerotic risk factors, including hypertension, hyperlipidemia, and diabetes mellitus (3). Obesity also appears to be a significant independent risk factor for non-fatal ASCVD outcomes.
An observational study of nearly 1 million individuals showed that overweight and obesity were associated with mildly increased total mortality over 12 year follow-up (22). However, the risk ratio decreased with advancing age and became 1.0 (no increased risk) at age ≥85 years. Nevertheless, the mortality risk attributable to obesity was much higher in older persons due to their higher overall mortality. The effect of obesity on CV mortality is more questionable (23). Furthermore, the effect of weight loss interventions on achieving long-term weight reduction in older adults as in younger persons have been modest (4).
In a systematic review of reported cohort studies across a broad age range, obese patients with CHD did not have increased total or CV mortality (23). Even patients with severe obesity (BMI >35) did not have increased total mortality, but did have the highest risk for CV mortality. The better outcomes for CV and total mortality seen in the overweight and mildly obese could not be explained by adjustment for known confounding factors (23). The authors speculated that this may have been due to inability of BMI to differentiate between body fat and lean mass. However, the few observational studies using more accurate methods of fat mass have noted similar results.
Weight reduction interventions have shown significant reductions in hypertension, including older adults. The TONE study showed that dietary weight reduction was equally effective in reducing blood pressure as sodium restriction, and both were additive (24). Weight reduction also improves insulin sensitivity and glucose control, but has inconsistent effects on hyperlipidemia. In a meta-analysis of 7 intervention trials of long-term weight loss using diet, physical activity, or both in obese older (> 60 years) adults, average weight loss was significant but relatively modest (3.0 kg) at 1 year (25). Total, high, and low density lipoprotein cholesterol, and triglycerides were unchanged. In a single study, recurrent hypertension and CV events were reduced. The authors concluded that although modest weight reductions were achieved, there was lack of high-quality evidence to support the efficacy of weight loss programs on atherosclerotic risk factors or events in older persons.
The first long-term follow-up mortality data from randomized, intentional weight loss intervention trials in adults ≥65 years old were recently published. In patients with osteoarthritis the initial 18-month dietary intervention showed an average 4.8 kg weight loss and improved physical function (26). At 7 year follow-up, there was a non-significant trend toward improved survival in the group randomized to weight loss, even in those who had regained weight after the intervention (27). In the second trial older adults with mild hypertension showed no long term difference in total mortality in the weight loss compared to non-weight loss group (28). In both studies, physical function improved with no deleterious effect of weight loss. Other studies have also shown improved physical function and quality-of-life following intentional weight loss in older persons (29). This is highly relevant since physical function and freedom from physical disability are unquestionably influenced by obesity, and both impact QOL (30,31). These outcomes are often particularly important in older persons, in whom mortality should not be seen as the sole definitive endpoint.
Even with the best methods, it is often difficult to discern the impact of fitness vs. fatness on outcomes, as both are interrelated (32). Indeed, dietary interventions are synergistic with exercise interventions for weight loss, and many older adults find it difficult to achieve significant weight loss without increasing physical activity. Further, as discussed elsewhere in this document, exercise can have other general health benefits for older persons.
A frequently unrecognized consequence of dietary weight loss, especially in older women, is that skeletal muscle, which is critical for physical function, is lost along with adipose tissue (33), likely accelerating age-related loss of skeletal muscle mass (34). Exercise, particularly strength training, may help retain skeletal muscle and function during caloric restriction. Dietary protein supplements have had mixed results in older adults (35).
Unfortunately, the majority of individuals who attempt to lose weight do not achieve significant weight loss. Furthermore, most of those who achieve significant weight loss do not sustain it. Since there is potential for harm, weight loss interventions in older adults should include attention to muscle preservation and specific strategies for long-term weight maintenance. Few data are available in this regard, and focused studies are needed.
Many routinely prescribed medications in older adults such as hypoglycemic drugs, antidepressants, and steroids, can compound tendencies for weight gain and muscle atrophy. Efforts should be taken to minimize weight gain in seniors when these medications are initiated.
Hypertension
Hypertension is extremely common among older men and women, with prevalence rates of ~70% in adults 75 years of age and older (36,37), and with lifetime risk in the Framingham study of 90% (3). Hypertension is more common in older women than men and in non-Hispanic blacks than other ethnic cohorts. Among older adults, hypertension is the most prevalent modifiable CV risk factor with the greatest population-attributable risk for CHD, cerebrovascular disease, and PAD. More than 70% of older adults with incident MI, stroke, acute aortic syndromes and heart failure have pre-existing hypertension. Hypertension is the most common antecedent of heart failure, particularly in the setting of a preserved ejection fraction, and of chronic kidney disease (3).
Aging is associated with a progressive increase in central conduit artery stiffness (e.g. aorta and great vessels) which is in part related to increase collagen cross-linking and concomitant degradation of elastin fibers (12, 37). This age-related arterial stiffening is exacerbated by sedentary lifestyle and high salt diets as well as the atherosclerosis-associated accumulation of arterial calcium with advancing age. Accordingly, systolic blood pressure (BP) progressively rises and diastolic BP plateaus in late middle-age (e.g. around 50–59 years of age) and declines slightly thereafter, resulting in a widened pulse pressure with age (12, 37). As a result, after age 70 years isolated systolic hypertension (ISH) accounts for >90% of all patients with hypertension (38). The prevalence of ISH is higher in women than in men, but the proportion of hypertension attributable to ISH in older adults is similar across racial and ethnic groups (3). Over the last few decades, several epidemiologic studies have provided compelling evidence that systolic or pulse pressure were independent predictors for CHD events (39–41), and clinical trials have shown benefits of treatment (42,43).
Although older patients with hypertension are more likely to be aware of their condition and receiving treatment than middle-aged patients (3, 36), BP control is poorer in older adults, especially after 75 years (37,44). This is related to many factors including a lingering misperception that hypertension is an adaptive physiologic phenomenon in very old adults required to ensure organ perfusion. The latter theory was disproven by the landmark HYVET Trial among 3,845 patients ≥80 years old with systolic BP ≥160 mm Hg, who demonstrated a 39% significant decrease in fatal stroke, 21% significant decrease in all-cause mortality and 64% significant decrease in heart failure with more versus less aggressive BP control over 1.8 years of mean follow-up (45). The higher prevalence of hypertension in older women whose BP is more difficult to control than that of older men (36), may contribute to overall patterns of poor BP control among seniors. Concomitant age-related changes in the kidney increase in salt and water retention, further contributing to high BP among older adults. Furthermore, most older patients require two or more agents to achieve satisfactory BP control, essentially multiplying the potential for side effects and reduced adherence. Similarly, increased use of non-steroidal anti-inflammatory agents and other medications among older adults also commonly raises BP levels, further undermining BP control. Dietary indiscretion is also more common as sodium restriction is harder to maintain amidst greater reliance on processed foods, especially for older patients whose mobility and/or finances are constrained. Age-related changes in taste also contribute to the tendency of many older adults to add salt as a means to bolster the flavor and appeal of their food (46).
Hypertension Management
Non-pharmacologic approaches to management of hypertension are always recommended as initial therapy, especially in older adults, in whom the benefits of such approaches can either avoid or reduce the need for pharmacologic therapy and their potential for adverse effects, biochemical changes, and high costs. For milder hypertension, lifestyle modifications may be the only treatment needed; such interventions (e.g. reduction in excess body weight, mental stress and intake of sodium and alcohol, smoking cessation, adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan [a diet rich in fruits, vegetables, and low-fat dairy products and low in saturated and total fat), as well as increased physical activity all may lead to a reduction in the number and dose of antihypertensive drugs (12, 24,37,) The declines in BP with both weight reduction and sodium restriction are usually larger in older than in younger adults (24, 37). However, data in patients older than 75 years is minimal. The generally recommended BP goal in patients with hypertension is <140/90 mm Hg, both in primary and secondary prevention. However, this target for older hypertensive patients is based on expert opinion rather than on data from randomized controlled trials (RCTs). The recent AHA/ACC expert consensus document on hypertension in older adults recommends that “achieved systolic blood pressure of <140 mm Hg is an appropriate goal for most patients <79 years of age; for those >80 years of age, 140 to 145 mm Hg, if tolerated, can be acceptable” (37).
Excessive lowering of diastolic BP should be avoided in older patients with CHD to prevent deleterious reductions in coronary blood flow. Although not a universal finding, some studies have found higher CHD rates when diastolic BP is reduced below 70–75 mmHg (37). Five major classes of antihypertensive drugs: diuretics, β-adrenergic blockers, angiotensin-converting–enzyme (ACE) inhibitors, angiotensin-receptor blockers, and calcium-channel blockers, have been shown in clinical trials to reduce CV events in older adults (37, 47,48). In approximately two thirds of seniors with hypertension, two or more drugs will be required to achieve target BP levels. Given the age-related changes in absorption, distribution, metabolism and excretion of pharmacologic agents, initiation of antihypertensive drugs in older adults should generally be at the lowest doses with gradual increments as tolerated.
Although relying on multiple medications to control BP adds some iatrogenic risk for an adverse reaction, combination drug therapy provides increased efficacy from additive and synergistic drug effects. With combination therapy, lower individual drug dosages are often sufficient, minimizing dose-dependent side effects and typically achieving longer duration of action and additive target organ protection (37, 49). The choice of specific agents is dictated by efficacy, tolerability, presence of specific comorbidities (Table 1), and cost. For more detailed guidelines of hypertension management in secondary prevention, recently published Consensus/Expert Statement (37) and JNC VII (48) should be consulted.
Table 1.
Selection of Antihypertensive Therapy for Older Adults Based on Comorbidities
| Compelling Indication | Initial Therapeutic Choice |
|---|---|
| Heart Failure | Thiazide, Beta Blocker, ACE Inhibitor, Angiotensin Receptor Antagonist, Calcium Channel Blocker, Aldosterone Antagonist |
| Prior Myocardial Infarction | Beta Blocker, ACE Inhibitor, Aldosterone Antagonist, Angiotensin Receptor Antagonist |
| CHD or High Risk CVD | Thiazide, Beta Blocker, ACE Inhibitor, Calcium Channel Blocker |
| Angina Pectoris | Beta Blocker, Calcium Channel Blocker |
| Aortopathy/Aortic Aneurysm | Beta Blocker, Angiotensin Receptor Antagonist, ACE Inhibitor, Thiazide, Calcium Channel Blocker |
| Diabetes | ACE Inhibitor, Angiotensin Receptor Antagonist, Calcium Channel Blocker, Thiazide, Beta Blocker |
| Chronic Kidney Disease | ACE Inhibitor, Angiotensin Receptor Antagonist |
| Recurrent Stroke Prevention | Thiazide, ACE Inhibitor, Angiotensin Receptor Antagonist, Calcium Channel Blocker |
| Early Dementia | Blood Pressure control |
Most patients will require combination therapy
Abbreviations: ACE =angiotensin converting enzyme; CHD= coronary heart disease; CVD= cardiovascular disease
Adapted from Aronow (37) ©2011 American Heart Association, Inc.
Lipids
The cumulative effects of comorbidities (e.g., cancer, malnutrition, and chronic inflammation) in older adults are often associated with reduced total serum cholesterol (TC), such that the U-shaped association between TC level and mortality becomes more prominent after the seventh decade (1, 49). This observation has challenged the rationale for lipid lowering therapy in the older adults. Although TC and low density lipoprotein (LDL)-C decline after the seventh decade, LDL-C remains strongly associated with CHD events in older adults (51,52).
Lipid lowering therapy is an important component of secondary prevention of ASCVD in older patients. Multiple RCTs prospectively substantiating statin efficacy for secondary ASCVD prevention have included some older patients (mainly 65–75 years). These trials show that relative risk reduction (RRR) is similar in older and younger patients (Table 2). The absolute risk reduction (ARR) for death and recurrent ASCVD events in these trials was up to two-fold higher in older versus younger patients because of the higher baseline risk in seniors (53,54). Accordingly, the number needed to treat (NNT) with statins to prevent ASCVD events and death is much lower in older than in younger patients.
Table 2.
Statin Trials for Secondary Prevention in Older Adults
| Trial (ref) | Intervention | Age Subgroup (n) | All- Cause Death RRR%/ARR% | CHD Death RRR%/ARR% | CHD Events RRR%/ARR% | Stroke RRR%/ARR% | Comment |
|---|---|---|---|---|---|---|---|
| 4S (187) | S20–40 vs. PL | 65–70 (1,021) | 34/6.21 | 43/6.0 | 34/13.3 33/7.13 | NR | ↓CV admissions by 21%. |
| LIPID (188) | P40 vs. PL | 65–75 (3,514) | 21/4.5 | 24/2.91 | 26/3.3 | 12/1.3 | |
| CARE (189) | P40 vs. PL | 65–75 (1,283) | NR | 45/4.5 | 32/91 39/6.7 2 | 40/2.9 | 32% RRR/5.2% ARR for PCI/CABG |
| HPS (55) | S40 vs. PL | 70–80 (5,806) | NR | NR | 18/5.1,2 | NR | 9.2% ARR in primary endpoint in pts 75–80 yrs old (n=1,263) |
| PROSPER (57) | P40 vs. PL | 70–82 (5,804) | NS) | 24/0.9 | 19/2.12 | NS | 25% ↑ cancer risk with P40 |
| PROVE-IT TIMI 22 (58) | A80vs. P40 | ≥70 (634) | NR | NR | 40/8 LDL-C < 70 vs LDL-C ≥70 mg/dl in death/MI/UAP1) | NR | AE rate similar to young |
| TNT (59) | A80 vs. A10 | 65–75 (3,809) | NS | NS | 19/2.31 (A80 vs. A10) | 21/0.9-NS | ↑LFTs w A80 vs. A10 |
| SAGE (60) | A80 vs. P40 | 65–85 (893) | 67/2.7 | 67/0.9 based on 8 deaths | 29/3.12 (P=0.11) | Too few to compare | ↑LFTs w A80 vs. P40 |
| Meta-analysis (53) | 65–82 (19,569) | 22/3.1 1 | 30/2.6 | 17/2.12 26/2.3 NFMI | 25/1.7 | 30%↓PCI/CABG |
Abbreviations: A=atorvastatin; P=pravastatin; PL=placebo; S=simvastatin; AE=adverse events; w=with; ARR=absolute risk reduction, RRR=relative risk reduction; CHD=coronary heart disease; CHF=congestive heart failure; LFTs=liver function tests; NFMI=nonfatal myocardial infarction; NR=not reported; NS=not significant;
Primary Endpoint;
Death or NFMI;
NFMI
More recent trials have also demonstrated benefits of LDL-C lowering therapy in older cohorts. The MRC/BHF Heart Protection Study (HPS) stratified over 20,000 subjects by age decade (53% of subjects≥ 65 and 28% ≥70 yr) and reported significant RRRs with simvastatin vs. placebo in all-cause mortality (13%), vascular death (18%), and stroke (25%) (55). First major vascular event RRR with simvastatin (24%) was similar across all age strata (<65, 65–69, ≥70 yr). The HPS was novel in that the pre-treatment LDL-C was relatively low, supporting the concept for more aggressive LDL lipid-lowering therapy lowering for secondary ASCVD prevention than the ATP III Guidelines had endorsed (56). Pravastatin in elderly individuals at risk of vascular disease (PROSPER), the first RCT specifically designed to exam the efficacy and safety of statins for ASCVD prevention in older patients (70–82 yr at baseline), showed a significant 22% pravastatin-related RRR in combined CHD death+MI+stroke in the 43% of the sample with known CV disease (57). Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) extended the concept of LDL-lowering benefit by assessing greater versus lesser intensity LDL-C lowering during or just after hospitalization for an acute MI. A subgroup analysis of PROVE-IT patients ≥70 yrs showed a 40% RRR in CHD death or MI at 30 days and a 40% RRR in CHD death in those taking high dose atorvastatin versus 40 mg pravastatin (58).
