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Epidemiology and Risk Factors
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The American Heart Association reports that 20% of men and 10% of women between 60 and 79 years of age have ischemic heart disease (IHD), and approximately half of these patients have experienced a previous MI.1 These proportions increase markedly with age, such that one of every four individuals aged 80 years and older has clinically evident CAD. In autopsy studies, the prevalence of obstructive coronary atherosclerosis increased from 10% to 20% for patients in their 40s to 50% to 70% among patients in their 80s.92 In patients referred for CABG in a large clinical trial, older age was associated with more diffuse coronary atherosclerosis, substantially higher rates of left main and triple-vessel disease, and greater degrees of left ventricular wall motion abnormalities and systolic dysfunction.93 In the United States, the average age of first MI is 65 years for men and 72 years for women, with approximately 80% of all coronary-related deaths occurring in the Medicare-aged population.1 Furthermore, nearly half of the 7 million deaths attributed to IHD across the globe each year occur in the small subgroup of patients ≥ 80 years old.3 For these reasons, a thorough understanding of the nuances in patient presentation, prognosis, and management of IHD among elderly patients is imperative for treating acute and chronic CAD in daily clinical practice.
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Risk assessment is the cornerstone of CVD management, and multiple studies have demonstrated the prominent role of age in predicting adverse outcomes in patients with IHD. For example, increasing age is the strongest predictor of IHD events in the Framingham Risk Score,94 and the impact of age on IHD risk is substantially greater than for other traditional risk factors, such as hypertension, smoking, or lipid profiles. Similarly, in updated algorithms such as the Reynolds Risk Score, age provides nearly threefold more statistical weight to the final risk estimate than any other risk factor.95,96 Older age also consistently identifies patients at higher risk for short-term clinical events after acute coronary syndrome (ACS), as noted in the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk models espoused by national guidelines.97,98 For example, age ≥ 80 years has nearly twice the prognostic significance in the GRACE ACS algorithm (91-100 points) than any other risk factor (46-59 points for the most severe clinical presentations, including profound hypotension or tachycardia, pulmonary edema, cardiac arrest, or renal failure).99
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Taken together, the structural and functional changes that occur with increasing age, along with the increasing prevalence of most atherosclerotic risk factors and a progressively sedentary lifestyle, all contribute to higher likelihood of developing IHD with increasing age. Furthermore, subclinical cardiovascular and other medical diseases are highly prevalent among older patients.100 As a result, older patients with IHD often present later and with more severe disease, resulting in substantially higher risks of adverse outcomes.
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Clinical Presentation
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Typical angina has been described most often in cohorts of middle-aged patients, the majority of whom are male and white. However, older patients with acute MI are more likely to be female and to present with dyspnea, nausea, diaphoresis, altered mental status, or other nonspecific symptoms such as malaise and fatigue (Fig. 65–5).5,101,102,103 As a result, the proportion of patients presenting with typical angina decreases with age, which makes the diagnosis of ACS more challenging and often more delayed than in younger individuals. Reduced functional capacity, competing diagnoses with similar symptoms (eg, chronic lung disease or indigestion), and cognitive impairment may further obscure the diagnosis.
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Although physical examination has limited utility for the diagnosis of IHD at all ages, the delayed recognition of ACS in elderly patients likely contributes to the higher proportion of patients with more advanced disease and complications at presentation, including signs of pulmonary edema or cardiogenic shock.5,101 Other findings of more advanced IHD in elderly ACS patients may include altered mental status or confusion, rales, tachycardia, hypoxia, jugulovenous distension, or peripheral edema. Electrocardiographic diagnosis of ACS may be confounded by pre-existing electrical abnormalities, including left bundle branch block, left ventricular hypertrophy, prior MI, repolarization changes from antiarrhythmic drugs, or the presence of ventricular paced rhythm5,104—again contributing to later recognition of MI in older patients.