Other recent clinical trials have examined the efficacy of more intensive lipid-lowering regimens in older adults with chronic ASCVD. In the Treating New Targets (TNT) trial, efficacy of high versus low dose atorvastatin on risk reduction was compared. In a subgroup aged 65–75 years, a significant 19% RRR in the composite primary endpoint (CHD death, all-cause mortality and CHD death/MI/cardiac arrest/stroke) was seen in the high dose vs. low dose arm (59). The Study Assessing Goals in the Elderly (SAGE) demonstrated a non-significant 29% RRR in CHD events but a 67% RRR in all-cause mortality (p=0.01) in 893 seniors 65–85 years old randomized to 80 mg atorvastatin compared with 40 mg pravastatin (60). While compelling, these trials had several limitations: fixed statin doses were tested in lieu of specific LDL-C levels such that none systematically achieved LDL-C levels <70 mg/dl. Also, none enrolled adults aged >85 years and/or older patients with extensive comorbidities.
Meta-analyses have also demonstrated benefits of statin therapy in older patients (53,54). In a meta-analysis of 19,569 older CHD patients (65–82 years) from 9 secondary statin RCTs, Afilalo et al. (53) demonstrated statin-related RRR in all-cause mortality (22%), CHD mortality (30%), non-fatal MI (26%), need for revascularization (30%) and stroke (25%), with NNT=28 to save one life. The Cholesterol Treatment Trialists’ meta-analysis of 26 RCT (N=170,000) showed 22% RRR of major vascular events in patients 66–75 years and 16% RRR in those ≥75 years, with age-related increasing ARR (54). Such data from RCTs and meta-analyses underlie the 2011 AHA/ACCF Secondary CHD Prevention Guidelines which endorse aggressive LDL-lowering therapy <100 mg/dl) with an optional target of <70 mg/dl in very high risk patients (5).
Statins also reduced the risk of incident stroke in older patients with ASCVD in RCTs, leading to 25% stroke RRR in a recent meta-analysis (53). A secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study showed a non-significant 10% RRR in fatal or non-fatal stroke over 5 years with atorvastatin 80 mg compared with placebo in 2249 patients ≥65 years old with a prior stroke or transient ischemic attack but without CHD, compared with a significant 26% RRR in younger patients (61). However, there was no statistically significant age interaction. Older patients with PAD also benefit from cholesterol-lowering therapy. A study of 69 PAD patients aged 60–85 years showed significantly improved treadmill walking time before onset of claudication, with 24% and 42% increases 6 and 12 months after statin initiation, respectively (62).
Despite observational studies suggesting statin therapy reduces risk and progression of dementia, RCTs (HPS, PROSPER) do not support this premise (55,57). In contrast, case series suggest that statins may worsen cognitive function and memory loss, a concern that has prompted a new advisory labeling, although this too has not been demonstrated in a RCT (63).
Overall evidence supporting lipid lowering medication for secondary CHD prevention is credible through about age 85. Secondary prevention guidelines advise lipid lowering therapy ‘regardless of age’ in the majority of older patients with ASCVD unless issues of frailty, comorbidity, and polypharmacy confound management. Despite this mandate, statins are notoriously under-prescribed and under-dosed in this cohort despite their higher risk of recurrent events (6,64,65). Only 24% of patients ≥65yo and 15% of those ≥80 years were receiving a statin at discharge after an MI in one analysis of 23,013 Medicare beneficiaries based on a 1998–2001 dataset (65). Ongoing adherence to lipid lowering drugs is particularly low in older patients (66). Several factors seem to determine this “treatment-risk paradox” including lack of knowledge of statin efficacy and ARR, fear of adverse events, polypharmacy (both in regard to costs and cumulative side effects), and the perception that benefits diminish in the context of reduced life expectancy and/or mounting comorbidities (6,66).
Despite concerns over statin-related adverse events in older patients, pooled analyses of many large clinical trials show no significant difference in adverse events in older versus younger patients (53,54,67). Dyspepsia is the most commonly reported side effect. However, few, if any, of these trials included patients over 80 years at baseline and/or with frailty or other significant comorbidities (67). In contrast, several recent aggressive lipid lowering trials (TNT, SAGE, PROVE-IT TIMI 22) have revealed higher incidence of abnormal liver function tests with high dose statins in older adults (58–60). However, in TNT, liver function tests increased similarly with statin dose in older and younger patients (59). Statins also cause a spectrum of muscle complaints that are more common among older adults, ranging from myalgias without CPK elevation to fulminant rhabdomyolysis. Included in this spectrum are neuropathies, balance problems and extremity weakness, which, along with myalgias, are common and often debilitating, particularly for a population inherently prone to frailty and/or diminished QOL (68).
Adding to management challenges, older patients and/or their families may be less likely to articulate pertinent complaints, assuming that such symptoms are related to arthritis or aging, itself. Although the etiology of statin-related muscular and neurologic complaints is unclear, it is often dose-related and certain risks have been identified: female gender, small stature/low BMI, concomitant fibrates and drugs using CytP450 enzyme pathway, use during surgery, decreased hepatic or renal function, fatty liver disease, hypothyroidism, diabetes, and heavy use of alcohol all increase statin-related adverse events (68,69).
Lipid Management
Although clinical practice is generally to administer statin therapy for older patients with ASCVD, just as for younger adults, decisions whether or not to prescribe a statin to an older patient mandate careful assessment of life expectancy, goals of therapy, time to treatment benefit, as well as comorbidities that could potentially complicate statin therapy (66). Life expectancy may be estimated using an appropriate multi-morbid tool (62), rather than actuarial data. Patients with conditions that severely compromise life expectancy or QOL (certain cancers, severe dementia, severe frailty) may not be suitable candidates for statins. Nonetheless, a patient may place more emphasis on statin-related stroke risk reduction or preventing worsening claudication despite negligible benefit on longevity. Important considerations include RCT data that indicate a 1 and 3 year lag time until benefit is demonstrable for CHD and stroke, respectively (53,54).
A lipid profile should be obtained on all older patients with ASCVD who are deemed candidates for lipid-lowering therapy (5, 56). The goal LDL-C level for most older as in younger patients is <100 mg/dl, but a relative decrease of 30–40% from the baseline LDL-C may provide greater risk reduction, given other factors that can also affect the baseline TC (5, 50,51,56). In ‘very high risk’ older patients, a target LDL-C of <70 mg/dl is considered optional, but this target should be approached with caution, given the increased AE risk with higher statin doses (56, 67). The non-HDL-C (LDL-C +VLDL) target should be <130 mg/dl in patients with TG ≥200 mg/dl.
Statins remain the first line therapy to for secondary ASCVD prevention in seniors and should be initiated at the lowest dose and judiciously titrated as tolerated to achieve a 30–40% reduction in LDL-C. Although statins remain relatively safe drugs in older adults, very advanced age, female sex, small body size, fatty liver disease, and multisystem disease may predispose to AE. In addition, lipophilic statins such as lovastatin, simvastatin, and atorvastatin, are metabolized via the cytochrome P450 system, increasing the likelihood of interactions with other drugs metabolized by this pathway (67).
Non-statin lipid altering agents may be helpful adjuvant or alternative therapy, although specific evidence supporting their use in older patients is sparse or lacking. Fibrates (gemfibrozil, fenofibrates) are effective in lowering TG and LDL-C and raising HDL-C, but a recent meta-analysis of 5 fibrate trials (n=21,065) does not support their primary use for ASCVD risk reduction; however, older patients were not adequately represented in these studies (71). While fibrates in combination with a statin are particularly appealing for those with elevated TG, the combination is associated with elevated risk of myopathy (gemfibrozil>fenofibrate), and extreme caution is warranted, particularly in seniors (5, 56).
Nicotinic acid, when added cautiously to statins, may further reduce LDL-C, TG and raise HDL-C, but the negative results of AIM-HIGH have dampened enthusiasm for its use (72). Outcome evidence is lacking to support the use of bile acid sequestrants (cholestyramine, cholestipol and colesevelam) to reduce ASCVD risk in older patients, especially given the potential for drug-drug interactions and a high rate of gastrointestinal adverse events.
The cholesterol absorption inhibitor, ezetimibe, appears safe in older patients and effective at lowering LDL-C when added to statin therapy, but hard ASCVD outcome data are not available (73). Use of herbals and nutraceuticals to lower secondary ASCVD risk have not been supported by clinical trials, and their common use in older patients, may lead to significant interactions with prescription drugs.
Although evidence supports statins as the most efficacious lipid lowering strategy to prevent recurrent ASCVD events (Class I), increased physical activity and a Step II AHA diet are considered fundamental at any age, despite limited data in seniors (5, 56). Ingestion of plant sterols and stanols as well as soluble fiber may play an additive role to diet in lowering TC and LDL-C. Patients aged ≥75 years who completed Phase II cardiac rehabilitation program had a significant decline in TC, LDL-C and depression score as well as an increase in HDL-C and QOL (74).
Lipid-lowering therapy should be carefully and continuously monitored with respect to treatment goals, medication interactions, life expectancy and comorbidities (66). Patients aged ≥80 years remain at highest risk for incident and recurrent cardiovascular events and suffer worst outcomes; thus future studies should clarify the efficacy and safety of lipid lowering therapy among the “oldest old”, including those with multi-morbidities, frailty, polypharmacy and possibly those living in assisted living and nursing homes. Finally, it remains important to develop better risk assessment tools to predict relevant outcomes in older adults, e.g., stroke, functionality/independence, and QOL, that can be used to gauge the rationale for and efficacy of lipid lowering therapy.
Diabetes
Advancing age is associated with both increased insulin resistance and impaired insulin secretion (75). The insulin resistance of aging results from decreased sensitivity to insulin at the level of target tissues, particularly skeletal muscle, and is associated with greater visceral adiposity and an overall higher ratio of fat-to-lean body mass. Impaired insulin secretion, on the other hand, has been attributed to inappropriately low pancreatic beta-cell function in older adults (76). The coupling of insulin resistance with impaired insulin secretion in aging contributes to greater glucose intolerance. Accordingly, the incidence and prevalence of Type 2 diabetes mellitus as well as that for ASCVD progressively rise with age, such that approximately 15% of persons ≥65 years have diagnosed diabetes and another 7% have undiagnosed diabetes. Approximately 30% of older adults with diabetes have concomitant CHD, double the prevalence of non-diabetic age peers (77). The diagnosis and management of diabetes in older adults with ASCVD present unique challenges. Diabetes tends to be under-diagnosed in older adults, who can often present with non-classical and nonspecific symptoms. Thus, routine screening for diabetes is strongly recommended for all older adults, particularly those with diagnosed ASCVD (78). Older individuals with diabetes experience excess morbidity and mortality compared to those without diabetes, even in the absence of CVD (79). Consequently, older adults with both diabetes and ASCVD are at especially high risk for adverse macrovascular and microvascular outcomes in addition to functional disability and geriatric syndromes (e.g., cognitive impairment, depression, urinary incontinence, falls, and chronic pain) (80). Due to the frequency of comorbidities as well as complications, older adults with prevalent diabetes and ASCVD comprise an extremely heterogeneous population, ranging from relatively fit individuals living independently in the community to frail individuals with multiple comorbidities and living in nursing homes. Thus, management of diabetes in this population must be specifically tailored for each individual.
Diabetes Management
The primary goals of care for all patients with diabetes include managing hyperglycemia and reducing risk of adverse clinical outcomes. However, a critically important additional goal in the seniors is the prevention of hypoglycemia (78,81). Because patient unawareness of hypoglycemia is common, even in functionally independent older adults (82), glucose management should include fingersticks after exercise and missed meals. Given the challenges related to managing diabetes in older adults, diabetes care should be coordinated with the patient’s primary provider and/or endocrinologist.
Therapeutic interventions for diabetes should begin with lifestyle modification. For older adults with obesity, weight loss can reduce insulin resistance (83) and improve glycemic control (83–85. Dietary interventions focused on optimizing macronutrient content in addition to overall calorie count can also improve glycemic control in older adults, independent of weight change (78). Thus, a medical nutrition evaluation is recommended for all older adults with diabetes. Current guidelines additionally recommend regular aerobic and resistance exercise, which has been shown to lower HbA1c by 0.5–1.0% (84). Structured exercise training has also been shown to improve insulin sensitivity in older adults, even without changes in body weight or fat mass (85). Although physical activity for many older adults is limited by health status and comorbidities, any exercises that help to improve aerobic capacity and preserve and increase muscle mass are likely to be beneficial.
Notwithstanding the benefits of lifestyle interventions, the majority of older patients with diabetes will require medications to achieve optimal glycemic control. Large clinical trials have investigated the effects of intensive versus standard glycemic control on adverse outcomes. Despite a possible reduction in microvascular outcomes (86), these trials have consistently observed either no effect on or even increased mortality in older patients receiving intensive glycemic therapy (86–88). Therefore, glycemic targets for older adults should be determined based on individual risk status. Whereas an HbA1c target of <7% may be appropriate for adults younger than 65 years or very healthy older adults, a less intensive target HbA1c of 7–7.9% is recommended for most older adults, particularly those with longstanding diabetes and chronic comorbidities including ASCVD (89). Even higher targets may be considered for older patients with frailty, increased risk for hypoglycemia, and/or short life expectancy (90).
The selection of pharmacologic therapy should be based on the presence or absence of comorbidities that can impact drug metabolism and tolerability (e.g. renal impairment, heart failure, and liver disease). Because polypharmacy is common in older patients with both ASCVD and diabetes, attention to possible drug-drug interactions is also required. In general, glucose lowering medications should be started at the lowest dose and uptitrated slowly. Metformin is favored as a first line therapy, given its low risk for hypoglycemia and other adverse effects. Additional options considered safer for older adults include the short-acting sulfonylurea, glipizide, and the short-acting insulin secretagogue, repaglinide (91). In cases where insulin therapy is needed, ultra long-acting basal and very short-acting prandial insulins are strongly preferred over intermediate-acting insulin formulations. When glycemic goals are not being met for any older patient, however, the clinical assessment should include a careful evaluation for possible contributors to non-adherence. Although glycemic control is important, greater CV risk reduction in diabetes may be achieved from control of concurrent risk factors such as hypertension and dyslipidemia (92).
Tobacco
Cigarette smoking remains the leading preventable cause of death worldwide, a large proportion of which are due to ASCVD. Tobacco smoking has multiple deleterious effects that include increased generation of free radicals, reduced nitric oxide bioavailability, enhanced leukocyte and platelet activation, and prothrombotic alterations in coagulation factors (93). Clinical and laboratory manifestation of tobacco smoking include increases in heart rate, inflammatory markers, and plasma catecholamines, and reduced flow-mediated arterial dilation and HDL-cholesterol. The cumulative effects of these smoking-induced changes is a proatherogenic, prothrombotic, and vasoconstrictive environment that further increase the older ASCVD patient’s already elevated risk status.
In 2008, 9.8% of men and 8.5% of women ≥65 years old were current smokers, representing rates less than half those of younger adults; another 54.3% of men and 28.9% of women ≥65 years were former smokers (3). Although some older smokers may have genetic protection from the noxious effects of tobacco to account for their longevity, multiple studies over the past three decades have demonstrated that continued smoking increases the rate for recurrent coronary and vascular events in both younger and older patients with known ASCVD as well as reduced CV event rates among those who quit smoking. A meta-analysis of 20 studies demonstrated a 36% lower crude mortality risk and 32% lower rate of non-fatal MI among patients with CHD who quit smoking compared to those who continued to smoke (94). A recent meta-analysis of 17 general population studies in over 1.2 million persons 60 years and older from 7 countries showed a dose-dependent increased all-cause mortality rates in current smokers, with a mean relative mortality of 1.83 compared with never smokers; in former smokers, the mortality risk was attenuated to 1.34. Benefits of smoking cessation were seen even in persons 80 years and older (95). Data from the Coronary Artery Surgery Study (CASS) registry showed a reduction in MI and death in former smokers aged 70 and above, similar to that in younger patients with CHD (96). In an ongoing registry of patients with CHD, the mortality rate was markedly lower in recent quitters than in persistent smokers (97). Furthermore, sudden cardiac death risk was also lower in quitters than in continual smokers among 3122 coronary patients (mean age 60 years) in the Bezafibrate Infarction Prevention Trial over a mean 8.2 year follow-up (98). As noted earlier, smoking cessation also reduces the risk of new or recurrent stroke (16,97) and improves claudication symptoms in PAD patients (18). Aside from the cardiovascular benefits of smoking cessation, the age-associated decline in pulmonary function is accelerated in smokers, and this accelerated decline is attenuated or abolished by smoking cessation (99).
Given the strong and consistent published findings supporting morbidity and mortality benefits from smoking cessation in both older and younger patients with ASCVD, the AHA/ACCF Secondary Prevention guidelines lists smoking cessation as a Class IA recommendation (5). In the Get With the Guidelines-CAD program, a similar increase in composite adherence to six quality measures, which included smoking cessation, was observed in patients ≥75 years old as in younger individuals between 2002 and 2007 (92). Despite these encouraging findings, the success rates for smoking cessation remain modest. Patient counseling combined with pharmacologic therapies such as nicotine replacement and psychotropic medications can improve cessation rates by two-to-threefold over non-aided cessation attempts. However, data on smoking cessation success rates in very old adults are extremely limited.
Psychosocial Issues in Secondary Prevention
Epidemiological Evidence
Personality factors
Although the Type A behavior pattern was originally touted as a risk factor for CHD that was comparable to such traditional risk factors, hostility is now recognized as the “toxic” component of Type A personality, in both healthy adults and cardiac populations (101). However, older adults remained largely excluded from these analyses, and even among younger adults, effect sizes of hostility on CHD development were modest.
Depression
Over the past two decades, clinical depression has emerged as an important psychosocial risk factor that is common in cardiac patients and is associated with increased adverse events. Major depressive disorder (MDD) or elevated depressive symptoms in various CHD populations (i.e., post-MI, CABG, HF, stable angina) are associated with 2–4 times the risk for all-cause mortality compared to non-depressed individuals (102–104). Older depressed post-MI patients may have up to four times the risk of dying four months after hospital discharge (104). A scientific panel commissioned by the AHA concluded that depression should be routinely assessesed, and treated when indicated in patients with CHD (105).
Anxiety
The prevalence rates of moderate to severe anxiety among hospitalized MI patients has been reported to be as high as 40% or more, and 15% to 20% of patients still report anxiety one year after hospital discharge. In a study of 516 older CHD patients (mean age = 68 yrs), the age-adjusted hazard ratio for anxiety was 1.97 (95% CI 1.03–3.78, p= 0.04) for non fatal MI or death (106). Older participants tended to report lower anxiety levels, although age did not appear to moderate the relationship between anxiety and increased risk of death or a cardiac event.
Stress
Stressful life events and emotional distress can trigger fatal CV events. In the international INTERHEART study of 15,152 individuals with their first MI (median age 59 years) and 14,820 age and sex-matched healthy individuals without CHD, stress was assessed by 4 questions about stress at work, home, finances, and major life events (107). Patients with CHD reported higher levels of stress in all categories and also were more depressed. The composite stress index had an odds ratio of 2.67 for fatal CHD, which was comparable to the “traditional” CHD risk factors. Although smoking, dyslipidemia, hypertension, and diabetes had a greater relative risk in younger acute MI patients compared to older patients, age did not moderate the adverse prognostic value of stress.
Socio-economic status and social support
Low socioeconomic status (SES) is a significant independent contributor to increased CV risk in healthy persons and to poor prognosis in CHD patients. Williams et al. (108) found that the 5-year mortality rate of CHD patients with incomes less than $10,000/year was 1.9 times higher than that among patients with incomes greater than $40,000/year. This effect was independent of social isolation and disease severity. In a study of 194 older post-MI patients, Berkman et al. (109) reported that the presence of emotional support prior to the MI was the most powerful and significant predictor of survival after the MI. At 1-year follow-up, 55% of patients without support had died, compared to only 27% with two or more sources of support.
Consequences of CHD
Acute MI and other clinical manifestations of CHD have a profound effect on psychosocial functioning, quality of life, and activities of daily living. There are data suggesting that age may moderate the relationship between CHD and psychological well-being. In a prospective cohort of 2498 survivors of acute MI, patients 65–74 years old had higher late mortality but reported fewer symptoms and better health related QOL at 1 year compared to younger patients, independent of baseline angina, QOL, and other clinical and demographic variables (110).
Dementia
Surveys indicate that, with the exception of cancer, older Americans fear developing dementia more than they do any other major illness, including ASCVD. Dementia affects almost 10% of adults over age 65, and up to 50% of adults aged 85 and older (111). More than twice as many are affected with significant cognitive impairment, but without meeting diagnostic criteria for dementia. Epidemiological data demonstrate that CVD also increases the risk of cognitive decline and Alzheimer’s disease. For example, in the Rotterdam study (112), cognitive function was lower among those with a history of stroke, electrocardiographic evidence of MI, PAD or plaques in the internal carotid arteries. The high rate of cognitive impairment among older adults with CHD has important implications for disease management, including issues of medication adherence.
Psychosocial Management
Psychological treatments
Despite the substantial epidemiological evidence for a stress-CHD relationship, the health benefit of reducing stress in CHD patients is not well-established. To our knowledge, no studies have examined the effects of stress reduction specifically in older CHD patients on clinical outcomes; thus, such benefits must be inferred from studies of middle-aged CHD patients.
A Cochrane meta-analysis of 36 trials examined the effects of RCTs of psychological interventions in 12,841 CHD patients (113). Approximately half of these studies were stress management interventions, and the quality of studies was generally poor. Results showed no differences between groups in cardiac mortality or revascularization, and only a small reduction in non-fatal re-infarction (113). Surprisingly, psychological outcomes were reported in relative few trials, with little attention to age as a potential moderator.
Depression has been the primary target of several recent psychological and pharmacological RCTs in coronary patients. In the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) trial, post-MI patients with an average age of 61 years, who were depressed or who had low social support, were randomized to receive either usual care or a 6-month cognitive behavioral therapy (CBT) intervention. The trial showed greater improvements in psychosocial outcomes, such as reduced depression and increased social support, in the treatment group compared to controls, but no improvement in event-free survival (114).
Pharmacologic treatments
The SADHART trial was a randomized, double-blind, placebo-controlled, 24-week trial of sertraline versus placebo for MDD among patients hospitalized for acute MI (115). Improvements in depressive symptoms were comparable in participants treated with sertraline and placebo, but patients with more severe depression benefitted more from sertraline. The study was a safety trial and was not powered to examine clinical outcomes.
Alternative approaches
Aerobic exercise has been studied as a treatment for depression. A Cochrane review found a large, clinically meaningful improvement associated with exercise in comparison with controls (standardized mean difference = −0.82 (95% CI −1.12 to −0.51). When analyses were limited to trials using the most rigorous methodologies, only a moderate antidepressant effect of exercise was noted (116). Studies of middle-aged and older adults showed that exercise was comparable to anti-depressant medication in reducing depressive symptoms, (117) but the impact of exercise on clinical outcomes was not assessed.
Comorbidities
Overall, secondary prevention of ASCVD risk factors for older adults entails a trade-off between benefits and risks of treatment. The trials which served as the basis of secondary prevention guidelines typically excluded older adults (especially those ≥85 years) or included only exceptional seniors who had few of the comorbidities typical of community-dwelling seniors (118). Therefore, while there is conceptual rationale to assume that favorable benefit: risk ratios of most medical therapies extend to very old adults, corroborating data are limited.
The potential for substantial risk reduction for older patients receiving secondary prevention therapy is counterbalanced by the potential for increased risks from therapy as well. Risks accrue from the medications themselves, particularly from aging changes in drug distribution and metabolism, and multiple comorbidities may further compound medication risks (119,120). Intrinsic medication risks escalate amid age-related changes in physiology such that cardiac reserve, hemodynamics, balance, hemostasis, renal function, and cognition are all more tenuous. Examples of age-related medication hazards include increased hemorrhagic risks from thienopyridenes, greater chronotropic incompetence from beta-blockers, increased falls and syncope from nitrates and/or ACE inhibitors, and increased myalgias or confusion from statins (119). Thus, many secondary prevention medications or procedures are more likely to induce greater iatrogenic sequelae in an older compared to a younger cardiac patient due to age-associated changes in metabolism and/or physiology (10,118,119).
Therapeutic risks associated with standard secondary prevention medications are also exacerbated by the presence of age-associated comorbidities (10,118,119). Anti-platelet agents are, for example, more likely to precipitate bleeding in the context of arteriovenous malformations, gastritis, hemorrhoids, and/or atrial fibrillation (i.e., using concomitant vitamin K antagonists or direct thrombin inhibitors). Rationale to implement secondary prevention strategies for ASCVD is counterbalanced by their potential to aggravate non-cardiac conditions.
Common iatrogenic effects of medications among older cardiac patients are listed in Table 3. Beta-blockers, for example, are more likely to precipitate bronchospasm in patients with chronic obstructive lung disease as well as heart block in those with conduction system disease, and/or exercise intolerance in those with chronotropic incompetence (119). Nitrates are more likely to precipitate falls in those with orthostatic or postprandial hypotension.
Table 3.
Common Iatrogenic Effects of Secondary Prevention Medications in Older Patients with ASCVD
| Medication class | Medication | General side-effects in older cardiac patients |
Medication-Medication side effects | Comorbid disease- Medication- interactions |
|---|---|---|---|---|
| Anti-ischemics and Anti-hypertensives | Beta-blockers |
|
|
|
| ACE-inhibitors |
|
|
|
|
| Nitrates |
|
|
|
|
| Diuretics |
|
|
|
|
| Calcium channel blockers |
|
|
|
|
| Anti-platelet | Aspirin |
|
|
|
| Thienopyridines |
|
|
|
|
| Cholesterol reduction | Statins |
|
|
|
| Fibric Acids |
|
|
|
Abbreviations: CHF-congestive heart failure; CKD-chronic kidney disease; GI-gastrointestinal
Polypharmacy is an overlapping source of risk; most older patients with ASCVD are taking numerous medications for multiple cardiac and non-cardiac conditions. Not only are the salutary effects of a multi-pill regimen for a frail elder unclear, but medication costs, adherence, and drug-patient/drug-drug interactions, become substantial concerns (119). High age-related use of over-the-counter medications (e.g., non-steroidal anti-inflammatory agents and dietary supplements) adds to these risks, potentially exacerbating risks of bleeding, renal insufficiency, and/or fluid retention. Likewise, the tendency of many providers to routinely prescribe pain and/or sleeping medications to their older patients can aggravate hazards as they increase the potential for confusion, somnolence, and impaired self-care. Non-specific medication side-effects such as confusion, weakness, and changes in mood, appetite, and sleep are all widespread in older cardiac patients, especially in association with hospitalizations, procedures, and other transitions of care that often disrupt clinical stability (120). Thus, even when conceptual value for a particular medication is strong, benefits are less clear amidst a multiple pill regimen.
Aging is also associated with sensory impairments (hearing, vision) and limitations in cognition that can diminish adherence to both medications and lifestyle interventions. Access to caregivers is often more limited, hindering assessments and monitoring; arthritis, Parkinsonism, cerebrovascular disease, or functional impairments often undercut physical activity goals; financial constraints and altered taste may frustrate dietary recommendations; limited finances may also discourage use of vital ancillary services.
The net effect of this inherent complexity of managing older patients with ASCVD is that use of evidence-based medications remains lower than recommended by guidelines, although rates have significantly improved in recent years (10,13,121). In a cohort of MI survivors age 65 and older (73% women) discharged in 2004, 61% filled prescriptions for statins, 80% for beta-blockers, and 58% for ACE-Is or ARBs within 90 days of discharge. However, only about 35% of patients in this cohort filled prescriptions for all 3 drug classes, and black patients were less likely to fill such prescriptions than their white counterparts (121). Older women with ASCVD are also less likely to receive aspirin in the acute and chronic settings. In an analysis of the GRACE registry with data collection from 1999–2007, women with ACS ages 65–74, 75–84, and 85 years or older were 14%, 32%, and 54% less likely to receive aspirin during their hospitalization than men under age 65 (122). Data from the 2000–2002 Medical Expenditure Panel Surveys, showed significantly lower rates of chronic aspirin use among older individuals and women with a history of CHD even after adjustment for contraindications against aspirin use, which were more frequent among women than men (123).
Lifestyle Therapy of ASCVD
General Dietary Guidelines
Although calorie and sodium restriction were already discussed relation to obesity and, hypertension, broader dietary principles require brief discussion. Diet is an important component for optimizing both general and CV health in older adults, but it frequently receives inadequate attention. Both cardiologists and primary care providers should assess the dietary habits of their older patients, provide general dietary advice, and refer them for more detailed dietary counseling if significant dietary deficiencies or malnutrition are suspected.
Undernutrition is a major concern among seniors due to a complex combination of medical and socioeconomic factors. An estimated 5–10% of community-dwelling adults older than 70 years are undernourished; this proportion rises to 30–65% among institutionalized elders (124). Protein intake should generally be at least 0.8 g/kg body weight unless severe renal insufficiency is present (125).
The Mediterranean diet, consisting of large proportions of fruits and vegetables, whole grains, fish, and nuts, and low levels of saturated fats, has consistently demonstrated favorable effects on CV risk factors and outcomes in older adults (126,127). Flavenoids, found primarily in fruits and vegetables, nuts, cocao, tea, and wine, promote antioxidant and anti-inflammatory properties. In a study of 98,000 adults of initial mean age 70 years who were then followed over 7 years, flavenoids were associated with lower risk of CV death (128). Adequate dietary fiber intake is generally beneficial in maintaining optimal bowel function, which is often impaired in older adults secondary to effects of age, medications, and inactivity.
Deficiencies of vitamins and minerals are common among the older adults due to inadequate dietary intake, reduced absorption, or disease/medication-specific factors; a daily multivitamin can reduce the risk of such deficiencies. Vitamin D deficiency has been increasingly identified among older adults, due to inadequate sun exposure and reduced capacity for synthesis in the skin (129). Recent studies have identified vitamin D deficiency as an independent risk factor for CV mortality in older adults (123, 124). Several clinical trials of vitamin D supplementation in older adults with ASCVD are ongoing. Although omega-3 fatty acid supplementation has been shown to reduce CV events in some studies, a recent randomized trial in patients 60–80 years old with prior MI showed no significant effects on new major CV events (132). There is little evidence to suggest a benefit from B vitamin supplementation in preventing CV disease in seniors (133).
Physical inactivity in older adults
The role of physical inactivity as a risk factor for chronic diseases, including hypertension, CHD, stroke and PAD, Type 2 diabetes, depression, osteoporosis, and certain cancers is well established (134,135). The seminal work of Morris, et al (136) established a significant association between physical inactivity and ASCVD disease risk six decades ago. Physical inactivity is also associated with increased CV mortality (137).
The health consequences and financial and societal costs of physical inactivity are especially relevant to older adults, since much of age-related ASCVD pathophysiology and morbidity is compounded by the biologic and clinical repercussions of a sedentary lifestyle. For older adults, physical inactivity also leads to diminished functional health, an increased risk of falling, worsened psychological status, and decreased cognitive function. Furthermore, the increased prevalence of inactivity with aging constitutes perhaps the most common modifiable CV risk factor in older adults after hypertension. Survey data from 2008 indicate that only 18% of persons ≥75 years old reported regular moderate or vigorous physical activity (3). Furthermore, only 14% of men and 8% of women ≥65 years old reported participating in aerobic and muscle strengthening activities that met the 2008 Federal physical activity guidelines (138,139). Patel and colleagues (140) recently found increased total mortality and especially CV mortality in older men and women who sat more than six hours a day compared to those sitting only 3 hours a day.
Research has clearly demonstrated that reducing physical inactivity dramatically improves health status. This holds true across age, gender, race and ethnicity (137,138). The benefits of moving from a physically inactive to a more active lifestyle are attributed to the strong influence that increased energy expenditure has on physiological functioning and psychological risk factors (138). Regular physical activity positively influences CHD risk factors, including serum lipids, blood pressure, insulin sensitivity, body weight, as well as bone density, muscular strength, functional capacity, and cognitive and psychological functioning, which are key elements of health and well being in older adults (137,138). Given the overwhelming evidence that physical inactivity is harmful for older adults, moving from the couch to the sidewalk or gym has become a major goal of federal, state, and professional health organizations, clinicians, and the public (141).