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Complications of Acute Myocardial Infarction
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In conjunction with age-related differences in clinical presentation, increasing age is associated with higher complication rates after MI, including striking increases in short-term mortality after age 65 years (Fig. 65–6).101,102,105,106 This increase in risk with age has been demonstrated for both ST-segment elevation MI (STEMI)107,108,109 and for non–ST-segment elevation ACS (NSTE-ACS).99,110,111 Of note, quantifiable indices of MI size, such as peak biomarkers or severity of electrocardiographic changes at presentation, are not substantially different between younger and older patients.102,107,109 Nonetheless, older patients experience markedly higher rates of HF, AF, and cardiogenic shock, which in part reflects age-related cardiovascular changes and diminished cardiovascular reserve.107,111
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With improvements in short-term survival following acute MI during the coronary reperfusion era, postinfarction HF affects a large proportion of elderly ACS patients and is associated with poor outcomes112 (see Chaps. 39 and 42). Right ventricular ischemia or infarction in patients with inferior STEMI is associated with particularly high mortality in elderly patients.113 Mechanical complications of acute MI (eg, left ventricular free wall rupture, papillary muscle dysfunction with acute mitral regurgitation, ventricular septal rupture, left ventricular aneurysm or pseudoaneurysm formation) have declined in frequency during the reperfusion era, but older age continues to be a risk factor for developing each of these potentially life-threatening complications.114 Electrical events also occur more commonly in older populations, particularly AF and heart block, perhaps as a result of having more extensive CAD and left ventricular dysfunction at the time of ACS presentation.
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Overall, the mechanisms underlying worse outcomes among older ACS patients are likely independent of the acute coronary occlusion itself, but instead are related to pathophysiologic changes with age, greater severity of CAD and left ventricular dysfunction at the time of diagnosis, and concomitant medical comorbidities and frailty. Additional aging processes, such as diminished collateral circulation to occluded coronary arteries and lower number and lesser function of endothelial progenitor cells to facilitate myocardial recovery after MI, also contribute to adverse outcomes in older patients.115,116,117
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Pharmacologic Considerations in Older Patients
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Older patients, women, and racial/ethnic minorities have been under-represented in randomized clinical trials of ACS therapies,118 despite the high incidence of ACS in the elderly119 and substantially worse outcomes among older patients.101 In general, elderly patients have more advanced atherosclerotic risk factors, more prolonged exposure to these risk factors, and multiple other medical problems that may impact the benefits and risks of all interventions, both pharmacologic and nonpharmacologic. Older patients are also more likely to present with NSTE-ACS than STEMI, which may significantly impact initial therapy.101,102,106 A large proportion of ACS presentations in older adults is caused by supply-demand mismatch in the setting of fixed coronary obstruction (ie, type II MI according to the World Health Organization classification).120 In these cases, there may be less benefit from anticoagulation therapies as a result of lack of intracoronary thrombus. Thus, treatment of older patients with NSTE-ACS often requires greater focus on the underlying factors precipitating the event, such as infection, uncontrolled hypertension, anemia, tachycardia, or other systemic insults (eg, noncardiac surgery, thyroid disease, cancer).5 Conversely, the value of aggressive pharmacologic and invasive management in this population is less well established.
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In the largest randomized comparison of aspirin versus placebo in patients with suspected acute STEMI, the benefit of aspirin increased with increasing age, from 1% absolute reduction in 5-week vascular mortality for patients younger than 60 years of age, to 4.7% absolute reduction among patients ≥ 70 years old.121 More than a decade later, clopidogrel was shown to reduce the composite end point of MI, stroke, or cardiovascular death by 20% when added to aspirin for 1 year after ACS, with similar benefits among patients older or younger than 65 years of age.122 Subsequently, prasugrel and ticagrelor were each compared with clopidogrel and demonstrated additional benefits for ACS patients. However, these more potent antiplatelet therapies had disparate effects on elderly patients. Specifically, prasugrel reduced recurrent MI more effectively than clopidogrel in patients younger than 75 years of age,123 but there was loss of benefit for patients aged ≥ 75 years and a significant increase in major bleeding complications (including intracranial hemorrhage) in this age group. In contrast, ticagrelor reduced recurrent MI and cardiovascular death when compared with clopidogrel during the first year after ACS, and ticagrelor was not associated with higher bleeding rates in the elderly. However, there was a somewhat attenuated benefit among the 15% of the 18,000 trial participants older than 75 years.124,125 In a follow-up trial evaluating ticagrelor versus placebo in patients with prior MI, the 12% of the trial patients ≥ 75 years old had similar benefits and bleeding risks as the overall trial population.126
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An additional medication, vorapaxar, was recently approved in the United States for patients with prior MI (> 2 weeks previously) or peripheral arterial disease at high risk of ischemic events. In a large trial, vorapaxar added to aspirin and clopidogrel reduced thrombotic events but was associated with higher bleeding rates.127 Because most patients with recent MI are already treated with aspirin and another oral antiplatelet medication, the principal role for vorapaxar in the geriatric population may be in select patients with peripheral arterial disease at low risk of bleeding.
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The role of intravenous antiplatelet therapy in ACS is more difficult to define, both for younger and older patients. Glycoprotein IIb/IIIa inhibitors appear to reduce reinfarction and overall infarct size at the time of NSTE-ACS, with patients at higher risk deriving the most benefit, but few studies have enrolled patients aged > 75 years, and the risk of bleeding complications increases with age.5,128 One study of ACS patients demonstrated higher event rates in octogenarians randomized to glycoprotein IIb/IIIa inhibitor therapy,129 and current guidelines recommend avoiding these medications entirely in the setting of fibrinolytic therapy for STEMI in patients ≥ 75 years of age.98 Because these drugs are associated with greater bleeding risks in the elderly, use of glycoprotein IIb/IIIa inhibitors should probably be limited to select older individuals with high thrombosis risk and low bleeding risk. The intravenous platelet inhibitor cangrelor has a different mechanism of action than the glycoprotein IIb/IIIa inhibitors, and clinical trials evaluating cangrelor demonstrated similar benefits among patients older and younger than age 75 years.130 However, the magnitude of bleeding risk associated with cangrelor remains unclear131; thus, the safety of this drug in elderly patients requires further study.
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Duration of Oral Antiplatelet Therapy
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In recent years, multiple studies have demonstrated benefit from continuing dual antiplatelet therapy beyond the first year after acute MI.126,132 However, the risk of bleeding during long-term therapy must be carefully weighed against the diminishing anti-ischemic benefit beyond the first year. For example, in the largest randomized trial to date evaluating prolonged dual antiplatelet therapy after drug-eluting stent placement, approximately 10% of the 10,000 study patients were ≥ 75 years old.133 These individuals appeared to have somewhat less benefit, but also lower bleeding rates, than the overall study population during the 18 additional months of clopidogrel therapy (perhaps representing a selection bias for enrolling “healthier” elderly patients eligible for prolonged antiplatelet therapy). Although the optimal duration of dual antiplatelet therapy requires further study, at present, it seems reasonable to limit extended use beyond 1 year to elderly patients with prior MI at lower risk of bleeding.
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Antithrombotic Therapy
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Intravenous unfractionated heparin has been a standard ACS therapy for decades, but recent guidelines have espoused the use of enoxaparin, bivalirudin, and related compounds as alternatives to heparin.97,98 Although these newer agents appear to provide more predictable or better targeted antithrombotic activity than heparin, nearly all of them are cleared through renal mechanisms. This is problematic in elderly ACS patients, given the age-related decline in renal function, thus contributing to the substantially higher risks of bleeding with age.134,135 Despite these risks, older and younger subjects in clinical trials derived similar benefits from the newer antithrombotic therapies.136,137 Thus, these agents appear to be reasonable choices as long as dosing is carefully adjusted to account for renal function, weight, and other factors (eg, frailty) in the elderly.