In both observational studies and RCTs, older adults with ASCVD have experienced benefits from undertaking an exercise program, including reductions in morbidity and mortality, less functional decline, less mobility disability, reduced recurrent CV events, and an increase in active life expectancy (141). Even modest amounts of physical activity have been associated with reduced CV risk in older adults. For example, men 71–93 years old in the Honolulu Heart Program who walked >1.5 miles/day experienced half the risk for new CHD than men who walked <0.25 miles/day over 2–4 years of follow-up (142); risk of incident dementia was similarly reduced (143). Even in frail older adults, regular physical activity has resulted in substantial physical, cognitive and psychological benefit (144). In such individuals, achievable goals for increasing physical activity include regular leisure activities such as walking, gardening, and housekeeping.
Exercise Training and Prescription
The prescription of exercise for increasing physical activity and fitness for older patients with ASCVD is an essential component of secondary prevention (5). Numerous studies have demonstrated that improvements in exercise capacity, lipids, and mental health are similar in older versus younger patients with ASCVD (145–147). Among seniors, exercise training is also associated with the prevention of falls, reduced ambulation limitations due to comorbidities, and improved cognition (145–148). Methods for prescribing exercise generally do not require major modification for older patients (149,150). The most important considerations include creating an exercise program that is achievable and avoids injury or exacerbation of known musculoskeletal disorders. In addition, the absolute starting work intensities will generally be lower than in younger patients, with smaller increments over time. The exercise prescription should define individual patient guidelines for activity while allowing for, and encouraging, variation in the exercise regimen. The exercise program should also promote all aspects of physical conditioning, including aerobic capacity, muscular strength and endurance, balance, and flexibility to achieve the greatest benefit to functional capacity, quality of life, and CV disease risk (149,150).
Initiating and reinforcing physical activity requires clinicians to strongly and repeatedly encourage participation, while carefully considering the appropriate and individualized recommendations for the exercise prescription. Consideration of differences in needs between women and men, occupational and leisure activities, activities of daily living, and diversity of activities are all relevant. Modification of the components of the exercise prescription should be considered for older patients, particularly those ≥75 years of age and those with significant comorbidities that limit mobility, e.g., arthritis, pulmonary disease, and PAD (150). Increasing caloric expenditure for overweight and obese patients and enhancement of functional mobility should be emphasized, as well as participation in activities that increase socialization with others, which may combat feelings of isolation and depression. Increasing frequency and duration of exercise sessions should supersede increases in intensity to reduce the potential for overuse injuries.
Patients with ASCVD generally benefit from a symptom-limited exercise test before initiating an exercise program. An exercise test helps to ascertain the safety of exercise by assessing for severe ECG ischemia or cardiac arrhythmias that would contraindicate exercise training or require additional therapeutic interventions before starting exercise training (151). It also helps clarify the baseline fitness level, pertinent symptoms, as well as an appropriate starting exercise workload. However for patients who do not undergo exercise testing and particularly for those with known ASCVD who do not plan to exercise in a supervised medial program such as cardiac rehabilitation, initiating only low-intensity activity should be the alternative training standard, with instructions to report symptoms such as chest pain or shortness of breath to their physician.
Accumulating evidence suggests that the extent of exercise benefits may increase in proportion to the intensity of exercise training. Reports in patients with established heart disease, including one study of patients with a mean age of 75 years, suggest that a high intensity aerobic interval training (HIT) can elicit greater improvement in exercise capacity than continuous exercise at a lower intensity (152). In general, HIT entails short periods of higher intensity exercise alternating with longer periods at lower exercise intensity, a training pattern that has been demonstrated to achieve higher training effects than continuous training, with preserved safety. Details regarding the specific intensities and duration of the training regimen must be tailored relative to each individual’s baseline capacities and circumstances. Despite such encouraging data, HIT is more complex than continuous training, necessitating more supervision for implementation and safety. Larger studies are needed to more definitively establish the efficacy and safety of high intensity interval training in broader populations of older patients.
Strength training for older patients as a component of the overall exercise prescription, as well as balance and flexibility training should improve neuromuscular function, muscular strength, and endurance. Such training is essential in improving responses to the various physical demands of daily living as well as occupational and recreational activities (145, 149), and to moderate the effects of sarcopenia, particularly in those struggling with disease and/or trying to lose weight. Furthermore, it is likely to improve self-esteem and functional independence, both critical issues among seniors.
Cardiac Rehabilitation
Cardiac rehabilitation (CR) constitutes structured exercise training integrated with broader secondary prevention reinforcements. Studies show that older patients with CHD benefit greatly from CR (145–147,150), improving from individualized prescription as well as its close supervision and support. Among 601,099 Medicare beneficiaries, those who participated in supervised CR experienced 21%–34% lower mortality than nonusers over the subsequent 5 years, independent of other risk factors (153). Furthermore, patients who attended at least 25 of the 36 CR sessions were 19% less likely to die than those who attended fewer sessions.
Cardiac Rehabilitation Referral, Participation, and Adherence
Despite the clear benefits of CR in the older adults with ASCVD (Table 4), the vast majority of older patients do not participate because of a variety of factors: lack of referral, patient-related factors, or societal and economic barriers. The cumulative effect of the above factors is abysmally poor CR utilization rates among the older adults. Overall CR participation in Medicare recipients is about 12%; within this population; older individuals, women, and nonwhites were less likely to receive CR (154). Thus, men and women aged 75 to 84 years were only 87% and 69%, respectively, as likely to receive CR as men aged 65 to 74 years. Gender-related differences in referral increased with age. Whites were 33% more likely to receive CR than nonwhites after adjustment for age and sex. Both CABG surgery and PCI during the index hospitalization were strong predictors of higher CR use (154) but this may reflect an implicit pre-selection in respect to which senior patients are referred for revascularization in the first place.
Table 4.
Benefits of Cardiac Rehabilitation for Older Adults
| Cardiac Rehabilitation Effects | Clinical implication |
|---|---|
| Exercise Training CV Effects | |
| Increased functional capacity (10% to 60%) with decrease myocardial work (10% to 25%) at standardized work with 12 weeks of exercise training post-hospitalization. |
|
| Training effect from improved skeletal muscle work capacity, although exercise may also improve health of the vasculature, autonomic balance, and cardiac performance. | Peripheral physiology is an important part of CV health |
| Absolute levels of functional gain are less in elderly than younger cohorts, particularly for those patients ≥75 years of age.4–6 | |
| Extended periods of training result in further modest gains. | Lifelong training is a worthwhile goal |
| Improved Heart Rate Recovery | Decreased susceptibility to arrhythmia |
| Exercise Training Noncardiovascular Effects | |
| Enhanced quality of life | Improved self-efficacy and self-worth |
| Reduced depression | Improved quality of life |
| Decreased BMI and body fat | Improved metabolism and decreased inflammation, increased joint stability |
| Improved lipid profiles | Decreased CV events and mortality |
| Cardiac Rehabilitation Effects on Diet and Lifestyle | |
| Comprehensive assessment and management in relation to diet, medications, exercise that can compensate reinforce compliance, monitor for iatrogenesis, and that can monitor/compensate for possible cognitive deficiencies. | Appropriate care for a population with predictable polypharmacy, multimorbidity, frailty, cognitive limitations, and atypical symptoms. |
Abbreviations: CV-cardiovascular; BMI-body mass index
Physician referral is a key determinant of CR enrollment; failure to refer is probably the major contributor to the under-representation of older adults, especially those 75 years and older, in secondary CHD prevention programs (150). Analyses of system-level factors that appear to impact CR referral and use include the degree of automation and physician assertiveness around securing CR referrals and the level of integration of CR within the hospital setting and physician community. In many cases this is already evident in cardiothoracic surgical programs that routinely refer to cardiac rehabilitation as part of post-op management. Automated referrals of all eligible patients, in combination with a discussion between the patient and a nurse or physiotherapist, can achieve over a doubling of CR participation rates (155).
Older patients may also be reluctant to enter a structured exercise program, which may be novel to them or in some instances, includes activities in which they have never participated or at a minimum, not for many years. Low functional capacity, multiple comorbidities, and chronic deconditioning may also deter patients from participating in CR programs (146). Recent data suggest that current smoking, a body mass index ≥30 kg/m2, diabetes, and cognitive dysfunction are associated with failure to enroll in outpatient CR in this age group (156). In addition, patients may often have logistical or personal barriers to attending CR including lack of transportation or the need to care for a sick spouse. Nonetheless, CR staff must recognize the importance of encouraging and supporting these patients by any available means, given the convincing data suggesting that older patients, including those with significant medical comorbidities or other barriers to participation, benefit substantially from CR participation (146). Providing the opportunity for the patient and family to participate in the design of the intervention, underscoring the importance of specific interests and concerns, and overcoming potential limitations to participation are essential to long-term adherence.
The financial commitment of CR program entry is another potential deterrent to CR participation by older adults. For eligible patients age 65 years of older, Medicare Part B reimburses for CR services in all states (157). However, individuals without supplemental insurance or Medicaid may still be responsible for 20% of the overall payment. For private insurance, copayments for each CR visit can also be problematic. Patients without insurance or who are underinsured may qualify for financial waivers in some cases, dependent upon institutional policy. Program staff can be a valuable resource for facilitating participation and various appeal processes related to insurance coverage. Lower cost options such as home-based or community center programs should be strongly considered to help overcome these financial barriers.
Coronary Revascularization
Revascularization procedures for ACS in older adults are discussed in separate AHA Scientific Statements (10,13). However, it is important to highlight the benefit of revascularization in chronic CHD, both as a means to treat symptoms, and/or in certain situations (multivessel disease, certain coronary lesions, large ischemic burden, left ventricular systolic dysfunction) to improve survival. Both coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) have been increasingly utilized in older patients, with about two-thirds % of all PCIs being performed in patients ≥60 years of age and 11% in those ≥80 years (158). Relevant outcomes in this age group include general well-being, functional status, QOL, as well as mortality.
Older patients tend to have more calcified, tortuous and multivessel coronary disease, and their peripheral vessels are also more often abnormal. The incidence of PAD approaches 25% in octogenarians. These factors can make both PCI and CABG more challenging, and lead to suboptimal results or complications with either procedure.
Percutaneous Coronary Intervention
Despite the challenges noted above, procedural success for PCI typically exceeds 90%, in older patients, and patient outcomes have also been improving. In an analysis of the NCDR Cath PCI Registry Database, in-hospital mortality for patients >80 years undergoing elective PCI declined from over 3.5% to 3% between 2001 and 2006 (158). However, non-mortal complications of PCI, including vascular and bleeding problems, are more frequent in older adults, particularly in very advanced age. Whether the use of radial artery for access may reduce complications in older adults, who may have upper extremity arterial disease, is uncertain.
The Trial of Invasive versus Medical therapy in Elderly patients (TIME) Trial randomized older patients (mean age 80 years) with refractory angina to invasive versus medical therapy; 74% of the invasive group underwent revascularization (73% PCI and 27% CABG) (159). There was a reduction in major adverse cardiac events in the invasive arm, primarily due to a decreased rate of rehospitalization for ACS. Quality of life, angina severity and health status were also better in the intervention group, and these differences persisted at 4 years (159).
In patients with stable angina, the COURAGE trial showed that addition of PCI (only 15% drug-eluting stents [DES]) to optimal medical therapy did not reduce the rate of death, nonfatal MI or hospitalization for ACS; results were similar for the 39% of patients who were >65 years of age (160). Patients in the PCI group, however, did undergo fewer subsequent revascularization procedures during follow-up. They also had improved health status and QOL measures in the first two years compared to the medical therapy group. These differences were more pronounced in those with more severe angina (160).
Thus, although a reduction in symptoms and antianginal medications, and greater QOL may initially accompany PCI, the greater potential for complications in older patients with other comorbid conditions must be considered. Thus, the decision whether to perform PCI in an older patient must be individualized.
Coronary Artery Bypass Grafting
Patients with left main, multivessel disease, those with depressed left ventricular systolic function and diabetics have traditionally been referred for CABG, based on RCT data. Older patients are at higher risk of morbidity and mortality after CABG. Post-operative complications such as prolonged intubation, inotropic dependence, intraaortic balloon pump placement, atrial fibrillation, bleeding, renal failure, infection and delirium are more common with increasing age. Those at increased risk include patients with renal dysfunction and those undergoing more complex or emergency procedures. Outcomes have been improving, however. In an analysis of CABG in octogenarians between 1990 and 2005, in-hospital mortality fell from 7.1 to 3.2%, and post-operative complications also fell significantly (161).
Modern series have suggested a rate of CABG-associated stroke of about 3% with advancing age associated with increased risk (161). Risks of cognitive changes secondary to CABG remain controversial, but a prominent study in New England Journal reported 53% of CABG patients with neurocognitive testing abnormalities at discharge, and 42% with persistent/worsening neurocognitive abnormalities at five years (162). Increasing age, diabetes, extent of atherosclerosis, and lower educational status, as well as operative events such as hypotension and hypoxia, are risk factors. The wide reported range of cognitive dysfunction is attributable to variable definitions, testing times and modalities. Studies performed several weeks after surgery typically show lower rates of impairment.
PCI versus CABG
Because of the potential complications of CABG in older patients, and the greater prevalence of left main and multivessel coronary disease in these patients, a comparison of PCI and surgical revascularization is relevant. The BARI trial, which compared CABG to PCI in the early 1990s, showed an advantage of CABG for MI-free survival in patients with diabetes and multivessel CHD, regardless of age (163). However, PCI in that study did not include stenting, and adjuvant therapy for PCI has also evolved since that time. A modern meta-analysis that included 66 studies of octogenarians undergoing PCI or CABG showed similar 30 day and 1 year mortality for the two strategies (164). Another meta-analysis of 10 trials of CABG versus PCI showed no difference in mortality at 6 years, although the data suggested an advantage for CABG with increasing age (165). However, the numbers of patients >75 years was very limited. In addition, less than half of the studies included PCI with bare metal stents, and none included DES. A recent observational study of nearly 190,000 patients non-emergently revascularized for multivessel coronary disease found a survival advantage for CABG over PCI; 78% of the PCI group received DES (166). The decision to pursue coronary revascularization in an older adult must be individualized, taking into account the possibility that this may provide greater reduction in symptoms, improved QOL, and increased function over medical therapy, at least in the short-term. CABG should be considered for standard indications, regardless of age, but the increased risk of periprocedural complications, including neurocognitive dysfunction should be factored into decision making. Whether the use of DES in multivessel or left main CHD provides an appropriate alternative to CABG is uncertain, particularly in this population.
Implantable Cardioverter-Defibrillator Therapy
Indications for implantable cardioverter defibrillator (ICD) therapy for sudden cardiac death (SCD) prevention have been published with comprehensive reviews of clinical evidence in the two most recent guideline statements (167,168). These guidelines were developed from pivotal trials that generally enrolled younger patient cohorts relative to those typically observed in the clinical setting. This section will critically appraise the current recommendations and level of evidence for primary and secondary SCD prevention in the older adult with CHD. Primary prevention of SCD refers to the use of ICDs in individuals who are at risk for but have not yet had an episode of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), or resuscitated cardiac arrest. Secondary prevention refers to prevention of SCD in those patients who have survived a prior sudden cardiac arrest or sustained VT.
Implantable Cardioverter-Defibrillator Therapy: Randomized Clinical Trials of Secondary Prevention
Prospective, randomized, multicenter trials have demonstrated ICD therapy is effective for secondary prevention of SCD by improving overall survival in selected populations (169–171). The Antiarrhythmics Versus Implantable Defibrillator (AVID) (169), Canadian Implantable Defibrillator Study (CIDS) (170) and Cardiac Arrest Study Hamburg (CASH) (171) provided evidence for the current secondary SCD prevention recommendations. The mean ages were 65+/−10 years, 64+/−10 years and 58+/−11 years in AVID, CIDS and CASH, respectively. The AVID trial demonstrated significant survival improvement from ICD therapy when compared to antiarrhythmic drug therapy. Survival benefit was not observed in patients with EF >35%. The CIDS and CASH trials enrolled smaller number of patients, and showed non-significant trends toward improved survival. In a meta-analysis of these 3 trials, the mean survival benefit was 4.4 months longer in the ICD cohorts than in those receiving medical therapy (172). Concerns of antiarrhythmic drug-mediated adverse effects and the low use of beta blocker therapy in the drug-treated control group may have potentially over-estimated the modest benefit of ICD therapy. In another meta analysis of the 1866 patients from these three secondary prevention trials, ICD therapy significantly reduced all-cause and arrhythmic death in the 86.5% of patients < 75 years old, but not in the 252 patients ≥75 years old (173). Although advanced age alone should not be the determinant to withhold ICD therapy in older patients with a history of malignant arrhythmias, the limited data available suggest that ICD therapy may not afford similar survival benefits as observed in younger patients (173, 174).