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Long-term oral antithrombotic medication (eg, warfarin, apixaban, rivaroxaban, dabigatran, edoxaban) in combination with dual antiplatelet therapy further increases bleeding risks, especially in older patients. Because the prevalence of AF, heart valve replacement, venous thromboembolism, and other indications for anticoagulation increases with age, the dilemma of “triple therapy” becomes more common when treating older patients with IHD. In an observational study, nearly 5000 older patients with AF undergoing percutaneous coronary intervention (PCI) for acute MI had substantially higher rates of major bleeding with triple therapy (vs those receiving dual antiplatelet therapy alone), with no difference in ischemic events.138 The concept of temporarily withholding aspirin is controversial and requires further study, but it appears to be a reasonable option for elderly patients at higher risk of bleeding. Alternatively, bare metal stents may be considered for these higher risk individuals,139,140 particularly when performing PCI for stable coronary disease, to provide shorter exposure to triple therapy (acknowledging that the risk of restenosis is higher with bare metal stents).
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As noted previously, older patients with acute MI often present later, with a greater burden of medical comorbidities, and with more extensive complications from the infarct. Increasing age is also associated with higher risk of complications from β-blocker therapy, including hypotension, bradycardia, HF, and cardiogenic shock.141 Nonetheless, when administered judiciously, β-blockers reduce mortality, recurrent ischemia, and arrhythmias in acute MI, and the 23% reduction in mortality among elderly patients (in a pooled analysis of multiple β-blocker trials) was significantly greater than the effect in younger patients.5 The same analysis demonstrated 6 lives saved per 100 older patients treated, whereas younger patients had only 2 lives saved per 100 treated. Furthermore, subgroup analyses from β-blocker trials suggest that the majority of the long-term survival benefit after MI occurs in patients aged ≥ 65 years.142,143 However, all of these studies were conducted prior to the reperfusion era, and the value of early β-blocker therapy in contemporary practice is less clear. To minimize side effects and complications associated with β-blocker therapy in the elderly, these drugs should be started at low doses and titrated slowly,5,98 and immediate intravenous β-blocker injection should be avoided in most elderly MI patients.141
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Angiotensin and Aldosterone Inhibitors
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A large meta-analysis of ACEI therapy for acute MI confirmed a significant reduction in mortality for older patients, particularly for those aged 65 to 74 years.144 The absolute benefit of ACEI was nearly three times greater for older patients than for younger patients, with most trials demonstrating 17% to 34% relative risk reductions in the geriatric subgroups.145,146,147 ARBs are reasonable alternatives to ACEIs in HF, but ACEIs are the preferred agents after acute MI in both younger and older populations.148 Because most of the benefits occur in MI patients with HF or left ventricular systolic dysfunction,144 more judicious use of these medications may be warranted in elderly patients with preserved systolic function. Both ACEIs and ARBs must be titrated carefully in older individuals, as the risk of medication-induced hypotension, renal failure, and hyperkalemia increases with age and comorbidity burden.
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The MRAs spironolactone and eplerenone reduce fibrosis and adverse remodeling after myocardial injury.149,150 In patients with acute MI and left ventricular dysfunction or HF treated with MRAs, those older or younger than 65 years of age experience similar reductions in morbidity and mortality.151 However, an analysis from Canada demonstrated much higher rates of hospitalization for hyperkalemia and renal failure after the widespread adoption of spironolactone for treating HF.152 Thus, given the increased prevalence of renal dysfunction in the geriatric population, the use of MRAs in elderly individuals requires meticulous monitoring of serum creatinine and potassium levels.
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In the absence of major contraindications, statins are indicated for all patients with established vascular disease, and particularly those with IHD or prior ACS.97,98,104,153 Numerous studies have confirmed the benefits of statins in older patients,154,155,156,157 although few patients over 80 years of age have been enrolled in clinical trials.158,159 Because elderly individuals are at increased risk for myalgias, fatigue, and both functional and cognitive impairment related to statin therapy,160,161,162,163 older patients should be monitored for these adverse drug effects. In addition, the use of statins in patients of advanced age should consider life expectancy, overall cardiovascular risk, and patient preferences. Nonetheless, the greatest benefits from statins occur in high-risk patients following vascular events,164 so statins are indicated in almost all older patients with established IHD and life expectancy of at least 1 to 2 years (although lower doses may be considered).