Implantable Cardioverter-Defibrillator Therapy: Randomized Clinical Trials of Primary Prevention
Randomized trials have established that ICD therapy is effective for primary prevention of SCD in selected populations with CHD and reduced left ventricular ejection fraction (175–179). The mean or median age of patients in these trials ranged from 60 to 67 years. The MADIT I (175), CABG-Patch (176), and DINAMIT (178) trials excluded patients >80 years of age. The 2006 guidelines indicate that the primary prevention of SCD in seniors does not differ from that in the general population, but the authors qualified the recommendation by stating “very elderly patients with multiple comorbidities and limited life expectancy may not be appropriate candidates for ICD therapy even if they meet the standard criteria” (167). The 2008 guidelines further emphasized that “all primary SCD prevention ICD recommendations apply only to patients who are receiving optimal medical therapy and have reasonable expectation of survival with good functional capacity for more than one year” (168). When evaluating seniors for ICD therapy, the clinical assessment that life expectancy is at least one year is particularly relevant, considering that the survival benefit does not become apparent until 1 to 2 years after ICD implantation, and the median survival for octogenarians with heart failure is approximately 2 years (180). Among the 4,915 patients from four randomized trials included in a recent meta-analysis, 579 (11.8%) were ≥75 years of age (181). The ICD was found to be efficacious in reducing all-cause mortality in this selected older patient population (HR 0.73, p = 0.03).
Registries of Implantable Cardioverter-Defibrillator Therapy
Older patients comprise a large and rapidly growing segment of cardiac patients. Comprehensive registry databases, although not suitable for the assessment of comparative effectiveness, are excellent sources for the general trend of day-to-day clinical practice. The NCDR National ICD Registry is the sole repository for ICD data for Medicare beneficiaries (182). Although initially intended for the Medicare population, approximately 90% of all ICD implants performed in the United States are reported to the registry. According to the 2009 data, more than 550,000 patients had been entered into the registry since 2006. The mean age was 68.1+/−12.8 years. Of the total, 29.6% were 70–79 years of age; 12.4% were octogenarians. The Advancements in ICD Therapy (ACT) Registry is a prospective 2-year study of new ICD implants from a single manufacture (183) and includes 4,566 patients from 264 centers in 38 states in the United States. Of the total, 29.0% were 70–79 years of age; 12.0% were octogenarians. The PREMIER Perspective Comprehensive Database includes data from several hundred hospitals and health care systems (184). Among 26,887 PREMIER patients who received an implantable cardiac devices for heart failure from 2004–2005, 93.3% received ICD with or without cardiac resynchronization therapy. The median age was 70.0 years and 17.5% were 80 years or older. Overall, registry data show that age is a strong predictor of survival. Mortality rates at two years follow-up were 8.0%, 15.0% and 17.8% in patients 60–69 years, 70–79 years and ≥80 years, respectively (183).
In contrast to consistent survival benefits of ICD in younger patients, benefits in adults aged 75–80 years are less clear. Projections of SCD prevention in older adults, extrapolated from younger patients studied in randomized trials, are not straightforward. The combination of advanced age and age-associated medical comorbidities increase risks of non-cardiac mortality and morbidity, which can diminish or even abolish beneficial effects of ICD in the prevention of SCD in many senior patients. Furthermore, increased depression and reduced QOL can result in many ICD recipients by inappropriate discharges and/or the apprehension they may occur, especially in those who are predisposed to such emotional flux (185). Similar ICD-related emotional distress may also extend to ICD patients’ families (185). Such stresses and potential clinical implications (e.g., depression, anxiety, and potentially even changes in cognition) merit greater study in relation to advanced age and cumulative infirmity.
For older patients with ICDs who may be facing subsequent facing end-of-life circumstances and decisions, open and early communication between the physician and the patient regarding withholding or withdrawing ICD therapy are recommended. Such decisions are increasingly relevant in this rapidly expanding segment of our population (186).
Final Considerations for Secondary Prevention of ASCVD in older adults
Given the greater attributable risk associated with ASCVD in older adults in relation to morbidity, mortality as well as to decreased QOL, physical function, personal independence as well as higher health care costs, older patients are particularly likely to benefit from secondary prevention strategies. Nonetheless, risks attributable to these therapies also increase for seniors in comparison to the younger populations from which evidence-based secondary prevention standards were based. Secondary prevention pharmacological, invasive, and lifestyle interventions are all technically feasible in older as well as younger adults with ASCVD, but their risk-benefit ratios vary significantly. Whereas some subsets of very old CHD patients will likely experience disproportionate benefit, with secondary therapy moderating greater likelihood of clinical decrements, others experience disproportionate iatrogenesis and/or the perception of unwanted therapeutic burden.
Further research is necessary to clarify which senior patients with ASCVD are likely to derive the most benefit from secondary prevention therapy. Pertinent risk assessment must be improved to address the concept of hazard among older adults in the context of age-related multimorbidity, polypharmacy, and altered lifestyle. Implications of costs, logistics, and the overall management complexity are also pertinent, particularly in relation to each patient’s circumstances. Improved health literacy among seniors and their families is also pertinent since expectations must correspond realistically to the advantages, burdens, and limitations of care. This also implies a need for effective communication amidst complicating dynamics of cognitive, visual and hearing impairments of old age. In addition to ascertaining whether or not secondary prevention measures yield overall favorable risk: benefit balance, it is incumbent on providers to ascertain whether their use is consistent with each older patient’s goals and perceived QOL.
Further research is needed to clarify the medication regimens, lifestyle modifications, and revascularization/ICD strategies that yield the greatest benefit/risk in this rapidly expanding age group. It is therefore essential to include older and very elderly patients in pertinent clinical trials, expand comprehensive national registries pertaining to medication, devices and procedures, develop educational programs designed specifically for older patients and their families, and to refine assessment of age- and gender-specific benefit/risk ratios for older patients with ASCVD with respect to short and long term morbidity and mortality, QOL, function, independence, cost-efficacy, and other relevant measures.
Executive Summary
While this document provides considerable data in support of secondary prevention in older patients with ASCVD, evidence is infrequently stratified by age or to the physiological and psychosocial complexities associated with aging. Therefore, implementation of secondary prevention principles first requires reflection regarding each patient’s broader health/psychosocial circumstances. The benefit of lifestyle modifications (tobacco cessation, weight loss, diet changes, and exercise) must be counterbalanced by clinical context, allowing for the potential that a patient may prefer to continue in a pattern which they feel provides greater satisfaction in spite of untreated, modifiable CV risks. Similarly, benefits of medications and procedures must be counterbalanced by considering therapeutic burden, i.e., allowing for the fact that polypharmacy, iatrogenesis, cost, and other implicit trade-offs may sometimes seem to supersede benefits. Such predictable equipoise mandates that patients be involved with secondary prevention decisions; improved health literacy among seniors is a key aspect of effective care. It is incumbent on providers to inform older patients with ASCVD regarding benefits and risks of secondary prevention, a priority that may be challenging amidst the dynamic cognitive, auditory, and visual changes of old age.
Secondary prevention lifestyle changes to increase longevity often seem inappropriate in the context of advanced age, but their utility to improve function, QOL, and independence is often clear-cut. For example, while mortality benefit of intentional weight loss is uncertain, improved glucose control, arthritic pain, mobility, dyspnea, and other endpoints are likely. Likewise, exercise training may not have intense appeal as a means to prolong life for someone who is older and deconditioned, but it may be much more compelling as a reliable means to foster independence, greater QOL, and personal choice. Similarly, many octogenarians may be reluctant to discontinue tobacco for assumed mortality benefits, especially for seniors who associate tobacco with comfort and pleasure. However, tobacco cessation may be appealing if/when presented as an option to reduce claudication and improve exercise capacity.
Therefore, secondary prevention lifestyle changes should be actively considered for every community dwelling older patient with ASCVD. Tobacco cessation use stands out as the risk factor most likely to reduce mortality, and exercise training (including aerobic, strength, balance, and flexibility) as the one most likely to reinforce a broader spectrum of qualitative benefits (including improved function, mood, and BPcontrol). Weight loss and diet control (glucose, salt, and caloric moderation) are similarly important. Ideally, providers should have teaching tools that provide information to patients clearly, including mode (e.g., large font and/or audio) and language commensurate with their physical and learning capacities. Despite its unequivocal utility in older adults, CR remains an underused resource for improving lifestyle habits and CV risk profile in this age group.
Pharmacological and procedural secondary prevention options remain equally important in older cardiac patients. Extended life expectancy and improved quality of life reinforce the rationale for revascularization and device therapy. Even octogenarians and nonagenarians may derive added years of life from implanted defibrillators and possibly coronary revascularization. Even more compelling is the potential for improved QOL, with reduced pain, reduced reliance on medications, and greater function/independence.
Data demonstrating life prolongation and reduced CV morbidity are relatively clear-cut for statins and antihypertensives through ages in the early 80s. While utility beyond these years is less certain, it remains eminently logical to consider these medications in those seniors who have suffered a CV event, i.e., who are thereby at greatest risk for repeat events and related disease progression. Nonetheless, such inferred benefits progressively diminish in patients who are more frail or who have other health liabilities that detract from potential benefits of these medications (e.g., patients with severe dementia and/or another life-threatening disease). Depression and mood instability are common and often insidious among adults struggling with disease, loss, and decline, and mandate appropriate therapy.
Inherent ambiguity between primary and secondary prevention among adults over 75 years is also important to highlight. Eventually, most seniors develop atherosclerosis as a function of age itself, especially in context of the lifestyle patterns in the United States and western cultures. Therefore, the most important secondary prevention is ultimately primary prevention; lifelong lifestyle and medical care oriented to minimizing CV risks, and promoting physical, mental, and emotional wellbeing provide the best foundation for moderating disease in old age.
Footnotes
The views expressed in this document are those of the authors and do not necessarily reflect those of the National Institutes of Health, the Department of Veteran Affairs, or the Department of Health and Human Services.
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on July 15, 2013. A copy of the document is available at http://my.americanheart.org/statements by selecting either the “By Topic” link or the “By Publication Date” link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com.
The American Heart Association requests that this document be cited as follows: Fleg JL, Forman DE, Berra K, Bittner V, Blumenthal JA, Chen M, Cheng S, Kitzman DW, Maurer MS, Rich MW, Shen WK, Williams MA, Zieman SJ; on behalf of the American Heart Association Committees on Older Populations and Exercise Cardiac Rehabilitation and Prevention of the Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, and Council on Lifestyle and Cardiometabolic Health. Secondary Prevention of Atherosclerotic Cardiovascular Disease in Older Adults: A Scientific Statement From the American Heart Association. Circulation. 2013;128:•••–•••.
Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the “Policies and Development” link.
Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright-Permission-Guidelines_UCM_300404_Article.jsp. A link to the “Copyright Permissions Request Form” appears on the right side of the page.
References
- 1.Williams MA, Fleg JL, Ades PA, Chaitman BR, Miller NH, Mohiuddin SM, Ockene IS, Taylor CB, Wenger NK. Secondary prevention of coronary heart disease in the elderly (with emphasis on patients ≥75 years of age). An American Heart Association Scientific Statement from the Council on Clinical cardiology Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention. Circulation. 2002;105:1735–1743. doi: 10.1161/01.cir.0000013074.73995.6c. [DOI] [PubMed] [Google Scholar]
- 2.US Census Bureau. Statistical Abstract of the US. 2012 http://www.census.gov/compendia/statab/
- 3.Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB, on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Heart disease and stroke statistics – 2012 update: a report from the American Heart Association. Circulation. 2012;125:e12–e230. doi: 10.1161/CIR.0b013e31823ac046. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Odden MC, Coxson PG, Moran A, Lightwood JM, Goldman L, Bibbins-Domingo K. The impact of the aging population on coronary heart disease in the United States. Am J Med. 2011;124:827–833. doi: 10.1016/j.amjmed.2011.04.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Smith SC, Jr, Benjamin EJ, Bonow RO, Braun LT, Creager MA, Franklin BA, Gibbons RJ, Grundy SM, Hiratzka LF, Jones DW, Lloyd-Jones DM, Minissian M, Mosca L, Peterson ED, Sacco RL, Spertus J, Stein JH, Taubert KA. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation. 2011;124(22):2458–73. doi: 10.1161/CIR.0b013e318235eb4d. [DOI] [PubMed] [Google Scholar]
- 6.Ko DT, Mamdani M, Alter DA. Lipid-lowering therapy with statins in high-risk elderly patients. The treatment-risk paradox JAMA. 2004;291:1864–70. doi: 10.1001/jama.291.15.1864. [DOI] [PubMed] [Google Scholar]
- 7.Kozak LJ, DeFrances CJ, Hall MJ. National Hospital Discharge Survey: 2004 annual summary with detailed diagnosis and procedure data. National Center for Health Statistics. Vital Health Stat. 2006;162:1–209. [PubMed] [Google Scholar]
- 8.Ness J, Aronow WS. Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital-based geriatrics practice. J Am Geriatr Soc. 1999;47:1255–1256. doi: 10.1111/j.1532-5415.1999.tb05208.x. [DOI] [PubMed] [Google Scholar]
- 9.Tresch D, Aronow W. Clinical manifestations and diagnosis of coronary artery disease. Clin Geriatr Med. 1996;12:89–100. [PubMed] [Google Scholar]
- 10.Alexander KP, Newby LK, Cannon CP, Armstrong PW, Gibler WB, Rich MW, Van de Werf F, White HD, Weaver WD, Naylor MD, Gore JM, Krumholz HM, Ohman EM. Acute coronary care in the elderly, part I: Non-ST-segment-elevation acute coronary syndromes: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology. Circulation. 2007;115:2549–2569. doi: 10.1161/CIRCULATIONAHA.107.182615. [DOI] [PubMed] [Google Scholar]
- 11.Canto JG, Rogers WJ, Goldberg RJ, Peterson ED, Wenger NK, Vaccarino V, Kiefe CI, Frederick PD, Sopko G, Zheng Z-J, MD, PhD, for the NRMI Investigators Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality. JAMA. 2012;307:813–22. doi: 10.1001/jama.2012.199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Lakatta EG. Age-associated cardiovascular changes in health: impact on cardiovascular disease in older persons. Heart Fail Rev. 2002;7:29–49. doi: 10.1023/a:1013797722156. [DOI] [PubMed] [Google Scholar]
- 13.Alexander KP, Newby LK, Armstrong PW, Cannon CP, Gibler WB, Rich MW, Van de Werf F, White HD, Weaver WD, Naylor MD, Gore JM, Krumholz HM, Ohman EM. Acute coronary care in the elderly, part II: ST-segment-elevation myocardial infarction: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology. Circulation. 2007;115:2570–2589. doi: 10.1161/CIRCULATIONAHA.107.182616. [DOI] [PubMed] [Google Scholar]
- 14.White HD, Barbash GI, Califf RM, et al. Age and outcome with contemporary thrombolytic therapy. Results from the GUSTO-I trial. Circulation. 1996;94:1826–1833. doi: 10.1161/01.cir.94.8.1826. [DOI] [PubMed] [Google Scholar]
- 15.Kelly-Hayes M, Beiser A, Kase CS, et al. The influence of gender and age on disability following ischemic stroke: the Framingham study. J Stroke Cerebrovasc Dis. 2003;12:119–126. doi: 10.1016/S1052-3057(03)00042-9. [DOI] [PubMed] [Google Scholar]
- 16.Adams HP. Secondary prevention of of atherothrombotic events after ischemic stroke. Mayo Clin Proc. 2009;84:43–51. doi: 10.4065/84.1.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Brott TG, Hobson RW, II, Howard G, et al. Stenting versus endarterectomy for treatment of carotid artery stenosis. N Engl J Med. 2010;363:11–23. doi: 10.1056/NEJMoa0912321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Aronow H. Peripheral arterial disease in the elderly. Recognition and managemen. Amer J Cardiovasc Drugs. 2008;8:353–364. doi: 10.2165/0129784-200808060-00002. [DOI] [PubMed] [Google Scholar]
- 19.Meijer WT, Hees AW, Rutgers D, et al. Peripheral arterial disease in the elderly: the Rotterdam Study. Arterioscler ThrombVasc Biol. 1998;18:185–192. doi: 10.1161/01.atv.18.2.185. [DOI] [PubMed] [Google Scholar]
- 20.Kindemann M, Adam O, Werner N, et al. Clinical trial updates and hotline sessions presented at the European Society of Cardiology 2007. Clin Res Cardiol. 2007;97:767–786. doi: 10.1007/s00392-008-0729-7. [DOI] [PubMed] [Google Scholar]
- 21.Gardner AW, poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain: a meta-analysis. JAMA. 1995;274:975–980. [PubMed] [Google Scholar]
- 22.Stevens J, Cai J, Pamuk ER, Williamson DF, Thun MJ, Wood JL. The Effect of Age on the Association between Body-Mass Index and Mortality. New England Journal of Medicine. 1998;338:1–7. doi: 10.1056/NEJM199801013380101. [DOI] [PubMed] [Google Scholar]
- 23.Romero-Corral A, Montori VM, Somers VK, Korinek J, Thomas RJ, Allison TG, et al. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. The Lancet. 2006;368:666–678. doi: 10.1016/S0140-6736(06)69251-9. [DOI] [PubMed] [Google Scholar]
- 24.Whelton PK, Appel LJ, Espeland MA, Applegate WB, Ettinger WH, Jr, Kostis JB, et al. Sodium Reduction and Weight Loss in the Treatment of Hypertension in Older Persons: A Randomized Controlled Trial of Nonpharmacologic Interventions in the Elderly (TONE) JAMA: The Journal of the American Medical Association. 1998;279:839–846. doi: 10.1001/jama.279.11.839. [DOI] [PubMed] [Google Scholar]
- 25.Witham MD, Avenell A. Interventions to achieve long-term weight loss in obese older people. Age and Ageing. 2010;39:176–184. doi: 10.1093/ageing/afp251. [DOI] [PubMed] [Google Scholar]
- 26.Miller GD, Nicklas BJ, Davis C, Loeser RF, Lenchik L, Messier SP. Intensive Weight Loss Program Improves Physical Function in Older Obese Adults with Knee Osteoarthritis. Obesity Res. 2006;14:1219–1230. doi: 10.1038/oby.2006.139. [DOI] [PubMed] [Google Scholar]
- 27.Shea MK, Houston DK, Nicklas BJ, Messier SP, Davis CC, Miller ME, et al. The Effect of Randomization to Weight Loss on Total Mortality in Older Overweight and Obese Adults: The ADAPT Study. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2010;65:519–525. doi: 10.1093/gerona/glp217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Shea MK, Nicklas BJ, Houston DK, Miller ME, Davis CC, Kitzman DW, et al. The effect of intentional weight loss on all-cause mortality in older adults: results of a randomized controlled weight-loss trial. Am J Clin Nutr. 2011;94:839–846. doi: 10.3945/ajcn.110.006379. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Williamson DA, Rejeski J, Lang W, Van Dorsten B, Fabricatore AN, Toledo K, et al. Impact of a Weight Management Program on Health-Related Quality of Life in Overweight Adults With Type 2 Diabetes. Archives of Internal Medicine. 2009;169:163–171. doi: 10.1001/archinternmed.2008.544. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Houston DK, Stevens J, Cai J, Morey MC. Role of Weight History on Functional Limitations and Disability in Late Adulthood: The ARIC Study. Obesity Res. 2005;13:1793–1802. doi: 10.1038/oby.2005.218. [DOI] [PubMed] [Google Scholar]
- 31.Houston DK, Ding J, Nicklas BJ, Harris TB, Lee JS, Nevitt MC, et al. Overweight and Obesity Over the Adult Life Course and Incident Mobility Limitation in Older Adults. Am J Epidemiol. 2009;169:927–936. doi: 10.1093/aje/kwp007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Lee Dc, Sui X, Church TS, Lavie CJ, Jackson AS, Blair SN. Changes in Fitness and Fatness on the Development of Cardiovascular Disease Risk Factors: Hypertension, Metabolic Syndrome, and Hypercholesterolemia. Journal of the American College of Cardiology. 2012;59:665–672. doi: 10.1016/j.jacc.2011.11.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Beavers KM, Lyles MF, Davis CC, Wang X, Beavers DP, Nicklas BJ. Is lost lean mass from intentional weight loss recovered during weight regain in postmenopausal women? The American Journal of Clinical Nutrition. 2011;94:767–774. doi: 10.3945/ajcn.110.004895. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Mitchell WK, Williams J, Atherton P, Larvin M, Land J, Narici M. Saecopenia, dyspnea, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. Frontiers in Physiology. 2012;3:1–18. doi: 10.3389/fphys.2012.00260. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Fiataroni MA, O’Neill EF, Ryan ND, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Eng J Med. 1994;330:1769–75. doi: 10.1056/NEJM199406233302501. [DOI] [PubMed] [Google Scholar]
- 36.Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age spectrum: current outcomes and control in the community. JAMA. 2005;294:466–72. doi: 10.1001/jama.294.4.466. [DOI] [PubMed] [Google Scholar]
- 37.Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2011;123:2434–506. doi: 10.1161/CIR.0b013e31821daaf6. [DOI] [PubMed] [Google Scholar]
- 38.Chobanian AV. Clinical practice. Isolated systolic hypertension in the elderly. N Engl J Med. 2007;357:789–96. doi: 10.1056/NEJMcp071137. [DOI] [PubMed] [Google Scholar]
- 39.Blacher J, Staessen JA, Girerd X, Gasowski J, Thijs L, Liu L, Wang JG, Fagard RH, Safar ME. Pulse pressure not mean pressure determines cardiovascular risk in older hypertensive patients. Arch Intern Med. 2000;160:1085–9. doi: 10.1001/archinte.160.8.1085. [DOI] [PubMed] [Google Scholar]
- 40.Chae CU, et al. Increased pulse pressure and risk of heart failure in the elderly. JAMA. 1999;281:634–9. doi: 10.1001/jama.281.7.634. [DOI] [PubMed] [Google Scholar]
- 41.Haider AW. Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med. 2003;138:10–6. doi: 10.7326/0003-4819-138-1-200301070-00006. [DOI] [PubMed] [Google Scholar]
- 42.Sutton-Tyrrell K, et al. Extent of cardiovascular risk reduction associated with treatment of isolated systolic hypertension. Arch Intern Med. 2003;163:2728–31. doi: 10.1001/archinte.163.22.2728. [DOI] [PubMed] [Google Scholar]
- 43.SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP) JAMA. 1991;265:3255–64. [PubMed] [Google Scholar]
- 44.Wong ND, et al. Inadequate control of hypertension in US adults with cardiovascular disease comorbidities in 2003–2004. Arch Intern Med. 2007;167:2431–6. doi: 10.1001/archinte.167.22.2431. [DOI] [PubMed] [Google Scholar]
- 45.Beckett NS, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887–98. doi: 10.1056/NEJMoa0801369. [DOI] [PubMed] [Google Scholar]
- 46.Schiffman SS. Taste and smell losses in normal aging and disease. JAMA. 1997;278:1357–62. [PubMed] [Google Scholar]
- 47.Chobanian AV. Does it matter how hypertension is controlled? N Engl J Med. 2008;359:2485–8. doi: 10.1056/NEJMe0808690. [DOI] [PubMed] [Google Scholar]
- 48.Chobanian AV, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560–72. doi: 10.1001/jama.289.19.2560. [DOI] [PubMed] [Google Scholar]
- 49.Weber MA, Frishman WH. Combination drug therapy. In: SE, Frishman WH, Sica DA, editors. Cardiovascular Pharmacotherapeutics. New York, NY: McGraw-Hill; 2003. [Google Scholar]
- 50.Kronmal RA, Cain KC, Ye Z, Omenn GS. Total serum cholesterol levels and mortality risk as a function of age. A report based on the Framingham data. Arch Intern Med. 1993;153:1065–73. [PubMed] [Google Scholar]
- 51.Wong ND, Wilson PW, Kannel WB. Serum cholesterol as a prognostic factor after myocardial infarction: the Framingham Study. Ann Intern Med. 1991;115:687–93. doi: 10.7326/0003-4819-115-9-687. [DOI] [PubMed] [Google Scholar]
- 52.Prospective Studies Collaboration. Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, Qizilbash N, Peto R, Collins R. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007;370:1829–39. doi: 10.1016/S0140-6736(07)61778-4. [DOI] [PubMed] [Google Scholar]
- 53.Afilalo J, Duque G, Steele R, Jukema JW, de Craen AJ, Eisenberg MJ. Statins for secondary prevention in elderly patients: a hierarchical bayesian meta-analysis. J Am Coll Cardiol. 2008;51:37–45. doi: 10.1016/j.jacc.2007.06.063. [DOI] [PubMed] [Google Scholar]
- 54.Cholesterol Treatment Trialists’ (CTT Collaboration. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–81. doi: 10.1016/S0140-6736(10)61350-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22. [Google Scholar]
- 56.Grundy SM, Cleeman JI, Merz CN, Brewer HB, Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Jr, Stone NJ, National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–39. doi: 10.1161/01.CIR.0000133317.49796.0E. [DOI] [PubMed] [Google Scholar]
- 57.Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG, PROSPER study group PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–30. doi: 10.1016/s0140-6736(02)11600-x. [DOI] [PubMed] [Google Scholar]
- 58.Ray KK, Bach RG, Cannon CP, Cairns R, Kirtane AJ, Wiviott SD, McCabe CH, Braunwald E, Gibson CM, PROVE IT-TIMI 22 Investigators Benefits of achieving the NCEP optional LDL-C goal among elderly patients with ACS. Eur Heart J. 2006;27:2310–6. doi: 10.1093/eurheartj/ehl180. [DOI] [PubMed] [Google Scholar]
- 59.Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK, Treating to New Targets Study Steering Committee and Investigators Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007;147:1–9. doi: 10.7326/0003-4819-147-1-200707030-00002. [DOI] [PubMed] [Google Scholar]
- 60.Deedwania P, Stone PH, Bairey Merz CN, Cosin-Aguilar J, Koylan N, Luo D, Ouyang P, Piotrowicz R, Schenck-Gustafsson K, Sellier P, Stein JH, Thompson PL, Tzivoni D. Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE) Circulation. 2007;115:700–7. doi: 10.1161/CIRCULATIONAHA.106.654756. [DOI] [PubMed] [Google Scholar]
- 61.Amarenco P, Bogousslavsky J, Callahan A, 3rd, Goldstein LB, Hennerici M, Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA, Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549–59. doi: 10.1056/NEJMoa061894. [DOI] [PubMed] [Google Scholar]
- 62.Aronow WS, Nayak D, Woodworth S, Ahn C. Effect of simvastatin versus placebo on treadmill exercise time until the onset of intermittent claudication in older patients with peripheral arterial disease at six months and at one year after treatment. Am J Cardiol. 2003;92:711–2. doi: 10.1016/s0002-9149(03)00833-6. [DOI] [PubMed] [Google Scholar]
- 63.Rojas-Fernandez CH, Cameron JC. Is Statin-Associated Cognitive Impairment Clinically Relevant? A Narrative Review and Clinical Recommendations. Ann Pharmacother. 2012;46:549–57. doi: 10.1345/aph.1Q620. [DOI] [PubMed] [Google Scholar]
- 64.Austin PC, Mamdani MM, Juurlink DN, Alter DA, Tu JV. Missed opportunities in the secondary prevention of myocardial infarction: an assessment of the effects of statin underprescribing on mortality. Am Heart J. 2006;151:969–75. doi: 10.1016/j.ahj.2005.06.034. [DOI] [PubMed] [Google Scholar]
- 65.Foody JM, Rathore SS, Galusha D, Masoudi FA, Havranek EP, Radford MJ, Krumholz HM. Hydroxymethylglutaryl-CoA reductase inhibitors in older persons with acute myocardial infarction: evidence for an age-statin interaction. J Am Geriatr Soc. 2006;54:421–30. doi: 10.1111/j.1532-5415.2005.00635.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Alexander KP, Blazing MA, Rosenson RS, Hazard E, Aronow WS, Smith SC, Jr, Ohman EM. Management of hyperlipidemia in older adults. J Cardiovasc Pharmacol Ther. 2009;14:49–58. doi: 10.1177/1074248408328927. [DOI] [PubMed] [Google Scholar]
- 67.Roberts CG, Guallar E, Rodriguez A. Efficacy and safety of statin monotherapy in older adults: a meta-analysis. J Gerontol A Biol Sci Med Sci. 2007;62:879–87. doi: 10.1093/gerona/62.8.879. [DOI] [PubMed] [Google Scholar]
- 68.Tomaszewski M, Stępień KM, Tomaszewska J, Czuczwar SJ. Statin-induced myopathies Pharmacol Rep. 2011;63:859–66. doi: 10.1016/s1734-1140(11)70601-6. [DOI] [PubMed] [Google Scholar]
- 69.McKenney JM, Davidson MH, Jacobson TA, Guyton JR, National Lipid Association Statin Safety Assessment Task Force Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006;97:89C–94C. doi: 10.1016/j.amjcard.2006.02.030. [DOI] [PubMed] [Google Scholar]
- 70.Minne L, Ludikhuize J, de Rooij SE, Abu-Hanna A. Characterizing predictive models of 1450 mortality for older adults and their validation for use in clinical practice. J Am Geriatr Soc. 2011;59:1110–5. doi: 10.1111/j.1532-5415.2011.03411.x. [DOI] [PubMed] [Google Scholar]
- 71.European Medicines Agency. Pharmacovigilance Working Party (PhVWP) Assessment Report on the risk:benefit of fibrates. 2010 http:/www.bfarm.de/cae/servlet/contentblob/1019926/publicationFile/79415/fibrate-ar.pdf.