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Other Anti-Ischemic Medications
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Nitrates, calcium channel blockers, morphine, and other anti-ischemic medications have not reduced mortality in ACS clinical trials; thus, the primary indication for these agents is to alleviate symptoms, with similar recommendations for older and younger patients.97,98,104,153 As always, careful titration is important in elderly patients, given the potential for increased side effects (eg, hypotension, bradycardia, mental status changes). Ranolazine is indicated for management of chronic stable angina, with patients older or younger than 65 years of age deriving similar benefits in exercise duration, frequency of angina attacks, and number of nitroglycerin tablets needed per week.165,166,167 However, side effects such as dizziness, constipation, nausea, headache, and abdominal discomfort were more common in patients aged > 65 years. In patients with NSTE-ACS, ranolazine is safe, but does not improve clinical outcomes, and effects were similar in patients older or younger than 75 years of age.168
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Reperfusion and Revascularization
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Acute Reperfusion for ST-Segment Elevation Myocardial Infarction
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Although the absolute benefit of fibrinolytic therapy is greatest in older patients at high risk for complications from STEMI, the risk of catastrophic bleeding also increases markedly after 75 years of age (see Fig. 65–6).105,169 In clinical trials of fibrinolysis for STEMI, intracranial hemorrhage occurred in approximately 1% to 2% of patients aged > 75 years versus 0.5% to 1% of younger patients.170,171 Thus, although older age is not a contraindication to fibrinolytic therapy, the risk-benefit ratio must be carefully evaluated in patients with frailty or advanced age, particularly because few patients aged > 85 years were enrolled in the fibrinolytic trials for acute MI.172,173,174
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Recent guidelines have moved toward recommending primary PCI over fibrinolysis in most patients with STEMI as a result of clinical trials showing greater efficacy and fewer serious bleeding events with contemporary PCI techniques.98 In particular, elderly patients enrolled in these studies had improved survival with primary PCI for STEMI,175,176 and a small trial limited to patients ≥ 75 years of age also demonstrated superiority of PCI over fibrinolysis.171 To minimize bleeding risks in patients of advanced age, an additional 30-minute delay beyond the standard 90-minute “door-to-balloon time” is permitted when the delay allows for primary PCI instead of thrombolysis in the geriatric population.104
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Reperfusion in Non–ST-Segment Elevation Acute Coronary Syndrome
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Older age is a major risk factor for adverse ACS outcomes, as well as for procedural complications, both from cardiovascular issues (eg, access site problems, complex vascular anatomy, coronary calcification precluding adequate stent delivery) and from other medical comorbidities (eg, renal dysfunction, cognitive impairment or agitation with sedation, bleeding risks in frail patients). Despite these concerns, in most studies, older patients treated with an early invasive approach to NSTE-ACS experienced reductions in death or recurrent MI.177,178 In a recent unblinded trial of 457 patients ≥ 80 years of age with NSTE-ACS, early coronary angiography and revascularization were associated with a significant reduction in urgent revascularization or recurrent MI over a median follow-up time of 1.5 years when compared with initial medical therapy alone.179 Of note, the benefit of invasive management declined with age and was no longer evident among patients ≥ 90 years of age. With these competing concerns in mind, the decision to pursue an invasive approach among patients with advanced age must be individualized, with consideration of anticipated benefits, potential risks, and patient preferences. Among elderly patients with lower risk ACS characteristics, intensification of medical management alone is often a reasonable option.
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Revascularization in Cardiogenic Shock
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In a clinical trial evaluating revascularization therapy for patients with ACS complicated by cardiogenic shock, patients younger than 75 years of age had lower mortality with early PCI or CABG, whereas patients aged > 75 years did not.180,181 However, patients enrolled in the trial registry (and thus removed from the randomization process) had improved outcomes with early revascularization, including elderly individuals.182 Newer data suggest higher rates of cardiogenic shock after STEMI during the past decade, with greater utilization of early PCI and circulatory support devices, along with lower in-hospital mortality over time.183 Of note, patients over 75 years of age continued to have lower utilization of early revascularization and support devices, and despite gradual reductions in mortality that mirrored the improvements seen in younger patients, overall mortality remained nearly twice as high in older patients. Larger support devices such as Impella (Abiomed, Danvers, MA) may help stabilize some of these patients while awaiting myocardial recovery after revascularization, but the impact of these interventions on clinical outcomes is uncertain, and optimal patient selection remains challenging (see Chap. 42).184,185 Nonetheless, with continued technological advancements and greater clinical experience, these devices may play an important role in managing select elderly patients with shock physiology complicating ACS.