- 72.The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67. doi: 10.1056/NEJMoa1107579. [DOI] [PubMed] [Google Scholar]
- 73.Pearson T, Denke M, McBride P, Battisti WP, Brady WE, Palmisano J. Effectiveness of the addition of ezetimibe to ongoing statin therapy in modifying lipid profiles and attaining low-density lipoprotein cholesterol goals in older and elderly patients: subanalyses of data from a randomized, double-blind, placebo-controlled trial. Am J Geriatr Pharmacother. 2005;3:218–28. [PubMed] [Google Scholar]
- 74.Lavie CJ, Milani RV. Effects of cardiac rehabilitation and exercise training programs in patients ≥ 75 years of age. Am J Cardiol. 1996;78:675–7. doi: 10.1016/s0002-9149(96)00393-1. [DOI] [PubMed] [Google Scholar]
- 75.Scheen AJ. Diabetes mellitus in the elderly: insulin resistance and/or impaired insulin secretion? Diabetes Metab. 2005;31(Spec 2):5S27–25S34. doi: 10.1016/s1262-3636(05)73649-1. [DOI] [PubMed] [Google Scholar]
- 76.Roder ME, Schwartz RS, Prigeon RL, Kahn SE. Reduced pancreatic B cell compensation to the insulin resistance of aging: impact on proinsulin and insulin levels. J Clin Endocrinol Metab. 2000;85:2275–2280. doi: 10.1210/jcem.85.6.6635. [DOI] [PubMed] [Google Scholar]
- 77.Selvin E, Coresh J, Brancati FL. The burden and treatment of diabetes in elderly individuals in the U.S. Diabetes Care. 2006;29:2415–19. doi: 10.2337/dc06-1058. [DOI] [PubMed] [Google Scholar]
- 78.Standards of medical care in diabetes–2011. Diabetes Care. 2011;34(Suppl 1):S11–61. doi: 10.2337/dc11-S011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 79.Bethel MA, Sloan FA, Belsky D, Feinglos MN. Longitudinal incidence and prevalence of adverse outcomes of diabetes mellitus in elderly patients. Arch Intern Med. 2007;167:921–7. doi: 10.1001/archinte.167.9.921. [DOI] [PubMed] [Google Scholar]
- 80.Kalyani RR, Saudek CD, Brancati FL, Selvin E. Association of diabetes, comorbidities, and A1C with functional disability in older adults: results from the National Health and Nutrition Examination Survey (NHANES), 1999–2006. Diabetes Care. 2010;33:1055–60. doi: 10.2337/dc09-1597. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81.Abbatecola AM, Paolisso G. Diabetes care targets in older persons. Diabetes Res Clin Pract. 2009;86:S35–40. doi: 10.1016/S0168-8227(09)70007-5. [DOI] [PubMed] [Google Scholar]
- 82.Bremer JP, Jauch-Chara K, Hallschmid M, Schmid S, Schultes B. Hypoglycemia unawareness in older compared with middle-aged patients with type 2 diabetes. Diabetes Care. 2009;32:1513–1517. doi: 10.2337/dc09-0114. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83.Ryan AS. Insulin resistance with aging: effects of diet and exercise. Sports Med. 2000;30:327–346. doi: 10.2165/00007256-200030050-00002. [DOI] [PubMed] [Google Scholar]
- 84.Wing RR, Hamman RF, Bray GA, Delahanty L, Edelstein SL, Hill JO, Horton ES, Hoskin MA, Kriska A, Lachin J, Mayer-Davis EJ, Pi-Sunyer X, Regensteiner JG, Venditti B, Wylie-Rosett J. Achieving weight and activity goals among diabetes prevention program lifestyle participants. Obes Res. 2004;12:1426–1434. doi: 10.1038/oby.2004.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85.Tonino RP. Effect of physical training on the insulin resistance of aging. Am J Physiol. 1989;256:E352–356. doi: 10.1152/ajpendo.1989.256.3.E352. [DOI] [PubMed] [Google Scholar]
- 86.Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–2572. doi: 10.1056/NEJMoa0802987. [DOI] [PubMed] [Google Scholar]
- 87.Gerstein HC, Miller ME, Byington RP, Goff DC, Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH, Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–2559. doi: 10.1056/NEJMoa0802743. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88.Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–139. doi: 10.1056/NEJMoa0808431. [DOI] [PubMed] [Google Scholar]
- 89.Ismail-Beigi F, Moghissi E, Tiktin M, Hirsch IB, Inzucchi SE, Genuth S. Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med. 2011;154:554–559. doi: 10.7326/0003-4819-154-8-201104190-00007. [DOI] [PubMed] [Google Scholar]
- 90.Lee SJ, Boscardin WJ, Stijacic Cenzer I, Huang ES, Rice-Trumble K, Eng C. The risks and benefits of implementing glycemic control guidelines in frail older adults with diabetes mellitus. J Am Geriatr Soc. 2011;59:666–672. doi: 10.1111/j.1532-5415.2011.03362.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91.Soe K, Sacerdote A, Karam J, Bahtiyar G. Management of type 2 diabetes mellitus in the elderly. Maturitas. 2011;70:151–159. doi: 10.1016/j.maturitas.2011.07.006. [DOI] [PubMed] [Google Scholar]
- 92.Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med. 2008;359:1565–1576. doi: 10.1056/NEJMoa0806359. [DOI] [PubMed] [Google Scholar]
- 93.Gaemperli O, Liga R, Bhamra-Ariza P, Rimoldi O. Nicotine addiction and coronary artery disease. Impact of cessation interventions. Curr Pharm Des. 2010;16:2586–2597. doi: 10.2174/138161210792062894. [DOI] [PubMed] [Google Scholar]
- 94.Critchley JA, Capewell S. Mortality risk reduction associated with smoking cessation in patients with coronary heart disease:a systematic review. JAMA. 2003;290:86–97. doi: 10.1001/jama.290.1.86. [DOI] [PubMed] [Google Scholar]
- 95.Gellert C, Schotker B, Brenner H. Smoking and all-cause mortality in older people. Systematic review and meta-analysis. Arch Int Med. 2012;172:837–44. doi: 10.1001/archinternmed.2012.1397. [DOI] [PubMed] [Google Scholar]
- 96.Hermanson B, Omenn GS, Kronmal RA, Gersh BJ. Beneficial six-year outcome of smoking cessation in older men and women with coronary heart disease. Results from the CASS Registry. N Engl J Med. 1988;319:1365–1369. doi: 10.1056/NEJM198811243192101. [DOI] [PubMed] [Google Scholar]
- 97.Alvarez LR, Balibrea JM, Suriñach JM, Coll R, Pascual MT, Toril J, López-Jiménez L, Monreal M. Smoking cessation and ourtcome in stable outpatients with coronary, cerebrovasvular, or peripheral artery disease. Eur J Cardiovasc Prev Rehab. 2011 Nov 21; doi: 10.1177/1741826711426090. [E-pub ahead of print] [DOI] [PubMed] [Google Scholar]
- 98.Goldenberg I, Jonas M, Tenenbaum A, et al. Current smoking, smoking cessation, anf the risk of sudden cardiac death in patients with coronary artery disease. Arch Intern Med. 2003;163:2301–2305. doi: 10.1001/archinte.163.19.2301. [DOI] [PubMed] [Google Scholar]
- 99.Lee PN, Fry JS. Systematic review of the evidence relating FEV1 decline to giving uo smoking. BMC Med. 2010;8:84. doi: 10.1186/1741-7015-8-84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 100.Lewis WR, Elrodt AG, Peterson E, et al. Trends in the use of evidence-based treatments for coronary artery disease among women and the elderly: findings from the get with the guidelines quality-improvement program. Circ Cardiovasc Qual Outcomes. 2009;2:633–641. doi: 10.1161/CIRCOUTCOMES.108.824763. [DOI] [PubMed] [Google Scholar]
- 101.Chida Y, Steptoe A. The association of anger and hostility with fututure coronary heart disease: a meta analytic review of prospective evidence. J Am Coll Cardiol. 2009;53:936–946. doi: 10.1016/j.jacc.2008.11.044. [DOI] [PubMed] [Google Scholar]
- 102.Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation. 1995;91:999–1005. doi: 10.1161/01.cir.91.4.999. [DOI] [PubMed] [Google Scholar]
- 103.Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosomatic Med. 2004;66:802–813. doi: 10.1097/01.psy.0000146332.53619.b2. [DOI] [PubMed] [Google Scholar]
- 104.Romanelli J, Fauerback JA, Bush DE, Ziegelstein RC. The significance of depression in older patients after myocardial infarction. Am Geriatr Soc. 2002;50:817–822. doi: 10.1046/j.1532-5415.2002.50205.x. [DOI] [PubMed] [Google Scholar]
- 105.Lichtman JH, Bigger JT, Jr, Blumenthal JA, et al. Depression and coronary heart disease. Recommendations for screening, referral, and treatment. Circulation. 2008;118:1768–75. doi: 10.1161/CIRCULATIONAHA.108.190769. [DOI] [PubMed] [Google Scholar]
- 106.Shibeshi WA, Young-Xu Y, Blatt CM. Anxiety worsens prognosis in patients with coronary artery disease. J Am Coll Cardiol. 2007;49:2021–2027. doi: 10.1016/j.jacc.2007.03.007. [DOI] [PubMed] [Google Scholar]
- 107.Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937–952. doi: 10.1016/S0140-6736(04)17018-9. [DOI] [PubMed] [Google Scholar]
- 108.Williams RB, Barefoot JC, Cliff RM, et al. Prognostic importance of social and economic resources among medically treated patients with angiographically documented coronary artery disease. JAMA. 1992;267:520–524. [PubMed] [Google Scholar]
- 109.Berkman LF, Leo-Summer L, Horowitz R. Emotional support and survival after myocardial infarction. Ann Intern Med. 1992;117:1009–1013. doi: 10.7326/0003-4819-117-12-1003. [DOI] [PubMed] [Google Scholar]
- 110.Ho PM, Eng MH, Rumsfeld JS, et al. The influence of age on health status outcomes after acute myocardial infarction. Am Heart J. 2008;155:855–861. doi: 10.1016/j.ahj.2007.11.032. [DOI] [PubMed] [Google Scholar]
- 111.Fitzpatrick AL, Kuller LH, Ives DG, et al. Incidence and prevalence of dementia in the Cardiovascular Health Study. J Am Geriatr Soc. 2004;52:195–204. doi: 10.1111/j.1532-5415.2004.52058.x. [DOI] [PubMed] [Google Scholar]
- 112.Breteler MMB, Claus JJ, Grobbee DE, Hofman A. Cardiovascular disease and distribution of cognitive function in elderly people: the Rotterdam study. BMJ. 1994;308:1604–8. doi: 10.1136/bmj.308.6944.1604. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113.Rees K, Bennett P, West R, Davey SG, Ebrahim S. Psychological interventions for coronary heart disease. Cochrane Database Syst Rev. 2004;(2):CD002902. doi: 10.1002/14651858.CD002902.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114.Writing Committee for the ENRICHD Investigators. Effects of treating depression and low perceived social support on clinical events after myocardial infarction. JAMA. 2003;289:3106–3116. doi: 10.1001/jama.289.23.3106. [DOI] [PubMed] [Google Scholar]
- 115.Glassman AH, O’Connor CM, Califf RM, Swedberg K, Schwartz P, Bigger JT, Jr, Krishnan KR, van Zyl LT, Swenson JR, Finkel MS, Landau C, Shapiro PA, Pepine CJ, Mardekian J, Harrison WM, Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) Group Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002;288:701–709. doi: 10.1001/jama.288.6.701. [DOI] [PubMed] [Google Scholar]
- 116.Mead GE, Morley W, Campbell P, Greig CA, McMurdo M, Lawlor DA. Exercise for depression. Cochrane Database Syst Rev. 2009:CD004. doi: 10.1002/14651858.CD004366.pub4. [DOI] [PubMed] [Google Scholar]
- 117.Blumenthal JA, Babyak MA, Doraiswamy M, Watkins L, Hoffman BM, Barbour KA, Herman S, Craighead WE, Brosse AL, Waugh R, Hinderliter A, Sherwood A. Exercise and pharmacotherapy in the treatment of major depressive disorder. Psychosom Med. 2007;69:587–596. doi: 10.1097/PSY.0b013e318148c19a. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 118.Forman DE, Rich MW, Alexander KP, Zieman S, Maurer MS, Najjar SS, Cleveland JC, Krumholz HM, Wenger NK. White Paper: Current care for older adults: Time for a new paradigm. J Am Coll Cardiol. 2011;57:1801–1810. doi: 10.1016/j.jacc.2011.02.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 119.Fleg JL, Aronow WS, Frishman WH. Cardiovascular drug therapy in the elderly: benefits and challenges. Nat Rev Cardiol. 2011;8:13–28. doi: 10.1038/nrcardio.2010.162. [DOI] [PubMed] [Google Scholar]
- 120.Tinetti ME, Bogardus ST, Jr, Agostini JV. Potential pitfalls of disease-specific guidelines for patients with multiple conditions. N Engl J Med. 2004;351:2870–4. doi: 10.1056/NEJMsb042458. [DOI] [PubMed] [Google Scholar]
- 121.Setoguchi S, Glynn RJ, Avorn J, Levin R, Winkelmayer WC. Ten-year trends of cardiovascular drug use after myocardial infarction among community-dwelling persons >65 years of age. Am J Cardiol. 2007;100:1061–1067. doi: 10.1016/j.amjcard.2007.04.052. [DOI] [PubMed] [Google Scholar]
- 122.Nguyen HL, Goldberg RJ, Gore JM, Fox KA, Eagle KA, Gurfinkel EP, Spencer FA, Reed G, Quill A, Anderson FA., Jr Age and sex differences, and changing trends, in the use of evidence- based therapies in acute coronary syndromes: perspectives from a multinational registry. Coron Artery Dis. 2010;21:336–344. doi: 10.1097/MCA.0b013e32833ce07c. [DOI] [PubMed] [Google Scholar]
- 123.Opotowsky AR, McWilliams JM, Cannon CP. Gender differences in aspirin use among adults with coronary heart disease in the United States. J Gen Int Med. 2007;22:55–61. doi: 10.1007/s11606-007-0116-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 124.van Staveren WA, deGrout LC. Evidence-based dietary guidance and the role of dairy products for appropriate nutrition in the elderly. J Am Coll Nutr. 2011;30(Suppl 1):429S–437S. doi: 10.1080/07315724.2011.10719987. [DOI] [PubMed] [Google Scholar]
- 125.Volkert D, Sieber CC. Protein requirements in the elderly. Int J Vitam Nutr Res. 2011;81:109–119. doi: 10.1024/0300-9831/a000061. [DOI] [PubMed] [Google Scholar]
- 126.McNaughton SA, Bates CJ, Mishra CD. Diet quality is associated with all-cause mortality in adults aged 65 years and older. J Nutr. 2012;142:320–325. doi: 10.3945/jn.111.148692. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 127.Jjogren P, Becker W, Wavengo E, et al. Mediterranean and carbohydrate-restricted diets and mortality among elderly men: a cohort study in Sweden. Am J Clin Nutr. 2010;92:967–974. doi: 10.3945/ajcn.2010.29345. [DOI] [PubMed] [Google Scholar]
- 128.McCullough ML, Peterson JJ, Patel R, Jacques PF, Shah R, Dwyer JT. Flavenoid intake and cardiovascular disease mortality in a prospective cohort of US adults. Am J Clin Nutr. 2012;95:454–64. doi: 10.3945/ajcn.111.016634. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 129.Lavie CJ, Lee JH, Milani RV. Vitamin D and cardiovascular disease. Will it live up to its hype? J Am Coll cardiol. 2011;58:1547–1556. doi: 10.1016/j.jacc.2011.07.008. [DOI] [PubMed] [Google Scholar]
- 130.Kestenbaum B, Katz R, deBoer I, et al. Vitamin D, parathyroid hormone, and cardiovascular events among older adults. J Am Coll Cardiol. 2011;58:1433–1441. doi: 10.1016/j.jacc.2011.03.069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 131.Ginde AA, Scragg R, Schwartz RS, Camargo CA., Jr Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults. J Am Geriatr Soc. 2009;57:1595–1603. doi: 10.1111/j.1532-5415.2009.02359.x. [DOI] [PubMed] [Google Scholar]
- 132.Kromhout D, Giltay EJ, Geleijnse JM, Alpha Omega Trial Group N-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010;363:2015–2026. doi: 10.1056/NEJMoa1003603. [DOI] [PubMed] [Google Scholar]
- 133.Buhr G, Bales CW. Nutritional supplements for older adults: review and recommendations-Part II. J Nutr Elder. 2010;29:42–71. doi: 10.1080/01639360903586464. [DOI] [PubMed] [Google Scholar]
- 134.Bauman AE. Updating the evidence that physical activity is good for health: an epidemiological review 2000–2003. J Sci Med Sport. 2004;7:6–19. doi: 10.1016/s1440-2440(04)80273-1. [DOI] [PubMed] [Google Scholar]
- 135.Hamilton MT, Hamilton DG, Zderic TW. Role of low energy expenditure and sitting in obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Diabetes. 2007;56:2655–2667. doi: 10.2337/db07-0882. [DOI] [PubMed] [Google Scholar]
- 136.Morris JN, Heady JA, Raffle PA, Roberts CG, Parks JW. Coronary heart disease and physical activity of work (parts 1 and 2) Lancet. 1953;265:1053–7. 1111–20. doi: 10.1016/s0140-6736(53)90665-5. [DOI] [PubMed] [Google Scholar]
- 137.Thompson PD, Buchner D, Pina IL, Balady GJ, Williams MA, Marcus BH, Berra K, Blair SN, Costa F, Franklin B, Fletcher GF, Gordon NF, Pate RR, Rodriguez BL, Yancey AK, Wenger NK. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity) Circulation. 2003;107:3109–3116. doi: 10.1161/01.CIR.0000075572.40158.77. [DOI] [PubMed] [Google Scholar]
- 138.Physical Activity Guidelines Advisory Committee. Physical Activity Guidelines Committee Report. Washington, DC: US Department of Health and Human Services; 2008. 2008. [Google Scholar]
- 139.OIder Americans. Key indicators of well-being. 2012 http://www.agingstats.gov.