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Stable Ischemic Heart Disease
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As with ACS, chronic angina may manifest differently or at a later stage in older patients. Prolonged exposure to risk factors, concomitant medical diseases, and aging processes likely contribute to the more advanced atherosclerosis discovered in older patients at the time of IHD diagnosis. For example, chronic lung disease, diabetic neuropathy, cognitive impairment, and sedentary lifestyle may contribute to delayed recognition of IHD in older patients.5 Medical therapies for chronic IHD are similar in older and younger patients, with emphasis on relief of symptoms and prevention of disease progression using statins, aspirin, and appropriate blood pressure and diabetes management (see Chap. 43). Dual antiplatelet therapy beyond the first year after ACS or coronary stent implantation appears to primarily benefit patients with prior MI—at a cost of higher bleeding rates—and should be considered for select elderly patients at higher risk of recurrent ischemic events and lower risk of bleeding.186,187
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Coronary revascularization should be considered for elderly patients with chronic IHD and either high-risk coronary anatomy or persistent ischemic symptoms despite optimal medical therapy.188 Complications of PCI and CABG are more common among patients ≥ 80 years old,189,190 but hospital mortality has continued to decline over the past two decades in both younger and older patients despite substantial increases in comorbidity.1 Increasing age is a potent risk factor for arrhythmias after CABG (especially AF; see Chap. 44), as well as for postoperative delirium and cognitive impairment.191
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Despite these concerns, revascularization is associated with excellent clinical outcomes among appropriately selected patients of advanced age (ie, octogenarians and nonagenarians), including fewer symptoms and improved quality of life compared with medical therapy alone.188,192,193,194 Thus, advanced age alone should not be considered a contraindication to either PCI or CABG. In the past decade, several studies have compared PCI and CABG in patients with left main or multivessel CAD, demonstrating higher rates of repeat revascularization after PCI, but similar rates of other clinical outcomes (MI, stroke, and death) between the two approaches.195,196 As a result, many elderly patients with severe IHD choose multivessel PCI over CABG, thus trading the higher perioperative risk and longer recovery time for the greater likelihood of needing repeat PCI during short-term follow-up. Coupled with additional improvements in PCI (ie, radial artery access, newer stents with lower restenosis and thrombosis rates, smaller catheters, and lower contrast volumes), these trends likely explain why CABG rates in the United States have continued to decline since 1997, whereas PCI rates in the geriatric population have remained relatively constant.1
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Nonpharmacologic Therapy
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Medication adherence and polypharmacy may challenge efforts to reduce the risk of recurrent cardiovascular events in older patients with established IHD. Cognitive impairment may lead to missed doses of medications, inability to recall instructions, or confusion about the multiple therapies prescribed. Substantial effort has been devoted to discussing these issues in contemporary guidelines188; instructions must be discussed clearly, caregivers should also receive these instructions, and close surveillance for drug-drug interactions or medication side effects should be implemented. These concerns are particularly relevant for antiplatelet therapies after ACS or stent placement, as premature discontinuation of these medications is the primary cause of short-term stent thrombosis, reinfarction, and cardiovascular death.197
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Other supportive measures during and after IHD events are important as well. For example, hospitalized patients with STEMI commonly receive narcotics and are relatively bedbound while recovering in the intensive care unit, so implementation of a bowel regimen is important for these individuals, many of whom already have impaired bowel function.188 Cardiac rehabilitation is markedly underused in the geriatric population, despite proven reductions in mortality and improvements in quality of life,198 although referral rates have increased in recent years.199 Older patients unable to attend formal cardiac rehabilitation for logistical or transportation reasons should be referred for a home-based rehabilitation program if available.