- 140.Patel AV, Bernstein L, Deka A, Feigelson S, Campbell PT, Gapstur SM, Colditz GA, Thun MJ. Leisure time spent sitting in relation to total mortality in a prospective cohort of US adults. Am J Epidemiol. 2010;172:419–429. doi: 10.1093/aje/kwq155. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 141.Fleg JL. Aerobic exercise in the elderly: a key to successful aging. Discovery Medicine. 2012;13:223–228. [PubMed] [Google Scholar]
- 142.Hakim AA, Curb JD, Ptrovitch H, et al. Effects of walking on coronary heart disease in elderly men: the Honolulu Heart Program. Circulation. 1999;100:9–13. doi: 10.1161/01.cir.100.1.9. [DOI] [PubMed] [Google Scholar]
- 143.Abbott RD, White LR, Curb JD, et al. walking and dementia in physically capable elderly men. JAMA. 2004;292:1447–1453. doi: 10.1001/jama.292.12.1447. [DOI] [PubMed] [Google Scholar]
- 144.Landi F, Abbatecola AM, Provinciali M, Corsonello, Bustacchini S, Manigrasso L, Cherubini A, Bernabei R, Lattanzio F. Moving against frailty: does physical activity matter? Biogerontology. 2010;11:537–545. doi: 10.1007/s10522-010-9296-1. [DOI] [PubMed] [Google Scholar]
- 145.Stewart KJ, Ratchford EV, Williams MA. Exercise for restoring health and preventing vascular disease. In: Blumenthal RS, Foody JM, Wong ND, editors. Preventive Cardiology. Elsevier; Philadelphia: 2011. pp. 541–551. [Google Scholar]
- 146.Listerman J, Bittner V, Sanderson BK, Brown TM. Cardiac rehabilitation outcomes: Impact of cormorbidities and age. J Cardiopulm Rehabil Prev. 2011;31:342–348. doi: 10.1097/HCR.0b013e31822f189c. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 147.Lavie CJ, Milani RV. Benefits of cardiac rehabilitation in the elderly. Chest. 2004;126:1010–1012. doi: 10.1378/chest.126.4.1010. [DOI] [PubMed] [Google Scholar]
- 148.Goel K, Shen J, Wolter AD, et al. Prevalence of musculoskeletal and balance disorders in patients enrolled in phase II cardiac rehabilitation. J Cardiopulm Rehabil Prev. 2010;30:235–239. doi: 10.1097/HCR.0b013e3181e17387. [DOI] [PubMed] [Google Scholar]
- 149.American College of Sports Medicine. ACSM’s Guidelines for Exercise Testing and Prescription. 8. Lippincott: Williams Wilkens, Philadelphia; 2010. pp. 207–224. [Google Scholar]
- 150.Audelin MC, Savage PD, Ades PA. Exercise-based cardiac rehabilitation for very old patients (≥75 years): Focus on physical function. J Cardiopulm Rehabil Prev. 2008;28:163–173. doi: 10.1097/01.HCR.0000320066.58599.e5. [DOI] [PubMed] [Google Scholar]
- 151.Fletcher GF, Ades PA, Kligfield P, Arena R, Balady GJ, Bittner VA, Coke LA, Fleg JL, Forman DE, Gerber TC, Gulati M, Madan K, Rhodes J, Thompson PD, Williams MA, on behalf of the American Heart Association Exercise, Cardiac Rehabilitation, and Prevention Committee of the Council on Clinical Cardiology, Council on Nutrition, Physical Activity and Metabolism, Council on Cardiovascular and Stroke Nursing, and Council on Epidemiology and Prevention Exercise standards for testing and training: a scientific statement from the American Heart Association. Circulation. 2013;128:873–934. doi: 10.1161/CIR.0b013e31829b5b44. [DOI] [PubMed] [Google Scholar]
- 152.Kemi OJ, Wisløff U. High-intensity aerobic exercise training improves the heart inhealth and disease. J Cardiopulm Rehabil Prev. 2010;30:2–11. doi: 10.1097/HCR.0b013e3181c56b89. [DOI] [PubMed] [Google Scholar]
- 153.Suaya JA, Stason WB, Ades PA, Normand SLT, Shepard DS. Cardiac rehabilitation and survival in older coronary patients. J Am Coll Cardiol. 2009;54:25–33. doi: 10.1016/j.jacc.2009.01.078. [DOI] [PubMed] [Google Scholar]
- 154.Suaya JA, Shepard DS, Normand SL, et al. Use of cardiac rehabilitation by Medicare beneficiaries after myocardial infarction or coronary bypass surgery. Circulation. 2007;116:1653–1662. doi: 10.1161/CIRCULATIONAHA.107.701466. [DOI] [PubMed] [Google Scholar]
- 155.Grace SL, Russell KL, Reid Rd, et al. effect of cardiac rehabilitation referral strategies on utilization rates: a prospective, controlled study. Arch Int Med. 2011;171:235–241. doi: 10.1001/archinternmed.2010.501. [DOI] [PubMed] [Google Scholar]
- 156.Weingarten MN, Salz KA, Thomas RJ, Squires RW. Rates of enrollment for men and women referred to outpatient cardiac rehabilitation. J Cardiopulm Rehabil Prev. 2011;31:217–222. doi: 10.1097/HCR.0b013e318207d2fa. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 157.Valencia HE, Savage PD, Ades PA. Cardiac rehabilitation participation in underserved populations. J Cardiopulm Rehabil Prev. 2011;31:203–210. doi: 10.1097/HCR.0b013e318220a7da. [DOI] [PubMed] [Google Scholar]
- 158.Singh M, Peterson ED, Roe MT, Ou FS, Spertus JA, Rumsfeld JS, Anderson HV, Klein LW, Ho KK, Holmes DR. Trends in the association between age and in-hospital mortality after percutaneous coronary intervention: National Cardiovascular Data Registry experience. Circ Cardiovasc Interv. 2009;2:20–26. doi: 10.1161/CIRCINTERVENTIONS.108.826172. [DOI] [PubMed] [Google Scholar]
- 159.Pfisterer M. Long-term outcome in elderly patients with chronic angina managed invasively versus by optimized medical therapy: four-year follow-up of the randomized Trial of Invasive versus Medical therapy in Elderly patients (TIME) Circulation. 2004;110:1213–1218. doi: 10.1161/01.CIR.0000140983.69571.BA. [DOI] [PubMed] [Google Scholar]
- 160.Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS. COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503–1516. doi: 10.1056/NEJMoa070829. [DOI] [PubMed] [Google Scholar]
- 161.Maganti M, Rao V, Brister S, Ivanov J. Decreasing mortality for coronary artery bypass surgery in octogenarians. Can J Cardiol. 2009;25:e32–35. doi: 10.1016/s0828-282x(09)70481-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 162.Newman MF, Kirchner JL, Phillips-Bute B, Gaver V, Grocott H, Jones RH, Mark DB, Reves JG, Blumenthal JA, Neurological Outcome Research Group and the Cardiothoracic Anesthesiology Research Endeavors Investigators Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med. 2001;344:395–402. doi: 10.1056/NEJM200102083440601. [DOI] [PubMed] [Google Scholar]
- 163.The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med. 1996;335:217–225. doi: 10.1056/NEJM199607253350401. [DOI] [PubMed] [Google Scholar]
- 164.McKellar SH, Brown ML, Frye RL, Schaff HV, Sundt TM., 3rd Comparison of coronary revascularization procedures in octogenarians: a systematic review and meta-analysis. Nat Clin Pract Cardiovasc Med. 2008;5:738–746. doi: 10.1038/ncpcardio1348. [DOI] [PubMed] [Google Scholar]
- 165.Hlatky MA, Boothroyd DB, Bravata DM, Boersma E, Booth J, Brooks MM, Carrie D, Clayton TC, Danchin N, Flather M, Hamm CW, Hueb WA, Kahler J, Kelsey SF, King SB, Kosinski AS, Lopes N, McDonald KM, Rodriguez A, Serruys P, Sigwart U, Stables RH, Owens DK, Pocock SJ. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet. 2009;373:1190–1197. doi: 10.1016/S0140-6736(09)60552-3. [DOI] [PubMed] [Google Scholar]
- 166.Weintraub WS, Grau-Sepulveda MV, Weiss JM, O’Brien SM, Peterson ED, Kolm P, Zhang Z, Klein LW, Shaw RE, McKay C, Ritzenthaler L, Popma JJ, Messenger JC, Shahian DM, Grover FL, Mayer JE, Shewan CM, Garratt KN, Moussa ID, Dangas GD, Edwards FH. Comparative effectiveness of revascularization strategies. N Engl J Med. 2012;366:1467–1476. doi: 10.1056/NEJMoa1110717. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 167.Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith SC, Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death) Circulation. 2006;114:e385–e484. doi: 10.1161/CIRCULATIONAHA.106.178233. [DOI] [PubMed] [Google Scholar]
- 168.Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA, 3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Smith SC, Jr, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato JP, Riegel B, Tarkington LG, Yancy CW. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices) Circulation. 2008;117:e350–408. doi: 10.1161/CIRCUALTIONAHA.108.189742. [DOI] [PubMed] [Google Scholar]
- 169.Anonymous. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhythmics Versus Implantable Defibrillators (AVID) investigators. New England Journal of Medicine. 1997;337:1576–1583. doi: 10.1056/NEJM199711273372202. [DOI] [PubMed] [Google Scholar]
- 170.Connolly SJ, Gent M, Roberts RS, Dorian P, Roy D, Sheldon RS, Mitchell LB, Green MS, Klein GJ, O’Brien B. Canadian Implantable Defibrillator Study (CIDS) : A randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation. 2000;101:1297–1302. doi: 10.1161/01.cir.101.11.1297. [DOI] [PubMed] [Google Scholar]
- 171.Kuck KH, Cappato R, Siebels J, Ruppel R. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest : The Cardiac Arrest Study Hamburg (CASH) Circulation. 2000;102:748–754. doi: 10.1161/01.cir.102.7.748. [DOI] [PubMed] [Google Scholar]
- 172.Connolly SJ, Hallstrom AP, Cappato R, Schron EB, Kuck KH, Zipes DP, Greene HL, Boczor S, Domanski M, Follmann D, Gent M, Roberts RS. Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics Versus Implantable Defibrillator study. Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study. Eur Heart J. 2000;21:2071–2078. doi: 10.1053/euhj.2000.2476. [DOI] [PubMed] [Google Scholar]
- 173.Healey JS, Hallstrom AP, Kuck KH, Nair G, Schron EP, Roberts RS, Morillo CA, Connolly SJ. Role of the implantable defibrillator among elderly patients with a history of life-threatening ventricular arrhythmias. Eur Heart J. 2007;28:1746–1749. doi: 10.1093/eurheartj/ehl438. [DOI] [PubMed] [Google Scholar]
- 174.Jahangir A, Bradley DJ, Shen WK. Icds for secondary prevention of sudden death in the older-elderly. Eur Heart J. 2007;28:1665–1667. doi: 10.1093/eurheartj/ehl549. [DOI] [PubMed] [Google Scholar]
- 175.Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, Levine JH, Saksena S, Waldo AL, Wilber D, Brown MW, Heo M. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial investigators. N Engl J Med. 1996;335:1933–1940. doi: 10.1056/NEJM199612263352601. [DOI] [PubMed] [Google Scholar]
- 176.Bigger JT., Jr Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch trial investigators. N Engl J Med. 1997;337:1569–1575. doi: 10.1056/NEJM199711273372201. [DOI] [PubMed] [Google Scholar]
- 177.Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia trial investigators. N Engl J Med. 1999;341:1882–1890. doi: 10.1056/NEJM199912163412503. [DOI] [PubMed] [Google Scholar]
- 178.Hohnloser SH, Kuck KH, Dorian P, Roberts RS, Hampton JR, Hatala R, Fain E, Gent M, Connolly SJ. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med. 2004;351:2481–2488. doi: 10.1056/NEJMoa041489. [DOI] [PubMed] [Google Scholar]
- 179.Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877–883. doi: 10.1056/NEJMoa013474. [DOI] [PubMed] [Google Scholar]
- 180.Croft JB, Giles WH, Pollard RA, Keenan NL, Casper ML, Anda RF. Heart failure survival among older adults in the United States: A poor prognosis for an emerging epidemic in the Medicare population. Arch Intern Med. 1999;159:505–510. doi: 10.1001/archinte.159.5.505. [DOI] [PubMed] [Google Scholar]
- 181.Kong MH, Al-Khatib SM, Sanders GD, Hasselblad V, Peterson ED. Use of implantable cardioverter-defibrillators for primary prevention in older patients: A systematic literature review and meta-analysis. Cardiol J. 2011;18:503–514. doi: 10.5603/cj.2011.0005. [DOI] [PubMed] [Google Scholar]
- 182.Hammill SC, Kremers MS, Stevenson LW, Heidenreich PA, Lang CM, Curtis JP, Wang Y, Berul CI, Kadish AH, Al-Khatib SM, Pina IL, Walsh MN, Mirro MJ, Lindsay BD, Reynolds MR, Pontzer K, Blum L, Masoudi F, Rumsfeld J, Brindis RG. Review of the registry’s fourth year, incorporating lead data and pediatric ICD procedures, and use as a national performance measure. Heart Rhythm. 2010;7:1340–1345. doi: 10.1016/j.hrthm.2010.07.015. [DOI] [PubMed] [Google Scholar]
- 183.Epstein AE, Kay GN, Plumb VJ, McElderry HT, Doppalapudi H, Yamada T, Shafiroff J, Syed ZA, Shkurovich S. Implantable cardioverter-defibrillator prescription in the elderly. Heart Rhythm. 2009;6:1136–1143. doi: 10.1016/j.hrthm.2009.04.010. [DOI] [PubMed] [Google Scholar]
- 184.Swindle JP, Rich MW, McCann P, Burroughs TE, Hauptman PJ. Implantable cardiac device procedures in older patients: Use and in-hospital outcomes. Arch Int Med. 2010;170:631–637. doi: 10.1001/archinternmed.2010.30. [DOI] [PubMed] [Google Scholar]
- 185.Van Den Broek KC, Heijmans N, Van Assen MA. Anxiety and Depression in Patients with an Implantable Cardioverter Defibrillator and Their Partners: A Longitudinal Study. Pacing Clin Electrophysiol. 2012 Dec 17; doi: 10.1111/pace.12055. [Epub ahead of print] [DOI] [PubMed] [Google Scholar]
- 186.Lampert R, Hayes DL, Annas GJ, Farley MA, Goldstein NE, Hamilton RM, Kay GN, Kramer DB, Mueller PS, Padeletti L, Pozuelo L, Schoenfeld MH, Vardas PE, Wiegand DL, Zellner R. Heart Rhythm Society Expert Consensus Statement on the Management of Cardiovascular Implantable Electronic Devices (CIEDs) in patients nearing end of life or requesting withdrawal of therapy. Heart Rhythm. 2010;7:1008–1026. doi: 10.1016/j.hrthm.2010.04.033. [DOI] [PubMed] [Google Scholar]
- 187.Miettinen TA, Pyörälä K, Olsson AG, Musliner TA, Cook TJ, Faergeman O, Berg K, Pedersen T, Kjekshus J. Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study (4S) Circulation. 1997;96:4211–8. doi: 10.1161/01.cir.96.12.4211. [DOI] [PubMed] [Google Scholar]
- 188.No authors cited. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349–57. doi: 10.1056/NEJM199811053391902. [DOI] [PubMed] [Google Scholar]
- 189.Lewis SJ, Moye LA, Sacks FM, Johnstone DE, Timmis G, Mitchell J, Limacher M, Kell S, Glasser SP, Grant J, Davis BR, Pfeffer MA, Braunwald E. Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial. Ann Intern Med. 1998;129:681–9. doi: 10.7326/0003-4819-129-9-199811010-00002. [DOI] [PubMed] [Google Scholar]